Citrate complexed complexes of orally delivered beta-lactamase inhibitors and uses thereof

Abstract

This document discloses a compound that is a (R)-(2-(3-(((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex or a pharmaceutically acceptable salt or solvation thereof. This document also discloses a method for treating bacteria with a compound in combination with cefbromide that is a (R)-(3-(((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex or a pharmaceutically acceptable salt or solvation thereof.

Description

Related applications

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 601,661, filed November 21, 2023, which is hereby incorporated by reference in its entirety. Statement on Federally Funded Research

[0002] This invention was made with government support under Contract No. HHSN272201600029C, granted by the National Institutes of Health (NIH). The government holds certain rights to this invention. Background of the Invention

[0003] Antibiotics are the most effective drugs for treating bacterial infections. They are widely used clinically due to their good antibacterial effects and limited side effects. Among them, β-lactam antibiotics (e.g., penicillins, cephalosporins, monocyclic lactams, and carbapenems) are preferred because they work by killing bacteria, and their targets are not present in eukaryotic cells, thus exhibiting low toxicity.

[0004] To counteract the effects of various β-lactams, bacteria have evolved to produce variants of β-lactam-inactivating enzymes called β-lactamases, and are able to share this tool vertically and horizontally between and within species. These β-lactamases are classified as "serine-based" or "metal-based," respectively, based on the presence of key serine or zinc in their active sites. The rapid induction, selection, and spread of this bacterial resistance mechanism severely limits the entire class of β-lactam treatment options in hospitals and communities. There is a need for stable, effective, and safe therapeutic agents combining β-lactam antibiotics and β-lactamase inhibitors to treat such resistant infections. There is also a need for such therapeutic agents that can be formulated into stable, immediate-release tablets. Invention Overview

[0005] This article discloses a compound that is a (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex: Or, or a pharmaceutically acceptable salt or solvate thereof.

[0006] This article also discloses a crystalline form of a compound, which is a (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex: Or, or a pharmaceutically acceptable salt or solvate thereof.

[0007] This article also discloses a pharmaceutical composition comprising:

[0008] (i) The compound is a (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex: Or, or a pharmaceutically acceptable salt or solvate thereof; and

[0009] (ii) Cefoxitin.

[0010] In some embodiments, cefobacterium is in the form of cefobacterium dihydrate.

[0011] In some embodiments, the compound is a (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex: .

[0012] This article also discloses a pharmaceutical composition comprising:

[0013] (i) The crystalline form of the compound, which is a (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex: Or, or a pharmaceutically acceptable salt solvate thereof; and

[0014] (ii) Cefoxitin.

[0015] In some embodiments, cefobacterium is in the form of cefobacterium dihydrate.

[0016] In some embodiments, the compound and cefbufen are formulated in a single dosage form.

[0017] In some embodiments, the crystalline form and cefbufen are formulated in a single dosage form.

[0018] In some embodiments, the single dosage form is a capsule.

[0019] This article also discloses a method for treating a bacterial infection in a subject, which involves administering the pharmaceutical composition disclosed herein to the subject.

[0020] In some embodiments, the bacterial infection is caused by carbapenem-resistant Enterobacteriaceae (CRE) or Gram-negative bacteria that produce extended-spectrum β-lactamases (ESBLs).

[0021] In some embodiments, the bacterial infection is an acute bacterial exacerbation of chronic bronchitis (ABECB), acute bacterial otitis media, pharyngitis, or tonsillitis.

[0022] In some embodiments, the bacterial infection is pneumonia, urinary tract infection, enteritis, or gastroenteritis.

[0023] In some embodiments, the bacterial infection is otitis media, streptococcal laryngitis, pneumonia, urinary tract infection, gonorrhea, or Lyme disease. Attached Figure Description

[0024] Figure 1 Dissolution profiles of fixed-dose capsule prototypes combining cefibromide dihydrate with either the ethanolate complex of compound 1 or the citrate coordination complex of compound 1 are shown.

[0025] Figure 2 An XRPD pattern of the citrate coordination complex form A of compound 1 is shown.

[0026] Figure 3 The DSC thermogram of citrate coordination complex form A of compound 1 is shown.

[0027] Figure 4 The TGA thermogram of citrate coordination complex form A of compound 1 is shown.

[0028] Figure 5 DVS analysis of citrate coordination complex form A of compound 1 is shown.

[0029] Figure 6 An XRPD pattern of compound 1 in citrate coordination complex form B is shown.

[0030] Figure 7 The DSC thermogram of compound 1 in citrate coordination complex form B is shown.

[0031] Figure 8 The TGA of compound 1 in citrate coordination complex form B is shown.

[0032] Figure 9 DVS analysis of citrate coordination complex form B of compound 1 is shown.

[0033] Figure 10 An XRPD pattern of the amorphous compound 1 citrate coordination complex is shown.

[0034] Figure 11 The single-crystal X-ray structure of compound 1 in citrate coordination complex form A is shown.

[0035] Figure 12 The dissolution profiles of a fixed-dose capsule prototype combining cefbromide dihydrate and compound 1 citrate coordination complex and a co-administered capsule of a SEDDS formulation of cefbromide dihydrate and compound 1 ethanolide complex are shown. Detailed Implementation

[0036] The challenge in developing a solid oral dosage form of a fixed-dose combination (FDC) of cefbufen and a prodrug for oral delivery of (R)-2-hydroxy-3-propamido-3,4-dihydro-2H-benzo[e][1,2]oxaborane-8-carboxylic acid is to find a prodrug and solid form of (R)-2-hydroxy-3-propamido-3,4-dihydro-2H-benzo[e][1,2]oxaborane-8-carboxylic acid that is stable when combined with cefbufen while providing the desired immediate-release dissolution profile and oral bioavailability.

[0037] definition

[0038] Unless the context clearly specifies otherwise, the singular forms “a / an” and “the” as used herein and in the appended claims include plural indicators. Thus, for example, reference to “pharmaceutical” includes a variety of such pharmaceuticals, and reference to “cell” includes reference to one or more cells and their equivalents known to those skilled in the art. When the scope is used herein with respect to physical properties (such as molecular weight) or chemical properties (such as chemical formula), it is intended to include all combinations and sub-combinations of the scope and specific embodiments thereof. When referring to a number or numerical range, the term “about” means that the referenced number or numerical range is an approximation within experimental variability (or within statistical experimental error), and therefore in some cases, the number or numerical range will vary between 1% and 15% of the stated number or numerical range. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude embodiments of certain other embodiments, such as any of the material compositions, compositions, methods, or processes described herein, from “consisting of” or “substantially consisting of” the stated features.

[0039] Unless otherwise specified, the following terms used in the specification and appended claims shall have the meanings indicated below.

[0040] "O" refers to =O.

[0041] "Amine" refers to -NH2.

[0042] "Hydroxy group" refers to -OH.

[0043] The "carboxyl group" refers to -COOH.

[0044] "Alkyl" refers to a monovalent group of a straight-chain or branched saturated hydrocarbon having one to 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, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl, as well as longer alkyl groups (such as heptyl, octyl, etc.). Whenever it appears in this document, numerical ranges such as “C1-C6 alkyl” mean that an alkyl group can consist of 1, 2, 3, 4, 5, or 6 carbon atoms, although this definition also covers the use of the term “alkyl” where no numerical range is specified. In some embodiments, an alkyl group is C1-C6. 10 Alkyl group. In some embodiments, the alkyl group is C1-C6 alkyl. In some embodiments, the alkyl group is C1-C5 alkyl. In some embodiments, the alkyl group is C1-C4 alkyl. In some embodiments, the alkyl group is C1-C3 alkyl. Unless otherwise specifically stated in the specification, the alkyl group may optionally be substituted with, for example, one or more oxo groups, halogens, amino groups, nitriles, hydroxyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylic acid esters, aryl groups, cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups. In some embodiments, the alkyl group is optionally substituted with one or more oxo groups, halogens, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl group is optionally substituted with one or more halogens, -CN, -OH, or -OMe. In some embodiments, the alkyl group is optionally substituted with a halogen.

[0045] "Alkenyl" refers to a monovalent group of a straight-chain or branched hydrocarbon having one or more carbon-carbon double bonds and having two to ten carbon atoms, more preferably two to six carbon atoms. The group may be cis or trans or Z or E conformations with respect to one or more double bonds, and should be understood to include both isomers. Examples include, but are not limited to, vinyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, etc. Whenever it appears herein, numerical ranges such as "C2-C6 alkenyl" mean that the alkenyl group can consist of 2, 3, 4, 5, or 6 carbon atoms, although this definition also covers the use of the term "alkenyl" where no numerical range is specified. Unless otherwise specifically stated in the specification, the alkenyl group may optionally be substituted with, for example, one or more oxo groups, halogens, amino groups, nitriles, hydroxyl groups, alkyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylic acid esters, aryl groups, cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups. In some embodiments, the alkenyl group may optionally be substituted with one or more oxo groups, halogens, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl group may optionally be substituted with one or more halogens, -CN, -OH, or -OMe. In some embodiments, the alkenyl group may optionally be substituted with halogens.

[0046] "Alynyl" refers to a monovalent group of a straight-chain or branched hydrocarbon having one or more carbon-carbon triple bonds and having two to ten carbon atoms, more preferably two to six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. Whenever it appears herein, numerical ranges such as "C2-C6 alkynyl" mean that the alkynyl group can consist of 2, 3, 4, 5, or 6 carbon atoms, although this definition also covers the use of the term "alkynyl" where no numerical range is specified. Unless otherwise specifically stated in the specification, the alkynyl group may optionally be substituted with, for example, one or more oxo groups, halogens, amino groups, nitriles, hydroxyl groups, alkyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylic acid esters, aryl groups, cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups. In some embodiments, the alkynyl group may optionally be substituted with one or more oxo groups, halogens, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl group is optionally substituted with one or more halogens, -CN, -OH, or -OMe. In some embodiments, the alkynyl group is optionally substituted with a halogen.

[0047] "alkylene" refers to a straight-chain or branched divalent hydrocarbon chain. Unless otherwise specified in the specification, alkylene may optionally be substituted with, for example, one or more oxo groups, halogens, amino groups, nitriles, hydroxyl groups, alkyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylic acid esters, aryl groups, cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups. In some embodiments, alkylene may optionally be substituted with one or more oxo groups, halogens, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkylene may optionally be substituted with one or more halogens, -CN, -OH, or -OMe. In some embodiments, alkylene may optionally be substituted with halogens.

[0048] "Alkoxy" refers to a group of the formula -O-alkyl, wherein the alkyl group is as defined above. Unless otherwise specifically stated in the specification, an alkoxy group may optionally be substituted with, for example, one or more oxo groups, halogens, amino groups, nitriles, hydroxyl groups, alkyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylic acid esters, aryl groups, cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups. In some embodiments, an alkoxy group may optionally be substituted with one or more halogens, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy group may optionally be substituted with one or more halogens, -CN, -OH, or -OMe. In some embodiments, an alkoxy group may optionally be substituted with a halogen.

[0049] "Aminoalkyl" refers to an alkyl group as defined above that is substituted with one or more amines. In some embodiments, the alkyl group is substituted with one amine. In some embodiments, the alkyl group is substituted with one, two, or three amines. Aminoalkyl groups include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl group is aminomethyl.

[0050] "Aryl" refers to a group derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused (when fused with a cycloalkyl or heterocyclic alkyl ring, the aryl group is bonded through aromatic ring atoms) or bridged ring system. In some embodiments, the aryl group is a 6- to 10-membered aryl group. In some embodiments, the aryl group is a 6-membered aryl (phenyl). Aryl groups include, but are not limited to, anthracene, naphthyl, phenanthrene, azulene, phenyl, phenylene, fluoranyl, fluorenyl, asymmetric indole, symmetric indole, indene, phenatenyl, phenanthrene, heptaenyl, pyrene, and triphenylene. Unless otherwise specifically stated in the specification, the aryl group may optionally be substituted with, for example, one or more halogens, amino groups, nitriles, nitro groups, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylic acid esters, aryl groups, cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups. In some embodiments, the aryl group may optionally be substituted with one or more halogens, methyl groups, ethyl groups, -CN groups, -COOH groups, -COOMe groups, -CF3 groups, -OH groups, -OMe groups, -NH2 groups, or -NO2 groups. In some embodiments, the aryl group may optionally be substituted with one or more halogens, methyl groups, ethyl groups, -CN groups, -CF3 groups, -OH groups, or -OMe groups. In some embodiments, the aryl group may optionally be substituted with a halogen.

[0051] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbon ring, which may include fused (when fused with an aryl or heteroaryl ring, the cycloalkyl is bonded by non-aromatic ring atoms), spiro, and / or bridging ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyl groups include, but are not limited to, cycloalkyl groups having the following number of carbon atoms: three to fifteen carbon atoms (e.g., C3-C4). 15 Fully saturated cycloalkyl or C3-C 15 Cycloalkenyl), three to ten carbon atoms (e.g., C3-C) 10 Fully saturated cycloalkyl or C3-C 10Cycloalkyl groups are 3 to 10-membered fully saturated cycloalkyl groups or 3 to 10-membered cycloalkenyl groups. In some embodiments, the cycloalkyl group is 3 to 6-membered fully saturated cycloalkyl groups or 3 to 6-membered cycloalkenyl groups. In some embodiments, the cycloalkyl group is 5 to 6-membered fully saturated cycloalkyl groups or 5 to 6-membered cycloalkenyl groups. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornel, decahydronaphthyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, cis-decahydronaphthyl, trans-decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl and bicyclo[3.3.2]decyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[3.1.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, spiro[4.2]heptyl, spiro[4.3]octyl, spiro[5.2]octyl, spiro[3.3]heptyl and spiro[5.3]nonyl. Partially saturated cycloalkyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specified in the specification, the cycloalkyl group is optionally substituted with, for example, one or more oxo groups, halogens, amino groups, nitriles, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylic acid esters, aryl groups, cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups. In some embodiments, the cycloalkyl group is optionally substituted with one or more oxo groups, halogens, methyl groups, ethyl groups, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the cycloalkyl group is optionally substituted with one or more oxo groups, halogens, methyl groups, ethyl groups, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl group is optionally substituted with halogens.

[0052] "Halogen" or "halogen" refers to bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine or chlorine. In some embodiments, the halogen is fluorine.

[0053] "Halogenated alkyl" refers to an alkyl group as defined above that is substituted with one or more halogenated groups as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 2-fluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0054] "Haloalkoxy" refers to -O-haloalkyl, where the haloalkyl is as defined above.

[0055] "Hydroxyalkyl" refers to an alkyl group as defined above that is substituted with one or more hydroxyl groups. In some embodiments, the alkyl group is substituted with one hydroxyl group. In some embodiments, the alkyl group is substituted with one, two, or three hydroxyl groups. Hydroxyalkyl groups include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl.

[0056] "Aminoalkyl" refers to an alkyl group as defined above that is substituted with one or more amines. In some embodiments, the alkyl group is substituted with one amine. In some embodiments, the alkyl group is substituted with one, two, or three amines. Aminoalkyl groups include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl group is aminomethyl.

[0057] "Deuterated alkyl" refers to an alkyl group as defined above that is substituted with one or more deuterium groups. In some embodiments, the alkyl group is substituted with one deuterium group. In some embodiments, the alkyl group is substituted with one, two, or three deuterium groups. In some embodiments, the alkyl group is substituted with one, two, three, four, five, or six deuterium groups. Deuterated alkyl groups include, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuterated alkyl group is CD3.

[0058] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms are selected from atoms other than carbon (e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof). The heteroalkyl group is attached to the remainder of the molecule at the carbon atom of the heteroalkyl group. In one aspect, the heteroalkyl group is a C1-C6 heteroalkyl group, wherein the heteroalkyl group consists 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 group is attached to the remainder of the molecule at the carbon atom of the heteroalkyl group. In another aspect, the heteroalkyl group is a C1-C6 heteroalkyl group, wherein the heteroalkyl group consists of 1 to 6 carbon atoms and one or two atoms (selected from the group consisting of oxygen, nitrogen, and sulfur), wherein the heteroalkyl group is attached to the remainder of the molecule at the carbon atom of the heteroalkyl group. Examples of such heteroalkyl groups are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless otherwise specifically stated in the specification, heteroalkyl groups are optionally substituted with, for example, one or more oxo groups, halogens, amino groups, nitriles, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, aryl groups, cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups. In some embodiments, the heteroalkyl group is optionally substituted with one or more oxo groups, halogens, methyl groups, ethyl groups, -CN groups, -CF3 groups, -OH groups, -OMe groups, -NH2 groups, or -NO2 groups. In some embodiments, the heteroalkyl group is optionally substituted with one or more oxo groups, halogens, methyl groups, ethyl groups, -CN groups, -CF3 groups, -OH groups, or -OMe groups. In some embodiments, the heteroalkyl group is optionally substituted with a halogen.

