WO2025212948A1 - Therapeutic compounds and methods - Google Patents

Abstract

The invention provides a compound of formula (I) or a salt thereof, wherein R¹-R³, X and L have any of the values described in the specification, as well as compositions comprising a compound of formula (I). The compounds are useful as antibacterial (e.g., Gram-negative bacteria) agents.

Description

UIRF 24058 VHPM 17023.294 THERAPEUTIC COMPOUNDS AND METHODS C^ROSS R^EFERENCE T^O R^ELATED A^PPLICATIONS This Application claims priority to United States Provisional Application Number 63/574,431, filed on 04 April 2024. The entire content of this United States Provisional Application is hereby incorporated by reference herein. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH This invention was made with government support under GM097373 awarded by National Institutes of Health. The government has certain rights in the invention. BACKGROUND More than half of all humans are infected with the gastrointestinal pathogen Helicobacter pylori (H. pylori ). (Hooi JKY, et al., Gastroenterology.2017, (2):420-429; PMID: 28456631) This Gram-negative bacterium is the primary cause of gastric cancer, the fifth most common and third deadliest cancer worldwide. (Rawla P, Barsouk A. Prz Gastroenterol.2019, 14(1):26-38; PMC6444111). Additionally, those infected with H. pylori are at greater risk for gastritis and peptic ulcers. (Malfertheiner, P., et al., Nat Rev Dis Primers, 2023, 9, 19). The current standard of care requires at least two non-selective antibiotics, often clarithromycin and metronidazole, causing widespread disruption of the gut microbiome. (David Y. Graham, Gastroenterology, 2015, 148, 4, 719-731). The lack of species-specific therapies combined with growing antibiotic resistance presents an urgent need for innovative antibiotic research to combat the pervasive health challenges posed by H. pylori infections. (Malfertheiner, P., et al., Nat Rev Dis Primers, 2023, 9, 19). Developing antibiotics that target H. pylori is particularly difficult due to the inherent complexities associated with Gram-negative bacteria. (Saxena, D., et al., Antimicrob Resist. 2023, 1, 17). Briefly, Gram-negative bacteria are characterized by a peptidoglycan layer encapsulated by an inner and outer membrane, a formidable barrier rendering species such as H. pylori resistant to a wide range of antimicrobial agents. (Liou JM, et al., Gut Liver.2022, 16(1):8-18; PMID: 33782215; and Boyanova L, et al., Antibiotics (Basel).2023, 12(2):332; PMID: 36830243). For compounds to penetrate this barrier, they must possess specific physicochemical properties that enable transit through the outer membrane's narrow porin channels while evading expulsion by efflux pumps. (Zhao, S., et al., Nat Chem Biol 2020, 16, 1293–1302). These properties typically include optimal molecular size, globularity, and a UIRF 24058 VHPM 17023.294 balance between hydrophilicity and hydrophobicity. (Zhao, S., et al., Nat Chem Biol 2020, 16, 1293–1302). The design of novel antibiotics for H. pylori and other Gram-negative bacteria necessitates a meticulous and strategic approach, focused on fine-tuning molecular properties to ensure effective penetration and retention within the bacterial cell. Current drug discovery campaigns are largely tackling antibiotic resistance by modifying existing therapeutic pharmacophores, resulting in a lack of structural diversity among antibiotics. (Butler, M.S., et al., J Antibiot 2023, 76, 431–473. As of 2021, only a quarter of all antibiotics in clinical development represented a novel structural class, and just four targeted Gram-negative pathogens. (Tracking the Global Pipeline of Antibiotics in Development, April 2020 (The Pew Charitable Trusts, 2020)). This lack of diversity presents inherent challenges as bacteria become increasingly less susceptible to commonly prescribed antibiotic classes. (Wright, G. Nat Rev Microbiol, 2007, 5, 175–186). Consequently, there is a pressing need for agents and methods to effectively target Gram-negative pathogens (e.g., H. pylori). SUMMARY Agents and methods for targeting Gram-negative pathogens are provided. In one aspect, a compound of formula (I): or a salt thereof, wherein: R¹ is a 5-membered heteroaryl ring that is optionally substituted with one or more groups independently selected from the group consisting of halo and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from halo; R² is H, R^a, or (C1-C3)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo and R^a; R³ is absent, a 3-8 membered heterocycle, aryl, a 5-membered heteroaryl, or a (C3- C8)cycloalkyl, which 3-8 membered heterocycle, aryl, a 5-membered heteroaryl, and (C3- C8)cycloalkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, nitro, cyano, hydroxy, (C1-C6)alkyl, oxo (=O), -C(=O)NR^eR^f, and (C1- C6)alkoxy; UIRF 24058 VHPM 17023.294 X is absent, O, S, or -NR^b-; L is a linking group having from 1-10 carbon atoms, wherein one or more of the carbon atoms is optionally replaced independently by -O-, -S, or -N(R^c)-, and wherein each carbon atom is optionally substituted with one or more substituents independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1- C6)alkoxycarbonyl, cyano, nitro, halo, -N(R^d)2, hydroxy, oxo (=O), and carboxy; R^a is a 5-membered heteroaryl ring that is optionally substituted with one or more groups independently selected from the group consisting of halo and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from halo; R^b is H or (C1-C3)alkyl; each R^c is independently H or (C1-C3)alkyl; each R^d is independently H or (C1-C3)alkyl; each R^e is independently H or (C1-C3)alkyl; and each R^f is independently H or (C1-C3)alkyl. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient is also provided. A method for treating or preventing a bacterial infection (e.g. a Gram-negative bacterial infection) in an animal (e.g., a mammal such as a human) comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to the animal is also provided. A method for promoting an antibacterial effect in a bacterial cell (e.g. a Gram-negative bacterial cell) comprising contacting the bacterial cell with a compound of formula (I) or a pharmaceutically acceptable salt thereof is also provided. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in medical therapy is also provided. A compound of formula (I) or a pharmaceutically acceptable salt thereof for the prophylactic or therapeutic treatment of a bacterial infection (e.g. a Gram-negative bacterial infection) is also provided. A compound of formula (I) or a pharmaceutically acceptable salt thereof for promoting an antibacterial effect in a bacterial cell (e.g. a Gram-negative bacterial cell is also provided. UIRF 24058 VHPM 17023.294 The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof to prepare a medicament for treating a bacterial infection (e.g. a Gram-negative bacterial infection) in an animal (e.g., a mammal such as a human) is also provided. