Penicillin-binding protein inhibitors

Abstract

Described herein are certain boron-containing compounds, compositions, preparations, and their use as modulators of the transpeptidase function of bacterial penicillin-binding proteins and as antibacterial agents. In some embodiments, the compounds described herein inhibit penicillin-binding proteins. In certain embodiments, the compounds described herein are useful in the treatment of bacterial infections.

Description

[0001] WSGR Docket No.41223-757.601 PENICILLIN-BINDING PROTEIN INHIBITORS CROSS-REFERENCE This application claims the benefit of U.S. Provisional Application Serial No. 63 / 598,888 filed November 14, 2023; which is hereby incorporated by reference in its entirety. STATEMENT AS TO FEDERALLY SPONSORED RESEARCH This invention was made with government support under contract 75N93020C00016, awarded by the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). The government has certain rights in the invention. BACKGROUND OF THE INVENTION Antibiotics are the most effective drugs for curing bacteria-related infectious diseases clinically. They are incredibly valuable therapeutic options that are currently losing efficacy due to the evolution and spread of drug resistance genes, leading to multidrug-resistant bacterial organisms. Among the different classes of antibiotics, the penicillin-binding protein-targeting beta-lactams (e.g., penicillins, cephalosporins, and carbapenems) are the most widely used antibiotic class because they have a strong bactericidal effect and low associated toxicity. Penicillin Binding Proteins (PBPs) are a family of essential bacterial enzymes involved in the synthesis of peptidoglycan, the major structural polymer found in the bacterial cell wall. Beta-lactam antibiotics bind with high affinity to PBPs and inhibit their transpeptidase function, resulting in disruption of peptidoglycan cell wall synthesis and rapid cell lysis of actively dividing bacteria. As there are no close mammalian homologues to PBPs, and beta-lactams are well-regarded for their safety and efficacy, PBPs represent an ideal target for antibacterials. INCORPORATION BY REFERENCE All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS The novel features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the present disclosure are utilized, and the accompanying drawings of which: FIG.1. shows the efficacy of equal doses (1 mg / kg SC q4h) of Example 8 and comparator Examples A2 and A4 against A. baumannii ATCC 19606 in a neutropenic murine lung infection model. FIG.2. shows Example 8 unbound plasma concentration-time profile and observed concentrations in the epithelial lining fluid in the neutropenic lung infection model following SC WSGR Docket No.41223-757.601 administration of a 3 mg / kg (single dose). Data are means ± standard deviations. ELF, epithelial lining fluid. SUMMARY OF THE INVENTION Described herein are compounds that inhibit the activity of penicillin-binding proteins, the bacterial enzyme class targeted by the beta-lactam antibiotics, and do provide significant antibacterial activity in vitro. Provided herein are compounds of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer, thereof: Formula (I) as described herein. Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient. Also disclosed herein is a method of treating a bacterial infection in a subject, comprising administering to the subject an effective amount of a disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the pharmaceutical composition disclosed herein. Also disclosed herein is a method of inhibiting a bacterial penicillin-binding protein in a human infected with a bacterial infection, comprising contacting said bacterial penicillin-binding protein with an effective amount of a disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the pharmaceutical composition disclosed herein. In some embodiments, the bacterial infection is caused by a Stenotrophomonas spp. In some embodiments, the bacterial infection is caused by a Burkholderia spp. In some embodiments, the bacterial infection is caused by a Pseudomonas spp. In some embodiments, the bacterial infection is caused by an Acinetobacter spp. In some embodiments, the bacterial infection is caused by a carbapenem-resistant Enterobacterales (CRE). WSGR Docket No.41223-757.601 INCORPORATION BY REFERENCE All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE INVENTION Over the decades of clinical use of beta-lactam antibiotics, bacteria have evolved resistance mechanisms that compromise beta-lactam utility, including production of easily transferable, broad- spectrum beta-lactamases that are able to efficiently hydrolyze the beta lactam ring. These enzymes, now counting >1300 variants, have spread throughout all Gram-negative pathogens such as Enterobacterales. The rapid spread of this mechanism of bacterial resistance severely limits beta-lactam therapeutic options. Novel non-beta-lactam compounds that inhibit the transpeptidase function of PBPs and are not degraded by beta-lactamases would represent a major advance in the treatment of resistant bacterial infections, essentially circumventing >70 years of bacterial evolution to protect the function of the penicillin-binding proteins in cell wall biosynthesis. The present invention is directed to certain boron- based compounds (boronic acids and cyclic boronic acid esters) which are PBP inhibitors and antibacterial compounds. The compounds and their pharmaceutically acceptable salts are useful for the treatment of bacterial infections, particularly antibiotic-resistant bacterial infections. Some embodiments include compounds, compositions, pharmaceutical compositions, use, and preparation thereof. The challenge for developing novel non-beta-lactam antibiotics is finding PBP inhibitors that are not susceptible to beta-lactamases, and that balance potent in vitro antibacterial activity (MIC), with suitable plasma stability, and the ability to inhibit both cell division and elongation (as measuring in the Filamentation Prevention assay). Definitions As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, WSGR Docket No.41223-757.601 method, or process, or the like, described herein, “consist of” or “consist essentially of” the described features. As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below. “Oxo” refers to =O. “Amino” refers to -NH2. “Hydroxyl” refers to -OH. “Carboxyl” refers to -COOH. “Alkyl” refers to a straight-chain or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1- butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3- dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as “C1-C6alkyl”, means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C1-C10 alkyl. In some embodiments, the alkyl is a C1-C6 alkyl. In some embodiments, the alkyl is a C1-C5 alkyl. In some embodiments, the alkyl is a C1-C4 alkyl. In some embodiments, the alkyl is a C1-C3 alkyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with one or more oxo, halogen, -CN, - COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen. “Alkenyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans or Z or E conformation about the double bond(s) and should be understood to include both isomers. Examples include, but are not limited to ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-C6alkenyl”, means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or WSGR Docket No.41223-757.601 heteroaryl, and the like. In some embodiments, the alkenyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen. “Alkynyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C2-C6alkynyl”, means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkynyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen. “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or - NO2. In some embodiments, the alkylene is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen. “Alkoxy” refers to a radical of the formula -Oalkyl where alkyl is defined as above. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with one or more halogen, -CN, -COOH, -COOMe, - OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen. “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl. “Aryl” refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, WSGR Docket No.41223-757.601 the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to anthracenyl, naphthyl, phenanthrenyl, azulenyl, phenyl, chrysenyl, fluoranthenyl, fluorenyl, as-indacenyl, s-indacenyl, indanyl, indenyl, phenalenyl, phenanthrenyl, pleiadenyl, pyrenyl, and triphenylenyl. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen. “Cycloalkyl” refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), spiro, and / or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C3-C15fully saturated cycloalkyl or C3-C15cycloalkenyl), from three to ten carbon atoms (e.g., C3-C10fully saturated cycloalkyl or C3-C10cycloalkenyl), from three to eight carbon atoms (e.g., C3-C8fully saturated cycloalkyl or C3-C8cycloalkenyl), from three to six carbon atoms (e.g., C3-C6fully saturated cycloalkyl or C3-C6cycloalkenyl), from three to five carbon atoms (e.g., C3-C5fully saturated cycloalkyl or C3-C5cycloalkenyl), or three to four carbon atoms (e.g., C3-C4fully saturated cycloalkyl or C3-C4cycloalkenyl). In some embodiments, the cycloalkyl is a 3- to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered fully saturated cycloalkyl or a 5- to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, cis-decalinyl, trans-decalinyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, and bicyclo[3.3.2]decyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[3.1.1]heptyl, 7,7-dimethyl- bicyclo[2.2.1]heptanyl, Spiro[4.2]heptyl, spiro[4.3]octyl, spiro[5.2]octyl, spiro[3.3]heptyl, and spiro[5.3]nonyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, - CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen. WSGR Docket No.41223-757.601 “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro. “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2- trifluoroethyl, 1,2-difluoroethyl, 2-fluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. “Haloalkoxy” refers to -O-haloalkyl, with haloalkyl as defined above. “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl. “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl. “Deuteroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums. Deuteroalkyl includes, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3. “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or two atoms selected from the group consisting of oxygen, nitrogen, and sulfur wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, - CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or - NO2. In some embodiments, a heteroalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen. WSGR Docket No.41223-757.601 “Heterocycloalkyl” refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl is C-linked. In some embodiments, the heterocycloalkyl is N-linked. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C2-C15fully saturated heterocycloalkyl or C2-C15heterocycloalkenyl), from two to ten carbon atoms (e.g., C2-C10fully saturated heterocycloalkyl or C2-C10heterocycloalkenyl), from two to eight carbon atoms (e.g., C2-C8fully saturated heterocycloalkyl or C2-C8heterocycloalkenyl), from two to seven carbon atoms (e.g., C2-C7fully saturated heterocycloalkyl or C2-C7heterocycloalkenyl), from two to six carbon atoms (e.g., C2-C6fully saturated heterocycloalkyl or C2-C7heterocycloalkenyl), from two to five carbon atoms (e.g., C2-C5fully saturated heterocycloalkyl or C2-C5heterocycloalkenyl), or two to four carbon atoms (e.g., C2-C4fully saturated heterocycloalkyl or C2-C4heterocycloalkenyl). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3- oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, WSGR Docket No.41223-757.601 the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8- membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl is optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heterocycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is optionally substituted with one or more halogen, methyl, ethyl, - CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen. “Heteroaryl” refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. In some embodiments, the heteroaryl is C-linked. In some embodiments, the heteroaryl is N-linked. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered ring comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, or sulfur. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 1- oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, WSGR Docket No.41223-757.601 phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the heteroaryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, - COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen. The term “one or more” when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, four, or more substituents. In some embodiments, the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents. An “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect. “Treatment” of an individual (e.g., a mammal, such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of the individual or cell. In some embodiments, treatment includes administration of a pharmaceutical composition, subsequent to the initiation of a pathologic event or contact with an etiologic agent and includes stabilization of the condition (e.g., condition does not worsen) or alleviation of the condition. In some embodiments, treatment also includes prophylactic treatment (e.g., administration of a composition described herein when an individual is suspected to be suffering from a bacterial infection). Compounds Described herein are compounds that modulate the activity of penicillin-binding proteins. In some embodiments, the compounds described herein inhibit beta-lactamase. In certain embodiments, the compounds described herein are useful in the treatment of bacterial infections. In some embodiments, the bacterial infection is an upper or lower respiratory tract infection, a urinary tract infection, an intra- abdominal infection, or a skin infection. In some embodiments, the bacterial infection is uncomplicated or complicated urinary tract infections, uncomplicated or complicated gonorrhea, upper or lower respiratory tract infections, skin or skin structure infections, intra-abdominal infections, central nervous system infections, blood stream infections, or systemic infections. WSGR Docket No.41223-757.601 Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: wherein: Ring A is aryl or heteroaryl; R1ais -OH, -ORa, or C1-C6alkyl; R1bis -OH, -ORa, or C1-C6alkyl; each R2is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; n is 0, 1, 2, 3, or 4; R3is hydrogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl; each Y1and Y2is independently -C(=O)- or -C(RY)2-; each RYis independently hydrogen, deuterium, halogen, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; q is 1 or 2; p is 1 or 2; Ring B is a 3- to 10-membered cycloalkyl; L1is -C(=O)NH-, -NHC(=O)-, -NHC(=O)NH-, -NHS(=O)2-, or -S(=O)2NH-; R4is aryl or heteroaryl; each independently optionally substituted with one or more R4a; each R4ais independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1- C6deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; each R5is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, C1-C6alkyl, C1- C6haloalkyl, C1-C6deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; or two R5on the same atom are taken together to form an oxo. m is 0, 1, 2, 3, or 4; WSGR Docket No.41223-757.601 R6is hydrogen or C1-C6alkyl; R7, R8, and R9are independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -SH, -SRa, -NRcRd, - NRcC(=O)Rb, -C(=O)NRcRd, ­C(=O)Ra, ­C(=O)ORa, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; X is -OH, -ORX, or -F; RXis C1-C6alkyl or cycloalkyl; Z is hydrogen, R11, -(R10)vOR11, -(R10)wO(R10)wOR11, -R10OC(=O)R11, -R10OC(=O)OR11, - R10OC(=O)NHR11, -R10OC(=O)N(R11)2, C1-C6alkyloxyC1-C6alkyl, acyloxyC1-C6alkyl, or C1-C6alkyl- [1,3]dioxol-2-one; each R10is independently -CH2-, -CH(CH3)-, -C(CH3)2-, or 1,1’-cyclopropylene; each R11is independently C1-C6alkyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R11are taken together with the nitrogen to which they are attached to form an heterocycloalkyl independently optionally substituted with one or more R; v is 1, 2, or 3; w is 2 or 3; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L- aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; and each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; each L is independently absent or C1-C6alkylene optionally substituted with one or more R; each R is independently halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, - S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, - C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1- C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1- C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl; WSGR Docket No.41223-757.601 or two R on the same atom form an oxo. In some embodiments of a compound of Formula (I), q is 2; each Y1is -C(RY)2-; p is 2; and each Y2is -C(=O)-. In some embodiments of a compound of Formula (I), q is 2; each Y1is -C(RY)2-; p is 1; and Y2is -C(=O)-. In some embodiments of a compound of Formula (I), q is 2; each Y1is -C(RY)2-; p is 2; one Y2is -C(RY)2- and one Y2is -C(=O)-. In some embodiments of a compound of Formula (I), q is 2; one Y1is -C(R5)2-, one Y1is - C(=O)-; p is 2; one Y2is -C(R5)2- and one Y2is -C(=O)-. In some embodiments of a compound of Formula (I), each RYis independently hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I), each RYis hydrogen. In some embodiments of a compound of Formula . In some embodiments of a compound of Formula (I), Ring A is aryl. In some embodiments of a compound of Formula (I), Ring A is phenyl. In some embodiments of a compound of Formula (I), Ring A is heteroaryl. In some embodiments of a compound of Formula (I), Ring A is 5- or 6-membered heteroaryl. In some embodiments of a compound of Formula (I), Ring A is 5-membered heteroaryl. In some embodiments of a compound of Formula (I), Ring A is 6-membered heteroaryl. In some embodiments of a compound of WSGR Docket No.41223-757.601 Formula (I), Ring A is pyridinyl, pyrimidinyl, or pyrazinyl. In some embodiments of a compound of Formula (I), Ring A is pyridinyl. In some embodiments of a compound of Formula (I), R1ais -OH or -ORa. In some embodiments of a compound of Formula (I), R1ais -OH. In some embodiments of a compound of Formula (I), R1ais C1-C6alkyl; In some embodiments of a compound of Formula (I), R1bis -OH or -ORa. In some embodiments of a compound of Formula (I), R1bis -OH. In some embodiments of a compound of Formula (I), R1bis C1-C6alkyl; In some embodiments of a compound of Formula (I), each R2is independently deuterium, halogen, -OH, -ORa, or C1-C6alkyl. In some embodiments of a compound of Formula (I), each R2is independently halogen or -OH. In some embodiments of a compound of Formula (I), each R2is independently -OH. In some embodiments of a compound of Formula (I), each R2is independently halogen. In some embodiments of a compound of Formula (I), n is 0, 1, or 2. In some embodiments of a compound of Formula (I), n is 0 or 1. In some embodiments of a compound of Formula (I), n is 0. In some embodiments of a compound of Formula (I), n is 1. In some embodiments of a compound of Formula some embodiments of a compound of Formula . In some embodiments of a compound of Formula (I), R3is hydrogen, C1-C6alkyl, or C1- C6haloalkyl. In some embodiments of a compound of Formula (I), R3is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I), R3is C1-C6alkyl. In some embodiments of a compound of Formula (I), R3is hydrogen. In some embodiments of a compound of Formula (I), R6is hydrogen. In some embodiments of a compound of Formula (I), R6is C1-C6alkyl. In some embodiments of a compound of Formula (I), L1is -C(=O)NH- or -NHC(=O)-. In some embodiments of a compound of Formula (I), L1is -C(=O)NH-. In some embodiments of a compound of Formula (I), L1is -NHC(=O)-. In some embodiments of a compound of Formula (I), L1is -NHC(=O)NH- . In some embodiments of a compound of Formula (I), L1is -NHS(=O)2-. In some embodiments of a compound of Formula (I), L1is -S(=O)2NH-. WSGR Docket No.41223-757.601 In some embodiments of a compound of Formula (I), L1is *-C(=O)NH- or *-NHC(=O)- wherein * indicates the attachment point to Ring B. In some embodiments of a compound of Formula (I), L1is *-C(=O)NH- wherein * indicates the attachment point to Ring B. In some embodiments of a compound of Formula (I), L1is *-NHC(=O)- wherein * indicates the attachment point to Ring B. In some embodiments of a compound of Formula (I), L1is *-NHC(=O)NH- wherein * indicates the attachment point to Ring B. In some embodiments of a compound of Formula (I), L1is *-NHS(=O)2- wherein * indicates the attachment point to Ring B. In some embodiments of a compound of Formula (I), L1is *- S(=O)2NH- wherein * indicates the attachment point to Ring B. In some embodiments of a compound of Formula (I), the compound is of Formula (Ia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: In some embodiments of a compound of Formula (I), the compound is of Formula (Ia-1), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: WSGR Docket No.41223-757.601 In some embodiments of a compound of Formula (I), the compound is of Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: In some embodiments of a compound of Formula (I), the compound is of Formula (Ib-1), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: In some embodiments of a compound of Formula (I), the compound is of Formula (Ic), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: WSGR Docket No.41223-757.601 In some embodiments of a compound of Formula (I), the compound is of Formula (Ic-1), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: In some embodiments of a compound of Formula (I), the compound is of Formula (Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

