Monocyclic β-lactam-siderophore mimic conjugates

Abstract

Monocyclic β-lactams with antibiotic activity were synthesized over 40 years ago. Early extensive structure-activity relationship (SAR) studies, particularly in the 1980s, highlighted the need for heteroatom activation of monocyclic β-lactams and led to the testing of oxamazines, monobactams, monosulfactams, and monocarbams with various side chain and terminal substitutions that revealed potent activity against selected strains of Gram-negative bacteria. Aztreonam, the only monobactam still in clinical use, has remarkable activity against many Gram-negative bacteria but limited activity against some of the most problematic multidrug-resistant (MDR) strains of Pseudomonas aeruginosa and Acinetobacter baumannii. The present invention reports that side chain extension of monocyclic β-lactams, particularly aztreonam, is tolerated and that coupling of the side chain free acid, in particular, with a bis-catechol siderophore mimetic, significantly improves activity against MDR strains of Gram-negative bacteria, including the most concerning multidrug-resistant and β-lactamase-producing strains. TIFF2024532211000072.tif117128

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 235,536, filed August 20, 2021, the disclosure of which is incorporated by reference in its entirety.

[0002] Government Rights Statement This invention was made with Government support under Grant No. 5R21AI098689 awarded by the National Institutes of Health. The Government has certain rights in this invention.

[0003] Field This invention describes the design, synthesis, and antibacterial testing of novel monocyclic β-lactam siderophore conjugates that exhibit enhanced antibacterial activity against Gram-negative bacteria, including the most concerning multidrug-resistant and β-lactamase-producing strains. [Background technology]

[0004] 2. Background of the Invention As the reactive warhead of classical penicillins, cephalosporins, carbapenems and related antibiotics, the β-lactam core has been called the "magic ring". These antibiotics have positively impacted life and contributed to a significant increase in life expectancy over the past century. As shown in Figure 1, β-lactam antibiotics are fused bicyclic compounds with pendant functional groups necessary for recognition in inducing bacterial cell wall destruction. The bicyclic ring system enhances the intrinsic reactivity for nucleophilic opening of the β-lactam ring while interfering with bacterial cell wall synthesis. The widespread beneficial use and overuse of these important antibiotics promotes the development of resistance to each generation of bicyclic β-lactams, and at the same time, is accompanied by a loss of efficacy, mainly due to the widespread proliferation of β-lactamases that destroy β-lactams before they can reach their targets. Health organizations have warned that the loss of antibiotic efficacy in the coming decades will result in millions of deaths and an economic burden of trillions of dollars. The WHO has identified several multidrug-resistant and even completely drug-resistant strains of bacteria of particular concern, including β-lactamase-producing strains of Acinetobacter baumannii and Pseudomonas aeruginosa.Thousands of derivatives of bicyclic β-lactams have been prepared, most of which rely on fermentation processes to provide the bicyclic scaffold for subsequent terminal modifications.

[0005] To date, there are no practical total chemical syntheses of penicillins or cephalosporins. In response, over 40 years ago, the hydroxamate-mediated N-C4 biomimetic cyclization process (5-6, Scheme 1) was developed, allowing the efficient synthesis of β-lactam cores from β-hydroxycarboxylic acids (4) with full control over terminal functional groups and stereochemistry. This process also introduced the concept of heteroatom activation, rather than merely bicyclic activation of the magic ring, as evidenced by the subsequent rapid disclosure of oxamazines (7), monosulfactams (8), monobactams (9), monocarbams (10) and other monocyclic β-lactams. This development in chemistry also coincides with the discovery of naturally occurring N-sulfated β-lactams (monobactams).

[0006] Scheme 1. Hydroxamate-mediated N-C4 biomimetic cyclization process TIFF2024532211000002.tif128167

[0007] Although the natural monobactams were not highly active antibiotics, the use of N-C4 cyclization chemistry enabled the synthesis of highly active anti-Gram-negative monocyclic β-lactam antibiotics. Extensive structure-activity relationship (SAR) studies optimized the termini (Figure 2), resulting in the first, and still only, commercially available monobactam, aztreonam (9a). Many other highly active monobactams have been reported, including carumonam (11) and LYS228 (12), but are not in clinical use, mainly due to marketing constraints. Aztreonam is derived from L-threonine, a natural and readily available amino acid, by modification of N-C4 cyclization chemistry. It was approved by the FDA in 1986 and is still used as an injectable antibiotic to treat infections due to Gram-negative bacteria, including some that produce β-lactamases. However, aztreonam is not effective against some of the most concerning MDR Gram-negative strains. Thus, there is a need to develop new compounds with improved efficacy against MDR Gram-negative strains. To address the need for improved antibiotic activity of monobactams against MDR Gram-negative bacteria, provided herein is an invention directed to conjugates of simple biscatechol siderophore mimetics with aztreonam (9a) (27 and 30) that have enhanced and potent activity against Gram-negative bacteria, including those resistant to aztreonam itself.

[0008] Design, synthesis, and testing of siderophore-antibiotic conjugates that mimic natural sideromycins take advantage of the essential iron sequestration process to actively transport the antibiotic to targeted pathogenic bacterial strains. Most active synthetic sideromycins incorporate β-lactams as the antibiotic ("warhead") component. Siderophore conjugates of penicillins (13, Figure 3) and cephalosporins (14, 15) often have enhanced activity through active transport and avoidance of efflux, but some are susceptible to deactivation by β-lactamases. However, cefiderocol (16), also called fetroja, based on the iron transport-mediated Trojan horse concept, is now stable against most β-lactamases and has been approved by the FDA. β-lactamases can be utilized to release the antibiotic from synthetic sideromycins. For example, a synthetic siderophore-cephalosporin-oxazolidinone conjugate (17) was highly active against cephalosporinase-producing strains of A. baumannii. By actively transporting the conjugate to the target bacteria using the siderophore, β-lactamase could destroy the cephalosporin, releasing the antibiotic, normally against gram-positive bacteria, intracellularly and killing gram-negative bacteria. Although effective, this dual drug conjugate requires extensive synthesis.

[0009] To circumvent the deleterious β-lactamase problems associated with classical penicillin-cephalosporin conjugates, siderophore conjugates of non-β-lactam antibiotics have been tested, including large and complex compounds such as daptomcyin and teicoplanin. In vitro and in vivo studies have demonstrated the efficacy of the sideromycin approach to repurpose antibiotics normally only directed against gram-positive bacteria to target gram-negative bacteria. The reduced susceptibility of monobactams to β-lactamases has also prompted further exploration of this class of small and structurally simpler compounds for siderophore conjugation. The first concern was that more extensive modifications of the monobactam terminus could adversely affect the previously established SAR (9a, Figure 2). However, decades ago, it was reported that iron-binding hydroxypyridone-substituted monocarbams such as U-78,608 (18) and pyrazumonam (SQ-83,360, 19), as well as catechol SQ-83,280 (20), had activity against Gram-negative bacteria even when incorporating extensive modifications beyond those suggested by the original monobactam SAR (Figure 4). Synthesis and testing of MC-1 (21), a hydroxypyridone-containing monocarbam with diol substitution, revealed that it was hydrolytically stable and exhibited potent antibacterial activity against Gram-negative bacteria. Monosulfactam BAL 30072 (22) and related compounds also replace the usual aminothiazoxime carboxylic acid with a substituted hydroxypyridone. Although hydroxypyridones are not common natural siderophore iron-binding ligands, they mimic catechol and its monocyclic β-lactam derivatives and exploit siderophore transport to promote activity against Gram-negative bacteria. At the time, none of these compounds were used in the clinic due to initial marketing restrictions and other factors. Their activity revealed that more extensive terminal modifications of the monocyclic β-lactam core were tolerated. Known syntheses of C4-substituted monobactams are time-consuming because the corresponding β-hydroxy-α-amino acid precursors (4, functionalized at R2) are not readily available and alternative syntheses are required. Thus, there is a need to develop simple alternative synthetic routes.Provided herein is an invention directed to the simple synthesis of a C4-substituted monobactam with a bis-catechol siderophore mimic. This conjugate (23) was highly active against problematic Gram-negative bacteria, including carbapenemase- and cephalosporinase-producing strains of P. aeruginosa and A. baumannii, but not aztreonam.

[0010] Although there has been skepticism about the clinical potential of siderophore-antibiotic conjugates (sideromycins), the potential of this so-called Trojan horse approach to enhance and even repurpose the activity of antibiotics and other drugs, usually against Gram-positive bacteria, merits continued attention. The recent FDA approval of cefiderocol (Fetroja, 16) highlights the value of this approach. It should also be recalled that natural sideromycins, including albomycins, were successfully used in the clinic to treat antibiotic-resistant infections even in the 1950s. Properly designed synthetic sideromycins have the potential to enable the development of both the broad-spectrum and narrow-targeted antibiotics that are needed. Summary of the Invention

[0011] Provided herein is an invention directed to a compound of formula (I), or a pharma- ceutically acceptable salt or zwitterion thereof: TIFF2024532211000003.tif35128 expression G is -OR A , -OCH2C(=O)X, OCHRC(=O)X, -C(=O)X, -S(=O)2X, -OS(=O)2X, -C(=O)NH-S(=O)2G', P(=O)X or -P(=O)X, G' is OR A , -OCH2C(=O)X, OCHRC(=O)X, -C(=O)X, -S(=O)2X, -OS(=O)2X, P(=O)X or -P(=O)X, X is H, -OR A or -N(R A )2, R1 is H or optionally substituted with X or Z -(C1-C 12 ) alkyl, Z is R A , -OR A , -SR A , -C(=O)N(R A )2, or -N(R A )2, R2 is -CH2C(=O)W, -CHR 4 C(=O)W, -C(R 4 )2C(=O)W, -C(R 4 )2C(=O)NHOCH2C(=O)W, -C(R 4 )2C(=O)NHOCH2C(=O)OH, -C(R 4 )2C(=O)NHOC(R 4 )2C(=O)OH, or -C(R 4 )2C(=O)NHOC(R 4 )2C(=O)W, R3 is H, Z, or R 4 and Each R 4 are independently H, Z, -(C1-C 12 )alkyl, -(C3-C8)cycloalkyl, -(C3-C6)heterocycloalkyl, or -(C1-C8)N(R A )R B or two R 4 together with the carbon atom to which they are attached form -(C3-C8)cycloalkyl or -(C3-C6)heterocycloalkyl; Each R A are independently H, -(C1-C 12 )alkyl, -(C3-C8)cycloalkyl, phenyl, aryl, or heteroaryl; R B is H, -(C1-C 12 ) alkyl, -(C3-C8) cycloalkyl, or phenyl; W is Sid or a linker-Sid; Sid is the siderophore moiety, the linker is -NH-QC(=O)O-, -NH-C(=O)-QC(=O)O-, -C(=O)-Q-, -C(=O)OQ-, -C(=O)-QC(=O)-NH-, -OQO-, -OQ-, -NH-Q-, -NH-Q-NH-, -NH-QO-, or combinations thereof; Q is -OH, -COOH, -(C1-C 12 ) alkyl, -(C1-C 12 ) alkenyl, -(C1-C 12 ) alkylene-OH, -(C1-C 12 ) alkylene-NH2, -NH-(C1-C 12 ) alkylene-COOH, -NH-C(=O)-(C1-C 12 ) alkylene-COOH, -C(=O)-(C1-C 12 ) alkylene-C(=O)-NH2, -O-(C1-C 12 ) alkylene-OH, -NH-(C1-C 12 ) alkylene-NH2, and -NH-(C1-C 12 ) alkylene-OH, -(C 12 ) alkylene.

[0012] Also provided herein is a method of treating a bacterial infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) as hereinbefore described or a pharma- ceutically acceptable salt or zwitterion thereof, or a pharmaceutical composition comprising a compound of formula (I) as hereinbefore described.

[0013] Further provided herein is a process for preparing a compound of formula (I), or a pharma- ceutically acceptable salt or zwitterion thereof, the process comprising: Compound of formula (I'-1) TIFF2024532211000004.tif36128 is a compound of formula (II'-1) or formula (II'-2) R8-U1-NH2(II'-1), or R8-U1-L'-NH2(II'-2) under suitable conditions to produce a compound having the formula (I) generating TIFF2024532211000005.tif35128, During the ceremony G is -OR A , -OCH2C(=O)X, OCHRC(=O)X, -C(=O)X, -S(=O)2X, -OS(=O)2X, -C(=O)NH-S(=O)2G', P(=O)X or -P(=O)X, G' is OR A , -OCH2C(=O)X, OCHRC(=O)X, -C(=O)X, -S(=O)2X, -OS(=O)2X, P(=O)X or -P(=O)X, X is H, -OR A or -N(R A )2, R1 is H or optionally substituted with X or Z -(C1-C 12 ) alkyl, Z is R A , -OR A , -SR A , -C(=O)N(R A )2, or -N(R A )2, R 2a -CH2C(=O)OH, -CHR 4 C(=O)OH, -C(R 4 )2C(=O)OH, or -C(R 4 )2C(=O)NHOCH2C(=O)OH, -C(R 4 )2C(=O)NHOC(R 4 )C(=O)OH, R2 is -CH2C(=O)W', -CHR 4 C(=O)W', -C(R 4 )2C(=O)W', -C(R 4 )2C(=O)NHOCH2C(=O)W', -C(R 4 )2C(=O)NHOCH2C(=O)OH, -C(R 4 )2C(=O)NHOC(R 4 )2C(=O)OH, or -C(R 4)2C(=O)NHOC(R 4 )2C(=O)W', R3 is H, Z, or R 4 and Each R 4 are independently H, Z, -(C1-C 12 )alkyl, -(C3-C8)cycloalkyl, -(C3-C6)heterocycloalkyl, or -(C1-C8)N(R A )R B or two R 4 together with the carbon atom to which they are attached form -(C3-C8)cycloalkyl or -(C3-C6)heterocycloalkyl; Each R A are independently H, -(C1-C 12 )alkyl, -(C3-C8)cycloalkyl, phenyl, aryl, or heteroaryl; R B is H, -(C1-C 12 ) alkyl, -(C3-C8) cycloalkyl, or phenyl; W' is -NH-U1-R8 or -NH-L'-U1- R8, L' is -QC(=O)O-, -C(=O)-QC(=O)O-, -C(=O)-Q-, -C(=O)OQ-, -C(=O)-QC(=O)-, -OQ-, -Q-, -Q-NH-, -QO-, or a combination thereof; Each Q is independently -OH, -COOH, =O, -NH2, -(C1-C 12 ) alkyl, -(C1-C 12 ) alkenyl, -(C1-C 12 ) alkylene-OH, -(C1-C 12 ) alkylene-NH2, -NH-(C1-C 12 ) alkylene-COOH, -NH-C(=O)-(C1-C 12 ) alkylene-COOH, -C(=O)-(C1-C 12 ) alkylene-C(=O)-NH2, -O-(C1-C 12 ) alkylene-OH, -NH-(C1-C 12) alkylene-NH2, and -NH-(C1-C 12 ) alkylene-OH, -(C 12 ) alkylene; U1 is a covalent bond or an optionally substituted -Q-, -C(=O)-, -OC(=O)-, -CHR8-, -CR 10 R8-, -C(=O)-NH-, -C(=O)-NR8-, -C(=O)-N(OH)-, -NH-, -NR8-, -NR 10 -, -NH-CHR8-C(=O)-, -R 11 - or a combination thereof, Each R8 is independently H, -OH, -COOH, -NH2, -Q-OH, -V, -QV, -NH-C(=O)-V, -Q-NH-C(=O)-V, -NR 10 -C(=O)-V, -NR 10 -V, -C(=O)-V, -OC(=O)-V, -C(=O)-R 11 -V, -NH-C(=O)-R 11 -V, -C(=O)-R 11 -aryl, or linker-H; R 10 is -NH-C(O)-Q-COOH, -C(O)-Q-COOH, -Q-COOH, or -COOH; R 11 is an optionally substituted ring selected from phenyl, 3- to 7-membered saturated or partially unsaturated carbocyclyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O and S, and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S; V is -N(OH)-C(=O)-NH2, -N(OH)-C(=O)H, N(OH)-C(=O)-linker, -N(OH)-C(=O)-(C1-C 12 ) alkyl, -N(OH)-C(=O)-(C1-C 12 ) alkenyl, -N(OH)-C(=O)-Q-OH, -N(OH)-C(=O)-Q-COOH, TIFF2024532211000006.tif90128, m is an integer selected from 0 to 3; n is an integer selected from 0 to 10; Each R5 is independently -(C1-C 12 ) alkyl, halogen, -OH, -COOH, -NH2, -linker-H, or -C(=O)-linker-H; and R6 and R7 are independently H, -COOH, or -OR A It is. [Brief description of the drawings]