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof to prepare a medicament for method for promoting an antibacterial effect in a bacterial cell (e.g. a Gram-negative bacterial cell) in an animal (e.g., a mammal such as a human) is also provided. The invention also provides processes and intermediates disclosed herein that are useful for preparing a compound of formula (I) or a salt thereof. BRIEF DESCRIPTION OF THE FIGURES Fig.1 shows data from Example 7. Fig.2 shows data from Example 7. Fig, 3 shows NMR data for the product of Example 1. Fig, 4 shows NMR data for the product of Example 2. Fig, 5 shows NMR data for the product of Example 3. Fig, 6 shows NMR data for the product of Example 4. DETAILED DESCRIPTION The following definitions are used, unless otherwise described: halo or halogen is fluoro, chloro, bromo, or iodo. Alkyl, alkoxy, etc. denote both straight and branched groups; but reference to an individual radical such as propyl embraces only the straight chain radical, a branched chain isomer such as isopropyl being specifically referred to. The term "alkyl", by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (i.e., C1-8 means one to eight carbons). Examples include (C1-C8)alkyl, (C2-C8)alkyl, C1-C6)alkyl, (C2-C6)alkyl and (C3-C6)alkyl. Examples of alkyl groups include methyl, ethyl, n- propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and and higher homologs and isomers. The term "alkoxy" refers to an alkyl groups attached to the remainder of the molecule via an oxygen atom (“oxy”). The term “cycloalkyl” refers to a saturated or partially unsaturated (non-aromatic) all carbon ring having 3 to 8 carbon atoms (i.e., (C3-C8)carbocycle). The term also includes multiple condensed, saturated all carbon ring systems (e.g., ring systems comprising 2, 3 or 4 UIRF 24058 VHPM 17023.294 carbocyclic rings). Accordingly, carbocycle includes multicyclic carbocyles such as a bicyclic carbocycles (e.g., bicyclic carbocycles having about 3 to 15 carbon atoms , about 6 to 15 carbon atoms, or 6 to 12 carbon atoms such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane), and polycyclic carbocycles (e.g tricyclic and tetracyclic carbocycles with up to about 20 carbon atoms). The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. For example, multicyclic carbocyles can be connected to each other via a single carbon atom to form a spiro connection (e.g., spiropentane, spiro[4,5]decane, etc), via two adjacent carbon atoms to form a fused connection (e.g., carbocycles such as decahydronaphthalene, norsabinane, norcarane) or via two non-adjacent carbon atoms to form a bridged connection (e.g., norbornane, bicyclo[2.2.2]octane, etc). Non-limiting examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptane, pinane, and adamantane. The term “aryl” as used herein refers to a single all carbon aromatic ring or a multiple condensed all carbon ring system wherein at least one of the rings is aromatic. For example, in certain embodiments, an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or 6 to 10 carbon atoms. Aryl includes a phenyl radical. Aryl also includes multiple condensed carbon ring systems (e.g., ring systems comprising 2, 3 or 4 rings) having about 9 to 20 carbon atoms in which at least one ring is aromatic and wherein the other rings may be aromatic or not aromatic (i.e., cycloalkyl. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the point of attachment of a multiple condensed ring system, as defined above, can be at any position of the ring system including an aromatic or a carbocycle portion of the ring. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, indanyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl, anthracenyl, and the like. The term “heterocycle” refers to a single saturated or partially unsaturated ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; the term also includes multiple condensed ring systems that have at least one such saturated or partially unsaturated ring, which multiple condensed ring systems are further described below. Thus, the term includes single saturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-membered rings) from about 1 to 6 carbon atoms and from about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and UIRF 24058 VHPM 17023.294 sulfur in the ring. The sulfur and nitrogen atoms may also be present in their oxidized forms. Exemplary heterocycles include but are not limited to azetidinyl, tetrahydrofuranyl and piperidinyl. The term “heterocycle” also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) wherein a single heterocycle ring (as defined above) can be condensed with one or more groups selected from cycloalkyl, aryl, and heterocycle to form the multiple condensed ring system. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the individual rings of the multiple condensed ring system may be connected in any order relative to one another. It is also to be understood that the point of attachment of a multiple condensed ring system (as defined above for a heterocycle) can be at any position of the multiple condensed ring system including a heterocycle, aryl and carbocycle portion of the ring. In one embodiment the term heterocycle includes a 3-15 membered heterocycle. In one embodiment the term heterocycle includes a 3-10 membered heterocycle. In one embodiment the term heterocycle includes a 3-8 membered heterocycle. In one embodiment the term heterocycle includes a 3-7 membered heterocycle. In one embodiment the term heterocycle includes a 3-6 membered heterocycle. In one embodiment the term heterocycle includes a 4-6 membered heterocycle. In one embodiment the term heterocycle includes a 3-10 membered monocyclic or bicyclic heterocycle comprising 1 to 4 heteroatoms. In one embodiment the term heterocycle includes a 3-8 membered monocyclic or bicyclic heterocycle heterocycle comprising 1 to 3 heteroatoms. In one embodiment the term heterocycle includes a 3-6 membered monocyclic heterocycle comprising 1 to 2 heteroatoms. In one embodiment the term heterocycle includes a 4-6 membered monocyclic heterocycle comprising 1 to 2 heteroatoms. Exemplary heterocycles include, but are not limited to aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4- tetrahydroquinolyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, spiro[cyclopropane-1,1'- isoindolinyl]-3'-one, isoindolinyl-1-one, 2-oxa-6-azaspiro[3.3]heptanyl, imidazolidin-2-one imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, and 1,4-dioxane. UIRF 24058 VHPM 17023.294 The term “heteroaryl” as used herein refers to a single aromatic ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; “heteroaryl” also includes multiple condensed ring systems that have at least one such aromatic ring, which multiple condensed ring systems are further described below. Thus, “heteroaryl” includes single aromatic rings of from about 1 to 6 carbon atoms and about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. The sulfur and nitrogen atoms may also be present in an oxidized form provided the ring is aromatic. Exemplary heteroaryl ring systems include but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl. “Heteroaryl” also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) wherein a heteroaryl group, as defined above, is condensed with one or more rings selected from cycloalkyl, aryl, heterocycle, and heteroaryl. It is to be understood that the point of attachment for a heteroaryl or heteroaryl multiple condensed ring system can be at any suitable atom of the heteroaryl or heteroaryl multiple condensed ring system including a carbon atom and a heteroatom (e.g., a nitrogen). Exemplary heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, and quinazolyl. As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si). As used herein, the term "protecting group" refers to a substituent that is commonly employed to block or protect a particular functional group on a compound. