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WO2025106525A1 - Inhibiteurs de protéines de liaison à la pénicilline - Google Patents

Inhibiteurs de protéines de liaison à la pénicilline Download PDF

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WO2025106525A1
WO2025106525A1 PCT/US2024/055692 US2024055692W WO2025106525A1 WO 2025106525 A1 WO2025106525 A1 WO 2025106525A1 US 2024055692 W US2024055692 W US 2024055692W WO 2025106525 A1 WO2025106525 A1 WO 2025106525A1
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compound
pharmaceutically acceptable
solvate
acceptable salt
stereoisomer
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Inventor
Nathan J. LINE
Steven A. Boyd
Guo-Hua Chu
Stephen M. Condon
David A. Six
Denis M. DAIGLE
Cullen L. MYERS
Tsuyoshi Uehara
Daniel C. Pevear
Cassandra L. CHATWIN
Fan Yi
Lindsay M. AVERY
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VenatoRx Pharmaceuticals Inc
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VenatoRx Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids

Definitions

  • Penicillin binding protein-targeting beta-lactams e.g., penicillins, cephalosporins, and carbapenems
  • PBPs Penicillin Binding Proteins
  • Beta-lactam antibiotics bind with high affinity to PBPs and inhibit their transpeptidase function, resulting in disruption of peptidoglycan cell wall synthesis and rapid cell lysis of actively dividing bacteria.
  • PBPs represent an ideal target for antibacterials.
  • FIG.1. shows the efficacy of equal doses (1 mg/kg SC q4h) of Example 8 and comparator Examples A2 and A4 against A. baumannii ATCC 19606 in a neutropenic murine lung infection model.
  • FIG.2. shows Example 8 unbound plasma concentration-time profile and observed concentrations in the epithelial lining fluid in the neutropenic lung infection model following SC WSGR Docket No.41223-757.601 administration of a 3 mg/kg (single dose). Data are means ⁇ standard deviations.
  • ELF epithelial lining fluid.
  • Described herein are compounds that inhibit the activity of penicillin-binding proteins, the bacterial enzyme class targeted by the beta-lactam antibiotics, and do provide significant antibacterial activity in vitro.
  • a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
  • Also disclosed herein is a method of treating a bacterial infection in a subject, comprising administering to the subject an effective amount of a disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the pharmaceutical composition disclosed herein. Also disclosed herein is a method of inhibiting a bacterial penicillin-binding protein in a human infected with a bacterial infection, comprising contacting said bacterial penicillin-binding protein with an effective amount of a disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the pharmaceutical composition disclosed herein. In some embodiments, the bacterial infection is caused by a Stenotrophomonas spp.
  • the bacterial infection is caused by a Burkholderia spp. In some embodiments, the bacterial infection is caused by a Pseudomonas spp. In some embodiments, the bacterial infection is caused by an Acinetobacter spp. In some embodiments, the bacterial infection is caused by a carbapenem-resistant Enterobacterales (CRE). WSGR Docket No.41223-757.601 INCORPORATION BY REFERENCE All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.
  • CRE carbapenem-resistant Enterobacterales
  • beta-lactam antibiotics Over the decades of clinical use of beta-lactam antibiotics, bacteria have evolved resistance mechanisms that compromise beta-lactam utility, including production of easily transferable, broad- spectrum beta-lactamases that are able to efficiently hydrolyze the beta lactam ring. These enzymes, now counting >1300 variants, have spread throughout all Gram-negative pathogens such as Enterobacterales. The rapid spread of this mechanism of bacterial resistance severely limits beta-lactam therapeutic options.
  • Novel non-beta-lactam compounds that inhibit the transpeptidase function of PBPs and are not degraded by beta-lactamases would represent a major advance in the treatment of resistant bacterial infections, essentially circumventing >70 years of bacterial evolution to protect the function of the penicillin-binding proteins in cell wall biosynthesis.
  • the present invention is directed to certain boron- based compounds (boronic acids and cyclic boronic acid esters) which are PBP inhibitors and antibacterial compounds.
  • the compounds and their pharmaceutically acceptable salts are useful for the treatment of bacterial infections, particularly antibiotic-resistant bacterial infections.
  • Some embodiments include compounds, compositions, pharmaceutical compositions, use, and preparation thereof.
  • Alkyl refers to a straight-chain or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1- butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3- dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl,
  • a numerical range such as “C 1 -C 6 alkyl” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • the alkyl is a C1-C10 alkyl.
  • the alkyl is a C1-C6 alkyl.
  • the alkyl is a C1-C5 alkyl.
  • the alkyl is a C1-C4 alkyl.
  • the alkyl is a C1-C3 alkyl.
  • an alkyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • the alkyl is optionally substituted with one or more oxo, halogen, -CN, - COOH, -COOMe, -OH, -OMe, -NH2, or -NO2.
  • the alkyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.
  • Alkenyl refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans or Z or E conformation about the double bond(s) and should be understood to include both isomers.
  • a numerical range such as “C 2 -C 6 alkenyl”, means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated.
  • an alkenyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or WSGR Docket No.41223-757.601 heteroaryl, and the like.
  • the alkenyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2.
  • the alkenyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.
  • Alkynyl refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like.
  • a numerical range such as “C 2 -C 6 alkynyl”, means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated.
  • an alkynyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • the alkynyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkynyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.
  • Alkylene refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • the alkylene is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or - NO 2 . In some embodiments, the alkylene is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen. “Alkoxy” refers to a radical of the formula -Oalkyl where alkyl is defined as above.
  • an alkoxy group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • the alkoxy is optionally substituted with one or more halogen, -CN, -COOH, -COOMe, - OH, -OMe, -NH2, or -NO2.
  • the alkoxy is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
  • “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.
  • Aryl refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring.
  • the aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, WSGR Docket No.41223-757.601 the aryl is bonded through an aromatic ring atom) or bridged ring systems.
  • the aryl is a 6- to 10-membered aryl.
  • the aryl is a 6-membered aryl (phenyl).
  • Aryl radicals include, but are not limited to anthracenyl, naphthyl, phenanthrenyl, azulenyl, phenyl, chrysenyl, fluoranthenyl, fluorenyl, as-indacenyl, s-indacenyl, indanyl, indenyl, phenalenyl, phenanthrenyl, pleiadenyl, pyrenyl, and triphenylenyl.
  • an aryl may be optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • the aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.
  • the aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
  • Cycloalkyl refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), spiro, and/or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C 3 -C 15 fully saturated cycloalkyl or C 3 -C 15 cycloalkenyl), from three to ten carbon atoms (e.g., C 3 -C 10 fully saturated cycloalkyl or C 3 -C 10 cycloalkenyl), from three to eight carbon atoms (e.g., C 3 -C 8 fully saturated cycloalkyl or C 3 -C 8 cycloalkenyl), from three to six carbon atoms (e.g., C 3 -C 6 fully saturated cycloalkyl or C 3 -C 6 cycloalkenyl), from three to five carbon atoms (e.g., C 3 -C 5 fully saturated cycloalkyl or C 3 -C 5 cycloalkenyl), or three to four carbon atoms (e.g.,
  • the cycloalkyl is a 3- to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered fully saturated cycloalkyl or a 5- to 6-membered cycloalkenyl.
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, cis-decalinyl, trans-decalinyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, and bicyclo[3.3.2]decyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[3.1.1]heptyl, 7,
  • Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • a cycloalkyl is optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • a cycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.
  • a cycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, - CF3, -OH, or -OMe.
  • the cycloalkyl is optionally substituted with halogen.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2- trifluoroethyl, 1,2-difluoroethyl, 2-fluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.
  • Haloalkoxy refers to -O-haloalkyl, with haloalkyl as defined above.
  • “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl. “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine.
  • the alkyl is substituted with one, two, or three amines.
  • Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.
  • “Deuteroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums.
  • Deuteroalkyl includes, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2.
  • the deuteroalkyl is CD3.
  • “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C1-C6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C1-C6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or two atoms selected from the group consisting of oxygen, nitrogen, and sulfur wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • heteroalkyl examples include, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, - CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2.
  • a heteroalkyl is optionally substituted for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • a heteroalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or - NO 2 .
  • a heteroalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • the heteroalkyl is optionally substituted with halogen.
  • Heterocycloalkyl refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl is C-linked. In some embodiments, the heterocycloalkyl is N-linked. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen.
  • the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C 2 -C 15 fully saturated heterocycloalkyl or C 2 -C 15 heterocycloalkenyl), from two to ten carbon atoms (e.g., C 2 -C 10 fully saturated heterocycloalkyl or C 2 -C 10 heterocycloalkenyl), from two to eight carbon atoms (e.g., C 2 -C 8 fully saturated heterocycloalkyl or C 2 -C 8 heterocycloalkenyl), from two to seven carbon atoms (e.g., C 2 -C 7 fully saturated heterocycloalkyl or C 2 -C 7 heterocycloalkenyl), from two to six carbon atoms (e.g., C 2 -C 6 fully saturated heterocycloalkyl or C 2 -C 7 heterocycloalkenyl), from two to five carbon atoms (e.g., C
  • heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyrany
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides.
  • heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring).
  • the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl.
  • the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, WSGR Docket No.41223-757.601 the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8- membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl.
  • the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl.
  • a heterocycloalkyl is optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the heterocycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the heterocycloalkyl is optionally substituted with one or more halogen, methyl, ethyl, - CN, -CF 3 , -OH, or -OMe.
  • the heterocycloalkyl is optionally substituted with halogen.
  • Heteroaryl refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen.
  • the heteroaryl comprises one to three nitrogens.
  • the heteroaryl comprises one or two nitrogens.
  • the heteroaryl comprises one nitrogen.
  • the heteroaryl is C-linked.
  • the heteroaryl is N-linked.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • the heteroaryl is a 5- to 10-membered heteroaryl.
  • the heteroaryl is a 5- to 6-membered heteroaryl.
  • the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered ring comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, or sulfur.
  • Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indoly
  • a heteroaryl is optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • the heteroaryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, - COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.
  • the heteroaryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
  • the term “one or more” when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, four, or more substituents. In some embodiments, the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents.