[0059] "Heterocyclic alkyl" refers to a 3- to 24-membered or fully saturated cyclic group comprising 2 to 23 carbon atoms and one to eight heteroatoms (selected from the group consisting of nitrogen, oxygen, phosphorus, silicon, and sulfur). In some embodiments, the heterocyclic alkyl is fully saturated. In some embodiments, the heterocyclic alkyl is C-linked. In some embodiments, the heterocyclic alkyl is N-linked. In some embodiments, the heterocyclic alkyl contains one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclic alkyl contains one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocyclic alkyl contains one to three nitrogen atoms. In some embodiments, the heterocyclic alkyl contains one or two nitrogen atoms. In some embodiments, the heterocyclic alkyl contains one nitrogen atom. In some embodiments, the heterocyclic alkyl contains one nitrogen atom and one oxygen atom. Unless otherwise specified in the specification, the heterocyclic alkyl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or heteroaryl ring, the heterocyclic alkyl group is bonded by non-aromatic ring atoms), spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atom in the heterocyclic alkyl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. Representative heterocyclic alkyl groups include, but are not limited to, heterocyclic alkyl groups having the following number of carbon atoms: two to fifteen carbon atoms (e.g., C2-C1). 15 Fully saturated heterocyclic alkyl or C2-C 15 Heterocyclic alkenyl groups, two to ten carbon atoms (e.g., C2-C) 10 Fully saturated heterocyclic alkyl or C2-C 10Heterocyclic alkenyl), two to eight carbon atoms (e.g., C2-C8 fully saturated heterocyclic alkyl or C2-C8 heterocyclic alkenyl), two to seven carbon atoms (e.g., C2-C7 fully saturated heterocyclic alkyl or C2-C7 heterocyclic alkenyl), two to six carbon atoms (e.g., C2-C6 fully saturated heterocyclic alkyl or C2-C7 heterocyclic alkenyl), two to five carbon atoms (e.g., C2-C5 fully saturated heterocyclic alkyl or C2-C5 heterocyclic alkenyl), or two to four carbon atoms (e.g., C2-C4 fully saturated heterocyclic alkyl or C2-C4 heterocyclic alkenyl). Examples of such heterocyclic alkyl groups include, but are not limited to, azirropropyl, azirrobutyl, oxacyclobutyl, dioxopentyl, thienyl[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperidylalkyl, oxazolylalkyl, piperidinyl, piperazine, 4-piperidinoneyl, and pyrrolidine. The term heterocyclic alkyl also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. In some embodiments, the heterocyclic alkyl group has 2 to 10 carbon atoms in the ring. It should be understood that when referring to the number of carbon atoms in a heterocyclic alkyl group, the number of carbon atoms in the heterocyclic alkyl group is different from the total number of atoms constituting the heterocyclic alkyl group (including heteroatoms, i.e., the skeletal atoms of the heterocyclic alkyl ring). In some embodiments, the heterocyclic alkyl group is a 3- to 8-membered heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 7-membered heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 6-membered heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 4- to 6-membered heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 5- to 6-membered heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 8-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 7-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 6-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 4- to 6-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 5- to 6-membered heterocyclic alkenyl group. Unless otherwise specifically stated in the specification, the heterocyclic alkyl group may optionally be substituted with, for example, one or more oxo groups, halogens, amino groups, nitriles, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylic acid esters, aryl groups, cycloalkyl groups, heterocyclic alkyl groups, heteroaryl groups, etc.In some embodiments, the heterocyclic alkyl group is optionally substituted with one or more oxo groups, halogens, methyl groups, ethyl groups, -CN groups, -COOH groups, -COOMe groups, -CF3 groups, -OH groups, -OMe groups, -NH2 groups, or -NO2 groups. In some embodiments, the heterocyclic alkyl group is optionally substituted with one or more halogens, methyl groups, ethyl groups, -CN groups, -CF3 groups, -OH groups, or -OMe groups. In some embodiments, the heterocyclic alkyl group is optionally substituted with a halogen.

[0060] "Heteroaryl" refers to a 5- to 14-membered ring system group comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl group comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group comprises one to three nitrogen atoms. In some embodiments, the heteroaryl group comprises one or two nitrogen atoms. In some embodiments, the heteroaryl group comprises one nitrogen atom. In some embodiments, the heteroaryl group is C-linked. In some embodiments, the heteroaryl group is N-linked. The heteroaryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocyclic alkyl ring, the heteroaryl group is bonded through aromatic ring atoms) or bridged ring system; and the nitrogen, carbon, or sulfur atoms in the heteroaryl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. In some embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5- or 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5- or 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, azazyl, acridine, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxacyclopentenyl, benzofuranyl, benzooxazolyl, benzothiadiazolyl, benzo[b][1,4]dioxazolyl, 1,4-benzodioxane, benzonaphthuryl, benzodioxane-hexenyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzofuranoneyl, benzothienyl (benzothienyl (benzothiophenyl)), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazole, cenolinyl, dibenzofuranyl, dibenzothienyl, furanyl, isothiazolyl Imidazolyl, indazolyl, indolyl, isoindolyl, indololinyl, isoindololinyl, isoquinolinyl, indolazinyl, isoxazolyl, naphridinyl, oxadiazolyl, 2-oxoazapyridine, oxazolyl, 1-pyridinyl oxide, 1-pyrimidinyl oxide, 1-pyrazinyl oxide, 1-pyridazinyl oxide, 1-phenyl-1H-pyrroleyl, phenazinyl, phenothiazinyl, phenothiazinyl, phthalazinyl, pteridineyl, purine, pyrroleyl, pyrazolyl, pyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl).Unless otherwise specifically stated in the specification, the heteroaryl group is optionally substituted with, for example, one or more halogens, amino groups, nitriles, nitro groups, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylic acid esters, aryl groups, cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups. In some embodiments, the heteroaryl group is optionally substituted with one or more halogens, methyl groups, ethyl groups, -CN groups, -COOH groups, -COOMe groups, -CF3 groups, -OH groups, -OMe groups, -NH2 groups, or -NO2 groups. In some embodiments, the heteroaryl group is optionally substituted with one or more halogens, methyl groups, ethyl groups, -CN groups, -CF3 groups, -OH groups, or -OMe groups. In some embodiments, the heteroaryl group is optionally substituted with a halogen.

[0061] When referring to optional substituents, the term "one or more" means that the subject group is optionally substituted by one, two, three, four, or more substituents. In some embodiments, the subject group is optionally substituted by one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted by one, two, or three substituents. In some embodiments, the subject group is optionally substituted by one or two substituents. In some embodiments, the subject group is optionally substituted by one substituent. In some embodiments, the subject group is optionally substituted by two substituents.

[0062] As used herein, the term "effective amount" or "therapeutic effective amount" refers to an adequate amount of the compound disclosed herein administered that will, to a certain extent, alleviate one or more symptoms of the disease or condition being treated (e.g., cancer or an inflammatory disease). In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising the compound disclosed herein required to provide a clinically significant reduction in disease symptoms. In some embodiments, in any single case, the appropriate "effective" amount is determined using techniques such as dose escalation studies.

[0063] As used herein, the term “substantially similar” means a powder X-ray diffraction pattern or differential scanning calorimeter that, when considered by a person of ordinary skill in the art, is not exactly the same as described herein, but falls within experimental error limits.

[0064] As used in this article, the term "therapeutic agent" means a medicine used to treat, counteract, alleviate, or improve an unwanted symptom or disease in a patient.

[0065] When used in conjunction with a treatment, “administration” means the systemic or local application of the therapeutic agent, such as directly into or onto the target tissue; or the administration of the therapeutic agent to a patient, thereby actively affecting the tissue to which it is targeted. “Administration” of a pharmaceutical composition can be accomplished by injection, local application, oral administration, or by other methods alone or in combination with other known techniques.

[0066] The term "pharmaceutically acceptable" means that the carrier, diluent, or excipient must be compatible with the other components of the composition and harmless to the recipient.

[0067] The term "pharmaceutical composition" means a composition comprising at least one active ingredient (such as a citrate coordination complex of compound 1) that is suitable for studying specific effective outcomes in mammals (e.g., but not limited to humans). Those skilled in the art will understand and recognize techniques suitable for determining, based on the needs of the technician, whether the active ingredient has the desired effective outcome.

[0068] As used herein, “therapeutic effective amount” or “effective amount” means the amount of an active compound or pharmaceutical preparation that elicits a biological or medical response sought by a researcher, veterinarian, physician or other clinical practitioner in an tissue, system, animal, individual or human, including one or more of the following: (1) inhibiting disease; for example, inhibiting disease, condition or disorder in an individual experiencing or exhibiting pathology or symptoms of disease, condition or disorder (i.e., preventing further development of pathology and / or symptoms); and (2) improving disease; for example, improving disease, condition or disorder in an individual experiencing or exhibiting pathology or symptoms of disease, condition or disorder (i.e., reversing pathology and / or symptoms).

[0069] As used herein, the term "treat (treated, treatment, or treating)" refers to therapeutic treatment in which the aim is to alleviate (reduce) an undesirable physical symptom, disorder, or disease, or to achieve a beneficial or desired clinical outcome. For the purposes described herein, a beneficial or desired clinical outcome includes, but is not limited to, the reduction of symptoms; a decrease in the severity of the symptom, disorder, or disease; stabilization of the state of the symptom, disorder, or disease (i.e., no worsening); a delay in the onset or a slowing of the progression of the symptom, disorder, or disease; an improvement in the state of the symptom, disorder, or disease; and detectable or undetectable remission (partial or complete) or enhancement or improvement of the symptom, disorder, or disease. Treatment includes causing a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival compared to the expected survival without treatment.

[0070] Compound 1

[0071] Compound 1 is (R)-2-hydroxy-3-propamido-3,4-dihydro-2H-benzo[e][1,2]oxaboranecyclohexene-8-carboxylic acid ((2-ethylbutyryl)oxy)methyl ester: However, it also exists in equilibrium with its open-ring form (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)boronic acid: (Compound 1), and also known as ledaborbactam etzadroxil.

[0072] .

[0073] Compound 1 ethanolide

[0074] The ethanolate of compound 1 is (R)-2-ethoxy-3-propamido-3,4-dihydro-2H-benzo[e][1,2]oxaboranecyclohexene-8-carboxylic acid ((2-ethylbutyryl)oxy)methyl ester: .

[0075] Compound 2

[0076] Compound 2 is (R)-2-hydroxy-3-propamido-3,4-dihydro-2H-benzo[e][1,2]oxaborane-cyclohexene-8-carboxylic acid: .

[0077] Compound 1 ester coordination complex

[0078] In some embodiments, the ester coordination complex of compound 1 is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof:

[0079]

[0080] Formula (I);

[0081] in:

[0082] Ring A is a 4- to 8-membered heterocyclic alkyl group that optionally contains one or two additional heteroatoms selected from the group consisting of O, N, and S;

[0083] Each R 1 Independently, it is halogen, -CN, -OH, -L-OR a -L-NR c R d -LC(=O)R a -LC(=O)OR b -LC(=O)NR c R dC1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0084] Or two R atoms on the same atom 1 Together they form an oxygen group;

[0085] n is 0, 1, 2, 3, 4, 5, or 6;

[0086] R 2 It is hydrogen, R 4 、-(R 3 ) q OR 4 、-(R 3 ) q O(R 3 ) q OR 4 -R 3 OC(=O)R 4 -R 3 OC(=O)OR 4 -R 3 OC(=O)NHR 5 or -R 3 OC(=O)N(R 5 )2;

[0087] Each q is independently 2, 3, 4, 5, or 6;

[0088] Each R 3 It is independently -CH2-, -CH(CH3)-, -C(CH3)2- or 1,1-cyclopropene;

[0089] R 4 It is C1-C 12 Alkyl, C1-C 12 Haloalkyl, C1-C 12 Hydroxyalkyl, C1-C 12 aminoalkyl, C1-C 12 Alkoxyalkyl, C2-C 12 alkenyl, C2-C 12 Alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl group is independently and optionally substituted by one or more R groups;

[0090] Each R 5Independently, it is C1-C 12 Alkyl, C1-C 12 Haloalkyl, C1-C 12 Hydroxyalkyl, C1-C 12 aminoalkyl, C1-C 12 Alkoxyalkyl, C2-C 12 alkenyl, C2-C 12 Alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl group is independently and optionally substituted by one or more R groups;

[0091] Or two Rs 5 Together with the nitrogen to which they are attached, they form heterocyclic alkyl groups that are independently and optionally substituted with one or more R groups;

[0092] Each R a Independently, it is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R;

[0093] Each R b Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R;

[0094] R c and R d Each of the following is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0095] Or R c and R d Together with the atoms to which they are attached, they form heterocyclic alkyl groups that are independently and optionally substituted with one or more R atoms; and

[0096] L is absent or is optionally substituted independently by one or more Rs in C1-C3 alkylene groups;

[0097] Each R is independently a halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -S(=O)(=NC1-C3 alkyl)(C1-C3 alkyl), -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -N=S(=O)(C1-C3 alkyl) 2. -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, -P(=O)(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl or C3-C6 cycloalkyl;

[0098] Or two R atoms on the same atom can form an oxo group.

[0099] In some embodiments of the compounds of formula (I), ring A is a 5- to 6-membered heterocyclic alkyl group that optionally contains one or two additional heteroatoms selected from the group consisting of O, N, and S. In some embodiments of the compounds of formula (I), ring A is a 5- to 6-membered heterocyclic alkyl group.

[0100] In some embodiments of the compounds of formula (I), ring A is a 5-membered heterocyclic alkyl group that optionally contains one or two additional heteroatoms selected from the group consisting of O, N, and S. In some embodiments of the compounds of formula (I), ring A is a 5-membered heterocyclic alkyl group.

[0101] In some embodiments of the compounds of formula (I), ring A is a 6-membered heterocyclic alkyl group that optionally contains one or two additional heteroatoms selected from the group consisting of O, N, and S. In some embodiments of the compounds of formula (I), ring A is a 6-membered heterocyclic alkyl group.

[0102] In some embodiments of the compounds of formula (I), n is 2, 3, 4, 5, or 6. In some embodiments of the compounds of formula (I), n is 2, 3, 4, or 5. In some embodiments of the compounds of formula (I), n is 2, 3, or 4. In some embodiments of the compounds of formula (I), n is 2. In some embodiments of the compounds of formula (I), n is 3. In some embodiments of the compounds of formula (I), n is 4.

[0103] In some embodiments of the compounds of formula (I), each R 1 Independently is -LC(=O)R a -LC(=O)OR b -LC(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or two R on the same atom 1 Together they form an oxygen group.

[0104] In some embodiments of the compounds of formula (I), each R 1 Independently is -LC(=O)OR b C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or two R on the same atom 1 Together they form an oxygen group.

[0105] In some embodiments of the compounds of formula (I), each R 1 Independently is -LC(=O)OR b Or two R atoms on the same atom 1 Together they form an oxygen group.

[0106] In some embodiments of the compounds of formula (I), each R 1 Independently is -C(=O)OR b or -CH2C(=O)OR b Or two R atoms on the same atom 1 Together they form an oxygen group.

[0107] In some embodiments of the compounds of formula (I), L is absent or is a C1-C3 alkylene group.

[0108] In some embodiments of the compounds of formula (I), L is absent. In some embodiments of the compounds of formula (I), L is a C1-C3 alkylene group.

[0109] In some embodiments, the compound of formula (I) is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvation thereof:

[0110]

[0111] Formula (Ia);

[0112] in:

[0113] R 1a It is hydrogen, halogen, -CN, -OH, -L-OR a -L-NR c Rd -LC(=O)R a -LC(=O)OR b -LC(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl group is independently and optionally substituted by one or more R; and

[0114] R 1b It is hydrogen, halogen, -CN, -OH, -L-OR a -L-NR c R d -LC(=O)R a -LC(=O)OR b -LC(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R.

[0115] In some embodiments, the compound of formula (I) or (Ia) is a compound of formula (Ia-1) or a pharmaceutically acceptable salt or solvation thereof:

[0116] .

[0117] Formula (Ia-1). In some embodiments, the compounds of formulas (I), (Ia), and (Ia-1) are compounds of formula (Ia-1a) or their pharmaceutically acceptable salts or solvates:

[0118] .

[0119] Equation (Ia-1a).

[0120] In some embodiments, the compounds of formula (I), (Ia), and (Ia-1) are compounds of formula (Ia-1b) or pharmaceutically acceptable salts or solvates thereof:

[0121]

[0122] Equation (Ia-1b).

[0123] In some embodiments, the compound of formula (I) is a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof:

[0124]

[0125] Formula (Ib);

[0126] in:

[0127] R 1a It is hydrogen, halogen, -CN, -OH, -L-OR a -L-NR c R d -LC(=O)R a -LC(=O)OR b -LC(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl group is independently and optionally substituted by one or more R; and

[0128] R 1b It is hydrogen, halogen, -CN, -OH, -L-OR a -L-NR c R d -LC(=O)R a -LC(=O)OR b -LC(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R.

[0129] Formula (Ib). In some embodiments, the compound of formula (I) or (Ib) is a compound of formula (Ib-1) or a pharmaceutically acceptable salt or solvation thereof:

[0130] .

[0131] Formula (Ib-1). In some embodiments, the compound of formula (I), (Ib), or (Ib-1) is a compound of formula (Ib-1a) or a pharmaceutically acceptable salt or solvation thereof:

[0132]

[0133] Equation (Ib-1a).

[0134] In some embodiments, the compounds of formula (I), (Ib), or (Ib-1) are compounds of formula (Ib-1b) or their pharmaceutically acceptable salts or solvates:

[0135]

[0136] Formula (Ib-1b).

[0137] In some embodiments of compounds of formula (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), R 1a It is hydrogen, -LC(=O)R a -LC(=O)OR b -LC(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 hydroxyalkyl.

[0138] In some embodiments of compounds of formula (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), R 1a It is hydrogen, -LC(=O)OR b C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 hydroxyalkyl.

[0139] In some embodiments of compounds of formula (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), R 1a It is -LC(=O)OR b .

[0140] In some embodiments of compounds of formula (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), R 1a It is -C(=O)OR b or -CH2C(=O)ORb .

[0141] In some embodiments of compounds of formula (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), R 1a It is -C(=O)OR b .

[0142] In some embodiments of compounds of formula (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), R 1a It is -C(=O)OH.

[0143] In some embodiments of compounds of formula (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), R 1a It is -CH2C(=O)OR b .

[0144] In some embodiments of compounds of formula (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), R 1a It is -CH2C(=O)OH.

[0145] In some embodiments of compounds of formula (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), R 1b It is hydrogen, -LC(=O)R a -LC(=O)OR b -LC(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 hydroxyalkyl.

[0146] In some embodiments of compounds of formula (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), R 1b It is hydrogen, -LC(=O)OR b C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 hydroxyalkyl.

[0147] In some embodiments of compounds of formula (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), R 1b It is -LC(=O)OR b .

[0148] In some embodiments of compounds of formula (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), R 1b It is -C(=O)OR b or -CH2C(=O)OR b .

[0149] In some embodiments of compounds of formula (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), R 1b It is -C(=O)OR b .

[0150] In some embodiments of compounds of formula (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), R 1b It is -C(=O)OH.

[0151] In some embodiments of compounds of formula (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), R 1b It is -CH2C(=O)OR b .

[0152] In some embodiments of compounds of formula (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), R 1b It is -CH2C(=O)OH.