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9- fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A "carboxy-protecting group" refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Common carboxy- protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2- (trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2- UIRF 24058 VHPM 17023.294 (diphenylphosphino)-ethyl, nitroethyl and the like. For a general description of protecting groups and their use, see P.G.M. Wuts and T.W. Greene, Greene's Protective Groups in Organic Synthesis 4^th edition, Wiley-Interscience, New York, 2006. A_{s used herein a wavy line “ ” that intersects a bond in a chemical structure indicates} the point of attachment of the bond that the wavy bond intersects in the chemical structure to the remainder of a molecule. The terms “treat”, “treatment”, or “treating” to the extent it relates to a disease or condition includes inhibiting the disease or condition, eliminating the disease or condition, and/or relieving one or more symptoms of the disease or condition. The terms “treat”, “treatment”, or “treating” also refer to both therapeutic treatment and/or prophylactic treatment or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as, for example, the development or spread of cancer. For example, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease or disorder, stabilized (i.e., not worsening) state of disease or disorder, delay or slowing of disease progression, amelioration or palliation of the disease state or disorder, and remission (whether partial or total), whether detectable or undetectable. “Treat”, “treatment”, or “treating,” can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the disease or disorder as well as those prone to have the disease or disorder or those in which the disease or disorder is to be prevented. In one embodiment “treat”, “treatment”, or “treating” does not include preventing or prevention, The phrase "therapeutically effective amount" or “effective amount” includes but is not limited to an amount of a compound of the that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The term “animal” includes mammals, fish, amphibians, reptiles, birds and invertebrates. The term “mammal” includes humans, higher non-human primates, rodents, domestic, cows, horses, pigs, sheep, dogs and cats. In one embodiment, the animal is a mammal. In one embodiment, the animal is a human. The term “patient” as used herein refers to any animal UIRF 24058 VHPM 17023.294 including mammals. In one embodiment, the patient is a mammalian patient. In one embodiment, the patient is a human patient. The compounds disclosed herein can also exist as tautomeric isomers in certain cases. Although only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the invention. It is understood by one skilled in the art that this invention also includes any compound claimed that may be enriched at any or all atoms above naturally occurring isotopic ratios with one or more isotopes such as, but not limited to, deuterium (²H or D). As a non-limiting example, a -CH3 group may be substituted with -CD3. The pharmaceutical compositions of the invention can comprise one or more excipients. When used in combination with the pharmaceutical compositions of the invention the term “excipients” refers generally to an additional ingredient that is combined with the compound of formula (I) or the pharmaceutically acceptable salt thereof to provide a corresponding composition. For example, when used in combination with the pharmaceutical compositions of the invention the term “excipients” includes, but is not limited to: carriers, binders, disintegrating agents, lubricants, sweetening agents, flavoring agents, coatings, preservatives, and dyes. Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the invention can contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they UIRF 24058 VHPM 17023.294 are mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity. It will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase. When a bond in a compound formula herein is drawn in a non-stereochemical manner (e.g. flat), the atom to which the bond is attached includes all stereochemical possibilities. When a bond in a compound formula herein is drawn in a defined stereochemical manner (e.g. bold, bold-wedge, dashed or dashed-wedge), it is to be understood that the atom to which the stereochemical bond is attached is enriched in the absolute stereoisomer depicted unless otherwise noted. In one embodiment, the compound may be at least 51% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 60% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 80% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 90% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 95 the absolute stereoisomer depicted. In another embodiment, the compound may be at least 99% the absolute stereoisomer depicted. Specific values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents. It is to be understood that two or more values may be combined. It is also to be understood that the values listed herein below (or subsets thereof) can be excluded. UIRF 24058 VHPM 17023.294 Specifically, (C1-C6)alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec- butyl, pentyl, 3-pentyl, or hexyl; (C3-C6)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (C1-C6)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy; aryl can be phenyl, indenyl, or naphthyl; and heteroaryl can be furyl, imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (or its N-oxide), thienyl, pyrimidinyl (or its N- oxide), indolyl, isoquinolyl (or its N-oxide) or quinolyl (or its N-oxide). A specific group of compounds and salts is a compound of formula (I) or a salt thereof, wherein: R¹ is a 5-membered heteroaryl ring that is optionally substituted with one or more groups independently selected from the group consisting of halo and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from halo; R² is H, R^a, or (C1-C3)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo and R^a; R³ is absent, a 3-8 membered heterocycle, or a (C3-C8)cycloalkyl, which 3-8 membered heterocycle, and (C3-C8)cycloalkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, nitro, cyano, hydroxy, (C1-C6)alkyl, oxo (=O), and (C1-C6)alkoxy; X is absent, O, S, or -NR^b-; L is a linking group having from 1-10 carbon atoms, wherein one or more of the carbon atoms is optionally replaced independently by -O-, -S, or -N(R^c)-, and wherein each carbon atom is optionally substituted with one or more substituents independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1- C6)alkoxycarbonyl, cyano, nitro, halo, -N(R^d)2, hydroxy, oxo (=O), and carboxy; R^a is a 5-membered heteroaryl ring that is optionally substituted with one or more groups independently selected from the group consisting of halo and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from halo; R^b is H or (C1-C3)alkyl; each R^c is independently H or (C1-C3)alkyl; and each R^d is independently H or (C1-C3)alkyl. UIRF 24058 VHPM 17023.294 A specific value for R¹ is a 5-membered heteroaryl ring that comprises one or more S and that is optionally substituted with one or more groups independently selected from the group consisting of halo and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from halo. A specific value for R¹ is thienyl that is optionally substituted with one or more groups independently selected from the group consisting of halo and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from halo. A specific value for R¹ is 2-thienyl that is optionally substituted with one or more groups independently selected from the group consisting of halo and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from halo. A specific value for R¹ is a 5-membered heteroaryl ring. A specific value for R¹ is thienyl. A specific value for R¹ is 2-thienyl. A specific value for R² is (C1-C3)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo and R^a. A specific value for R² is (C1-C3)alkyl that is substituted with one or more groups independently selected from the group consisting of halo and R^a. A specific value for R² is (C1-C3)alkyl that is substituted with R^a. A specific value for R² is R^a. A specific value for R² is H. A specific value for R^a is a 5-membered heteroaryl ring that comprises one or more S and that is optionally substituted with one or more groups independently selected from the group consisting of halo and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from halo. A specific value for R^a is thienyl that is optionally substituted with one or more groups independently selected from the group consisting of