[0014] [Figure 1] FIG. 1 describes classical bicyclic β-lactam antibiotics. [Diagram 2] FIG. 2 provides a summary of the SAR of the structures of aztreonam (9a) and related monobactams. [Diagram 3] FIG. 3 provides representative known biscatechol antibiotic conjugates. [Figure 4] FIG. 4 depicts monocarbam, monosulfactam and monobactam conjugates. [Figure 5a] FIG. 5a provides representative siderophores, analogs and mimetics of amino acid-based hydroxamic acids. [Figure 5b] FIG. 5b provides representative siderophores, analogs and mimetics of aminoalkane-based hydroxamic acids. [Figure 5c] Figure 5c provides representative siderophores, analogs and mimetics of catechol and hydroxylpyridine. [Figure 5d] Figure 5d provides representative siderophores, analogs and mimetics of mixed-ligand siderophores and mimetics. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] Detailed Description of the Invention Unless otherwise defined, all technical and scientific terms have the same meaning as commonly understood by those skilled in the art to which the disclosed embodiment belongs.If there are multiple definitions for terms cited herein, the definition in this section shall prevail unless otherwise stated.All patents, applications, published applications, and other publications cited herein are incorporated by reference in their entirety.

[0016] As used herein, the terms "a" or "an" mean "at least one" or "one or more," unless the context clearly indicates otherwise.

[0017] The term "about" as used herein means that the numerical value is approximate and that slight variations will not significantly affect the implementation of the disclosed embodiment. When numerical limitations are used, unless otherwise indicated by the context, "about" means that the numerical value may vary by ±10% and remain within the range of the disclosed embodiment.

[0018] The term "additive" or "coupling additive" as used herein means a reagent suitable in combination with a coupling reagent in a coupling reaction to inhibit side reactions and reduce or eliminate racemization. In some embodiments, the additive is, but is not limited to, ethyl cyanohydroxyiminoacetate, N-hydroxysuccinimide (HOSu), N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), 1-hydroxybenzotriazole (HOBt), 6-chloro-1-hydroxybenzotriazole (6-Cl-HOBt), 1-hydroxy-7-azabenzotriazole (HOAt) or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HODhbt), aza derivative of 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HODhat), 4-(N,N-dimethylamino)pyridine) (DMAP), N-hydroxysuccinimide (HOSu), N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), or any combination thereof.

[0019] The term "alcohol" as used herein refers to any organic compound in which a hydroxyl group (-OH) is bonded to a carbon atom which is in turn bonded to other hydrogens and / or carbon atoms. For example, the term "alcohol" refers to a straight or branched alkyl-OH group of 1-20 carbon atoms, including, but not limited to, methanol, ethanol, n-propanol, isopropanol, t-butanol, and the like. In some embodiments, the alkyl-OH chain is 1-10 carbon atoms long, 1-8 carbon atoms long, 1-6 carbon atoms long, 1-4 carbon atoms long, 2-10 carbon atoms long, 2-8 carbon atoms long, 2-6 carbon atoms long, or 2-4 carbon atoms long.

[0020] The terms "alkoxy", "phenyloxy", "benzoxy" and "pyrimidinyloxy" as used herein refer to an alkyl, phenyl, benzyl or pyrimidinyl group, each of which may be substituted, attached through an oxygen atom. For example, the term "alkoxy" refers to a straight or branched -O-alkyl group of 1-20 carbon atoms, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, and the like. In some embodiments, the alkoxy chain is 1-10 carbon atoms long, 1-8 carbon atoms long, 1-6 carbon atoms long, 1-4 carbon atoms long, 2-10 carbon atoms long, 2-8 carbon atoms long, 2-6 carbon atoms long, or 2-4 carbon atoms long.

[0021] The term "alkyl" as used herein means a linear or branched saturated hydrocarbon group. The alkyl group may contain 1-20, 2-20, 1-10, 2-10, 1-8, 2-8, 1-6, 2-6, 1-4, 2-4, 1-3, or 2 or 3 carbon atoms. Examples of alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, t-butyl, isobutyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-3-propyl, 2-methyl-4-propyl, 2-methyl-5-propyl, 2-methyl-6-propyl, 2-methyl-7-propyl, 2-methyl-8-propyl, 2-methyl-9-propyl, 2-methyl-10-propyl, 2-methyl-11-propyl, 2-methyl-12-propyl, 2-methyl-13-propyl, 2-methyl-14-propyl, 2-methyl-15-propyl, 2-methyl-16-propyl, 2-methyl-17-propyl, 2-methyl-18-propyl, 2-methyl-19-propyl, 2-methyl-20-propyl, 2-methyl-21-propyl, 2-methyl-22-propyl, 2-methyl-23-propyl, 2-methyl-24-propyl, 2-methyl-25-propyl, 2-methyl-26-propyl, 2-methyl-27-propyl, 2-methyl-28-propyl, 2-methyl-29-propyl, 2-methyl-29-propyl These include, but are not limited to, propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2-methyl-1-pentyl, 2,2-dimethyl-1-propyl, 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, and the like.

[0022] The term "alkylene" or "alkylenyl" as used herein refers to a divalent alkyl linking group. Examples of alkylene (or alkylenyl) are methylene or methyleneyl (-CH-).

[0023] The term "alkynyl" as used herein means a straight or branched alkyl group having one or more triple carbon-carbon bonds and 2 to 20 carbon atoms, including, but not limited to, acetylene, 1-propylene, 2-propylene, etc. In some embodiments, the alkynyl chain is 2 to 10 carbon atoms in length, 2 to 8 carbon atoms in length, 2 to 6 carbon atoms in length, or 2 to 4 carbon atoms in length.

[0024] The terms "ambient temperature" and "room temperature" or "RT" as used herein are understood in the art and generally refer to a temperature, e.g., the reaction temperature, which is about the temperature of the room in which the reaction is carried out, e.g., a temperature of about 20°C to about 30°C, e.g., 25°C or about 25°C.

[0025] The term "amide" as used herein refers to a functional group containing a carbonyl group linked to a nitrogen atom, or any compound containing an amide functional group. For example, an amide is derived from a carboxylic acid and an amine.

[0026] The term "aryl" as used herein means a monocyclic, bicyclic, or polycyclic (e.g., having 2, 3, or 4 fused rings) aromatic hydrocarbon. In some embodiments, the aryl group has 6 to 20 carbon atoms or 6 to 10 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthyl, and the like. Examples of aryl groups include: These include, but are not limited to: TIFF2024532211000007.tif197156TIFF2024532211000008.tif169160.

[0027] The term "carbocycle" as used herein means a 5-6 or 7 membered, saturated or unsaturated cyclic ring optionally containing an S or N atom as part of the ring. Examples of carbocycles include, but are not limited to, cyclopentyl, cyclohexyl, cyclopenta-1,3-diene, phenyl, and any of the heterocycles listed above.

[0028] As used herein, the term "compound" refers to all stereoisomers, tautomers, and isotopes of the compounds described herein.

[0029] As used herein, "comprising" (and any form of comprising, e.g., "comprise," "comprises," and "comprised"), "having" (and any form of having, e.g., "have" and "has"), "including" (and any form of including, e.g., "includes" and "include"), or "containing" (and any form of containing, e.g., "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0030] The terms "contacting" or "mixing" or "adding" as used herein means bringing two compounds / atoms together to form at least one covalent bond between the compounds or atoms.

[0031] The term "coupling reagent" or "peptide coupling reagent" as used herein refers to a reagent that promotes the formation of an amide bond between an amine and a carboxylic acid, including, but not limited to, carbodiimides, aminium / uronium and phosphonium salts, and propanephosphonic anhydride. For example, coupling reagents include diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, EDAC or EDCI), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, hexafluorophosphate azabenzotriazole tetramethyluronium (HATU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, hexafluorophosphate benzotriazole tetramethyluronium, and the like. tetramethyluronium (HBTU), O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU), benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), 7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), propanephosphonic anhydride (PPAA, T3P), or any combination thereof.

[0032] The term "cyano" as used herein means --CN.

[0033] The term "cycloalkyl" as used herein means a non-aromatic cyclic hydrocarbon containing up to 20 ring-forming carbon atoms, including cyclized alkyl, alkenyl, and alkynyl groups. Cycloalkyl groups can include monocyclic or polycyclic ring systems, such as fused, bridged, and spiro ring systems. In some embodiments, polycyclic ring systems contain 2, 3, or 4 fused rings. Cycloalkyl groups can contain 3 to 15, 3 to 10, 3 to 8, 3 to 6, 4 to 6, 3 to 5, or 5 or 6 ring-forming carbon atoms. The ring-forming carbon atoms of a cycloalkyl group may be substituted with oxo or sulfido. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, etc. Similarly, included within the definition of cycloalkyl are moieties having one or more aromatic rings fused (having a bond in common) to the cycloalkyl ring, e.g., benzo or thienyl derivatives of pentane, pentene, hexane, etc. (e.g., 2,3-dihydro-1H-inden-1-yl, or 1H-inden-2(3H)-on-1-yl).

[0034] As used herein, the term "cycloheteroalkyl" when used alone or as part of another group refers to a cycloheteroalkyl group that can be optionally linked through a carbon or heteroatom, if possible, by a linker (CH2) n (where n is 0, 1, 2 or 3). The above groups may contain 1 to 4 substituents such as alkyl, halo, oxo and / or any of the substituents for alkyl or aryl provided herein. Additionally, any cycloheteroalkyl ring may be fused to a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.

[0035] As used herein, the terms "for example" and "such as" and their grammatical equivalents.

[0036] The term "halo" as used herein means a halogen group, including, but not limited to, fluoro, chloro, bromo, and iodo.

[0037] The term "haloalkoxy" as used herein refers to an -O-haloalkyl group. An example of a haloalkoxy group is OCF3.

[0038] As used herein, the term "haloalkyl" refers to a C alkyl group having one or more halogen substituents. 1-6 means an alkyl group. Examples of haloalkyl groups include, but are not limited to, CF3, C2F5, CH2F, CHF2, CCl3, CHCl2, CH2CF3, and the like.

[0039] The term "heteroaryl" as used herein refers to an aromatic heterocycle having up to 20 ring-forming atoms (e.g., C) and at least one heteroatom ring member (ring-forming atom) such as sulfur, oxygen, or nitrogen. In some embodiments, a heteroaryl group has at least one or more heteroatom ring-forming atoms, each of which is independently sulfur, oxygen, or nitrogen. In some embodiments, a heteroaryl group has 3-20 ring-forming atoms, 3-10 ring-forming atoms, 3-6 ring-forming atoms, or 3-5 ring-forming atoms. In some embodiments, a heteroaryl group contains 2-14 carbon atoms, 2-7 carbon atoms, or 5 or 6 carbon atoms. In some embodiments, a heteroaryl group has 1-4 heteroatoms, 1-3 heteroatoms, or 1 or 2 heteroatoms. Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3, or 4 fused rings) systems. Examples of heteroaryl groups include pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl (e.g., indol-3-yl), pyrrolyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, pyranyl, These include, but are not limited to, oxadiazolyl, isoxazolyl, triazolyl, thianthrenyl, indolizinyl, isoindolyl, isobenzofuranyl, benzoxazolyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, 3H-indolyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinazolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furanyl, phenoxazinyl groups and the like.Suitable heteroaryl groups include 1,2,3-triazole, 1,2,4-triazole, 5-amino-1,2,4-triazole, imidazole, oxazole, isoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 3-amino-1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, pyridine, and 2-aminopyridine.

[0040] The term "heterocycle" or "heterocyclic ring" as used herein refers to a 5-7 membered monocyclic or bicyclic or 7-10 membered bicyclic heterocyclic ring system, any of which rings may be saturated or unsaturated and consist of carbon atoms and 1-3 heteroatoms selected from N, O and S, where the N and S heteroatoms may be optionally oxidized and the N heteroatom may be optionally quaternized, including any bicyclic group in which any of the heterocyclic rings defined above are fused to a benzene ring. Particularly useful are rings containing one oxygen or sulfur, one to three nitrogen atoms, or a combination of one oxygen or sulfur and one or two nitrogen atoms. The heterocyclic ring may be attached at any heteroatom or carbon atom that creates a stable structure. Examples of heterocyclic groups include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl. Examples of aryl groups include, but are not limited to, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl. Morpholino is the same as morpholinyl.

[0041] The term "heterocycloalkyl" as used herein means a non-aromatic heterocycle having up to 20 ring-forming atoms, including cyclized alkyl, alkenyl, and alkynyl groups, in which one or more of the ring-forming carbon atoms are replaced with a heteroatom, such as an O, N, or S atom. Heterocycloalkyl groups can be monocyclic or polycyclic (e.g., fused, bridged, or spiro). In some embodiments, heterocycloalkyl groups have 1-20 carbon atoms, or 3-20 carbon atoms. In some embodiments, heterocycloalkyl groups contain 3-14 ring-forming atoms, 3-7 ring-forming atoms, or 5 or 6 ring-forming atoms. In some embodiments, heterocycloalkyl groups have 1-4 heteroatoms, 1-3 heteroatoms, or 1 or 2 heteroatoms. In some embodiments, heterocycloalkyl groups contain 0-3 double bonds. In some embodiments, heterocycloalkyl groups contain 0-2 triple bonds. Examples of heterocycloalkyl groups include, but are not limited to, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, pyrazolidinyl, thiazolidinyl, imidazolidinyl, pyrrolidin-2-one-3-yl, etc. In addition, ring-forming carbon atoms and heteroatoms of heterocycloalkyl groups can be substituted with oxo or sulfido. For example, ring-forming S atoms can be substituted with one or two oxos (forming S(O) or S(O)2). In another example, ring-forming C atoms can be substituted with oxo (forming carbonyl).Similarly, included within the definition of heterocycloalkyl are moieties having one or more aromatic rings fused (having a common bond) to a non-aromatic heterocyclic ring, including, but not limited to, pyridinyl, thiophenyl, phthalimidyl, naphthalimidyl, and benzo derivatives of heterocycles such as indolene, isoindolene, 4,5,6,7-tetrahydrothieno[2,3-c]pyridin-5-yl, 5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one-5-yl, isoindolin-1-one-3-yl, and 3,4-dihydroisoquinolin-1(2H)-one-3-yl groups. Ring-forming carbon atoms and heteroatoms of heterocycloalkyl groups may be optionally substituted with oxo or sulfido.