[0153] In some embodiments of compounds of formula (I), (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), R 2 It is hydrogen, R 4 -R 3 OC(=O)R 4 or -R 3 OC(=O)OR 4In some embodiments of compounds of formula (I), (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), R 2 It is hydrogen. In some embodiments of compounds of formula (I), (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), R 2 It is R 4 In some embodiments of compounds of formula (I), (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), R 2 Yes -R 3 OC(=O)R 4 or -R 3 OC(=O)OR 4 In some embodiments of compounds of formula (I), (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), R 2 Yes -R 3 OC(=O)R 4 In some embodiments of compounds of formula (I), (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), R 2 Yes -R 3 OC(=O)OR 4 .

[0154] In some embodiments of compounds of formula (I), (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), each R 3 Independently, it is -CH2- or -CH(CH3)-. In some embodiments of compounds of formula (I), (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), each R 3 It is -CH2- independently.

[0155] In some embodiments of compounds of formula (I), (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), R 4 It is C1-C 12Alkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, aryl, and heteroaryl group is optionally substituted independently by one or more R groups.

[0156] In some embodiments of compounds of formula (I), (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), R 4 It is C1-C 12 alkyl.

[0157] In some embodiments of compounds of formula (I), (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), R 4 yes , , , , , , , or In some embodiments of compounds of formula (I), (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), R 4 yes .

[0158] In some embodiments of compounds of formula (I), (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), each R a Independently, each alkyl, cycloalkyl, or heterocycloalkyl group is a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 hydroxyalkyl group, a C1-C6 aminoalkyl group, a C1-C6 heteroalkyl group, an -L-cycloalkyl group, or an -L-heterocycloalkyl group; wherein each alkyl, cycloalkyl, or heterocycloalkyl group is independently and optionally substituted by one or more R groups. In some embodiments of compounds of formula (I), (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), each R group is substituted by one or more R groups. a Independently, each alkyl group is a C1-C6 alkyl or C1-C6 haloalkyl group; wherein each alkyl group is independently and optionally substituted by one or more R groups. In some embodiments of compounds of formula (I), (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), each R group is substituted by one or more R groups. aIndependently, it is a C1-C6 alkyl or a C1-C6 haloalkyl. In some embodiments of compounds of formula (I), (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), each R a It is independently a C1-C6 alkyl group.

[0159] In some embodiments of compounds of formula (I), (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), each R b Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently and optionally substituted by one or more R. In some embodiments of compounds of formula (I), (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), each R b Independently, it is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; wherein each alkyl group is independently and optionally substituted by one or more R. In some embodiments of compounds of formula (I), (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), each R b Independently, it is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of formula (I), (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), each R b Independently, it is hydrogen or a C1-C6 alkyl group. In some embodiments of compounds of formula (I), (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), each R b It is hydrogen. In some embodiments of compounds of formula (I), (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), each R b It is independently a C1-C6 alkyl group.

[0160] In some embodiments of compounds of formula (I), (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), R c and R d Each is independently hydrogen, a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 hydroxyalkyl, a C1-C6 aminoalkyl, a C1-C6 heteroalkyl, an -L-cycloalkyl, or an -L-heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is optionally independently substituted by one or more R. In some embodiments of compounds of formula (I), (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), R c and R d Each is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group; wherein each alkyl group is independently and optionally substituted by one or more R groups. In some embodiments of compounds of formula (I), (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), R c and R d Each is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of formula (I), (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), R c and R d Each is independently hydrogen or a C1-C6 alkyl group. In some embodiments of compounds of formula (I), (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), R c and R d Each is hydrogen. In some embodiments of compounds of formula (I), (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), R c and R d Each is independently a C1-C6 alkyl group.

[0161] In some embodiments of compounds of formula (I), (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), L is absent or is a C1-C3 alkylene group. In some embodiments of compounds of formula (I), (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), L is absent. In some embodiments of compounds of formula (I), (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), L is a C1-C3 alkylene group.

[0162] In some embodiments of compounds of formula (I), (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), each R is independently a halogen, -CN, -OH, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, or C3-C6 cycloalkyl. In some embodiments of compounds of formula (I), (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), each R is independently a halogen, -CN, -OH, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, or C3-C6 cycloalkyl. In some embodiments of compounds of formula (I), (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), each R is independently a halogen, -CN, -OH, -NH2, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, or C3-C6 cycloalkyl. In some embodiments of compounds of formula (I), (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), each R is independently a halogen, -CN, -OH, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, C1-C3 alkyl, or C1-C3 haloalkyl. In some embodiments of compounds of formula (I), (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ib), (Ib-1), (Ib-1a), or (Ib-1b), each R is independently a halogen, C1-C3 alkyl, or C1-C3 haloalkyl.

[0163] Compound 1 citrate coordination complex

[0164] In some embodiments, compound 1 exists in solid form as a covalently bonded citrate coordination complex. In some embodiments, the citrate coordination complex of compound 1 is (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex.

[0165] In some embodiments, the citrate coordination complex of compound 1 is (R)-2,2'-(2-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)-5-oxo-1,3,2-dioxacyclopentaborane-4,4-diyl)diacetic acid:

[0166] .

[0167] In some embodiments, the citrate coordination complex of compound 1 is converted to the closed-ring form of compound 1 upon contact with water:

[0168] .

[0169] Alternative compound 1: citrate coordination complex

[0170] In some embodiments, the citrate coordination complex of compound 1 is 4-(carboxymethyl)-2-((R)-2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)-6-oxo-1,3,2-dioxaborane-4-carboxylic acid: In some embodiments, the alternative compound 1 citrate coordination complex is a racemic mixture. In some embodiments, the alternative compound 1 citrate coordination complex is a pure stereoisomer.

[0171] In some embodiments, an alternative compound 1 citrate coordination complex is (S)-4-(carboxymethyl)-2-((R)-2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)-6-oxo-1,3,2-dioxaborane-4-carboxylic acid: .

[0172] In some embodiments, an alternative compound 1 citrate coordination complex is (R)-4-(carboxymethyl)-2-((R)-2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)-6-oxo-1,3,2-dioxaborane-4-carboxylic acid: .

[0173] In some embodiments, an alternative compound 1 citrate coordination complex is .

[0174] In some embodiments, the alternative compound 1 citrate coordination complex is converted to the closed-ring form of compound 1 upon contact with water:

[0175] .

[0176] In some embodiments, citrate coordination complexes allow for the development of dry powder immediate-release formulations compared to other forms (e.g., ethanolides) that cannot be directly formulated as immediate-release preparations. This is in Figure 1 The study compared a fixed-dose combination of cefbufen dihydrate and citrate coordination complex (see Example 15a) with a comparable fixed-dose combination of cefbufen dihydrate and ethanolate complex (see Example 15b). Dissolution tests were performed using 900 mL of 50 mM sodium bicarbonate buffer at pH 6.8 and a paddle rate of 75 RPM (Apparatus II method). The dissolution profile of the ethanolate complex showed <40% release of the active pharmaceutical ingredient at 60 minutes, while the citrate coordination complex of Compound 1 showed 100% release by 10 minutes.

[0177] Another form of the complex disclosed in this article

[0178] In some embodiments, the amide oxygen atom of the citrate coordination complex of compound 1 can be coordinated with a boron atom in solution or solid form, and therefore the compounds described herein can be plotted (or depicted) as or However, both of them are merely descriptions of the citrate coordination complex of compound 1 of formula (I).

[0179] Similarly, the citrate coordination complex of compound 1 can be plotted (or depicted) as or However, both of them are merely descriptions of the citrate coordination complex of compound 1.

[0180] Accordingly, the alternative compound 1 citrate coordination complex can be plotted (or depicted) as or However, both of them are merely descriptions of alternative compound 1 citrate coordination complexes.

[0181] Similarly, the citrate coordination complex of compound 1 can be plotted (or depicted) as or However, both of them are merely descriptions of the citrate coordination complex of compound 1.

[0182] Accordingly, the alternative compound 1 citrate coordination complex can be plotted (or depicted) as or However, both of them are merely descriptions of alternative compound 1 citrate coordination complexes.

[0183] Isomers / stereoisomers

[0184] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, E (entgegen) (E), and Z (zusammen) isomers and their respective mixtures. In some cases, the compounds described herein have one or more chiral centers, and each center exists independently in an R or S configuration. The compounds described herein include all diastereomers, enantiomers, and epimers and their respective mixtures. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers produced by a single preparation step, combination, or interconversion can be used for the applications described herein. In some embodiments, the compounds described herein are prepared as separate stereoisomers by reacting a racemic mixture of compounds with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated by utilizing these differences. In some embodiments, diastereomers are separated by chiral chromatography, or preferably by separation / resolution techniques based on solubility differences. In some embodiments, the optically pure enantiomers are then recovered along with the resolving agent by any practical means that do not cause racemization.

[0185] Labeled compounds

[0186] In some embodiments, the compounds described herein are present in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds as a pharmaceutical composition. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are the same as those listed herein, but in the fact that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those normally found in nature. Examples of isotopes that may be incorporated into the compounds disclosed herein include isotopes of hydrogen, boron, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as... 2 H, 3 H, 10 B 13 C 14 C l5 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. Other isotopes of the compounds described herein containing the aforementioned isotopes and / or other atoms, as well as their pharmaceutically acceptable salts, solvates, or stereoisomers, are within the scope of this invention. Certain isotope-labeled compounds (e.g., those doped with radioactive isotopes such as...) 3 H and 14 Compounds containing C can be used for drug and / or substrate tissue distribution assays. Tritized isotopes (i.e., 3 H) and carbon-14 (i.e., ... 14 C) Isotopes are particularly preferred because they are easy to prepare and detect. Furthermore, heavy isotopes such as deuterium (i.e., 2 H) substitution produces certain therapeutic advantages derived from higher metabolic stability (e.g., prolonged in vivo half-life or reduced dose requirements). In some embodiments, one or more hydrogen atoms in the compounds disclosed herein have been replaced by deuterium atoms. In some embodiments, one or more alkyl substituents in the compounds disclosed herein have been replaced by deuterated alkyl substituents.

[0187] In some embodiments, the compounds described herein are labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labeling, or chemiluminescent labeling.

[0188] Pharmaceutically acceptable salts

[0189] In some embodiments, the compounds described herein are present as pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts as a pharmaceutical composition.

[0190] In some embodiments, the compounds described herein have acidic or basic groups and thus react with a number of inorganic or organic bases and any of inorganic and organic acids to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein or their solvates or stereoisomers, or prepared separately by reacting the purified compounds in their free form with a suitable acid or base and isolating the resulting salts.

[0191] Examples of pharmaceutically acceptable salts include those prepared by reacting the compounds described herein with mineral acids, organic acids, or inorganic bases. These salts include, but are not limited to, acetates, acrylates, adipates, alginates, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, bisulfites, bromides, butyrates, butyn-1,4-dicitates, camphorates, camphorsulfonates, hexanoates, octanoates, chlorobenzoates, chlorides, citrates, cyclopentanepropionates, decanoates, digluconates, gluconates, dihydrogen phosphates, dinitrobenzoates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucono-2-heptates, glycerophosphates, glycolates, hemisulfates, heptahydrates, hexyn-1,6-dicitates, and hydroxybenzoic acid. Salts, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, pyrosulfonate, pyrophosphate, propynate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, octanoate, sebacic acid salt, sulfonate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and xylenesulfonate.

[0192] Furthermore, the compounds described herein can be prepared as pharmaceutically acceptable salts by reacting the free base form of the compounds 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, metaphosphoric acid, etc.; 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) It is formed by reacting benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-en-1-carboxylic acid, glucoheponic acid, 4,4'-methylenebis-(3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecyl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and mucoconic acid. In some embodiments, other acids (such as oxalic acid), although not pharmaceutically acceptable on their own, are used to prepare salts that can be used as intermediates to obtain the compounds disclosed herein, their solvates or stereoisomers, and their pharmaceutically acceptable acid addition salts.

[0193] In some embodiments, those compounds comprising a free acid group described herein react with a suitable base (such as a hydroxide, carbonate, bicarbonate, or sulfate) of a pharmaceutically acceptable metal cation, ammonia, or a pharmaceutically acceptable primary, secondary, tertiary, or quaternary organic amine. Representative salts include alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium, and magnesium salts, as well as aluminum salts. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, and N2SO4. + (C 1- C4 alkyl)4 hydroxides, etc. In some embodiments, the compounds described herein are sodium salts. In some embodiments, the compounds described herein are disodium salts.

[0194] Representative organic amines used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. It should be understood that the compounds described herein also include quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water-soluble or oil-soluble or dispersible products are obtained via such quaternization.

[0195] solvates

[0196] In some embodiments, the compounds described herein are present as solvates. The present invention provides a method for treating a disease by administering such solvates. The present invention further provides a method for treating a disease by administering such solvates as a pharmaceutical composition.

[0197] The solvates contain stoichiometric or non-stoichiometric amounts of solvent, and in some embodiments, are formed using pharmaceutically acceptable solvents such as water, ethanol, etc. When the solvent is water, a hydrate is formed, or when the solvent is an alcohol, an alcohol is formed. The solvates of the compounds described herein can be conveniently prepared or formed during the methods described herein. By way of example only, the hydrates of the compounds described herein can be conveniently prepared from aqueous / organic solvent mixtures using organic solvents (including, but not limited to, dioxane, tetrahydrofuran, or methanol). Furthermore, the compounds provided herein can exist in both solvated and non-solvated forms. Generally, for the purposes of the compounds and methods provided herein, the solvated form is considered equivalent to the non-solvated form.

[0198] tautomer

[0199] In some cases, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that can interconvert through the migration of hydrogen atoms, accompanied by the conversion of single bonds and adjacent double bonds. In bond arrangements where tautomerization is possible, a chemical equilibrium of tautomers will exist. All tautomer forms of the compounds disclosed herein are considered. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0200] solid form

[0201] This document provides (R)-(2-(3-(((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) or a pharmaceutically acceptable salt or solvation thereof in a solid form. In some embodiments, the solid form is a crystalline form. In some embodiments, the solid form is crystalline (R)-(2-(3-(((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) as a free form. In some embodiments, the solid form is crystalline (R)-(2-(3-(((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) as a pharmaceutically acceptable salt or solvation thereof. In some embodiments, the solid form is crystalline (R)-(2-(3-(((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) as its pharmaceutically acceptable salt. In some embodiments, the solid form is crystalline (R)-(2-(3-(((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) as its pharmaceutically acceptable solvate.

[0202] Polymorphic form A

[0203] The term "polymorphic form A" or "form A" refers to the crystalline form of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (the citrate coordination complex of compound 1), which exhibits the same characteristics as... Figure 2 The X-ray powder diffraction pattern shown is substantially the same as and / or similar to that shown. Figure 3 The DSC thermograms shown are essentially the same.

[0204] In some embodiments, polymorph A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) exhibits an X-ray powder diffraction pattern characterized by the diffraction patterns summarized in Table 1. In some embodiments, polymorph A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) contains at least three peaks (± 0.1° 2θ) as shown in Table 1. In some embodiments, polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) contains at least 4 peaks (±0.1° 2θ) of Table 1, at least 5 peaks (±0.1° 2θ) of Table 1, at least 6 peaks (±0.1° 2θ) of Table 1, at least 7 peaks (±0.1° 2θ) of Table 1, at least 8 peaks (±0.1° 2θ) of Table 1, or at least 9 peaks (±0.1° 2θ) of Table 1.

[0205] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) contains characteristic peaks at 5.9° ± 0.1° 2θ, 11.1° ± 0.1° 2θ, and 13.9° ± 0.1° 2θ.

[0206] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) contains characteristic peaks at 5.9° ± 0.1° 2θ, 11.1° ± 0.1° 2θ, and 13.9° ± 0.1° 2θ.

[0207] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) contains a characteristic peak at 11.1° ± 0.1° 2θ.

[0208] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) contains a characteristic peak at 13.9° ± 0.1° 2θ.

[0209] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) further includes characteristic peaks at 9.5° ± 0.1° 2θ and 11.9° ± 0.1° 2θ.

[0210] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) further includes a characteristic peak at 7.7° ± 0.1° 2θ.

[0211] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) further includes a characteristic peak at 11.4° ± 0.1° 2θ.

[0212] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) further includes a characteristic peak at 17.7° ± 0.1° 2θ.

[0213] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) further includes a characteristic peak at 13.3° ± 0.1° 2θ.

[0214] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) further includes a characteristic peak at 14.4° ± 0.1° 2θ.

[0215] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) further includes a characteristic peak at 19.8° ± 0.1° 2θ.

[0216] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) contains characteristic peaks at 5.9° ± 0.1° 2θ, 7.7° ± 0.1° 2θ, 9.5° ± 0.1° 2θ, 11.1° ± 0.1° 2θ, 11.4° ± 0.1° 2θ, 11.9° ± 0.1° 2θ, 13.9° ± 0.1° 2θ, and 17.7° ± 0.1° 2θ.

[0217] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) comprises at least three characteristic peaks selected from the group consisting of: 5.9° ± 0.1° 2θ, 7.7° ± 0.1° 2θ, 9.5° ± 0.1° 2θ, 11.1° ± 0.1° 2θ, 11.4° ± 0.1° 2θ, 11.9° ± 0.1° 2θ, 13.9° ± 0.1° 2θ, and 17.7° ± 0.1° 2θ.

[0218] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) comprises at least four characteristic peaks selected from the group consisting of: 5.9° ± 0.1° 2θ, 7.7° ± 0.1° 2θ, 9.5° ± 0.1° 2θ, 11.1° ± 0.1° 2θ, 11.4° ± 0.1° 2θ, 11.9° ± 0.1° 2θ, 13.9° ± 0.1° 2θ, and 17.7° ± 0.1° 2θ.

[0219] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) comprises at least five characteristic peaks selected from the group consisting of: 5.9° ± 0.1° 2θ, 7.7° ± 0.1° 2θ, 9.5° ± 0.1° 2θ, 11.1° ± 0.1° 2θ, 11.4° ± 0.1° 2θ, 11.9° ± 0.1° 2θ, 13.9° ± 0.1° 2θ, and 17.7° ± 0.1° 2θ.

[0220] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) comprises at least six characteristic peaks selected from the group consisting of: 5.9° ± 0.1° 2θ, 7.7° ± 0.1° 2θ, 9.5° ± 0.1° 2θ, 11.1° ± 0.1° 2θ, 11.4° ± 0.1° 2θ, 11.9° ± 0.1° 2θ, 13.9° ± 0.1° 2θ, and 17.7° ± 0.1° 2θ.