halo and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from halo. A specific value for R^a is 2-thienyl that is optionally substituted with one or more groups independently selected from the group consisting of halo and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from halo. A specific value for R^a is a 5-membered heteroaryl ring. UIRF 24058 VHPM 17023.294 A specific value for R^a is thienyl. A specific value for R^a is 2-thienyl. A specific value for R³ is absent. A specific value for R³ is a 3-8 membered heterocycle that is optionally substituted with one or more groups independently selected from the group consisting of halo, nitro, cyano, hydroxy, (C1-C6)alkyl, oxo (=O), and (C1-C6)alkoxy. A specific value for R³ is a (C3-C8)cycloalkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, nitro, cyano, hydroxy, (C1-C6)alkyl, oxo (=O), and (C1-C6)alkoxy. A specific value for R³ is: . A specific value for R³ is:. A specific value for X is absent. A specific value for X is O. A specific value for X is S. A specific value for X is -NR^b-. A specific value for L is a linking group having from 1-10 carbon atoms, wherein one or more of the carbon atoms is replaced independently by -O-, -S, or -N(R^c)-, and wherein each carbon atom is optionally substituted with one or more substituents independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1- C6)alkoxycarbonyl, cyano, nitro, halo, -N(R^d)2, hydroxy, oxo (=O), and carboxy. A specific value for L is a linking group having from 1-10 carbon atoms, wherein one or more of the carbon atoms is replaced independently by -O-, -S, or -N(R^c)-, and wherein each carbon atom is optionally substituted with one or more substituents independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, halo, -N(R^d)2, hydroxy, and oxo (=O). UIRF 24058 VHPM 17023.294 A specific value for L is a linking group having from 1-10 carbon atoms, wherein one or more of the carbon atoms is replaced independently by -O-, -S, or -N(R^c)-, and wherein each carbon atom is substituted with one or more substituents independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1- C6)alkoxycarbonyl, cyano, nitro, halo, -N(R^d)2, hydroxy, oxo (=O), and carboxy. A specific value for L is a linking group having from 1-10 carbon atoms, wherein one or more of the carbon atoms is replaced independently by -O-, -S, or -N(R^c)-, and wherein each carbon atom is substituted with one or more substituents independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, halo, -N(R^d)2, hydroxy, and oxo (=O). A specific value for L is a linking group having from 1-5 carbon atoms, wherein one or more of the carbon atoms is replaced independently by -O-, -S, or -N(R^c)-, and wherein each carbon atom is optionally substituted with one or more substituents independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1- C6)alkoxycarbonyl, cyano, nitro, halo, -N(R^d)2, hydroxy, oxo (=O), and carboxy. A specific value for L is a linking group having from 1-5 carbon atoms, wherein one or more of the carbon atoms is replaced independently by -O-, -S, or -N(R^c)-, and wherein each carbon atom is optionally substituted with one or more substituents independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, halo, -N(R^d)2, hydroxy, and oxo (=O). A specific value for L is a linking group having from 1-5 carbon atoms, wherein one or more of the carbon atoms is replaced independently by -O-, -S, or -N(R^c)-, and wherein each carbon atom is substituted with one or more substituents independently selected from the group consisting of (C¹-C⁶)alkyl, (C¹-C⁶)alkoxy, (C¹-C⁶)alkanoyl, (C¹-C⁶)alkanoyloxy, (C¹- C6)alkoxycarbonyl, cyano, nitro, halo, -N(R^d)2, hydroxy, oxo (=O), and carboxy. A specific value for L is a linking group having from 1-5 carbon atoms, wherein one or more of the carbon atoms is replaced independently by -O-, -S, or -N(R^c)-, and wherein each carbon atom is substituted with one or more substituents independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, halo, -N(R^d)2, hydroxy, and oxo (=O). A specific value for L is -CH2-, -CH2CH2-, -CH2C(=O)N(H)-, or -CH2C(=O)N(H)C(=O)N(H)-. UIRF 24058 VHPM 17023.294 A specific compound or salt is selected from the group consisting of: and salts thereof. A specific compound or salt is selected from the group consisting of: and salts thereof. In cases where compounds are sufficiently basic or acidic, a salt of a compound of formula (I) can be useful as an intermediate for isolating or purifying a compound of formula (I). Additionally, administration of a compound of formula (I) as a pharmaceutically acceptable acid or base salt may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, α- ketoglutarate, and α-glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts. UIRF 24058 VHPM 17023.294 Salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made. The compounds of formula (I) can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes. Thus, the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained. The tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should UIRF 24058 VHPM 17023.294 be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices. The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions. UIRF 24058 VHPM 17023.294 For topical administration, the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid. Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers. Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user. Examples of useful dermatological compositions which can be used to deliver the compounds of formula (I) to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No.4,608,392), Geria (U.S. Pat. No.4,992,478), Smith et al. (U.S. Pat. No.4,559,157) and Wortzman (U.S. Pat. No.4,820,508). Useful dosages of the compounds of formula (I) can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No.4,938,949. The amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced UIRF 24058 VHPM 17023.294 administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye. Compounds of the invention can also be administered in combination with other therapeutic agents, for example, other antibiotic agents. Accordingly, in one embodiment the invention also provides a composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, and a pharmaceutically acceptable diluent or carrier. The invention also provides a kit comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, packaging material, and instructions for administering the compound of formula (I) or the pharmaceutically acceptable salt thereof and the other therapeutic agent or agents to an animal to treat a bacterial infection. The invention will now be illustrated by the following non-limiting Examples.

UIRF 24058 VHPM 17023.294 EXAMPLES Example 1. Synthesis of The title compound can be prepared from known starting materials as illustrated in the following scheme.

UIRF 24058 VHPM 17023.294 The title compound was confirmed by mass spec: Molecular weight 439.6; exact mass 439.02. NMR data for the title compound (Compound 1) is shown in Fig.3. Example 2. Synthesis of The title compound can be prepared from known starting materials as illustrated in the following scheme. UIRF 24058 VHPM 17023.294

UIRF 24058 VHPM 17023.294 The title compound was confirmed by mass spec: Molecular weight 432.58; exact mass 432.09. NMR data for the title compound (Compound 2) is shown in Fig.4. Example 3. Synthesis of The title compound can be prepared from known starting materials as illustrated in the following scheme.

UIRF 24058 VHPM 17023.294 The title compound was confirmed by mass spec: Molecular weight 405.56; exact mass 405.08. NMR data for the title compound (Compound 3) is shown in Fig.5. UIRF 24058 VHPM 17023.294 Example 4. Synthesis of The title compound can be prepared from known starting materials as illustrated in the following scheme.

