Boronic acid derivatives and their therapeutic uses

Abstract

Disclosed herein are antibacterial compounds, polymorphic forms, compositions, pharmaceutical compositions, and methods of use and preparation thereof. Some embodiments relate to boronic acid derivatives and their use as therapeutic agents, e.g., as beta-lactamase inhibitors (BLIs). The boronic acid derivatives disclosed herein can be used in combination with various antibiotics to treat resistant bacteria. In some embodiments, provided herein are pharmaceutical compositions comprising a therapeutically effective amount of a compound described herein and a pharmaceutically acceptable excipient. In some embodiments, the composition may further comprise an additional agent. In some embodiments, the additional agent may be selected from the group consisting of an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, and an antiallergic agent.

Description

[Technical Field]

[0001] Statement Regarding Federally Funded R&D This invention was made with United States Government support under Department of Health and Human Services Contract No. HHSO100201600026C. The United States Government has certain rights in this invention. background Field This application relates to the fields of chemistry and medicine. More particularly, this application relates to boronic acid antibacterial compounds, compositions, their preparation, and their use as therapeutic agents. [Background technology]

[0002] 2. Description of Related Art Antibiotics have been effective tools for the treatment of infectious diseases for the past half century. From the development of antibiotic therapy until the late 1980s, bacterial infections were almost completely controlled in developed countries. However, in response to the pressures of antibiotic use, multiple resistance mechanisms have become widespread, threatening the clinical usefulness of antimicrobial therapy. The increase in antibiotic-resistant strains is particularly prevalent in major hospitals and care centers. The consequences of the increase in resistance include higher morbidity and mortality, longer patient hospital stays, and increased treatment costs.

[0003] Various bacteria have evolved β-lactam-inactivating enzymes, or β-lactamases, that counteract the effectiveness of various β-lactam antibiotics. β-lactamases can be classified into four classes based on their amino acid sequence: Ambler's classes A, B, C, and D. Classes A, C, and D enzymes include active-site serine β-lactamases, while the less frequently encountered class B enzymes are zinc-dependent. These enzymes catalyze the chemical degradation of β-lactam antibiotics, rendering them inactive. Some β-lactamases can be transferred within and between various bacterial strains and species. The rapid spread of bacterial resistance and the evolution of multidrug-resistant strains significantly limits available β-lactam treatment options.

[0004] The rise of class D β-lactamase-expressing bacterial strains, such as Acinetobacter baumannii, poses a new multidrug-resistant threat. A. baumannii strains express β-lactamases of the A, C, and D classes. Class D β-lactamases, such as those of the OXA family, are particularly effective at destroying carbapenem-type β-lactam antibiotics, such as imipenem, the active carbapenem component of Merck's Primaxin® (Montefour, K. et al., Crit. Care Nurse 2008, 28, 15; Perez, F. et al., Expert Rev. Anti Infect. Ther. 2008, 6, 269; Bou, G., Martinez-Beltran, J., Antimicrob. Agents Chemother. 2000, 40, 428; 2006, 50, 2280; Bou, G. et al., J. Antimicrob. Agents Chemother. 2000, 44, 1556). This poses an imminent threat to the effective use of this category of drugs to treat and prevent bacterial infections. Indeed, the number of classified serine β-lactamases has exploded from fewer than 10 in 1970 to more than 300 variants. These problems prompted the development of five "generations" of cephalosporins. When first released into clinical practice, broad-spectrum cephalosporins resisted hydrolysis by the prevalent class A β-lactamases, TEM-1 and SHV-1. However, the development of resistant strains due to the evolution of single amino acid substitutions in TEM-1 and SHV-1 led to the emergence of the extended-spectrum β-lactamase (ESBL) phenotype.