[0221] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) comprises at least seven characteristic peaks selected from the group consisting of: 5.9° ± 0.1° 2θ, 7.7° ± 0.1° 2θ, 9.5° ± 0.1° 2θ, 11.1° ± 0.1° 2θ, 11.4° ± 0.1° 2θ, 11.9° ± 0.1° 2θ, 13.9° ± 0.1° 2θ, and 17.7° ± 0.1° 2θ.

[0222] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) contains characteristic peaks at 5.9° ± 0.1° 2θ, 7.7° ± 0.1° 2θ, 9.5° ± 0.1° 2θ, 11.1° ± 0.1° 2θ, 11.4° ± 0.1° 2θ, 11.9° ± 0.1° 2θ, 13.3° ± 0.1° 2θ, 13.9° ± 0.1° 2θ, 14.4° ± 0.1° 2θ, 17.7° ± 0.1° 2θ, and 19.8° ± 0.1° 2θ.

[0223] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) comprises at least three characteristic peaks selected from the group consisting of: 5.9° ± 0.1° 2θ, 7.7° ± 0.1° 2θ, 9.5° ± 0.1° 2θ, 11.1° ± 0.1° 2θ, 11.4° ± 0.1° 2θ, 11.9° ± 0.1° 2θ, 13.3° ± 0.1° 2θ, 13.9° ± 0.1° 2θ, 14.4° ± 0.1° 2θ, 17.7° ± 0.1° 2θ, and 19.8° ± 0.1° 2θ.

[0224] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) comprises at least four characteristic peaks selected from the group consisting of: 5.9° ± 0.1° 2θ, 7.7° ± 0.1° 2θ, 9.5° ± 0.1° 2θ, 11.1° ± 0.1° 2θ, 11.4° ± 0.1° 2θ, 11.9° ± 0.1° 2θ, 13.3° ± 0.1° 2θ, 13.9° ± 0.1° 2θ, 14.4° ± 0.1° 2θ, 17.7° ± 0.1° 2θ, and 19.8° ± 0.1° 2θ.

[0225] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) comprises at least five characteristic peaks selected from the group consisting of: 5.9° ± 0.1° 2θ, 7.7° ± 0.1° 2θ, 9.5° ± 0.1° 2θ, 11.1° ± 0.1° 2θ, 11.4° ± 0.1° 2θ, 11.9° ± 0.1° 2θ, 13.3° ± 0.1° 2θ, 13.9° ± 0.1° 2θ, 14.4° ± 0.1° 2θ, 17.7° ± 0.1° 2θ, and 19.8° ± 0.1° 2θ.

[0226] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) comprises at least six characteristic peaks selected from the group consisting of: 5.9° ± 0.1° 2θ, 7.7° ± 0.1° 2θ, 9.5° ± 0.1° 2θ, 11.1° ± 0.1° 2θ, 11.4° ± 0.1° 2θ, 11.9° ± 0.1° 2θ, 13.3° ± 0.1° 2θ, 13.9° ± 0.1° 2θ, 14.4° ± 0.1° 2θ, 17.7° ± 0.1° 2θ, and 19.8° ± 0.1° 2θ.

[0227] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) comprises at least seven characteristic peaks selected from the group consisting of: 5.9° ± 0.1° 2θ, 7.7° ± 0.1° 2θ, 9.5° ± 0.1° 2θ, 11.1° ± 0.1° 2θ, 11.4° ± 0.1° 2θ, 11.9° ± 0.1° 2θ, 13.3° ± 0.1° 2θ, 13.9° ± 0.1° 2θ, 14.4° ± 0.1° 2θ, 17.7° ± 0.1° 2θ, and 19.8° ± 0.1° 2θ.

[0228] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) contains characteristic peaks at 5.9° ± 0.1° 2θ, 9.5° ± 0.1° 2θ, 11.1° ± 0.1° 2θ, 11.9° ± 0.1° 2θ, and 13.9° ± 0.1° 2θ.

[0229] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) contains a characteristic peak at 5.9° ± 0.1° 2θ.

[0230] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) contains a characteristic peak at 9.5° ± 0.1° 2θ.

[0231] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) contains a characteristic peak at 11.1° ± 0.1° 2θ.

[0232] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) contains a characteristic peak at 11.9° ± 0.1° 2θ.

[0233] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) contains a characteristic peak at 13.9° ± 0.1° 2θ.

[0234] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) contains characteristic peaks at 11.4° ± 0.1° 2θ, 13.3° ± 0.1° 2θ, 14.4° ± 0.1° 2θ, and 17.7° ± 0.1° 2θ.

[0235] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) further includes characteristic peaks at 8.1° ± 0.1° 2θ, 8.3° ± 0.1° 2θ, 11.5° ± 0.1° 2θ, and 17.2° ± 0.1° 2θ.

[0236] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)boronic acid citrate (compound 1 citrate coordination complex) is contained in 5.9° ± 0.1° 2θ, 8.1° ± 0.1° 2θ, 8.3° ± 0.1° 2θ, 9.5° ± 0.1° 2θ, 11.1° ± 0.1° 2θ, 11.4° ± 0.1° 2θ, 11.5° ± 0.1° 2θ, 11.9° ± 0.1° 2θ, 13.3° ± 0.1° 2θ, 13.9° ± 0.1° 2θ, 14.4° ± 0.1° 2θ, 17.2° ± 0.1° 2θ, and 17.7° ± The characteristic peak at 0.1° 2θ.

[0237] In some embodiments, polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)boronic acid citrate (compound 1 citrate coordination complex) contains at least one characteristic peak selected from the group consisting of: 5.9° ± 0.1° 2θ, 8.1° ± 0.1° 2θ, 8.3° ± 0.1° 2θ, 9.5° ± 0.1° 2θ, 11.1° ± 0.1° 2θ, 11.4° ± 0.1° 2θ, 11.5° ± 0.1° 2θ, 11.9° ± 0.1° 2θ, 13.3° ± 0.1° 2θ, 13.9° ± 0.1° 2θ, 14.4° ± 0.1° 2θ, 17.2° ± 0.1° 2θ and 17.7° ± 0.1° 2θ.

[0238] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)boronic acid citrate (compound 1 citrate coordination complex) comprises at least two characteristic peaks selected from the group consisting of: 5.9° ± 0.1° 2θ, 8.1° ± 0.1° 2θ, 8.3° ± 0.1° 2θ, 9.5° ± 0.1° 2θ, 11.1° ± 0.1° 2θ, 11.4° ± 0.1° 2θ, 11.5° ± 0.1° 2θ, 11.9° ± 0.1° 2θ, 13.3° ± 0.1° 2θ, 13.9° ± 0.1° 2θ, 14.4° ± 0.1° 2θ, 17.2° ± 0.1° 2θ and 17.7° ± 0.1° 2θ.

[0239] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)boronic acid citrate (compound 1 citrate coordination complex) comprises at least three characteristic peaks selected from the group consisting of: 5.9° ± 0.1° 2θ, 8.1° ± 0.1° 2θ, 8.3° ± 0.1° 2θ, 9.5° ± 0.1° 2θ, 11.1° ± 0.1° 2θ, 11.4° ± 0.1° 2θ, 11.5° ± 0.1° 2θ, 11.9° ± 0.1° 2θ, 13.3° ± 0.1° 2θ, 13.9° ± 0.1° 2θ, 14.4° ± 0.1° 2θ, 17.2° ± 0.1° 2θ and 17.7° ± 0.1° 2θ.

[0240] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)boronic acid citrate (compound 1 citrate coordination complex) comprises at least four characteristic peaks selected from the group consisting of: 5.9° ± 0.1° 2θ, 8.1° ± 0.1° 2θ, 8.3° ± 0.1° 2θ, 9.5° ± 0.1° 2θ, 11.1° ± 0.1° 2θ, 11.4° ± 0.1° 2θ, 11.5° ± 0.1° 2θ, 11.9° ± 0.1° 2θ, 13.3° ± 0.1° 2θ, 13.9° ± 0.1° 2θ, 14.4° ± 0.1° 2θ, 17.2° ± 0.1° 2θ and 17.7° ± 0.1° 2θ.

[0241] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)boronic acid citrate (compound 1 citrate coordination complex) comprises at least five characteristic peaks selected from the group consisting of: 5.9° ± 0.1° 2θ, 8.1° ± 0.1° 2θ, 8.3° ± 0.1° 2θ, 9.5° ± 0.1° 2θ, 11.1° ± 0.1° 2θ, 11.4° ± 0.1° 2θ, 11.5° ± 0.1° 2θ, 11.9° ± 0.1° 2θ, 13.3° ± 0.1° 2θ, 13.9° ± 0.1° 2θ, 14.4° ± 0.1° 2θ, 17.2° ± 0.1° 2θ and 17.7° ± 0.1° 2θ.

[0242] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)boronic acid citrate (compound 1 citrate coordination complex) comprises at least six characteristic peaks selected from the group consisting of: 5.9° ± 0.1° 2θ, 8.1° ± 0.1° 2θ, 8.3° ± 0.1° 2θ, 9.5° ± 0.1° 2θ, 11.1° ± 0.1° 2θ, 11.4° ± 0.1° 2θ, 11.5° ± 0.1° 2θ, 11.9° ± 0.1° 2θ, 13.3° ± 0.1° 2θ, 13.9° ± 0.1° 2θ, 14.4° ± 0.1° 2θ, 17.2° ± 0.1° 2θ and 17.7° ± 0.1° 2θ.

[0243] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)boronic acid citrate (compound 1 citrate coordination complex) comprises at least seven characteristic peaks selected from the group consisting of: 5.9° ± 0.1° 2θ, 8.1° ± 0.1° 2θ, 8.3° ± 0.1° 2θ, 9.5° ± 0.1° 2θ, 11.1° ± 0.1° 2θ, 11.4° ± 0.1° 2θ, 11.5° ± 0.1° 2θ, 11.9° ± 0.1° 2θ, 13.3° ± 0.1° 2θ, 13.9° ± 0.1° 2θ, 14.4° ± 0.1° 2θ, 17.2° ± 0.1° 2θ and 17.7° ± 0.1° 2θ.

[0244] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)boronic acid citrate (compound 1 citrate coordination complex) comprises at least eight characteristic peaks selected from the group consisting of: 5.9° ± 0.1° 2θ, 8.1° ± 0.1° 2θ, 8.3° ± 0.1° 2θ, 9.5° ± 0.1° 2θ, 11.1° ± 0.1° 2θ, 11.4° ± 0.1° 2θ, 11.5° ± 0.1° 2θ, 11.9° ± 0.1° 2θ, 13.3° ± 0.1° 2θ, 13.9° ± 0.1° 2θ, 14.4° ± 0.1° 2θ, 17.2° ± 0.1° 2θ and 17.7° ± 0.1° 2θ.

[0245] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)boronic acid citrate (compound 1 citrate coordination complex) comprises at least nine characteristic peaks selected from the group consisting of: 5.9° ± 0.1° 2θ, 8.1° ± 0.1° 2θ, 8.3° ± 0.1° 2θ, 9.5° ± 0.1° 2θ, 11.1° ± 0.1° 2θ, 11.4° ± 0.1° 2θ, 11.5° ± 0.1° 2θ, 11.9° ± 0.1° 2θ, 13.3° ± 0.1° 2θ, 13.9° ± 0.1° 2θ, 14.4° ± 0.1° 2θ, 17.2° ± 0.1° 2θ and 17.7° ± 0.1° 2θ.

[0246] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) comprises at least ten characteristic peaks selected from the group consisting of: 5.9° ± 0.1° 2θ, 8.1° ± 0.1° 2θ, 8.3° ± 0.1° 2θ, 9.5° ± 0.1° 2θ, 11.1° ± 0.1° 2θ, 11.4° ± 0.1° 2θ, 11.5° ± 0.1° 2θ, 11.9° ± 0.1° 2θ, 13.3° ± 0.1° 2θ, 13.9° ± 0.1° 2θ, 14.4° ± 0.1° 2θ, 17.2° ± 0.1° 2θ and 17.7° ± 0.1° 2θ.

[0247] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) comprises at least 11 characteristic peaks selected from the group consisting of: 5.9° ± 0.1° 2θ, 8.1° ± 0.1° 2θ, 8.3° ± 0.1° 2θ, 9.5° ± 0.1° 2θ, 11.1° ± 0.1° 2θ, 11.4° ± 0.1° 2θ, 11.5° ± 0.1° 2θ, 11.9° ± 0.1° 2θ, 13.3° ± 0.1° 2θ, 13.9° ± 0.1° 2θ, 14.4° ± 0.1° 2θ, 17.2° ±0.1° 2θ and 17.7° ± 0.1° 2θ.

[0248] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)boronic acid citrate (compound 1 citrate coordination complex) comprises at least 12 characteristic peaks selected from the group consisting of: 5.9° ± 0.1° 2θ, 8.1° ± 0.1° 2θ, 8.3° ± 0.1° 2θ, 9.5° ± 0.1° 2θ, 11.1° ± 0.1° 2θ, 11.4° ± 0.1° 2θ, 11.5° ± 0.1° 2θ, 11.9° ± 0.1° 2θ, 13.3° ± 0.1° 2θ, 13.9° ± 0.1° 2θ, 14.4° ± 0.1° 2θ, 17.2° ±0.1° 2θ and 17.7° ± 0.1° 2θ.

[0249] In some embodiments, the polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) has a single endothermic temperature starting at about 143.7°C in DSC.

[0250] In some embodiments, polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) crystallizes as needle-like structures and is thermodynamically stable. In some embodiments, polymorphic form A of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) is thermodynamically more stable than polymorphic form B of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex).

[0251] Table 1: Characteristic XRPD signals of form A (2θ, Cu)

[0252]

[0253] Polymorphic form B

[0254] The term "polymorphic form B" or "form B" refers to the crystalline form of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (the citrate coordination complex of compound 1), which exhibits the same characteristics as... Figure 6 The X-ray powder diffraction pattern shown is substantially the same as and / or similar to that shown. Figure 7 The DSC thermograms shown are essentially the same.

[0255] In some embodiments, polymorphic form B of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) exhibits an X-ray powder diffraction pattern characterized by the diffraction patterns summarized in Table 2. In some embodiments, polymorphic form B of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) contains at least three peaks (± 0.1° 2θ) as shown in Table 2. In some embodiments, polymorphic form B of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) contains at least 4 peaks (±0.1° 2θ) of Table 2, at least 5 peaks (±0.1° 2θ) of Table 2, at least 6 peaks (±0.1° 2θ) of Table 2, at least 7 peaks (±0.1° 2θ) of Table 2, at least 8 peaks (±0.1° 2θ) of Table 2, or at least 9 peaks (±0.1° 2θ) of Table 2.

[0256] In some embodiments, the polymorphic form B of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) contains characteristic peaks at 10.1° ± 0.1° 2θ and 12.7° ± 0.1° 2θ.

[0257] In some embodiments, the polymorphic form B of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) further includes a characteristic peak at 16.3° ± 0.1° 2θ.

[0258] In some embodiments, the polymorphic form B of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) further includes a characteristic peak at 18.1° ± 0.1° 2θ.

[0259] In some embodiments, the polymorphic form B of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) further includes a characteristic peak at 8.2° ± 0.1° 2θ.

[0260] In some embodiments, the polymorphic form B of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) further includes a characteristic peak at 13.3° ± 0.1° 2θ.

[0261] In some embodiments, the polymorphic form B of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) further includes a characteristic peak at 15.2° ± 0.1° 2θ.

[0262] In some embodiments, the polymorphic form B of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) further includes a characteristic peak at 19.9° ± 0.1° 2θ.

[0263] In some embodiments, the polymorphic form B of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) further includes a characteristic peak at 22.2° ± 0.1° 2θ.

[0264] In some embodiments, the polymorphic form B of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) contains characteristic peaks at 10.1° ± 0.1° 2θ, 12.7° ± 0.1° 2θ, 16.3° ± 0.1° 2θ, and 18.1° ± 0.1° 2θ.

[0265] In some embodiments, the polymorphic form B of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) contains at least three characteristic peaks selected from the group consisting of: 10.1° ± 0.1° 2θ, 12.7° ± 0.1° 2θ, 16.3° ± 0.1° 2θ, and 18.1° ± 0.1° 2θ.

[0266] In some embodiments, the polymorphic form B of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) contains characteristic peaks at 8.2° ± 0.1° 2θ, 10.1° ± 0.1° 2θ, 12.7° ± 0.1° 2θ, 13.3° ± 0.1° 2θ, 15.2° ± 0.1° 2θ, 16.3° ± 0.1° 2θ, 18.1° ± 0.1° 2θ, 19.9° ± 0.1° 2θ, and 22.2° ± 0.1° 2θ.

[0267] In some embodiments, the polymorphic form B of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) comprises at least three characteristic peaks selected from the group consisting of: 8.2° ± 0.1° 2θ, 10.1° ± 0.1° 2θ, 12.7° ± 0.1° 2θ, 13.3° ± 0.1° 2θ, 15.2° ± 0.1° 2θ, 16.3° ± 0.1° 2θ, 18.1° ± 0.1° 2θ, 19.9° ± 0.1° 2θ, and 22.2° ± 0.1° 2θ.

[0268] In some embodiments, the polymorphic form B of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) comprises at least four characteristic peaks selected from the group consisting of: 8.2° ± 0.1° 2θ, 10.1° ± 0.1° 2θ, 12.7° ± 0.1° 2θ, 13.3° ± 0.1° 2θ, 15.2° ± 0.1° 2θ, 16.3° ± 0.1° 2θ, 18.1° ± 0.1° 2θ, 19.9° ± 0.1° 2θ, and 22.2° ± 0.1° 2θ.

[0269] In some embodiments, the polymorphic form B of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) comprises at least five characteristic peaks selected from the group consisting of: 8.2° ± 0.1° 2θ, 10.1° ± 0.1° 2θ, 12.7° ± 0.1° 2θ, 13.3° ± 0.1° 2θ, 15.2° ± 0.1° 2θ, 16.3° ± 0.1° 2θ, 18.1° ± 0.1° 2θ, 19.9° ± 0.1° 2θ, and 22.2° ± 0.1° 2θ.