UIRF 24058 VHPM 17023.294 The title compound was confirmed by mass spec: Molecular weight 391.53; exact mass 391.06. NMR data for the title compound (Compound 4) is shown in Fig.6. Example 5. Synthesis of Additional Representative Compounds Using procedures similar to those described herein, the following compounds (5-9) were also prepared.

UIRF 24058 VHPM 17023.294 Example 6. Biological Screening Enzyme-coupled Activity Assay Dose response curves were generated using a coupled assay to measure the conversion of D-glutamate to L-glutamate. Oxidation of L-glutamate to 2-oxoglutarate was catalyzed by L-glutamic acid dehydrogenase (LGDH), generating reduced β-nicotinamide adenine dinucleotide (NADH). NADH was then utilized by diaphorase to reduce iodonitrotetrazolium (INT), producing an absorption peak at 500 nm. Triplicate enzymatic reactions were conducted in clear flat-bottom 96-well microtiter plates at 25°C, at a final volume of 100μL. Plates were read for 500nM absorbance using a Cary 300 UV-VIS Spectrophotometer (Varian) . The final assay composition was: 50mM Tris at pH 8.0, 5mM oxidized β- nicotinamide adenine dinucleotide (NAD+), 37.5 units of LGDH, 2mM adenosine diphosphate, 0.65mM INT, 2 units diaphorase, 1mM glutathione, and 1μM HpMurI. The reaction was read for 1 hour immediately following addition of 50μM D-glutamate. Reaction rates were calculated via linear regression of raw absorbance data. Rate values were fit to the log(inhibitor) vs response (four parameters) function inside Graphpad-Prism 9.2.0 DSF Ligand effects on HpMurI thermal stability were carried out in triplicate using 96-well PCR plates. Purified HpMurI samples were diluted to 0.7mg/ml in storage buffer supplemented with 10mM D-glutamate. Test ligands in 100% DMSO were added to wells at 5% DMSO final, along with 6.25X SYPRO orange. Using a CFX Duet Real-Time PCR System, the temperature was increased at 0.5°C per minute, while fluorescence emission was continuously monitored. Spectral data was processed using Melt Traceur to determine melting temperature Tm, and final plots were made in Graphpad-Prism 9.2.0. MIC Determination Antibacterial activity was tested against two different strains of H .pylori : ATCC 43504 (metronidazole-resistant reference strain), and ATCC 700684 (clarithromycin-resistant reference strain) following previously established protocols. (González A et al., Scientific Reports.2019 9(1):11294; PMID: 31383920) H. pylori liquid cultures were grown in Brucella broth UIRF 24058 VHPM 17023.294 supplemented with 10% FBS and placed inside humidified microaerobic incubator (84% N2, 10% CO2, 6% O2) at 37 °C for 72 h. Prior to assay setup, each culture was diluted to a final optical density at 600 nm of 0.01 in culture media.196μL of diluted bacteria was added to all wells in the top row of a sterile 96-well flat-bottom microtiter plate, and 100 μL was added to all other wells. Next, 4μL of 3.2 g/L compound stock (or 1.6g/L in the case of metronidazole, clarithromycin, compound A) in 100% DMSO for each inhibitor were added to wells of the first row and carried over in a two-fold serial dilution. DMSO, metronidazole, clarithromycin and compound A were included as controls. Each inhibitor was tested in a concentration range from 64mg/L (or 32mg/L for controls) to 0.5mg/L (or 0.25mg/L for controls) in triplicate. Plates were incubated under microaerobic conditions at 37 °C and measured for absorbance at 600 nm after 72 hours. MIC values were defined as the lowest concentration of compound that showed no deviation from the antibiotic positive control (Clarithromycin for ATCC 43504 and metronidazole for ATCC 700684). MIC 50 values were obtained by averaging the DMSO and fully inhibited wells, and finding the lowest concentration that dropped below that value for each compound. For MIC determination against E. coli MG1655, E. faecalis OG1RF, and B. subtilis PY79, this protocol was adapted for growth in a humidified incubator. Liquid cultures using Luria broth supplemented with 10% FBS were growth for 16 hours at 37 °C with shaking. Cultures were then diluted to an optical density of 0.01 at 600 nm and plated as described previously. Compound activity was determined by measuring the absorbance at 600 nm after 48 hrs. LogP LogP values for each compound were generated using the SwissADME server. The LogP reported is the consensus of 5 different predictive models. (Daina, A., et al., Scientific Reports.2017, (7)42717; PMID: 28256516) Data for representative compounds is provided in the following table. Data for the following Compound A is provided for comparison. UIRF 24058 VHPM 17023.294 (Compound A) a HpMurI unfolding stabilization determined from DSF. b Coupled enzymatic activity measuring HpMurI mediated turnover of D-glutamate to L-glutamate. c Dissociation constant measured via SPR. d Log octanol/water coefficient, reported as the consensus of various lipophilicity measurements from SwissADME. (Daina, A., et al., Scientific Reports.2017, (7)42717; PMID: 28256516) Example 7. Additional Biological Data HpMurI Expression and Induction The gene encoding HpMurI (ATCC 700824) was inserted into pET15-b after the 6XHis tag. Separately, the chaperone GroEL/ES was inserted into pCH1. Both plasmids were transfected into E. coli BL21 DE3 pLysS cells and grown on Agar plates with 50 μg/ml ampicillin, 30 μg/ml chloramphenicol, and 100 μg/ml kanamycin. Single colonies were cultured overnight at 37 °C with shaking at 180 RPM in 50 ml of Terrific Broth (TB) divided into 5 tubes (10 ml each) supplemented with 50 μg/ml ampicillin, 30 μg/ml chloramphenicol, and 100 μg/ml kanamycin. The 5x10 ml starter cultures were combined and diluted into 4 flasks each containing 750 ml of TB medium with antibiotics. The cultures grew at 37 °C with shaking until the OD600 reached 0.8–1.0. Protein expression was induced upon addition of 0.1 mM IPTG and UIRF 24058 VHPM 17023.294 expressed for 16–18 h at 20 °C with shaking at 180 RPM. Cells were harvested by centrifugation at 5,000 x g at 4 °C for 20 min. Supernatant was discarded and cell pellets were either frozen for storage or resuspended in buffer for purification. HpMurI Protein Purification Cell pellets of BL21 DE3 pLysS overexpressing HpMurI were resuspended in 2X ml per gram buffer A (100 mM Tris, 100 mM NaCl, 10 mM imidazole, 1 mM TCEP, pH 8.0) and supplemented with protease inhibitors. After vortexing to homogenize, 45 µl of 10 mg/ml DNaseI was added. The resuspension was passed through an Emulsiflex homogenizer at least three times at 10,000 psi. Insoluble matter was removed by centrifugation at 30,000 X g for 75 min at 4 °C and the supernatant was passed through a 0.22 μm filter. A HisTrap IMAC HP (GE Healthcare) cobalt resin column was equilibrated with buffer A (10 ml at 1 ml/min). Clarified lysate was then loaded onto the HisTrap column at 1 ml/min. HpMurI was then eluted by running a gradient of buffer A to buffer B (100 mM Tris, 100 mM NaCl, 500 mM imidazole, 1 mM TCEP, pH 8.0) over 50 ml. Selected fractions were run on a SDS-PAGE Gel to determine purity and which fractions to pool. Pooled fractions were concentrated utilizing a 10,000 MWCO