[0002] WSGR Docket No.41223-757.601 Formula (Id). In some embodiments of a compound of Formula (I), the compound is of Formula (Id-1), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), R7is hydrogen, halogen, -OH, -ORa, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), R7is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), R7is hydrogen or halogen. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), R7is hydrogen. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), R7is halogen. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), R8is hydrogen, halogen, -OH, -ORa, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), R8is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), R8is hydrogen or halogen. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), R8is hydrogen. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), R8is halogen. WSGR Docket No.41223-757.601 In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), R9is hydrogen, halogen, -OH, -ORa, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), R9is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), R9is hydrogen or halogen. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), R9is hydrogen. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), R9is halogen. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), X is -OH. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), X is -ORX. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), RXis C1- C6alkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), Z is hydrogen. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), Z is R11and R11is C1-C6alkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), Z is - R10OC(=O)R11or -R10OC(=O)OR11; R10is -CH2- or -CH(CH3)-; and R11is C1-C6alkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), Z is -R10OC(=O)R11; R10is -CH2-; and R11is C1-C6alkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), R10is -CH2- or - CH(CH3)-. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), R10 is -CH2-. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), R11 is , some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), R11is In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), , WSGR Docket No.41223-757.601 In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), each R5is independently deuterium, halogen, -OH, -ORa, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), each R5is independently deuterium, halogen, C1- C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id- 1), each R5is independently halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), each R5is independently halogen or C1-C6alkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), m is 0, 1, or 2. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), m is 0 or 1. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), m is 0. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), m is 1. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), m is 2. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), Ring B is a 4- to 8-membered cycloalkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), Ring B is a 4- to 8-membered monocyclic cycloalkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), Ring B is a 4- to 6-membered monocyclic cycloalkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), Ring B is a 4-membered monocyclic cycloalkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), Ring B is cyclobutyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), Ring B is a 5-membered monocyclic cycloalkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), Ring B is cyclopentyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), Ring B is a 6-membered monocyclic cycloalkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), Ring B is cyclohexyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), Ring B is a 5- to 12-membered bicyclic cycloalkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia- 1)-(Id-1), Ring B is a 5- to 10-membered bicyclic cycloalkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), Ring B is a 5- to 8-membered bicyclic cycloalkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), Ring B is a 6- to 8-membered bicyclic cycloalkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), B is a WSGR Docket No.41223-757.601 6-membered bicyclic cycloalkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)- (Id-1), B is a 7-membered bicyclic cycloalkyl. In some embodiments of a compound of formula (I), (Ia)- (Id), or (Ia-1)-(Id-1), Ring B is a 8-membered bicyclic cycloalkyl. In some embodiments of a compound of Formula (I), R4is aryl independently optionally substituted with one or more R4a. In some embodiments of a compound of Formula (I), R4is phenyl independently optionally substituted with one or more R4a. In some embodiments of a compound of Formula (I), R4is heteroaryl independently optionally substituted with one or more R4a. In some embodiments of a compound of Formula (I), R4is 5- or 6- membered heteroaryl, each independently optionally substituted with one or more R4a. In some embodiments of a compound of Formula (I), R4is 5-membered heteroaryl independently optionally substituted with one or more R4a. In some embodiments of a compound of Formula (I), R4is 6-membered heteroaryl independently optionally substituted with one or more R4a. In some embodiments of a compound of Formula (I), R4is pyridinyl, pyrimidinyl, or pyrazinyl, each independently optionally substituted with one or more R4a. In some embodiments of a compound of Formula (I), R4is pyridinyl independently optionally substituted with one or more R4a. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), each R4ais independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), each R4ais independently halogen, -OH, -ORa, or C1-C6alkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), each R4ais independently halogen or -OH. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), R4is In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), R4is . In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, -L- cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, or C1-C6heteroalkyl; wherein each alkyl and heteroalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, cycloalkyl, and WSGR Docket No.41223-757.601 heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl or C1-C6haloalkyl; wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Rais independently C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, C1- C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, -L- cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; wherein each alkyl and heteroalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, C1-C6alkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, C1-C6alkyl or C1-C6haloalkyl; wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, C1-C6alkyl, or C1- C6haloalkyl. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen or C1-C6alkyl. In some embodiments of a compound disclosed herein, each Rbis hydrogen. In some embodiments of a compound disclosed herein, each Rbis independently C1-C6alkyl. In some embodiments of a compound disclosed herein, each Rbis independently C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1- C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; wherein each alkyl and heteroalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, C1-C6alkyl, -L-cycloalkyl, or - L-heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, C1-C6alkyl or C1-C6haloalkyl; wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen or C1-C6alkyl. WSGR Docket No.41223-757.601 In some embodiments of a compound disclosed herein, each Rcand Rdare hydrogen. In some embodiments of a compound disclosed herein, each Rcand Rdare independently C1-C6alkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare independently C1-C6haloalkyl. In some embodiments of a compound disclosed herein, Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each L is independently absent. In some embodiments of a compound disclosed herein, each L is independently C1-C6alkylene optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each L is independently C1alkylene optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each L is independently C2alkylene optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each L is independently C3alkylene optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each L is independently absent, -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments of a compound disclosed herein, each L is independently -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments of a compound disclosed herein, each L is independently absent or -CH2-. In some embodiments of a compound disclosed herein, each L is independently absent or -CH2CH2-. In some embodiments of a compound disclosed herein, each L is independently absent or -CH2CH2CH2-. In some embodiments of a compound disclosed herein, each L is independently -CH2-. In some embodiments of a compound disclosed herein, each L is independently -CH2CH2-. In some embodiments of a compound disclosed herein, each L is independently -CH2CH2CH2-. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -SF5, -SH, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1- C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1-C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1- C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3- C6cycloalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH2, C1-C3alkyl, C1-C3alkoxy, or C1- C3haloalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, C1-C3alkyl or C1-C3haloalkyl; or two R on the same atom form an oxo. Further Forms of Compounds Disclosed Herein Isomers / Stereoisomers In some embodiments, due to the oxophilic nature of the boron atom, the compounds described herein may convert to, or exist in equilibrium with, alternate forms, particularly in milieu that contain water (aqueous solution, plasma, etc.). Accordingly, the compounds described herein may exist in an WSGR Docket No.41223-757.601 equilibrium between a “closed” cyclic form as drawn and an “open” acyclic form. In addition, the compounds described herein may associate into intramolecular dimers, trimers, and related combinations. In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent. Labeled compounds In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds described herein, or a solvate, or stereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as2H,3H,13C,14C,l5N,18O,17O,31P,32P,35S,18F, and36Cl, respectively. Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this disclosure. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e.,2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. WSGR Docket No.41223-757.601 In some embodiments, the abundance of deuterium in each of the substituents disclosed herein is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of a total number of hydrogen and deuterium. In some embodiments, one or more of the substituents disclosed herein comprise deuterium at a percentage higher than the natural abundance of deuterium. In some embodiments, one or more hydrogens are replaced with one or more deuteriums in one or more of the substituents disclosed herein. In some embodiments, the isotopically labeled compound or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof is prepared by any suitable method. In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Pharmaceutically acceptable salts In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions. In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or a solvate, or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed. Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, but not limited to, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, gluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate. WSGR Docket No.41223-757.601 Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-1- carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, other acids, such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts. In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-C4alkyl)4hydroxide, and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization. Solvates In some embodiments, the compounds described herein exist as solvates. The disclosure provides for methods of treating diseases by administering such solvates. The disclosure further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. WSGR Docket No.41223-757.601 Pharmaceutical Compositions / Formulations In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer, thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition further comprises a beta-lactam antibiotic. In certain embodiments, the beta-lactam antibiotic is a penicillin, cephalosporin, carbapenem, monobactam, bridged monobactam, or a combination thereof. In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999), herein incorporated by reference for such disclosure. A pharmaceutical composition, as used herein, refers to a mixture of a compound described herein with other chemical components (i.e., pharmaceutically acceptable inactive ingredients), such as carriers, excipients, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, or one or more combination thereof. The pharmaceutical composition facilitates administration of the compound to an organism. In practicing the methods of treatment or use provided herein, therapeutically effective amounts of compounds described herein are administered in a pharmaceutical composition to a mammal having a disease, disorder, or condition to be treated. In some embodiments, the mammal is a human. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. The compounds can be used singly or in combination with one or more therapeutic agents as components of mixtures. The pharmaceutical formulations described herein are administered to a subject by appropriate administration routes, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, WSGR Docket No.41223-757.601 pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations. Methods The present disclosure also provides methods for inhibiting bacterial growth, such methods comprising contacting a bacterial cell culture, or a bacterially infected cell culture, tissue, or organism, with a penicillin-binding protein inhibitor described herein. Preferably, the bacteria to be inhibited by administration of a penicillin-binding protein inhibitor described herein are bacteria that are resistant to beta-lactam antibiotics. The term “resistant” is well-understood by those of ordinary skill in the art (see, e.g., Payne et al., Antimicrobial Agents and Chemotherapy 38767-772 (1994), Hanaki et al., Antimicrobial Agents and Chemotherapy 301120-1126 (1995)). In some embodiments, the penicillin- binding protein inhibitor described herein is used to treat a bacterial infection that is resistant to a beta- lactam antibiotic. In some embodiments, the penicillin-binding protein inhibitor described herein is used to treat a bacterial infection that has an acquired or altered beta-lactamase enzyme(s). These methods are useful for inhibiting bacterial growth in a variety of contexts. In certain embodiments, a compound described herein is administered to an experimental cell culture in vitro to prevent the growth of beta-lactam resistant bacteria. In some embodiments, a compound described herein is administered to a mammal, including a human, to prevent the growth of beta-lactam resistant bacteria in vivo. The method according to this embodiment comprises administering a therapeutically effective amount of a penicillin-binding protein inhibitor described herein for a therapeutically effective period of time to a mammal, including a human. Preferably, the penicillin-binding protein inhibitor described herein is administered in the form of a pharmaceutical composition as described above. In another aspect provided herein are methods of treating a bacterial infection, which method comprises administering to a subject a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer, thereof, and a pharmaceutically acceptable excipient. In some embodiments, the methods of treating a bacterial infection in a subject comprises administering to the subject a pharmaceutical composition as described herein. In some embodiments, the bacterial infection is an upper or lower respiratory tract infection, a urinary tract infection, an intra-abdominal infection, or a skin infection. In some embodiments, the bacterial infection is an upper or lower respiratory tract infection, a urinary tract infection, an intra-abdominal infection, or a skin infection. In some embodiments, the bacterial infection is uncomplicated or complicated urinary tract infections, uncomplicated or complicated gonorrhea, upper or lower respiratory tract infections, skin or skin structure infections, intra-abdominal infections, central nervous system infections, blood stream infections, or systemic infections. In some embodiments, the infection that is treated or prevented is cause by a bacteria that includes Aeromonas hydrophilia, Achromobacter ruhlandii, Achromobacter xylosoxidans, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter dijkshoorniae, Acinetobacter haemolyticus, Acinetobacter nosocomialis, Acinetobacter pittii, Acinetobacter seifertii, Alcaligenes faecalis, WSGR Docket No.41223-757.601 Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Borrelia burgdorferi, Burkholderia cepacia, Burkholderia dolsa, Burkholderia gladioli, Burkholderia humptydooensis, Burkholderia multivorans, Burkholderia pseudomallei, Burkholderia thailandensis, Burkholderia vietnamiensis, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Citrobacter amalonaticus, Citrobacter braakii, Citrobacter farmeri, Citrobacter freundii, Citrobacter koseri, Citrobacter sedlakii, Citrobacter portucalensis, Citrobacter youngae, Clostridium difficile, Corynebacterium diphtheriae, Corynebacterium ulcerans, Escherichia coli, Elizabethkingia anopheles, Elizabethkingia meningoseptica, Elizabethkingia miricola, Enterobacter agglomerans, Enterobacter asburiae, Enterobacter bugandensis, Enterobacter cloacae, Enterobacter gergoviae, Enterobacter kobei, Enterobacter ludwigii, Enterobacter sakazakii, Enterobacter xiangfangensis, Enterococcus faecalis, Enterococcus faecium, Francisella tularensis, Gardnerella vaginalis, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi, Helicobacter pylori, Klebsiella aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Klebsiella ozaenae, Klebsiella variicola, Kluyvera ascorbate, Legionella pneumophila, Listeria monocytogenes, Moraxella catarrhalis, Morganella morganii, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Neisseria bacilliformis, Neisseria cinerea, Neisseria elongate, Neisseria gonorrhoeae, Neisseria lactamica, Neisseria meningitidis, Neisseria oralis, Neisseria weaver, Oligella ureolytica, Kingella kingae, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Pseudomonas aeruginosa, Pseudomonas mendocina, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Pseudomonas lundensis, Pseudomonas fragi, Pseudomonas oryzihabitans, Pseudomonas stutzeri, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus, Staphylococcus haemolyticus, Staphylococcus hominis, or Staphylococcus saccharolyticus, Stenotrophomonas maltophilia, Salmonella concord, Salmonella corvallis, Salmonella cubana, Salmonella enteritidis, Salmonella Heidelberg, Salmonella infantis, Salmonella Newport, Salmonella senftenberg, Salmonella stanley, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Serratia fonticols, Serratia liquefaciens, Serratia marcescens, Serratia odorifera, Serratia rubidaea, Serratia ureilytica, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Vibrio cholerae, Vibrio parahaemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, and Yersinia intermedia. In some embodiments, the infection that is treated or prevented is caused by Enterobacterales bacteria. In some embodiments, the infection that is treated or prevented is caused by bacteria that include Escherichia spp, Klebsiella spp., Enterobacter spp., Citrobacter spp., Morganella spp., Proteus spp., Salmonella spp., Serratia spp., Shigella spp., or Yersinia spp. WSGR Docket No.41223-757.601 In some embodiments, the compounds disclosed herein are useful in the treatment or prevention of infection associated with non-fermenting bacteria. In some embodiments, the compounds disclosed herein are useful in the treatment or prevention of infection associated with non-fermenting gram-negative bacteria. In some embodiments, the non-fermenting gram-negative bacteria are Pseudomonas spp. (for example, P. aeruginosa, P. mendocina, P. acidovorans, P. alcaligenes, P. lundensis, P. fragi, P. oryzihabitans, P. stutzeri, P. fluorescens, and P. putida), Acinetobacter spp. (for example, A. baumannii, A. calcoaceticus, A. dijkshoorniae, A. haemolyticus, A. nosocomialis, A. pittii, A. seifertii), Stenotrophomonas spp. (for example, S. maltophilia), Elizabethkingia spp. (for example, E. meningoseptica and E. anopheles), Burkholderia spp. (including B. cepacia complex, B. dolosa, B. gladioli, B. humptydooensis, B. mallei, B. multivorans, B. pseudomallei, B. thailandensis, and B. vietnamiensis). In some embodiments, the infection that is treated or prevented is tuberculosis. In some embodiments, the infection that is treated or prevented is caused by Mycobacterium tuberculosis. In some embodiments, the infection that is treated or prevented is caused by bacteria that are non-TB mycobacterial species. In some embodiments, the non-TB mycobacterial species is M. abscessus, M. africanum, M. asiaticum, M. avium, M. bovis, M. caprae, M. chelonae, M. fortuitum, M. gordonae, M. intracellulare, M. kansasii, M. marinum, M. mucogenicum, M. peregrinum, or M. smegmatis. In some embodiments, the infection that is treated or prevented is gonorrhea. In some embodiments, the infection that is treated or prevented is caused by Neisseria gonorrhoeae. In some embodiments, the infection that is treated or prevented is meningitis and other forms of meningococcal disease such as meningococcemia. In some embodiments, the infection that is treated or prevented is caused by Neisseria meningitidis. In some embodiments, the infection that is treated or prevented is caused by a bacterium that is Neisseria gonorrhoeae. In some embodiments, the infection that is treated or prevented is caused by a bacterium that is Pseudomonas aeruginosa. In some embodiments, the infection that is treated or prevented is caused by a bacterium that is Acinetobacter baumannii. In some embodiments, the infection that is treated or prevented is caused by a bacterium that is a carbapenem-resistant Enterobacterales (CRE). In some embodiments of the methods described herein, the compound described herein is not administered with a β-lactam antibiotic. In some embodiments of the methods described herein, the compound described herein is not administered with a β-lactamase inhibitor. In some embodiments of the methods described herein, the compound described herein is not administered with a combination of a β- lactam antibiotic and a β-lactamase inhibitor. Combination Treatment The compounds described herein may be used in combination with one or more antibiotics in the treatment of bacterial infections. Such antibiotics may be administered, by a route and in an amount commonly used therefore, contemporaneously, or sequentially with a compound described herein. When WSGR Docket No.41223-757.601 a compound described herein is used contemporaneously with one or more antibiotic, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present invention is preferred. However, the combination therapy may also include therapies in which the compound described herein and one or more antibiotic are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more antibiotics, the antibiotics may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention also include those that contain one or more antibiotics, in addition to a compound described herein. In some embodiments, a pharmaceutical composition comprising a compound described herein further comprises a beta-lactam antibiotic. In certain embodiments, the beta-lactam antibiotic is a penicillin, cephalosporin, carbapenem, monobactam, bridged monobactam, or a combination thereof. In some embodiments, one or more antibiotics are selected from beta-lactam antibiotics. Beta- lactam antibiotics include, but are not limited to, penicillins, penems, carbapenems, cephalosporins, cephamycins, monobactams, or combinations thereof. Penicillins include, but are not limited to, amoxicillin, ampicillin, azidocillin, azlocillin, bacampicillin, benzathinebenzylpenicillin, benzathinephenoxymethylpenicillin, benzylpenicillin (penicillin G), carbenicillin, carindacillin, clometocillin, cloxacillin, dicloxacillin, epicillin, flucloxacillin, hetacillin, mecillinam, metampicillin, meticillin, mezlocillin, nafcillin, oxacillin, penamecillin, pheneticillin, phenoxymethylpenicillin (V), piperacillin, pivampicillin, pivmecillinam, procaine benzylpenicillin, propicillin, sulbenicillin, talampicillin, temocillin, and ticarcillin. Penems include, but are not limited to, faropenem. Carbapenems include, but are not limited to, biapenem, ertapenem, doripenem, imipenem, meropenem, and panipenem. Cephalosporins / cephamycins include, but are not limited to, cefacetrile, cefaclor, cefadroxil, cefalexin, cefaloglycin, cefalonium, cefaloridine, cefalotin, cefamandole, cefapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cefbuperazone, cefcapene, cefdaloxime, cefdinir, cefditoren, cefepime, cefetamet, cefiderocol, cefixime, cefmenoxime, cefmetazole, cefminox, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotetan, cefotiam, cefovecin, cefoxitin, cefozopran, cefpimizole, cefpiramide, cefpirome, cefpodoxime, cefprozil, cefquinome, cefquinome, cefradine, cefroxadine, cefsulodin, ceftarolinefosamil, ceftazidime, cefteram, ceftezole, ceftibuten, ceftiofur, ceftiolene, ceftizoxime, ceftobiprole, ceftolozane, ceftriaxone, cefuroxime, cefuzonam, flomoxef, latamoxef, and loracarbef. Monobactams include, but are not limited to, aztreonam, carumonam, nocardicin A, and tigemonam. In some embodiments, the compounds described herein are used in combination with one or more beta-lactamase inhibitors in the treatment of bacterial infections. Certain beta-lactamase inhibitors also may inhibit penicillin-binding proteins. Certain beta-lactamase inhibitors may reduce non-productive binding interactions with beta-lactamases. Thus, certain beta-lactamase inhibitors may synergize with compounds of the present invention to improve antibacterial efficacy. In some embodiments, the beta- lactamase inhibitor is avibactam, clavulanic acid, durlobactam, nacubactam, relebactam, sulbactam, tazobactam, or zidebactam. In some embodiments, the beta-lactamase inhibitor is taniborbactam. In some embodiments, the beta-lactamase inhibitor is ETX0462 or NXL-105. WSGR Docket No.41223-757.601 EXAMPLES General Examples for the Preparation of Compounds. The starting materials and intermediates for the compounds of this invention may be prepared by the application or adaptation of the methods described below, their obvious chemical equivalents, or, for example, as described in literature such as The Science of Synthesis, Volumes 1-8. Editors E. M. Carreira, et al., Thieme publishers (2001-2008). The use of protective groups may be as described in methodology compendia such as Greene's Protective Groups in Organic Synthesis, Fifth Edition. John Wiley & Sons, Inc.2014. Certain compounds of Formula I (Scheme 1) are prepared from the corresponding functional- group-protected boronic acid esters A by treatment with a Lewis acid in a solvent such as dichloromethane, at a temperature between -78 °C and 0 °C followed by an aqueous quench. SCHEME 1 Amide intermediates A may be prepared according to the route outlined in Scheme 2. Chloro- boronates B, prepared by methods described previously (e.g., see WO2014089365), is reacted with silylamine bases such as lithium hexamethyldisilazide, and the non-isolated intermediate silylamine (C’) is treated with hydrochloric acid to generate ammonium salt C, typically isolated as a solid. Ammonium salt C is treated with carboxylic acids D under amide-forming coupling conditions (such as with carbodiimide dehydrating reagents, HATU, or other coupling reagents) to provide protected amides A. Alternatively, the above amine salt C is allowed to react with acid chlorides E to provide A. Carboxylic acids (D) or acid chlorides (E) may be obtained from commercial sources, prepared according to known methods in the literature, or prepared by a number of different reaction sequences. Formation of the acid chloride (E) involves treatment of (D) with a chlorinating agent such as thionyl chloride, phosphorous pentachloride or oxalyl chloride, in a solvent such as dichloromethane, in the presence of a catalyst such as DMF, at around room temperature. In certain cases, DMF is also used as a co-solvent. Formation of the anhydride (F) involves treatment of acid (D) with a sterically hindered acid chloride or WSGR Docket No.41223-757.601 chloroformate, such as trimethylacetyl chloride or isopropylchloroformate, in an inert solvent such as dichloromethane, in the presence of a non-nucleophilic base, such as triethyl amine or diisopropylethylamine at room temperature or below. Formation of the activated ester (G) involves treatment of (D) with an activating reagent system such as EDCI, EDCI / HOBt, DCC / HOBt, HATU, BOP reagents or TBTU, in a solvent such as DMF, DMA, NMP or dichloromethane at room temperature or below (International Journal of Pharmaceutical Sciences Review and Research (2011), 8(1), 108-119). Alternatively, solutions of bis-silylamine intermediate C’ may be used in place of ammonium salt C under the above reaction conditions to provide intermediates A. SCHEME 2 Chloroboronates B may be prepared from aryl halides or aryl triflates H (X=Br, I or OTf) in the manner described in Scheme 3. Compounds H (X=Br, I or OTf) may be converted into boronic acids I by treatment with alkyl lithium reagents, for example n-butyllithium, and then quenching the intermediate aryllithium species with trialkylboronates, followed by aqueous work-up. The boronic acids I may be converted into protected boronate esters J by treatment with 1,2-diols, such as (+)-pinanediol or pinacol. Alternatively, aryl halides H may be converted to boronate esters J by transition-metal-catalyzed reaction with diboron compounds, for example bis[(+)-pinanediolato]diboron and palladium catalysts. Two sequential Matteson reactions as described previously, using J as starting material to yield intermediate boronate K, provide chloroboronates B bearing a wide range of substituents Ra, Rb, and Rc. Another variant consists of reaction of H with chloromethyl boronate L and isopropylmagnesium chloride to provide intermediate K directly. WSGR Docket No.41223-757.601 SCHEME 3 While there are common themes and strategies among the illustrative examples cited below, the selection of an appropriate reaction sequence (including protecting group requirements) is dictated by the nature and arrangement of the functionality present in the target molecule and, therefore, may involve obvious adaptations of the illustrated methods in order to be applied in a particular case. General Method A: Deprotection with boron trichloride or boron tribromide. To a solution of the protected precursor A (0.4 mmol) in anhydrous DCM (15 mL) at -78 °C under argon was added dropwise BCl3 or BBr3 (1.0 M in DCM, 2.4-4 mL, 2.4-4 mmol, 6-10 equivalents). The reaction mixture was allowed to slowly warm to 0 °C over 1 h, and stirred between 0-5 °C for an additional 1-2 h, then quenched with water (2 mL) and methanol (20 mL), evaporated to remove DCM, washed with hexane, and concentrated to a volume of ~ 4-5 mL. The crude product was purified by reversed phase preparative HPLC and dried using lyophilization to afford the product I. General Method B: Deprotection with aluminum chloride. WSGR Docket No.41223-757.601 To a solution of the protected precursor A (0.4 mmol) in anhydrous DCM (15 mL) was added AlCl3 (535 mg, 4 mmol, 10 equivalents) in one portion at RT. The reaction mixture was stirred at RT for 24 h, then quenched with water (2 mL) and methanol (20 mL), evaporated to remove DCM, and washed with hexane, and concentrated to a volume of ~ 4-5 mL. The crude product was purified by reversed phase preparative HPLC and dried using lyophilization to afford the product I. General Method C: Conversion of chloro-boronates to amides. To a solution of the chloride B (4 mmol) in anhydrous THF (16 mL) was added dropwise LiHMDS (1.0 M in THF, 4.5 mL, 4.5 mmol) at -60 °C under argon. The reaction mixture was allowed to slowly warm to 0 °C over 45 min and stirred at RT for an additional 2 h. WSGR Docket No.41223-757.601 In a separate flask was charged the carboxylic acid D (4.2 mmol) and anhydrous DMA (20 mL), to this mixture was added HATU (1.68 g, 4.4 mmol) followed by diisopropylethylamine (0.49 mL, 4.4 mmol). The reaction mixture was stirred at RT for 2 h, at which time the solution from the above reaction was added to the flask, and the reaction mixture was stirred at RT overnight, then diluted with EtOAc, washed with water, brine, and dried over Na2SO4, concentrated in vacuo to afford the crude product, which was purified by flash chromatography on silica gel (hexane-EtOAc, 20:1-1:1, or hexane- acetone, 10:1-1:1, or DCM-MeOH, 30:1-10:1) to afford the product A. Alternatively, a solution of chloride B (27.8 mmol) in THF (100 mL) was cooled to -78 °C. LiHMDS (1 M in THF, 29.2 mL, 29.2 mmol, 1.05 eq) was added dropwise and the mixture was warmed to ambient temperature for 1 h. The solution was cooled to 0 °C and HCl (4 M in dioxane, 27.8 mL, 111.2 mmol, 4.0 eq.) was added dropwise. The reaction mixture was warmed to ambient temperature for 1 h then concentrated to dryness. Hexanes (400 mL) was added and stirred at ambient temperature for 10 minutes then concentrated to dryness to provide amine hydrochloride salt C as a yellow solid (18.5 g). This material was dissolved in DMA (100 mL) followed by the addition of desired carboxylic acid D (1.0 equiv.) and HATU (1.25 eq). The reaction mixture was cooled to 0 °C and DIPEA (3.0 eq) was added dropwise. The reaction was stirred at 0 °C for 1 h then quenched with HCl (1 M, 60 mL). EtOAc (50 mL) was added, and the layers were separated. The aq. layer was extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with H2O (3 × 10 mL) then brine (10 mL), dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (hexane- EtOAc, 20:1-1:1, or hexane-acetone, 10:1-1:1, or DCM-MeOH, 30:1-10:1) to afford the product A. Exemplary compounds are found in Table 1. Table 1. Exemplary compounds. WSGR Docket No.41223-757.601 WSGR Docket No.41223-757.601 WSGR Docket No.41223-757.601 WSGR Docket No.41223-757.601 WSGR Docket No.41223-757.601 Example 1. (R)-3-((R)-2-(3-((1r,3R)-3-(3-(2-chloro-5-fluoro-3,4- dihydroxyphenyl)ureido)cyclobutyl)-2-oxoimidazolidine-1-carboxamido)-2-(4- phosphonophenyl)acetamido)-7-fluoro-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8- carboxylic acid. Part 1. Synthesis of (R)-2-((tert-butoxycarbonyl)amino)-2-(4-(diethoxyphosphoryl)phenyl)acetic acid (1f) Step 1-1. Synthesis of (R)-2-(benzyloxy)-1-(4-hydroxyphenyl)-2-oxoethan-1-aminium chloride (1b). To a 3-neck RBF (2 L) attached with a mechanical stirrer was added amino acid 1a (10 g, 59.8 mmol, 1.0 equiv.) followed by BnOH (240 mL) (NOTE: Mixture was heterogeneous). The mixture was cooled to 0 °C and SOCl2 (17.5 mL, 240 mmol, 4.0 eq) was added dropwise (NOTE: Mixture becomes homogeneous halfway through addition then becomes thick slurry upon full addition). The ice-bath was removed, and the reaction was warmed to room temperature then heated to 80 °C for 16 h (NOTE: Solution becomes homogeneous). Following full conversion, the reaction was cooled to room temperature and MTBE (1 L) was added slowly. Product precipitation occurred and the slurry was aged for 30 minutes. The solid was filtered, the filter cake washed with MTBE (3 × 100 mL), and dried. The product 1b (14.7 g, 84%) was obtained as a white solid. ESI-MS m / z 258 (M+H)+. Step 1-2. Synthesis of benzyl (R)-2-((tert-butoxycarbonyl)amino)-2-(4-hydroxyphenyl)acetate (1c). To a solution of amine 1b (14.7 g, 50.0 mmol, 1.0 eq) in DCM (100 mL) at 0 °C was added TEA (14.0 mL, 100 mmol, 2.0 eq) slowly followed by Boc2O (12.0 mL, 52.5 mmol, 1.05 eq). The reaction was warmed to room temperature for 5 h then diluted with EtOAc (400 mL) (NOTE: TEA·HCl salts crash out of solution). The mixture was filtered, and the filtrate concentrated. The crude material was purified by silica gel chromatography (0-50% EtOAc / Hexanes) to provide 1c (11.8 g, 66%) as a white solid. ESI-MS m / z 358 (M+H)+. Step 1-3. Synthesis of benzyl (R)-2-((tert-butoxycarbonyl)amino)-2-(4- (((trifluoromethyl)sulfonyl)oxy)phenyl)acetate (1d). A mixture of phenol 1c (11.8 g, 33.1 mmol, 1.0 eq) in DCM (133 mL) under Ar was cooled to 0 °C. Pyridine (8.0 mL, 99.4 mmol, 3.0 eq) was added followed by slow addition of Tf2O (1.0 M in DCM, 38 mL, 38.1 mmol, 1.15 eq). The reaction was stirred at 0 °C for 15 minutes then quenched with WSGR Docket No.41223-757.601 HCl (1 M, 100 mL). The layers were separated, and the aq. layer was extracted with DCM (100 mL). The combined organic layers were washed with H2O (50 mL), dried (Na2SO4), filtered, and concentrated. The crude material was purified by silica gel chromatography (0-40% EtOAc / Hexanes) to yield triflate 1d (15.5 g, 95%, 99% ee) as a white solid. ESI-MS m / z 490 (M+H)+. Step 1-4. Synthesis of benzyl (R)-2-((tert-butoxycarbonyl)amino)-2-(4- (diethoxyphosphoryl)phenyl)acetate (1e). To a 3-neck RBF (250 mL) was added triflate 1d (8.0 g, 16.3 mmol, 1.0 eq) followed by ACN (150 mL). The mixture was stirred under Ar until homogeneous (15 minutes). Diethyl phosphite (2.63 mL, 20.4 mmol, 1.25 eq) and DIPEA (2.70 mL, 15.5 mmol, 0.95 eq) were added sequentially. The solution was sparged with Ar for 10 minutes then heated to 85 °C under Ar until complete conversion was observed by LCMS (~2.5 h). The reaction was cooled to room temperature, filtered through Celite, and concentrated. The crude material was purified by silica gel chromatography (50-80% EtOAc / Hexanes) to yield product 1e (5.46, 70%, 92% ee) as a white solid. ESI-MS m / z 478 (M+H)+.Step 1-5. Synthesis of (R)-2-((tert-butoxycarbonyl)amino)-2-(4-(diethoxyphosphoryl)phenyl)acetic acid (1f) To a flask containing ester 1e (5.46 g, 11.4 mmol, 1.0 eq) in EtOH (50 mL) was added 10% Pd / C (546 mg, 10 wt%). The flask was purged with Ar then purged with H2and stirred at room temperature under H2atmosphere for 2 h. The flask was purged with Ar and the solution was filtered through Celite and concentrated to provide acid 1f (4.4 g, 99%) as a white solid. ESI-MS m / z 388 (M+H)+. Part 2. Synthesis of tert-butyl ((1r,3r)-3-(3-(chlorocarbonyl)-2-oxoimidazolidin-1- yl)cyclobutyl)carbamate (1k). Step 2-1. Synthesis of tert-butyl ((1r,3r)-3-((2- (((benzyloxy)carbonyl)amino)ethyl)amino)cyclobutyl)carbamate (1h). To a solution of tert-butyl ((1r,3r)-3-aminocyclobutyl)carbamate 1g (16 g, 85.9 mmol) in dioxane (200 mL) at ambient temperature were added benzyl (2-bromoethyl) carbamate (33.3 g, 128.85 mmol, 1.5 eq) and DIEA (33.5 g, 257.7 mmol, 3 eq). The mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (3×200 mL). The organic extracts WSGR Docket No.41223-757.601 were combined then washed consecutively with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The product was purified by flash chromatography on silica gel (0-10% MeOH / DCM) to give the desired intermediate 1h (10 g, 32%). ESI-MS m / z 364 (M+H)+. Step 2-2. Synthesis of tert-butyl ((1r,3r)-3-((2-aminoethyl)amino)cyclobutyl)carbamate (1i). A solution of tert-butyl ((1r,3r)-3-((2- (((benzyloxy)carbonyl)amino)ethyl)amino)cyclobutyl)carbamate (10 g, 27.5 mmol) in MeOH (150 mL) was added 10% Pd / C (2 g). The mixture was stirred in the H2 atmosphere overnight. The heterogeneous mixture was filtered through Celite and concentrated in vacuo to provide the title compound 1i (5.4 g, 87%). ESI-MS m / z 230 (M+H)+. Step 2-3. Synthesis of tert-butyl ((1r,3r)-3-(2-oxoimidazolidin-1-yl)cyclobutyl)carbamate (1j). A solution of tert-butyl ((1r,3r)-3-((2-aminoethyl)amino)cyclobutyl)carbamate (5.4 g, 23.55 mmol) in THF was added N,N’-carbonyldiimidazole (4.2 g, 25.9 mmol, 1.1 eq). The mixture was stirred at 60 °C overnight. The reaction mixture was purified by flash chromatography on silica gel (0-10% MeOH / DCM) to give the desired 1j (3 g, 50%). ESI-MS m / z 253 (M+H)+. Step 2-4. Synthesis of tert-butyl ((1r,3r)-3-(3-(chlorocarbonyl)-2-oxoimidazolidin-1- yl)cyclobutyl)carbamate (1k). To a solution of triphosgene (77 mg, 0.260 mmol, 0.7 eq) in THF (3.7 mL) at 0 °C was added TEA (62 µL, 0.445 mmol, 1.2 eq) followed by portionwise addition of tert-butyl ((1r,3r)-3-(2- oxoimidazolidin-1-yl)cyclobutyl)carbamate (94.7 mg, 0.371 mmol, 1.0 eq). The mixture was warmed to room temperature for 1 h. The heterogeneous mixture was filtered, and the filtrate concentrated to yield a crude solid. Hexanes (3 mL) was added, and the suspension was triturated for 16 h, filtered, washed with hexanes (3 mL), and the solid 1k was dried under vacuum. The material was used without further purification. ESI-MS m / z 318 (M+H)+. Part 3. Synthesis of phenyl (2-chloro-5-fluoro-3,4-dimethoxyphenyl)carbamate (1s)