[0270] In some embodiments, the polymorphic form B of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) comprises at least six characteristic peaks selected from the group consisting of: 8.2° ± 0.1° 2θ, 10.1° ± 0.1° 2θ, 12.7° ± 0.1° 2θ, 13.3° ± 0.1° 2θ, 15.2° ± 0.1° 2θ, 16.3° ± 0.1° 2θ, 18.1° ± 0.1° 2θ, 19.9° ± 0.1° 2θ, and 22.2° ± 0.1° 2θ.

[0271] In some embodiments, the polymorphic form B of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) comprises at least seven characteristic peaks selected from the group consisting of: 8.2° ± 0.1° 2θ, 10.1° ± 0.1° 2θ, 12.7° ± 0.1° 2θ, 13.3° ± 0.1° 2θ, 15.2° ± 0.1° 2θ, 16.3° ± 0.1° 2θ, 18.1° ± 0.1° 2θ, 19.9° ± 0.1° 2θ, and 22.2° ± 0.1° 2θ.

[0272] In some embodiments, the polymorphic form B of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) comprises at least eight characteristic peaks selected from the group consisting of: 8.2° ± 0.1° 2θ, 10.1° ± 0.1° 2θ, 12.7° ± 0.1° 2θ, 13.3° ± 0.1° 2θ, 15.2° ± 0.1° 2θ, 16.3° ± 0.1° 2θ, 18.1° ± 0.1° 2θ, 19.9° ± 0.1° 2θ, and 22.2° ± 0.1° 2θ.

[0273] In some embodiments, the polymorphic form B of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate (compound 1 citrate coordination complex) has a single endothermic temperature starting at about 136.0°C in DSC.

[0274] Table 2: Characteristic XRPD signals of form B (2θ, Cu Kα1)

[0275]

[0276] Pharmaceutical Composition

[0277] This article discloses a pharmaceutical composition comprising:

[0278] (i) an ester coordination complex of compound 1 of formula (I) or a pharmaceutically acceptable salt or solvate thereof; and

[0279] (ii) Cefoxitin:

[0280]

[0281] Formula (I);

[0282] in:

[0283] Ring A is a 4- to 8-membered heterocyclic alkyl group that optionally contains one or two additional heteroatoms selected from the group consisting of O, N, and S;

[0284] Each R 1 Independently, it is halogen, -CN, -OH, -L-OR a -L-NR c R d -LC(=O)R a -LC(=O)OR b -LC(=O)NRc R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0285] Or two R atoms on the same atom 1 Together they form an oxygen group;

[0286] n is 0, 1, 2, 3, 4, 5, or 6;

[0287] R 2 It is hydrogen, R 4 、-(R 3 ) q OR 4 、-(R 3 ) q O(R 3 ) q OR 4 -R 3 OC(=O)R 4 -R 3 OC(=O)OR 4 -R 3 OC(=O)NHR 5 or -R 3 OC(=O)N(R 5 )2;

[0288] Each q is independently 2, 3, 4, 5, or 6;

[0289] Each R 3 It is independently -CH2-, -CH(CH3)-, -C(CH3)2- or 1,1-cyclopropene;

[0290] R 4 It is C1-C 12 Alkyl, C1-C 12 Haloalkyl, C1-C 12 Hydroxyalkyl, C1-C 12 aminoalkyl, C1-C 12 Alkoxyalkyl, C2-C 12 alkenyl, C2-C 12 Alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl group is independently and optionally substituted by one or more R groups;

[0291] Each R 5 Independently, it is C1-C 12 Alkyl, C1-C 12 Haloalkyl, C1-C 12 Hydroxyalkyl, C1-C 12 aminoalkyl, C1-C 12 Alkoxyalkyl, C2-C 12 alkenyl, C2-C 12 Alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl group is independently and optionally substituted by one or more R groups;

[0292] Or two Rs 5 Together with the nitrogen to which they are attached, they form heterocyclic alkyl groups that are independently and optionally substituted with one or more R groups;

[0293] Each R a Independently, it is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R;

[0294] Each R b Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R;

[0295] R c and R d Each of the following is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0296] Or R c and R d Together with the atoms to which they are attached, they form heterocyclic alkyl groups that are independently and optionally substituted with one or more R atoms; and

[0297] L is absent or is optionally substituted independently by one or more Rs in C1-C3 alkylene groups;

[0298] Each R is independently a halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -S(=O)(=NC1-C3 alkyl)(C1-C3 alkyl), -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -N=S(=O)(C1-C3 alkyl) 2. -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, -P(=O)(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl or C3-C6 cycloalkyl;

[0299] Or two R atoms on the same atom can form an oxo group.

[0300] In some embodiments, cefobacterium is in the form of cefobacterium dihydrate.

[0301] This article discloses a pharmaceutical composition comprising:

[0302] (i) A compound that is a (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex or a pharmaceutically acceptable salt or solvation thereof; and

[0303] (ii) Cefoxitin.

[0304] In some embodiments, cefobacterium is in the form of cefobacterium dihydrate.

[0305] In some embodiments of the pharmaceutical composition, the compound is a (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex.

[0306] In some embodiments of the pharmaceutical composition, the compounds are:

[0307] Or its pharmaceutically acceptable salts or solvates.

[0308] In some embodiments of the pharmaceutical composition, the compounds are:

[0309]

[0310] In some embodiments of the pharmaceutical composition, the compounds are:

[0311] As a monosodium salt .

[0312] In some embodiments of the pharmaceutical composition, the compounds are:

[0313] As a disodium salt .

[0314] In some embodiments of the pharmaceutical composition, the compounds are:

[0315] Or its pharmaceutically acceptable salts or solvates.

[0316] In some embodiments of the pharmaceutical composition, the compounds are:

[0317] .

[0318] In some embodiments of the pharmaceutical composition, the compounds are:

[0319] As a monosodium salt .

[0320] In some embodiments of the pharmaceutical composition, the compounds are:

[0321] As a disodium salt .

[0322] In some embodiments of the pharmaceutical composition, the (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex or a pharmaceutically acceptable salt solvation thereof is crystalline.

[0323] This article discloses a pharmaceutical composition comprising:

[0324] (i) the crystalline form of the compound, which is (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex or a pharmaceutically acceptable salt or solvation thereof; and

[0325] (ii) Cefoxitin.

[0326] In some embodiments, cefobacterium is in the form of cefobacterium dihydrate.

[0327] In some embodiments of the pharmaceutical composition, the compound is a (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex.

[0328] In some embodiments of the pharmaceutical composition, the compounds are:

[0329] Or its pharmaceutically acceptable salts or solvates.

[0330] In some embodiments of the pharmaceutical composition, the compounds are:

[0331] .

[0332] In some embodiments of the pharmaceutical composition, the compounds are:

[0333] As a monosodium salt .

[0334] In some embodiments of the pharmaceutical composition, the compounds are:

[0335] As a disodium salt .

[0336] In some embodiments of the pharmaceutical composition, the compounds are:

[0337] Or its pharmaceutically acceptable salts or solvates.

[0338] In some embodiments of the pharmaceutical composition, the compounds are:

[0339] .

[0340] In some embodiments of the pharmaceutical composition, the compounds are:

[0341] As a monosodium salt .

[0342] In some embodiments of the pharmaceutical composition, the compounds are:

[0343] As a disodium salt .

[0344] In some embodiments of the pharmaceutical composition, the compound and cefbufen are formulated in a single dosage form.

[0345] In some embodiments of the pharmaceutical composition, the crystalline form and cefbufen are formulated in a single dosage form.

[0346] In some embodiments of the pharmaceutical composition, the single dosage form is a capsule.

[0347] In some embodiments of the pharmaceutical composition, the single dosage form is a tablet.

[0348] In some embodiments of the pharmaceutical composition, a single dosage form comprises the compound and cefbufen dihydrate, the ratio of which is adjusted to correspond to between approximately 1:1 and approximately 1:4. And cefoperazone.

[0349] In some embodiments of the pharmaceutical composition, a single dosage form comprises the compound and cefbufen dihydrate, the ratio of which is adjusted to correspond to between approximately 1:1 and approximately 1:3. And cefoperazone.

[0350] In some embodiments of the pharmaceutical composition, a single dosage form comprises the compound and cefbufen dihydrate, the ratio of which is adjusted to correspond to between about 1:1 and about 1:2. And cefoperazone.

[0351] In some embodiments of the pharmaceutical composition, a single dosage form comprises the compound and cefbufen dihydrate, the ratio of which is adjusted to correspond to between about 1:1 and about 1:1.5. And cefoperazone.

[0352] In some embodiments of the pharmaceutical composition, a single dosage form comprises the compound and cefbufen dihydrate, the ratio of which is adjusted to correspond to approximately 1:1. And cefoperazone.

[0353] In some embodiments of the pharmaceutical composition, a single dosage form comprises between about 100 mg and about 250 mg of cefbufen dihydrate.

[0354] In some embodiments of the pharmaceutical composition, a single dosage form comprises between about 150 mg and about 250 mg of cefbufen dihydrate.

[0355] In some embodiments of the pharmaceutical composition, a single dosage form comprises between about 150 mg and about 200 mg of cefbuprofen dihydrate.

[0356] In some embodiments of the pharmaceutical composition, a single dosage form comprises between about 200 mg and about 250 mg of cefbufen dihydrate.

[0357] In some embodiments of the pharmaceutical composition, a single dosage form comprises between about 210 mg and about 240 mg of cefbuprofen dihydrate.

[0358] In some embodiments of the pharmaceutical composition, a single dosage form comprises between about 210 mg and about 220 mg of cefbuprofen dihydrate.

[0359] In some embodiments of the pharmaceutical composition, a single dosage form comprises between about 220 mg and about 230 mg of cefbufen dihydrate.

[0360] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 100 mg of cefbufen dihydrate.

[0361] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 110 mg of cefbufen dihydrate.

[0362] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 120 mg of cefbufen dihydrate.

[0363] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 130 mg of cefbufen dihydrate.

[0364] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 140 mg of cefbufen dihydrate.

[0365] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 150 mg of cefbufen dihydrate.

[0366] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 160 mg of cefbufen dihydrate.

[0367] In some embodiments of the pharmaceutical composition, a single dosage form comprises approximately 170 mg of cefbufen dihydrate.

[0368] In some embodiments of the pharmaceutical composition, a single dosage form comprises approximately 180 mg of cefbufen dihydrate.

[0369] In some embodiments of the pharmaceutical composition, a single dosage form comprises approximately 190 mg of cefbufen dihydrate.

[0370] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 200 mg of cefbufen dihydrate.

[0371] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 210 mg of cefbufen dihydrate.

[0372] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 220 mg of cefbufen dihydrate.

[0373] In some embodiments of the pharmaceutical composition, a single dosage form comprises approximately 230 mg of cefbufen dihydrate.

[0374] In some embodiments of the pharmaceutical composition, a single dosage form comprises cefobacterium dihydrate adjusted to an amount corresponding to 200 mg of cefobacterium.

[0375] In some embodiments of the pharmaceutical composition, a single dosage form comprises a (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex between about 50 mg and about 100 mg.

[0376] In some embodiments of the pharmaceutical composition, a single dosage form comprises a (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex between about 60 mg and about 90 mg.

[0377] In some embodiments of the pharmaceutical composition, a single dosage form comprises a (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex between about 70 mg and about 80 mg.

[0378] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 72 mg of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate.

[0379] In some embodiments of the pharmaceutical composition, a single dosage form comprises a (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex between about 200 mg and about 350 mg.

[0380] In some embodiments of the pharmaceutical composition, a single dosage form comprises a (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex between about 260 mg and about 310 mg.

[0381] In some embodiments of the pharmaceutical composition, a single dosage form comprises a (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex between about 270 mg and about 300 mg.

[0382] In some embodiments of the pharmaceutical composition, a single dosage form comprises a (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex between about 280 mg and about 290 mg.

[0383] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 50 mg of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex.

[0384] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 60 mg of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex.

[0385] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 70 mg of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex.

[0386] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 80 mg of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex.

[0387] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 90 mg of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex.

[0388] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 100 mg of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex.

[0389] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 110 mg of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex.

[0390] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 120 mg of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex.

[0391] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 130 mg of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex.

[0392] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 140 mg of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex.

[0393] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 150 mg of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex.

[0394] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 160 mg of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex.

[0395] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 170 mg of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex.

[0396] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 180 mg of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex.

[0397] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 190 mg of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex.

[0398] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 200 mg of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex.

[0399] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 210 mg of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex.

[0400] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 220 mg of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex.

[0401] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 230 mg of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex.

[0402] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 240 mg of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex.

[0403] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 250 mg of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex.

[0404] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 260 mg of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex.

[0405] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 270 mg of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex.

[0406] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 280 mg of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex.

[0407] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 290 mg of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex.

[0408] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 300 mg of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex.

[0409] In some embodiments of the pharmaceutical composition, a single dosage form comprises about 310 mg of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex.

[0410] In some embodiments of the pharmaceutical composition, a single dosage form comprises (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex, the amount of which is adjusted to correspond to 200 mg. (Compound 1).

[0411] In some embodiments of the pharmaceutical composition, a single dosage form comprises (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex, the amount of which is adjusted to correspond to 50 mg. (Compound 1).

[0412] Treatment

[0413] This document discloses methods for inhibiting bacterial growth by, for example, reducing bacterial resistance to β-lactam antibiotics. Such methods include contacting bacterial cell cultures or bacterial-infected cell cultures, tissues, or organisms, and include administering a pharmaceutical composition comprising a citrate coordination complex of compound 1 or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, the pharmaceutical composition further comprises an antibiotic. In some embodiments, the pharmaceutical composition further comprises a β-lactam antibiotic. In some embodiments, the β-lactam antibiotic is cefbumin. In some embodiments, the β-lactam antibiotic is cefbumin dihydrate.

[0414] In some embodiments, the bacteria inhibited by application of the compounds or pharmaceutical compositions described herein are bacteria resistant to β-lactam antibiotics. The term “resistance” is well understood by those skilled in the art (see, for example, Payne et al., Antimicrobial Agents and Chemotherapy 38 767-772 (1994), Hanaki et al., Antimicrobial Agents and Chemotherapy 30 1120-1126 (1995)).

[0415] These methods can be used to inhibit bacterial growth in a variety of environments. In some embodiments, the compounds or pharmaceutical compositions described herein are administered in vitro to experimental cell cultures to prevent the growth of β-lactam-resistant bacteria. In some other embodiments, the compounds or pharmaceutical compositions described herein are administered to mammals (including humans) to prevent the growth of β-lactam-resistant bacteria in vivo. In some embodiments, the method includes administering a therapeutically effective amount of a β-lactamase inhibitor, such as the compounds or pharmaceutical compositions described herein, to mammals (including humans) for a duration of therapeutic effectiveness. Preferably, the β-lactamase inhibitor is administered in the form of a pharmaceutical composition as described herein. In some embodiments, an antibiotic is co-administered with a β-lactamase inhibitor. In some embodiments, the antibiotic is a β-lactam antibiotic. In some embodiments, the β-lactam antibiotic is cefbumin. In some embodiments, the β-lactam antibiotic is cefbumin dihydrate.

[0416] This document discloses a method for treating a bacterial infection, which includes administering to a subject a compound or pharmaceutical composition described herein. In some embodiments, the bacterial infection is an upper or lower respiratory tract infection, a urinary tract infection, an intra-abdominal infection, or a skin infection.

[0417] In some embodiments, the bacterial infection is caused by carbapenem-resistant Enterobacteriaceae (CRE) or Gram-negative bacteria that produce extended-spectrum β-lactamases (ESBLs).

[0418] In some embodiments, the bacterial infection is an acute bacterial exacerbation of chronic bronchitis (ABECB), acute bacterial otitis media, pharyngitis, or tonsillitis.

[0419] In some embodiments, the bacterial infection is pneumonia, urinary tract infection, enteritis, or gastroenteritis.

[0420] In some embodiments, the bacterial infection is otitis media, streptococcal laryngitis, pneumonia, urinary tract infection, gonorrhea, or Lyme disease.

[0421] In some embodiments, the treated infection comprises bacteria, including: Elizabethkingia meningoseptica, Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonas hydrophila, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, and Salmonella paratyphimurium. The following bacteria are listed: *Salmonella paratyphi*, *Salmonella enteritidis*, *Shigella dysenteriae*, *Shigella flexneri*, *Shigella sonnei*, *Enterobacter cloacae*, *Enterobacter aerogenes*, *Klebsiella pneumoniae*, *Klebsiella oxytoca*, *Serratia marcescens*, *Francisella tularensis*, *Morganella morganii*, *Proteus mirabilis*, *Proteus vulgaris*, and *Providencia alkaliformis*. *Alcalifaciens*, *Providencia rettgeri*, *Providencia stuartii*, *Acinetobacter baumannii*, *Acinetobacter calceate*The following bacteria are listed: *Acinetobacter haemolyticus*, *Yersinia enterocolitica*, *Yersinia pestis*, *Yersinia pseudotuberculosis*, *Yersinia intermedia*, *Bordetella pertussis*, *Bordetella parapertussis*, *Bordetella bronchiseptica*, *Haemophilus influenzae*, *Haemophilus parainfluenzae*, *Haemophilus haemolyticus*, *Haemophilus parahaemolyticus*, *Haemophilus ducreyi*, *Pasteurella multocida*, and *Pasteurella hemolytica*. The following bacteria are listed: *Helicobacter pylori*, *Campylobacter fetus*, *Campylobacter jejuni*, *Campylobacter coli*, *Borrelia burgdorferi*, *Vibrio cholerae*, *Vibrio parahaemolyticus*, *Legionellapneumophila*, *Listeria monocytogenes*, *Neisseria gonorrhoeae*, *Neisseria meningitidis*, *Kingella*, *Moraxella*, *Gardnerella vaginalis*, *Bacteroides fragilis*, and *Bacteroides dignitaries*. distasonis), Bacteroides 3452A homology group3452A homology group), Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes The bacteria include *Staphylococcus pyogenes*, *Enterococcus faecalis*, *Enterococcus faecium*, *Staphylococcus aureus*, *Staphylococcus epidermidis*, *Staphylococcus saprophyticus*, *Staphylococcus intermedius*, *Staphylococcus hyicus subsp. hyicus*, *Staphylococcus haemolyticus*, *Staphylococcus hominis*, and *Staphylococcus saccharolyticus*.