Amicon centrifugal filter device. After all selected fractions were combined and concentrated to less than 5 ml, the protein was diluted into SEC buffer (10 mM Tris, 100 mM NaCl, 1 mM TCEP, 10% glycerol, pH 8.0) in less than 2 ml. This was then loaded onto a pre-equilibrated HiLoad 16/200 Superdex column (GE Healthcare) and run with SEC buffer at 0.6 ml/min. Final fractions for pooling were determined via SDS-PAGE, and then concentrated to 5–7 mg/ml for storage at -80 °C. D-glutamate Rescue of H. pylori Growth Liquid cultures of H. pylori strain ATCC 43504 were grown in Brucella broth supplemented with 10% FBS and placed inside humidified microaerobic incubator (84% N2, 10% CO2, 6% O2) at 37 °C for 72 hr. After the OD600 reached 0.5, cultures were diluted into fresh Brucella broth containing 10% FBS, 50mM NaCl, and 0.5mM EDTA (pH 7.0) to enhance membrane permeability. Cells grew at a reduced replication rate for 72 hr, or once the OD600 reached about 0.8. Brucella broth with 10% FBS with the addition of 1mM D-glutamate was brought to pH 7.0. Liquid H. pylori cultures were diluted to an OD600 of 0.01 in Brucella broth UIRF 24058 VHPM 17023.294 10% FBS with and without additional D-glutamate. MICs were determined for compounds A, 2, metronidazole, and DMSO following the protocol discussed above. Cellular growth was normalized to the DMSO (for 100% growth) and metronidazole control (0% growth) to examine changes in antibacterial activity. Scanning Electron Microscopy Strain ATCC 43504 was cultured in liquid media and exposed to compound 2 at concentrations of 2X to 1/8X MIC of (32 to 2 µg/ml), as well as DMSO. After three days of growth inside a humidified microaerobic incubator, 1 ml of each sample was centrifuged for 10 minutes at 14,000 X g. Culture media was aspirated, and 1 ml of 2.5% glutaraldehyde was added to each sample. Each sample was vortexed and left to incubate at 4 °C for 48 hours. Following incubation, samples were briefly spun at 5,000 X g before being loaded onto 0.08 μm pore size filters wetted with 2 ml Dulbecco’s phosphate buffered saline. Sample filters were washed with 2 ml of 50%, 70%, 85%, 95% and 100% ethanol in increasing concentration, and subsequently dried with hexamethyldisilazane before being sputter-coated with gold. The prepared specimens were then examined using a Hitachi S-4000 scanning electron microscope operated at an accelerating voltage of 5.0 kV. Antibiotic Activity Each of the inhibitors showed improved antibacterial activity towards the two antibiotic resistant strains of H. pylori (Table 2). However, only the most potent and hydrophobic inhibitor, 2, was capable of fully preventing H. pylori growth. Compounds 3 and 4 still displayed improved growth inhibition compared to 1 and were capable of fully inhibiting ATCC 700392 (no antibiotic resistance) at the highest concentration tested. From this, it appeared that raising LogP improved H. pylori growth inhibition. Data is shown in the following Table. UIRF 24058 VHPM 17023.294 Loss of Antibiotic Activity with Excess D-glutamate To provide additional evidence for HpMurI being the antibacterial target of the inhibitors, modified MIC experiments were performed in the presence of 1mM D-glutamate. While one would expect poor bacterial penetration from D-glutamate, H. pylori has a well characterized glutamate transporter. A modified MIC assay was developed to examine the impact of extracellular D-glutamate on H. pylori growth inhibition. Compound 2 and compound A both show reduced antibacterial activity in the presence of D-glutamate. In contrast, metronidazole showed full growth inhibition at 32 µg/ml weather or not D-glutamate was present. The loss of antibacterial activity for the HpMurI targeting compounds suggests that they disrupt proper D-glutamate production, which is solely produced by HpMurI. See Fig.1 and Fig.2. Scanning Electron Microscopy The impact of 2 on H. pylori morphology was evaluated. Liquid cultures of H. pylori exposed to varying concentration of 2 were incubated for 72 hours and mounted for Scanning Electron Microscopy (SEM). Each sample showed H. pylori in helical, rod, and coccoid forms to differing degrees. The antibiotic-free sample showed the most classical representation of H. pylori, with most in the helical shape associated with pathogenicity. Altered H. pylori cell envelope structure was observed when treated with sub-MIC concentrations of 2, with the UIRF 24058 VHPM 17023.294 appearance of small ruptures at 2 µg/ml, and reduced helical populations at 4 µg/ml. The samples treated with the highest concentration of 2 appeared to both lose helical structure and have an altered cell wall surface. MIC Values The MIC values for several additional compounds is provided in the following Table. Table aIC50 values along with regression error from the 95% confidence interval of the curve fit are reported. bPPB estimate created by taking the consensus value from three different PPB prediction models. *Value taken from Geng, B., et al., Bioorg Med Chem Lett 2009, 19 (3), 930–936. doi.org/10.1016/j.bmcl.2008.11.113 UIRF 24058 VHPM 17023.294 Species Specificity To evaluate antibiotic specificity, inhibitors were tested against three common gut bacterial strains: E. coli MG1655 (Leatham, M. P., et al., Infection and Immunity 2009, 77 (7), 2876–2886. doi.org/10.1128/iai.00059-09), E. Faecalis OG1RF (PMC. www.ncbi.nlm.nih.gov/pmc/ articles/PMC8470767/ (accessed 2024-05-14)), and B. Subtilis PY79 (PMC. www.ncbi.nlm. nih.gov/pmc/articles/PMC8470767/ (accessed 2024-05-14)). The compounds were administered at concentrations ranging from 0.5 to 64 µg/ml. Data is shown in the following Table. Table HpMurI inhibitors bacterial selectivity Example 8. The following illustrate representative pharmaceutical dosage forms, containing a compound of formula (I) ('Compound X'), for therapeutic or prophylactic use in humans. (i) Tablet 1 mg/tablet Compound X= 100.0 Lactose 77.5 Povidone 15.0 Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5 Magnesium stearate 3.0 300.0 UIRF 24058 VHPM 17023.294 (ii) Tablet 2 mg/tablet Compound X= 20.0 Microcrystalline cellulose 410.0 Starch 50.0 Sodium starch glycolate 15.0 Magnesium stearate 5.0 500.0 (iii) Capsule mg/capsule Compound X= 10.0 Colloidal silicon dioxide 1.5 Lactose 465.5 Pregelatinized starch 120.0 Magnesium stearate 3.0 600.0 (iv) Injection 1 (1 mg/ml) mg/ml Compound X= (free acid form) 1.0 Dibasic sodium phosphate 12.0 Monobasic sodium phosphate 0.7 Sodium chloride 4.5 1.0 N Sodium hydroxide solution (pH adjustment to 7.0-7.5) q.s. Water for injection q.s. ad 1 mL UIRF 24058 VHPM 17023.294 (v) Injection 2 (10 mg/ml) mg/ml Compound X= (free acid form) 10.0 Monobasic sodium phosphate 0.3 Dibasic sodium phosphate 1.1 Polyethylene glycol 400 200.0 1.0 N Sodium hydroxide solution (pH adjustment to 7.0-7.5) q.s. Water for injection q.s. ad 1 mL (vi) Aerosol mg/can Compound X= 20.0 Oleic acid 10.0 Trichloromonofluoromethane 5,000.0 Dichlorodifluoromethane 10,000.0 Dichlorotetrafluoroethane 5,000.0 The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. All publications, patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.