[0005] New β-lactamases that hydrolyze the carbapenem class of antibacterial agents, including imipenem, biapenem, doripenem, meropenem, and ertapenem, as well as other β-lactam antibiotics, have evolved in recent years. These carbapenemases belong to molecular classes A, B, and D. KPC-type class A carbapenemases have primarily been reported in Klebsiella pneumoniae, but have now also been reported in other Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii. KPC carbapenemases were first reported in North Carolina in 1996 and have since become widespread in the United States. This has been a particular problem in the New York City area, where several reports have documented their spread within major hospitals and patient morbidity. These enzymes have also recently been reported in France, Greece, Sweden, and the United Kingdom, with a recent outbreak reported in Germany. Treatment of resistant strains with carbapenems may be associated with poor outcomes.

[0006] Zinc-dependent class B metallo-β-lactamases are primarily represented by VIM, IMP, and NDM types. IMP- and VIM-producing K. pneumoniae were first observed in Japan in the 1990s and in southern Europe in 2001, respectively. IMP-positive strains remain highly prevalent in Japan and have caused hospital outbreaks in China and Australia. However, the spread of IMP-producing Enterobacteriaceae in the rest of the world appears to be somewhat limited. VIM-producing Enterobacteriaceae are frequently isolated in Mediterranean countries, threatening outbreaks in Greece. Isolation of VIM-producing strains remains low in northern Europe and the United States. In stark contrast, NDM-producing K. pneumoniae isolates are characterized by rapid spread from their origin in the Indian subcontinent to Western Europe, North America, Australia, and the Middle East. Furthermore, the NDM gene has rapidly spread to various species other than K. pneumonia.

[0007] Plasmid-expressed class D carbapenemases belong to the OXA-48 group. OXA-48 producing K. pneumoniae was first detected in turkey in 2001. The Middle East and North Africa remain the major centers of infection. However, recent isolation of OXA-48 producing organisms in India, Senegal, and Argentina suggests the potential for global spread. The isolation of OXA-48 in bacteria other than K. pneumonia clearly demonstrates the potential for OXA-48 to spread.

[0008] Treatment of strains producing any of these carbapenemases with carbapenems can be associated with poor outcomes.

[0009] Another mechanism of β-lactamase-mediated resistance to carbapenems involves the combination of permeability or efflux mechanisms in combination with β-lactamase overproduction. One example is the loss of porins combined with ampC β-lactamase overproduction, resulting in resistance to imipenem in Pseudomonas aeruginosa. Overexpression of efflux pumps combined with ampC β-lactamase overproduction can also result in resistance to carbapenems such as meropenem. In view of β-lactamase-mediated resistance, new β-lactamase inhibitors (BLIs) are needed. [Prior art documents] [Non-patent literature]

[0010] [Non-Patent Document 1] Montefour, K. et al., Crit.Care Nurse 2008,28,15 [Non-patent document 2] Perez, F. et al., Expert Rev. Anti Infect. Ther. 2008, 6, 269 [Non-patent document 3] Bou, G., Martinez-Beltran, J., Antimicrob.Agents Chemother.2000,40,428.2006,50,2280 [Non-patent document 4] , Bou, G. et al., J. Antimicrob. Agents Chemother. 2000, 44, 1556 Summary of the Invention [Means for solving the problem]

[0011] Summary of the Invention In some embodiments, compound II' [ka] or a crystalline form of a solvate thereof. Provided herein are crystalline forms of the compound II', or a solvate thereof. In some embodiments, the crystalline form may exhibit a powder X-ray diffraction pattern comprising at least three characteristic peaks selected from the group consisting of 4.3, 7.0, 7.2, 8.3, 11.0, 12.5, 15.0, 16.7, 17.5, 18.2, 19.1, 20.3, 22.3, 22.7, and 25.6 degrees 2θ. In some embodiments, the crystalline form of compound II' may exhibit a powder X-ray diffraction pattern comprising at least three characteristic peaks selected from the group consisting of 4.3, 7.0, 7.2, 8.3, 11.0, 12.5, 15.0, 16.7, 17.5, 18.2, 19.1, 20.3, 22.3, 22.7, and 25.6 degrees 2θ.

[0012] In some embodiments, the crystalline form of Compound II' may have an endotherm at about 141°C.