  • the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.
  • An “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect. “Treatment” of an individual (e.g., a mammal, such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of the individual or cell.
  • treatment includes administration of a pharmaceutical composition, subsequent to the initiation of a pathologic event or contact with an etiologic agent and includes stabilization of the condition (e.g., condition does not worsen) or alleviation of the condition.
  • treatment also includes prophylactic treatment (e.g., administration of a composition described herein when an individual is suspected to be suffering from a bacterial infection).
  • prophylactic treatment e.g., administration of a composition described herein when an individual is suspected to be suffering from a bacterial infection.
  • Compounds Described herein are compounds that modulate the activity of penicillin-binding proteins.
  • the compounds described herein inhibit beta-lactamase.
  • the compounds described herein are useful in the treatment of bacterial infections.
  • the bacterial infection is an upper or lower respiratory tract infection, a urinary tract infection, an intra- abdominal infection, or a skin infection.
  • the bacterial infection is uncomplicated or complicated urinary tract infections, uncomplicated or complicated gonorrhea, upper or lower respiratory tract infections, skin or skin structure infections, intra-abdominal infections, central nervous system infections, blood stream infections, or systemic infections.
  • Ring A is aryl or heteroaryl
  • R 1a is -OH, -OR a , or C 1 -C 6 alkyl
  • R 1b is -OH, -OR a , or C 1 -C 6 alkyl
  • R 6 is hydrogen or C1-C6alkyl
  • X is -OH, -OR X , or -F;
  • R X is C1-C6alkyl or -F;
  • each R Y is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), each R Y is hydrogen. In some embodiments of a compound of Formula . In some embodiments of a compound of Formula (I), Ring A is aryl. In some embodiments of a compound of Formula (I), Ring A is phenyl.
  • Ring A is heteroaryl. In some embodiments of a compound of Formula (I), Ring A is 5- or 6-membered heteroaryl. In some embodiments of a compound of Formula (I), Ring A is 5-membered heteroaryl. In some embodiments of a compound of Formula (I), Ring A is 6-membered heteroaryl. In some embodiments of a compound of WSGR Docket No.41223-757.601 Formula (I), Ring A is pyridinyl, pyrimidinyl, or pyrazinyl. In some embodiments of a compound of Formula (I), Ring A is pyridinyl.
  • R 1a is -OH or -OR a . In some embodiments of a compound of Formula (I), R 1a is -OH. In some embodiments of a compound of Formula (I), R 1a is C1-C6alkyl; In some embodiments of a compound of Formula (I), R 1b is -OH or -OR a . In some embodiments of a compound of Formula (I), R 1b is -OH.
  • R 1b is C 1 -C 6 alkyl; In some embodiments of a compound of Formula (I), each R 2 is independently deuterium, halogen, -OH, -OR a , or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), each R 2 is independently halogen or -OH. In some embodiments of a compound of Formula (I), each R 2 is independently -OH. In some embodiments of a compound of Formula (I), each R 2 is independently halogen. In some embodiments of a compound of Formula (I), n is 0, 1, or 2. In some embodiments of a compound of Formula (I), n is 0 or 1.
  • n is 0. In some embodiments of a compound of Formula (I), n is 1. In some embodiments of a compound of Formula some embodiments of a compound of Formula . In some embodiments of a compound of Formula (I), R 3 is hydrogen, C1-C6alkyl, or C1- C6haloalkyl. In some embodiments of a compound of Formula (I), R 3 is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I), R 3 is C1-C6alkyl. In some embodiments of a compound of Formula (I), R 3 is hydrogen. In some embodiments of a compound of Formula (I), R 6 is hydrogen.
  • R 6 is C 1 -C 6 alkyl.
  • the compound is of Formula (Ia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: In some embodiments of a compound of Formula (I), the compound is of Formula (Ia-1), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: WSGR Docket No.41223-757.601 In some embodiments of a compound of Formula (I), the compound is of Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: In some embodiments of a compound of Formula (I), the compound is of Formula (Ib-1), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: In some embodiments of a compound of Formula (I), the compound is of Formula (Ic), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: WSGR Docket No.41223-757.601 In some embodiments of a compound of Formula (I), the compound is of Formula (Ia), or a pharmaceutically acceptable
  • Formula (Id) WSGR Docket No.41223-757.601 Formula (Id).
  • the compound is of Formula (Id-1), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
  • R 7 is hydrogen, halogen, -OH, -OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 7 is hydrogen, halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), R 7 is hydrogen or halogen. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), R 7 is hydrogen. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), R 7 is halogen.
  • R 8 is hydrogen, halogen, -OH, -OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), R 8 is hydrogen, halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), R 8 is hydrogen or halogen.
  • R 8 is hydrogen. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), R 8 is halogen. WSGR Docket No.41223-757.601 In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), R 9 is hydrogen, halogen, -OH, -OR a , C1-C6alkyl, or C1-C6haloalkyl.
  • R 9 is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), R 9 is hydrogen or halogen. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), R 9 is hydrogen. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), R 9 is halogen.
  • X is -OH. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), X is -OR X . In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), R X is C 1 - C 6 alkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), Z is hydrogen.
  • Z is R 11 and R 11 is C 1 -C 6 alkyl.
  • R 10 is -CH 2 - or -CH(CH 3 )-; and
  • R 11 is C 1 -C 6 alkyl.
  • R 10 is -CH 2 -; and
  • R 11 is C 1 -C 6 alkyl.
  • R 10 is -CH2- or - CH(CH3)-.
  • R10 is -CH2-.
  • R11 is , some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), R 11 is In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), , WSGR Docket No.41223-757.601 In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), each R 5 is independently deuterium, halogen, -OH, -OR a , C1-C6alkyl, or C1-C6haloalkyl.
  • each R 5 is independently deuterium, halogen, C1- C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id- 1), each R 5 is independently halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), each R 5 is independently halogen or C 1 -C 6 alkyl.
  • m is 0, 1, or 2. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), m is 0 or 1. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), m is 0. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), m is 1.
  • m is 2. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), m is 2. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), Ring B is a 4- to 8-membered cycloalkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), Ring B is a 4- to 8-membered monocyclic cycloalkyl.
  • Ring B is a 4- to 6-membered monocyclic cycloalkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), Ring B is a 4-membered monocyclic cycloalkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), Ring B is cyclobutyl.
  • Ring B is a 5-membered monocyclic cycloalkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), Ring B is cyclopentyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), Ring B is a 6-membered monocyclic cycloalkyl.
  • Ring B is cyclohexyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), Ring B is a 5- to 12-membered bicyclic cycloalkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia- 1)-(Id-1), Ring B is a 5- to 10-membered bicyclic cycloalkyl.
  • B is a 7-membered bicyclic cycloalkyl. In some embodiments of a compound of formula (I), (Ia)- (Id), or (Ia-1)-(Id-1), Ring B is a 8-membered bicyclic cycloalkyl.
  • R 4 is aryl independently optionally substituted with one or more R 4a . In some embodiments of a compound of Formula (I), R 4 is phenyl independently optionally substituted with one or more R 4a .
  • R 4 is heteroaryl independently optionally substituted with one or more R 4a .
  • R 4 is 5- or 6- membered heteroaryl, each independently optionally substituted with one or more R 4a .
  • R 4 is 5-membered heteroaryl independently optionally substituted with one or more R 4a .
  • R 4 is 6-membered heteroaryl independently optionally substituted with one or more R 4a .
  • R 4 is pyridinyl, pyrimidinyl, or pyrazinyl, each independently optionally substituted with one or more R 4a .
  • R 4 is pyridinyl independently optionally substituted with one or more R 4a .
  • each R 4a is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R 4a is independently halogen, -OH, -OR a , or C 1 -C 6 alkyl. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), each R 4a is independently halogen or -OH. In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), R 4 is In some embodiments of a compound of formula (I), (Ia)-(Id), or (Ia-1)-(Id-1), R 4 is .
  • each R a is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, -L- cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R a is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, or C1-C6heteroalkyl; wherein each alkyl and heteroalkyl is independently optionally substituted with one or more R.
  • each R a is independently C1-C6alkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, cycloalkyl, and WSGR Docket No.41223-757.601 heterocycloalkyl is independently optionally substituted with one or more R.
  • each R a is independently C1-C6alkyl or C1-C6haloalkyl; wherein each alkyl is independently optionally substituted with one or more R.
  • each R a is independently C1-C6alkyl or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each R a is independently C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each R a is independently C1-C6alkyl.
  • each R b is independently hydrogen, C1- C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, -L- cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 - C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl; wherein each alkyl and heteroalkyl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; wherein each alkyl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, or C 1 - C 6 haloalkyl.
  • each R b is independently hydrogen or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, each R b is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, each R b is hydrogen. In some embodiments of a compound disclosed herein, each R b is independently C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, each R b is independently C 1 -C 6 haloalkyl.
  • each R c and R d are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C 6 heteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R c and R d are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1- C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; wherein each alkyl and heteroalkyl is independently optionally substituted with one or more R.
  • each R c and R d are independently hydrogen, C1-C6alkyl, -L-cycloalkyl, or - L-heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R c and R d are independently hydrogen, C1-C6alkyl or C1-C6haloalkyl; wherein each alkyl is independently optionally substituted with one or more R.
  • each R c and R d are independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each R c and R d are independently hydrogen or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each R c and R d are independently hydrogen or C1-C6alkyl.
  • WSGR Docket No.41223-757.601 In some embodiments of a compound disclosed herein, each R c and R d are hydrogen. In some embodiments of a compound disclosed herein, each R c and R d are independently C1-C6alkyl.
  • each R c and R d are independently C1-C6haloalkyl. In some embodiments of a compound disclosed herein, R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each L is independently absent. In some embodiments of a compound disclosed herein, each L is independently C 1 -C 6 alkylene optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each L is independently C 1 alkylene optionally substituted with one or more R.
  • each L is independently C 2 alkylene optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each L is independently C 3 alkylene optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each L is independently absent, -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -. In some embodiments of a compound disclosed herein, each L is independently -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -. In some embodiments of a compound disclosed herein, each L is independently absent or -CH 2 -.