[0042] The term "heterocycloalkylalkyl" as used herein refers to a C1-6 alkyl substituted with a heterocycloalkyl.

[0043] The term "hydroxy" or "hydroxyl" as used herein refers to an --OH group.

[0044] The term "hydroxyalkyl" or "hydroxylalkyl" as used herein refers to an alkyl group substituted with a hydroxyl group. Examples of hydroxylalkyl include, but are not limited to, -CHOH and -CHCHOH.

[0045] The terms "infection" and "bacterial infection" may refer to gynecological infections. In another aspect, the terms "infection" and "bacterial infection" may refer to respiratory tract infections (RTIs). In yet another aspect, the terms "infection" and "bacterial infection" may refer to sexually transmitted diseases. In yet another aspect, the terms "infection" and "bacterial infection" may refer to urinary tract infections (UTIs). In a further aspect, the terms "infection" and "bacterial infection" may refer to acute exacerbation of chronic bronchitis (ACEBs). In a further aspect, the terms "infection" and "bacterial infection" may refer to acute otitis media. In one aspect, the terms "infection" and "bacterial infection" may refer to acute sinusitis. In another aspect, the terms "infection" and "bacterial infection" may refer to infections caused by drug-resistant bacteria. In yet another aspect, the terms "infection" and "bacterial infection" may refer to catheter-associated sepsis. In yet another aspect, the terms "infection" and "bacterial infection" may refer to chancroid. In a further aspect, the terms "infection" and "bacterial infection" may refer to chlamydia. In a further aspect, the terms "infection" and "bacterial infection" may refer to community-acquired pneumonia (CAP). In a further aspect, the terms "infection" and "bacterial infection" may refer to complicated skin and skin structure infections. In one aspect, the terms "infection" and "bacterial infection" may refer to uncomplicated skin and skin structure infections. In another aspect, the terms "infection" and "bacterial infection" may refer to endocarditis. In yet another aspect, the terms "infection" and "bacterial infection" may refer to febrile neutropenia. In yet another aspect, the terms "infection" and "bacterial infection" may refer to gonococcal cervicitis. In a further aspect, the terms "infection" and "bacterial infection" may refer to gonococcal urethritis. In a further aspect, the terms "infection" and "bacterial infection" may refer to hospital-acquired pneumonia (HAP). In yet another aspect, the terms "infection" and "bacterial infection" may refer to osteomyelitis. In a further aspect, the terms "infection" and "bacterial infection" may refer to sepsis.In a further aspect, the terms "infection" and "bacterial infection" may refer to syphilis. In a further aspect, the terms "infection" and "bacterial infection" may refer to intraabdominal infection (IAI).

[0046] In one embodiment of the present invention, the terms "infection" and "bacterial infection" refer to an infection caused by gram-negative bacteria, also called "gram-negative infection". In one aspect of this embodiment, the gram-negative infection is an infection that is resistant to one or more antibiotics. In one aspect of this embodiment, the gram-negative infection is a multi-drug resistant infection.

[0047] The term "patient" as used herein means any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, such as humans.

[0048] As used herein, the term "isolated" means that the compounds described herein are separated from other components of a synthetic organic chemical reaction mixture by conventional techniques, such as filtration.

[0049] As used herein, the term "mammal" refers to a rodent (i.e., mouse, rat, or guinea pig), monkey, cat, dog, cow, horse, pig, or human. In some embodiments, the mammal is a human.

[0050] The term "nitro" as used herein means --NO.sub.2.

[0051] As used herein, the term "n-membered," where n is an integer, typically refers to the number of ring-forming atoms of a moiety, where the number of ring-forming atoms is n. For example, pyridine is an example of a 6-membered heteroaryl ring, and thiophene is an example of a 5-membered heteroaryl ring.

[0052] The phrase "optionally substituted" as used herein means that substitution is optional, and thus includes both unsubstituted and substituted atoms and moieties. "Substituted" atom or moiety indicates that any hydrogen on the specified atom or moiety can be replaced with one selected from the indicated substituents, provided that the normal valence of the specified atom or moiety is not exceeded and the replacement results in a stable compound. For example, when a methyl group is optionally substituted, three hydrogen atoms on the carbon atom can be replaced with a substituent.

[0053] As used herein, the phrase "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues. In some embodiments, "pharmaceutical acceptable" means approved by a federal or state regulatory agency or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in animals, more specifically humans.

[0054] The term "zwitterion" as used herein refers to a functional group molecule that has at least one positive charge and one negative charge. Provided herein is the invention of a compound of formula (I), or its pharma- ceutically acceptable salt or zwitterion. The compounds of the invention are directed to pharma- ceutically acceptable salts or zwitterion forms of the compounds.

[0055] In some embodiments, the salt of the compound described herein is its pharmaceutically acceptable salt.As used herein, the phrase "pharmaceutically acceptable salt" includes, but is not limited to, salts of acidic or basic groups.Compounds that are basic in nature can form a variety of salts with various inorganic and organic acids. Acids which may be used to prepare pharma- ceutically acceptable acid addition salts of such basic compounds are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including sulfate, thiosulfate, citrate, maleate, acetate, oxalate, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, bisulfite, phosphate, acid phosphate, isonicotinate, borate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate. Examples of suitable salts include, but are not limited to, bicarbonate, malonate, mesylate, esylate, napsydisylate, tosylate, besylate, orthophosphate, trifluoroacetate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds containing an amino moiety may form pharma-ceutically acceptable salts with various amino acids in addition to the acids mentioned above. Compounds that are acidic in nature may form base salts with various pharma-ceutically acceptable cations. Examples of such salts include, but are not limited to, alkali metal or alkaline earth metal salts, particularly calcium, magnesium, ammonium, sodium, lithium, zinc, potassium, and iron salts. The present embodiments also include quaternary ammonium salts of the compounds described herein, where the compounds have one or more tertiary amine moieties. Provided herein is an invention of a compound of formula (I), or a pharma-ceutically acceptable salt or zwitterion thereof.The compounds of the present invention are directed to pharma- ceutically acceptable salts or zwitterionic forms of the compounds.

[0056] The term "phenyl" as used herein means -C6H5. A phenyl group can be unsubstituted or substituted with one, two, or three suitable substituents.

[0057] The term "siderophore" as used herein is a low molecular weight moiety that can bind ferric iron. Once bound, these "iron carriers" can facilitate the transport of molecules into bacterial cells. The term "siderophore" is used according to its general meaning and refers to high affinity iron chelating compounds that can be secreted by microorganisms (e.g., bacteria, fungi, grasses). As defined herein, siderophore compounds can be synthetic or natural compounds. Synthetic siderophore compounds include synthetic analogs and derivatives of natural siderophore compounds. The term "siderophore moiety" or "Sid" is the moiety resulting from the removal of the terminal -COOH, -NH2, or -OH group from a free siderophore compound. In some embodiments, the siderophore moiety is linked to the remainder of the compound to which it is directed or in the form of Sid-CO-, Sid-COO-, Sid-NH-, or Sid-O-. In some embodiments, the free siderophore compound from which the "siderophore moiety" is derived is represented as Sid-COOH, Sid-NH2, or Sid-OH.

[0058] The term "solution" as used herein refers to a liquid composition in which a first portion of an active agent is present in solution and a second portion of the active agent is present in particulate form in suspension in a liquid matrix.

[0059] The term "solvent" as used herein means a substance, usually liquid, capable of dissolving or dispersing one or more other substances, including water, inorganic non-aqueous solvents, and organic solvents. The term "inorganic non-aqueous solvent" means a solvent other than water that is not an organic compound. Examples of "inorganic non-aqueous solvents" include, but are not limited to: liquid ammonia, liquid sulfur dioxide, sulfuryl chloride and sulfuryl fluoride chloride, phosphoryl chloride, dinitrogen tetroxide, antimony trichloride, bromine pentafluoride, hydrogen fluoride, pure sulfuric acid, and other inorganic acids. The term "organic solvent" means a carbon-based solvent. Examples of "organic solvents" include, but are not limited to: aromatic compounds, such as benzene and toluene, alcohols, such as methanol, ethanol, and propanol, esters and ethers, ketones, such as acetone, amines, nitrated and halogenated hydrocarbons. "Organic solvent" includes both polar and non-polar organic solvents. "Polar organic solvent" refers to an organic solvent with a large dipole moment (also known as "partial charge"), and generally, organic solvents with a dielectric constant greater than about 5 are considered "polar organic solvents", while those with a dielectric constant less than 5 are considered "non-polar organic solvents". Examples of "polar organic solvents" include, but are not limited to, acetic acid, methanol, acetone, and acetonitrile, DMSO, and DMF. Examples of non-polar organic solvents include, but are not limited to, benzene, carbon tetrachloride, and n-hexane. "Organic solvents" include both protic and aprotic organic solvents. The term "protic organic solvent" refers to an organic solvent that has a hydrogen atom bonded to an oxygen or nitrogen (acidic hydrogen atom). Examples of "protic organic solvents" include, but are not limited to, methanol, ethanol, propanol, isopropanol, butanol, hexanol, phenol, acetic acid, benzoic acid, and their partially fluorinated compounds.Examples of "aprotic organic solvents" include, but are not limited to: ethylene glycol dimethyl ether, ethylene glycol methyl ethyl ether, diethylene glycol dimethyl ether, diethylene glycol methyl ethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol diethyl ether, 1,3-dimethoxypropane, 1,2-dimethoxypropane, propylene glycol dimethyl ether, dipropylene glycol dimethyl ether, dioxane, dimethyl carbonate, ethyl methyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate, 2,3-dimethylethylene carbonate, butylene carbonate, acetonitrile, methoxyacetonitrile, propionitrile, butyrolactone, valerolactone, dimethoxyethane, sulforane, methylsulforane, sulfolene, dimethylsulfone, ethylmethylsulfone, and isopropylmethylsulfone.

[0060] As used herein, the phrase "suitable substituent" or "substituent" refers to a group that does not negate the synthetic or pharmaceutical usefulness of the compounds described herein or intermediates useful for preparing them. Examples of suitable substituents include, but are not limited to: C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C5-C6 aryl, C1-C6 alkoxy, C3-C5 heteroaryl, C3-C6 cycloalkyl, C5-C6 aryloxy, -CN, -OH, oxo, halo, haloalkyl, -NO2, -CO2H, -NH2, -NH(C1-C8 alkyl), -N(C1-C8 alkyl)2, -NH(C6 aryl), -N(C5-C6 aryl)2, -CHO, -CO(C1-C6 alkyl), -CO((C5-C6) aryl), -CO2((C1-C6) alkyl), -CO2((C5-C6) aryl). One of skill in the art can readily select appropriate substituents based on the stability and pharmacological and synthetic activity of the compounds described herein.

[0061] As used herein, the term "and without limitation" is understood to extend beyond the scope of the present invention unless expressly stated otherwise.

[0062] At various points in the present specification, substituents of compounds may be disclosed as groups or ranges. It is specifically intended that the embodiments include each and every individual subcombination of the members of such groups and ranges. For example, the term "C1-C6 alkyl" is specifically intended to individually disclose methyl, ethyl, propyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0063] In the case of compounds in which a variable appears multiple times, each variable may be a different moiety selected from the Markush group that defines the variable. For example, when a structure is described with two R groups that are present simultaneously on the same compound, the two R groups may represent different moieties selected from the Markush group that defines R. In another example, when an optional multiple substituent is specified, for example, in the form: R, ...

[0064] It will be further understood that certain features described herein are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features that are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0065] It is understood that the present embodiment encompasses the process of the stereoisomers, diastereomers and optical stereoisomers of the compound, as well as mixtures thereof, if applicable. In addition, it is understood that the stereoisomers, diastereomers and optical stereoisomers of the compound, as well as mixtures thereof, are within the scope of the embodiment. As a non-limiting example, the mixture may be racemic, or the mixture may contain unequal proportions of one particular stereoisomer relative to other stereoisomers. In addition, the compound may be provided as substantially pure stereoisomers, diastereomers and optical stereoisomers (e.g., epimers).

[0066] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended to be included within the scope of the embodiments unless otherwise indicated. Compounds containing asymmetrically substituted carbon atoms can be isolated as optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials, such as by resolution of racemic mixtures or stereoselective synthesis, are known in the art. Many geometric isomers of olefins, C=N double bonds, and the like, may also be present in the compounds described herein, and all such stable isomers are provided herein. Cis and trans geometric isomers of the compounds are also included in the embodiments, and may be isolated as a mixture of isomers or as separate isomers. When a compound capable of stereoisomerism or geometric isomerism is depicted in its structure or name without reference to a specific R / S or cis / trans configuration, it is intended that all such isomers are contemplated.

[0067] In some embodiments, the compositions comprise a compound, or a pharma- ceutically acceptable salt thereof, that is enantiomerically at least 90%, at least 95%, at least 98%, or at least 99%, or 100% pure, meaning that the ratio of one enantiomer to the other in the composition is at least 90:1, at least 95:1, at least 98:1, or at least 99:1, or is entirely in the form of one enantiomer relative to the other.

[0068] Resolution of racemic mixtures of compounds can be carried out by any of a number of methods known in the art, including, for example, chiral HPLC, fractional recrystallization using chiral resolving acids that are optically active salt-forming organic acids. Suitable resolving agents for fractional recrystallization include, but are not limited to, optically active acids, such as D- and L-forms of various optically active camphorsulfonic acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, and β-camphorsulfonic acid. Other suitable resolving agents for fractional recrystallization include, but are not limited to, stereoisomerically pure forms of α-methylbenzylamine (e.g., S- and R-forms, or diastereoisomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like. Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). The appropriate elution solvent composition can be determined by one skilled in the art.

[0069] Compounds may also include tautomers. Tautomers occur by swapping a single bond with an adjacent double bond with the concomitant migration of a proton. Tautomers include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of prototropic tautomers include, but are not limited to, ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and rings in which protons may occupy multiple positions in a heterocyclic ring system, including, but not limited to, 1H- and 3H-imidazoles, 1H-, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles. Tautomers may be in equilibrium or sterically locked into one form by appropriate substitution.

[0070] The compounds may also include zwitterionic forms.

[0071] The compounds include hydrates and solvates, as well as anhydrous and unsolvated forms.

[0072] Compounds may also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0073] In some embodiments, the compound or its salt is substantially isolated. Partial separation can include, for example, a composition enriched in the compound. Substantial separation can include a composition that contains at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the compound or its salt. Methods for isolating compounds and their salts are routine in the art.