[0013] In some embodiments, the crystalline form may exhibit an X-ray powder diffraction pattern comprising at least three characteristic peaks selected from the group consisting of 4.3, 7.0, 7.2, 8.3, 11.0, 12.5, 15.0, 16.7, 17.5, 18.2, 19.1, 20.3, 22.3, 22.7, and 25.6 degrees 2θ. In some embodiments, the crystalline form of Compound II′ may exhibit an X-ray powder diffraction pattern comprising at least three characteristic peaks selected from the group consisting of 4.3, 7.0, 7.2, 8.3, 11.0, 12.5, 15.0, 16.7, 17.5, 18.2, 19.1, 20.3, 22.3, 22.7, and 25.6 degrees 2θ.

[0014] In some embodiments, the crystalline form of Compound II' may have an endotherm at about 141°C.

[0015] In some embodiments, the crystalline form of Compound II' may have an endotherm at about 152°C.

[0016] In some embodiments, the crystalline form of Compound II' can be unsolvated.

[0017] In some embodiments, [ka] Provided herein are compounds having the structure: or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the pharmaceutically acceptable salt is a sodium salt.

[0018] In some embodiments, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound described herein and a pharmaceutically acceptable excipient. In some embodiments, the composition may further comprise an additional agent. In some embodiments, the additional agent may be selected from the group consisting of an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, and an antiallergic agent.

[0019] In some embodiments, the pharmaceutical composition may include a β-lactam antibacterial agent, such as amoxicillin, ampicillin (pivampicillin, hetacillin, bacampicillin, metampicillin, talampicillin), epicillin, carbenicillin (carindacillin), ticarcillin, temocillin, azlocillin, piperacillin, mezlocillin, mecillinam (pivmecillinam), sulbenicillin, benzylpenicillin (G), or clometocillin. , benzathine benzylpenicillin, procaine benzylpenicillin, azidocillin, penamecillin, phenoxymethylpenicillin (V), propicillin, benzathine phenoxymethylpenicillin, phenethicillin, cloxacillin (dicloxacillin, flucloxacillin), oxacillin, methicillin, nafcillin, faropenem, tomopenem, razupenem, cefazolin, cefacetrile, Cefadroxil, cephalexin, cephaloglycin, cephalonium, cephaloridine, cephalothin, cephapirin, cefatrizine, cefazedone, cefazaflour, cephradine, cefroxadine, ceftezole, cefaclor, cefamandole, cefminox, cefonicid, ceforanide, cefotiam, cefprozil, cefbuperazone, cefuroxime, cefuzonam, cefo Cefoxitin, Cefotetan, Cefmetazole, Loracarbef, Cefixime, Ceftriaxone, Cefcapene, Cefdaloxime, Cefdinir, Cefidericol, Cefditoren, Cefetamet, Cefmenoxime, Cefodizime, Cefoperazone, Cefotaxime, Cefpimizole, Cefpiramide, Cefpodoxime, Cefpodoxime Proxetil protexil), cefsulodin, cefteram, ceftibuten, ceftiolene, ceftizoxime, flomoxef, latamoxef, cefepime, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftaroline, ceftolozane (CXA-101), RWJ-54428, MC-04,546, ME1036, ceftiofur, cefquinome, cefovecin, RWJ-442831, RWJ-333441, and RWJ-333442.In other embodiments, the β-lactam antibacterial agent may be selected from the group consisting of ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, tebipenem, tebipenem pivoxil, apapenem, and panipenem. In still other embodiments, the β-lactam antibacterial agent may be selected from the group consisting of aztreonam, tigemonam, BAL30072, SYN 2416, and carumonam.