  • each L is independently absent or -CH 2 CH 2 -. In some embodiments of a compound disclosed herein, each L is independently absent or -CH 2 CH 2 CH 2 -. In some embodiments of a compound disclosed herein, each L is independently -CH 2 -. In some embodiments of a compound disclosed herein, each L is independently -CH 2 CH 2 -. In some embodiments of a compound disclosed herein, each L is independently -CH 2 CH 2 CH 2 -.
  • each R is independently halogen, -CN, -OH, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl; or two R on the same atom form an oxo.
  • each R is independently halogen, -CN, -OH, -NH2, C1-C3alkyl, C1-C3alkoxy, or C1- C3haloalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, C1-C3alkyl or C1-C3haloalkyl; or two R on the same atom form an oxo.
  • the compounds described herein may convert to, or exist in equilibrium with, alternate forms, particularly in milieu that contain water (aqueous solution, plasma, etc.). Accordingly, the compounds described herein may exist in an WSGR Docket No.41223-757.601 equilibrium between a “closed” cyclic form as drawn and an “open” acyclic form. In addition, the compounds described herein may associate into intramolecular dimers, trimers, and related combinations. In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds.
  • the compounds presented herein include all cis, trans, syn, anti,
  • E
  • Z
  • the compounds described herein possess one or more chiral centers and each center exists in the R configuration or S configuration.
  • the compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers.
  • dissociable complexes are preferred.
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities.
  • the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent.
  • Labeled compounds In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds described herein, or a solvate, or stereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2 H, 3 H, 13 C, 14 C, l5 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this disclosure.
  • isotopically-labeled compounds for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., 2 H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • the abundance of deuterium in each of the substituents disclosed herein is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of a total number of hydrogen and deuterium.
  • one or more of the substituents disclosed herein comprise deuterium at a percentage higher than the natural abundance of deuterium.
  • one or more hydrogens are replaced with one or more deuteriums in one or more of the substituents disclosed herein.
  • the isotopically labeled compound or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof is prepared by any suitable method.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • Pharmaceutically acceptable salts In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
  • the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or a solvate, or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
  • Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, but not limited to, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, gluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6
  • the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid,
  • inorganic acids such as hydrochloric acid, hydrobromic
  • acids such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.
  • those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • suitable base such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1- C 4 alkyl) 4 hydroxide, and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.
  • the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.
  • Solvates In some embodiments, the compounds described herein exist as solvates. The disclosure provides for methods of treating diseases by administering such solvates.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer, thereof, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition further comprises a beta-lactam antibiotic.
  • the beta-lactam antibiotic is a penicillin, cephalosporin, carbapenem, monobactam, bridged monobactam, or a combination thereof.
  • the compounds described herein are formulated into pharmaceutical compositions.
  • compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • a summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed.
  • a pharmaceutical composition refers to a mixture of a compound described herein with other chemical components (i.e., pharmaceutically acceptable inactive ingredients), such as carriers, excipients, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, or one or more combination thereof.
  • the pharmaceutical composition facilitates administration of the compound to an organism.
  • therapeutically effective amounts of compounds described herein are administered in a pharmaceutical composition to a mammal having a disease, disorder, or condition to be treated.
  • the mammal is a human.
  • a therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors.
  • the compounds can be used singly or in combination with one or more therapeutic agents as components of mixtures.
  • the pharmaceutical formulations described herein are administered to a subject by appropriate administration routes, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes.
  • the pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, WSGR Docket No.41223-757.601 pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.
  • the present disclosure also provides methods for inhibiting bacterial growth, such methods comprising contacting a bacterial cell culture, or a bacterially infected cell culture, tissue, or organism, with a penicillin-binding protein inhibitor described herein.
  • the bacteria to be inhibited by administration of a penicillin-binding protein inhibitor described herein are bacteria that are resistant to beta-lactam antibiotics.
  • resistant is well-understood by those of ordinary skill in the art (see, e.g., Payne et al., Antimicrobial Agents and Chemotherapy 38767-772 (1994), Hanaki et al., Antimicrobial Agents and Chemotherapy 301120-1126 (1995)).
  • the penicillin- binding protein inhibitor described herein is used to treat a bacterial infection that is resistant to a beta- lactam antibiotic. In some embodiments, the penicillin-binding protein inhibitor described herein is used to treat a bacterial infection that has an acquired or altered beta-lactamase enzyme(s). These methods are useful for inhibiting bacterial growth in a variety of contexts.
  • a compound described herein is administered to an experimental cell culture in vitro to prevent the growth of beta-lactam resistant bacteria. In some embodiments, a compound described herein is administered to a mammal, including a human, to prevent the growth of beta-lactam resistant bacteria in vivo.
  • the method according to this embodiment comprises administering a therapeutically effective amount of a penicillin-binding protein inhibitor described herein for a therapeutically effective period of time to a mammal, including a human.
  • the penicillin-binding protein inhibitor described herein is administered in the form of a pharmaceutical composition as described above.
  • methods of treating a bacterial infection which method comprises administering to a subject a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer, thereof, and a pharmaceutically acceptable excipient.
  • the methods of treating a bacterial infection in a subject comprises administering to the subject a pharmaceutical composition as described herein.
  • the bacterial infection is an upper or lower respiratory tract infection, a urinary tract infection, an intra-abdominal infection, or a skin infection. In some embodiments, the bacterial infection is an upper or lower respiratory tract infection, a urinary tract infection, an intra-abdominal infection, or a skin infection. In some embodiments, the bacterial infection is uncomplicated or complicated urinary tract infections, uncomplicated or complicated gonorrhea, upper or lower respiratory tract infections, skin or skin structure infections, intra-abdominal infections, central nervous system infections, blood stream infections, or systemic infections.
  • the infection that is treated or prevented is cause by a bacteria that includes Aeromonas hydrophilia, Achromobacter ruhlandii, Achromobacter xylosoxidans, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter dijkshoorniae, Acinetobacter haemolyticus, Acinetobacter nosocomialis, Acinetobacter pittii, Acinetobacter seifertii, Alcaligenes faecalis, WSGR Docket No.41223-757.601 Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, Bordetella pertussis, Bordetella
  • the infection that is treated or prevented is caused by Enterobacterales bacteria. In some embodiments, the infection that is treated or prevented is caused by bacteria that include Escherichia spp, Klebsiella spp., Enterobacter spp., Citrobacter spp., Morganella spp., Proteus spp., Salmonella spp., Serratia spp., Shigella spp., or Yersinia spp. WSGR Docket No.41223-757.601
  • the compounds disclosed herein are useful in the treatment or prevention of infection associated with non-fermenting bacteria.
  • the compounds disclosed herein are useful in the treatment or prevention of infection associated with non-fermenting gram-negative bacteria.
  • the non-fermenting gram-negative bacteria are Pseudomonas spp. (for example, P. aeruginosa, P. mendocina, P. acidovorans, P. alcaligenes, P. lundensis, P. fragi, P. oryzihabitans, P. stutzeri, P. fluorescens, and P. putida), Acinetobacter spp. (for example, A. baumannii, A. calcoaceticus, A. dijkshoorniae, A.
  • Pseudomonas spp. for example, P. aeruginosa, P. mendocina, P. acidovorans, P. alcaligenes, P. lundensis, P. fragi, P. oryzihabitans, P. stutzer
  • the infection that is treated or prevented is tuberculosis.
  • the infection that is treated or prevented is caused by Mycobacterium tuberculosis.
  • the infection that is treated or prevented is caused by bacteria that are non-TB mycobacterial species.
  • the non-TB mycobacterial species is M. abscessus, M. africanum, M. asiaticum, M. avium, M. bovis, M. caprae, M. chelonae, M. fortuitum, M. gordonae, M. intracellulare, M. kansasii, M. marinum, M. mucogenicum, M. peregrinum, or M. smegmatis.
  • the infection that is treated or prevented is gonorrhea.
  • the infection that is treated or prevented is caused by Neisseria gonorrhoeae. In some embodiments, the infection that is treated or prevented is meningitis and other forms of meningococcal disease such as meningococcemia. In some embodiments, the infection that is treated or prevented is caused by Neisseria meningitidis. In some embodiments, the infection that is treated or prevented is caused by a bacterium that is Neisseria gonorrhoeae. In some embodiments, the infection that is treated or prevented is caused by a bacterium that is Pseudomonas aeruginosa.
  • the infection that is treated or prevented is caused by a bacterium that is Acinetobacter baumannii. In some embodiments, the infection that is treated or prevented is caused by a bacterium that is a carbapenem-resistant Enterobacterales (CRE).
  • the compound described herein is not administered with a ⁇ -lactam antibiotic. In some embodiments of the methods described herein, the compound described herein is not administered with a ⁇ -lactamase inhibitor. In some embodiments of the methods described herein, the compound described herein is not administered with a combination of a ⁇ - lactam antibiotic and a ⁇ -lactamase inhibitor.
  • the compounds described herein may be used in combination with one or more antibiotics in the treatment of bacterial infections. Such antibiotics may be administered, by a route and in an amount commonly used therefore, contemporaneously, or sequentially with a compound described herein.
  • antibiotics may be administered, by a route and in an amount commonly used therefore, contemporaneously, or sequentially with a compound described herein.
  • a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present invention is preferred.
  • the combination therapy may also include therapies in which the compound described herein and one or more antibiotic are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more antibiotics, the antibiotics may be used in lower doses than when each is used singly.
  • compositions of the present invention also include those that contain one or more antibiotics, in addition to a compound described herein.
  • a pharmaceutical composition comprising a compound described herein further comprises a beta-lactam antibiotic.
  • the beta-lactam antibiotic is a penicillin, cephalosporin, carbapenem, monobactam, bridged monobactam, or a combination thereof.
  • one or more antibiotics are selected from beta-lactam antibiotics.
  • Beta- lactam antibiotics include, but are not limited to, penicillins, penems, carbapenems, cephalosporins, cephamycins, monobactams, or combinations thereof.