[0074] Although the disclosed compounds are suitable, other functional groups can be incorporated into the compounds with similar results expected. In particular, thioamides and thioesters are expected to have very similar properties. The distance between aromatic rings can affect the geometric pattern of the compounds, and this distance can be changed by incorporating aliphatic chains of various lengths, which may be substituted or may include amino acids, dicarboxylic acids, or diamines. The distance between monomers in the compounds and the relative orientation of the monomers can also be changed by replacing the amide bond with a substitute that has an additional atom. Thus, replacing the carbonyl group with a dicarbonyl changes the distance between the monomers and the tendency of the dicarbonyl unit to adopt an anti-arrangement of the two carbonyl moieties, changing the periodicity of the compounds. Pyromellitic anhydride is yet another alternative to simple amide bonds that can change the conformation and physical properties of the compounds. Modern methods of solid phase organic chemistry (E. Atherton and RC Sheppard, Solid Phase Peptide Synthesis A Practical Approach IRL Press Oxford 1989) now allow the synthesis of homodisperse compounds with molecular weights approaching 5,000 daltons. Other substitution patterns are equally valid.

[0075] Various process embodiments for preparing compounds of formula (I) and salts thereof are provided. Where a variable is not specifically recited, the variable may be any option described herein unless otherwise stated or indicated by context.

[0076] In some embodiments, the process for preparing a compound of formula (I) or a pharma- ceutically acceptable salt thereof is as set forth in the accompanying exemplary, non-limiting claims.

[0077] Provided herein is an invention directed to a compound of formula (I), or a pharma- ceutically acceptable salt or zwitterion thereof: TIFF2024532211000009.tif35128 expression G is -OR A , -OCH2C(=O)X, OCHRC(=O)X, -C(=O)X, -S(=O)2X, -OS(=O)2X, -C(=O)NH-S(=O)2G', P(=O)X or -P(=O)X, G' is OR A , -OCH2C(=O)X, OCHRC(=O)X, -C(=O)X, -S(=O)2X, -OS(=O)2X, P(=O)X or -P(=O)X, X is H, -OR A or -N(R A )2, R1 is H or optionally substituted with X or Z -(C1-C 12 ) alkyl, Z is R A , -OR A , -SR A , -C(=O)N(R A )2, or -N(R A )2, R2 is -CH2C(=O)W, -CHR 4 C(=O)W, -C(R 4 )2C(=O)W, -C(R 4 )2C(=O)NHOCH2C(=O)W, -C(R 4 )2C(=O)NHOCH2C(=O)OH, -C(R 4 )2C(=O)NHOC(R 4 )2C(=O)OH, or -C(R 4 )2C(=O)NHOC(R 4 )2C(=O)W, R3 is H, Z, or R 4 and Each R 4 are independently H, Z, -(C1-C 12 )alkyl, -(C3-C8)cycloalkyl, -(C3-C6)heterocycloalkyl, or -(C1-C8)N(R A )R B or two R 4together with the carbon atom to which they are both attached form -(C3-C8)cycloalkyl or -(C3-C6)heterocycloalkyl; Each R A are independently H, -(C1-C 12 )alkyl, -(C3-C8)cycloalkyl, phenyl, aryl, or heteroaryl; R B is H, -(C1-C 12 ) alkyl, -(C3-C8) cycloalkyl, or phenyl; W is Sid or a linker-Sid; Sid is the siderophore moiety, the linker is -NH-QC(=O)O-, -NH-C(=O)-QC(=O)O-, -C(=O)-Q-, -C(=O)OQ-, -C(=O)-QC(=O)-NH-, -OQO-, -OQ-, -NH-Q-, -NH-Q-NH-, -NH-QO-, -NH-OQ-, or combinations thereof; Each Q is independently -OH, -COOH, =O, -NH2, -(C1-C 12 ) alkenyl, -(C1-C 12 ) alkylene-OH, -(C1-C 12 ) alkylene-NH2, -NH-(C1-C 12 ) alkylene-COOH, -NH-C(=O)-(C1-C 12 ) alkylene-COOH, -C(=O)-(C1-C 12 ) alkylene-C(=O)-NH2, -O-(C1-C 12 ) alkylene-OH, -NH-(C1-C 12 ) alkylene-NH2, and -NH-(C1-C 12 ) alkylene-OH, -(C 12 ) alkylene.

[0078] In some embodiments, Sid-OH, Sid-NH2, Sid-COOH, or -Linker-Sid is represented by formula (II): R8-U1-R9(II) During the ceremony U1 is a covalent bond or an optionally substituted -Q-, -C(=O)-, -OC(=O)-, -CHR8-, -CR 10 R8-, -C(=O)-NH-, -C(=O)-NR8-, -C(=O)-N(OH)-, -NH-, -NR8-, -NR 10 -, -NH-CHR8-C(=O)-, -R 11 - or a combination thereof, Each R8 is independently H, -OH, -COOH, -NH2, -Q-OH, -V, -QV, -NH-C(=O)-V, -Q-NH-C(=O)-V, -NR 10 -C(=O)-V, -NR 10 -V, -C(=O)-V, -OC(=O)-V, -C(=O)-R 11 -V, -NH-C(=O)-R 11 -V, -C(=O)-R 11 -aryl, or linker-H; R9 is H, -OH, -COOH, -NH2, -Q-OH, -V, -QV, -NH-C(=O)-V, -Q-NH-C(=O)-V, -NR 10 -C(=O)-V, -NR 10 -V, -C(=O)-V, -OC(=O)-V, -C(=O)-R 11 -V, -NH-C(=O)-R 11 -V, -C(=O)-R 11 -aryl, or linker-H; or R8 and R9 are joined together via a covalent bond to form a ring; R 10 is -NH-C(O)-Q-COOH, -C(O)-Q-COOH, -Q-COOH, or -COOH; R 11 is an optionally substituted ring selected from phenyl, 3- to 7-membered saturated or partially unsaturated carbocyclyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O and S, and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S; V is -N(OH)-C(=O)-NH2, -N(OH)-C(=O)H, -N(OH)-C(=O)-linker, -N(OH)-C(=O)-(C1-C 12 ) alkyl, -N(OH)-C(=O)-(C1-C 12 ) alkenyl, -N(OH)-C(=O)-Q-OH, -N(OH)-C(=O)-Q-COOH, TIFF2024532211000010.tif90128, m is an integer selected from 0 to 3; n is an integer selected from 0 to 10; Each R5 is independently -(C1-C 12 ) alkyl, halogen, -OH, -COOH, -NH, -linker-H, or -C(=O)-linker-H; and R6 and R7 are independently H, -COOH, or -OR A It is.

[0079] In some embodiments, the compound of formula (I) is TIFF2024532211000011.tif35128 or a salt or zwitterion thereof, During the ceremony G is -OR A , -OCH2C(=O)X, OCHRC(=O)X, -C(=O)X, -S(=O)2X, -OS(=O)2X, -P(=O)X2 or -P(=O)X2, where X is -OR A or -N(R A )2, R 1 is H or -(C1-C 12 ) alkyl, Z is -OR A , -SR A , or -N(R A )2, R2 is CH2C(=O)W, CHR 4 C(=O)W, C(R 4 )2C(=O)W;C(R 4 )2C(=O)NHOCH2C(=O)W,C(R 4)2C(=O)NHOC(R 4 )2C(=O)W, R 4 is Z or H, -(C1-C 12 )alkyl, -(C3-C8)cycloalkyl, -(C3-C6)heterocycloalkyl, or -(C1-C8)N(R A )R B and Each R A are independently H, -(C1-C 12 ) alkyl, -(C3-C8) cycloalkyl, phenyl, aryl, or heteroaryl; R B is H, -(C1-C 12 ) alkyl, -(C3-C8) cycloalkyl, phenyl; W is a siderophore (Sid) or a linker-siderophore; R3 is H, Z, or R 4 and The linker is NH-R 1 -NH, OR 1 -NH, or OR 1 -O.

[0080] In some embodiments, the compounds of formula (I) have portions of structures that are moieties of oxamazines (7), monosulfactams (8), monobactams (9), and monocarbams (10).

[0081] In some embodiments, U1 is -U 11 -U 12 -U 13 -U 14 -U 15 -U 16 - (II-1) and During the ceremony U 11 , U 12 , U 13 , U 14 , U 15 , and U 16are independently a covalent bond or optionally substituted -Q-, -C(=O)-, -OC(=O)-, -CHR8-, -CR 10 R8-, -C(=O)-NH-, -C(=O)-NR8-, -C(=O)-N(OH)-, -NH-, -NR8-, -NR 10 -, -NH-CHR8-C(=O)-, or -R 11 -It is.

[0082] In some embodiments, G is O-CH2-COOH, S(=O)2OH, OS(=O)2OH, or C(=O)NH-S(=O)2G'.

[0083] In some embodiments, G is S(=O)2OH.

[0084] In some embodiments, R is -(C 12 ) alkyl.

[0085] In some embodiments, R1 is -CH3.

[0086] In some embodiments, R2 is -C(R 4 )2C(=O)W, C(R 4 )2C(=O)NHOCH2C(=O)OH, or -C(R 4 )2C(=O)NHOC(R 4 )2C(=O)W.

[0087] In some embodiments, R 4 is -CH3.

[0088] In some embodiments, R3 is -NH2.

[0089] In some embodiments, formula (I) Represented as TIFF2024532211000012.tif49128.

[0090] In some embodiments, formula (I) Represented as TIFF2024532211000013.tif50128.

[0091] In some embodiments, formula (I) Represented as TIFF2024532211000014.tif57128.

[0092] In some embodiments, formula (I) Represented as TIFF2024532211000015.tif56128.

[0093] In some embodiments, formula (I) Represented as TIFF2024532211000016.tif56135.

[0094] In some embodiments, formula (I) Represented as TIFF2024532211000017.tif56128.

[0095] In some embodiments, formula (I) Represented as TIFF2024532211000018.tif36128.

[0096] In some embodiments, V is The file is TIFF2024532211000019.tif24128.

[0097] In some embodiments, the linker is -NH-Q-NH- or -NH-OQ, or a combination thereof. In some embodiments, the linker is -NH-CH2CH2-NH- or -NH-O-CH2CH2-, -NH-O-CH2C(=O)-, or a combination thereof.

[0098] In some embodiments, R8 or R9 is COOH. In some embodiments, one of R8 and R9 is COOH and the other of R8 and R9 is -NH-C(=O)-V.

[0099] In some embodiments, W is represented by -C(=O)-U1-R8 or -NH-U1-R8. In some embodiments, W is represented by the linker-U1-R8. In some embodiments, W is represented by the linker-C(=O)-U1-R8. In some embodiments, W is represented by the linker-NH-U1-R8.

[0100] In some embodiments, U1 is -Q-NR8-Q-, where each Q is independently optionally substituted with one or more selected from the group consisting of -OH, -COOH, ═O, and -NH2, -(C1-C 12 ) alkylene.

[0101] In some embodiments, W is Sid, and Sid-COOH or Sid-OH is represented by R8-U1-R9; During the ceremony R8 is -NH-C(=O)-V; R9 is -COOH; U1 is -Q-NR8-Q-, V is TIFF2024532211000020.tif24128, R5 is Cl, and m is 0 or 1.

[0102] In some embodiments, W is represented by -C(=O)-U1-R8 or -NH-U1-R8; During the ceremony R8 is -NH-C(=O)-V; U1 is -Q-NR8-Q-, V is TIFF2024532211000021.tif24128, R5 is Cl, and m is 0 or 1.