[0020] Also provided herein are methods for treating a bacterial infection, comprising administering a compound described herein to a subject in need of treatment for a bacterial infection. In some embodiments, the method further comprises administering an additional agent to the subject. In some embodiments, the additional agent may be an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, or an antiallergic agent. In some embodiments, the additional agent is a β-lactam antibacterial agent.In some embodiments, the beta-lactam antibacterial agent is amoxicillin, ampicillin (pivampicillin, hetacillin, bacampicillin, metampicillin, talampicillin), epicillin, carbenicillin (carindacillin), ticarcillin, temocillin, azlocillin, piperacillin, mezlocillin, mecillinam (pivmecillinam), sulbenicillin, benzylpenicillin (G), clometocillin, benzathine benzylpenicillin, procaine benzylpenicillin, azidocillin, penamecillin, Phenoxymethylpenicillin (V), propicillin, benzathine phenoxymethylpenicillin, phenethicillin, cloxacillin (dicloxacillin, flucloxacillin), oxacillin, methicillin, nafcillin, faropenem, tomopenem, rasppenem, cefazolin, cephacetrile, cefadroxil, cephalexin, cephaloglycin, cephalonium, cephaloridine, cephalothin, cephapirin, cefatrizine, cefazedone, cefazaflour, cephradine, cefroxil Sajin, ceftezole, cefaclor, cefamandole, cefminox, cefonicid, ceforanide, cefotiam, cefprozil, cefbuperazone, cefuroxime, cefuzonam, cefoxitin, cefotetan, cefmetazole, loracarbef, cefixime, ceftriaxone, cefcapene, cefdaloxime, cefdinir, cefidericol, cefditoren, cefetamet, cefmenoxime, cefodizime, cefoperazone, cefotaxime, cefpimizole, cefpiramide, cefpo doxime, cefpodoxime proxetil, cefsulodin, cefteram, ceftibuten, ceftiolene, ceftizoxime, flomoxef, latamoxef, cefepime, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftaroline, ceftolozane (CXA-101), RWJ-54428, MC-04,546, ME1036, ceftiofur, cefquinome, cefovecin, RWJ-442831, RWJ-333441, and RWJ-333442. In other embodiments, the beta-lactam antibacterial agent may be selected from the group consisting of ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, tebipenem, tebipenem pivoxil, apapenem, and panipenem.In still other embodiments, the beta-lactam antibacterial agent may be selected from the group consisting of aztreonam, tigemonam, BAL30072, SYN 2416, and carumonam.

[0021] In some embodiments, the subject is a mammal. In some particular embodiments, the mammal is a human.

[0022] In some embodiments, the infection is caused by Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Burkholderia cepacia, Aeromonas hydrophilia, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter baumannii, Bordetella pertussis, Bordetella para pertussis, Bordetella bronchiseptica, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Borrelia burgdorferi, Kingella, Gardnerella vaginalis, Bacteroides distasonis, Bacteroides 3452A homology group, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis、Enterococcus faecium、Staphylococcus aureus、Staphylococcus epidermidis、Staphylococcus saprophyticus、Staphylococcus intermedius、Staphylococcus hyicussubsp.hyicus、Staphylococcus haemolyticus、Staphylococcus hominis、およびStaphylococcus saccharolyticus is a slightly different type of Pseudomonas aeruginosa、Pseudomonas fluorescens、Stenotrophomonas maltophilia、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、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 coli、Vibrio cholerae、Vibrio parahaemolyticus、Legionella pneumophila、Listeria monocytogenes、Neisseria gonorrhoeae、Neisseria meningitidis、Moraxella、Bacteroides fragilis、BacteroidesThe bacteria include bacteria selected from the group consisting of Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, and Bacteroides splanchnicus.

[0023] Also provided herein is a method for preparing crystalline Form A of Compound II', the method comprising the steps of dissolving Compound II' in a solvent system to form a crystallization solution, wherein the solvent system comprises isopropyl acetate; heating the crystallization solution to about 50°C; adding heptane to the crystallization solution; and adding seed crystals of crystalline Form A of Compound II' to the crystallization solution.

[0024] Also provided herein is a method for preparing crystalline Form A of Compound II', the method comprising the steps of dissolving Compound II' in a solvent system to form a crystallization solution, the solvent system consisting of isopropyl acetate and isopropanol, adding heptane to the crystallization solution, and adding seed crystals of crystalline Form B of Compound II' to the crystallization solution. In some embodiments, the solvent system consists of isopropyl acetate and isopropanol in a 1:1 (v / v) ratio.