[0422] In some embodiments, the treated infection includes bacteria, including: *Escherichia coli*, *Citrobacter freundii*, *Salmonella typhimurium*, *Salmonella typhi*, *Salmonella paratyphi*, *Salmonella enteritidis*, *Shigella dysenteriae*, *Shigella flexneri*, *Shigella sonnei*, *Enterobacter cloacae*, *Enterobacter aerogenes*, *Klebsiella pneumoniae*, *Klebsiella oxytoca*, *Serratia marcescens*, and *Morganella*. *Proteus mirabilis*, *Proteus vulgaris*, *Providencia alcalifaciens*, *Providencia rettgeri*, *Providencia stuartii*, *Acinetobacter baumannii*, *Acinetobacter calcoaceticus*, *Acinetobacter haemolyticus*, *Yersinia enterocolitica*, *Yersinia pestis*, *Yersinia pseudotuberculosis*, *Yersinia intermedia*, *Haemophilus influenzae*, *Haemophilus parainfluenzae*, and *Haemophilus haemolyticus*. Haemophilus parahaemolyticus, Haemophilus dulcisThe bacteria listed include *Pasteurella ducreyi*, *Pasteurella multocida*, *Pasteurella haemolytica*, *Branhamella catarrhalis*, *Borrelia burgdorferi*, *Vibrio cholerae*, *Vibrio parahaemolyticus*, *Legionellapneumophila*, *Neisseria gonorrhoeae*, *Neisseria meningitidis*, *Moraxella*, *Streptococcus pneumoniae*, *Streptococcus agalactiae*, and *Streptococcus pyogenes*.

[0423] In some embodiments, the treated infection includes bacteria, including: Elizabethkingia meningoseptica, Pseudomonas aeruginosa, Pseudomonas fluorescens, Stenotrophomonas maltophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, and Enterobacter cloacae. *Enterobacter aerogenes*, *Klebsiella pneumoniae*, *Klebsiella oxytoca*, *Serratia marcescens*, *Acinetobacter calcoaceticus*, *Acinetobacter haemolyticus*, *Yersinia enterocolitica*, *Yersinia pestis*, *Yersinia pseudotuberculosis*, *Yersinia intermedia*, *Haemophilus influenzae*, *Haemophilus parainfluenzae*, *Haemophilus haemolyticus*, *Haemophilus parahaemolyticus*, *Helicobacter pylori* Campylobacter fetus, Campylobacter jejuni, Campylobacter coliThe following bacteria are listed: *Vibrio cholerae*, *Vibrio parahaemolyticus*, *Legionella pneumophila*, *Listeria monocytogenes*, *Neisseria gonorrhoeae*, *Neisseria meningitidis*, *Moraxella*, *Bacteroides fragilis*, *Bacteroides vulgatus*, *Bacteroides ovalus*, *Bacteroides thetaiotaomicron*, *Bacteroides uniformis*, *Bacteroides eggerthii*, or *Bacteroides splanchnicus*.

[0424] In some embodiments, the treated infection includes bacteria, including: *Escherichia coli*, *Citrobacter freundii*, *Salmonella typhimurium*, *Salmonella typhimurium*, *Salmonella paratyphimurium*, *Salmonella enteritidis*, *Shigella dysenteriae*, *Shigella freundii*, *Shigella sonnei*, *Enterobacter cloacae*, *Enterobacter aerogenes*, *Klebsiella pneumoniae*, *Klebsiella oxytocinae*, *Serratia marcescens*, *Yersinia enterocolitica*, *Yersinia plague*, *Yersinia pseudotuberculosis*, *Yersinia intermedia*, *Haemophilus influenzae*, *Haemophilus parainfluenzae*, *Haemophilus hemolyticus*, *Haemophilus parahemolyticus*, *Vibrio cholerae*, *Vibrio parahemolyticus*, *Legionella pneumophila*, *Listeria monocytogenes*, *Neisseria gonorrhoeae*, and *Neisseria meningitidis* and *Moraxella* spp. Example

[0425] Analytical methods

[0426] Mass spectrometry (MS)

[0427] Mass spectra of the citrate coordination complex of compound 1 were obtained using a Waters Single Quad 3100 mass spectrometer operating in electrospray ionization (ESI) negative ion polarity mode. The sample was prepared in acetonitrile at a concentration of approximately 87 µg / mL. The sample solution was injected directly from the UPLC system into the mass spectrometer, and parameters were optimized for the compound.

[0428] The sample of the citrate coordination complex of compound 1 produced a [MH]- peak at m / z 564.04, consistent with the molecular formula C1 of compound 1. 25 H32 BNO 13 The monoisotope masses are consistent. The molecular weight of the citrate coordination complex of compound 1 is 565.34 Da, and the exact mass is 564.04 Da.

[0429] X-ray powder diffraction

[0430] XRPD patterns were acquired using 40 kV / 40 mA Cu Kα radiation with a Bruker D8 Advance sensor. Data were acquired using a LynxEye detector with Bragg-Brentano reflection geometry and a step size of 0.02. 2q, step length 37s, range 2.5-50 seconds. 2q. Powder samples were measured in silicon single-crystal sample holders with a depth of 0.05 mm, which were covered with Kapton foil to prevent moisture absorption. The samples were placed in an inert atmosphere (a glove box filled with N2), but no special treatment was used during sample preparation except for applying slight pressure to obtain a flat surface. All samples were rotated during the measurement.

[0431] Polarization optical microscopy (PLM)

[0432] Polarization optical microscopy was performed using a Leica MZ12.5 or Fisher Scientific Stereomaster stereomicroscope. Samples were observed using 0.8–10x objectives with cross-polarizers.

[0433] Differential scanning calorimetry (DSC) analysis

[0434] Routine DSC experiments were performed using a Q100 instrument (TA® Instruments, Newcastle, Delaware, USA) equipped with a cryocooling system (RCS90). The sample cell was purged with dry nitrogen at a flow rate of 50 mL / min. Accurately weighed samples (2–5 mg) placed in a TZero pan with pinholes were scanned at a heating rate of 10°C / min within the desired temperature range.

[0435] Dynamic vapor adsorption (DVS) analysis

[0436] Moisture adsorption / desorption data were collected on a DVS-intrinsic vapor adsorption analyzer (Surface Measurement Systems North America, Allentown, PA, USA) and operated using DVS-intrinsic control software (version 1.0.5.1). Samples were not dried prior to analysis. Adsorption and desorption data were collected in 10% RH increments over a range of 5% to 98% relative humidity (RH) under nitrogen purging. The equilibrium criterion used for analysis was a weight change of less than 0.005% over 10 min, with a maximum equilibrium time of 3 h.

[0437] Thermogravimetric analysis (TGA)

[0438] TGA was performed using a Discovery TGA 5500 instrument (TA® Instruments, Newcastle, Delaware, USA) with TRIOS software (version 5.0). Samples were placed in an aluminum pan. The sample cell was purged with dry nitrogen at a flow rate of 15 mL / min. Heating rates of 10°C / min were used in all experiments, ranging from 25°C to 350°C.

[0439] Nuclear magnetic resonance (NMR)

[0440] All 1D and 2D NMR data were collected at 300 K using a Bruker-Biospin AVANCE 500 MHz NMR spectrometer with a Bruker-Biospin 5 mm gradient broadband probe. 1D proton, 1D carbon, and 1D boron spectra were acquired at 500 MHz, 125 MHz, and 160 MHz, respectively. Tetramethylsilane resonances were used as a reference for the spectra, and for… 1 H and 13 Both C and J are set to 0.0 ppm. Using TMS as a reference, all chemical shifts (δ) are given in ppm, and J values ​​are given in Hz. Chemical shifts (δ) in the low-field direction are specified as positive relative to the reference standard.

[0441] Example 1: Preparation and characterization of amorphous compound 1 citrate coordination complex.

[0442]

[0443] At 75°C, form A of 2-[4-(carboxymethyl)-2-[(1R)-2-[3-({[(2-ethylbutyryl)oxy]methoxy}carbonyl)-2-hydroxyphenyl]-1-propamidoethyl]-5-oxo-1,3,2-dioxaneborane-4-yl]acetic acid was dissolved in isopropyl acetate. Once all the solids were completely dissolved, the hot solution was transferred to heptane at room temperature, resulting in a precipitate. The solids were filtered and washed with heptane. The solids were dried and analyzed by XRPD, indicating that the material was amorphous. Figure 10 ).

[0444] Example 2: Preparation and characterization of citrate coordination complex form A of compound 1.

[0445]

[0446] (R)-2-hydroxy-3-propamido-3,4-dihydro-2H-benzo[e][1,2]oxaboranecyclohexene-8-carboxylic acid ((2-ethylbutyryl)oxy)methyl ester (compound 1, 125 g, 1 equivalent, 95.0 w / w%) was dissolved in acetonitrile (1250 ml, 10 volumes), followed by the addition of citric acid (anhydrous, 54.4 g, 1 equivalent) to produce a heterogeneous solution. The mixture was stirred at ambient temperature for two hours or until a homogeneous solution was formed. The acetonitrile was distilled under vacuum to 3–4 volumes, followed by the addition of 10 volumes of isopropyl acetate. The batch was distilled under vacuum to 3–4 volumes, followed by the addition of 10 volumes of isopropyl acetate twice or until the water content was below 1000 ppm. The batch volume was adjusted to 9–10 volumes of isopropyl acetate and then heated to 65°C. The batch was cooled to 45–50°C and inoculated with 0.1 w / w% of compound 1 citrate form A, and held for 30 min to allow crystal formation. Once a seed bed was formed, the batch was cooled to 20–25°C and held for 16 h. The batch was then cooled to 5°C, held for 2 h, and then filtered and washed with cold (5°C) isopropyl acetate / heptane (3x3v, 3 / 1 v / v). The solid was dried on a filter and then under vacuum to constant weight to give 144 g of white solid. The above method provides compound 1 citrate coordination complex form A in 90% yield with a UHPLC purity of 99.9% and a qNMR purity of 99.3 w / w (ethylene carbonate as internal standard).

[0447] Alternative Synthesis of Compound 1 Citrate Coordination Complex Form A

[0448]

[0449] 2.105 g of compound 1 ethanolide and 0.968 g of citric acid (1:1 molar ratio) were added to a 100 mL round-bottom flask containing 15 mL of anhydrous ethyl acetate. The resulting solution was heated and maintained at 80°C for 3.5 hours. An inert atmosphere (N2) was maintained throughout the reaction. The solution obtained from step 1 was evaporated. The resulting gel-like material was further dried by purging with N2 for approximately 15 hours. The solid obtained from step 2 was treated with 20 mL of diethyl ether and stirred for 1 hour. 20 mL of n-heptane was added to the suspension and stirred for another 24 hours. The resulting solid was filtered and dried at room temperature for approximately 2 hours.

[0450] Mass spectrometry

[0451] Mass spectra of compound 1 in citrate coordination complex form A were obtained using an Agilent 6120 quadrupole LC / mass spectrometer with an electrospray ionization source. The instrument and data were controlled using ChemStation vB04.03 software. The mass spectrometer was calibrated immediately prior to analysis, and the electrospray ionization (ESI) source was operated in both positive and negative ionization modes. Samples were prepared by dilution in HPLC-grade acetonitrile at a concentration of 1 mg / mL and eluted with 100% acetonitrile through a pre-equilibrated HPLC column (XBridge BEH C18 column, 130 Å, 3.5 µm, 4.6 mm x 50 mm) before infusion into the ion source.

[0452] Mass spectrometry includes [MH] at m / z 564. - [M+Na] peak with m / z of 588 + Peak, and the proposed molecular formula C 25 H 32 BNO 13 The monoisotope masses are consistent. The molecular weight of compound 1, citrate coordination complex form A, is 565.34 Da, and the exact mass is 565.20 Da.

[0453] Nuclear magnetic resonance (NMR) spectroscopy

[0454] Approximately 25 mg of the compound 1 citrate coordination complex sample was dissolved in 1 mL of 99.9% deuterated acetone-d6 containing 0.05% (v / v) tetramethylsilane as the solvent. The following data were collected: 1D proton, 1D carbon, 1D boron, 1 H- 1 H-gradient COSY (correlation spectroscopY), with distortion-free polarization transfer enhancement. 1 H- 13Heteronuclear single quantum coherence (HSQC-DEPT) and heteronuclear multibonded coherence (HMBC) experiments were conducted. All 1D and 2D NMR data were collected at 300 K using a Bruker-Biospin AVANCE 500 MHz NMR spectrometer with a Bruker-Biospin 5 mm gradient broadband probe. 1D proton, 1D carbon, and 1D boron spectra were acquired at 500 MHz, 125 MHz, and 160 MHz, respectively. The spectra were compared using tetramethylsilane resonances, and for… 1 H and 13 C was set to 0.0 ppm. The chemical shift of the boron resonance was determined by incorporating methylboric acid into the sample; methylboric acid was set to 31.90 ppm, and the citrate coordination complex of compound 1 relative to methylboric acid... 11 The chemical shift of B is 12.88 ppm.

[0455] 1D proton spectroscopy revealed the expected chemical shifts, splits, and integrals consistent with the structure of the citrate coordination complex of compound 1. Repeated patterns were observed. 1 H and 13 C-resonance (due to the presence of conformational isomers with amide functional groups). The data are summarized in Table 3.

[0456] Table 3: Citrate coordination complex form A of compound 1 in acetone-d6 [300K] 1 H and 13 C10 NMR chemical shift assignment

[0457]

[0458] s = singlet, t = triplet, q = quartet, dt = double triplet, m = multiplet, br = broad peak, ppm = parts per million. NA = not applicable.

[0459] ¥ Integrals of 1-OH and 21,23-OH.

[0460] § Due to the presence of conformational isomers, the 13C resonance of C2, C5, C6, C7, C10, C11, C13, C16, C18, C19, C20, C21, C22 and C23 splits.

[0461] # The two CH2CO2H atoms in the boron-citric acid coordination complex are in an unequal state.

[0462] Example 2. Solubility study of compound 1 citrate coordination complex form A.

[0463] Visual solubility estimates of compound 1 citrate coordination complex form A were determined in a variety of solvents and solvent mixtures using the aliquot addition method to aid experimental design. Generally, compound 1 citrate coordination complex form A exhibits good solubility in most test solvents. Low solubility (< 1 mg / mL) was observed in heptane and cyclohexane. Solubility results are provided in Table 4.

[0464] Table 4: Estimated solubility of compound 1 citrate coordination complex form A at ambient temperature

[0465]

[0466] Solubility is calculated based on the total solvent used to provide the solution; the actual solubility may be higher due to the volume of solvent used or a slow dissolution rate. Solubility is rounded to the nearest mg / mL.

[0467] Example 3. XRPD characterization of compound 1 citrate coordination complex form A.

[0468] XRPD analysis indicates that compound 1, citrate form A from Example 1, is composed of crystalline material. Figure 2 An XRPD pattern of citrate form A of compound 1 is shown.

[0469] Example 4. Thermal analysis of compound 1 in citrate coordination complex form A.

[0470] Thermal analysis of compound 1 citrate coordination complex form A presents the following: Figure 3 and Figure 4 DSC thermogram of citrate coordination complex A of compound 1 (Form A) Figure 3 The TGA (thermo-gamma) exhibits a sharp peak, consistent with the onset of a single endothermic reaction at 146.22°C (peak maximum). The TGA (thermo-gamma) range between 24.8°C and 120°C... Figure 4 A weight loss of 0.1% was observed in the study.

[0471] Example 5: Dynamic vapor adsorption (DVS) analysis of citrate coordination complex form A of compound 1.

[0472] DVS analysis of citrate coordination complex form A of compound 1. Figure 5Form A was measured in 10% RH increments from 0% RH to 98% RH and back to 0% RH. With increasing RH, the sample showed a 0.5 wt% increase between 0% RH and 85% RH, indicating that form A is non-hygroscopic in the 0–85% RH range. Above 85% RH, the citrate coordination complex of compound 1 showed a 4.0% weight increase and remained solid. Decreasing RH from 98% to 0% resulted in minimal hysteresis in the sample, and XRPD analysis showed that the sample remained crystalline, representing form A. These data are summarized in Table 5.

[0473] Table 5. Time process of water absorption of compound 1 citrate coordination complex form A under gradually increasing relative humidity.

[0474]

[0475] Example 6. Mass spectrometry analysis of citrate coordination complex form A of compound 1. Evidence for the conversion of the citrate coordination complex of compound 1 to (R)-2-hydroxy-3-propamido-3,4-dihydro-2H-benzo[e][1,2]oxaboranecyclohexene-8-carboxylic acid ((2-ethylbutyryl)oxy)methyl ester (compound 1) in aqueous solution.

[0476] Mass spectrometry (MS) analysis was performed to confirm the structure of compound 1 citrate coordination complex form A and to evaluate the ability of citric acid to dissociate from compound 1 citrate coordination complex in water. Compound 1 citrate coordination complex form A was diluted in an acetonitrile-water mixture (2 / 1 v / v) and analyzed by mass spectrometry. The mass spectrum of compound 1 citrate coordination complex form A diluted in anhydrous acetonitrile shows a (MH) relationship with compound 1 citrate coordination complex (nominal 564 Da). - The sodium-bound ion [M+Na] at the nominal 588 Da. + The main peak is consistent with the main peak.

[0477] The mass spectrum of the citrate coordination complex of compound 1 diluted in water showed a main peak with the following nominal value: [MH] at m / z 390.1. - [M+H] peak with m / z of 392.2 + Peak, and the proposed molecular formula C 19 H 26 The monoisotopic mass of BNO7 is consistent. The molecular weight of compound 1 is 391.23 Da, and the exact mass is 391.18 Da.

[0478] Example 7. Single-crystal X-ray structure of compound 1 citrate coordination complex form A was determined.

[0479] It will have 0.29 × 0.09 × 0.03 mm 3 Colorless, plate-like crystals of approximate size were randomly oriented and arranged on polymer rings. Preliminary examination and data collection were performed on a Rigaku SuperNova diffractometer equipped with a copper anode microfocusing sealed X-ray tube (Cu Kα λ = 1.54184 Å) and a DectrisPilatus3 R 200K hybrid pixel array detector.