[0103] In some embodiments, Sid is derived from a catecholate, hydroxamate, carboxylate, ferrichrome, deferoxamine, desferrioxamine, fusarinin C, ornibactin, rhodotruric acid, enterobactin, bacillibactin, vibriobactin, azotobactin, pyoverdin, yersiniabactin, aerobactin, simochelin, alcaligin, mycobactin, staphyloferrin A, or petrobactin. In some embodiments, Sid is selected from the group consisting of achromobactin, acinetobactin, acinetoferrin, aerobactin, aergic acid, agrobactin, agrobactin A, albomycin 271, alcaligin 230, alterobactin A, alterobactin B, aminochelin 262, amonabactin P693, amonabactin P750, amonabactin T732, amonabactin T789, amphibactin B, amphibactin C, amphibactin D, amphibactin E, amphibactin F, amphibactin G, amphibactin H, amphibactin I ... amphibactin D, amphibactin E, amphibactin F, amphibactin G, amphibactin H, amphibactin I, amycolachrome 235, anachelin 1, anachelin 2, anguibactin 247, aquachelin A, aquachelin B, aquachelin C, 2, aquachelin D, arthrobactin, arthrobactin 199, asperchrome A, asperchrome B1, asperchrome B2, asperchrome B3, asperchrome C, asperchrome D Asperchrome D1, asperchrome D2, asperchrome D3, asperchrome E, asperchrome F1, asperchrome F2, asperchrome F3, aspergillic acid, avenic acid, awaitin A, awaitin B, awaitin C, azotobactin 236, azotobactin D, azotobactin 87, azotochelin, azotochelin 236, azoverdin 174, basilibactin 85, basidiochrome 46, biscatechol, viscaverin 232, kale Ruboxymycobactin 107, Carboxymycobactin 1, Carboxymycobactin 2, Carboxymycobactin 3, Carboxymycobactin 4, Sepabactin 266, Chrysobactin 261, Citric acid 260, Coelichelin 72, 3, Coprogen 51, Coprogen B, Corynebactin 84, Danoxamine, Deoxydisticonic acid, 2'-Deoxymugineic acid, Deoxyschizokinen 251, Des(diserylglycyl)-ferrirhodin 45,Desferrioxamine A1, Desferrioxamine A2, Desferrioxamine B, Desferrioxamine D1, Desferrioxamine D2, Desferrioxamine E, Desferrioxamine Et1 21A, Desferrioxamine Et2 21B, Desferrioxamine Et3 21C, Desferrioxamine G1, Desferrioxamine G2A, Desferrioxamine G2B, Desferrioxamine G2C, Desferrioxamine H, Desferrioxamine P1, Desferrioxamine T1, Desferrioxamine T2, Desferrioxamine T3, Desferrioxamine T7, Desferrioxamine T8, Desferrioxamine Te1 21D, Desferrioxamine Te2 21E, Desferrioxamine Te3 21F, desferrioxamine X1, desferrioxamine X2, 4, desferrioxamine X3, desferrioxamine X4, desferrithiocin, diamine biscatechol, dihydrobenzolate, 2,3-dihydroxybenzoylserine, dimermic acid, dimethylcoprogen, dimethylneocoprogen I, dimethyltriornisine, disticonic acid, enantiorhizoferrin, enantiopiochelin, enterobactin, enterochelin, exochelin MN, exochelin MS, ferrichrome, ferrichrome A, ferrichrome C, ferricrysin, ferricrocin, ferrioxamine, ferrimycin A, ferrilosin, ferrirubin, ferrocin A, fimusbactin A, fluvibactin, formobactin, foroxymitin, fusari Nin A, Fusarinin B, Fusarinin C, Heterobactin A, Heterobactin B, Hydroxycopropene, Hydroxypyridone, Hydroxyisoneocoprogen I, 3-Hydroxymugineic acid, 5, Hydroxyneocoprogene I, Isoneocoprogen I, Isopyoverdine BTP1, Isopyoverdine 6.7, Isopyoverdine 7.13, Isopyoverdine 90-33, Isopyoverdine 90-44, Isopyoverdine 10.7, Isotriornisine, Ithoic acid, Reuchkelin A, Reuchkelin B, Reuchkelin C, Reuchkelin D, Reuchkelin E, Reuchkelin F, Maduraferin, Malonichrome, Marinobactin A, Marinobactin B, Marinobactin C, Marinobactin D1, Marinobactin D2, Marinobactin E, Micacocidin,Mugineic acid, mycobactin, mycobactin A, mycobactin Av, mycobactin F, mycobactin H, mycobactin J, mycobactin M, mycobactin N, 6, mycobactin NA, mycobactin P, mycobactin R, mycobactin S, mycobactin T, mycochelin, ω-N-acetyl-ω-N-hydroxyl-α-aminoalkane, ε-N-acetyl-ε-N-hydroxyl L-lysine, δ-N-acetyl-δ-N-hydroxyl L-ornithine, nannochelin A, nannochelin B, nannochelin C, neocoprogen I, necoprogen I, Ocoprogen II, neurosporin, nocobactin, nocobactin NA, ochrobactin A, ochrobactin B, ochrobactin C, ornibactin-C4, ornibactin-C6, ornibactin-C8, ornicorgatin, palmitoyl coprogen, parabactin, parabactin A, petrobactin, petrobactin disulfonate, petrobactin sulfonate, pistilarin, polyamine biscatechol, protochelin, pseudoalterobactin A, pseudoalterobactin B, pseudobactin 112, pseudobactin 589A, 7 , putrebactin, pyochelin, pyoverdine A214, pyoverdine BTP2, pyoverdine C, pyoverdine CHAO, pyoverdine D-TR133, pyoverdine E, pyoverdine GR, pyoverdine GM, pyoverdine I-III, pyoverdine P19, pyoverdine Pau, pyoverdine PL8, pyoverdine PVD, pyoverdine R', pyoverdine Thai, pyoverdine TII, pyoverdine 1, pyoverdine 11370, pyoverdine 13525, pyoverdine 1547, pyoverdine 17400, pyoverdine 18-1, pyoverdine Pyoverdine 19310, Pyoverdine 2192, Pyoverdine 2392, Pyoverdine 2461, Pyoverdine 2798, Pyoverdine 51W, Pyoverdine 9AW, Pyoverdine 90-51, Pyoverdine 95-275, Pyoverdine 96-312, Pyoverdine 96-318, Pyoverdine, Pyoverdine 6.1, Pyoverdine 6.2, Pyoverdine 6.3, Pyoverdine 6.4, Pyoverdine 6.5, Pyoverdine 6.6, Pyoverdine 6.8, Pyoverdine 7.1, Pyoverdine 7.2, Pyoverdine 7.3, Pyoverdine 7.4, Pyoverdine 7.5,Pyoverdine 7.6, Pyoverdine 7.7, Pyoverdine 7.8, Pyoverdine 7.9, Pyoverdine 7.10, Pyoverdine 7.11, Pyoverdine 7.12, Pyoverdine 7.14, Pyoverdine 7.15, Pyoverdine 7.16, Pyoverdine 7.17, Pyoverdine 7.18, Pyoverdine 7.19, Pyoverdine 8.1, Pyoverdine 8.2, Pyoverdine 8.3, Pyoverdine 8.4, Pyoverdine 8.5, Pyoverdine 8.6, Pyoverdine Pyoverdine 8.7, Pyoverdine 8.8, Pyoverdine 8.9, Pyoverdine 9.1, Pyoverdine 9.2, Pyoverdine 9.3, Pyoverdine 9.4, Pyoverdine 9.5, Pyoverdine 9.6, Pyoverdine 9.7, Pyoverdine 9.8, Pyoverdine 9.9, Pyoverdine 9.10, Pyoverdine 9.11, Pyoverdine 9.12, Pyoverdine 10.1, Pyoverdine 10.2, Pyoverdine 10.3, Pyoverdine 10.4, Pyoverdine 1 0.5, Pyoverdine 10.6, Pyoverdine 10.8, Pyoverdine 10.9, Pyoverdine 10.10, Pyoverdine 11.1, Pyoverdine 11.2, Pyoverdine 12, Pyoverdine 12.1, Pyoverdine 12.2, Pyoverdine (Pyoverdine), Pyridoxathin, Quinolobactin, Rhizobactin, 10, Rhizobactin, Rhizoferrin, Rhizoferrin analogues 88A-88E, Rhodotorulic acid, Salmochelin S1, Salmochelin S 2, salmochelin S4, salmochelin SX, salmycin A, schizokinen, serratiochelin, siderochelin A, sunocobactin A, sunocobactin B, sunocobactin C, staphyloferrin A, staphyloferrin B, tetraglycine ferrichrome, thiazostatin, triacetylfusarinin, tricatechol, triornisine, vibriobactin, vibrioferrin, vicibactin, varnibactin, or yersiniabactin. In some embodiments, the Sid is derived from aerobactin, agrobactin, arthrobactin, awaitin A, awaitin B, awaitin C, azotochelin, biscatechol, danoxamine, dihydrobenzolate, enterobactin, ferricrocin, ferrioxamine, fimusbactin A, foloximitin, hydroxypyridone, mycobactin, ω-N-acetyl-ω-N-hydroxyl-α-aminoalkane,Derived from ε-N-acetyl-ε-N-hydroxyl L-lysine, δ-N-acetyl-δ-N-hydroxyl L-ornithine, parabactin, pyoverdine, rhodotruric acid, schizokinen, or tricatechol.

[0104] Also provided herein is an invention directed to a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt or zwitterion thereof, and at least one pharma- ceutically acceptable carrier, diluent, or excipient.

[0105] In some embodiments, the compound of formula (I) is TIFF2024532211000022.tif159149TIFF2024532211000023.tif104140.

[0106] Further provided herein is a method of treating a bacterial infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt or zwitterion thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I).

[0107] In some embodiments, the bacterial infection is a gram-negative infection. In some embodiments, the bacterial infection is caused by Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumonia.

[0108] In some embodiments, the subject is a human subject. In some embodiments, the subject is an animal subject. In some embodiments, the subject is a mammalian subject.

[0109] In some embodiments, the method of treating a bacterial infection further comprises administering an effective amount of an additional antibiotic agent. In some embodiments, the additional antibiotic compound is penicillin, methicillin, oxacillin, nafcillin, cloxacillin, dicloxacillin, flucloxacillin, temocillin, amoxicillin, ampicillin, co-amoxiclav, azlocillin, carbenicillin, ticarcillin, mezlocillin, piperacillin, cephalexin, cephalothin, CXA-101, cefazolin, cefaclor, cefuroxime, cefamandole, cefotetan, cefoxitin, ceftriaxone, cefotaxime, cefpodoxime, cefixime, ceftazidime, ceftobiprole medcaril, cefepime, cefpirome, ceftaroline, imipenem, meropenem, ertapenem, faropenem, sulopenem, doripenem, PZ-601 (Protez Pharmaceuticals), ME1036 (Forest Labs), BAL30072, MC-1, tomopenem, tebipenem, aztreonam, tigemonam, nocardicin A, or tabtoxinine-β-lactam.

[0110] In some embodiments, the bacterial infection is resistant to one or more antibiotics.

[0111] In some embodiments, the bacterial infection causes a disease selected from the group consisting of a urinary tract infection, pneumonia, prostatitis, skin and soft tissue infections, sepsis, and intraperitoneal infections.

[0112] Further provided herein is an invention directed to a process for preparing a compound of formula (I), or a pharma- ceutically acceptable salt or zwitterion thereof, comprising: Compound of formula (I'-1) TIFF2024532211000024.tif36128 is a compound of formula (II'-1) or formula (II'-2) R8-U1-NH2(II'-1), or R8-U1-L'-NH2(II'-2) under suitable conditions to produce a compound having the formula (I) generating TIFF2024532211000025.tif35128, During the ceremony G is -OR A , -OCH2C(=O)X, OCHRC(=O)X, -C(=O)X, -S(=O)2X, -OS(=O)2X, -C(=O)NH-S(=O)2G', P(=O)X or -P(=O)X, G' is OR A , -OCH2C(=O)X, OCHRC(=O)X, -C(=O)X, -S(=O)2X, -OS(=O)2X, P(=O)X or -P(=O)X, X is H, -OR A or -N(R A )2, R1 is H or optionally substituted with X or Z -(C1-C 12 ) alkyl, Z is R A , -OR A , -SR A , -C(=O)N(R A )2, or -N(R A )2, R 2a -CH2C(=O)OH, -CHR 4 C(=O)OH, -C(R 4 )2C(=O)OH, or -C(R 4 )2C(=O)NHOCH2C(=O)OH, -C(R 4 )2C(=O)NHOC(R 4 )C(=O)OH, R2 is -CH2C(=O)W', -CHR 4 C(=O)W', -C(R 4 )2C(=O)W', -C(R 4 )2C(=O)NHOCH2C(=O)W', -C(R 4 )2C(=O)NHOCH2C(=O)OH, -C(R 4 )2C(=O)NHOC(R 4 )2C(=O)OH, or -C(R 4 )2C(=O)NHOC(R4 )2C(=O)W', R3 is H, Z, or R 4 and Each R 4 are independently H, Z, -(C1-C 12 )alkyl, -(C3-C8)cycloalkyl, -(C3-C6)heterocycloalkyl, or -(C1-C8)N(R A )R B or two R 4 together with the carbon atom to which they are both attached form -(C3-C8)cycloalkyl or -(C3-C6)heterocycloalkyl; Each R A are independently H, -(C1-C 12 )alkyl, -(C3-C8)cycloalkyl, phenyl, aryl, or heteroaryl; R B is H, -(C1-C 12 ) alkyl, -(C3-C8) cycloalkyl, or phenyl; Each R 4 are independently H, Z, -(C1-C 12 )alkyl, -(C3-C8)cycloalkyl, -(C3-C6)heterocycloalkyl, or -(C1-C8)N(R A )R B and Each R A are independently H, -(C1-C 12 )alkyl, -(C3-C8)cycloalkyl, phenyl, aryl, or heteroaryl; R B is H, -(C1-C 12 ) alkyl, -(C3-C8) cycloalkyl, or phenyl; W' is -NH-U1-R8 or -NH-L'-U1- R8, L' is -QC(=O)O-, -C(=O)-QC(=O)O-, -C(=O)-Q-, -C(=O)OQ-, -C(=O)-QC(=O)-, -OQ-, -Q-, -Q-NH-, -QO-, or a combination thereof; Each Q is independently -OH, -COOH, =O, -NH2, -(C1-C 12 ) alkyl, -(C1-C 12 ) alkenyl, -(C1-C 12 ) alkylene-OH, -(C1-C 12 ) alkylene-NH2, -NH-(C1-C 12 ) alkylene-COOH, -NH-C(=O)-(C1-C 12 ) alkylene-COOH, -C(=O)-(C1-C 12 ) alkylene-C(=O)-NH2, -O-(C1-C 12 ) alkylene-OH, -NH-(C1-C 12 ) alkylene-NH2, and -NH-(C1-C 12 ) alkylene-OH, -(C 12 ) alkylene; U1 is a covalent bond or an optionally substituted -Q-, -C(=O)-, -OC(=O)-, -CHR8-, -CR 10 R8-, -C(=O)-NH-, -C(=O)-NR8-, -C(=O)-N(OH)-, -NH-, -NR8-, -NR 10 -, -NH-CHR8-C(=O)-, -R 11 - or a combination thereof, Each R8 is independently H, -OH, -COOH, -NH2, -Q-OH, -V, -QV, -NH-C(=O)-V, -Q-NH-C(=O)-V, -NR 10 -C(=O)-V, -NR 10 -V, -C(=O)-V, -OC(=O)-V, -C(=O)-R 11 -V, -NH-C(=O)-R 11 -V, -C(=O)-R 11 -aryl, or L'-H; R 10 is -NH-C(O)-Q-COOH, -C(O)-Q-COOH, -Q-COOH, or -COOH; R 11is an optionally substituted ring selected from phenyl, 3- to 7-membered saturated or partially unsaturated carbocyclyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O and S, and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S; V is -N(OH)-C(=O)-NH2, -N(OH)-C(=O)H, N(OH)-C(=O)-L', -N(OH)-C(=O)-(C1-C 12 ) alkyl, -N(OH)-C(=O)-(C1-C 12 ) alkenyl, -N(OH)-C(=O)-Q-OH, -N(OH)-C(=O)-Q-COOH, TIFF2024532211000026.tif90128, m is an integer selected from 0 to 3; n is an integer selected from 0 to 10; Each R5 is independently -(C1-C 12 ) alkyl, halogen, -OH, -COOH, -NH2, -L'-H, or -C(=O)-L'-H; and R6 and R7 are independently H, -COOH, or -OR A It is.

[0113] In some embodiments, the process for preparing a compound of formula (I) comprises coupling a compound of (I'-1) with a compound of formula (II'-1) or formula (II'-2) to produce a compound of formula (I).

[0114] In some embodiments, the process for preparing a compound of formula (I) comprises coupling at room temperature.

[0115] In some embodiments, the process for preparing a compound of formula (I) comprises coupling, comprising contacting a compound of (I'-1) and a compound of formula (II'-1) or formula (II'-2) with a coupling reagent.

[0116] In some embodiments, the process for preparing a compound of formula (I) comprises the steps of: (a) combining a compound of formula (I'-1) in a solvent with a coupling reagent; (b) stirring to obtain a solution; (c) combining a compound of formula (II'-1) or (II'-2) in a solvent with the solution of step (b), and optionally adding additional coupling reagent; (d) stirring, and (e) Removing the solvent to obtain a compound of formula (I).

[0117] In some embodiments of the process for preparing a compound of formula (I) above, the stirring in step (b) or step (d) is performed at room temperature. In some embodiments, step (e) comprises evaporation under reduced pressure. In some embodiments, the solvent in step (a) or step (c) is water, tetrahydrofuran (THF), dimethylformamide (DMF), or a mixture thereof.

[0118] In some embodiments, the process for preparing a compound of formula (I) comprises the steps of: (a) mixing a compound of formula (I'-1) and a compound of formula (II'-1) or formula (II'-2) in a solvent to form a solution; (b) maintaining or adjusting the pH of the solution; (c) dissolving a coupling reagent in a solvent; and (d) mixing the solution of step (c) and the solution of step (b) while maintaining or adjusting the pH of the solutions; and (e) obtaining a compound of formula (I).

[0119] In some embodiments of the process for preparing a compound of formula (I) above, the pH of the solution in step (b) or step (d) is about 4.5. In some embodiments, the coupling reagent is HBTU, DIPEA, N-hydroxysuccinimide, EDC·HCl, or a mixture thereof. In some embodiments, the coupling reagent is HBTU, DIPEA, N-hydroxysuccinimide, EDC·HCl, or a mixture thereof.

[0120] In some embodiments, the process for preparing a compound of formula (I) comprises contacting a compound of formula (I'-1), wherein in the compound of formula (I'-1), G is S(=O)2OH.

[0121] In some embodiments, the process for preparing a compound of formula (I) comprises contacting a compound of formula (I'-1), wherein in the compound of formula (I'-1), R1 is -(C1-C 12 ) alkyl. In some embodiments, R1 is -CH3.

[0122] In some embodiments, the process for preparing a compound of formula (I) comprises contacting a compound of formula (I'-1) with a compound of formula (II'-1) or formula (II'-2), wherein in the compound of formula (II'-1) or formula (II'-2), V is The file is TIFF2024532211000027.tif24128.