  • Penicillins include, but are not limited to, amoxicillin, ampicillin, azidocillin, azlocillin, bacampicillin, benzathinebenzylpenicillin, benzathinephenoxymethylpenicillin, benzylpenicillin (penicillin G), carbenicillin, carindacillin, clometocillin, cloxacillin, dicloxacillin, epicillin, flucloxacillin, hetacillin, mecillinam, metampicillin, meticillin, mezlocillin, nafcillin, oxacillin, penamecillin, pheneticillin, phenoxymethylpenicillin (V), piperacillin, pivampicillin, pivmecillinam, procaine benzylpenicillin, propicillin, sulbenicillin, talampicillin, temocillin, and ticarcillin.
  • Penems include, but are not limited to, faropenem.
  • Carbapenems include, but are not limited to, biapenem, ertapenem, doripenem, imipenem, meropenem, and panipenem.
  • Cephalosporins/cephamycins include, but are not limited to, cefacetrile, cefaclor, cefadroxil, cefalexin, cefaloglycin, cefalonium, cefaloridine, cefalotin, cefamandole, cefapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cefbuperazone, cefcapene, cefdaloxime, cefdinir, cefditoren, cefepime, cefetamet, cefiderocol, cefixime, cefmenoxime, cefmetazole, cefminox, cefodizime, cefonicid
  • Monobactams include, but are not limited to, aztreonam, carumonam, nocardicin A, and tigemonam.
  • the compounds described herein are used in combination with one or more beta-lactamase inhibitors in the treatment of bacterial infections.
  • Certain beta-lactamase inhibitors also may inhibit penicillin-binding proteins.
  • Certain beta-lactamase inhibitors may reduce non-productive binding interactions with beta-lactamases. Thus, certain beta-lactamase inhibitors may synergize with compounds of the present invention to improve antibacterial efficacy.
  • the beta- lactamase inhibitor is avibactam, clavulanic acid, durlobactam, nacubactam, relebactam, sulbactam, tazobactam, or zidebactam. In some embodiments, the beta-lactamase inhibitor is taniborbactam. In some embodiments, the beta-lactamase inhibitor is ETX0462 or NXL-105. WSGR Docket No.41223-757.601 EXAMPLES General Examples for the Preparation of Compounds.
  • the starting materials and intermediates for the compounds of this invention may be prepared by the application or adaptation of the methods described below, their obvious chemical equivalents, or, for example, as described in literature such as The Science of Synthesis, Volumes 1-8. Editors E. M. Carreira, et al., Thieme publishers (2001-2008).
  • the use of protective groups may be as described in methodology compendia such as Greene's Protective Groups in Organic Synthesis, Fifth Edition. John Wiley & Sons, Inc.2014.
  • Certain compounds of Formula I are prepared from the corresponding functional- group-protected boronic acid esters A by treatment with a Lewis acid in a solvent such as dichloromethane, at a temperature between -78 °C and 0 °C followed by an aqueous quench.
  • SCHEME 1 Amide intermediates A may be prepared according to the route outlined in Scheme 2.
  • Chloro- boronates B prepared by methods described previously (e.g., see WO2014089365), is reacted with silylamine bases such as lithium hexamethyldisilazide, and the non-isolated intermediate silylamine (C’) is treated with hydrochloric acid to generate ammonium salt C, typically isolated as a solid.
  • Ammonium salt C is treated with carboxylic acids D under amide-forming coupling conditions (such as with carbodiimide dehydrating reagents, HATU, or other coupling reagents) to provide protected amides A.
  • amide-forming coupling conditions such as with carbodiimide dehydrating reagents, HATU, or other coupling reagents
  • the above amine salt C is allowed to react with acid chlorides E to provide A.
  • Carboxylic acids (D) or acid chlorides (E) may be obtained from commercial sources, prepared according to known methods in the literature, or prepared by a number of different reaction sequences.
  • Formation of the acid chloride (E) involves treatment of (D) with a chlorinating agent such as thionyl chloride, phosphorous pentachloride or oxalyl chloride, in a solvent such as dichloromethane, in the presence of a catalyst such as DMF, at around room temperature. In certain cases, DMF is also used as a co-solvent.
  • a chlorinating agent such as thionyl chloride, phosphorous pentachloride or oxalyl chloride
  • a solvent such as dichloromethane
  • DMF is also used as a co-solvent.
  • Formation of the anhydride (F) involves treatment of acid (D) with a sterically hindered acid chloride or WSGR Docket No.41223-757.601 chloroformate, such as trimethylacetyl chloride or isopropylchloroformate, in an inert solvent such as dichloromethane, in the presence of a non-nucleophilic base, such as triethyl amine or diisopropylethylamine at room temperature or below.
  • a sterically hindered acid chloride or WSGR Docket No.41223-757.601 chloroformate such as trimethylacetyl chloride or isopropylchloroformate
  • an inert solvent such as dichloromethane
  • Compounds H may be converted into boronic acids I by treatment with alkyl lithium reagents, for example n-butyllithium, and then quenching the intermediate aryllithium species with trialkylboronates, followed by aqueous work-up.
  • the boronic acids I may be converted into protected boronate esters J by treatment with 1,2-diols, such as (+)-pinanediol or pinacol.
  • aryl halides H may be converted to boronate esters J by transition-metal-catalyzed reaction with diboron compounds, for example bis[(+)-pinanediolato]diboron and palladium catalysts.
  • reaction mixture was stirred at RT for 2 h, at which time the solution from the above reaction was added to the flask, and the reaction mixture was stirred at RT overnight, then diluted with EtOAc, washed with water, brine, and dried over Na2SO4, concentrated in vacuo to afford the crude product, which was purified by flash chromatography on silica gel (hexane-EtOAc, 20:1-1:1, or hexane- acetone, 10:1-1:1, or DCM-MeOH, 30:1-10:1) to afford the product A.
  • a solution of chloride B (27.8 mmol) in THF (100 mL) was cooled to -78 °C.
  • Step 1-3 Synthesis of benzyl (R)-2-((tert-butoxycarbonyl)amino)-2-(4- (((trifluoromethyl)sulfonyl)oxy)phenyl)acetate (1d).
  • Step 3-2 Synthesis of 3-fluoro-5-hydroxy-4-methoxybenzaldehyde (1m).
  • Li2CO3 370 g, 5 mol, 1.5 eq
  • MeI 473 g, 3.33 mol, 1 eq
  • the reaction mixture was stirred at 45 °C for 24 h.
  • the reaction was diluted with EtOAc, washed with NaCl (saturated aq.), dried over Na2SO4, and evaporated in vacuo.
  • Step 3-3 Synthesis of 2-chloro-5-fluoro-3-hydroxy-4-methoxybenzaldehyde (1n).
  • Step 3-4 Synthesis of 2-chloro-5-fluoro-3,4-dimethoxybenzaldehyde (1o). To a solution of crude 1n (310 g, ⁇ 1.41 mol) in DMF (3 L) was added Cs 2 CO 3 (685 g, 2.1 mol, 1.5 eq), MeI (241.4 g, 1.7 mol, 1.2 eq) at 0 °C. The mixture was stirred overnight at RT.
  • Step 3-6 Synthesis of tert-butyl (2-chloro-5-fluoro-3,4-dimethoxyphenyl)carbamate (1q).
  • Step 3-7 Synthesis of 2-chloro-5-fluoro-3,4-dimethoxyaniline (1r). To a solution of 1q (91.5 g, 300 mmol) in dioxane (1 L) was added 4 N HCl/dioxane (1 L) dropwise. The reaction mixture was stirred at RT for 4 h and then concentrated in vacuo to give desired product 1r as a white solid (73 g, 100%). ESI-MS m/z 206 (M+H) + .
  • Step 3-8 Synthesis of phenyl (2-chloro-5-fluoro-3,4-dimethoxyphenyl)carbamate (1s).
  • reaction mixture was stirred at room temperature for 1 h [NOTE: After 30 min, check pH of reaction mixture to ensure pH 6-9. If the pH is too low, slowly add saturated aqueous NaHCO 3 until desired pH is obtained].
  • the reaction mixture was diluted with EtOAc and acidified to pH 2 with 2 M aqueous HCl. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated.
  • the crude product was purified by flash silica gel chromatography (0-25% MeOH/EtOAc) to yield 8f as a white solid (102.1 g, 67%).
  • Example 8 Large-scale synthesis of Example 8: (R)-3-((R)-2-(3-((1s,4S)-4-(2-chloro-5-fluoro-3,4- dihydroxybenzamido)cyclohexyl)-2-oxoimidazolidine-1-carboxamido)-2-(4- phosphonophenyl)acetamido)-7-fluoro-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8- carboxylic acid. Part 1.
  • Step 2 Compound 8b (1.87 kg, 4.78 mol, 1.0 equiv.) was charged into a 10 L autoclave at RT followed by a charge of MeOH (5.6 L, 3 v/w). The vessel was degassed with nitrogen three times then put under H2 atmosphere (50 psi). The mixture was stirred at 25-30 °C for 24 h then analyzed via in- process control (IPC) by LCMS.
  • IPC in- process control
  • N,N’- carbonyldiimidazole (2.5 kg, 15.4 mol, 1.1 equiv.) was added slowly to the reactor at RT then the reaction was heated to 40 °C for 3-5 h. IPC by LCMS showed full conversion and the reactor was cooled to RT. The organics were washed with H 2 O (54 L, 15 v/w) then citric acid solution (10%, 54 L, 15 v/w) then H 2 O (36 L, 10 v/w). The organic layer was concentrated under vacuum at 40-45 °C to ⁇ 18 L (5 v/w). To this solution was charged iPrOAc (18 L, 5 v/w) and concentrated under vacuum to ⁇ 18 L (5 v/w).
  • 2,2,4,4-Tetramethylpiperidine (227 g, 1.61 mol, 0.1 equiv.) was added to the reactor and heated to 90-100 °C.
  • a solution of SO 2 Cl 2 (2.61 kg, 19.34 mol, 1.2 equiv.) in toluene (9 L, 3 v/w) was added dropwise into the reactor at 90-100 °C over 2 h.
  • the mixture was cooled to 0-5 °C slowly over 16 hrs., filtered, and washed with toluene.
  • the solid was slurried with DCM (18 L, 6 v/w), cooled to 0-10 °C, filtered, and washed with DCM (3 L, 1 v/w) twice.