[0003] WSGR Docket No.41223-757.601 Step 3-1. Synthesis of 3-fluoro-4,5-dihydroxybenzaldehyde (1l). To a solution of 3-fluoro-4-hydroxy-5-methoxybenzaldehyde (600 g, 3.53 mol) in DCM (6 L) was added BBr3 (600 mL, 6.24 mol, 1.77 eq) at -78 °C. The reaction mixture was stirred overnight at RT. The reaction was quenched by MeOH at -30 °C and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (40% EtOAc / PE) to give the desired product 1l as a white solid (520 g, 95%). ESI-MS m / z 157 (M+H)+. Step 3-2. Synthesis of 3-fluoro-5-hydroxy-4-methoxybenzaldehyde (1m). To a solution of 1l (520 g, 3.33 mol) in DMF (5 L) was added Li2CO3 (370 g, 5 mol, 1.5 eq), followed by MeI (473 g, 3.33 mol, 1 eq). The reaction mixture was stirred at 45 °C for 24 h. The reaction was diluted with EtOAc, washed with NaCl (saturated aq.), dried over Na2SO4, and evaporated in vacuo. The product was purified by flash chromatography on silica gel (20% EtOAc / PE) to give the desired product 1m (240 g, 42 %) as a white solid. ESI-MS m / z 171 (M+H)+. Step 3-3: Synthesis of 2-chloro-5-fluoro-3-hydroxy-4-methoxybenzaldehyde (1n). To a solution of 1m (240 g, 1.41 mol) in toluene (3 L) was added diisobutylamine (54.6 g, 0.423 mol, 0.3 eq). The mixture was heated to 70 °C in an oil bath, and sulfuryl chloride was added (200 g, 1.48 mol, 1.05 eq) at 70 °C. The reaction mixture was stirred for 2 h at 70 °C. The resulting mixture was concentrated in vacuo to give 310 g of crude 1n. ESI-MS m / z 205 (M+H)+. Step 3-4: Synthesis of 2-chloro-5-fluoro-3,4-dimethoxybenzaldehyde (1o). To a solution of crude 1n (310 g, ~ 1.41 mol) in DMF (3 L) was added Cs2CO3(685 g, 2.1 mol, 1.5 eq), MeI (241.4 g, 1.7 mol, 1.2 eq) at 0 °C. The mixture was stirred overnight at RT. The reaction mixture was diluted with EA, washed with water, dried over Na2SO4, concentrated in vacuo. The WSGR Docket No.41223-757.601 crude product was purified by flash chromatography on silica gel (4% EtOAc / PE) to give the desired product (240 g, 78%) as a white solid. ESI-MS m / z 219 (M+H)+. Step 3-5. Synthesis of 2-chloro-5-fluoro-3,4-dimethoxybenzoic acid (1p). To a solution of 1o (240 g, 1.1 mol) in dioxane (3.6 L) was added sulfamic acid (213.4 g, 2.42 mol, 2.2 eq) in water (2.1 L), followed by NaClO2 (199 g, 2.42 mol, 2.2 eq) in water (1 L) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. The reaction was quenched with NaHSO3 (503.4 g, 4.84 mol, 4.4 eq) in water (2.5 L), extracted with EA washed with NaCl (aq), dried over Na2SO4, and evaporated in vacuo. The product was purified by flash chromatography on silica gel (30% EtOAc / PE) to give the desired product 1p (225 g, 87%) as a white solid. ESI-MS m / z 233.0 (M-H)- (negative mode) Step 3-6: Synthesis of tert-butyl (2-chloro-5-fluoro-3,4-dimethoxyphenyl)carbamate (1q). To a solution of 1p (220 g, 0.94 mol) in toluene (2 L) was added TEA (142.4 g, 1.41 mol, 1.5 eq), DPPA (388 g, 1.41 mol, 1.5 eq), followed by t-BuOH (348 g, 4.7 mol, 5 eq). The reaction mixture was stirred at 120 °C for 15 h. The resulting mixture was concentrated in vacuo, diluted with water, extracted with EA, dried over Na2SO4, concentrated in vacuo. The product was purified by flash chromatography on silica gel (10% EtOAc / PE) to give desired product 1q as a white solid (220 g, 77 %). ESI-MS m / z 306 (M+H)+. Step 3-7: Synthesis of 2-chloro-5-fluoro-3,4-dimethoxyaniline (1r). To a solution of 1q (91.5 g, 300 mmol) in dioxane (1 L) was added 4 N HCl / dioxane (1 L) dropwise. The reaction mixture was stirred at RT for 4 h and then concentrated in vacuo to give desired product 1r as a white solid (73 g, 100%). ESI-MS m / z 206 (M+H)+. Step 3-8: Synthesis of phenyl (2-chloro-5-fluoro-3,4-dimethoxyphenyl)carbamate (1s). To a solution of 1r (1.03 g, 5 mol) in THF (21 mL) was added a saturated aq. solution of NaHCO3 (35 mL). The reaction was stirred at room temperature for 5 minutes. Phenyl carbonochloridate (864 mg, 5.5 mmol, 1.1 equiv.) was added dropwise. The mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc (100 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 40 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated. The crude material was purified by silica gel chromatography (0- 25% MeOH / EtOAc) to yield 1s (1.32 g, 81%) as a white solid. ESI m / z 326 (M+H)+. Part 4. Synthesis of (R)-3-((R)-2-(3-((1r,3R)-3-(3-(2-chloro-5-fluoro-3,4- dihydroxyphenyl)ureido)cyclobutyl)-2-oxoimidazolidine-1-carboxamido)-2-(4- WSGR Docket No.41223-757.601 phosphonophenyl)acetamido)-7-fluoro-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8- carboxylic acid (1). WSGR Docket No.41223-757.601 Step 4-1. Synthesis of (R)-2-(3-((1r,3R)-3-((tert-butoxycarbonyl)amino)cyclobutyl)-2- oxoimidazolidine-1-carboxamido)-2-(4-(diethoxyphosphoryl)phenyl)acetic acid (1u). To a solution of acid 1f (2.04 g, 5.27 mmol, 1.00 eq) in DCM (21 mL) at 0 °C was added TFA (5.3 mL) slowly. The reaction was warmed to room temperature for 1 h then concentrated. The crude 1t was used in the next step without further purification. ESI m / z 288 (M+H)+. To a solution of crude 1t in THF (21 mL) was added a saturated aq. solution of NaHCO3 (35 mL) slowly (NOTE: Gas evolution was observed). The reaction was stirred at room temperature for 5 minutes. Carbamoyl chloride 1k (1.84 g, 5.79 mmol, 1.1 eq) was added portionwise. The mixture was stirred at room temperature for 1 h (NOTE: After 30 minutes, check pH of reaction to ensure pH 6-9. If the pH is too low, slowly add saturated aq. NaHCO3until desired pH is obtained). The mixture was diluted with EtOAc (100 mL) and acidified to pH 2 with aqueous HCl (2 M). The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 40 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated. The crude material was purified by silica gel chromatography (0-25% MeOH / EtOAc) to yield 1u (2.5 g, 75%) as a white solid. ESI m / z 569 (M+H)+. Step 4-2. Synthesis of (R)-2-(3-((1r,3R)-3-(3-(2-chloro-5-fluoro-3,4- dimethoxyphenyl)ureido)cyclobutyl)-2-oxoimidazolidine-1-carboxamido)-2-(4- (diethoxyphosphoryl)phenyl)acetic acid (1w). To a solution of 1u (2.5 g, 3.95 mmol, 1.00 eq) in DCM (18 mL) at 0 °C was added TFA (4.4 mL) slowly. The reaction was warmed to room temperature for 1 h then concentrated. The material (1v) was used in the next step without further purification. ESI m / z 469 (M+H)+. To a solution of crude 1v in THF (18 mL) was added a saturated aq. solution of NaHCO3 (30 mL) slowly (NOTE: Gas evolution was observed). The reaction was stirred at room temperature for 5 minutes. Phenyl carbamate 1s (1.42 g, 4.35 mmol, 1.1 eq) was added followed by DMAP (49 mg, 0.4 mmol, 0.10 eq). The mixture was stirred at room temperature for 16 h (NOTE: After 30 minutes, check pH of reaction to ensure pH 6-9. If the pH is too low, slowly add saturated aq. NaHCO3 until desired pH is obtained). The mixture was diluted with EtOAc (100 mL) and acidified to pH 2 with aqueous HCl (2 M). The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 40 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated. The crude material was purified by silica gel chromatography (0-20% MeOH / EtOAc) to yield acid 1w (982 mg, 35.5%) as a white solid. ESI m / z 700 (M+H)+. Step 4-3. Synthesis of tert-butyl 3-((R)-2-((R)-2-(3-((1r,3R)-3-(3-(2-chloro-5-fluoro-3,4- dimethoxyphenyl)ureido)cyclobutyl)-2-oxoimidazolidine-1-carboxamido)-2-(4- (diethoxyphosphoryl)phenyl)acetamido)-2-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[d][1,3,2]dioxaborol-2-yl)ethyl)-6-fluoro-2-methoxybenzoate (1x). To a round-bottom flask was added acid 1w (985 mg, 1.4 mmol, 1.00 eq), C (740 mg, 1.54 mmol, 1.1 eq, and HATU (665 mg, 1.75 mmol, 1.25 eq). DMA (15 mL) was added followed by DIPEA (0.49 mL, 2.8 mmol, 2.00 eq). The reaction was stirred at room temperature for 1 h (NOTE: DO NOT WSGR Docket No.41223-757.601 run reaction for extended period of time). The mixture was diluted with MTBE (100 mL) and quenched with HCl (0.5 M, 40 mL). The layers were separated, and the aq. layer was extracted with MTBE (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated. The crude material was purified by silica gel chromatography (0-5% MeOH / EtOAc) to yield 1x (1.02 g, 64.8%) as an off-white solid. ESI m / z 1129 (M+H)+. Step 4-4. Synthesis of (R)-3-((R)-2-(3-((1r,3R)-3-(3-(2-chloro-5-fluoro-3,4- dihydroxyphenyl)ureido)cyclobutyl)-2-oxoimidazolidine-1-carboxamido)-2-(4- phosphonophenyl)acetamido)-7-fluoro-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8- carboxylic acid (1). To a solution of 1x (1.02 g, 0.91 mmol, 1.00 eq) in DCM (10 mL) at -78 °C was added TMSBr (1.2 mL, 9.1 mmol, 10.0 eq) slowly. The mixture was allowed to warm to room temperature over 16 h then concentrated in vacuo. MeOH (25 mL) was added and stirred at room temperature for 30 min, then concentrated. To remove residual MeOH, the crude material was azeotroped with DCM (3 × 25 mL) and the crude material (1y) was used in the next step without further purification. ESI m / z 1073 (M+H)+. To a solution of crude 1y in DCM (10 mL) at -78 °C was added BBr3(1 M, 9.1 mL, 9.1 mmol, 10.0 eq) slowly. The reaction was allowed to warm to room temperature over 16 h. The reaction was cooled to 0 °C, quenched with H2O (5 mL), warmed to room temperature, stirred for 15 minutes, and concentrated. The crude material was azeotroped with ACN (20 mL) to remove residual H2O. The crude solid was triturated with ACN (100 mL), filtered, washed with ACN (2 × 20 mL), and dried. The resulting crude product was purified by reverse-phase HPLC to yield 1 (140 mg). ESI m / z 823 (M+H)+. Example 2. (R)-3-((R)-2-(3-((1s,3S)-3-(3-(2-chloro-5-fluoro-3,4- dihydroxyphenyl)ureido)cyclobutyl)-2-oxoimidazolidine-1-carboxamido)-2-(4-