[0123] In some embodiments, the process for preparing a compound of formula (I) comprises contacting a compound of formula (I'-1) with a compound of formula (II'-1) or formula (II'-2), where in the compound of formula (II'-1) or formula (II'-2), L'-NH2 is -NH-Q-NH2 or -QO-NH2, or a combination thereof. In some embodiments, L'-NH2 is -NH-CH2CH2-NH2, -CH2CH2-ONH2, -C(=O)CH2-ONH2, or a combination thereof.

[0124] In some embodiments, the process for preparing a compound of formula (I) comprises contacting a compound of formula (I'-1) with a compound of formula (II'-1) or formula (II'-2), wherein in the compound of formula (II'-1) or formula (II'-2), R8 is -NH-C(=O)-V.

[0125] In some embodiments, the process for preparing a compound of formula (I) comprises contacting a compound of formula (I'-1) with a compound of formula (II'-1) or formula (II'-2), wherein in the compound of formula (II'-1) or formula (II'-2), U1 is -Q-NR8-Q-, and each Q is independently optionally substituted with one or more selected from the group consisting of -OH, -COOH, =O, and -NH2, -(C1-C 12 ) alkylene.

[0126] In some embodiments, the process for preparing a compound of formula (I) comprises contacting a compound of formula (I'-1) with a compound of formula (II'-1) or formula (II'-2), wherein in the compound of formula (II'-1) or formula (II'-2): R8 is -NH-C(=O)-V and U1 is -Q-NR8-Q- V is TIFF2024532211000028.tif24128, R5 is Cl, and m is 0 or 1.

[0127] In some embodiments, the process for preparing a compound of formula (I) comprises contacting a compound of formula (I'-1) with a compound of formula (II'-1) or formula (II'-2), wherein the compound of formula (I) is In some embodiments, formula (I) is represented by TIFF2024532211000029.tif50128. In some embodiments, formula (I) is represented by TIFF2024532211000030.tif49128. Represented as TIFF2024532211000031.tif48128.

[0128] In some embodiments, the process for preparing a compound of formula (I) comprises contacting a compound of formula (I'-1), wherein formula (I'-1) is Represented as TIFF2024532211000032.tif54128.

[0129] In some embodiments, the process for preparing a compound of formula (I) comprises contacting a compound of formula (I'-1), wherein formula (I'-1) is a compound of formula (I'-2): Represented as TIFF2024532211000033.tif49128.

[0130] In some embodiments, formula (I'-1) is represented by formula (I'-3): Represented as TIFF2024532211000034.tif49128.

[0131] In some embodiments, Formula (II'-1) or Formula (II'-2) is TIFF2024532211000035.tif48128TIFF2024532211000036.tif98128.

[0132] The compounds described herein may be shown with a specific stereochemistry around certain atoms, such as cis or trans, but the compounds can also be made in the opposite orientation or racemic mixture.Such isomers or racemic mixtures are encompassed by this disclosure.In addition, the compounds are summarized in a table, but any compound or its pharmaceutically acceptable salt can be selected from the table and used in the embodiments provided herein.

[0133] In some embodiments, a pharmaceutical composition is provided comprising any compound described herein, or a pharma- ceutically acceptable salt thereof.

[0134] The compounds described herein can be prepared according to the methods described herein and in the examples.The methods described herein can be adapted based on the compounds desired and described herein.In some embodiments, the methods can be used to prepare one or more compounds described herein, and it will be clear to those skilled in the art which compounds can be prepared according to the methods described herein.

[0135] Conditions and temperatures can be varied as shown in the examples described herein. These schemes are non-limiting synthetic schemes, and the synthetic routes can be modified as would be apparent to one skilled in the art upon reading the present specification. Compounds can also be prepared according to the schemes described in the examples.

[0136] Although the compounds in the Tables or Examples section above are shown with a particular stereochemistry around certain atoms, e.g., cis or trans, the compounds can also be made in the opposite orientation or as racemic mixtures.

[0137] In some embodiments, the present aspects provide a pharmaceutical composition comprising any compound described herein, or a pharmaceutical salt thereof.

[0138] In some embodiments, the compounds are made according to the schemes described in the Examples. The schemes can be used to prepare the compounds and compositions described herein. Conditions and temperatures can be varied, or the synthesis can be performed according to the Examples described herein, with readily apparent modifications based on the compound being synthesized.

[0139] Conditions and temperatures can be varied as shown in the examples described herein. These schemes are non-limiting synthetic schemes, and the synthetic routes can be modified as would be apparent to one of skill in the art upon reading this specification.

[0140] The present disclosure also provides the following non-limiting aspects.

[0141] In order to more efficiently understand the embodiments disclosed herein, examples are provided below. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the embodiments in any manner.

[0142] The following examples are illustrative, but not limiting, of the processes described herein. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered in the therapeutic, synthetic, and other embodiments disclosed herein are within the spirit and scope of the embodiments. EXAMPLES

[0143] New conjugates (27 and 30) were synthesized by linking a bis-catechol siderophore directly to the side chain aminothiazoloxime (ATMO) carboxylic acid of commercially available aztreonam (9a). Another new conjugate, hydroxamic acid (32), was also synthesized derived from aminooxyacetic acid. A new conjugate corresponding to the bis-catechol conjugate (30) was also synthesized. The bis-catechol antibiotic conjugates (13–15) were active, indicating that bis-catechols enhance uptake by Gram-negative bacteria that are normally MDR-resistant. SQ83,280 (20) and BAL30072 (22), which do not contain free carboxylic acids, retained potent in vitro activity. Hydroxamic acids (pKa approx. 8.5–9.5) are less acidic than carboxylic acids. The activity of derivative 32 was compared with aztreonam and the corresponding amide (27) and hydroxamic acid (30) conjugates. The synthesis offers a simple and advantageous route, requiring only the coupling of readily available derivatives of siderophore mimetics (26 and 29) with commercially available aztreonam (9a).

[0144] In some embodiments, examples of siderophore moieties include, but are not limited to, those shown below and further described in Hider, RC, and Kong, XL Chemistry and biology of siderophores. Nat. Prod. Rep. 2010, 27, 637-657.

[0145] Representative siderophores, analogs and mimetics (Figure 5a-d) include, but are not limited to, hydroxamic acids, catechols, α-hydroxy acids, oxazolines, oxazoles, and hydroxypyridines.

[0146] Example 1. Synthesis of new conjugates Schemes 2a and 2b provide synthetic routes to both dihydroxybenzoate biscatechol conjugates and chlorodihydroxybenzoate biscatechol conjugates, respectively. For the dihydroxybenzoate conjugates, the chemistry began with the reaction of ethane 1,2-diamine with CbzCl to give the mono-Cbz-protected diamine 24. Formation of the active ester of tetrabenzyl bis-catechol (25) afforded the siderophore derivative (26) with an amine suitable for coupling with aztreonam (9a) to give conjugate 27. Alternatively, prior coupling of the siderophore amine 26 with Boc-protected aminooxyacetic acid (28) afforded the hydroxylamine 29. Treatment of an aqueous solution of hydroxylamine 29 and aztreonam (9a) with EDC in aqueous THF at pH 4.5 afforded the final conjugate with a hydroxamate linkage, 30. The control aminooxyacetic acid derivative 32 was prepared by EDC / NHS activation of aztreonam followed by reaction with aminooxyacetic acid (31). For the chlorodihydroxybenzoate conjugate, the protected biscatechol methyl ester 33 was first saponified to give the free acid 34. This free acid was coupled to diamine 24 to give the protected chlorodihydroxybenzoate (35) with a Cbz protected linker. Complete hydrogenolysis deprotection gave the free amine 36, which was then coupled with aztreonam (9a) to give the final conjugate (37).

[0147] Scheme 2a. Synthesis of dihydroxybenzoate biscatechol conjugates TIFF2024532211000037.tif114163TIFF2024532211000038.tif163161

[0148] Scheme 2b. Synthesis of chlorodihydroxybenzoate biscatechol conjugates TIFF2024532211000039.tif215166

[0149] Example 2. Antibacterial Assay Antibacterial assay results of the new aztreonam derivatives (27, 30, 32, and 37), aztreonam (9a), and previous data for conjugate 23 are shown in Table 1. Assays were performed as previously described using iron-deficient medium suitable for screening siderophore conjugates. The aminooxyacetic acid derivative 32 showed activity comparable to aztreonam (9a) itself. As expected, none of the compounds showed activity against Gram-positive S. aureus. However, conjugates (27, 30, and 37) showed remarkable and unexpected activity against Gram-negative bacteria resistant to aztreonam. Of particular interest is the remarkable inhibitory activity against problematic strains of A. baumannii and P. aeruginosa, including cephalosporinase- and carbapenemase-producing strains (A. baumannii TCC 17978 pNT320 and ATCC 17978 pNT165, respectively), which are on the World Health Organization (WHO) list of multidrug-resistant (MDR) pathogens of greatest concern. Notably, the activity of the new conjugates (27, 30, and 37) was comparable to or even exceeded that of the previously described, more synthetically complex biscatechol conjugate 23.

[0150] (Table 1) Duplicate in vitro antibacterial assay results of new compounds 27, 30, 32 and 37 compared with aztreonam (9a) and the biscatechol monobactam derivative 23. TIFF2024532211000040.tif107165TIFF2024532211000041.tif156165 a Cephalosporinase-producing strains b Carbapenemase-producing strains NT = Not Tested

[0151] The above example demonstrated the direct coupling of a siderophore-like compound to the free carboxylic acid of the commercially available monobactam, aztreonam (9a). The present invention provides a rapid method to obtain conjugates with significantly enhanced antibacterial activity, including activity against MDR strains.

[0152] Example 3. Detailed Description of Synthesis 3.1 Methods and Materials Unless otherwise stated, all solvents and reagents were obtained from commercial sources and used without further purification. Silica gel (230-400 mesh) was purchased from Silicycle, Quebec City, Canada. All compounds were >98% pure by HPLC analysis. All compounds were analyzed for purity by HPLC and analyzed using a Bruker 500 MHz NMR spectrometer. 1 H and 13 The compounds were characterized by C NMR. Mass spectral values ​​are reported as m / z, and HRMS analysis was performed using a Bruker MicroOTOF-Q II, electrospray ionization time-of-flight mass spectrometer. Liquid chromatography mass spectrometry (LC / MS) analysis was performed on a Waters ZQ instrument consisting of a chromatography module Alliance HT, a photodiode array detector 2996, and a mass spectrometer Micromass ZQ, using a 3 × 50 mm Pro C18 YMC reversed-phase column. Mobile phase: 10 mM ammonium acetate in HPLC grade water (A) and HPLC grade acetonitrile (B). The gradient was formed from 5% to 80% B in 10 min at 0.7 mL / min. The MS electrospray source was operated at a capillary voltage of 3.5 kV and a desolvation temperature of 300 °C.

[0153] 3.2 (2-Aminoethyl)carbamic acid benzyl ester (24) A solution of benzyl chloroformate (1.3 mL, 9 mmol) in anhydrous DCM (25 mL) was added to a solution of ethylenediamine (6 mL, 90 mmol) in anhydrous DCM (90 mL) at 0° C. under argon atmosphere over 1.5 h. The mixture was stirred at 0° C. for 2 h and then washed with brine (30 mL×3). The DCM layer was dried over Na2SO4 and concentrated under reduced pressure. Compound 24 was obtained as a white solid and used directly in the next step without purification.

[0154] 3.3 N-(2-((2-aminoethyl)amino)-2-oxoethyl)-N-(4-(2,3-dihydroxybenzamido)butyl)-2,3-dihydroxybenzamide (26) To a solution of compound 25 (1 mmol, 779 mg) in 10 mL of anhydrous DMF was added N-hydroxysuccinimide (1.5 mmol, 172 mg) and EDC.HCl (2 mmol, 382 mg). The mixture was stirred at room temperature and monitored by TLC. Once starting material 25 was completely consumed, compound 24 (1.2 mmol, 233 mg) was added to the reaction mixture, stirred for several hours and monitored by LC / MS. Once the reaction was complete, the solution was diluted with H2O and extracted with EtOAc (30 mL x 3). The EtOAc layers were combined, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM and 2-propanol (100:3) to give benzyl (2-(2-(2,3-bis(benzyloxy)-N-(4-(2,3-bis(benzyloxy)benzamido)butyl)benzamido)acetamido)ethyl)carbamate as a colorless oil in 79% yield (753 mg, 0.79 mmol). TIFF2024532211000042.tif27166

[0155] To a solution of (2-(2-(2,3-bis(benzyloxy)-N-(4-(2,3-bis(benzyloxy)benzamido)butyl)benzamido)acetamido)ethyl)benzylcarbamate (0.5 mmol, 477 mg) in 15 mL of MeOH was added 10% Pd / C (47 mg, 10% by weight of oil) under argon atmosphere. The reaction flask was degassed and then back-filled with H2 via a balloon. After stirring overnight, the reaction was complete, therefore the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give compound 26 as a pale purple solid in 76% yield, which was used directly in the next step without purification.

[0156] 3.4 (2S,3S)-3-((Z)-18-(2-aminothiazol-4-yl)-7-(2,3-dihydroxybenzoyl)-1-(2,3-dihydroxy-phenyl)-15,15-dimethyl-1,9,14-trioxo-16-oxa-2,7,10,13,17-pentaazanonadec-17-en-19-amido)-2-methyl-4-oxoazetidine-1-sulfonic acid (27) To a solution of aztreonam (9a, 0.5 mmol, 217 mg) in 10 mL of DMF was added HBTU (0.76 mmol, 288 mg) and DIPEA (2 mmol, 348 μL). The mixture was stirred at room temperature for 10 min. Compound 26 (0.5 mmol, 230 mg) in 2 mL of DMF was then added to the above reaction mixture. The solution was stirred overnight and monitored by LC / MS. Upon completion of the reaction, the solvent was removed under reduced pressure evaporation and the residue was purified by preparative HPLC to give compound 27 as a white solid in 18.3% yield (80 mg, 0.09 mmol). TIFF2024532211000043.tif56166

[0157] 3.5 2-(((tert-butoxycarbonyl)amino)oxy)acetic acid (28) To a round bottom flask was added carboxymethoxylamine hemihydrochloride (31, 2 mmol, 220 mg) in 15 mL of anhydrous DCM. The solution was cooled to 0° C. and Et3N (6 mmol, 424 μL) was added. To the mixture was added a solution of (Boc)2O (3 mmol, 1.3 g) in 10 mL of DCM. The reaction mixture was stirred at 0° C. for 30 min and then warmed to room temperature. Upon completion of the reaction, the solution was washed with water. The aqueous portion was extracted with 20 mL of EtOAc, which was discarded. The pH value of the aqueous portion was then adjusted to 3.5 with 1N HCl and extracted with EtOAc (30 mL×3 times). The EtOAc layers were combined and concentrated under reduced pressure to give compound 28 as a white solid, which was used directly without purification.