[0480] Using 26,685 reflections within the range of 3.7980° < θ < 75.3640°, the cell constants and orientation matrix for data collection were refined using the least squares method. The space group was determined to be P1 using the CRYSALISPRO program. Data were collected at room temperature, with a maximum diffraction angle (2θ) reaching 151.736°.

[0481] The structure was resolved using a direct method with SHELXT. The remaining atoms were located by subsequent difference Fourier synthesis. The structure was refined using SHELXL-2014. Hydrogen atoms on nitrogen were refined independently. All other hydrogen atoms were included in the refinement but were restricted to riding on the atoms they were bonded to. The structure was refined by minimizing a function using full matrix least squares:

[0482]

[0483] The weight w is defined as 1 / [σ 2 (F o 2 ) + (0.1475P) 2 ], where P = (F o 2 +2F c 2 ) / 3.

[0484] The scattering factor was taken from the "International Crystallographic Tables". Of the 21,610 reflections used for refinement, only 17,355 reflections with an intensity greater than twice their uncertainty [I > 2σ(I)] were used to calculate the fitting residual R. The final round of refinement included 1,475 variable parameters, 18 constraints, and the unweighted and weighted consistency factors after convergence were as follows:

[0485]

[0486]

[0487] Table 6 summarizes the parameters obtained from the refined structure. Figure 11 A rendering of the ball-and-stick model of the three-dimensional structure derived from this X-ray crystallography experiment is shown.

[0488] Table 6. Single-crystal X-ray data and collection parameters, form A of compound 1 citrate coordination complex.

[0489]

[0490] Example 8. Preparation of compound 1 citrate coordination complex form B.

[0491] In the initial experiments, a unique crystalline material was observed, named Form B, resulting in a citrate coordination complex of Compound 1. The ethanolate of Compound 1 and citric acid (1:1 molar ratio) were added to a 100 mL round-bottom flask containing 15 mL of anhydrous ethyl acetate. The resulting solution was heated under an inert atmosphere and maintained at 80°C for 3.5 hours. The resulting solution was evaporated to obtain a viscous oil, which was further dried by purging with N2 for approximately 15 hours. The material was then treated with diethyl ether and stirred for 1 hour. Heptane was then added to the suspension and stirred for another 24 hours. The solid was filtered and dried at room temperature for approximately 2 hours.

[0492] Example 9. XRPD characterization of compound 1 citrate coordination complex form B.

[0493] The index XRPD diagram of compound 1 citrate coordination complex form B is shown in [the image]. Figure 6 It is shown in the figure, and indicates crystalline materials with some amorphous content.

[0494] Example 10. Thermal analysis of compound 1 in citrate coordination complex form B.

[0495] Thermal analysis of compound 1 in citrate coordination complex form B is presented in Figure 7 and Figure 8 DSC thermogram of compound 1 in citrate coordination complex form B (in Chinese). Figure 7 The TGA (thermo-gamma) exhibits a sharp peak, consistent with the onset of a single endothermic reaction at 142.10°C (peak maximum). The TGA (thermo-gamma) range between 24.8°C and 120°C... Figure 8 A weight loss of 0.7% was observed in the study.

[0496] Example 11: Dynamic vapor adsorption (DVS) analysis of citrate coordination complex form B of compound 1.

[0497] DVS analysis of compound 1 citrate coordination complex form B was performed in 10% RH increments from 0% RH to 98% RH and back to 0% RH. Figure 9The DVS isotherm of Form B is qualitatively similar to that of Form A. Form B loses 0.1 wt% after equilibrium at approximately 0% RH. With increasing RH, the sample shows an increase of approximately 1.0 wt% between 0% RH and 85% RH. Above 85% RH, the material weight increases to 11.2%, but recovers to the initial weight with minimal hysteresis (Table 7). Following DVS analysis, it was noted that the XRPD of the sample matched that of the material before DVS analysis.

[0498] Table 7. Time process of water absorption of compound 1 citrate coordination complex form B under gradually increasing relative humidity.

[0499]

[0500] Example 12. Interconversion of slurries.

[0501] The difference in free energy between solid phases of the same composition (i.e., true polymorphs) is related to their relative solubility; the most stable polymorph has the lowest solubility in any solvent compared to the metastable polymorph. Therefore, a saturated solution of the most stable form is undersaturated relative to the less stable form. Consequently, in the presence of seeds of different polymorphs, the less stable polymorph dissolves over time, leading to further growth of the most stable form.

[0502] Competitive suspension equilibrium experiments of two polymorphs of the compound 1 citrate coordination complex in dry isopropyl acetate and dry TBME confirmed that form A is thermodynamically more stable than form B at 25°C. Approximately equal amounts of form A and form B (containing a small amount of form A) were added to a filtered saturated solution, and the suspensions were slurried at room temperature for approximately 2 weeks. The separated solids were observed by polarized optical microscopy (PLM) and analyzed by XRPD. The XRPD plots of the solids separated from both slurries were consistent with those of form A. These data indicate that form A is the stable form at room temperature.

[0503] Example 13: Stability of the blend of cefobacterium and compound 1 citrate coordination complex.

[0504] The physical stability of the cefiboxane dihydrate and compound 1 citrate coordination complex crystal form A was confirmed by X-ray powder diffraction (XRPD) and Raman spectroscopy to evaluate the change in crystal form of either drug substance when combined in a 1:1 (w / w) dry powder mixture.

[0505] XRPD data showed that the physical blend of the two active pharmaceutical ingredients was a combination of cefbufen dihydrate and compound 1 citrate coordination complex, with no other peaks observed.

[0506] A 1:1 physical blend of cefibromene dihydrate and compound 1 citrate coordination complex was prepared and evaluated by XRPD. The resulting powder was stored in a sealed container at ambient temperature for three days, and then XRPD tests were repeated to evaluate any changes in crystal form. The superposition of XRPD data from the initial scan and the third day scan showed no change in crystal form.

[0507] Raman spectra of a 1:1 physical mixture of cefbromide dihydrate and compound 1 citrate coordination complex showed no change after four days compared to the initial scan.

[0508] Analysis of XRPD and Raman data showed that the two samples were nearly a perfect match, indicating that there was no change in crystal form or water exchange between the two active pharmaceutical ingredients.

[0509] The chemical stability of the binary blends was confirmed by monitoring the HPLC purity (peak area %) of each active pharmaceutical ingredient and binary blend during stability testing at 25°C and 40°C. Table 8 summarizes the data collected over 12 weeks and shows that the citrate coordination complex of compound 1 did not degrade under all conditions, and the temperature-dependent degradation of cefobromide dihydrate was comparable to that of the cefobromide dihydrate control at the same temperature.

[0510] Table 8: Summary of stability of cefibromide dihydrate and compound 1 citrate coordination complexes and blends

[0511]

[0512] Example 14: Compatibility of excipients with blends of cefbufen dihydrate and compound 1 citrate coordination complexes

[0513] The compatibility of the active pharmaceutical ingredient (API) with the selected functional excipients was confirmed by comparing the content and purity of samples stored at 50°C for 5 weeks with a control sample of the API. The excipients tested included: microcrystalline cellulose (binder); magnesium stearate (lubricant); sodium starch glycolate (disintegrant); and colloidal silica (flow aid). Blend samples were prepared by first combining the two APIs at a 1:1 weight ratio, and then blending them with equal weights of each excipient to produce a final ratio of 1:1:2 for cefibromide dihydrate / compound 1 citrate coordination complex / excipient. Samples were transferred to three-flask glass vials with tightly fitting caps and placed in a 50°C oven. A summary of compatibility data is provided in Table 9.

[0514] Table 9: Summary of HPLC peak purity data for excipient compatibility at 50°C

[0515]

[0516] Accelerated data showed that the chemical stability of the cefobacterium and compound 1 citrate coordination complex in the presence of excipients was comparable to that of the drug substance control, confirming the compatibility of the excipients with each drug substance.

[0517] Example 15a: Preparation of a fixed-dose combination (FDC) capsule formulation of cefbufen dihydrate-compound 1 citrate coordination complex.

[0518] General description of the capsule manufacturing process

[0519] The process of manufacturing solid oral dosage forms of cefobromide dihydrate / compound 1 citrate coordination complex allows formulations containing any ratio of cefobromide dihydrate and compound 1 citrate coordination complex, as well as the addition of common excipients (fillers, binders, lubricants, flow aids, etc.) to facilitate processing or excipients (disintegrants) to regulate the drug properties of the capsule.

[0520] The manufacturing process involves combining two active pharmaceutical ingredients and desired excipients, and blending the mixture to produce a homogeneous powder. The resulting blend is then densified using a rolling mill to produce a strip, which is then sieved and ground into granules. The rolling process is repeated on the granules to further densify them and ensure the homogeneity of the blend. The final granules are then encapsulated into appropriately sized capsules and sealed using an automated capsule sealing machine. The physical and chemical stability of the capsules is evaluated using standard analytical and pharmaceutical techniques.

[0521] Preparation of 200 mg compound 1 / 200 mg cefbufen capsules

[0522] Prepare fixed-dose capsules containing the equivalent of 200 mg cefbufen (as cefbufen dihydrate) and the equivalent of 200 mg compound 1 (as compound 1 citrate coordination complex) from the formulation compositions shown in Table 10.

[0523] Table 10: Formulations of 200 mg Compound 1 and 200 mg Cefbuspirone FDC Capsules

[0524]

[0525] a Equivalent to 200.0 mg of cefbufen per capsule

[0526] b This is equivalent to 200.0 mg of compound 1 per capsule (correction factor x 0.6922).

[0527] Weigh each ingredient, sieve to remove any lumps, and transfer to a glass jar. Use Turbula. ®The resulting mixture was blended to homogeneity using a mixer, and the homogeneous powder blend was transferred to a feed hopper and compressed into strips using a FreundVector TFC-Lab roller press. The strips were ground through a stainless steel sieve to produce a coarse powder, which was then further densified by passing it a second time through the roller press, followed by sieving to produce the final granules. The granules were encapsulated into No. 00 gelatin capsules using a manual 100-unit capsule tray filler, with a target fill weight of 579.6 mg. Sealing was then performed using a Schaeffer Technologies laboratory-scale tape sealer.

[0528] Preparation of 50 mg compound 1 / 200 mg cefbufen capsules

[0529] Prepare fixed-dose capsules containing the equivalent of 200 mg cefbufen (as cefbufen dihydrate) and the equivalent of 50 mg compound 1 (as compound 1 citrate coordination complex) from the formulation compositions shown in Table 11.

[0530] Table 11: Formulations of 50 mg Compound 1 and 200 mg Cefbuspirone FDC Capsules

[0531]

[0532] a Equivalent to 200.0 mg of cefbufen per capsule

[0533] b This is equivalent to 50.0 mg of compound 1 per capsule (correction factor x 0.6922).

[0534] Sift appropriate amounts of each component of the formulation to remove any lumps and transfer them to glass jars. Use Turbula. ® The resulting mixture was blended in a mixer until homogeneous. The powder blend was transferred to a feed hopper and compressed into a strip using a Freund Vector TFC-Lab Micro roller press. The strip was sieved to produce granules, which were then further densified by passing through the roller press a second time, followed by sieving to produce final granules. The granules were encapsulated into size 0 gelatin capsules using a manual 100-unit capsule tray filler, with a target fill weight of 335.7 mg. Sealing was then performed using a Schaefer Technologies laboratory-scale tape sealer.

[0535] Example 15b: Preparation of a fixed-dose combination (FDC) capsule formulation of cefbufen dihydrate-compound 1 ethanolate.

[0536] Preparation of 200 mg compound 1 / 200 mg cefbufen capsules

[0537] Prepare fixed-dose capsules containing the equivalent of 200 mg of cefbufen (as cefbufen dihydrate) and the equivalent of 200 mg of compound 1 (as ethanol of compound 1) from the formulation compositions shown in Table 12.

[0538] Table 12: Formulations of 200 mg Compound 1 and 200 mg Cefbuspirone FDC Capsules

[0539]

[0540] a Equivalent to 200.0 mg of cefbufen per capsule

[0541] b This is equivalent to 200.0 mg of compound 1 per capsule (correction factor x 0.9141).

[0542] Weigh each ingredient, sieve to remove any lumps, and transfer to a glass jar. Blend the resulting mixture until homogeneous, and compact the homogeneous powder blend using a manual milling process. Grind the resulting clump through a stainless steel sieve to produce a coarse powder, further densify the coarse powder through a second manual compaction step, and then sieve to produce the final granules. Encapsulate the granules into No. 00 gelatin capsules by hand filling, with a target fill weight of 507.97 mg.

[0543] Example 16: Polymorphic stability of compound 1 citrate coordination complex and cefbufen dihydrate in FDC capsules

[0544] The physical (crystalline) stability of the co-encapsulated cefibromene and compound 1 citrate coordination complex capsules was confirmed using X-ray powder diffraction (XRPD). The first experiment evaluated the effect of rolling by comparing XRPD data collected on the particles with historical data on the physical blend of the two active pharmaceutical ingredients.

[0545] XRPD comparisons of the physical blends of cefbufen dihydrate / compound 1 citrate coordination complex and the drug product particles showed no change in the crystal form of either active pharmaceutical ingredient during rolling and encapsulation. A second experiment evaluated the stability of the crystal form of the cefbufen dihydrate and compound 1 citrate coordination complex by measuring the XRPD and Raman spectra of FDC capsules stored at 2–8°C and 25°C for approximately 8 months.

[0546] Regarding the FDC capsules, comparable diffraction patterns were observed between capsules stored at 2–8°C and those stored at 25°C. The XRPD data for the stability samples were comparable to those for the initial blends, confirming no change in crystal form during the stability study.

[0547] Regarding the FDC capsules, comparable Raman spectra were observed between capsules stored at 2–8°C and those stored at 25°C. XRPD data for the stable samples were comparable to those for the initial blends, confirming no change in crystal form during eight months of storage at either 2–8°C or 25°C.

[0548] Example 17: Chemical stability of compound 1 citrate coordination complex and cefbufen dihydrate in FDC capsules

[0549] The chemical stability of cefbufen dihydrate and compound 1 citrate coordination complex capsules was evaluated by measuring the content and purity of each active pharmaceutical ingredient in the capsules, which underwent stability testing at 25°C and 40°C. The appearance, percentage of labeled amount (%), related substances, and dissolution of the capsules were analyzed at each time point. Data for 25°C and 40°C are summarized in Tables 13 and 14, respectively.

[0550] Table 13: Summary of 40°C stability data for 200 mg / 200 mg FDC capsules of cefbufen dihydrate-compound 1 citrate coordination complex.

[0551]

[0552] Capsule appearance: White, opaque, hard capsule, without holes, cuts, cracks, or dents.

[0553] Table 14. Summary of 25°C stability data for 200 mg / 200 mg FDC capsules of cefbufen dihydrate-compound 1 citrate coordination complex.

[0554]

[0555] Capsule appearance: White, opaque, hard capsule, without holes, cuts, cracks, or dents.

[0556] Example 18: In vitro and in vivo comparison of compound 1 citrate coordination complex / cefbuprofen dihydrate FDC capsules with co-administered compound 1 ethanolate capsules and cefbuprofen capsules.

[0557] Self-emulsifying drug delivery system (SEDDS) capsules of compound 1 ethanolide

[0558] 200 mg SEDDS capsules were prepared from a 400 mg / mL solution of Compound 1. A 20 mL batch of 400 mg / mL Compound 1 SEDDS formulation was prepared by combining 8.71 g of the Compound 1 ethanolate complex and 12.3 g of the mediator stock solution (20 / 20 / 60 v% propylene glycol / PEG-400 / Tocophersolan) into a 100 mL round-bottom flask equipped with a magnetic stir bar and mixing on a hot plate at approximately 60°C until a clear, homogeneous solution was obtained. The resulting solution was then filled into No. 1 white opaque capsules by volume (0.500 mL) using a positive displacement pipette. The capsules were stored at 2–8°C before use.

[0559] In vitro studies

[0560] Dissolution tests (Apparatus II method) performed on the above-mentioned FDC capsule prototype using 900 mL of pH 6.8 50 mM sodium bicarbonate buffer and a paddle speed of 75 RPM showed that the release of the cefiboxane and compound 1 citrate coordination complex was comparable to the release of the "co-administered" (separate capsule) formulation of compound 1 ethanolide and cefiboxane, as shown in the figure. Figure 12 As shown in the table. Although the SEDDS-based capsule formulation of the ethanolate of compound 1 exhibits immediate release of compound 1, the formulation is unstable when stability tests are performed under standard ICH stability conditions at 25°C / 60% RH and 40°C / 65% RH. Table 15 shows the HPLC purity (peak area %) of the capsule formulations of the ethanolate of compound 1 and the citrate complex of compound 1.

[0561] Table 15: Summary of the stability of formulations of compound 1 ethanolide SEDDS capsules and compound 1 citrate coordination complex FDC capsules

[0562]

[0563] In vivo studies

[0564] A single-dose comparative pharmacokinetic (PK) study of the FDC and single-component formulations was conducted in cynomolgus monkeys. The study was conducted by administration of a single FDC capsule (200 mg cefiboxem / 200 mg compound 1 citrate coordination complex) or two capsules (200 mg cefiboxem and 200 mg compound 1 ethanolate SEDDS formulation). Each formulation was administered in six monkeys (n = 3 / sex), with a seven-day washout period between cohorts. Cefiboxem has been reported to have low bioavailability in monkeys (approximately 20%), therefore the PK of cefiboxem was not evaluated in this study. Standardized pharmacokinetic parameters for compound 2 from both formulations were calculated, and the mean values ​​are reported in Table 16. Furthermore, oral bioavailability of compound 2 from each formulation was estimated based on existing intravenous PK studies of compound 2 in cynomolgus monkeys (also presented in Table 16). The two formulations showed comparable plasma levels for compound 2 and compound 1, but the oral bioavailability of compound 2 was higher than that of the formulation containing the compound 1 citrate coordination complex.