Claims

UIRF 24058 VHPM 17023.294 CLAIMS What is claimed is: 1. A compound of formula (I): or a salt thereof, wherein: R¹ is a 5-membered heteroaryl ring that is optionally substituted with one or more groups independently selected from the group consisting of halo and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from halo; R² is H, R^a, or (C¹-C³)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo and R^a; R³ is absent, a 3-8 membered heterocycle, aryl, a 5-membered heteroaryl, or a (C3- C8)cycloalkyl, which 3-8 membered heterocycle, aryl, a 5-membered heteroaryl, and (C3- C8)cycloalkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, nitro, cyano, hydroxy, (C1-C6)alkyl, oxo (=O), -C(=O)NR^eR^f, and (C1- C6)alkoxy; X is absent, O, S, or -NR^b-; L is a linking group having from 1-10 carbon atoms, wherein one or more of the carbon atoms is optionally replaced independently by -O-, -S, or -N(R^c)-, and wherein each carbon atom is optionally substituted with one or more substituents independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1- C6)alkoxycarbonyl, cyano, nitro, halo, -N(R^d)2, hydroxy, oxo (=O), and carboxy; R^a is a 5-membered heteroaryl ring that is optionally substituted with one or more groups independently selected from the group consisting of halo and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from halo; R^b is H or (C1-C3)alkyl; UIRF 24058 VHPM 17023.294 each R^c is independently H or (C1-C3)alkyl; each R^d is independently H or (C1-C3)alkyl; each R^e is independently H or (C1-C3)alkyl; and each R^f is independently H or (C1-C3)alkyl. 2. The compound or salt of claim 1, wherein: R¹ is a 5-membered heteroaryl ring that is optionally substituted with one or more groups independently selected from the group consisting of halo and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from halo; R² is H, R^a, or (C1-C3)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo and R^a; R³ is absent, a 3-8 membered heterocycle, or a (C3-C8)cycloalkyl, which 3-8 membered heterocycle, and (C3-C8)cycloalkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, nitro, cyano, hydroxy, (C1-C6)alkyl, oxo (=O), and (C1-C6)alkoxy; X is absent, O, S, or -NR^b-; L is a linking group having from 1-10 carbon atoms, wherein one or more of the carbon atoms is optionally replaced independently by -O-, -S, or -N(R^c)-, and wherein each carbon atom is optionally substituted with one or more substituents independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1- C6)alkoxycarbonyl, cyano, nitro, halo, -N(R^d)2, hydroxy, oxo (=O), and carboxy; R^a is a 5-membered heteroaryl ring that is optionally substituted with one or more groups independently selected from the group consisting of halo and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from halo; R^b is H or (C1-C3)alkyl; each R^c is independently H or (C1-C3)alkyl; and each R^d is independently H or (C1-C3)alkyl. UIRF 24058 VHPM 17023.294 3. The compound or salt of claim 1, wherein R¹ is a 5-membered heteroaryl ring that comprises one or more S and that is optionally substituted with one or more groups independently selected from the group consisting of halo and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from halo. 4. The compound or salt of claim 1, wherein R¹ is thienyl that is optionally substituted with one or more groups independently selected from the group consisting of halo and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from halo. 5. The compound or salt of claim 1, wherein R¹ is 2-thienyl that is optionally substituted with one or more groups independently selected from the group consisting of halo and (C1- C6)alkyl that is optionally substituted with one or more groups independently selected from halo. 6. The compound or salt of claim 1, wherein R¹ is a 5-membered heteroaryl ring. 7. The compound or salt of claim 1, wherein R¹ is thienyl. 8. The compound or salt of claim 1, wherein R¹ is 2-thienyl. 9. The compound or salt of any one of claims 1-8, wherein R² is (C1-C3)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo and R^a. 10. The compound or salt of any one of claims 1-8, wherein R² is (C1-C3)alkyl that is substituted with one or more groups independently selected from the group consisting of halo and R^a. 11. The compound or salt of any one of claims 1-8, wherein R² is (C1-C3)alkyl that is substituted with R^a. 12. The compound or salt of any one of claims 1-8, wherein R² is R^a. UIRF 24058 VHPM 17023.294 13. The compound or salt of any one of claims 1-8, wherein R² is H. 14. The compound or salt of any one of claims 1-13, wherein R^a is a 5-membered heteroaryl ring that comprises one or more S and that is optionally substituted with one or more groups independently selected from the group consisting of halo and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from halo. 15. The compound or salt of any one of claims 1-13, wherein R^a is thienyl that is optionally substituted with one or more groups independently selected from the group consisting of halo and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from halo. 16. The compound or salt of any one of claims 1-13, wherein R^a is 2-thienyl that is optionally substituted with one or more groups independently selected from the group consisting of halo and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from halo. 17. The compound or salt of any one of claims 1-13, wherein R^a is a 5-membered heteroaryl ring. 18. The compound or salt of any one of claims 1-13, wherein R^a is thienyl. 19. The compound or salt of any one of claims 1-13, wherein R^a is 2-thienyl. 20. The compound or salt of any one of claims 1-19, wherein R³ is absent. 21. The compound or salt of any one of claims 1-19, wherein R³ is a 3-8 membered heterocycle that is optionally substituted with one or more groups independently selected from the group consisting of halo, nitro, cyano, hydroxy, (C1-C6)alkyl, oxo (=O), and (C1-C6)alkoxy. UIRF 24058 VHPM 17023.294 22. The compound or salt of any one of claims 1-19, wherein R³ is a (C3-C8)cycloalkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, nitro, cyano, hydroxy, (C1-C6)alkyl, oxo (=O), and (C1-C6)alkoxy. 