[0158] 3.6 N-(2-((2-(2-(aminooxy)acetamido)ethyl)amino)-2-oxoethyl)-N-(4-(2,3-dihydroxy-benzamido)butyl)-2,3-dihydroxybenzamide (29) To a solution of 28 (0.98 mmol, 187 mg) in DMF (5 mL), HBTU (1.34 mmol, 505 mg) and DIPEA (3.56 mmol, 656 μL) were added and the mixture was stirred at room temperature for 10 min. Then, compound 26 (409 mg, 0.89 mmol) in DMF (2 mL) was added to the above solution and the reaction was continued overnight. Upon completion of the reaction, the solvent was removed by evaporation under reduced pressure and the residue was purified by silica gel column chromatography eluting with DCM and MeOH (20:1) to give tert-butyl ((7-(2,3-dihydroxybenzoyl)-1-(2,3-dihydroxyphenyl)-1,9,14-trioxo-2,7,10,13-tetraazapentadecan-15-yl)oxy)carbamate as a pale yellow solid in 45% yield (170 mg, 0.27 mmol). TIFF2024532211000044.tif27165

[0159] tert-Butyl ((7-(2,3-dihydroxybenzoyl)-1-(2,3-dihydroxyphenyl)-1,9,14-trioxo-2,7,10,13-tetraazapentadecan-15-yl)oxy)carbamate (80 mg, 0.13 mmol) was dissolved in 15 mL of anhydrous DCM, followed by the addition of 1 mL of TFA. The mixture was stirred at room temperature and monitored by LC / MS. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure to give compound 29, which was used directly in the next step without further purification.

[0160] 3.7 (2S,3S)-3-((Z)-22-(2-aminothiazol-4-yl)-7-(2,3-dihydroxybenzoyl)-1-(2,3-dihydroxyphenyl)-19,19-dimethyl-1,9,14,18-tetraoxo-16,20-dioxa-2,7,10,13,17,21-hexaazatricho-21-en-23-amido)-2-methyl-4-oxoazetidine-1-sulfonic acid (30) Compound 29 (67 mg, 0.12 mmol) and aztreonam (9a, 156 mg, 0.36 mmol) were dissolved in HO / THF (2 mL / 2 mL) to obtain a solution. The pH value of the solution was adjusted to 4.5 by adding NaOH (1N). EDC.HCl (46 mg, 0.24 mmol) was dissolved in 2 mL of HO and then added slowly to the above mixture while maintaining the pH value at 4.5 by adding HCl (1N). If the pH did not change during the addition of EDC.HCl, the reaction was complete, as confirmed by LC / MS. The resulting solution was directly purified by preparative HPLC without any workup. Compound 30 was obtained as a white solid in 35% yield (40 mg, 0.04 mmol). TIFF2024532211000045.tif77166

[0161] 3.8 (Z)-2-(2-aminothiazol-4-yl)-5,5-dimethyl-1-(((2S,3S)-2-methyl-4-oxo-1-sulfoazetidin-3-yl)amino)-1,6-dioxo-4,8-dioxa-3,7-diazadec-2-en-10-oic acid DIPEA salt (32) To a solution of aztreonam (9a, 0.3 mmol, 130 mg) in 4 mL of DMF was added N-hydroxysuccinimide (1.2 mmol, 138 mg) and EDC.HCl (1.5 mmol, 287 mg). The reaction mixture was stirred at room temperature and monitored by LC / MS. Once LC / MS showed complete conversion of aztreonam to NHS active ester, carboxymethoxylamine hemihydrochloride (31, 3 mmol, 327 mg) was added to the reaction solution followed by DIPEA (6 mmol, 1.1 mL). The reaction mixture was kept stirring at room temperature for several hours and monitored by LC / MS. Once the reaction was complete, the solution was concentrated by evaporation under reduced pressure and the residue was purified by preparative HPLC. Compound 32 was obtained as a colorless oil in 75% yield (115 mg, 0.23 mmol). TIFF2024532211000046.tif41165

[0162] 3.9 N-(4-(3,4-bis(benzyloxy)-2-chlorobenzamido)butyl)-N-(3,4-bis(benzyloxy)-2-chlorobenzoyl)glycine (34) To a solution of 33 (2 mmol, 1.72 g) in THF / H2O (10 mL / 5 mL), NaOH (2.8 mmol, 112 mg) was added. The mixture was stirred at room temperature for 3 h. When 33 was completely consumed, 1N HCl was added to adjust the pH value to 5. The solution was extracted with EtOAc (30 mL x 3), and the organic layer was dried over Na2SO4 and concentrated under reduced pressure evaporation. The product 34 was obtained as a yellow solid (1.56 g, 92% yield) and was used directly in the next step reaction without further purification.

[0163] 3.10 (2-(2-(3,4-bis(benzyloxy)-N-(4-(3,4-bis(benzyloxy)-2-chlorobenzamido)butyl)-2-chlorobenzamido)acetamido)ethyl)benzylcarbamate (35) To a solution of 34 (1.84 mmol, 1.56 g) in anhydrous DMF (20 mL) was added N-hydroxysuccinimide (2.76 mmol, 317 mg) and EDC.HCl (3.68 mmol, 705 mg). The mixture was stirred at room temperature for 3 h and monitored by LC / MS. Once 34 was completely consumed, (2-aminoethyl)benzylcarbamate (2 mmol, 388 mg) and DIPEA (4 mmol, 736 mg) were added to the reaction mixture. The mixture was stirred overnight and monitored by LC / MS. Once the reaction was complete, the solvent was concentrated by evaporation under reduced pressure. The residue was purified by silica gel chromatography to give 35 as a white solid (1.53 g, 81% yield). TIFF2024532211000047.tif27165

[0164] 3.11 N-(2-((2-aminoethyl)amino)-2-oxoethyl)-2-chloro-N-(4-(2-chloro-3,4-dihydroxybenzamido)butyl)-3,4-dihydroxybenzamide (36) To 35 (120 mg, 0.12 mmol) in 20 mL of MeOH was added 10% Pd / C (24 mg, 10% by weight of 35) under an argon atmosphere. The reaction flask was degassed and then back-filled with H2 via a balloon. After stirring overnight, the reaction was complete, therefore the reaction mixture was filtered and the filtrate was concentrated under reduced pressure evaporation to give 36 as a colorless oil, which was used directly in the next step without purification.

[0165] 3.12 2S,3S)-3-((Z)-18-(2-aminothiazol-4-yl)-7-(2-chloro-3,4-dihydroxybenzoyl)-1-(2-chloro-3,4-dihydroxyphenyl)-15,15-dimethyl-1,9,14-trioxo-16-oxa-2,7,10,13,17-pentaazanonadec-17-ene-19-amido)-2-methyl-4-oxoazetidine-1-sulfonic acid (37) To a solution of aztreonam (9a, 68 mg, 0.13 mmol) in 6 mL of DMF was added HBTU (0.17 mmol, 63 mg) and DIPEA (0.44 mmol, 81 μL). The mixture was stirred at room temperature for 10 min. Then 36 (0.11 mmol, 53 mg) in 2 mL of DMF was added to the above reaction mixture. The solution was stirred overnight and monitored by LC / MS. Upon completion of the reaction, the solvent was removed under reduced pressure evaporation and the residue was purified by preparative HPLC to give 37a as an off-white solid in 63.5% yield (66 mg, 0.069 mmol). TIFF2024532211000048.tif27166

[0166] References All subject matter contained in the above description or defined in the appended claims is intended to be interpreted as illustrative and exemplary of the present invention, since various modifications may be made to the subject matter described below without departing from the scope and spirit of the present invention. Many modifications and variations of the present invention are possible in light of the above teachings. Accordingly, the present description is intended to embrace all such alternatives, modifications, and variations that fall within the scope of the appended claims. All patents, applications, publications, test methods, literature, and other materials cited in this specification are incorporated herein by reference in their entirety, as if physically present in this specification. TIFF2024532211000049.tif77164TIFF2024532211000050.tif216165TIFF20245322110 00051.tif223165TIFF2024532211000052.tif216165TIFF2024532211000053.tif120163

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt or zwitterion thereof: During the ceremony G is -OR A , -OCH 2 C(=O)X, OCHRC(=O)X, -C(=O)X, -S(=O) 2 X, -OS(=O) 2 X, -C(=O)NH-S(=O) 2 G', P(=O)X or -P(=O)X; G' is OR A , -OCH 2 C(=O)X, OCHRC(=O)X, -C(=O)X, -S(=O) 2 X, -OS(=O) 2 X, P(=O)X or -P(=O)X, X is H, -OR A or -N(R A ) 2 and R 1 is H or optionally substituted with X or Z -(C 1 -C 12 ) alkyl, Z is R A , -OR A , -SR A , -C(=O)N(R A ) 2 , or -N(R A ) 2 and R 2 は-CH 2 C(=O)W、-QC(=O)W、-CHR 4 C(=O)W、-C(R 4 ) 2 C(=O)W、-C(R 4 ) 2 C(=O)NHOCH 2 C(=O)W、-QC(=O)NHO-QC(=O)W、-QC(=O)NHO-QC(=O)OH、-C(R 4 ) 2 C(=O)NHOCH 2 C(=O)OH、-C(R 4 ) 2 C(=O)NHOC(R 4 ) 2 C(=O)OH、または-C(R 4 ) 2 C(=O)NHOC(R 4 ) 2 C(=O)Wであり、 R 3 is H, Z, or R 4 and Each R 4 are independently H, Z, -(C 1 -C 12 ) alkyl, -(C 3 -C 8 ) cycloalkyl, -(C 3 -C 6 ) heterocycloalkyl, or -(C 1 -C 8 )N(R A )R B or two R 4 together with the carbon atom to which they are both attached, -(C 3 -C 8 ) cycloalkyl or -(C 3 -C 6 ) forming a heterocycloalkyl, Each R A are independently H, -(C 1 -C 12 ) alkyl, -(C 3 -C 8 ) cycloalkyl, phenyl, aryl, or heteroaryl; R B is H, -(C 1 -C 12 ) alkyl, -(C 3 -C 8 ) cycloalkyl, or phenyl; W is Sid or linker-Sid; Sid is the siderophore moiety, the linker is -NH-QC(=O)O-, -NH-C(=O)-QC(=O)O-, -C(=O)-Q-, -C(=O)OQ-, -C(=O)-QC(=O)-NH-, -OQO-, -OQ-, -NH-Q-, -NH-Q-NH-, -NH-QO-, -NH-OQ-, or a combination thereof; Each Q is independently -OH, -COOH, ═O, or -NH 2 , -(C 1 -C 12 ) alkyl, -(C 1 -C 12 ) alkenyl, -(C 1 -C 12 ) alkylene-OH, -(C 1 -C 12 )Alkylene-NH 2 , -NH-(C 1 -C 12 ) alkylene-COOH, -NH-C(=O)-(C 1 -C 12 ) alkylene-COOH, -C(=O)-(C 1 -C 12 )Alkylene-C(=O)-NH 2 , -O-(C 1 -C 12 ) alkylene-OH, -NH-(C 1 -C 12 )Alkylene-NH 2 , and -NH-(C 1 -C 12 ) alkylene-OH, -(C 1 -C 12 ) alkylene.

2. Sid-OH, Sid-NH 2 , Sid-COOH, or -linker-Sid is represented by formula (II), R 8 -U 1 -R 9 (II) During the ceremony U 1 is a covalent bond or optionally substituted -Q-, -C(=O)-, -OC(=O)-, -CHR 8 -, -CR 10 R 8 -, -C(=O)-NH-, -C(=O)-NR 8 -, -C(=O)-N(OH)-, -NH-, -NR 8 -, -NR 10 -, -NH-CHR 8 -C(=O)-, -R 11 - or a combination thereof, Each R 8 are independently H, -OH, -COOH, and -NH 2 , -Q-OH, -V, -QV, -NH-C(=O)-V, -Q-NH-C(=O)-V, -NR 10 -C(=O)-V, -NR 10 -V, -C(=O)-V, -OC(=O)-V, -C(=O)-R 11 -V, -NH-C(=O)-R 11 -V, -C(=O)-R 11 -aryl, or linker-H; R 9 H, -OH, -COOH, -NH 2 , -Q-OH, -V, -QV, -NH-C(=O)-V, -Q-NH-C(=O)-V, -NR 10 -C(=O)-V, -NR 10 -V, -C(=O)-V, -OC(=O)-V, -C(=O)-R 11 -V, -NH-C(=O)-R 11 -V, -C(=O)-R 11 -aryl, or linker-H, or R 8 and R 9 and are covalently bonded together to form a ring, R 10 is -NH-C(O)-Q-COOH, -C(O)-Q-COOH, -Q-COOH, or -COOH; R 11 is an optionally substituted ring selected from phenyl, 3- to 7-membered saturated or partially unsaturated carbocyclyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O and S, and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S; V is -N(OH)-C(=O)-NH 2 , -N(OH)-C(=O)H, -N(OH)-C(=O)-linker, -N(OH)-C(=O)-(C 1 -C 12 ) alkyl, -N(OH)-C(=O)-(C 1 -C 12 ) alkenyl, -N(OH)-C(=O)-Q-OH, -N(OH)-C(=O)-Q-COOH, and m is an integer selected from 0 to 3; n is an integer selected from 0 to 10; Each R 5 is independently -(C 1 -C 12 )Alkyl, halogen, -OH, -COOH, -NH 2 , -linker-H, or -C(=O)-linker-H, and R 6 and R 7 are independently H, -COOH, or -OR A That is, 10. The compound of claim 1, or a pharmaceutically acceptable salt or zwitterion thereof.

3. U 1 but -IN 11 -IN 12 -IN 13 -IN 14 -IN 15 -IN 16 - (II-1) and During the ceremony U 11 , U 12 , U 13 , U 14 , U 15 , and U 16 are independently a covalent bond or optionally substituted -Q-, -C(=O)-, -OC(=O)-, or -CHR 8 -, -CR 10 R 8 -, -C(=O)-NH-, -C(=O)-NR 8 -, -C(=O)-N(OH)-, -NH-, -NR 8 -, -NR 10 -, -NH-CHR 8 -C(=O)- or -R 11 -is, 3. The compound of claim 2, or a pharmaceutically acceptable salt or zwitterion thereof.

4. G is O-CH 2 -COOH, S(=O) 2 OH, OS(=O) 2 OH, or C(=O)NH-S(=O) 2 G'; R2 is -C(R4)2C(=O)W, C(R4)2C(=O)NHOCH2C(=O)OH, or -C(R4)2C(=O)NHOC(R4)2C(=O)W; and 10. The compound of claim 1, wherein R<1> is -(Ci-Ci2) alkyl.

5. Formula (I) 3. The compound of claim 2, wherein the compound is represented by: or a pharmaceutically acceptable salt or zwitterion thereof.

6. Formula (I) 2. The compound of claim 1, wherein:

7. V 2. The compound of claim 1, wherein:

8. W is -C(=O)-U 1 -R 8 or -NH-U 1 -R 8 3. The compound of claim 2, wherein the compound is represented by: or a pharmaceutically acceptable salt or zwitterion thereof.

9. U 1 Ga-Q-NR 8 -Q- and Each Q is independently -OH, -COOH, =O, and -NH 2 -(C 1 -C 12 ) alkylene; 6. The compound of claim 5, or a pharmaceutically acceptable salt or zwitterion thereof.