[0004] WSGR Docket No.41223-757.601 phosphonophenyl)acetamido)-7-fluoro-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8- carboxylic acid. Part 1. Synthesis of tert-butyl ((1s,3s)-3-(3-(chlorocarbonyl)-2-oxoimidazolidin-1- yl)cyclobutyl)carbamate (2e). The title compound 2e was prepared according to the procedure of Example 1, Part 2, substituting tert-butyl ((1s,3s)-3-aminocyclobutyl)carbamate for tert-butyl ((1r,3r)-3- aminocyclobutyl)carbamate (1g) in Step 2-1. The material was used without further purification. Part 2. Synthesis of (R)-3-((R)-2-(3-((1s,3S)-3-(3-(2-chloro-5-fluoro-3,4- dihydroxyphenyl)ureido)cyclobutyl)-2-oxoimidazolidine-1-carboxamido)-2-(4- phosphonophenyl)acetamido)-7-fluoro-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8- carboxylic acid (2). The title compound was prepared in a similar manner to the synthesis of Example 1, substituting tert-butyl ((1s,3s)-3-(3-(chlorocarbonyl)-2-oxoimidazolidin-1-yl)cyclobutyl)carbamate (2f) WSGR Docket No.41223-757.601 for tert-butyl ((1r,3r)-3-(3-(chlorocarbonyl)-2-oxoimidazolidin-1-yl)cyclobutyl)carbamate (1u) in Step 4- 1. After reversed phase HPLC purification using an XBridge C18 column in Step 4, the title compound 2 was collected as the second eluting peak. ESI-MS m / z 823 (M+H)+. Example 3. (R)-3-((R)-2-(3-((1r,4R)-4-(3-(2-chloro-5-fluoro-3,4- dihydroxyphenyl)ureido)cyclohexyl)-2-oxoimidazolidine-1-carboxamido)-2-(4- phosphonophenyl)acetamido)-7-fluoro-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8- carboxylic acid. Part 1. Synthesis of tert-butyl ((1r,4r)-4-(3-(chlorocarbonyl)-2-oxoimidazolidin-1- yl)cyclohexyl)carbamate (3e). The title compound 3e was prepared according to the procedure of Example 1, Part 2, substituting tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (3a) for tert-butyl ((1r,3r)-3- aminocyclobutyl)carbamate (1g) in Step 2-1. The material was used without further purification. Part 2. Synthesis of (R)-3-((R)-2-(3-((1r,4R)-4-(3-(2-chloro-5-fluoro-3,4- dihydroxyphenyl)ureido)cyclohexyl)-2-oxoimidazolidine-1-carboxamido)-2-(4- phosphonophenyl)acetamido)-7-fluoro-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8- carboxylic acid (3). The title compound was prepared in a similar manner to the synthesis of Example 1, substituting tert-butyl ((1r,4r)-4-(3-(chlorocarbonyl)-2-oxoimidazolidin-1-yl)cyclohexyl)carbamate for tert-butyl ((1r,3r)-3-(3-(chlorocarbonyl)-2-oxoimidazolidin-1-yl)cyclobutyl)carbamate (1u) in Step 4-1. After reversed phase HPLC purification using an XBridge C18 column in Step 4, the title compound 3 was collected as the second eluting peak. ESI-MS m / z 851 (M+H)+. Example 4. (R)-3-((R)-2-(3-((1s,4S)-4-(3-(2-chloro-5-fluoro-3,4- dihydroxyphenyl)ureido)cyclohexyl)-2-oxoimidazolidine-1-carboxamido)-2-(4- WSGR Docket No.41223-757.601 phosphonophenyl)acetamido)-7-fluoro-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8- carboxylic acid. Part 1. Synthesis of tert-butyl ((1s,4s)-4-(3-(chlorocarbonyl)-2-oxoimidazolidin-1- yl)cyclohexyl)carbamate (4e). The title compound was prepared in analogy to Example 3, Step 1, utilizing tert-butyl ((1s,4s)- 4-aminocyclohexyl)carbamate (4a) in place of tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate 3a. The resulting 4e was used without further purification. Part 2. Synthesis of (R)-3-((R)-2-(3-((1s,4S)-4-(3-(2-chloro-5-fluoro-3,4- dihydroxyphenyl)ureido)cyclohexyl)-2-oxoimidazolidine-1-carboxamido)-2-(4- phosphonophenyl)acetamido)-7-fluoro-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8- carboxylic acid (4). The title compound was prepared in a similar manner to the synthesis of Example 1, substituting tert-butyl ((1s,4s)-4-(3-(chlorocarbonyl)-2-oxoimidazolidin-1-yl)cyclohexyl)carbamate for tert-butyl ((1r,3r)-3-(3-(chlorocarbonyl)-2-oxoimidazolidin-1-yl)cyclobutyl)carbamate (1u) in Step 4-1. After reversed phase HPLC purification using an XBridge C18 column in Step 4, the title compound 4 was collected as the second eluting peak. ESI-MS m / z 851 (M+H)+. Example 5. (R)-3-((R)-2-(3-((1r,3R)-3-(2-chloro-5-fluoro-3,4-dihydroxybenzamido)cyclobutyl)-2- oxoimidazolidine-1-carboxamido)-2-(4-phosphonophenyl)acetamido)-7-fluoro-2-hydroxy-3,4- dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid. Part 1. Synthesis of 2-chloro-5-fluoro-3,4-dimethoxybenzoyl chloride (5a). To a solution of 1p (234 mg, 1 mmol, 1.00 eq) in DCM (5 mL) at 0 °C was added DMF (1 drop) and SOCl2 (3 mL). The mixture was allowed to warm to room temperature and stirred at room temperature for 2 h then concentrated to give crude 5a, which was used in the next step without further purification. WSGR Docket No.41223-757.601 Part 2. Synthesis of (R)-3-((R)-2-(3-((1r,3R)-3-(2-chloro-5-fluoro-3,4- dihydroxybenzamido)cyclobutyl)-2-oxoimidazolidine-1-carboxamido)-2-(4- phosphonophenyl)acetamido)-7-fluoro-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8- carboxylic acid. The title compound was prepared in a similar manner to the synthesis of Example 1, substituting 2-chloro-5-fluoro-3,4-dimethoxybenzoyl chloride (5a) for phenyl (2-chloro-5-fluoro-3,4- WSGR Docket No.41223-757.601 dimethoxyphenyl)carbamate (1s) in Step 4-2. After reversed phase HPLC purification using an XBridge C18 column in Step 4, the title compound 5 was collected as the second eluting peak. ESI-MS m / z 808 (M+H)+. Example 6. (R)-3-((R)-2-(3-((1s,3S)-3-(2-chloro-5-fluoro-3,4-dihydroxybenzamido)cyclobutyl)-2- oxoimidazolidine-1-carboxamido)-2-(4-phosphonophenyl)acetamido)-7-fluoro-2-hydroxy-3,4- dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid. The title compound was prepared according to the procedure of Example 5, substituting (R)-2- (3-((1s,3S)-3-aminocyclobutyl)-2-oxoimidazolidine-1-carboxamido)-2-(4- (diethoxyphosphoryl)phenyl)acetic acid (3g) for (R)-2-(3-((1r,3R)-3-aminocyclobutyl)-2- oxoimidazolidine-1-carboxamido)-2-(4-(diethoxyphosphoryl)phenyl)acetic acid (1v) in Part 2. After reversed phase HPLC purification using an XBridge C18 column in Part 2, title compound 6 was collected as the second eluting peak. ESI-MS m / z 808 (M+H)+. Example 7. (R)-3-((R)-2-(3-((1r,4R)-4-(2-chloro-5-fluoro-3,4-dihydroxybenzamido)cyclohexyl)-2- oxoimidazolidine-1-carboxamido)-2-(4-phosphonophenyl)acetamido)-7-fluoro-2-hydroxy-3,4- dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid. The title compound was prepared in a similar manner to the synthesis of Example 3, substituting 2-chloro-5-fluoro-3,4-dimethoxybenzoyl chloride (5a) for phenyl (2-chloro-5-fluoro-3,4- dimethoxyphenyl)carbamate (1s) in Part 2. After reversed phase HPLC purification using an XBridge C18 column in Part 2, title compound 7 was collected as the second eluting peak. ESI-MS m / z 836 (M+H)+. Example 8. (R)-3-((R)-2-(3-((1s,4S)-4-(2-chloro-5-fluoro-3,4-dihydroxybenzamido)cyclohexyl)-2- oxoimidazolidine-1-carboxamido)-2-(4-phosphonophenyl)acetamido)-7-fluoro-2-hydroxy-3,4- dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid. Part 1. Synthesis of 2-chloro-5-fluoro-3,4-dimethoxybenzoyl chloride (5a). To a solution of 2-chloro-5-fluoro-3,4-dimethoxybenzoic acid 1p (117.3 g, 500 mmol, 1.00 eq) in DCM (1200 mL) at 0 °C was added DMF (1 mL) and SOCl2(145 mL, 2 mol, 4 eq). The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 2 h then concentrated to give crude 5a as a yellow oil (135 g) which was used without further purification. WSGR Docket No.41223-757.601 Part 2. Synthesis of tert-butyl ((1s,4s)-4-(3-(chlorocarbonyl)-2-oxoimidazolidin-1-yl)cyclohexyl) carbamate (8e). Step 2-1. Synthesis of tert-butyl ((1s,4s)-4-((2- (((benzyloxy)carbonyl)amino)ethyl)amino)cyclohexyl)- carbamate (8b). To a solution of tert-butyl ((1s,4s)-4-aminocyclohexyl)carbamate (8a, 184 g, 859 mmol) in dioxane (3700 mL) at ambient temperature were added benzyl (2-bromoethyl) carbamate (177.4 g, 687 mmol, 0.8 eq) and DIEA (335 g, 2577 mmol, 3 eq). The reaction mixture was stirred at 100 °C for 16 h. The product was purified by flash silica gel chromatography (0-10% MeOH / DCM) to give 8b as white solid (144 g, 43%). ESI-MS m / z 392 (M+H)+. Step 2-2. Synthesis of tert-butyl ((1s,4s)-3-((2-aminoethyl)amino)cyclohexyl)carbamate (8c). To a solution of 8b (140 g, 356.4 mmol) in MeOH (2000 mL) was added 10% Pd / C (20 g). The mixture was stirred beneath a H2 atmosphere (60 psi) overnight. The heterogeneous mixture was filtered through Celite and concentrated in vacuo to provide 8c (90 g) as a yellow oil which was used without further purification. ESI-MS m / z 258 (M+H)+. Step 2-3. Synthesis of tert-butyl ((1s,4s)-4-(2-oxoimidazolidin-1-yl)cyclohexyl)carbamate (8d). A solution of 8c (90 g, 350 mmol) in THF (700 mL) was added CDI (62.3 g, 385 mmol, 1.1 eq). The mixture was stirred at 60 °C overnight. The reaction mixture was purified by flash silica gel chromatography (0-10% MeOH / DCM) to give 8d (83 g, 83%) as a white solid. ESI-MS m / z 284 (M+H)+. Step 2-4. Synthesis of tert-butyl ((1s,4s)-4-(3-(chlorocarbonyl)-2-oxoimidazolidin-1- yl)cyclohexyl)carbamate (8e). To a solution of triphosgene (70.2 g, 236 mmol, 0.7 eq) in THF (700 mL) at 0 °C was added TEA (41.01 g, 406 mmol, 1.2 eq) followed by portion wise addition of 8d (95.7 g, 338 mmol, 1.0 eq). The reaction mixture was warmed to room temperature for 1 h. The heterogeneous mixture was filtered, and the filtrate concentrated to yield a crude solid. Hexanes (500 mL) was added, and the suspension was triturated for 16 h, filtered, washed with hexanes (300 mL), and the solid was dried under vacuum to give carbamoyl chloride 8e as a white solid (92.8 g) which was used without further purification. ESI-MS m / z 346 (M+H)+. Part 3. Synthesis of (R)-2-(3-((1s,4S)-4-(2-chloro-5-fluoro-3,4-dimethoxybenzamido)cyclohexyl)-2- oxoimidazolidine-1-carboxamido)-2-(4-(diethoxyphosphoryl)phenyl)acetic acid (8h). WSGR Docket No.41223-757.601 Step 3-1. Synthesis of (R)-2-amino-2-(4-(diethoxyphosphoryl)phenyl)acetic acid trifluoroacetate salt (1t). To a solution of acid 1f (100 g, 258 mmol, 1.00 eq) in DCM (1000 mL) at 0 °C was added TFA (200 mL) slowly. The reaction mixture was warmed to room temperature for 1 h then concentrated. The crude 1t was obtained as a white solid (103 g, 100%) which was used in the next step without further purification. ESI-MS m / z 288 (M+H)+. Step 3-2. Synthesis of (R)-2-(3-((1s,4S)-4-((tert-butoxycarbonyl)amino)cyclohexyl)-2-oxoimid- azolidine-1-carboxamido)-2-(4-(diethoxyphosphoryl)phenyl)acetic acid (8f). To a solution of crude amino acid 1t (103 g, 255.4 mmol) in THF (500 mL) was added saturated aq. NaHCO3(500 mL) slowly [NOTE: CO2evolution was observed]. The reaction mixture was stirred at room temperature for 5 min. Carbamoyl chloride 8e (92.8 g, 268.2 mmol 1.05 eq) was added portion wise. The reaction mixture was stirred at room temperature for 1 h [NOTE: After 30 min, check pH of reaction mixture to ensure pH 6-9. If the pH is too low, slowly add saturated aqueous NaHCO3until desired pH is obtained]. The reaction mixture was diluted with EtOAc and acidified to pH 2 with 2 M aqueous HCl. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (0-25% MeOH / EtOAc) to yield 8f as a white solid (102.1 g, 67%). ESI-MS m / z 597 (M+H)+. WSGR Docket No.41223-757.601 Step 3-3. Synthesis of (R)-2-(3-((1s,4S)-4-aminocyclohexyl)-2-oxoimidazolidine-1-carboxamido)-2- (4-(diethoxyphosphoryl)phenyl)acetic acid trifluoroacetate salt (8g). To a solution of 8f (14 g, 23.46 mmol) in DCM (44 mL) at 0 °C was added TFA (11 mL) slowly. The reaction mixture was warmed to room temperature for 1 h then concentrated. The crude 8g (15 g, white solid) was used in the next step without further purification. ESI-MS m / z 497 (M+H)+. Step 3-4. Synthesis of (R)-2-(3-((1s,4S)-4-(2-chloro-5-fluoro-3,4-dimethoxybenzamido)cyclohexyl)- 2-oxoimidazolidine-1-carboxamido)-2-(4-(diethoxyphosphoryl)phenyl)acetic acid (8h). To a solution of crude 8g (15 g, 23.46 mmol) in THF (250 mL) was added saturated aqueous NaHCO3(250 mL) slowly [NOTE: CO2evolution was observed]. The reaction mixture was stirred at room temperature for 5 min. Acid chloride 5a (6.53 g, 25.8 mmol, 1.1 eq) was added followed by DMAP (286 mg, 0.10 eq). The reaction mixture was stirred at room temperature for 16 h [NOTE: After 30 min, check pH of reaction to ensure pH 6-9. If the pH is too low, slowly add saturated aq. NaHCO3until desired pH is obtained]. The reaction mixture was diluted with EtOAc and acidified to pH 2 with 2 M HCl. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (0-20% MeOH / EtOAc) to yield 8h as a white solid (10 g, 59%). ESI-MS m / z 713 (M+H)+. Part 4. Synthesis of (R)-3-((R)-2-(3-((1s,4S)-4-(2-chloro-5-fluoro-3,4-dihydroxybenzamido)- cyclohexyl)-2-oxoimidazolidine-1-carboxamido)-2-(4-phosphonophenyl)acetamido)-7-fluoro-2- hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid (8). WSGR Docket No.41223-757.601 Step 4-1. Synthesis of tert-butyl 3-((R)-2-((R)-2-(3-((1s,4S)-4-(2-chloro-5-fluoro-3,4- dimethoxybenzamido)cyclohexyl)-2-oxoimidazolidine-1-carboxamido)-2-(4-(diethoxyphosphoryl)- phenyl)acetamido)-2-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]- dioxaborol-2-yl)ethyl)-6-fluoro-2-methoxybenzoate (8i). To a solution containing 8h (10 g, 14 mmol), intermediate C (7.5 g, 15.4 mmol, 1.1 eq), and HATU (6.65 g, 17.5 mmol, 1.25 eq) in DMA (140 mL) was added DIPEA (3.6 g, 28 mmol, 2.00 eq). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with MTBE and quenched with 0.5 M HCl. The layers were separated, and the aqueous layer was extracted with MTBE. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (0-5% MeOH / EtOAc) to yield 8i as an off-white solid (14 g, 87%). ESI-MS m / z 1142 (M+H)+. Step 4-2. Synthesis of (4-((R)-2-(((R)-2-(3-(tert-butoxycarbonyl)-4-fluoro-2-methoxyphenyl)-1- ((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]-dioxaborol-2- yl)ethyl)amino)-1-(3-((1s,4S)-4-(2-chloro-5-fluoro-3,4-dimethoxybenzamido)-cyclohexyl)-2- oxoimidazolidine-1-carboxamido)-2-oxoethyl)phenyl)phosphonic acid (8j). To a solution of 8i (14 g, 12.25 mmol) in DCM (140 mL) at -78 °C was added TMSBr (18.75 g, 122.5 mmol, 10.0 eq) slowly. The reaction mixture was allowed to warm to room temperature over 16 h then concentrated. MeOH was added and the reaction mixture was stirred at room temperature for 30 min then concentrated. The crude residue was dissolved in DCM then concentrated to dryness three times to remove residual MeOH. The crude 8j (pale yellow solid) was used in the next step without further purification. ESI-MS m / z 1086 (M+H)+. Step 4-3. Synthesis of (R)-3-((R)-2-(3-((1s,4S)-4-(2-chloro-5-fluoro-3,4-dihydroxybenzamido)- cyclohexyl)-2-oxoimidazolidine-1-carboxamido)-2-(4-phosphonophenyl)acetamido)-7-fluoro-2- hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid (8). To a solution of crude 8j (12.25 mmol) in DCM (140 mL) at -78 °C was added BBr3 (23.5 mL, 20.0 eq) slowly. The reaction mixture was allowed to warm to room temperature for 2 h. The reaction mixture was then cooled to 0 °C, quenched with water, warmed to room temperature, stirred for 15 min, and concentrated. The crude product was dissolved in acetonitrile then concentrated to dryness to remove WSGR Docket No.41223-757.601 residual water. The crude solid was triturated with acetonitrile, filtered, washed with acetonitrile (2 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. Crude 1 was purified by RP-HPLC to yield 8 as a white solid (4.3 g). Mass spectrum, (ESI) m / z 836 (M+H)+. Large-scale synthesis of Example 8: (R)-3-((R)-2-(3-((1s,4S)-4-(2-chloro-5-fluoro-3,4- dihydroxybenzamido)cyclohexyl)-2-oxoimidazolidine-1-carboxamido)-2-(4- phosphonophenyl)acetamido)-7-fluoro-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8- carboxylic acid. Part 1. Large Scale Synthesis of tert-butyl ((1s,4s)-4-(2-oxoimidazolidin-1-yl)cyclohexyl)carbamate (8d, RSM-1). Step 1. Compound 8a (3.6 kg, 16.8 mol, 1.0 equiv.) was charged into a 100 L reactor at RT followed by ACN (43 L, 12 v / w). Benzyl (2-bromoethyl)carbamate (5.6 kg, 21.9 mol, 1.3 equiv.) and K2CO3 (5.8 kg, 42.1 mol, 2.5 equiv.) were charged sequentially at RT. The mixture was heated to 80 °C for 20 h. Following an IPC by HPLC, GC, and LCMS the reaction was cooled to 25-30 °C and filtered. The filter cake was rinsed with ACN (7.2 L, 2.0 v / w) twice and the solution containing Compound 1-3 in ACN was charged into a 100 L reactor at RT. The reactor was charged with fumaric acid (2.05 kg, 17.6 mol, 1.05 equiv.) and stirred at 20-30 °C for 3 h. The solid was filtered and dried to obtain a crude fumaric salt as a white solid. The solid was freebased with NaOH solution (0.6 N, 72 L, 10 v / w of salt) and the product was extracted with DCM (72 L, 10 v / w) then DCM (21 L, 3 v / w). The combined organic layers were washed with H2O (36 L, 5 v / w) then brine (36 L, 5 v / w), dried over Na2SO4, filtered, and concentrated under vacuum at 45-50 °C to yield Compound 8b (5.6 kg, 85.1% yield, 99.4% purity) as a colorless oil. Step 2. Compound 8b (1.87 kg, 4.78 mol, 1.0 equiv.) was charged into a 10 L autoclave at RT followed by a charge of MeOH (5.6 L, 3 v / w). The vessel was degassed with nitrogen three times then put under H2 atmosphere (50 psi). The mixture was stirred at 25-30 °C for 24 h then analyzed via in- process control (IPC) by LCMS. The mixture was filtered through a Celite pad and the cake was washed WSGR Docket No.41223-757.601 with MeOH (2.8 L, 2 v / w). The combined filtrate of three batches were concentrated to obtain crude Compound 8c (3.6 kg) as a colorless oil which was used in the next step without further purification. Step 3. Crude Compound 8c (3.6 kg, 140 mol, 1.0 equiv.) was charged into a 20 L reactor followed by DCM (54 L, 15 v / w) and TEA (3.0 kg, 29.5 mol, 2.1 equiv.) sequentially at RT. N,N’- carbonyldiimidazole (2.5 kg, 15.4 mol, 1.1 equiv.) was added slowly to the reactor at RT then the reaction was heated to 40 °C for 3-5 h. IPC by LCMS showed full conversion and the reactor was cooled to RT. The organics were washed with H2O (54 L, 15 v / w) then citric acid solution (10%, 54 L, 15 v / w) then H2O (36 L, 10 v / w). The organic layer was concentrated under vacuum at 40-45 °C to ~18 L (5 v / w). To this solution was charged iPrOAc (18 L, 5 v / w) and concentrated under vacuum to ~18 L (5 v / w). iPrOAc (25 L, 7 v / w) was again charged and the mixture was heated to 85 °C for 30 min, then cooled to RT and stirred for 12-16 h. The suspension was filtered and the cake washed with iPrOAc (7.2 L, 2 v / w). The solid was dried to yield 8d (RSM-1) (3.2 kg, 81.0% yield, 99.95% purity) as a white solid. Part 2. Large Scale Synthesis of 3,4-bis(benzyloxy)-2-chloro-5-fluorobenzoic acid (RSM-2b). To a 100 L reactor was charged Compound 8-2-a (6.6 kg, 42.28 mol, 1.0 equiv.) followed by MeOH (33.0 L, 5 v / w) at RT. The mixture was cooled to 0-5 °C. SOCl2(5.78 kg, 48.62 mol, 1.15 equiv.) was slowly added to the reactor to maintain a temperature between 0-10 °C. The reaction was heated to 40-45 °C and stirred for 19 h, then cooled to RT. The reaction was concentrated to remove MeOH followed by addition of DCM (13.2 L, 2 v / w). The mixture was concentrated, and n-heptane (20 L, 3 v / w) was added and concentrated twice. The residue was re-slurried with a final addition of n- heptane (20 L, 3 v / w), cooled to 0-10 °C, filtered, and the solid was washed with n-heptane (13.2 L, 2 v / w). The crude Compound 8-2-b (6.95 kg, 96.7% yield, 99.8% purity) was dried under vacuum to obtain an off-white solid which was used in the next step without further purification. Step 2. Compound 8-2-b (3.0 kg, 17.6 mol, 1.0 equiv.) and TFA (15 L, 5 v / w) were charged to a 20 L flask sequentially at RT. The mixture was cooled to 0-10 °C and HMTA (4.94 kg, 35.3 mol, 2.0 equiv.) was added portionwise to not exceed 10 °C. (NOTE: Addition of HMTA was extremely exothermic!). WSGR Docket No.41223-757.601 The reaction was warmed to RT for 10 min. then heated to 100 °C for 16 h. (NOTE: The solution becomes thick / sticky resulting in difficulty stirring). The mixture was cooled to 40-50 °C, poured into a 100 L reactor containing H2O (75 L, 5 v / v for TFA), and stirred for 15 min at RT. The suspension was filtered and the solid was washed with H2O. The solid was dissolved in EtOAc (33 L, 11 v / w) and the organic layer was washed with H2O (6 L, 2 v / w), dried with Na2SO4, filtered, and concentrated. The residue was slurried with petroleum ether (PE, 5 L), filtered, and the cake washed with PE. The solid was dried under vacuum to yield Compound 8-2-c (2.78 kg, 79.7% yield, 99.8% purity) as an off-white solid. Step 3. A 100 L reactor was charged Compound 8-2-c (4.65 kg, 23.47 mol, 1.0 equiv.) and THF (28 L, 6 v / w) at RT. The mixture was cooled to 0-10 °C and NaOH (1.03 kg, 25.81 mol, 1.1 equiv. in H2O (14 L)) was added. The reaction was warmed to RT and stirred for 15-20 min. then charged with H2O2(30%, 3.991 kg, 35.20 mol, 1.5 equiv.). The mixture was stirred at RT for 16 h, cooled to 0-5 °C, and quenched with Na2S2O3(1.85 kg, 12.91 mol, 0.5 equiv.). The aqueous layer was extracted twice with EtOAc (23 L, 5 v / w each time). The combined organic layers were dried with Na2SO4, filtered, and concentrated to ~10 L. n-Heptane (10 L) was added, and the solution was again concentrated to ~10 L. PE (15 L) was added to the suspension and cooled to 0-10 °C. The solid was filtered, washed with PE, and dried under vacuum to yield crude Compound 8-2-d (4.27 kg, 97.9% yield, 98.8% purity) as an off-white solid. Step 4. Compound 8-2-d (3.0 kg, 16.12 mol, 1.0 equiv.) and toluene (51 L, 17 v / w) was charged to a 100 L reactor at RT. 2,2,4,4-Tetramethylpiperidine (227 g, 1.61 mol, 0.1 equiv.) was added to the reactor and heated to 90-100 °C. A solution of SO2Cl2(2.61 kg, 19.34 mol, 1.2 equiv.) in toluene (9 L, 3 v / w) was added dropwise into the reactor at 90-100 °C over 2 h. The mixture was cooled to 0-5 °C slowly over 16 hrs., filtered, and washed with toluene. The solid was slurried with DCM (18 L, 6 v / w), cooled to 0-10 °C, filtered, and washed with DCM (3 L, 1 v / w) twice. The solid was dried under vacuum to yield crude Compound 8-2-e (3.08 kg) as an off-white solid that was used in the next step without further purification. Step 5. A 100 L reactor was charged with Compound 8-2-e (1.83 kg, 8.27 mol, 1.0 equiv.), DMF (9.1 L, 5 v / w), K2CO3 (2.86 kg, 20.7 mol, 2.5 equiv.) and BnBr (3.11 kg, 18.2 mol, 2.2 equiv.) at RT sequentially. The mixture was stirred at 20-30 °C for 2-3 h. The reaction was poured into a mixture of H2O (45 L, 5 v / v for DMF) and EtOAc (18 L, 10 v / w for 2-4). The layers were separated, and the aq. layer was extracted with EtOAc (10 L, 5 v / w). The combined organic layers were washed with H2O (10 L, 5 v / w) then brine (10 L, 5 v / w), dried over Na2SO4, filtered, and concentrated to dryness yielding crude Compound 8-2-f (3.79 kg) as a yellow oil that was used directly in the next step without further purification. WSGR Docket No.41223-757.601 Step 6. Crude Compound 8-2-f (3.79 kg, 8.27 mol, 1.0 equiv.) was charged into a 100 L reactor followed by H2O (12.8 L, 7 v / w), THF (12.8 L, 7 v / w) and LiOH·H2O (694 g, 16.5 mol, 2.0 equiv.) sequentially. The reaction was stirred at 20-30 °C for 16 h then concentrated to remove the THF. MTBE (9.1 L, 5 v / w) and H2O (24 L, 13 v / w) were added. The layers were separated, and the aqueous layer was washed with MTBE (9.1 L, 5 v / w). The aqueous layer was charged with MTBE (19 L, 10 v / w) and the pH was adjusted to 1-2 with HCl (conc.). The layers were separated, and the aqueous layer was extracted with MTBE (9.1 L, 5 v / w). The combined organic layers were washed with H2O (9.1 L, 5 v / w) then brine (9.1 L, 5 v / w) and concentrated under vacuum (T<50 °C) to 5-7 v / w). The solution was charged with n-heptane (18.3 L, 10 v / w), cooled to 0-10 °C, filtered, and the cake was washed with n-heptane. The solid was dried under vacuum (T = 50 °C) to obtain Compound 8-2-g (RSM-2b) (3.01 kg, 92.8% yield, 99.8% purity) as a white solid. Part 3. Large Scale Synthesis of (R)-2-(benzyloxy)-1-(4-((diethyl-l3-oxidaneyl)(l1- oxidaneyl)phosphoryl)phenyl)-2-oxoethan-1-aminium 2,2,2-trifluoroacetate (8-3-a, RSM-3). Step 1. A 100 L reactor was charged with BnOH (20 L, 20 v / w) followed by Compound 1a (1.0 kg, 5.98 mol, 1.0 equiv.) at RT. The mixture was cooled to 0-10 °C. SOCl2(2.85 kg, 23.93 mol, 4.0 equiv.) was added dropwise maintaining the temperature below 10 °C. The reaction was heated to 80-85 °C and stirred for 16 h then cooled to RT. The reactor was slowly charged with MTBE (70 L, 70 v / w) and cooled to 0-10 °C. The resulting solid was filtered, washed with MTBE (5 L, 5 v / w), and dried under vacuum to yield crude Compound 1b (1.4 kg) as a white solid that was used directly in the next step without further purification. Step 2. DCM (29.75 L, 7 v / w) and Compound 1b (5.0 kg, 14.47 mol, 1.0 equiv.) were charged into a 100 L reactor at RT and cooled to 0-10 °C. TEA (3.66 kg, 361.7 mol, 2.5 equiv.) was added dropwise at 0-10 °C followed by Boc2O (3.80 kg, 17.36 mol, 1.2 equiv.) dropwise at 0-10 °C. The mixture was warmed to RT and stirred for 16 h. An additional charge of Boc2O (158 g, 0.72 mol, 0.05 equiv.) was added at RT and stirred for 2-3 h. H2O (20 L, 4 v / w) was added to the mixture and the layers were WSGR Docket No.41223-757.601 separated. The organic layer was washed with HCl (1 N, 30 L, 6 v / w) then NaHCO3 (sat. aq., 20 L, 4 v / w) and finally brine (20 L, 4 v / w). The solution was dried with Na2SO4, filtered, and concentrated to 5 v / w. PE (75 L, 15 v / w) was added to the mixture, concentrated to 5-8 v / w, followed by a final charge of PE (50 L, 10 v / w). The mixture was cooled to 0-10 °C and stirred for 30 min., filtered, and the solid was dried to provide Compound 1c (3.64 kg, 70% yield, 92.5% purity) as a white solid. Step 3. Compound 1c (3.64 kg, 10.2 mol, 1.0 equiv.) and DCM (44 L, 12 v / w) were charged to a 100 L reactor at RT then cooled to 0-10 °C. Pyridine (2.42 kg, 30.6 mol, 3.0 equiv.) was added dropwise followed by Tf2O (3.30 kg, 11.7 mol, 1.15 equiv.) dropwise at 0-10 °C. The reaction was stirred for 30 min at 0-10 °C then quenched with HCl (1 N, 22 L, 6 v / w). The layers were separated, and the organic layer was washed with NaHCO3(sat. aq., 14.5 L, 4 v / w) then brine (14.5 L, 4 v / w) and concentrated to dryness. The residue was slurried with PE (18 L, 5 v / w), filtered, and dried to provide Compound 1d (4.0 kg, 80% yield, 98.1% purity) as a yellow solid which was used in the next step without further purification. Step 4. A 20 L reactor was charged with Pd(OAc)2(27.8 g, 0.12 mol, 0.075 equiv.), dppf (135 g, 0.25 mol, 0.1 equiv.) and KOAc (32.1 g, 0.32 mol, 0.2 equiv.) at RT. The atmosphere was replaced with N2three times then THF (13.6 L, 17 v / w) and DIPEA (200.9 g, 1.5 mol, 0.95 equiv.) were charged to the reactor. The atmosphere was again exchanged with N2three times. The reaction was warmed to 60-65 °C for 15-30 min. then cooled to 50-55 °C. The reactor was charged with diethyl phosphite (282.0 g, 2.04 mol, 1.25 equiv.) followed by a solution of Compound 1d (800 g, 1.6 mol, 1.0 equiv.) in THF (2.4 L, 3 v / w) at 50-55 °C and stirred for 3 h. The mixture was cooled to RT and concentrated to dryness. The crude residue was filtered through silica gel pad (EtOAc:PE 9-35% gradient) and the fractions containing product were concentrated to dryness. This procedure was repeated 6 times and combined to produce a single batch of crude Compound 1e (4.4 kg, 98.8% ee) as a red oil which was used in the next step without further purification. Step 5. DCM (16.5 L, 4 v / w), Compound 1e (4.14 kg, 8.67 mol, 1.0 equiv.) and TFA (4.94 kg, 43.35 mol, 5.0 equiv.) were sequentially charged to a reactor. The mixture was stirred at RT for 16 h then concentrated to dryness. The residue was charged with MTBE (62 L, 15 v / w) and stirred for 1-2 h. The slurry was filtered and the solid was washed with MTBE and dried under vacuum (T<45°C) to yield target 8-3-a (RSM-3, 3.57 kg, 83.8% yield, 99.7% purity, 98.8% ee) as an off-white solid. Part 4. Large Scale Synthesis of (R)-3-((R)-2-(3-((1s,4S)-4-(2-chloro-5-fluoro-3,4- dihydroxybenzamido)cyclohexyl)-2-oxoimidazolidine-1-carboxamido)-2-(4- phosphonophenyl)acetamido)-7-fluoro-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8- carboxylic acid (Example 8). WSGR Docket No.41223-757.601 Step 1. A 50 L reactor was charged with THF (33 L, 20 v / w) at RT. BTC (1.21 kg, 4.08 mol, 0.7 equiv.) was added to the reactor at RT under N2atmosphere. The solution was cooled to 0 °C and TEA (707 g, 6.99 mol, 1.2 equiv.) was added dropwise followed by a charge of 8d (RSM-1, 1.65 kg, 5.82 mol, 1.0 equiv). The mixture was warmed to RT slowly and then stirred for 1 h. The suspension was filtered and the filtrate was concentrated under vacuum at 40 °C. n-Heptane (33 L, 20 v / w) was added and the slurry was stirred for 1 h. The solid was filtered, washed with n-heptane, and dried under vacuum to provide 8e (1.98 kg, 98.4% yield, 99.1% purity) as a yellow solid that was used directly in Step 3. Step 2. A 10 L reactor was charged with RSM-3 (600 g, 1.22 mol, 1.0 equiv.) at RT. H2O (6.0 L, 10 v / w) was added to the reactor followed by TFA (139 g, 1.22 mol, 1.0 equiv.) at RT. Pd / C catalyst (10% w / w, 60 g) was added at RT. The atmosphere was replaced with N2three times followed by a H2atmosphere replacement three times. The mixture was stirred under the H2atmosphere (50 psi) then warmed to 35 °C for 16 h. The reaction was cooled and the H2atmosphere was replaced with N2three times. The mixture was filtered, the cake was washed with H2O (1.2 L, 2.0 v / w) and the aq. solution was washed with MTBE (4.2 L, 7 v / w) twice. The crude aq. solution of RSM-3a (structure not shown) was used in the next step without further purification. WSGR Docket No.41223-757.601 Step 3. To a 20 L flask under N2was added THF (3.84 L, 6.4 v / w based on 8-4-a (RSM-3, starting material from Step 2]) and the aqueous solution of 8-4-a (RSM-3a, 1.22 mol, 1.0 equiv.). NaHCO3(512 g, 6.1 mol, 5.0 equiv.) was added to the reactor slowly [CAUTION: Excessive gas evolution observed]. The mixture was stirred at RT for 5 min then charged with 7 [from Step 1] (395 g, 1.14 mol, 0.935 equiv.) in four portions. The reaction was stirred at RT for 1-2 h then washed with MTBE (3.0 L, 5 v / w). The aqueous layer was diluted with EtOAc (6.0 L, 10 v / w) and acidified to pH 1-2 with HCl (2 M). The layers were separated and the aqueous layer was extracted with EtOAc (6.0 L, 10 v / w). The combined organic layers were washed with brine (3.0 L, 5 v / w), dried with Na2SO4, filtered, and concentrated to 5 v / w (for RSM-3) under vacuum at 45 °C. The residue was charged with n-heptane (0.84 L, 1.4 v / w) dropwise at RT and stirred for 16 h. A second charge of n-heptane (3.84 L, 6.4 v / w) was added and the mixture was cooled to 0-10 °C. The solid was filtered, washed with n-heptane, and dried under vacuum (T <45 °C). [NOTE: Steps 2 & 3 were repeated five times and all batches were combined at this stage for further processing.] The solid was charged into a 50 L reactor containing a mixture of EtOAc (16 L, 5 v / w) and n-heptane (16 L, 5 v / w). The slurry was stirred at RT for 3-4 h, filtered, and dried under vacuum to yield 8f (3.02 kg, 83.0% yield, 98.9% purity, 99.4% ee) as an off-white solid. Step 4. A reactor was charged with 8-2-g (RSM-2b,145 g, 374.9 mol, 1.0 equiv.) and DCM (1.45 L, 10 v / w) at RT. The mixture was cooled to 0-10 °C and charged with N-hydroxysuccinimide (77.7 g, 674.8 mol, 1.8 equiv.). EDCI (129.4 g, 674.8 mol, 1.8 equiv.) was added in portions at 0-10 °C. The reaction was warmed to RT and stirred for 2-3 h. The mixture was quenched with brine (1.45 L, 10 v / w) and the layers were separated. The organic layer was washed with NaHCO3 (sat. aq., 725 mL, 5 v / w) then brine (1.45 L, 10 v / w) and then concentrated to 2-3 v / w. The solution was charged with PE (290 mL, 2 v / w), concentrated to 2-3 v / w, charged again with PE (725 mL, 5 v / w), cooled to 0-10 °C, and WSGR Docket No.41223-757.601 stirred for 2-3 h. The solid was filtered, washed with PE (145 mL, 1 v / w), and dried under vacuum (T = 45 °C) to provide Compound 8-4-b (173.9 g, 95.9% yield, 99.5% purity) as a white solid. Step 5. Compound 8f [Step 3] (170 g, 284.9 mol, 1.0 equiv.) and DCM (1.5 L, 10 v / w) were charged to a reactor at RT under N2atmosphere. The solution was cooled to 0-10 °C and TFA (422.4 g, 3.17 mol, 13.0 equiv.) was added slowly to maintain the temperature below 5 °C. The mixture was warmed slowly to RT, stirred for 4-5 h, then concentrated under vacuum (T = 40-45 °C) to 2-3 v / w. The residue was charged with THF (680 mL, 4 v / w), concentrated to 2-3 v / w, charged again with THF (680 mL, 4 v / w), and concentrated to 2-3 v / w to provide crude 8-4-c which was used directly in the next step without further purification. Step 6. To a 10 L reactor was charged the solution of crude Compound 8-4-c and H2O (2.55 L, 15 v / w for 8f used in Step 5) at RT. The solution was washed with MTBE (1.7 L, 10 v / w for 8f used in Step 5) twice and the organic layers were discarded. ACN (2.55 L, 15 v / w for 8f used in Step 5) was added to the retained aqueous layer followed by addition of NaHCO3(251.4 g, 2.99 mol, 10.5 equiv.) slowly at RT [CAUTION: Excessive gas evolution observed]. A solution of 8-4-b [Step 4] (136.5 g, 284.9 mol, 1.0 equiv.) in ACN (850 mL, 5 v / w for 6) was added slowly and the reaction was stirred at RT for 16 h. The mixture was filtered, and the filtrate was concentrated to remove the ACN. The aqueous layer was washed with EtOAc (1.7 L, 10 v / w) twice (organics discarded). The remaining aqueous layer was acidified to pH 2-3 with HCl (2 N), and extracted with EtOAc (2.55 L, 15 v / w) twice. The combined WSGR Docket No.41223-757.601 organic layers were washed with brine (1.7 L, 10 v / w), dried with Na2SO4, filtered, and concentrated to 5-6 v / w. The solution was charged with THF (1.36 L, 8 v / w), concentrated to 5-6 v / w, charged again with THF (680 mL, 4 v / w), concentrated to 5-6 v / w, and finally poured into n-heptane (2.55 L, 15 v / w) at 10-20 °C. The slurry was stirred for 20-30 min. then filtered and the isolated solid was dried under vacuum (T<45 °C) to yield Compound 8-4-d (238 g, 89.7% yield, 97.5% purity, 99.1% ee) as a white solid. A reactor was charged with 8-4-e (RSM-4, 80.0 g, 171.4 mol, 1.0 equiv., described in WO2022250776, Example 200) and THF (640 mL, 8 v / w) at RT under N2atmosphere. The mixture was cooled to -65--60 °C and charged with LiHMDS (1.0 M in THF, 180 mL, 180 mL, 180 mL, 180 mol 1.05 equiv.) while maintaining the temperature below -60 °C. The reaction was warmed to 15-20 °C and stirred for 1-2 h then cooled to 0-5 °C. HCl (4 M in dioxane, 171 mL, 685 mol, 4.0 equiv.) was added dropwise maintaining the temperature below 10 °C. The mixture was warmed to 15-20 °C, stirred for 1- 2 h, and then concentrated to dryness under vacuum (T = 40 °C). The residue was charged with THF (560 mL, 7 v / w) then n-heptane (840 mL, 10.5 v / w). The mixture was stirred at 15-20 °C for 30 min. and the resulting slurry was filtered. The cake was washed with hexane / THF (3:2, 2 v / w) and the combined filtrates were concentrated to 2 v / w. DCM (5-10 v / w) was added and the mixture was concentrated to dryness to give crude 8-4-f (104.7 g) as a yellow solid which was used in the next step without further purification. Step 8. WSGR Docket No.41223-757.601 Compound 8-4-d [Step 6] (102 g, 109.8 mol, 1.0 equiv.), DCM (2.0 L, 20 v / w) and 8-4-f [Step 7] (97.2 g, 159.2 mol, 1.45 equiv.) were added to a reactor sequentially under N2 atmosphere. The mixture was cooled to -5-0 °C. DIPEA (58.8 g, 455.7 mol, 4.15 equiv.) was added followed by T3P®(50% w / w in EtOAc, 112 g, 175.7 mol, 1.6 equiv.). The reaction was warmed to 15-20 °C and stirred for 1-2 h. The reaction was cooled to 10-15 °C and quenched with HCl (0.25 N, 1.0 L, 10 v / w). The layers were separated, and the organic layer was washed with H2O (1.0 L, 10 v / w) three times, then brine (1.0 L, 10 v / w). The organic layer was dried with Na2SO4, filtered, and concentrated to 6-7 v / w. The mixture was charged