[0025] Also provided herein is a method for preparing crystalline Form A of Compound II', the method comprising the steps of dissolving Compound II' in a solvent system to form a crystallization solution, wherein the solvent system comprises isopropyl acetate; heating the crystallization solution; adding heptane to the crystallization solution; and adding seed crystals of crystalline Form A of Compound II' to the crystallization solution.

[0026] In some embodiments, the crystallization solution may be heated to a temperature of from 30° C. to 80° C. In other embodiments, the crystallization solution may be heated to a temperature of from 40° C. to 70° C. In some embodiments, the crystallization solution may be heated to a temperature of 50° C.

[0027] Also provided herein is a method for preparing crystalline Form B of Compound II', the method comprising the steps of dissolving Compound II' in a solvent system to form a crystallization solution, the solvent system consisting of isopropyl acetate and isopropanol, adding heptane to the crystallization solution, and adding seed crystals of crystalline Form B of Compound II' to the crystallization solution. In some embodiments, the solvent system may consist of isopropyl acetate and isopropanol in a 1:1 (v / v) ratio.

[0028] Also provided herein is a method for preparing crystalline Form A of Compound II', the method comprising the steps of dissolving Compound II' in a solvent system to form a crystallization solution, wherein the solvent system consists of hexane and ethyl acetate; heating the crystallization solution; initially cooling the crystallization solution; stirring the crystallization solution; further cooling the crystallization solution to room temperature; and allowing the crystallization mixture to stand at room temperature.

[0029] In some embodiments, the crystallization solution may be heated to a temperature of 30° C. to 80° C. In other embodiments, the crystallization solution may be heated to a temperature of 50° C. to 70° C. In some embodiments, the crystallization solution may be heated to a temperature of 65° C.

[0030] In some embodiments, the crystallization solution may be first cooled to a temperature of 30° C. to 50° C. In some embodiments, the crystallization solution may be first cooled to a temperature of 50° C.

[0031] In some embodiments, the crystallization solution may be stirred for an additional 12 to 36 hours. In some particular embodiments, the crystallization solution may be stirred for an additional 24 hours. In some embodiments, the crystallization solution may be left at room temperature for an additional 72 hours.

[0032] In some embodiments, a method for preparing crystalline form A of compound II' is provided, the method comprising dissolving compound II' in isopropanol to form a crystallization solution, heating the crystallization solution, and cooling the crystallization solution to room temperature.

[0033] In another embodiment, provided herein is a method for preparing compound II', comprising combining compound I or a salt thereof, a halomethyl isobutyrate, and a base in a polar organic solvent to form a reaction mixture, and heating the reaction mixture.

[0034] In some embodiments, the reaction mixture may further comprise an iodide source. In some particular embodiments, the iodide source may be sodium iodide, potassium iodide, or cesium iodide.

[0035] In some embodiments, the base can be NaH2PO4. In other embodiments, the base can be Na2B4O7.

[0036] In some embodiments, the molar ratio of base to compound I can be from about 0.5 to about 2.0. In some embodiments, the molar ratio of base to compound I can be 1.0. In other embodiments, the molar ratio of base to compound I can be 1.5.

[0037] In some embodiments, the solvent can be acetonitrile. In some particular embodiments, the acetonitrile can be anhydrous.

[0038] In some embodiments, the halomethyl isobutyrate can be chloromethyl isobutyrate.

[0039] In some embodiments, the reaction mixture may be heated to a temperature of about 50° C. to about 80° C. In some embodiments, the reaction mixture may be heated to a temperature of 60° C. In other embodiments, the reaction mixture may be heated to a temperature of 70° C. In yet other embodiments, the reaction mixture may be heated to a temperature of 80° C.

[0040] In some embodiments, the reaction mixture may be heated for about 0.5 hours to about 24 hours. In some embodiments, the reaction mixture may be heated for about 4 hours to about 18 hours. In some embodiments, the reaction mixture may be heated for 6 hours. In other embodiments, the reaction mixture may be heated for 8 hours. In some embodiments, the reaction mixture may be heated for 16 hours. [Brief explanation of the drawings]

[0041] [Figure 1] FIG. 1 is a powder X-ray diffraction pattern of crystalline Form A of Compound II'.