10. Sid includes achromobactin, acinetobactin, acinetoferrin, aerobactin, aeruginous acid, agrobactin, agrobactin A, albomycin 271, alcaligin 230, alterobactin A, alterobactin B, aminochelin 262, amonabactin P693, amonabactin P750, amonabactin T732, amonabactin T789, amphibactin B, amphibactin C, amphibactin D, amphibactin E, amphibactin F, and amphibactin G. , Amphibactin H, Amphibactin I, Amycolachrome 235, Anachelin 1, Anachelin 2, Anguibactin 247, Aquachelin A, Aquachelin B, Aquachelin C, 2, Aquachelin D, Arthrobactin, Arthrobactin 199, Asperchrome A, Asperchrome B1, Asperchrome B2, Asperchrome B3, Asperchrome C, Asperchrome D1, Asperchrome D2, Asperchrome D3, Asperchrome E, Asperchrome F1, Asperchrome F2, Asper Chromium F3, aspergillic acid, avenic acid, awaitin A, awaitin B, awaitin C, azotobactin 236, azotobactin D, azotobactin 87, azotochelin, azotochelin 236, azoverdin 174, basilibactin 85, basidiochrome 46, biscatechol, viscaverin 232, carboxymycobactin 107, carboxymycobactin 1, carboxymycobactin 2, carboxymycobactin 3, carboxymycobactin 4, cepabactin 266 , chrysobactin 261, citric acid 260, coelichelin 72, 3, coprogen 51, coprogen B, corynebactin 84, danoxamine, deoxydisticonic acid, 2'-deoxymugineic acid, deoxyschizokinen 251, des(diserylglycyl)ferrirosin 45, desacetylcoprogen 52, desferrioxamine A1, desferrioxamine A2, desferrioxamine B, desferrioxamine D1, desferrioxamine D2, desferrioxamine E, desferrioxamine Et1 21A, desferrioxamine Et2 21B, desferrioxamine Et3 21C, desferrioxamine G1, desferrioxamine G2A, desferrioxamine G2B, desferrioxamine G2C, desferrioxamine H,Desferrioxamine P1, Desferrioxamine T1, Desferrioxamine T2, Desferrioxamine T3, Desferrioxamine T7, Desferrioxamine T8, Desferrioxamine Te1 21D, Desferrioxamine Te2 21E, Desferrioxamine Te3 21F, Desferrioxamine X1, Desferrioxamine X2, 4, Desferrioxamine X3, Desferrioxamine X4, Desferrithiocin, Diamine Biscatechol, Dihydrobenzolate, 2,3-Dihydroxybenzoylserine, Dimermic Acid, Dimethylcoprogen, Dimethylneocoprogen I, Dimethyltriornisine, Disticonic Acid, Enantiorhizoferrin, Enantiopiochelin, Enterobactin, Enterochelin, Exochelin MN, Exochelin Methylpropene MS, ferrichrome, ferrichrome A, ferrichrome C, ferricrysin, ferricrocin, ferrioxamine, ferrimycin A, ferrilogin, ferrirubin, ferrocin A, fimusbactin A, fluvibactin, formobactin, foroxymitin, fusarinin A, fusarinin B, fusarinin C, heterobactin A, heterobactin B, hydroxycopropene, hydroxypyridone, hydroxyisoneocopropene I, 3-hydroxymugineic acid, 5-hydroxyneocopropene, 5-hydroxyiso ... Coprogen I, isoneocoprogen I, isopyoverdine BTP1, isopyoverdine 6.7, isopyoverdine 7.13, isopyoverdine 90-33, isopyoverdine 90-44, isopyoverdine 10.7, isotriornisine, itonic acid, reuchkelin A, reuchkelin B, reuchkelin C, reuchkelin D, reuchkelin E, reuchkelin F, maduraferin, malonichrome, marinobactin A, marinobactin B, marinobactin C, marinobactin D1, Marinobactin D2, Marinobactin E, Mycacocidin, Mugineic acid, Mycobactin, Mycobactin A, Mycobactin Av, Mycobactin F, Mycobactin H, Mycobactin J, Mycobactin M, Mycobactin N, Mycobactin NA, Mycobactin P, Mycobactin R, Mycobactin S, Mycobactin T, Myxochelin, ω-N-acetyl-ω-N-hydroxyl-α-aminoalkane, ε-N-acetyl-ε-N-hydroxyl L-lysine,δ-N-acetyl-δ-N-hydroxyl L-ornithine, nannochelin A, nannochelin B, nannochelin C, neocoprogen I, neocoprogen II, neurosporin, nocobactin, nocobactin NA, ochlobactin A, ochlobactin B, ochlobactin C, ornibactin-C4, ornibactin-C6, ornibactin-C8, ornicorgatin, palmitoyl coprogen, parabactin, parabactin A, petrobactin, petrobactin disulfonate, petrobactin sulfonate, pistilarin, polyamine biscatechol, Protochelin, pseudoalterobactin A, pseudoalterobactin B, pseudobactin 112, pseudobactin 589A, 7, putrebactin, pyochelin, pyoverdine A214, pyoverdine BTP2, pyoverdine C, pyoverdine CHAO, pyoverdine D-TR133, pyoverdine E, pyoverdine GR, pyoverdine GM, pyoverdine I-III, pyoverdine P19, pyoverdine Pau, pyoverdine PL8, pyoverdine PVD, pyoverdine R', pyoverdine Thai, pyoverdine TII, pyoverdine 1, pyoverdine Ludine 11370, Pyoverdine 13525, Pyoverdine 1547, Pyoverdine 17400, Pyoverdine 18-1, Pyoverdine 19310, Pyoverdine 2192, Pyoverdine 2392, Pyoverdine 2461, Pyoverdine 2798, Pyoverdine 51W, Pyoverdine 9AW, Pyoverdine 90-51, Pyoverdine 95-275, Pyoverdine 96-312, Pyoverdine 96-318, Pyoverdine, Pyoverdine 6.1, Pyoverdine 6.2, Pyoverdine 6.3, Pyoverdine 6.4, Pyoverdine 6.5, Pyoverdine 6.6, Pyoverdin 6.8, Pyoverdin 7.1, Pyoverdin 7.2, Pyoverdin 7.3, Pyoverdin 7.4, Pyoverdin 7.5, Pyoverdin 7.6, Pyoverdin 7.7, Pyoverdin 7.8, Pyoverdin 7.9, Pyoverdin 7.10, Pyoverdin 7.11, Pyoverdin 7.12, Pyoverdin 7.14, Pyoverdin 7.15, Pyoverdin 7.16, Pyoverdin 7.17, Pyoverdin 7.18, Pyoverdin 7.19, Pyoverdin 8.1, Pyoverdin 8.2, Pyoverdin 8.3, Pyoverdin 8.4, Pyoverdin 8.5,Pyoverdin 8.6, Pyoverdin 8.7, Pyoverdin 8.8, Pyoverdin 8.9, Pyoverdin 9.1, Pyoverdin 9.2, Pyoverdin 9.3, Pyoverdin 9.4, Pyoverdin 9.5, Pyoverdin 9.6, Pyoverdin 9.7, Pyoverdin 9.8, Pyoverdin 9.9, Pyoverdin 9.10, Pyoverdin 9.11, Pyovergi Pyoverdine 9.12, Pyoverdine 10.1, Pyoverdine 10.2, Pyoverdine 10.3, Pyoverdine 10.4, Pyoverdine 10.5, Pyoverdine 10.6, Pyoverdine 10.8, Pyoverdine 10.9, Pyoverdine 10.10, Pyoverdine 11.1, Pyoverdine 11.2, Pyoverdine 12, Pyoverdine 12.1, Pyoverdine 12. The compound of claim 1, which is derived from 2, pyoverdine, pyridoxathin, quinolobactin, rhizobactin, 10, rhizobactin, rhizoferrin, rhizoferrin analogs 88A-88E, rhodotrulic acid, salmochelin S1, salmochelin S2, salmochelin S4, salmochelin SX, salmycin A, schizokinen, serratiochelin, siderochelin A, sunocactin A, sunocactin B, sunocactin C, staphyloferrin A, staphyloferrin B, tetraglycine ferrichrome, thiazostatin, triacetylfusarinine, tricatechol, triornisine, vibriobactin, vibrioferrin, bicibactin, barnibactin, or yersiniabactin.

11. The compound is 2. The compound of claim 1, or a pharmaceutically acceptable salt or zwitterion thereof, selected from the group consisting of:

12. 10. A pharmaceutical composition for treating a bacterial infection in a subject in need thereof, comprising a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt or zwitterion thereof.

13. 13. The pharmaceutical composition of claim 12, wherein the bacterial infection is a gram-negative bacterial infection.

14. 13. The pharmaceutical composition of claim 12, wherein the bacterial infection is caused by Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, or Klebsiella pneumonia.

15. 13. The pharmaceutical composition of claim 12, used in combination with an effective amount of an additional antibiotic agent.

16. Additional antibiotic compounds may be Penicillin, methicillin, oxacillin, nafcillin, cloxacillin, dicloxacillin, flucloxacillin, temocillin, amoxicillin, ampicillin, co-amoxiclav, azlocillin, carbenicillin, ticarcillin, mezlocillin, piperacillin, cephalexin, cephalothin, CXA-101, cefazolin, cefaclor, cefuroxime, cefamandole, cefotetan, cefoxitin, ceftriaxone, cefotaxime, cefpodoxime, cefixime, ceftazidime, ceftobiprole medcaril, cefepime, cefpirome, ceftaroline, imipenem, meropenem, ertapenem, faropenem, sulopenem, doripenem, PZ-601 (Protez Pharmaceuticals), ME1036 (Forest Labs), BAL30072, MC-1, tomopenem, tebipenem, aztreonam, tigemonam, nocardicin A, and tabtoxin-β-lactam 16. The pharmaceutical composition of claim 15, wherein the compound is selected from the group consisting of:

17. 13. The pharmaceutical composition of claim 12, wherein the bacterial infection is resistant to one or more antibiotics.

18. A process for preparing a compound of formula (I), or a pharmaceutically acceptable salt or zwitterion thereof, said process comprising: Compound of formula (I'-1) with a compound of formula (II'-1) or formula (II'-2) R 8 -U 1 -NH 2 (II'-1) or R 8 -U 1 -L'-NH 2 (II'-2) under suitable conditions to produce a compound having formula (I) generating During the ceremony G is -OR A , -OCH 2 C(=O)X, OCHRC(=O)X, -C(=O)X, -S(=O) 2 X, -OS(=O) 2 X, -C(=O)NH-S(=O) 2 G', P(=O)X or -P(=O)X; G' is OR A , -OCH 2 C(=O)X, OCHRC(=O)X, -C(=O)X, -S(=O) 2 X, -OS(=O) 2 X, P(=O)X or -P(=O)X, X is H, -OR A or -N(R A ) 2 and R 1 is H or optionally substituted with X or Z -(C 1 -C 12 ) alkyl, Z is R A , -OR A , -SR A , -C(=O)N(R A ) 2 , or -N(R A ) 2 and R 2a Ha-CH 2 C(=O)OH, -CHR 4 C(=O)OH, -C(R 4 ) 2 C(=O)OH, or -C(R 4 ) 2 C(=O)NHOCH 2 C(=O)OH, -C(R 4 ) 2 C(=O)NHOC(R 4 ) 2 C(=O)OH, R 2 は-CH 2 C(=O)W'、-CHR 4 C(=O)W'、-C(R 4 ) 2 C(=O)W'、-C(R 4 ) 2 C(=O)NHOCH 2 C(=O)W'、-C(R 4 ) 2 C(=O)NHOCH 2 C(=O)OH、-C(R 4 ) 2 C(=O)NHOC(R 4 ) 2 C(=O)OH、または-C(R 4 ) 2 C(=O)NHOC(R 4 ) 2 C(=O)W'であり、 R 3 is H, Z, or R 4 and Each R 4 are independently H, Z, -(C 1 -C 12 ) alkyl, -(C 3 -C 8 ) cycloalkyl, -(C 3 -C 6 ) heterocycloalkyl, or -(C 1 -C 8 )N(R A )R B or two R 4 together with the carbon atom to which they are both attached, -(C 3 -C 8 ) cycloalkyl or -(C 3 -C 6 ) forming a heterocycloalkyl, Each R A are independently H, -(C 1 -C 12 ) alkyl, -(C 3 -C 8 ) cycloalkyl, phenyl, aryl, or heteroaryl; R B is H, -(C 1 -C 12 ) alkyl, -(C 3 -C 8 ) cycloalkyl, or phenyl; W'-NH-U 1 -R 8 or -NH-L'-U 1 - R 8 and L' is -QC(=O)O-, -C(=O)-QC(=O)O-, -C(=O)-Q-, -C(=O)OQ-, -C(=O)-QC(=O)-, -OQ-, -Q-, -Q-NH-, -QO-, or a combination thereof; Each Q is independently -OH, -COOH, ═O, or -NH 2 , -(C 1 -C 12 ) alkyl, -(C 1 -C 12 ) alkenyl, -(C 1 -C 12 ) alkylene-OH, -(C 1 -C 12 )Alkylene-NH 2 , -NH-(C 1 -C 12 ) alkylene-COOH, -NH-C(=O)-(C 1 -C 12 ) alkylene-COOH, -C(=O)-(C 1 -C 12 )Alkylene-C(=O)-NH 2 , -O-(C 1 -C 12 ) alkylene-OH, -NH-(C 1 -C 12 )Alkylene-NH 2 , and -NH-(C 1 -C 12 ) alkylene-OH, -(C 1 -C 12 ) alkylene, U 1 is a covalent bond or optionally substituted -Q-, -C(=O)-, -OC(=O)-, -CHR 8 -, -CR 10 R 8 -, -C(=O)-NH-, -C(=O)-NR 8 -, -C(=O)-N(OH)-, -NH-, -NR 8 -, -NR 10 -, -NH-CHR 8 -C(=O)-, -R 11 - or a combination thereof, Each R 8 are each independently H, -OH, -COOH, or -NH 2 , -Q-OH, -V, -QV, -NH-C(=O)-V, -Q-NH-C(=O)-V, -NR 10 -C(=O)-V, -NR 10 -V, -C(=O)-V, -OC(=O)-V, -C(=O)-R 11 -V, -NH-C(=O)-R 11 -V, -C(=O)-R 11 -aryl, or L'-H; R 10 is -NH-C(O)-Q-COOH, -C(O)-Q-COOH, -Q-COOH, or -COOH; R 11 is an optionally substituted ring selected from phenyl, 3- to 7-membered saturated or partially unsaturated carbocyclyl, 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from N, O and S, and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S; V is -N(OH)-C(=O)-NH 2 , -N(OH)-C(=O)H, N(OH)-C(=O)-L', -N(OH)-C(=O)-(C 1 -C 12 ) alkyl, -N(OH)-C(=O)-(C 1 -C 12 ) alkenyl, -N(OH)-C(=O)-Q-OH, -N(OH)-C(=O)-Q-COOH, and m is an integer selected from 0 to 3; n is an integer selected from 0 to 10; Each R 5 is independently -(C 1 -C 12 )Alkyl, halogen, -OH, -COOH, -NH 2 , -L'-H, or -C(=O)-L'-H, and R 6 and R 7 are independently H, -COOH, or -OR A That is, process.

19. coupling a compound of formula (I'-1) with a compound of formula (II'-1) or formula (II'-2) to produce a compound of formula (I), 20. The process of claim 18, wherein said coupling comprises contacting a compound of formula (I'-1) and a compound of formula (II'-1) or formula (II'-2) with a coupling reagent.

20. 20. The process of claim 19, wherein the coupling reagent is HBTU, DIPEA, N-hydroxysuccinimide, EDC.HCl, or a mixture thereof.

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