with EtOAc (1.0 L, 10 v / w), concentrated to 6-7 v / w, charged again with EtOAc (1.0 L, 10 v / w), concentrated to 7 v / w, and poured into n-heptane (3.2 L, 32 v / w for theoretical 8-4-g). The solid was filtered and dried under vacuum ( T<45 °C) to yield Compound 8-4-b (142.2 g, 97% yield, 90.5% purity, 97.4% de) as a white solid. Step 9. Compound 8-4-g (120.0 g, 92.6 mol, 1.0 equiv.) was charged into a reactor under N2atmosphere. DCM (2.4 L, 20 v / w) was added and the reaction was cooled to -60--50 °C. TMSBr (486.7 g, 2.71 mol, 35.0 equiv.) was added in a single portion then the reaction was warmed to 25-30 °C, stirred for 5-6 h, and concentrated (T = 40 °C) to remove DCM. The residue was charged with MTBE (1.2 L, 10 v / w), concentrated to 3-4 v / w, charged with MTBE (1.2 L, 10 v / w), concentrated to 3-4 v / w, and finally charged with MTBE (1.2 L, 10 v / w). The mixture was cooled to 0-10 °C and stirred for 15-20 min. The resulting solid was filtered, washed with MTBE (240 mL, 2 v / w), and dried under vacuum (T = 40 °C) to provide a crude yellow solid (135 g) which was used directly in the next step without further purification. The crude solid was charged to a reactor containing HBr (33% in AcOH, 720 mL, 6 v / w for 8-4-g) at 0-5 °C. H2O (12.0 mL, 0.1 v / w) was added [CAUTION: Extreme exothermic event observed]. The reaction was warmed to 5-7 °C and stirred for 36-48 h. The mixture was poured into cooled (0-10 °C) EtOAc (9.0 L, 12.5 v / w for AcOH) and stirred at 0-10 °C for 10-20 min. The solid was filtered and washed with EtOAc. The cake was slurried in ACN (1.8 L, 15 v / w for 8-4-g), filtered, washed with ACN, and dried under vacuum (T = 25-30 °C) to yield crude 8. The crude solid (~125 g) was slurried in WSGR Docket No.41223-757.601 cold H2O (0-10 °C) for 30 min. then lyophilized to dryness to obtain Example 8 (119 g, 58.3% yield (from 8-4-d), 94.64% purity, 92.8% de). Example 9. (R)-7-fluoro-3-((R)-2-(3-((1s,4S)-4-(3-fluoro-4,5-dihydroxybenzamido)cyclohexyl)-2- oxoimidazolidine-1-carboxamido)-2-(4-phosphonophenyl)acetamido)-2-hydroxy-3,4-dihydro-2H- benzo[e][1,2]oxaborinine-8-carboxylic acid. The title compound was prepared in a similar manner to the synthesis of Example 8, substituting 3-fluoro-4,5-dihydroxybenzoyl chloride for 2-chloro-5-fluoro-3,4-dimethoxybenzoyl chloride (5a) in Step 3-4. After reversed phase HPLC purification using an XBridge C18 column, title compound 9 was collected as the second eluting peak as a white solid. ESI-MS m / z 802 (M+H)+. Example 10. (R)-3-((R)-2-(3-((1s,4S)-4-(2-chloro-5-fluoro-3,4-dihydroxybenzamido)cyclohexyl)-2- oxoimidazolidine-1-carboxamido)-2-(4-phosphonophenyl)acetamido)-2-hydroxy-3,4-dihydro-2H- benzo[e][1,2]oxaborinine-8-carboxylic acid. The title compound was prepared in a similar manner to the synthesis of Example 8, substituting tert-butyl 3-((R)-2-amino-2-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[d][1,3,2]dioxaborol-2-yl)ethyl)-2-methoxybenzoate (PCT Int. Appl. WO2022 / 250776) for tert-butyl 3-((R)-2-amino-2-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[d][1,3,2]dioxaborol-2-yl)ethyl)-6-fluoro-2-methoxybenzoate (C) in Part 4, Step 4-1. After reversed phase HPLC purification using an XBridge C18 column, 10 was collected as the second eluting peak as a white solid. ESI-MS m / z 818 (M+H)+. Example 11. (R)-3-((R)-2-(3-((1s,4S)-4-(2-chloro-3,4-dihydroxybenzamido)cyclohexyl)-2- oxoimidazolidine-1-carboxamido)-2-(4-phosphonophenyl)acetamido)-7-fluoro-2-hydroxy-3,4- dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid. The title compound was prepared in a similar manner to the synthesis of Example 8, substituting 2-chloro-3,4-dimethoxybenzoyl chloride for 2-chloro-5-fluoro-3,4-dimethoxybenzoyl chloride (5a) in Step 3-4. After reversed phase HPLC purification using an XBridge C18 column, title compound 11 was collected as the second eluting peak as a white solid. ESI-MS m / z 836 (M+H)+. Example 12. (R)-3-((R)-2-(3-((1r,3R)-3-((2-chloro-5-fluoro-3,4- dihydroxyphenyl)sulfonamido)cyclobutyl)-2-oxoimidazolidine-1-carboxamido)-2-(4- phosphonophenyl)acetamido)-7-fluoro-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8- carboxylic acid. The title compound was prepared in a similar manner to the synthesis of Example 1, substituting 2-chloro-5-fluoro-3,4-dihydroxybenzenesulfonyl chloride for phenyl (2-chloro-5-fluoro-3,4- dimethoxyphenyl)carbamate (1s) in Step 4-2. After reversed phase HPLC purification using an XBridge C18 column, title compound 12 was collected as the second eluting peak as a white solid. ESI-MS m / z 844 (M+H)+. Example 13. (R)-3-((R)-2-(3-((1s,3S)-3-((2-chloro-5-fluoro-3,4- dihydroxyphenyl)sulfonamido)cyclobutyl)-2-oxoimidazolidine-1-carboxamido)-2-(4- WSGR Docket No.41223-757.601 phosphonophenyl)acetamido)-7-fluoro-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8- carboxylic acid. The title compound was prepared in a similar manner to the synthesis of Example 2, substituting 2-chloro-5-fluoro-3,4-dihydroxybenzenesulfonyl chloride for phenyl (2-chloro-5-fluoro-3,4- dimethoxyphenyl)carbamate (1s) in Part 2. After reversed phase HPLC purification using an XBridge C18 column, title compound 13 was collected as the second eluting peak as a white solid. ESI-MS m / z 844 (M+H)+. Example 14. (R)-3-((R)-2-(3-((1r,4R)-4-((2-chloro-5-fluoro-3,4- dihydroxyphenyl)sulfonamido)cyclohexyl)-2-oxoimidazolidine-1-carboxamido)-2-(4- phosphonophenyl)acetamido)-7-fluoro-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8- carboxylic acid. The title compound was prepared in a similar manner to the synthesis of Example 3, substituting 2-chloro-5-fluoro-3,4-dihydroxybenzenesulfonyl chloride for phenyl (2-chloro-5-fluoro-3,4- dimethoxyphenyl)carbamate (1s) in Part 2. After reversed phase HPLC purification using an XBridge C18 column, title compound 14 was collected as the second eluting peak as a white solid. ESI-MS m / z 872 (M+H)+. Example 15. (R)-3-((R)-2-(3-((1s,4S)-4-((2-chloro-5-fluoro-3,4- dihydroxyphenyl)sulfonamido)cyclohexyl)-2-oxoimidazolidine-1-carboxamido)-2-(4- phosphonophenyl)acetamido)-7-fluoro-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8- carboxylic acid. The title compound was prepared in a similar manner to the synthesis of Example 8, substituting 2-chloro-5-fluoro-3,4-dihydroxybenzenesulfonyl chloride for 2-chloro-5-fluoro-3,4- dimethoxybenzoyl chloride (5a) in Step 3-4. After reversed phase HPLC purification using an XBridge C18 column, title compound 15 was collected as the second eluting peak as a white solid. ESI-MS m / z 872 (M+H)+. Example 16. (R)-3-((R)-2-(3-((1r,4R)-4-((2-chloro-5-fluoro-3,4- dihydroxyphenyl)carbamoyl)cyclohexyl)-2-oxoimidazolidine-1-carboxamido)-2-(4- phosphonophenyl)acetamido)-7-fluoro-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8- carboxylic acid. Part 1. Synthesis of tert-butyl (1r,4r)-4-(3-(chlorocarbonyl)-2-oxoimidazolidin-1-yl)cyclohexane-1- carboxylate (16e). WSGR Docket No.41223-757.601 Title compound 16e was prepared according to the procedure of Example 1, Part 2, substituting tert-butyl (1r,4r)-4-aminocyclohexane-1-carboxylate for tert-butyl ((1r,3r)-3- aminocyclobutyl)carbamate (1g) in Step 2-1. The resulting crude 16e was used without further purification. Part 2. Synthesis of (R)-2-(3-((1r,4R)-4-((2-chloro-5-fluoro-3,4- dimethoxyphenyl)carbamoyl)cyclohexyl)-2-oxoimidazolidine-1-carboxamido)-2-(4- (diethoxyphosphoryl)phenyl)acetic acid (16k). WSGR Docket No.41223-757.601 Step 2-1. Synthesis of methyl (R)-2-((tert-butoxycarbonyl)amino)-2-(4- (diethoxyphosphoryl)phenyl)acetate (16f). Into a 100-ml pear-shaped flask were introduced 3.87 g (10 mmol) of an (R)-2-((tert- butoxycarbonyl)amino)-2-(4-(diethoxyphosphoryl)phenyl)acetic acid, 1.2 g (12 mmol) of an N- methylmorpholine solution in 50 ml of methanol, which were stirred at room temperature for 10 min, followed by the addition of 2.75 g (10 mmol) of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4- methylmorpholinium chloride to conduct the reaction at room temperature for 16 h. The product was purified by flash chromatography on silica gel (50% EtOAc / PE) to give the desired product 16f (3.3 g, 82 %) as a white solid. ESI-MS m / z 402 (M+H)+. Step 2-2. Synthesis of tert-butyl (1R,4r)-4-(3-(((R)-1-(4-(diethoxyphosphoryl)phenyl)-2-methoxy-2- oxoethyl)carbamoyl)-2-oxoimidazolidin-1-yl)cyclohexane-1-carboxylate (16h). To a solution of methyl (R)-2-((tert-butoxycarbonyl)amino)-2-(4- (diethoxyphosphoryl)phenyl)acetate 16f (1.1 g, 2.74 mmol, 1.00 eq) in DCM (21 mL) at 0 °C was added TFA (5.3 mL) slowly. The reaction was warmed to room temperature for 1 h then concentrated. The crude 16g (white solid) was used in the next step without further purification. ESI-MS m / z 302 (M+H)+. To a solution of crude 16g in THF (21 mL) was added a saturated aq. solution of NaHCO3(35 mL) slowly (NOTE: Gas evolution was observed). The reaction was stirred at room temperature for 5 minutes. Carbamoyl chloride 16e (998 mg, 3.01 mmol, 1.1 eq) was added portionwise. The mixture was stirred at room temperature for 1 h (NOTE: After 30 minutes, check pH of reaction to ensure pH 6-9. If the pH is too low, slowly add saturated aq. NaHCO3 until desired pH is obtained). The mixture was diluted with EtOAc (100 mL) and acidified to pH 2 with HCl (2 M). The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 40 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated. The crude material was purified by silica gel chromatography (0-25% MeOH / EtOAc) to yield 16h (1.2 g, 73.5%) as a white solid. ESI-MS m / z 596 (M+H)+. WSGR Docket No.41223-757.601 Step 2-3. Synthesis of methyl (R)-2-(3-((1r,4R)-4-((2-chloro-5-fluoro-3,4- dimethoxyphenyl)carbamoyl)cyclohexyl)-2-oxoimidazolidine-1-carboxamido)-2-(4- (diethoxyphosphoryl)phenyl)acetate (16j). To a solution of 16h (1.2 g, 2.01 mmol, 1.00 eq) in DCM (21 mL) at 0 °C was added TFA (5.3 mL) slowly. The reaction was warmed to room temperature for 1 h then concentrated to yield 16i as a white solid. The crude 16i was used in the next step without further purification. ESI-MS m / z 540 (M+H)+. To a RBF was added acid 16i (290 mg, 0.54 mmol, 1.00 eq), 2-chloro-5-fluoro-3,4- dimethoxyaniline (221 mg, 1.54 mmol, 2.0 eq), and BOP-Cl (205 mg, 0.81 mmol, 1.5 eq). DCM (25 mL) was added followed by TEA (108.6 mg, 1.075 mmol, 2.00 eq). The reaction was stirred at room temperature for 16 h. The mixture was diluted with MTBE (100 mL), the layers were separated, and the aqueous layer was extracted with MTBE (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated. The crude material was purified by silica gel chromatography (0-5% MeOH / EtOAc) to yield 16j (100 mg, 25.6%) as a colorless oil. ESI m / z 727 (M+H)+. Step 2-4. Synthesis of (R)-2-(3-((1r,4R)-4-((2-chloro-5-fluoro-3,4- dimethoxyphenyl)carbamoyl)cyclohexyl)-2-oxoimidazolidine-1-carboxamido)-2-(4- (diethoxyphosphoryl)phenyl)acetic acid (16k). To a solution of 16j (100 mg, 0.1377 mmol, 1.00 eq) in THF / H2O (6 mL) at 0 °C was added LiOH (11.6 mg, 0.2754 mmol, 2.00 eq). The reaction was warmed to room temperature for 1 h. The crude material was purified by reverse-phase HPLC to yield 16k (68 mg, 69.2%) as a white solid. ESI m / z 713 (M+H)+. Part 3. Synthesis of (R)-3-((R)-2-(3-((1r,4R)-4-((2-chloro-5-fluoro-3,4- dihydroxyphenyl)carbamoyl)cyclohexyl)-2-oxoimidazolidine-1-carboxamido)-2-(4- phosphonophenyl)acetamido)-7-fluoro-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8- carboxylic acid (16). WSGR Docket No.41223-757.601 Step 3-1. Synthesis of tert-butyl 3-((R)-2-((R)-2-(3-((1r,4R)-4-((2-chloro-5-fluoro-3,4- dimethoxyphenyl)carbamoyl)cyclohexyl)-2-oxoimidazolidine-1-carboxamido)-2-(4- (diethoxyphosphoryl)phenyl)acetamido)-2-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[d][1,3,2]dioxaborol-2-yl)ethyl)-6-fluoro-2-methoxybenzoate (16l). To a round-bottom flask was added acid 16k (68 mg, 0.0954 mmol, 1.00 eq), C (55 mg, 0.1144 mmol, 1.2 eq), and HATU (54.4 mg, 0.143 mmol, 1.5 eq). DMA (1.5 mL) was added followed by DIPEA (27 mg, 0.21 mmol, 2.2 eq). The reaction was stirred at room temperature for 1 h (NOTE: Do NOT run reaction for unnecessary extended period of time). The mixture was diluted with MTBE (50 mL) and quenched with HCl (0.5 M, 10 mL). The layers were separated, and the aqueous layer was extracted with MTBE (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated. The crude material was purified by silica gel chromatography (0- 5% MeOH / EtOAc) to yield 16l (88 mg, 80%) as an oil. Step 3-2. Synthesis of (R)-3-((R)-2-(3-((1r,4R)-4-((2-chloro-5-fluoro-3,4- dihydroxyphenyl)carbamoyl)cyclohexyl)-2-oxoimidazolidine-1-carboxamido)-2-(4- phosphonophenyl)acetamido)-7-fluoro-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8- carboxylic acid (16). To a solution of 16l (88 mg, 0.077 mmol, 1.00 eq) in DCM (2 mL) at -78 °C was added TMSBr (0.5 mL) slowly. The mixture was allowed to warm to room temperature for 4 h. then concentrated to a white solid. The crude 16m was used in the next step without further purification. ESI- MS m / z 1086 (M+H)+. To a solution of crude 16m in DCM (2 mL) at -78 °C was added BBr3 (1 M, 3 mL) slowly. The reaction was allowed to warm to room temperature over 16 h. The reaction was cooled to 0 °C, quenched with H2O (5 mL), warmed to room temperature, stirred for 15 minutes, and concentrated. The crude material was azeotroped with ACN (20 mL) to remove residual H2O. The crude solid was triturated with ACN (100 mL), filtered, washed with ACN (2 × 20 mL), and dried. The resulting crude product was purified by reverse-phase HPLC to yield 16 (10 mg) as a white solid. ESI m / z 836 (M+H)+. WSGR Docket No.41223-757.601 Example 17. (R)-3-((R)-2-(3-((1s,4S)-4-aminocyclohexyl)-2-oxoimidazolidine-1-carboxamido)-2-(4- phosphonophenyl)acetamido)-7-fluoro-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8- carboxylic acid. Part 1. Synthesis of (R)-2-(3-((1r,3R)-3-((tert-butoxycarbonyl)amino)cyclobutyl)-2- oxoimidazolidine-1-carboxamido)-2-(4-(diethoxyphosphoryl)phenyl)acetic acid (4f). To a solution of acid 1f (2.04 g, 5.27 mmol, 1.00 eq) in DCM (21 mL) at 0 °C was added TFA (5.3 mL) slowly. The reaction was warmed to room temperature for 1 h then concentrated to yield 1t as a white solid. The crude 1t was used in the next step without further purification. ESI-MS m / z 288 (M+H)+. To a solution of crude 1t in THF (21 mL) was added a saturated NaHCO3solution (35 mL) slowly (NOTE: Gas evolution was observed). The reaction was stirred at room temperature for 5 min. Carbamoyl chloride 4e (2.02 g, 5.79 mmol, 1.1 eq) was added portionwise. The mixture was stirred at room temperature for 1 h (NOTE: After 30 min, check pH of reaction to ensure pH 6-9. If the pH is too WSGR Docket No.41223-757.601 low, slowly add saturated aq. NaHCO3 until desired pH is obtained). The mixture was diluted with EtOAc (100 mL) and acidified to pH 2 with HCl (2 M). The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 40 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated. The crude material was purified by silica gel chromatography (0-25% MeOH / EtOAc) to yield 4f (2.36 g, 75%) as a white solid. ESI-MS m / z 597 (M+H)+. Part 2. Synthesis of tert-butyl 3-((R)-2-((R)-2-(3-((1s,4S)-4-((tert- butoxycarbonyl)amino)cyclohexyl)-2-oxoimidazolidine-1-carboxamido)-2-(4- (diethoxyphosphoryl)phenyl)acetamido)-2-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[d][1,3,2]dioxaborol-2-yl)ethyl)-6-fluoro-2-methoxybenzoat (17a). To a RBF was added acid 4f (836 mg, 1.4 mmol, 1.00 eq), C (740 mg, 1.54 mmol, 1.1 eq), and HATU (665 mg, 1.75 mmol, 1.25 eq). DMA (15 mL) was added followed by DIPEA (0.49 mL, 2.8 mmol, 2.00 eq). The reaction was stirred at room temperature for 1 h (NOTE: Do NOT run reaction for unnecessary extended period of time). The mixture was diluted with MTBE (100 mL) and quenched with HCl (0.5 M, 40 mL). The layers were separated, and the aq. layer was extracted with MTBE (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated. The crude material was purified by silica gel chromatography (0-5% MeOH / EtOAc) to yield 17a (931 mg, 64.8%) as an off-white solid. ESI-MS m / z 1026 (M+H)+. Part 3. Synthesis of (R)-3-((R)-2-(3-((1s,4S)-4-aminocyclohexyl)-2-oxoimidazolidine-1- carboxamido)-2-(4-phosphonophenyl)acetamido)-7-fluoro-2-hydroxy-3,4-dihydro-2H- benzo[e][1,2]oxaborinine-8-carboxylic acid (17). To a solution of 17a (931 mg, 0.91 mmol, 1.00 eq) in DCM (10 mL) at -78 °C was added TMSBr (1.2 mL, 9.1 mmol, 10.0 eq) slowly. The mixture was allowed to warm to room temperature over 16 h. then concentrated. MeOH (25 mL) was added and stirred at room temperature for 30 minutes then concentrated. To remove residual MeOH, the crude material was azeotroped with DCM (3 × 25 mL) to yield crude 17b as a white solid, which was used in the next step without further purification. ESI-MS m / z 970 (M+H)+. To a solution of crude 17b in DCM (10 mL) at -78 °C was added BBr3 (1 M, 9.1 mL, 9.1 mmol, 10.0 eq) slowly. The reaction was allowed to warm to room temperature over 16 h. The reaction was cooled to 0 °C, quenched with H2O (5 mL), warmed to room temperature, stirred for 15 min, and then concentrated. The crude material was azeotroped with ACN (20 mL) to remove residual H2O. The crude solid was triturated with ACN (100 mL), filtered, washed with ACN (2 × 20 mL), and dried. The resulting crude product was purified by reverse-phase HPLC to yield 17 (120 mg) as a white solid. ESI m / z 648 (M+H)+. Example A1: Parenteral Composition To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100 mg of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer, WSGR Docket No.41223-757.601 thereof, is dissolved in DMSO and then mixed with 10 mL of 0.9% sterile saline solution. The mixture is incorporated into a dosage unit suitable for administration by injection. Example A2: Oral Composition To prepare a pharmaceutical composition for oral delivery, 400 mg of compound disclosed and the following ingredients are mixed intimately and pressed into single scored tablets. Tablet Formulation Ingredient Quantity per tablet (mg) compound 400 cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5 The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule. Capsule Formulation Ingredient Quantity per capsule (mg) compound 200 lactose spray dried 148 magnesium stearate 2 Biological Examples Example I: Experimental Method for Penicillin-Binding Protein Binding Assays with Bocillin-FL via Fluorescence Polarization To determine the ability of boronic acid-based test PBP inhibitors to bind Penicillin Binding Proteins (PBPs), Bocillin-FL (fluorescently-labeled penicillin V; ThermoFisher Scientific) was used in a fluorescence polarization (FP) competition binding assay to assess inhibitor binding to PBP3 from Escherichia coli (K-12), PBP3 from Pseudomonas aeruginosa (PAO1), and PBP3 from Acinetobacter baumannii (ATCC 19606). PBPs were cloned and purified as described previously (E. coli PBP3, King, D.T, et al., ACS Infectious Diseases 2015, 1, 175-184; P. aeruginosa PBP3, Han et. al., PNAS 2010, 107 (51), 22002-22007; A. baumannii PBPs, Penwell et. al., Antimicrob. Agents Chemother.2015, 59 (3), 1680 – 1689). To establish assay conditions for competition binding, enzyme titration / saturation binding experiments were initially performed. Bocillin-FL was prepared at 0.2 µM in a buffer comprised of 50 mM HEPES (pH 8.0), 300 mM NaCl and 10% (v / v) glycerol for reactions with E. coli and P. aeruginosa PBPs, and 25 mM Tris (pH 8.0), 200 mM NaCl, 10% (v / v) glycerol and 0.005% (v / v) Tween 20 for reactions with A. baumannii PBP3. Saturation binding was performed by mixing 40 µL of PBP solutions ranging in concentrations from 0 – 24 µM with 40 µL of the 0.2 µM Bocillin-FL solution, in individual wells of a black 384-well microplate. FP was measured immediately upon mixing (Excitation, 490 nm; Emission, 520 nm; g-factor, 0.96), using a Cytation3 (BioTek) microplate reader and measured continuously for up to 120 min. The FP response stabilized after 15 min for P. aeruginosa and A. baumannii PBP3, 30 min for E. coli PBP3 and A. baumannii PBP1a. In all instances, the FP signal showed a dose dependence on PBP concentration. The competition binding assay (80 µL final volume) was validated using beta-lactams and PBPs at final concentrations of: 1.5 µM for E. coli PBP3; 0.75 mM WSGR Docket No.41223-757.601 for P. aeruginosa PBP3; and 0.2 mM for A. baumannii PBP3. Bocillin-FL was at 0.1 µM (0.05 mM with A. baumannii PBP1a) and beta-lactam concentrations ranged from 0 – 1,000 µM. E. coli PBP3 was incubated with increasing concentrations of ampicillin in a black 384-well microplate (Corning) for 30 min. P. aeruginosa PBP3 was incubated for 15 min with aztreonam, whereas A. baumannii PBP1a and PBP3 were incubated for 15 minutes with meropenem, and then Bocillin-FL was added followed immediately by the FP measurement for up to 60 min. The beta-lactam potency was reported as the concentration of beta-lactam required to reduce the amount of PBP bound-Bocillin-FL by 50% (EC50), calculated according to the following equation: where y is the fraction bound at a given inhibitor concentration, yminis the fraction bound when the enzyme is completely inactivated, ymaxis the maximum (uninhibited) fraction bound, and x is the inhibitor concentration. The EC50of ampicillin for E. coli PBP3 was determined to be 1.4 µM. The EC50of aztreonam was determined to be < 0.5 mM for P. aeruginosa PBP3. EC50s for meropenem with A. baumannii PBP1a and PBP3 were determined to be <0.5 µM and 0.23 mM, respectively. Binding assays for boronic acid PBP inhibitors were performed in an identical fashion for the respective PBPs. Fluorescence polarization assay conditions for measurement of EcPBP2 binding affinities were determined in a similar fashion as for PBP3 enzymes, using 5-TAMRA ampicillin instead of Bocillin FL (Shapiro, et al. ACS Infectious Diseases (2019), 5(6), 863 – 872). Competition binding assays for determination were performed with a final enzyme concentration of 0.3 µM and 5-TAMRA ampicillin at 0.1 µM. Enzyme was incubated with various concentrations of test compounds for 30 minutes, followed by addition of 5-TAMRA ampicillin after which the FP (excitation, 540 nm; emission, 590 nm) was measured for up to 60 min. Representative results for binding to E. coli PBP2 are shown in Table 2, where A represents a potency of >50 μM, B represents a potency between 10 μM and 50 μM inclusive, C represents a potency between 1 μM and 10 μM, and D represents potency <1 μM. NT = Not Tested. Table 2. Binding affinity to E. coli PBP2 by Exemplary Compounds in fluorescence polarization competition binding assay using 5-TAMRA ampicillin. Representative results for binding to P. aeruginosa PBP3 are shown in Table 3, where A represents a potency of >50 μM, B represents a potency between 10 μM and 50 μM inclusive, C represents a potency between 1 μM and 10 μM, and D represents potency <1 μM. NT = Not Tested. WSGR Docket No.41223-757.601 Table 3. Binding affinity to P. aeruginosa PBP3 by Exemplary Compounds in fluorescence polarization competition binding assay using Bocillin-FL. Representative results for binding to A. baumannii PBP3 are shown in Table 4, where A represents a potency of >50 μM, B represents a potency between 10 μM and 50 μM inclusive, C represents a potency between 1 μM and 10 μM, and D represents potency <1 μM. NT = Not Tested. Table 4. Binding affinity to A. baumannii and PBP3 by Exemplary Compounds in the fluorescence polarization competition binding assay using Bocillin-FL. Example II: Experimental method for penicillin-binding protein binding assays with Bocillin-FL via gel filtration Affinity to A. baumannii PBP1a and PBP2 was assessed in a competitive equilibrium binding assay using Bocillin-FL as the reporter molecule. Enzyme was pre-incubated with increasing concentrations of inhibitors, prior to addition of Bocillin and further incubation for 15 min. PBP bound with Bocillin-FL was separated by gel filtration using 96-well Zeba Spin size exclusion plates, and the fluorescence measured. The inhibitor affinity (reported as the EC50) was determined by plotting the fraction of PBP bound with Bocillin-FL at each inhibitor concentration against the inhibitor concentration, and fitting the data to the following equation: where y is the fraction bound at a given inhibitor concentration, ymin is the fraction bound when the enzyme is completely inactivated, ymax is the maximum (uninhibited) fraction bound, n is the Hill coefficient, and x is the inhibitor concentration. WSGR Docket No.41223-757.601 Representative results for binding to A. baumannii PBP1a and PBP2 are shown in Table 5, where A represents a potency of >50 μM, B represents a potency between 10 μM and 50 μM inclusive, C represents a potency between 1 μM and 10 μM, and D represents potency <1 μM. NT = Not Tested. Table 5. Binding affinity to A. baumannii PBP1a and PBP2 by Exemplary Compounds in competition binding assay using Bocillin-FL via gel filtration. Example III: Experimental method for A. baumannii penicillin-binding protein-5 and penicillin- binding-protein 7 binding assays Affinity to A. baumannii PBP5 and PBP7 was assessed in a competitive equilibrium binding assay using Bocillin-FL as the reporter molecule. Enzyme was pre-incubated with increasing concentrations of inhibitors for 90 min (30 min for PBP7), prior to the addition of Bocillin and further incubation for 15 min. PBP bound with Bocillin-FL was separated by sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE), followed by fluorescence imaging of the SDS-PAGE gel and densitometric analysis. The inhibitor affinity (reported as the IC50in µM) was determined by plotting the fraction of PBP bound with Bocillin-FL at each inhibitor concentration against the inhibitor concentration, and fitting the data to the following equation: Representative results for binding to A. baumannii PBP5 and A. baumannii PBP7 are shown in Table 6, where A represents a potency of >50 μM, B represents a potency between 10 μM and 50 μM inclusive, C represents a potency between 1 μM and 10 μM, and D represents potency <1 μM. NT = Not Tested. Table 6. Binding affinity to A. baumannii PBP5 and PBP7 by Exemplary Compounds in competition binding assay using Bocillin-FL via SDS-PAGE. WSGR Docket No.41223-757.601 Example IV: Primary MIC screening assays in cation-adjusted Mueller Hinton broth To determine the ability of test compounds to inhibit the growth of bacterial strains, classic cell-based broth microdilution minimum inhibitory concentration (MIC) assays were employed. MIC assays are performed according to CLSI methods except where otherwise noted (CLSI, 2018 and CLSI, 2024). The reference type strain E. coli ATCC 25922; the wild-type parent strain E. coli AG100; the hyperpermeable E. coli 901C and E. coli D22; and the E. coli AG100A strain lacking the acrAB efflux pump encoding genes were used to determine the ability of the PBP inhibitors to penetrate the outer membrane of gram-negative bacteria and inhibit bacterial growth. Three additional challenge isolates of Klebsiella pneumoniae (K. pneumoniae 848844 producing SHV-11 and KPC-2, K. pneumoniae UMM producing SHV-5 and KPC-2 and K. pneumoniae SI-117 producing VIM-1) were used to further assess antibacterial activity in Enterobacterales and demonstrate activity of the PBP inhibitors irrespective of the beta-lactamase content of these organisms. The P. aeruginosa ATCC 27853 and A. baumannii ATCC 19606, along with the hyper-permeable P. aeruginosa ATCC 35151 and an engineered efflux pump- compromised strain of P. aeruginosa (ΔmexAB-oprM) were used to determine the ability of PBP inhibitors to penetrate the outer membrane of P. aeruginosa and A. baumannii and assess antibacterial activity against these important gram-negative organisms. Finally, a BSL-2 Burkholderia pseudomallei ΔpurM adenine auxotroph strain, Bp82, was used to assess potential utility against this bioweapon pathogen. Briefly, cryo-preserved bacterial cultures of challenge strains are streaked for isolation on appropriate agar medium, in this case cation-adjusted Mueller Hinton agar (Enterobacterales, P. aeruginosa, and A. baumannii) or cation-adjusted Mueller Hinton agar supplemented with 0.6 mM adenine (B. pseudomallei Bp82). Following incubation to allow growth of the colonies, plates are sealed with parafilm and stored refrigerated for up to two weeks. For preparation of assay inoculum and to ensure low variability, at least 5 colonies are picked from the agar plates with an inoculating loop and aseptically transferred to a culture tube containing either 3 mL of cation-adjusted Mueller Hinton broth (CAMHB) for Enterobacterales, P. aeruginosa and A. baumannii, or 3 mL of cation-adjusted Mueller Hinton broth supplemented with 0.6 mM adenine for B. pseudomallei Bp82. Alternatively, a direct suspension was prepared in PBS or saline. The broth culture is grown for 3-5 hours at 37 °C with shaking at 200 rpm (Enterobacterales, P. aeruginosa and A. baumannii) or in a stationary ambient air incubator at 37 °C (B. pseudomallei Bp82). Meanwhile, 2-fold serial dilutions of test compounds are conducted in a 96-well plate with a final volume of 50 μL per well at 2-fold the final desired concentration. After the dilution plates are set up the growing cultures are then diluted in a cuvette containing CAMHB and the optical density is measured at 600 nm. The inoculum is diluted such that 50 μL of this culture in WSGR Docket No.41223-757.601 CAMHB (supplemented with 2 × 0.6 mM adenine for B. pseudomallei Bp82) results in a starting bacterial concentration of 2-8 × 105CFU / mL when added to the dilution plates. The plates are incubated for 16-20 hours for Enterobacterales and P. aeruginosa and 20-24 hours for A. baumannii and B. pseudomallei at 37 °C. The MIC values are read visually as the lowest concentration well with no bacterial growth. Representative results for MIC testing in Enterobacterales are shown in Table 7, where A represents an MIC ≥ 128 μg / mL, B represents an MIC of 16 to 64 μg / mL, C represents an MIC from 2 to 8 μg / mL, and D represents an MIC ≤1 µg / mL. NT = Not Tested. Table 7: Inhibition of bacterial growth. Minimum inhibitory concentrations of Exemplary Compounds for Enterobacterales in CAMHB. Representative results for testing in P. aeruginosa and A. baumannii strains are shown in Table 8, where A represents an MIC ≥ 128 μg / mL, B represents an MIC of 16 to 64 μg / mL, C represents an MIC from 2 to 8 μg / mL, and D represents an MIC ≤1 µg / mL. NT = Not Tested. Table 8: Inhibition of bacterial growth. Minimum inhibitory concentrations of Exemplary Compounds for P. aeruginosa and A. baumannii strains in CAMHB. Example V: Primary MIC screening assays in iron-depleted cation-adjusted Mueller Hinton broth To determine the ability of test compounds to inhibit the growth of bacterial strains under conditions of iron-depletion, classic cell-based broth microdilution minimum inhibitory concentration (MIC) assays were employed. MIC assays are performed according to CLSI methods except where otherwise noted (CLSI, 2018 and CLSI, 2024). The reference type strain E. coli ATCC 25922 was used WSGR Docket No.41223-757.601 to determine the ability of the PBP inhibitors to inhibit the growth of Enterobacterales. Wild-type P. aeruginosa ATCC 27853, A. baumannii ATCC 17978 and A. baumannii ATCC 19606, along with the hyper-permeable P. aeruginosa ATCC 35151, an engineered efflux pump-compromised strain of P. aeruginosa (ΔmexAB-oprM) was used to determine the ability of PBP inhibitors to penetrate the outer membrane of P. aeruginosa and assess antibacterial activity against these important gram-negative organisms. Additionally, four challenge isolates of Pseudomonas aeruginosa (P. aeruginosa CDC-0054 producing VIM-4, OXA-50, and PDC; P. aeruginosa CDC-0090 producing KPC-5, OXA-50, and PDC; P. aeruginosa CDC-0095 producing OXA-50, and PDC), and five challenge isolates of Acinetobacter baumannii (A. baumannii 1258916 producing ADC-33, OXA-23, and OXA-82; A. baumannii CDC-0033 producing NDM-1, and OXA-94; A. baumannii CDC-0036 producing OXA-65, and OXA-24; A. baumannii CDC-0045 producing TEM-1D, OXA-23, and OXA-69; and A. baumannii 1179589 producing PER-1, OXA-58, ADC-76, OXA-68) were used to further assess antibacterial activity in non- fermenters and demonstrate activity of the PBP inhibitors irrespective of the beta-lactamase content of these organisms. Additionally, two Burkholderia bioweapon pathogen surrogate strains, B. thailandensis ATCC 700388 and B. humptydooensis ATCC BAA-2767, were used to assess potential biodefense applications. Briefly, cryo-preserved bacterial cultures of challenge strains are streaked for isolation on appropriate agar medium, in this case cation-adjusted Mueller Hinton agar. Following incubation to allow growth of the colonies, plates are sealed with parafilm and stored refrigerated for up to two weeks. For preparation of assay inoculum and to ensure low variability, at least 5 colonies are picked from the agar plates with an inoculating loop and aseptically transferred to a culture tube containing 3 mL of iron- depleted cation-adjusted Mueller Hinton broth (IDM) – see below for IDM preparation. Alternatively, a direct suspension was prepared in PBS or saline. The broth culture is grown for 3-5 hours at 37 °C with shaking at 200 rpm. Meanwhile, 2-fold serial dilutions of test compounds are conducted in a 96-well plate with a final volume of 50 μL per well at 2-fold the final desired concentration. After the dilution plates are set up the growing cultures are then diluted in a cuvette containing IDM and the optical density is measured at 600 nm. The inoculum is diluted such that 50 μL of this culture in IDM results in a starting bacterial concentration of 2-8 × 105CFU / mL when added to the dilution plates. The plates are incubated for 16-20 hours for Enterobacterales and P. aeruginosa and 20-24 hours for A. baumannii at 37 °C. The MIC values are read visually as the lowest concentration well with no bacterial growth. Additionally, the major reduction MIC where 80% of the bacterial growth is inhibited is also recorded. Method for iron-depleted cation-adjusted Mueller Hinton broth (IDM) preparation: • Prepare cation-adjusted Mueller Hinton broth as per the manufacturer’s recommendations and autoclave. o Add 100 g / L Chelex 100 resin, cover with foil and incubate with stirring for 6 h o Remove Chelex 100 resin by filtration with 0.45 µm filter flask o Add the following back to the medium: o CaCl2 dihydrate: 82.5 mg / L WSGR Docket No.41223-757.601 o MgCl2 hexahydrate: 94.1 mg / L o ZnSO4: 10 µM o Adjust pH of medium to 7.3 with 5 N HCl o Sterilize using a 0.22 µm filter flask Representative results for testing compounds in iron-depleted media conditions are shown in Tables 9, 10, and 11, where A represents an MIC > 64 μg / mL, B represents an MIC of 16 to 64 μg / mL, C represents an MIC from 2 to 8 μg / mL, and D represents an MIC ≤1 µg / mL. NT = Not Tested. Table 9: Inhibition of bacterial growth. Minimum inhibitory concentrations of Exemplary Compounds for P. aeruginosa strains in iron-depleted CAMHB (IDM). Table 10: Inhibition of bacterial growth. Minimum inhibitory concentrations of Exemplary Compounds for A. baumannii strains in iron-depleted CAMHB (IDM). WSGR Docket No.41223-757.601 Table 11: Inhibition of bacterial growth. Minimum inhibitory concentrations of Exemplary Compounds for Burkholderia strains in iron-depleted CAMHB (IDM). Example VI: Secondary MIC screening assay testing against Acinetobacter baumannii To determine the ability of test compounds to inhibit the growth of Acinetobacter baumannii, broth microdilution MIC assays were performed using iron-depleted cation-adjusted Mueller Hinton broth (IDM). MIC assays are performed according to CLSI methods except where otherwise noted (CLSI, 2018 and CLSI, 2024). Forty A. baumannii clinical isolates were tested to observe the antibacterial activity of the test compounds versus this challenging bacteria species. These strains have been collected from several sources including CDC & FDA Antimicrobial