[0565] Table 16: Comparison of pharmacokinetic parameters of formulations in non-human primates

[0566]

[0567] Compared to SEDDS-based capsules prepared from the ethanolide of compound 1, FDC capsules prepared from the citrate coordination complex of compound 1 resulted in better overall in vivo exposure and oral bioavailability of compound 2. The mean AUC was approximately 50% higher than that of the SEDDS capsules, and the T... max The changes were smaller than those of the SEDDS capsules, resulting in an estimated 60% increase in the oral bioavailability of compound 2.

[0568] Stability Study

[0569] Stability studies were conducted on FDC capsules containing 200 mg of compound 1 citrate coordination complex and 200 mg of cefiboxane. Samples were stored at 40°C, 25°C, and 2–8°C to assess stability over time. After 6 months at 40°C, a significant increase in cefiboxane-related impurity 14 was observed, reaching 11.72% (see Tables 17a and 17b). At 25°C, impurity 14 increased to 0.68% after 24 months (see Tables 18a and 18b). Notably, capsules stored at 2–8°C remained stable, with no impurity growth detected (for a summary of stability data at 2–8°C, see Tables 19a and 19b).

[0570] Table 17a: Summary of stability data at 40°C for 200 mg / 200 mg FDC capsules of cefbufen-compound 1 citrate coordination complex (T = 0 to 2 months)

[0571]

[0572] Table 17b: Summary of stability data at 40°C for 200 mg / 200 mg FDC capsules of cefbufen-compound 1 citrate coordination complex (T = 3 months to 6 months)

[0573]

[0574] Table 18a: Summary of stability data at 25°C for 200 mg / 200 mg FDC capsules of cefbufen-compound 1 citrate coordination complex (T = 0 to 4 months)

[0575]

[0576] Table 18b: Summary of 25°C stability data for 200 mg / 200 mg FDC capsules of cefbufen-compound 1 citrate coordination complex (T = 6 months to 24 months)

[0577]

[0578] Table 19a: Summary of stability data for 200 mg / 200 mg FDC capsules of cefbufen-compound 1 citrate coordination complex at 2–8°C (T = 0 to 9 months)

[0579]

[0580] Table 19b: Summary of stability data for 200 mg / 200 mg FDC capsules of cefbufen-compound 1 citrate coordination complex at 2–8°C (T = 12 months to 24 months)

[0581] .

Claims

1. A compound, said compound being a (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex: Or, or a pharmaceutically acceptable salt or solvate thereof.

2. The compound of claim 1, wherein the compound is: 。 3. A crystalline form of a compound, said compound being a (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex: or its pharmaceutically acceptable salt solvates.

4. The crystalline form as described in claim 3, wherein the compound is: 。 5. The crystalline form as described in claim 3 or 4, wherein the crystalline form has a substantially identical X-ray powder diffraction (XRPD) pattern as shown in FIG2.

6. The crystalline form of claim 5, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at 5.9° ± 0.1° 2θ, 9.5° ± 0.1° 2θ, 11.1° ± 0.1° 2θ, 11.9° ± 0.1° 2θ, and 13.9° ± 0.1° 2θ.

7. The crystalline form of claim 6, wherein the X-ray powder diffraction (XRPD) pattern further includes characteristic peaks at 11.4° ± 0.1° 2θ, 13.3° ± 0.1° 2θ, 14.4° ± 0.1° 2θ, and 17.7° ± 0.1° 2θ.

8. The crystalline form as claimed in claim 6 or 7, wherein the X-ray powder diffraction (XRPD) pattern further includes characteristic peaks at 8.1° ± 0.1° 2θ, 8.3° ± 0.1° 2θ, 11.5° ± 0.1° 2θ, and 17.2° ± 0.1° 2θ.

9. The crystalline form according to any one of claims 6-8, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at 5.9° ±0.1° 2θ, 8.1° ± 0.1° 2θ, 8.3° ± 0.1° 2θ, 9.5° ± 0.1° 2θ, 11.1° ± 0.1° 2θ, 11.4° ± 0.1° 2θ, 11.5° ± 0.1° 2θ, 11.9° ± 0.1° 2θ, 13.3° ± 0.1° 2θ, 13.9° ± 0.1° 2θ, 14.4° ± 0.1° 2θ, 17.2° ± 0.1° 2θ, and 17.7° ± 0.1° 2θ.

10. The crystalline form of claim 5, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at 5.9° ± 0.1° 2θ, 11.1° ± 0.1° 2θ, and 13.9° ± 0.1° 2θ.

11. The crystalline form of claim 10, wherein the X-ray powder diffraction (XRPD) pattern further includes characteristic peaks at 9.5° ± 0.1° 2θ and 11.9° ± 0.1° 2θ.

12. The crystalline form as claimed in claim 10 or 11, wherein the X-ray powder diffraction (XRPD) pattern further includes a characteristic peak at 7.7° ± 0.1° 2θ.

13. The crystalline form according to any one of claims 10-12, wherein the X-ray powder diffraction (XRPD) pattern further includes a characteristic peak at 11.4° ± 0.1° 2θ.

14. The crystalline form according to any one of claims 10-13, wherein the X-ray powder diffraction (XRPD) pattern further includes a characteristic peak at 17.7° ± 0.1° 2θ.

15. The crystalline form according to any one of claims 10-14, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at 5.9° ± 0.1° 2θ, 7.7° ± 0.1° 2θ, 9.5° ± 0.1° 2θ, 11.1° ± 0.1° 2θ, 11.4° ± 0.1° 2θ, 11.9° ± 0.1° 2θ, 13.9° ± 0.1° 2θ, and 17.7° ± 0.1° 2θ.

16. The crystalline form according to any one of claims 5-15, wherein the crystalline form has a DSC thermogram substantially the same as that shown in FIG3.

17. The crystalline form according to any one of claims 5-16, wherein the crystalline form has a DSC thermogram having an endothermic start at about 143.7°C.

18. The crystalline form as claimed in claim 3 or 4, wherein the crystalline form has a substantially identical X-ray powder diffraction (XRPD) pattern as shown in FIG.

6.

19. The crystalline form of claim 18, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at 10.1° ± 0.1° 2θ and 12.7° ± 0.1° 2θ.

20. The crystalline form of claim 19, wherein the X-ray powder diffraction (XRPD) pattern further includes a characteristic peak at 16.3° ± 0.1° 2θ.

21. The crystalline form as claimed in claim 19 or 20, wherein the X-ray powder diffraction (XRPD) pattern further includes a characteristic peak at 18.1° ± 0.1° 2θ.

22. The crystalline form according to any one of claims 18-21, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at 10.1° ± 0.1° 2θ, 12.7° ± 0.1° 2θ, 16.3° ± 0.1° 2θ, and 18.1° ± 0.1° 2θ.

23. The crystalline form according to any one of claims 18-22, wherein the crystalline form has a DSC thermogram substantially the same as that shown in FIG7.

24. The crystalline form according to any one of claims 18-23, wherein the crystalline form has a DSC thermogram having an endothermic start at about 136.0°C.

25. A pharmaceutical composition comprising: (i) A compound, said compound being a (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex: Or, or a pharmaceutically acceptable salt or solvate thereof; and (ii) Cefoxitin.

26. The pharmaceutical composition of claim 25, wherein cefbufen is in the form of cefbufen dihydrate.

27. The pharmaceutical composition of claim 25 or 26, wherein the compound is: 。 28. A pharmaceutical composition comprising: (i) The crystalline form of the compound, which is a (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex: or its pharmaceutically acceptable salt solvates; and (ii) Cefoxitin.

29. The pharmaceutical composition of claim 28, wherein cefbufen is in the form of cefbufen dihydrate.

30. The pharmaceutical composition of claim 28 or 29, wherein the compound is: 。 31. The pharmaceutical composition according to any one of claims 28-30, wherein the crystalline form has a substantially the same X-ray powder diffraction (XRPD) pattern as shown in FIG2.

32. The crystalline form of claim 31, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at 5.9° ± 0.1° 2θ, 9.5° ± 0.1° 2θ, 11.1° ± 0.1° 2θ, 11.9° ± 0.1° 2θ, and 13.9° ± 0.1° 2θ.

33. The crystalline form of claim 32, wherein the X-ray powder diffraction (XRPD) pattern further includes characteristic peaks at 11.4° ± 0.1° 2θ, 13.3° ± 0.1° 2θ, 14.4° ± 0.1° 2θ, and 17.7° ± 0.1° 2θ.

34. The crystalline form as claimed in claim 32 or 33, wherein the X-ray powder diffraction (XRPD) pattern further includes characteristic peaks at 8.1° ± 0.1° 2θ, 8.3° ± 0.1° 2θ, 11.5° ± 0.1° 2θ, and 17.2° ± 0.1° 2θ.

35. The crystalline form according to any one of claims 32-34, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at 5.9° ± 0.1° 2θ, 8.1° ± 0.1° 2θ, 8.3° ± 0.1° 2θ, 9.5° ± 0.1° 2θ, 11.1° ± 0.1° 2θ, 11.4° ± 0.1° 2θ, 11.5° ± 0.1° 2θ, 11.9° ± 0.1° 2θ, 13.3° ± 0.1° 2θ, 13.9° ± 0.1° 2θ, 14.4° ± 0.1° 2θ, 17.2° ± 0.1° 2θ, and 17.7° ± 0.1° 2θ.

36. The pharmaceutical composition of claim 31, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at 5.9° ± 0.1° 2θ, 11.1° ± 0.1° 2θ, and 13.9° ± 0.1° 2θ.

37. The pharmaceutical composition of claim 36, wherein the X-ray powder diffraction (XRPD) pattern further includes characteristic peaks at 9.5° ± 0.1° 2θ and 11.9° ± 0.1° 2θ.

38. The pharmaceutical composition of claim 36 or 37, wherein the X-ray powder diffraction (XRPD) pattern further includes a characteristic peak at 7.7° ± 0.1° 2θ.

39. The pharmaceutical composition of any one of claims 36-38, wherein the X-ray powder diffraction (XRPD) pattern further includes a characteristic peak at 11.4° ± 0.1° 2θ.

40. The pharmaceutical composition of any one of claims 36-39, wherein the X-ray powder diffraction (XRPD) pattern further includes a characteristic peak at 17.7° ± 0.1° 2θ.

41. The pharmaceutical composition of any one of claims 36-40, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at 5.9° ± 0.1° 2θ, 7.7° ± 0.1° 2θ, 9.5° ± 0.1° 2θ, 11.1° ± 0.1° 2θ, 11.4° ± 0.1° 2θ, 11.9° ± 0.1° 2θ, 13.9° ± 0.1° 2θ, and 17.7° ± 0.1° 2θ.

42. The pharmaceutical composition according to any one of claims 31-41, wherein the crystalline form has a DSC thermogram substantially the same as that shown in FIG3.

43. The pharmaceutical composition of any one of claims 31-42, wherein the crystalline form has a DSC thermogram having an endothermic start at about 143.7°C.

44. The pharmaceutical composition of any one of claims 28-30, wherein the crystalline form has a substantially identical X-ray powder diffraction (XRPD) pattern as shown in FIG6.

45. The pharmaceutical composition of claim 44, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at 10.1° ± 0.1° 2θ and 12.7° ± 0.1° 2θ.

46. ​​The pharmaceutical composition of claim 44, wherein the X-ray powder diffraction (XRPD) pattern further includes a characteristic peak at 16.3° ± 0.1° 2θ.

47. The pharmaceutical composition of claim 45 or 46, wherein the X-ray powder diffraction (XRPD) pattern further includes a characteristic peak at 18.1° ± 0.1° 2θ.

48. The pharmaceutical composition of any one of claims 44-47, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising characteristic peaks at 10.1° ± 0.1° 2θ, 12.7° ± 0.1° 2θ, 16.3° ± 0.1° 2θ, and 18.1° ± 0.1° 2θ.

49. The pharmaceutical composition according to any one of claims 44-48, wherein the crystalline form has a DSC thermogram substantially the same as that shown in FIG7.

50. The pharmaceutical composition of any one of claims 44-49, wherein the crystalline form has a DSC thermogram having an endothermic start at about 136.0°C.

51. The pharmaceutical composition of any one of claims 25-27, wherein the compound and cefbufen are formulated in a single dosage form.

52. The pharmaceutical composition of any one of claims 28-50, wherein the crystalline form and cefbufen are formulated in a single dosage form.

53. The pharmaceutical composition of claim 51 or 52, wherein the single dosage form is a capsule.

54. The pharmaceutical composition of any one of claims 51-53, wherein the single dosage form comprises the compound and cefbuprofen dihydrate, the ratio of the compound to cefbuprofen dihydrate being adjusted to correspond to a ratio between about 1:1 and about 1:

4. And cefoperazone.

55. The pharmaceutical composition of any one of claims 51-53, wherein the single dosage form comprises the compound and cefbuprofen dihydrate, the ratio of the compound to cefbuprofen dihydrate being adjusted to correspond to a ratio between about 1:1 and about 1:

3. And cefoperazone.

56. The pharmaceutical composition of any one of claims 51-53, wherein the single dosage form comprises the compound and cefbufen dihydrate, the ratio of the compound to cefbufen dihydrate being adjusted to correspond to a ratio between about 1:1 and about 1:

2. And cefoperazone.

57. The pharmaceutical composition of any one of claims 51-53, wherein the single dosage form comprises the compound and cefbuprofen dihydrate, the ratio of the compound to cefbuprofen dihydrate being adjusted to correspond to a ratio between about 1:1 and about 1:1.

5. And cefoperazone.

58. The pharmaceutical composition of any one of claims 51-53, wherein the single dosage form comprises the compound and cefbufen dihydrate, the ratio of the compound to cefbufen dihydrate being adjusted to correspond to about 1:

1. And cefoperazone.

59. The pharmaceutical composition of any one of claims 51-53, wherein the single dosage form comprises cefbufen dihydrate of about 100 mg to about 250 mg.

60. The pharmaceutical composition of any one of claims 51-53, wherein the single dosage form comprises cefbufen dihydrate at a concentration between about 150 mg and about 250 mg.

61. The pharmaceutical composition of any one of claims 51-53, wherein the single dosage form comprises cefbufen dihydrate of about 200 mg to about 250 mg.

62. The pharmaceutical composition of any one of claims 51-53, wherein the single dosage form comprises cefbufen dihydrate at a concentration between about 210 mg and about 240 mg.

63. The pharmaceutical composition of any one of claims 51-53, wherein the single dosage form comprises cefbufen dihydrate at a concentration between about 220 mg and about 230 mg.

64. The pharmaceutical composition of any one of claims 51-53, wherein the single dosage form comprises about 230 mg of cefbufen dihydrate.

65. The pharmaceutical composition of any one of claims 51-53 or 59-64, wherein the single dosage form comprises a (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex between about 260 mg and about 310 mg.

66. The pharmaceutical composition of any one of claims 51-53 or 59-64, wherein the single dosage form comprises a (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex between about 270 mg and about 300 mg.

67. The pharmaceutical composition of any one of claims 51-53 or 59-64, wherein the single dosage form comprises a (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex between about 280 mg and about 290 mg.

68. The pharmaceutical composition of any one of claims 51-53 or 59-64, wherein the single dosage form comprises about 290 mg of (R)-(2-(3-((((2-ethylbutyryl)oxy)methoxy)carbonyl)-2-hydroxyphenyl)-1-propamidoethyl)borate citrate coordination complex.

69. A method of treating a subject for a bacterial infection, the method comprising administering to the subject a pharmaceutical composition as described in any one of claims 25-68.

70. The method of claim 69, wherein the bacterial infection is caused by carbapenem-resistant Enterobacteriaceae (CRE) or Gram-negative bacteria producing extended-spectrum β-lactamase (ESBL).

71. The method of claim 69 or 70, wherein the bacterial infection is an acute bacterial exacerbation of chronic bronchitis (ABECB), acute bacterial otitis media, pharyngitis, or tonsillitis.

72. The method of claim 69 or 70, wherein the bacterial infection is pneumonia, urinary tract infection, enteritis, or gastroenteritis.

73. The method of claim 69 or 70, wherein the bacterial infection is otitis media, streptococcal laryngitis, pneumonia, urinary tract infection, gonorrhea, or Lyme disease.

74. The method of any one of claims 69-73, wherein the bacterial infection is caused by the following bacteria: *Escherichia coli*, *Citrobacter freundii*, *Salmonella typhimurium*, *Salmonella typhimurium*, *Salmonella paratyphimurium*, *Salmonella enteritidis*, *Shigella dysenteriae*, *Shigella freundii*, *Shigella sonnei*, *Enterobacter cloacae*, *Enterobacter aerogenes*, *Klebsiella pneumoniae*, *Klebsiella oxytocinata*, *Serratia marcescens*, *Morganella morganii*, *Proteus mirabilis*, *Proteus vulgaris*, *Providens alkaloide*, *Providens retinatum*, *Providens spp.* Acinetobacter baumannii, Acinetobacter calcium acetate, Acinetobacter hemolyticus, Yersinia enterocolitica, Yersinia plague, Yersinia pseudotuberculosis, Yersinia intermedia, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus hemolyticus, Haemophilus parahemolyticus, Haemophilus dulcis, Pasteurella multocida, Pasteurella hemolyticus, Blanhamella bronchiseptica, Leptospira brevicornu, Vibrio cholerae, Vibrio parahemolyticus, Legionella pneumophila, Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella spp., Streptococcus pneumoniae, Streptococcus agalactiae, or Streptococcus pyogenes.

75. The method of any one of claims 69-73, wherein the bacterial infection is caused by the following bacteria: *Escherichia coli*, *Citrobacter freundii*, *Salmonella typhimurium*, *Salmonella typhimurium*, *Salmonella paratyphimurium*, *Salmonella enteritidis*, *Shigella dysenteriae*, *Shigella freundii*, *Shigella sonnei*, *Enterobacter cloacae*, *Enterobacter aerogenes*, *Klebsiella pneumoniae*, *Klebsiella pneumoniae*, *Serratia marcescens*, *Yersinia enterocolitica*, *Yersinia plague*, *Yersinia pseudotuberculosis*, *Yersinia intermedia*, *Haemophilus influenzae*, *Haemophilus parainfluenzae*, *Haemophilus hemolyticus*, *Haemophilus parahemolyticus*, *Vibrio cholerae*, *Vibrio parahemolyticus*, *Legionella pneumophila*, *Listeria monocytogenes*, *Neisseria gonorrhoeae*, *Neisseria meningitidis*, or *Moraxella* spp.

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