23. The compound or salt of any one of claims 1-19, wherein R³ is: . 24. The compound or salt of any one of claims 1-19, wherein R³ is: . 25. The compound or salt of any one of claims 1-24, wherein X is absent. 26. The compound or salt of any one of claims 1-24, wherein X is O. 27. The compound or salt of any one of claims 1-24, wherein X is S. 28. The compound or salt of any one of claims 1-24, wherein X is -NR^b-. 29. The compound or salt of any one of claims 1-28, wherein L is a linking group having from 1-10 carbon atoms, wherein one or more of the carbon atoms is replaced independently by -O-, -S, or -N(R^c)-, and wherein each carbon atom is optionally substituted with one or more substituents independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, (C¹-C⁶)alkanoyl, (C¹-C⁶)alkanoyloxy, (C¹-C⁶)alkoxycarbonyl, cyano, nitro, halo, -N(R^d)², hydroxy, oxo (=O), and carboxy. 30. The compound or salt of any one of claims 1-28, wherein L is a linking group having from 1-10 carbon atoms, wherein one or more of the carbon atoms is replaced independently by -O-, -S, or -N(R^c)-, and wherein each carbon atom is optionally substituted with one or more UIRF 24058 VHPM 17023.294 substituents independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, halo, -N(R^d)2, hydroxy, and oxo (=O). 31. The compound or salt of any one of claims 1-28, wherein L is a linking group having from 1-10 carbon atoms, wherein one or more of the carbon atoms is replaced independently by -O-, -S, or -N(R^c)-, and wherein each carbon atom is substituted with one or more substituents independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, (C1- C6)alkanoyl, (C1-C6)alkanoyloxy, (C1-C6)alkoxycarbonyl, cyano, nitro, halo, -N(R^d)2, hydroxy, oxo (=O), and carboxy. 32. The compound or salt of any one of claims 1-28, wherein L is a linking group having from 1-10 carbon atoms, wherein one or more of the carbon atoms is replaced independently by -O-, -S, or -N(R^c)-, and wherein each carbon atom is substituted with one or more substituents independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, halo, -N(R^d)2, hydroxy, and oxo (=O). 33. The compound or salt of any one of claims 1-28, wherein L is a linking group having from 1-5 carbon atoms, wherein one or more of the carbon atoms is replaced independently by -O-, -S, or -N(R^c)-, and wherein each carbon atom is optionally substituted with one or more substituents independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1-C6)alkoxycarbonyl, cyano, nitro, halo, -N(R^d)2, hydroxy, oxo (=O), and carboxy. 34. The compound or salt of any one of claims 1-28, wherein L is a linking group having from 1-5 carbon atoms, wherein one or more of the carbon atoms is replaced independently by -O-, -S, or -N(R^c)-, and wherein each carbon atom is optionally substituted with one or more substituents independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, halo, -N(R^d)2, hydroxy, and oxo (=O). 35. The compound or salt of any one of claims 1-28, wherein L is a linking group having from 1-5 carbon atoms, wherein one or more of the carbon atoms is replaced independently by UIRF 24058 VHPM 17023.294 -O-, -S, or -N(R^c)-, and wherein each carbon atom is substituted with one or more substituents independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, (C1- C6)alkanoyl, (C1-C6)alkanoyloxy, (C1-C6)alkoxycarbonyl, cyano, nitro, halo, -N(R^d)2, hydroxy, oxo (=O), and carboxy. 36. The compound or salt of any one of claims 1-28, wherein L is a linking group having from 1-5 carbon atoms, wherein one or more of the carbon atoms is replaced independently by -O-, -S, or -N(R^c)-, and wherein each carbon atom is substituted with one or more substituents independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, halo, -N(R^d)2, hydroxy, and oxo (=O). 37. The compound or salt of any one of claims 1-28, wherein L is -CH2-, -CH2CH2-, -CH2C(=O)N(H)-, or -CH2C(=O)N(H)C(=O)N(H)-. 38. The compound or salt of claim 1, which is selected from the group consisting of: and salts thereof.

UIRF 24058 VHPM 17023.294 39. The compound or salt of claim 1, which is selected from the group consisting of: and salts thereof. 40. A pharmaceutical composition comprising a compound as described in any one of claims 1-39 and a pharmaceutically acceptable excipient. 41. A method for treating or preventing a bacterial infection in an animal comprising administering a compound of formula (I) as described in any one of claims 1-39 or a pharmaceutically acceptable salt thereof to the animal. 42. A method for promoting an antibacterial effect in a bacterial cell comprising contacting the bacterial cell with a compound of formula (I) as described in any one of claims 1-39 or a salt thereof. 43. A compound of formula (I) as described in any one of claims 1-39 or a pharmaceutically acceptable salt thereof for use in medical therapy. 44. A compound of formula (I) as described in any one of claims 1-39 or a pharmaceutically acceptable salt thereof for the prophylactic or therapeutic treatment of a bacterial infection. 45. A compound of formula (I) as described in any one of claims 1-39 or a pharmaceutically acceptable salt thereof for promoting an antibacterial effect in a bacterial cell. UIRF 24058 VHPM 17023.294 46. The use of a compound of formula (I) as described in any one of claims 1-39 or a pharmaceutically acceptable salt thereof to prepare a medicament for treating a bacterial infection in an animal. 47. The use of a compound of formula (I) as described in any one of claims 1-39 or a pharmaceutically acceptable salt thereof to prepare a medicament for method for promoting an antibacterial effect in a bacterial cell.