Resistance Isolate Bank (Atlanta, GA, USA); IHMA (Schaumberg, IL, USA); and University of Sienna, Courtesy of Dr. Jean- Denis Doquier (Siena, Italy). Briefly, cryo-preserved bacterial cultures of challenge strains are streaked for isolation on appropriate agar medium, in this case cation-adjusted Mueller Hinton agar. Following incubation to allow growth of the colonies, plates are sealed with parafilm and stored refrigerated for up to two weeks. For preparation of assay inoculum and to ensure low variability, at least 5 colonies are picked from the agar plates with an inoculating loop and aseptically transferred to a culture tube containing 3 mL of iron- depleted cation-adjusted Mueller Hinton broth (IDM) as described in Example V. Alternatively, a direct suspension was prepared in PBS or saline. The broth culture is grown for 3-5 hours at 37 °C with shaking at 200 rpm. Meanwhile, 2-fold serial dilutions of test compounds are conducted in a 96-well plate with a final volume of 50 μL per well at 2-fold the final desired concentration. After the dilution plates are set up the growing cultures are then diluted in a cuvette containing IDM and the optical density is measured at 600 nm. The inoculum is diluted such that 50 μL of this culture in IDM results in a starting bacterial concentration of 2-8 × 105CFU / mL when added to the dilution plates. The plates are incubated for 20-24 hours at 37 °C. The MIC values are read visually as the lowest concentration well with a major reduction in growth where 80% of the bacterial growth is inhibited. WSGR Docket No.41223-757.601 MIC results for testing compounds in the A. baumannii secondary screening assay in iron- depleted media conditions are shown in Table 12, values are µg / mL. The MIC50 and MIC90 are determined by first sorting the MIC values in order from low to high values and then selecting the MIC value of the 20thand 36thstrains. This value is the concentration of test compound required to rescue 50 and 90%, respectively, of isolates in the panel. The structures of the Comparator Examples are shown in Table 22 below. Table 12: Summary of Secondary Acinetobacter baumannii MIC Screening Assay Data. Example VII: Tertiary screening of Multidrug-Resistant Organism Repository and Surveillance Network (MRSN) Acinetobacter baumannii diversity strain collection. Test compounds were evaluated versus a large panel of 100 clinical A. baumannii strains with a wide variety of resistance profiles and mechanisms. This published panel was assembled from >3,500 A. baumannii strains in the Multidrug-Resistant Organism Repository and Surveillance Network collection isolated globally and captures the genetic diversity of the collection (Galac, M.R.; Snesrud, E.; Lebreton, F.; Stam, J.; Julius, M.; Ong, A. C.; Maybank, R.; Jones, A. R.; Kwak, Y. I.; Hinkle, K.; Waterman, P. E.; Lesho, E. P.; Bennett, J. W.; Mc Gann, P. A Diverse Panel of Clinical Acinetobacter baumannii for Research and Development. Antimicrob Agents Chemother.64(10):e00840-20. https: / / doi.org / 10.1128 / aac.00840-20). The set includes one pan-drug resistant strain, 35 extensively drug-resistant strains, 27 multidrug-resistant strains and 34 carbapenem-resistant strains. Briefly, cryo-preserved bacterial cultures of challenge strains are streaked for isolation on appropriate agar medium, in this case cation-adjusted Mueller Hinton agar. Following incubation to allow growth of the colonies, plates are sealed with parafilm and stored refrigerated for up to two weeks. For preparation of assay inoculum and to ensure low variability, at least 5 colonies are picked from the agar plates with an inoculating loop and aseptically transferred to a culture tube containing 3 mL of iron- depleted cation-adjusted Mueller Hinton broth (IDM) as described in Example V. Alternatively, a direct suspension was prepared in PBS or saline. The broth culture is grown for 3-5 hours at 37 °C with shaking at 200 rpm. Meanwhile, 2-fold serial dilutions of test compounds are conducted in a 96-well plate with a final volume of 50 μL per well at 2-fold the final desired concentration. After the dilution plates are set up the growing cultures are then diluted in a cuvette containing IDM and the optical density is measured at 600 nm. The inoculum is diluted such that 50 μL of this culture in IDM results in a starting bacterial concentration of 2-8 × 105CFU / mL when added to the dilution plates. The plates are incubated for 20-24 WSGR Docket No.41223-757.601 hours at 37 °C. The MIC values are read visually as the lowest concentration well with a major reduction in growth where 80% of the bacterial growth is inhibited. MIC results for testing compounds in the A. baumannii secondary screening assay in iron- depleted media conditions are shown in Table 13, values are µg / mL. The MIC50 and MIC90 are determined by first sorting the MIC values in order from low to high values and then selecting the MIC value of the 50thand 90thstrains. This value is the concentration of test compound required to rescue 50 and 90%, respectively, of isolates in the panel. The structures of the Comparator Examples are shown in Table 22 below. Table 13: MRSN A. baumannii diversity panel MIC testing results. WSGR Docket No.41223-757.601 WSGR Docket No.41223-757.601 WSGR Docket No.41223-757.601 Example VIII: Acinetobacter baumannii – calcoaceticus complex panel testing Test compounds were evaluated versus a panel of 100 non-baumannii Acinetobacter clinical isolates. This panel included 20 strains each of Acinetobacter calcoaceticus, Acinetobacter dijkshoorniae, Acinetobacter nosocomialis, Acinetobacter pittii, and Acinetobacter seifertii. Briefly, cryo-preserved bacterial cultures of challenge strains are streaked for isolation on appropriate agar medium, in this case cation-adjusted Mueller Hinton agar. Following incubation to allow growth of the colonies, plates are sealed with parafilm and stored refrigerated for up to two weeks. For preparation of assay inoculum and to ensure low variability, at least 5 colonies are picked from the agar plates with an inoculating loop and aseptically transferred to a culture tube containing 3 mL of iron- depleted cation-adjusted Mueller Hinton broth (IDM) as described in Example V. Alternatively, a direct suspension was prepared in PBS or saline. The broth culture is grown for 3-5 hours at 37 °C with shaking at 200 rpm. Meanwhile, 2-fold serial dilutions of test compounds are conducted in a 96-well plate with a final volume of 50 μL per well at 2-fold the final desired concentration. After the dilution plates are set up the growing cultures are then diluted in a cuvette containing IDM and the optical density is measured at 600 nm. The inoculum is diluted such that 50 μL of this culture in IDM results in a starting bacterial concentration of 2-8 × 105CFU / mL when added to the dilution plates. The plates are incubated for 20-24 hours at 37°C. The MIC values are read visually as the lowest concentration well with a major reduction in growth where 80% of the bacterial growth is inhibited. Results for each species are shown in Tables 14-18, MIC values are µg / mL. The MIC50and MIC90are determined by first sorting the MIC values in order from low to high values and then selecting the MIC value of the 10thand 18thstrains. This value is the concentration of test compound required to rescue 50 and 90%, respectively, of isolates in the panel. The structures of the Comparator Examples are shown in Table 22 below. Table 14. Acinetobacter calcoaceticus MIC testing results. WSGR Docket No.41223-757.601 Table 15. Acinetobacter dijkshoorniae MIC testing results Table 16. Acinetobacter nosocomialis MIC testing results. WSGR Docket No.41223-757.601 Table 17. Acinetobacter pittii MIC testing results. WSGR Docket No.41223-757.601 Table 18. Acinetobacter seifertii MIC testing results. Example IX: Colistin resistant Acinetobacter baumannii MIC testing Test compounds were evaluated versus a panel of 20 colistin-resistant Acinetobacter baumannii clinical isolates. Briefly, cryo-preserved bacterial cultures of challenge strains are streaked for isolation on appropriate agar medium, in this case cation-adjusted Mueller Hinton agar. Following incubation to allow growth of the colonies, plates are sealed with parafilm and stored refrigerated for up to two weeks. For preparation of assay inoculum and to ensure low variability, at least 5 colonies are picked from the agar plates with an inoculating loop and aseptically transferred to a culture tube containing 3 mL of iron- depleted cation-adjusted Mueller Hinton broth (IDM) as described in Example V. Alternatively, a direct suspension was prepared in PBS or saline. The broth culture is grown for 3-5 hours at 37 °C with shaking at 200 rpm. Meanwhile, 2-fold serial dilutions of test compounds are conducted in a 96-well plate with a final volume of 50 μL per well at 2-fold the final desired concentration. After the dilution plates are set up the growing cultures are then diluted in a cuvette containing IDM and the optical density is measured at 600 nm. The inoculum is diluted such that 50 μL of this culture in IDM results in a starting bacterial concentration of 2-8 × 105CFU / mL when added to the dilution plates. The plates are incubated for 20-24 hours at 37 °C. The MIC values are read visually as the lowest concentration well with a major reduction in growth where 80% of the bacterial growth is inhibited. Colistin-resistant Acinetobacter baumannii MIC testing results are shown in Table 19. MIC values are µg / mL. The MIC50and MIC90are determined by first sorting the MIC values in order from WSGR Docket No.41223-757.601 low to high values and then selecting the MIC value of the 10thand 18thstrains. This value is the concentration of test compound required to rescue 50 and 90%, respectively, of isolates in the panel. The structures of the Comparator Examples are shown in Table 22 below. Table 19. Colistin-resistant Acinetobacter baumannii testing results. Example X: Acinetobacter baumannii Monogue panel MIC testing Test compounds were evaluated in a panel of 35 strains with published cefiderocol in vivo efficacy data (Monogue, M. L.; Tsuji, M.; Yamano, Y.; Echols, R.; Nicolau, D.P. Efficacy of Humanized Exposures of Cefiderocol (S-649266) against a Diverse Population of Gram-Negative Bacteria in a Murine Thigh Infection Model. ASM Journals, Antimicrobial Agents and Chemotherapy, Vol.61, No.11). These strains have a variety of resistance mechanisms. Briefly, cryo-preserved bacterial cultures of challenge strains are streaked for isolation on appropriate agar medium, in this case cation-adjusted Mueller Hinton agar. Following incubation to allow growth of the colonies, plates are sealed with parafilm and stored refrigerated for up to two weeks. For preparation of assay inoculum and to ensure low variability, at least 5 colonies are picked from the agar plates with an inoculating loop and aseptically transferred to a culture tube containing 3 mL of iron- depleted cation-adjusted Mueller Hinton broth (IDM) as described in Example V. Alternatively, a direct suspension was prepared in PBS or saline. The broth culture is grown for 3-5 hours at 37 °C with shaking at 200 rpm. Meanwhile, 2-fold serial dilutions of test compounds are conducted in a 96-well plate with a final volume of 50 μL per well at 2-fold the final desired concentration. After the dilution plates are set WSGR Docket No.41223-757.601 up the growing cultures are then diluted in a cuvette containing IDM and the optical density is measured at 600 nm. The inoculum is diluted such that 50 μL of this culture in IDM results in a starting bacterial concentration of 2-8 × 105CFU / mL when added to the dilution plates. The plates are incubated for 20-24 hours at 37 °C. The MIC values are read visually as the lowest concentration well with a major reduction in growth where 80% of the bacterial growth is inhibited. MIC testing results are shown in Table 20. MIC values are µg / mL. The MIC50 and MIC90 are determined by first sorting the MIC values in order from low to high values and then selecting the MIC value of the 18thand 32ndstrains. This value is the concentration of test compound required to rescue 50 and 90%, respectively, of isolates in the panel. The structures of the Comparator Examples are shown in Table 22 below. Table 20. Monogue, et al. set of Acinetobacter baumannii MIC testing results. WSGR Docket No.41223-757.601 Example XI: Experimental method for determining Filamentation Prevention Concentration (FPC) using a microscopy-based assay A microscopy-based assay was performed to determine the ability of boronic acid-based test PBP inhibitors to inhibit PBPs in the cellular context. This assay was established because inhibition of AbPBP3 (essential for cell division) induced the formation of long filamentous cells, whereas inhibition of AbPBP2 or AbPBP5 (either indispensable for cell elongation) in addition to inhibition of AbPBP3 did not induce long filamentous cells but shorter filamentous cells or spherical cells. Specifically, A. baumannii ATCC 19606 cells were treated with a PBP inhibitor for 3 h at 37 °C in IDM in a 96-well plate and imaged using the oCelloScope microscope (BioSense Solutions ApS. Farum, Denmark). The cell images taken were analyzed computationally using the oCelloScope software UniExplorer version 12.1 to determine the boundary of cells (maximum number of cells 500) and generate the shape parameters of each cell including the average cell width and length, followed by the calculation of geomean of the ratios of average cell length to average cell width for all cells analyzed in each image. Using the cutoff of the geomean cell length / width ratio at less than 4 for cells treated with different concentrations of a PBP inhibitor, the “Filamentation Prevention Concentration” (FPC) for each PBP inhibitor was determined. Representative results for filamentation prevention testing of compounds in iron-depleted media conditions are shown in Table 21, where A represents an FPC > 64 μg / mL, B represents an FPC of 16 to 64 μg / mL, C represents an FPC from 2 to 8 μg / mL, and D represents an FPC ≤1 µg / mL. NT = Not Tested. The structures of the Comparator Examples are shown in Table 22 below. Table 21. A. baumannii ATCC 19606 Filamentation Prevention Concentrations (FPC) for exemplary compounds, plus comparators WSGR Docket No.41223-757.601 Table 22. Structures of Comparator Compounds. WSGR Docket No.41223-757.601 Example XII: Experimental Method for Determining Plasma Stability Using a UPLC-MS / MS Based Assay An ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS / MS) based assay was performed to determine the metabolic stability of boronic acid-based PBP inhibitors in human and mouse plasma with K2EDTA as the anticoagulant. Stock solutions of test compounds (exemplary and comparator) were prepared at 2 mg / mL concentration in dimethyl sulfoxide (DMSO). Then, the stock WSGR Docket No.41223-757.601 solution of each test compound was diluted with pre-warmed pH-adjusted plasma (BioIVT, Westbury, NY) (pH 7.4, adjusted with 1M HCl) to a concentration of 20 µg / mL. The plasma samples were incubated in a 37 °C water bath. Three aliquots of 20 µL of the plasma samples were taken at 0, 10, 30, and 60 minutes. The collected samples were stored in – 80 °C freezer before analysis. After all samples were collected, 20 µL of 3% formic acid in H2O and 20 µL of internal standard (IS) spike [1000 ng / mL levofloxacin (USP, North Bethesda, MD) in 50 / 50 acetonitrile (ACN) / H2O] were added to the samples. The mixtures were thawed in the 37 °C water bath for 1 minute before vortexing for 5 minutes at room temperature (RT). After the vortex, 200 µL of ACN was added to the mixture and mixed well with vortex for an additional 5 minutes to precipitate plasma proteins. Then, the mixtures were centrifuged at 3000 ×g for 2 minutes to pellet the precipitated protein.190 µL of the supernatant was taken and dried under a nitrogen stream. The final samples were reconstituted with 150 µL of 90 / 10 ACN / H2O before UPLC- MS / MS injection. The assay was performed with a Waters Xevo TQS-micro mass spectrometry (with electrospray ionization source) coupled with Waters I-class UPLC (Waters Corp, Milford, MA). A Waters Acquity BEH C8 (50×2.1 mm, 1.7 µm) reverse phase column was used for the compound retention. For the UPLC, the mobile phase (MP) A was 0.5% formic acid in H2O; MP B was 0.5% formic acid in ACN; weak needle wash was 90 / 10 H2O / MeOH with 0.02% NH4OH (pH 10); strong needle wash was 10 / 90 H2O / ACN and seal wash was 90 / 10 H2O / ACN. (All solvents and additives used on UPLC- MSMS assay were Optima®grade obtained from Fisher Scientific, Waltham, MA). With a flow rate of 0.6 mL / min, the UPLC gradient started with 15% MP B, and the content of MP B increased to 30% from 0.2 to 0.8 min and then increased to 95% from 0.8 to 1.2 min. The gradient was held at 95% MP B for 0.4 minutes before returning to 15% MP B at 1.61 min, then re-equilibrated at 15% MP B until 2 min. For the MS / MS, the compounds were monitored via multiple reaction monitoring (MRM) with the transitions listed in Table 23 (m / z = mass-to-charge ratio; V = voltage, ESI = electrospray ionization). Table 23. Test compounds MRM transition monitored in the plasma stability assay. WSGR Docket No.41223-757.601 Representative results for K2EDTA human and mouse plasma stability on testing compounds are shown in Table 24. The structures of the Comparator Examples are shown in Table 22. Table 24. Plasma stability in human and mouse plasma (K2EDTA as the anticoagulant) for part of the exemplary compounds, plus comparators. Example XIII: Experimental Method for Determining Plasma Stability Using a UPLC-MS / MS Based Assay Example compounds were evaluated for metabolic stability in plasma from four different species (mouse, rat, dog, and monkey). Test compounds were incubated in these matrices at 1 μM in a 37 °C water bath for 120 minutes. Test compounds and control compounds (tetracaine, bisacodyl, diltiazem, and propantheline) were dissolved in DMSO to obtain 10 mM stock solutions. These stock solutions were diluted to 200 μM working solution in DMSO. Preparation of internal standard solutions: 1 mg / mL terfenadine and 1 mg / mL tolbutamide stock solutions were prepared in DMSO, respectively. The Internal Standard (IS) working solutions were prepared by serially diluting the stock solutions in acetonitrile. The final IS concentration of terfenadine and tolbutamide was 5 ng / mL and 10 ng / mL, respectively. Plasma samples were purchased from commercial vendors (e.g. BioIVT). Study Procedure: • Blank plasma was pre-warmed in a 37 °C water bath for 15 min.2 μL of working solution of control / test compound were added into 398 μL of plasma (n=1). The reaction mixtures were mixed well by pipetting. • At each time point (0, 5, 15, 30, 60 and 120 min), 30 μL of reaction mixture was aliquoted to 300 μL quenching solutions. WSGR Docket No.41223-757.601 • After the incubation, samples were mixed well by vertexing for 1 minute and centrifuged at 4,000 rpm for 15 min at 4°C.150 μL supernatants were mixed with 150 μL distilled water for LC-MS / MS semi-quantitative analysis (assay is not a qualified method). Calculations: The concentrations of test compound and controls in plasma were semi-quantitatively determined by LC / MS / MS method after protein precipitation. The reactions in plasma were assumed as first order kinetics. Therefore, equations of first order kinetics as following were used to calculate t1 / 2. The remaining percentages of test compounds were calculated by the follow equations: • Linear regression was made by plotting Ln (% remaining) versus time. • R2and ke were calculated based on time point and Ln (% remaining). • t1 / 2 was calculated by equation below: ^^1 / 2 = Ln(2) / ^^eResults: After incubation for 120 minutes in mouse, rat, dog, and monkey plasma, all the metabolic half-life (t1 / 2) values for Example 8 were greater than 372.8 min. The detailed data are summarized in Table 25. Table 25. Half-life of Example 8 and Control Compounds in Plasma from Mouse, Rat, Dog and Cynomolgus Monkey. Example XIV: Experimental Method for Determining Hepatocyte Stability Using a UPLC-MS / MS Based Assay Hepatocyte stability assays are widely used as an in vitro model to characterize the metabolic conversion of new chemical entities by both phase I and phase II enzymes within the intact cell. Compared to liver microsomes, the metabolic stability assay using hepatocytes can assess not only reticular, but also cytosolic and mitochondrial enzymes. Since metabolism is known to be highly variable in different species, hepatocytes metabolic stability assay is commonly run across multiple species. The most popularly used species include humans, rodents (mice and rats), and nonrodents (dogs and monkeys). The metabolic stability is generally evaluated by calculating the elimination rate constant (ke) to calculate the in vitro clearance in hepatocytes isolated from selected species. In this study, the metabolic stability of test compounds in CD-1 mouse, Sprague-Dawley rat, beagle dog, cynomolgus WSGR Docket No.41223-757.601 monkey and human hepatocytes was determined. Example compounds were incubated with hepatocytes from the species above, and the remaining percentage of compounds at designated time points were determined using LC-MS / MS. This data was used to calculate the half-life (T½), intrinsic clearance (In vitro CLint), in vivo hepatic clearance (CLhepatic) and hepatic extraction ratio. Preparation of Solutions Preparation of Thawing Medium Human recombinant insulin solution (4 mg / mL): dilute the acetic acid 100-fold with distilled water, weigh a certain amount of human recombinant insulin and dissolve it to achieve a final concentration of 4 mg / mL. Dexamethasone solution (10 mM): weigh a certain amount of dexamethasone and dissolve it in DMSO to achieve a final concentration of 10 mM. The thawing medium was prepared according to the following formula and stored it on 4 °C for no more than 30 days: Preparation of Incubation Medium Incubation Medium was prepared by adding 6.122 mL glutamine (200 mM) into 300 mL Williams’ E medium and mixed thoroughly, then transferred an aliquot of 15 mL solution above to each 15 mL tube and stored it on 4 °C for no more than 30 days. Preparation of Example Compound Working Solution Stock solution of Example Compounds were prepared at 2 mM in DMSO. The stock solution was further diluted by adding 1 μL to 999 μL of the hepatocyte incubation medium (Williams’ E medium containing 4 mM glutamine) as working solution. The final incubating concentration of Example Compounds were 1 μM. Preparation of Control Compound Working Solutions An aliquot of 20 μL 7-ethoxycoumarin (7-EC) stock solution of 10 mM was diluted with 80 μL of DMSO to prepare a working stock solution of 7-EC at 2 mM, then previous solution was further diluted by adding 1 μL to 999 μL of hepatocyte incubation medium (Williams’ E medium containing 4 mM glutamine) to prepare the phase II control compound working solution at 2 μM. Preparation of Internal Standard Solution (IS, 5 & 10 ng / mL) Terfenadine and tolbutamide stock solutions were prepared at 1 mg / mL in DMSO, respectively, then the internal standard solution was prepared by diluting both stock solutions together in WSGR Docket No.41223-757.601 acetonitrile. The concentration of terfenadine was 5 ng / mL and the concentration of tolbutamide was 10 ng / mL. Study Procedure Cell Thawing The thawing medium was pre-warmed in a 37 °C water bath incubator at least 30 minutes prior to use. Then frozen hepatocytes from mouse, rat, dog, monkey, and human were quickly thawed, then washed with 1 mL of cryopreserved hepatocyte recovery medium (GIBCO). After centrifugation at 100 g for 10 minutes, the pellets were gently mixed with approximately 2 mL of Williams’ E media containing 4 mM glutamine. Cell Counting and Dilution Cell suspension of 50 µL was diluted with 400 µL incubation medium and stained by adding 50 µL Trypan Blue. Diluted cell suspension of 10 µL was removed for cell counting under a microscope. The viability was 74.4 %, 74.3 %, 76.7 %, 85.6 % and 82.2 % for mouse, rat, dog, monkey, and human hepatocytes, respectively. The cell suspensions were diluted to a concentration of 2 million viable cells / mL, and then pre-incubated in a CO2incubator (5% CO2tension) at 37 °C for 20 minutes without the presence of Example Compound or control compound. Metabolic Stability Study Pre-incubated hepatocytes (2.0 million cells / mL, 400 µL) in Williams’ E media containing 4 mM glutamine were added to each well of a 24-well microtiter plate containing 400 µL of test compound working solution (Example Compounds and 7-EC) (n=1). Then the plate was incubated at 37 °C for 120 min with gentle agitation. At pre-determined time points (0, 15, 30, 60, 90, and 120 minutes for mouse, rat, dog, monkey and human), aliquot of 30 µL was withdrawn from each well and transferred to 300 µL of internal standard solution. After vortexing for ~1 min, the quenched reaction mixtures were centrifuged (4,000 rpm × 15 minutes, 4 °C), and 100 µL of each supernatant was removed to a 96-well plate and mixed with 100 µL distilled water with 0.5% FA for LC-MS / MS semi-quantitative analysis (assay not qualified under GLP). Data Analysis For Example or control compounds, the percentages of remaining compound at each time point were calculated from the peak area ratio of the analyte to the internal standard (terfenadine or tolbutamide). The percent remaining for analyte was logarithmically transferred and plotted as the Ln (%remaining) vs time to get the rate constant (slope = -ke) for disappearance. The half-life was calculated from the following equation: Half- life (T1 / 2) = - Ln (2) / Slope In vitro intrinsic clearance (In vitro CLint), in vivo intrinsic clearance (CLint), and hepatic clearance (CLhepatic) were calculated from the following equations: • In vitro CLint(μL / min / million cells) = Ln (2) *1000 / T1 / 2 / Cell Density • CLint(mL / min / kg) = In vitro CLint* cell numbers / liver weight * liver weight / body weight WSGR Docket No.41223-757.601 • CLhepatic (mL / min / kg) = (Qhep * Fu * CLint) / (Qhep + Fu * CLint) The fraction unbound (Fu) in hepatocytes mixture was assumed as 100%. • The CLhepatic(mL / min / kg) = (Qhep* CLint) / (Qhep + CLint) • Hepatic extraction ratio = CLhepatic / QhepThe physiological variables used in the prediction are shown below: Results The metabolic stability parameters obtained in human hepatocytes for Example 8, Comparative Example A2, and 7-ethoxycoumarin are shown in Table 26. The metabolic stability results and calculated intrinsic clearance values for the control compound 7-EC were consistent with internal historical data, indicating that the hepatocytes were reliable in the conditions set in the study and can be used to evaluate compound stability. The metabolic stability parameters obtained in hepatocytes from cynomolgus monkey, dog, rat, and mouse for Example 8 and 7-ethoxycoumarin are shown in Tables 27-30. Example 8 was stable in mouse, rat, dog, monkey and human hepatocytes. Comparative Example A2 was not stable to human hepatocytes. Table 26. Human hepatocyte stability parameters determined for Example 8, Comparative Example A2, and control compound 7-ethoxycoumarin. Table 27. Cynomolgus monkey hepatocyte stability parameters determined for Example 8 and control compound. Table 28. Dog hepatocyte stability parameters determined for Example 8 and control compound. WSGR Docket No.41223-757.601 Table 29. Rat hepatocyte stability parameters determined for Example 8 and control compound. Table 30. Mouse hepatocyte stability parameters determined for Example 8 and control compound. Example XV: Experimental Methods and Results for Pharmacokinetic and Pharmacodynamic Efficacy Studies in a Neutropenic Murine Lung Infection Model Antibacterial activity of Example 8, Comparator Example A2, and Comparator Example A4 against A. baumannii was evaluated in a translational neutropenic murine lung infection model (performed by Dr. Kamilia Abdelraouf and Dr. David Nicolau, Hartford Hospital, Hartford, CT). The activity associated with a human-simulated regimen (HSR) of cefiderocol (PMID: 29471305) was also evaluated. Female ICR mice, following a 48-hour acclimatization period, were rendered neutropenic by injecting cyclophosphamide intraperitoneally (IP) at a dose of 250 mg / kg and 100 mg / kg of body weight four days and one day before lung inoculation, respectively. Uranyl nitrate (5 mg / kg, IP) was administered three days prior to infection to produce a controlled degree of renal impairment. Bacterial suspensions of the strains selected for assessment (Table 31) were instilled intranasally under light anesthesia in a volume of 0.05 mL to produce lung infection 2 hours prior to the planned initiation of antimicrobial therapy. Animals sacrificed for lung bacterial titers prior to antibiotic initiation served as 0 h control animals (n=6), representing initial bacterial burden. The target initial bacterial burden in the lung was 6 – 7 log10CFU / lungs in the 0 h control animals. Treatment mice (n=6) received escalating subcutaneous doses of Comparator Examples A2 or A4, Example 8, or a cefiderocol HSR and were sacrificed at the end of the 24 hour period. Following aseptic collection of lung tissue, all lung samples were homogenized in sterile saline prior to CFU enumeration by serial dilution and plating techniques. Antibacterial activity (efficacy) was defined as the change in bacterial density obtained in treated mice after 24 h compared with the 0 h control density. Vehicle-dosed control animals (n=6) received 100 – 125 mM sodium bicarbonate in the same route and schedule as test compounds. WSGR Docket No.41223-757.601 Table 31. Efficacy of Example 8 in a Neutropenic Murine Lung infection Model Against a Large Diverse Panel of Acinetobacter baumannii-calcoaceticus complex Strains (N=21) Abbreviations: AB, Acinetobacter baumannii; AN, Acinetobacter nosocomialis; AP, Acinetobacter pittii; I, intermediate susceptibility; MEM; meropenem (susceptibility); Q4H, administered every 4 hours; R, resistant; S, susceptible; SC, subcutaneousaMeropenem minimum inhibitory concentrations by reference broth microdilution susceptibility testing procedure ≤2 μg / mL were defined as susceptible; 4 μg / mL, intermediate; ≥8 μg / mL, resistantbThe measured average (± standard deviation) initial burden was 6.7 (± 0.3) log10 CFU / lungs (N=21). All strains grew in the model, as evidenced by growth to 9.4 ± 0.3 log10 CFU / lungs (N=21). WSGR Docket No.41223-757.601cLesion (truncation) identified in piuA Example 8 and Comparator Examples A2 and A4, each administered subcutaneously (SC) q4h, demonstrated dose-responses against A. baumannii ATCC 19606 and IHMA 921969 wherein higher doses were associated with greater efficacies. Example 8 demonstrated improved potency over Comparator Examples A2 and A4 against ATCC 19606, as the lowest dose level administered (1 mg / kg SC q4h) achieved the translational threshold of 1-log10 CFU reduction from initial bacterial burden (FIG.1). Against ATCC 19606, A2 and Example 8 achieved >2-log10 CFU reductions with standard deviation (SD) <1-log at the 10 mg / kg dose level, while A4 required the 30 mg / kg dose level to achieve the same level of activity. Only Example 8 demonstrated >1-log10CFU reduction with SD <1- log at the 3 mg / kg level. Against IHMA 921969, a cefiderocol-resistant strain of A. baumannii, the cefiderocol HSR was ineffective and allowed growth, consistent with the in vitro susceptibility testing result. Comparator Example A4 and Example 8 achieved >2-log10CFU reduction at the 10 mg / kg and 30 mg / kg dose level, respectively. While a dose-response was also observed with Comparator Example A2 against this strain, log reductions were not observed consistently and SDs were ≥2-log at the highest dose levels evaluated (10 and 30 mg / kg). Example 8 was further characterized against 19 additional strains (Table 31). CFU reductions or no change in bacterial density (bacteriostasis) were observed against all strains at various dose levels when the MIC of Example 8 ranged from 0.002 µg / mL to 2 µg / mL, with the exception of strains R3393 and R3397, which was consistent with elevated MICs observed against these strains to >32 µg / mL. Example XVI: Murine pharmacokinetics in the neutropenic murine lung infection model. The pharmacokinetic samples were collected from female ICR mice (N=48) prepared for the infection model as described above and inoculated with ATCC 19606. All animals were administered a single-dose of Example 8 of 3 mg / kg SC, and terminal blood samples following CO2-asphyxiation were collected at various time points (6 mice per time point) via cardiac puncture and placed in K2EDTA BD Microtainer® tubes. A bronchoalveolar lavage (BAL) with sterile 0.9% sodium chloride was performed on each mouse. Plasma and BAL fluid were separated by centrifugation for 10 minutes at 4 °C at 10,000 ×g then transferred into polypropylene tubes. The plasma and BAL samples were stored at -80 °C prior to concentration determination using liquid chromatography with tandem mass spectrometry (LC / MS) methods. PK parameters and exposures were estimated (WinNonlin, Version 8.1). The free plasma concentration-time profile of Example 8 (corrected for 48.8% mouse plasma protein binding) and the measurable concentrations in the epithelial lining fluid (ELF) following a 3 mg / kg subcutaneous (SC) single dose administered to lung-infected mice are depicted in FIG.2. Plasma data were best described by a one-compartment model. The best-fit plasma pharmacokinetic (PK) parameters after a 3 mg / kg single dose are provided in Table 32. As ELF concentrations were below the limit of quantification by the 4-h time point, a PK model was not fit to the ELF data. The available measured concentrations from BAL fluid indicate excellent penetration into the murine ELF compartment; concentrations in ELF were calculated from those in each BAL sample, in accordance with the industry-standard, with the following equation (PMID: 34383901): WSGR Docket No.41223-757.601 [^^^^^^] = [^^^^^^] × {[^^^^^^^^ ^^^^ ^^^^^^^^^^^^] ÷ [^^^^^^^^ ^^^^ ^^^^^^]}Penetration ratios (plasma:ELF) between 0.5 and 1, as observed for Example 8 through hour 2 in FIG.2, have been observed for efficacious antibacterial agents in this infection model (PMID: 36640133). Table 32. Best-fit pharmacokinetic parameters of Example 8 in the murine thigh infection model. V / F, volume of distribution relative to bioavailability; Ka, absorption rate constant; Kel, elimination rate constant Summary of findings The piperidinyl-urea comparator compound A2 showed potent in vitro antibacterial activities (MICs) across a panel of A. baumannii clinical isolates, promising Filamentation Prevention Concentration (FPC) results in clinical strains of A. baumannii, but it was not stable when exposed to plasma enzymes (human and preclinical species) or to basic aqueous conditions. The subclass of cycloalkyl-linked catechols described herein showed potent inhibition of penicillin-binding proteins (PBP1a, PBP2, PBP3, PBP5, PBP7) from A. baumannii and P. aeruginosa. This new subclass also possessed potent MICs across panels of drug-resistant A. baumannii and P. aeruginosa clinical isolates. The ability of compounds to inhibit both cell division and cell elongation, as determined using the FPC assay, is highly unpredictable. In some embodiments, simple changes (e.g. H for F) result in substantial loss of potency in this assay. The most-potent, cycloalkyl-amide-linked compounds (Examples 5-11) were shown to have suitable stability in plasma (human and preclinical species). Of those, Example 8 showed a well-balanced combination of plasma stability, FPC, and MIC, which could not be predicted based on its structure or its performance in one particular study. While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