  • Step 5 A 100 L reactor was charged with Compound 8-2-e (1.83 kg, 8.27 mol, 1.0 equiv.), DMF (9.1 L, 5 v/w), K2CO3 (2.86 kg, 20.7 mol, 2.5 equiv.) and BnBr (3.11 kg, 18.2 mol, 2.2 equiv.) at RT sequentially. The mixture was stirred at 20-30 °C for 2-3 h. The reaction was poured into a mixture of H2O (45 L, 5 v/v for DMF) and EtOAc (18 L, 10 v/w for 2-4).
  • the aqueous layer was charged with MTBE (19 L, 10 v/w) and the pH was adjusted to 1-2 with HCl (conc.). The layers were separated, and the aqueous layer was extracted with MTBE (9.1 L, 5 v/w). The combined organic layers were washed with H 2 O (9.1 L, 5 v/w) then brine (9.1 L, 5 v/w) and concentrated under vacuum (T ⁇ 50 °C) to 5-7 v/w). The solution was charged with n-heptane (18.3 L, 10 v/w), cooled to 0-10 °C, filtered, and the cake was washed with n-heptane.
  • H2O (20 L, 4 v/w) was added to the mixture and the layers were WSGR Docket No.41223-757.601 separated.
  • the organic layer was washed with HCl (1 N, 30 L, 6 v/w) then NaHCO3 (sat. aq., 20 L, 4 v/w) and finally brine (20 L, 4 v/w).
  • the solution was dried with Na2SO4, filtered, and concentrated to 5 v/w.
  • PE 75 L, 15 v/w was added to the mixture, concentrated to 5-8 v/w, followed by a final charge of PE (50 L, 10 v/w).
  • Step 3 Compound 1c (3.64 kg, 10.2 mol, 1.0 equiv.) and DCM (44 L, 12 v/w) were charged to a 100 L reactor at RT then cooled to 0-10 °C. Pyridine (2.42 kg, 30.6 mol, 3.0 equiv.) was added dropwise followed by Tf 2 O (3.30 kg, 11.7 mol, 1.15 equiv.) dropwise at 0-10 °C.
  • a 20 L reactor was charged with Pd(OAc) 2 (27.8 g, 0.12 mol, 0.075 equiv.), dppf (135 g, 0.25 mol, 0.1 equiv.) and KOAc (32.1 g, 0.32 mol, 0.2 equiv.) at RT.
  • the atmosphere was replaced with N 2 three times then THF (13.6 L, 17 v/w) and DIPEA (200.9 g, 1.5 mol, 0.95 equiv.) were charged to the reactor.
  • the atmosphere was again exchanged with N 2 three times.
  • the reaction was warmed to 60-65 °C for 15-30 min. then cooled to 50-55 °C.
  • Step 2 A 10 L reactor was charged with RSM-3 (600 g, 1.22 mol, 1.0 equiv.) at RT. H 2 O (6.0 L, 10 v/w) was added to the reactor followed by TFA (139 g, 1.22 mol, 1.0 equiv.) at RT. Pd/C catalyst (10% w/w, 60 g) was added at RT. The atmosphere was replaced with N 2 three times followed by a H 2 atmosphere replacement three times.
  • the aqueous layer was diluted with EtOAc (6.0 L, 10 v/w) and acidified to pH 1-2 with HCl (2 M). The layers were separated and the aqueous layer was extracted with EtOAc (6.0 L, 10 v/w). The combined organic layers were washed with brine (3.0 L, 5 v/w), dried with Na 2 SO 4 , filtered, and concentrated to 5 v/w (for RSM-3) under vacuum at 45 °C. The residue was charged with n-heptane (0.84 L, 1.4 v/w) dropwise at RT and stirred for 16 h.
  • n-heptane (3.84 L, 6.4 v/w) was added and the mixture was cooled to 0-10 °C.
  • the solid was filtered, washed with n-heptane, and dried under vacuum (T ⁇ 45 °C).
  • Steps 2 & 3 were repeated five times and all batches were combined at this stage for further processing.
  • the solid was charged into a 50 L reactor containing a mixture of EtOAc (16 L, 5 v/w) and n-heptane (16 L, 5 v/w).
  • Step 4 A reactor was charged with 8-2-g (RSM-2b,145 g, 374.9 mol, 1.0 equiv.) and DCM (1.45 L, 10 v/w) at RT. The mixture was cooled to 0-10 °C and charged with N-hydroxysuccinimide (77.7 g, 674.8 mol, 1.8 equiv.). EDCI (129.4 g, 674.8 mol, 1.8 equiv.) was added in portions at 0-10 °C.
  • the reaction was warmed to RT and stirred for 2-3 h.
  • the mixture was quenched with brine (1.45 L, 10 v/w) and the layers were separated.
  • the organic layer was washed with NaHCO3 (sat. aq., 725 mL, 5 v/w) then brine (1.45 L, 10 v/w) and then concentrated to 2-3 v/w.
  • the solution was charged with PE (290 mL, 2 v/w), concentrated to 2-3 v/w, charged again with PE (725 mL, 5 v/w), cooled to 0-10 °C, and WSGR Docket No.41223-757.601 stirred for 2-3 h.
  • Step 5 Compound 8f [Step 3] (170 g, 284.9 mol, 1.0 equiv.) and DCM (1.5 L, 10 v/w) were charged to a reactor at RT under N 2 atmosphere. The solution was cooled to 0-10 °C and TFA (422.4 g, 3.17 mol, 13.0 equiv.) was added slowly to maintain the temperature below 5 °C.
  • a reactor was charged with 8-4-e (RSM-4, 80.0 g, 171.4 mol, 1.0 equiv., described in WO2022250776, Example 200) and THF (640 mL, 8 v/w) at RT under N 2 atmosphere.
  • the mixture was cooled to -65--60 °C and charged with LiHMDS (1.0 M in THF, 180 mL, 180 mL, 180 mL, 180 mol 1.05 equiv.) while maintaining the temperature below -60 °C.
  • the reaction was warmed to 15-20 °C and stirred for 1-2 h then cooled to 0-5 °C.
  • Step 8 WSGR Docket No.41223-757.601
  • Example 8 (R)-7-fluoro-3-((R)-2-(3-((1s,4S)-4-(3-fluoro-4,5-dihydroxybenzamido)cyclohexyl)-2- oxoimidazolidine-1-carboxamido)-2-(4-phosphonophenyl)acetamido)-2-hydroxy-3,4-dihydro-2H- benzo[e][1,2]oxaborinine-8-carboxylic acid.
  • Step 2-2 Synthesis of tert-butyl (1R,4r)-4-(3-(((R)-1-(4-(diethoxyphosphoryl)phenyl)-2-methoxy-2- oxoethyl)carbamoyl)-2-oxoimidazolidin-1-yl)cyclohexane-1-carboxylate (16h).
  • Example A1 Parenteral Composition To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100 mg of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer, WSGR Docket No.41223-757.601 thereof, is dissolved in DMSO and then mixed with 10 mL of 0.9% sterile saline solution. The mixture is incorporated into a dosage unit suitable for administration by injection.
  • Example A2 Oral Composition To prepare a pharmaceutical composition for oral delivery, 400 mg of compound disclosed and the following ingredients are mixed intimately and pressed into single scored tablets.
  • Tablet Formulation Ingredient Quantity per tablet (mg) compound 400 cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5 The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule.
  • Capsule Formulation Ingredient Quantity per capsule (mg) compound 200 lactose spray dried 148 magnesium stearate 2 Biological Examples
  • Example I Experimental Method for Penicillin-Binding Protein Binding Assays with Bocillin-FL via Fluorescence Polarization To determine the ability of boronic acid-based test PBP inhibitors to bind Penicillin Binding Proteins (PBPs), Bocillin-FL (fluorescently-labeled penicillin V; ThermoFisher Scientific) was used in a fluorescence polarization (FP) competition binding assay to assess inhibitor binding to PBP3 from Escherichia coli (K-12), PBP3 from Pseudomonas aeruginosa (PAO1), and PBP3 from Acinetobacter
  • PBPs were cloned and purified as described previously (E. coli PBP3, King, D.T, et al., ACS Infectious Diseases 2015, 1, 175-184; P. aeruginosa PBP3, Han et. al., PNAS 2010, 107 (51), 22002-22007; A. baumannii PBPs, Penwell et. al., Antimicrob. Agents Chemother.2015, 59 (3), 1680 – 1689). To establish assay conditions for competition binding, enzyme titration/ saturation binding experiments were initially performed.
  • Bocillin-FL was prepared at 0.2 ⁇ M in a buffer comprised of 50 mM HEPES (pH 8.0), 300 mM NaCl and 10% (v/v) glycerol for reactions with E. coli and P. aeruginosa PBPs, and 25 mM Tris (pH 8.0), 200 mM NaCl, 10% (v/v) glycerol and 0.005% (v/v) Tween 20 for reactions with A. baumannii PBP3.
  • Saturation binding was performed by mixing 40 ⁇ L of PBP solutions ranging in concentrations from 0 – 24 ⁇ M with 40 ⁇ L of the 0.2 ⁇ M Bocillin-FL solution, in individual wells of a black 384-well microplate.
  • FP was measured immediately upon mixing (Excitation, 490 nm; Emission, 520 nm; g-factor, 0.96), using a Cytation3 (BioTek) microplate reader and measured continuously for up to 120 min.
  • the FP response stabilized after 15 min for P. aeruginosa and A. baumannii PBP3, 30 min for E. coli PBP3 and A. baumannii PBP1a. In all instances, the FP signal showed a dose dependence on PBP concentration.
  • the competition binding assay (80 ⁇ L final volume) was validated using beta-lactams and PBPs at final concentrations of: 1.5 ⁇ M for E. coli PBP3; 0.75 mM WSGR Docket No.41223-757.601 for P. aeruginosa PBP3; and 0.2 mM for A. baumannii PBP3.
  • Bocillin-FL was at 0.1 ⁇ M (0.05 mM with A. baumannii PBP1a) and beta-lactam concentrations ranged from 0 – 1,000 ⁇ M.