WSGR Docket No.41223-757.601 CLAIMS WHAT IS CLAIMED IS:

1. A compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (I); wherein: Ring A is aryl or heteroaryl; R1ais -OH, -ORa, or C1-C6alkyl; R1bis -OH, -ORa, or C1-C6alkyl; each R2is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; n is 0, 1, 2, 3, or 4; R3is hydrogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl; each Y1and Y2is independently -C(=O)- or -C(RY)2-; each RYis independently hydrogen, deuterium, halogen, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; q is 1 or 2; p is 1 or 2; Ring B is a 3- to 10-membered cycloalkyl; L1is -C(=O)NH-, -NHC(=O)-, -NHC(=O)NH-, -NHS(=O)2-, or -S(=O)2NH-; R4is aryl or heteroaryl; each independently optionally substituted with one or more R4a; each R4ais independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1- C6deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; each R5is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, C1-C6alkyl, C1- C6haloalkyl, C1-C6deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; or two R5on the same atom are taken together to form an oxo.WSGR Docket No.41223-757.601 m is 0, 1, 2, 3, or 4; R6is hydrogen or C1-C6alkyl; R7, R8, and R9are independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -SH, -SRa, -NRcRd, - NRcC(=O)Rb, -C(=O)NRcRd, ­C(=O)Ra, ­C(=O)ORa, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; X is -OH, -ORX, or -F; each RXis independently C1-C6alkyl or cycloalkyl; Z is hydrogen, R11, -(R10)vOR11, -(R10)wO(R10)wOR11, -R10OC(=O)R11, -R10OC(=O)OR11, - R10OC(=O)NHR11, -R10OC(=O)N(R11)2, C1-C6alkyloxyC1-C6alkyl, acyloxyC1-C6alkyl, or C1-C6alkyl- [1,3]dioxol-2-one; each R10is independently -CH2-, -CH(CH3)-, -C(CH3)2-, or 1,1’-cyclopropylene; each R11is independently C1-C6alkyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or two R11are taken together with the nitrogen to which they are attached to form an heterocycloalkyl independently optionally substituted with one or more R; v is 1, 2, or 3; w is 2 or 3; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; and each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, - L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; each L is independently absent or C1-C6alkylene optionally substituted with one or more R; each R is independently halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, - S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, - C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1- C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1- C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl;WSGR Docket No.41223-757.601 or two R on the same atom form an oxo.

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein q is 2; each Y1is -C(RY)2-; p is 2; and each Y2is -C(=O)-.

3. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein q is 2; each Y1is -C(RY)2-; p is 1; and Y2is -C(=O)-.

4. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein q is 2; each Y1is -C(RY)2-; p is 2; one Y2is -C(RY)2- and one Y2is -C(=O)-.

5. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein q is 2; one Y1is -C(R5)2-, one Y1is -C(=O)-; p is 2; one Y2is -C(R5)2- and one Y2is - C(=O)-.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each RYis independently hydrogen or C1-C6alkyl.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each RYis hydrogen.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, or9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein10. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is phenyl.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R1ais -OH.WSGR Docket No.41223-757.601 13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R1bis -OH.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R2is independently deuterium, halogen, -OH, -ORa, or C1- C6alkyl.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R2is independently halogen or -OH.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 0 or 1.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R3is hydrogen.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R6is hydrogen.

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein L1is -C(=O)NH-.

20. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein L1is -NHC(=O)-.

21. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein L1is -NHC(=O)NH-.

22. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein L1is -NHS(=O)2-.

23. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein L1is -S(=O)2NH-.

24. The compound of claim 1, wherein the compound of Formula (I) is of Formula (Ia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:WSGR Docket No.41223-757.601 25. The compound of claim 24, wherein the compound of Formula (Ia) is of Formula (Ia-1), or a pharmaceutically acceptable salt, solvate, or stereoisomer:

26. The compound of claim 1, wherein the compound of Formula (I) is of Formula (Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

27. The compound of claim 26, wherein the compound of Formula (Id) is of Formula (Id-1), or a pharmaceutically acceptable salt, solvate, or stereoisomer:WSGR Docket No.41223-757.601Formula (Id-1).

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R7is hydrogen, halogen, -OH, -ORa, C1-C6alkyl, or C1- C6haloalkyl.

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R7is hydrogen, halogen, or C1-C6alkyl.

30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R7is hydrogen or halogen.

31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R7is hydrogen.

32. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R8is hydrogen, halogen, -OH, -ORa, C1-C6alkyl, or C1- C6haloalkyl.

33. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R8is hydrogen, halogen, or C1-C6alkyl.

34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R8is hydrogen or halogen.

35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R8is hydrogen.

36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R9is hydrogen, halogen, -OH, -ORa, C1-C6alkyl, or C1- C6haloalkyl.

37. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R9is hydrogen, halogen, or C1-C6alkyl.

38. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R9is hydrogen or halogen.WSGR Docket No.41223-757.601 39. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R9is hydrogen.

40. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R9is halogen.

41. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein X is -OH.

42. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein X is -ORX.

43. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is hydrogen.

44. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is R11and R11is C1-C6alkyl.

45. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is -R10OC(=O)R11or -R10OC(=O)OR11; R10is -CH2- or - CH(CH3)-; and R11is C1-C6alkyl.

46. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is -R10OC(=O)R11; R10is -CH2-; and R11is C1-C6alkyl.

47. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or48. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or49. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, orWSGR Docket No.41223-757.601 50. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein51. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R5is independently deuterium, halogen, -OH, -ORa, C1- C6alkyl, or C1-C6haloalkyl.

52. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein m is 0 or 1.

53. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein m is 0.

54. The compound of any one of claims 1-53, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring B is a 4- to 8-membered cycloalkyl.

55. The compound of any one of claims 1-53, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring B is a 4- to 8-membered monocyclic cycloalkyl.

56. The compound of any one of claims 1-53, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring B is a 4- to 6-membered monocyclic cycloalkyl.

57. The compound of any one of claims 1-53, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring B is a 4-membered monocyclic cycloalkyl.

58. The compound of any one of claims 1-53, wherein Ring B is a 5-membered monocyclic cycloalkyl.

59. The compound of any one of claims 1-53, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring B is a 6-membered monocyclic cycloalkyl.

60. The compound of any one of claims 1-53, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring B is a 5- to 8-membered bicyclic cycloalkyl.

61. The compound of any one of claims 1-53, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring B is a 6- to 8-membered bicyclic cycloalkyl.

62. The compound of any one of claims 1-53, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring B is a 6-membered bicyclic cycloalkyl.

63. The compound of any one of claims 1-53, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring B is a 7-membered bicyclic cycloalkyl.

64. The compound of any one of claims 1-53, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring B is a 8-membered bicyclic cycloalkyl.

65. The compound of any one of claims 1-64, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R4is phenyl independently optionally substituted with one or more R4a.WSGR Docket No.41223-757.601 66. The compound of any one of claims 1-65, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R4ais independently halogen, -CN, -OH, -ORa, -NRcRd, C1- C6alkyl, or C1-C6haloalkyl.

67. The compound of any one of claims 1-66, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R4ais independently halogen, -OH, -ORa, or C1-C6alkyl.

68. The compound of any one of claims 1-67, each R4ais independently halogen or -OH.

69. A compound selected from a compound of table 1, or a pharmaceutically acceptable salt, solvate, stereoisomer thereof.

70. A pharmaceutical composition comprising the compound of any one of claims 1-69, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

71. A method of treating a bacterial infection in a subject, comprising administering to the subject an effective amount of the compound of any one of claims 1-69, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the pharmaceutical composition of claim 70.

72. A method of inhibiting a bacterial penicillin-binding protein in a human infected with a bacterial infection, comprising contacting said bacterial penicillin-binding protein with an effective amount of the compound of any one of claims 1-69, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the pharmaceutical composition of claim 70.

73. The method of claim 71 or 72, wherein the bacterial infection is caused by a Stenotrophomonas spp.

74. The method of claim 71 or 72, wherein the bacterial infection is caused by a Burkholderia spp.

75. The method of claim 71 or 72, wherein the bacterial infection is caused by a Pseudomonas spp.

76. The method of claim 71 or 72, wherein the bacterial infection is caused by an Acinetobacter spp.

77. The method of claim 71 or 72, wherein the bacterial infection is caused by a carbapenem- resistant enterobacterales (CRE).

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