  • E. coli PBP3 was incubated with increasing concentrations of ampicillin in a black 384-well microplate (Corning) for 30 min. P.
  • aeruginosa PBP3 was incubated for 15 min with aztreonam, whereas A. baumannii PBP1a and PBP3 were incubated for 15 minutes with meropenem, and then Bocillin-FL was added followed immediately by the FP measurement for up to 60 min.
  • the beta-lactam potency was reported as the concentration of beta-lactam required to reduce the amount of PBP bound-Bocillin-FL by 50% (EC50), calculated according to the following equation: where y is the fraction bound at a given inhibitor concentration, y min is the fraction bound when the enzyme is completely inactivated, y max is the maximum (uninhibited) fraction bound, and x is the inhibitor concentration.
  • coli PBP3 was determined to be 1.4 ⁇ M.
  • the EC 50 of aztreonam was determined to be ⁇ 0.5 mM for P. aeruginosa PBP3.
  • EC 50 s for meropenem with A. baumannii PBP1a and PBP3 were determined to be ⁇ 0.5 ⁇ M and 0.23 mM, respectively.
  • Binding assays for boronic acid PBP inhibitors were performed in an identical fashion for the respective PBPs. Fluorescence polarization assay conditions for measurement of EcPBP2 binding affinities were determined in a similar fashion as for PBP3 enzymes, using 5-TAMRA ampicillin instead of Bocillin FL (Shapiro, et al.
  • Example II Experimental method for penicillin-binding protein binding assays with Bocillin-FL via gel filtration Affinity to A. baumannii PBP1a and PBP2 was assessed in a competitive equilibrium binding assay using Bocillin-FL as the reporter molecule. Enzyme was pre-incubated with increasing concentrations of inhibitors, prior to addition of Bocillin and further incubation for 15 min. PBP bound with Bocillin-FL was separated by gel filtration using 96-well Zeba Spin size exclusion plates, and the fluorescence measured.
  • the inhibitor affinity (reported as the EC50) was determined by plotting the fraction of PBP bound with Bocillin-FL at each inhibitor concentration against the inhibitor concentration, and fitting the data to the following equation: where y is the fraction bound at a given inhibitor concentration, ymin is the fraction bound when the enzyme is completely inactivated, ymax is the maximum (uninhibited) fraction bound, n is the Hill coefficient, and x is the inhibitor concentration.
  • WSGR Docket No.41223-757.601 Representative results for binding to A.
  • baumannii PBP1a and PBP2 are shown in Table 5, where A represents a potency of >50 ⁇ M, B represents a potency between 10 ⁇ M and 50 ⁇ M inclusive, C represents a potency between 1 ⁇ M and 10 ⁇ M, and D represents potency ⁇ 1 ⁇ M.
  • NT Not Tested. Table 5. Binding affinity to A. baumannii PBP1a and PBP2 by Exemplary Compounds in competition binding assay using Bocillin-FL via gel filtration.
  • Example III Experimental method for A. baumannii penicillin-binding protein-5 and penicillin- binding-protein 7 binding assays Affinity to A.
  • baumannii PBP5 and PBP7 was assessed in a competitive equilibrium binding assay using Bocillin-FL as the reporter molecule.
  • Enzyme was pre-incubated with increasing concentrations of inhibitors for 90 min (30 min for PBP7), prior to the addition of Bocillin and further incubation for 15 min.
  • PBP bound with Bocillin-FL was separated by sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE), followed by fluorescence imaging of the SDS-PAGE gel and densitometric analysis.
  • Example IV Primary MIC screening assays in cation-adjusted Mueller Hinton broth To determine the ability of test compounds to inhibit the growth of bacterial strains, classic cell-based broth microdilution minimum inhibitory concentration (MIC) assays were employed. MIC assays are performed according to CLSI methods except where otherwise noted (CLSI, 2018 and CLSI, 2024).
  • aeruginosa ATCC 35151 and an engineered efflux pump- compromised strain of P. aeruginosa ( ⁇ mexAB-oprM) were used to determine the ability of PBP inhibitors to penetrate the outer membrane of P. aeruginosa and A. baumannii and assess antibacterial activity against these important gram-negative organisms.
  • ⁇ mexAB-oprM engineered efflux pump- compromised strain of P. aeruginosa
  • Bp82 Burkholderia pseudomallei ⁇ purM adenine auxotroph strain
  • aeruginosa and A. baumannii
  • B. pseudomallei Bp82 cation-adjusted Mueller Hinton agar supplemented with 0.6 mM adenine
  • plates are sealed with parafilm and stored refrigerated for up to two weeks.
  • at least 5 colonies are picked from the agar plates with an inoculating loop and aseptically transferred to a culture tube containing either 3 mL of cation-adjusted Mueller Hinton broth (CAMHB) for Enterobacterales, P. aeruginosa and A.
  • CAMHB cation-adjusted Mueller Hinton broth
  • baumannii or 3 mL of cation-adjusted Mueller Hinton broth supplemented with 0.6 mM adenine for B. pseudomallei Bp82.
  • a direct suspension was prepared in PBS or saline. The broth culture is grown for 3-5 hours at 37 °C with shaking at 200 rpm (Enterobacterales, P. aeruginosa and A. baumannii) or in a stationary ambient air incubator at 37 °C (B. pseudomallei Bp82). Meanwhile, 2-fold serial dilutions of test compounds are conducted in a 96-well plate with a final volume of 50 ⁇ L per well at 2-fold the final desired concentration.
  • the growing cultures are then diluted in a cuvette containing CAMHB and the optical density is measured at 600 nm.
  • the inoculum is diluted such that 50 ⁇ L of this culture in WSGR Docket No.41223-757.601 CAMHB (supplemented with 2 ⁇ 0.6 mM adenine for B. pseudomallei Bp82) results in a starting bacterial concentration of 2-8 ⁇ 10 5 CFU/mL when added to the dilution plates.
  • the plates are incubated for 16-20 hours for Enterobacterales and P. aeruginosa and 20-24 hours for A. baumannii and B. pseudomallei at 37 °C.
  • baumannii strains are shown in Table 8, where A represents an MIC ⁇ 128 ⁇ g/mL, B represents an MIC of 16 to 64 ⁇ g/mL, C represents an MIC from 2 to 8 ⁇ g/mL, and D represents an MIC ⁇ 1 ⁇ g/mL.
  • NT Not Tested.
  • Table 8 Inhibition of bacterial growth. Minimum inhibitory concentrations of Exemplary Compounds for P. aeruginosa and A. baumannii strains in CAMHB.
  • Example V Primary MIC screening assays in iron-depleted cation-adjusted Mueller Hinton broth To determine the ability of test compounds to inhibit the growth of bacterial strains under conditions of iron-depletion, classic cell-based broth microdilution minimum inhibitory concentration (MIC) assays were employed. MIC assays are performed according to CLSI methods except where otherwise noted (CLSI, 2018 and CLSI, 2024). The reference type strain E. coli ATCC 25922 was used WSGR Docket No.41223-757.601 to determine the ability of the PBP inhibitors to inhibit the growth of Enterobacterales. Wild-type P. aeruginosa ATCC 27853, A. baumannii ATCC 17978 and A.
  • P. aeruginosa CDC-0054 producing VIM-4, OXA-50, and PDC
  • P. aeruginosa CDC-0090 producing KPC-5, OXA-50, and PDC;
  • Aeruginosa CDC-0095 producing OXA-50, and PDC
  • five challenge isolates of Acinetobacter baumannii A. baumannii 1258916 producing ADC-33, OXA-23, and OXA-82
  • A. baumannii CDC-0033 producing NDM-1, and OXA-94
  • A. baumannii CDC-0036 producing OXA-65, and OXA-24
  • A. baumannii CDC-0045 producing TEM-1D, OXA-23, and OXA-69; and A.
  • baumannii 1179589 producing PER-1, OXA-58, ADC-76, OXA-68) were used to further assess antibacterial activity in non- fermenters and demonstrate activity of the PBP inhibitors irrespective of the beta-lactamase content of these organisms.
  • two Burkholderia bioweapon pathogen surrogate strains, B. thailandensis ATCC 700388 and B. humptydooensis ATCC BAA-2767 were used to assess potential biodefense applications. Briefly, cryo-preserved bacterial cultures of challenge strains are streaked for isolation on appropriate agar medium, in this case cation-adjusted Mueller Hinton agar.
  • 2-fold serial dilutions of test compounds are conducted in a 96-well plate with a final volume of 50 ⁇ L per well at 2-fold the final desired concentration.
  • the growing cultures are then diluted in a cuvette containing IDM and the optical density is measured at 600 nm.
  • the inoculum is diluted such that 50 ⁇ L of this culture in IDM results in a starting bacterial concentration of 2-8 ⁇ 10 5 CFU/mL when added to the dilution plates.
  • the plates are incubated for 16-20 hours for Enterobacterales and P. aeruginosa and 20-24 hours for A. baumannii at 37 °C.
  • the MIC values are read visually as the lowest concentration well with no bacterial growth.
  • NT Not Tested.
  • Table 9 Inhibition of bacterial growth. Minimum inhibitory concentrations of Exemplary Compounds for P. aeruginosa strains in iron-depleted CAMHB (IDM).
  • Table 10 Inhibition of bacterial growth. Minimum inhibitory concentrations of Exemplary Compounds for A. baumannii strains in iron-depleted CAMHB (IDM).
  • Table 11 Inhibition of bacterial growth.
  • Example VI Secondary MIC screening assay testing against Acinetobacter baumannii To determine the ability of test compounds to inhibit the growth of Acinetobacter baumannii, broth microdilution MIC assays were performed using iron-depleted cation-adjusted Mueller Hinton broth (IDM). MIC assays are performed according to CLSI methods except where otherwise noted (CLSI, 2018 and CLSI, 2024). Forty A. baumannii clinical isolates were tested to observe the antibacterial activity of the test compounds versus this challenging bacteria species.
  • IDM iron-depleted cation-adjusted Mueller Hinton broth
  • the growing cultures are then diluted in a cuvette containing IDM and the optical density is measured at 600 nm.
  • the inoculum is diluted such that 50 ⁇ L of this culture in IDM results in a starting bacterial concentration of 2-8 ⁇ 10 5 CFU/mL when added to the dilution plates.
  • the plates are incubated for 20-24 hours at 37 °C.
  • the MIC values are read visually as the lowest concentration well with a major reduction in growth where 80% of the bacterial growth is inhibited.
  • WSGR Docket No.41223-757.601 MIC results for testing compounds in the A. baumannii secondary screening assay in iron- depleted media conditions are shown in Table 12, values are ⁇ g/mL.
  • the MIC50 and MIC90 are determined by first sorting the MIC values in order from low to high values and then selecting the MIC value of the 20 th and 36 th strains. This value is the concentration of test compound required to rescue 50 and 90%, respectively, of isolates in the panel.
  • Table 22 The structures of the Comparator Examples are shown in Table 22 below.
  • Table 12 Summary of Secondary Acinetobacter baumannii MIC Screening Assay Data.
  • Example VII Tertiary screening of Multidrug-Resistant Organism Repository and Surveillance Network (MRSN) Acinetobacter baumannii diversity strain collection. Test compounds were evaluated versus a large panel of 100 clinical A. baumannii strains with a wide variety of resistance profiles and mechanisms. This published panel was assembled from >3,500 A.
  • MRSN Multidrug-Resistant Organism Repository and Surveillance Network
  • the set includes one pan-drug resistant strain, 35 extensively drug-resistant strains, 27 multidrug-resistant strains and 34 carbapenem-resistant strains. Briefly, cryo-preserved bacterial cultures of challenge strains are streaked for isolation on appropriate agar medium, in this case cation-adjusted Mueller Hinton agar. Following incubation to allow growth of the colonies, plates are sealed with parafilm and stored refrigerated for up to two weeks.
  • the growing cultures are then diluted in a cuvette containing IDM and the optical density is measured at 600 nm.
  • the inoculum is diluted such that 50 ⁇ L of this culture in IDM results in a starting bacterial concentration of 2-8 ⁇ 10 5 CFU/mL when added to the dilution plates.
  • the plates are incubated for 20-24 WSGR Docket No.41223-757.601 hours at 37 °C.
  • the MIC values are read visually as the lowest concentration well with a major reduction in growth where 80% of the bacterial growth is inhibited.
  • MIC results for testing compounds in the A. baumannii secondary screening assay in iron- depleted media conditions are shown in Table 13, values are ⁇ g/mL.
  • the MIC50 and MIC90 are determined by first sorting the MIC values in order from low to high values and then selecting the MIC value of the 50 th and 90 th strains. This value is the concentration of test compound required to rescue 50 and 90%, respectively, of isolates in the panel.
  • Table 22 The structures of the Comparator Examples are shown in Table 22 below.
  • Table 13 MRSN A. baumannii diversity panel MIC testing results.
  • Acinetobacter baumannii – calcoaceticus complex panel testing Test compounds were evaluated versus a panel of 100 non-baumannii Acinetobacter clinical isolates. This panel included 20 strains each of Acinetobacter calcoaceticus, Acinetobacter dijkshoorniae, Acinetobacter nosocomialis, Acinetobacter pittii, and Acinetobacter seifertii.
  • cryo-preserved bacterial cultures of challenge strains are streaked for isolation on appropriate agar medium, in this case cation-adjusted Mueller Hinton agar. Following incubation to allow growth of the colonies, plates are sealed with parafilm and stored refrigerated for up to two weeks.
  • agar medium in this case cation-adjusted Mueller Hinton agar.
  • IDM iron- depleted cation-adjusted Mueller Hinton broth
  • a direct suspension was prepared in PBS or saline.
  • the broth culture is grown for 3-5 hours at 37 °C with shaking at 200 rpm. Meanwhile, 2-fold serial dilutions of test compounds are conducted in a 96-well plate with a final volume of 50 ⁇ L per well at 2-fold the final desired concentration. After the dilution plates are set up the growing cultures are then diluted in a cuvette containing IDM and the optical density is measured at 600 nm. The inoculum is diluted such that 50 ⁇ L of this culture in IDM results in a starting bacterial concentration of 2-8 ⁇ 10 5 CFU/mL when added to the dilution plates. The plates are incubated for 20-24 hours at 37°C.
  • the MIC values are read visually as the lowest concentration well with a major reduction in growth where 80% of the bacterial growth is inhibited. Results for each species are shown in Tables 14-18, MIC values are ⁇ g/mL.
  • the MIC 50 and MIC 90 are determined by first sorting the MIC values in order from low to high values and then selecting the MIC value of the 10 th and 18 th strains. This value is the concentration of test compound required to rescue 50 and 90%, respectively, of isolates in the panel.
  • the structures of the Comparator Examples are shown in Table 22 below. Table 14.
  • Example IX Colistin resistant Acinetobacter baumannii MIC testing Test compounds were evaluated versus a panel of 20 colistin-resistant Acinetobacter baumannii clinical isolates. Briefly, cryo-preserved bacterial cultures of challenge strains are streaked for isolation on appropriate agar medium, in this case cation-adjusted Mueller Hinton agar.
  • the growing cultures are then diluted in a cuvette containing IDM and the optical density is measured at 600 nm.
  • the inoculum is diluted such that 50 ⁇ L of this culture in IDM results in a starting bacterial concentration of 2-8 ⁇ 10 5 CFU/mL when added to the dilution plates.
  • the plates are incubated for 20-24 hours at 37 °C.
  • the MIC values are read visually as the lowest concentration well with a major reduction in growth where 80% of the bacterial growth is inhibited. Colistin-resistant Acinetobacter baumannii MIC testing results are shown in Table 19. MIC values are ⁇ g/mL.
  • the MIC 50 and MIC 90 are determined by first sorting the MIC values in order from WSGR Docket No.41223-757.601 low to high values and then selecting the MIC value of the 10 th and 18 th strains. This value is the concentration of test compound required to rescue 50 and 90%, respectively, of isolates in the panel.
  • the structures of the Comparator Examples are shown in Table 22 below. Table 19. Colistin-resistant Acinetobacter baumannii testing results.
  • Example X Acinetobacter baumannii Monogue panel MIC testing Test compounds were evaluated in a panel of 35 strains with published cefiderocol in vivo efficacy data (Monogue, M.
  • the growing cultures are then diluted in a cuvette containing IDM and the optical density is measured at 600 nm.
  • the inoculum is diluted such that 50 ⁇ L of this culture in IDM results in a starting bacterial concentration of 2-8 ⁇ 10 5 CFU/mL when added to the dilution plates.
  • the plates are incubated for 20-24 hours at 37 °C.
  • the MIC values are read visually as the lowest concentration well with a major reduction in growth where 80% of the bacterial growth is inhibited. MIC testing results are shown in Table 20. MIC values are ⁇ g/mL.
  • the MIC50 and MIC90 are determined by first sorting the MIC values in order from low to high values and then selecting the MIC value of the 18 th and 32 nd strains. This value is the concentration of test compound required to rescue 50 and 90%, respectively, of isolates in the panel.
  • Table 22 The structures of the Comparator Examples are shown in Table 22 below. Table 20. Monogue, et al. set of Acinetobacter baumannii MIC testing results. WSGR Docket No.41223-757.601
  • Example XI Experimental method for determining Filamentation Prevention Concentration (FPC) using a microscopy-based assay A microscopy-based assay was performed to determine the ability of boronic acid-based test PBP inhibitors to inhibit PBPs in the cellular context.
  • FPC Filamentation Prevention Concentration
  • the cell images taken were analyzed computationally using the oCelloScope software UniExplorer version 12.1 to determine the boundary of cells (maximum number of cells 500) and generate the shape parameters of each cell including the average cell width and length, followed by the calculation of geomean of the ratios of average cell length to average cell width for all cells analyzed in each image.
  • the “Filamentation Prevention Concentration” (FPC) for each PBP inhibitor was determined.
  • Example XII Experimental Method for Determining Plasma Stability Using a UPLC-MS/MS Based Assay An ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) based assay was performed to determine the metabolic stability of boronic acid-based PBP inhibitors in human and mouse plasma with K2EDTA as the anticoagulant.
  • Stock solutions of test compounds (exemplary and comparator) were prepared at 2 mg/mL concentration in dimethyl sulfoxide (DMSO).
  • the stock WSGR Docket No.41223-757.601 solution of each test compound was diluted with pre-warmed pH-adjusted plasma (BioIVT, Westbury, NY) (pH 7.4, adjusted with 1M HCl) to a concentration of 20 ⁇ g/mL.
  • the plasma samples were incubated in a 37 °C water bath. Three aliquots of 20 ⁇ L of the plasma samples were taken at 0, 10, 30, and 60 minutes. The collected samples were stored in – 80 °C freezer before analysis.
  • the assay was performed with a Waters Xevo TQS-micro mass spectrometry (with electrospray ionization source) coupled with Waters I-class UPLC (Waters Corp, Milford, MA).
  • a Waters Acquity BEH C8 (50 ⁇ 2.1 mm, 1.7 ⁇ m) reverse phase column was used for the compound retention.
  • the mobile phase (MP) A was 0.5% formic acid in H 2 O; MP B was 0.5% formic acid in ACN; weak needle wash was 90/10 H 2 O/MeOH with 0.02% NH 4 OH (pH 10); strong needle wash was 10/90 H 2 O/ACN and seal wash was 90/10 H 2 O/ACN.
  • All solvents and additives used on UPLC- MSMS assay were Optima ® grade obtained from Fisher Scientific, Waltham, MA). With a flow rate of 0.6 mL/min, the UPLC gradient started with 15% MP B, and the content of MP B increased to 30% from 0.2 to 0.8 min and then increased to 95% from 0.8 to 1.2 min.
  • Plasma stability in human and mouse plasma for part of the exemplary compounds, plus comparators.
  • Example XIII Experimental Method for Determining Plasma Stability Using a UPLC-MS/MS Based Assay
  • Example compounds were evaluated for metabolic stability in plasma from four different species (mouse, rat, dog, and monkey). Test compounds were incubated in these matrices at 1 ⁇ M in a 37 °C water bath for 120 minutes. Test compounds and control compounds (tetracaine, bisacodyl, diltiazem, and propantheline) were dissolved in DMSO to obtain 10 mM stock solutions. These stock solutions were diluted to 200 ⁇ M working solution in DMSO.
  • terfenadine and 1 mg/mL tolbutamide stock solutions were prepared in DMSO, respectively.
  • the Internal Standard (IS) working solutions were prepared by serially diluting the stock solutions in acetonitrile.
  • the final IS concentration of terfenadine and tolbutamide was 5 ng/mL and 10 ng/mL, respectively.
  • Example XIV Experimental Method for Determining Hepatocyte Stability Using a UPLC-MS/MS Based Assay Hepatocyte stability assays are widely used as an in vitro model to characterize the metabolic conversion of new chemical entities by both phase I and phase II enzymes within the intact cell. Compared to liver microsomes, the metabolic stability assay using hepatocytes can assess not only reticular, but also cytosolic and mitochondrial enzymes. Since metabolism is known to be highly variable in different species, hepatocytes metabolic stability assay is commonly run across multiple species. The most popularly used species include humans, rodents (mice and rats), and nonrodents (dogs and monkeys).
  • the metabolic stability is generally evaluated by calculating the elimination rate constant (ke) to calculate the in vitro clearance in hepatocytes isolated from selected species.
  • ke elimination rate constant
  • the metabolic stability of test compounds in CD-1 mouse, Sprague-Dawley rat, beagle dog, cynomolgus WSGR Docket No.41223-757.601 monkey and human hepatocytes was determined.
  • Example compounds were incubated with hepatocytes from the species above, and the remaining percentage of compounds at designated time points were determined using LC-MS/MS. This data was used to calculate the half-life (T1 ⁇ 2), intrinsic clearance (In vitro CLint), in vivo hepatic clearance (CLhepatic) and hepatic extraction ratio.
  • Preparation of Solutions Preparation of Thawing Medium
  • Human recombinant insulin solution (4 mg/mL): dilute the acetic acid 100-fold with distilled water, weigh a certain amount of human recombinant insulin and dissolve it to achieve a final concentration of 4 mg/mL.
  • the thawing medium was prepared according to the following formula and stored it on 4 °C for no more than 30 days: Preparation of Incubation Medium Incubation Medium was prepared by adding 6.122 mL glutamine (200 mM) into 300 mL Williams’ E medium and mixed thoroughly, then transferred an aliquot of 15 mL solution above to each 15 mL tube and stored it on 4 °C for no more than 30 days. Preparation of Example Compound Working Solution Stock solution of Example Compounds were prepared at 2 mM in DMSO. The stock solution was further diluted by adding 1 ⁇ L to 999 ⁇ L of the hepatocyte incubation medium (Williams’ E medium containing 4 mM glutamine) as working solution.
  • Example Compounds were 1 ⁇ M.
  • Preparation of Control Compound Working Solutions An aliquot of 20 ⁇ L 7-ethoxycoumarin (7-EC) stock solution of 10 mM was diluted with 80 ⁇ L of DMSO to prepare a working stock solution of 7-EC at 2 mM, then previous solution was further diluted by adding 1 ⁇ L to 999 ⁇ L of hepatocyte incubation medium (Williams’ E medium containing 4 mM glutamine) to prepare the phase II control compound working solution at 2 ⁇ M.
  • hepatocyte incubation medium Woods’ E medium containing 4 mM glutamine
  • hepatocytes from mouse, rat, dog, monkey, and human were quickly thawed, then washed with 1 mL of cryopreserved hepatocyte recovery medium (GIBCO). After centrifugation at 100 g for 10 minutes, the pellets were gently mixed with approximately 2 mL of Williams’ E media containing 4 mM glutamine. Cell Counting and Dilution Cell suspension of 50 ⁇ L was diluted with 400 ⁇ L incubation medium and stained by adding 50 ⁇ L Trypan Blue. Diluted cell suspension of 10 ⁇ L was removed for cell counting under a microscope.
  • GEBCO cryopreserved hepatocyte recovery medium
  • the viability was 74.4 %, 74.3 %, 76.7 %, 85.6 % and 82.2 % for mouse, rat, dog, monkey, and human hepatocytes, respectively.
  • the cell suspensions were diluted to a concentration of 2 million viable cells/mL, and then pre-incubated in a CO 2 incubator (5% CO 2 tension) at 37 °C for 20 minutes without the presence of Example Compound or control compound.
  • the plate was incubated at 37 °C for 120 min with gentle agitation.
  • aliquot of 30 ⁇ L was withdrawn from each well and transferred to 300 ⁇ L of internal standard solution.
  • the quenched reaction mixtures were centrifuged (4,000 rpm ⁇ 15 minutes, 4 °C), and 100 ⁇ L of each supernatant was removed to a 96-well plate and mixed with 100 ⁇ L distilled water with 0.5% FA for LC-MS/MS semi-quantitative analysis (assay not qualified under GLP).
  • Example 8 was stable in mouse, rat, dog, monkey and human hepatocytes. Comparative Example A2 was not stable to human hepatocytes.
  • Table 26 Human hepatocyte stability parameters determined for Example 8, Comparative Example A2, and control compound 7-ethoxycoumarin.
  • Table 27 Cynomolgus monkey hepatocyte stability parameters determined for Example 8 and control compound.
  • Table 28 Dog hepatocyte stability parameters determined for Example 8 and control compound.
  • WSGR Docket No.41223-757.601 Table 29 Rat hepatocyte stability parameters determined for Example 8 and control compound.
  • Example XV Experimental Methods and Results for Pharmacokinetic and Pharmacodynamic Efficacy Studies in a Neutropenic Murine Lung Infection Model Antibacterial activity of Example 8, Comparator Example A2, and Comparator Example A4 against A. baumannii was evaluated in a translational neutropenic murine lung infection model (performed by Dr. Kamilia Abdelraouf and Dr. David Nicolau, Hartford Hospital, Hartford, CT). The activity associated with a human-simulated regimen (HSR) of cefiderocol (PMID: 29471305) was also evaluated.
  • HSR human-simulated regimen
  • mice Female ICR mice, following a 48-hour acclimatization period, were rendered neutropenic by injecting cyclophosphamide intraperitoneally (IP) at a dose of 250 mg/kg and 100 mg/kg of body weight four days and one day before lung inoculation, respectively.
  • Uranyl nitrate (5 mg/kg, IP) was administered three days prior to infection to produce a controlled degree of renal impairment.
  • Bacterial suspensions of the strains selected for assessment (Table 31) were instilled intranasally under light anesthesia in a volume of 0.05 mL to produce lung infection 2 hours prior to the planned initiation of antimicrobial therapy.
  • the target initial bacterial burden in the lung was 6 – 7 log 10 CFU/lungs in the 0 h control animals.
  • Treatment mice received escalating subcutaneous doses of Comparator Examples A2 or A4, Example 8, or a cefiderocol HSR and were sacrificed at the end of the 24 hour period. Following aseptic collection of lung tissue, all lung samples were homogenized in sterile saline prior to CFU enumeration by serial dilution and plating techniques.
  • Example 8 Against ATCC 19606, A2 and Example 8 achieved >2-log10 CFU reductions with standard deviation (SD) ⁇ 1-log at the 10 mg/kg dose level, while A4 required the 30 mg/kg dose level to achieve the same level of activity. Only Example 8 demonstrated >1-log 10 CFU reduction with SD ⁇ 1- log at the 3 mg/kg level.
  • a cefiderocol-resistant strain of A. baumannii the cefiderocol HSR was ineffective and allowed growth, consistent with the in vitro susceptibility testing result. Comparator Example A4 and Example 8 achieved >2-log 10 CFU reduction at the 10 mg/kg and 30 mg/kg dose level, respectively.
  • Example 8 was further characterized against 19 additional strains (Table 31). CFU reductions or no change in bacterial density (bacteriostasis) were observed against all strains at various dose levels when the MIC of Example 8 ranged from 0.002 ⁇ g/mL to 2 ⁇ g/mL, with the exception of strains R3393 and R3397, which was consistent with elevated MICs observed against these strains to >32 ⁇ g/mL.
  • Example XVI Murine pharmacokinetics in the neutropenic murine lung infection model.
  • BAL bronchoalveolar lavage
  • the plasma and BAL samples were stored at -80 °C prior to concentration determination using liquid chromatography with tandem mass spectrometry (LC/MS) methods. PK parameters and exposures were estimated (WinNonlin, Version 8.1).
  • the free plasma concentration-time profile of Example 8 (corrected for 48.8% mouse plasma protein binding) and the measurable concentrations in the epithelial lining fluid (ELF) following a 3 mg/kg subcutaneous (SC) single dose administered to lung-infected mice are depicted in FIG.2.
  • Plasma data were best described by a one-compartment model.
  • the best-fit plasma pharmacokinetic (PK) parameters after a 3 mg/kg single dose are provided in Table 32.
  • Example 5-11 The most-potent, cycloalkyl-amide-linked compounds (Examples 5-11) were shown to have suitable stability in plasma (human and preclinical species). Of those, Example 8 showed a well-balanced combination of plasma stability, FPC, and MIC, which could not be predicted based on its structure or its performance in one particular study. While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne certains composés contenant du bore, des compositions, des préparations et leur utilisation en tant que modulateurs de la fonction transpeptidase de protéines de liaison à la pénicilline bactérienne et en tant qu'agents antibactériens. Dans certains modes de réalisation, les composés de la présente invention inhibent les protéines de liaison à la pénicilline. Dans certains modes de réalisation, les composés de la présente invention sont utiles dans le traitement d'infections bactériennes.
PCT/US2024/055692 2023-11-14 2024-11-13 Inhibiteurs de protéines de liaison à la pénicilline Pending WO2025106525A1 (fr)

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US63/598,888 2023-11-14

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022250776A1 (fr) * 2021-05-26 2022-12-01 VenatoRx Pharmaceuticals, Inc. Inhibiteurs de protéines de liaison à la pénicilline

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022250776A1 (fr) * 2021-05-26 2022-12-01 VenatoRx Pharmaceuticals, Inc. Inhibiteurs de protéines de liaison à la pénicilline

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