[0042] [Figure 2] FIG. 2 shows the differential scanning calorimetry analysis of crystalline Form A of Compound II'.

[0043] [Figure 3] FIG. 3 shows the results of thermogravimetric analysis of crystalline Form A of Compound II'.

[0044] [Figure 4] FIG. 4 shows the dynamic water vapor sorption results for crystalline Form A of Compound II'.

[0045] [Figure 5] FIG. 5 shows the results obtained by FTIR spectroscopy for crystalline form B of compound II′.

[0046] [Figure 6] FIG. 6 shows the results obtained by FT Raman spectroscopy for crystalline form B of compound II′.

[0047] [Figure 7] FIG. 7 shows an optical microscope image of crystals of crystalline Form B of Compound II′.

[0048] [Figure 8]FIG. 8 is a powder X-ray diffraction pattern of crystalline Form B of Compound II'.

[0049] [Figure 9] FIG. 9 shows the differential scanning calorimetry analysis of crystalline Form B of Compound II'.

[0050] [Figure 10] FIG. 10 shows the results of thermogravimetric analysis of crystalline Form B of Compound II'.

[0051] [Figure 11] FIG. 11 shows the dynamic water vapor sorption results for crystalline Form B of Compound II'.

[0052] [Figure 12] FIG. 12 shows the results obtained by FTIR spectroscopy for crystalline Form B of Compound II'.

[0053] [Figure 13] FIG. 13 shows the results obtained by FT Raman spectroscopy for crystalline form B of compound II′.

[0054] [Figure 14] FIG. 14 shows an optical microscope image of crystals of crystalline Form B of Compound II′. DETAILED DESCRIPTION OF THE INVENTION

[0055] Detailed Description of the Embodiments Compound I and its pharmaceutically acceptable salts are described in International Application No. PCT / US2017 / 039787, which is incorporated herein by reference in its entirety. Compound I is a β-lactamase inhibitor that is effective in treating bacterial infections when used in combination with a β-lactam antibiotic. [ka]

[0056] Disclosed herein is Compound II, a prodrug of Compound I. Compound II is a β-lactamase inhibitor effective in treating bacterial infections when used in combination with a β-lactam antibiotic. [ka]

[0057] When the compounds disclosed herein contain at least one chiral center, they may exist as individual enantiomers and diastereomers, or as mixtures of such isomers, including racemates. Separation of individual isomers or selective synthesis of individual isomers can be achieved by applying various methods known to those skilled in the art. Unless otherwise indicated, all such isomers and mixtures thereof are included within the scope of the compounds disclosed herein. Furthermore, the compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms are included within the scope of the compounds disclosed herein, including any polymorphs. Furthermore, some of the compounds disclosed herein may form solvates with water (i.e., hydrates) or common organic solvents. Unless otherwise indicated, such solvates are included within the scope of the compounds disclosed herein.

[0058] Those skilled in the art will understand that some structures depicted herein may be resonance forms or tautomers of compounds that can be more appropriately represented, even kinetically, by other chemical structures, and that such structures may represent only a small sample of such compounds. Although such compounds are considered to be within the scope of the depicted structures, such resonance forms or tautomers are not depicted herein.

[0059] Synthesis of Compound II Compound II and its pharmaceutically acceptable salts can be prepared from Compound I or its salt by treatment with chloromethyl isobutyrate under basic conditions. A general method for preparing (isobutyryloxy)methyl esters is described in International Publication No. 2018 / 005662, the entire contents of which are incorporated herein by reference. The synthesis of Compound II is shown in the following examples. In some embodiments, the sodium salt of Compound II (Compound II') can be formed. [ka]

[0060] In some embodiments, compound II' can be prepared from compound I or a salt thereof according to the following scheme: Compound I or a salt thereof can be treated with a halomethyl isobutyrate in the presence of a base and optionally an iodine source to form compound II'. [ka]

[0061] In some embodiments, an excess of halomethyl isobutyrate is used in the reaction. For example, in some embodiments, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, or more molar equivalents of halomethyl isobutyrate relative to Compound I can be used in the reaction. In some embodiments, the halomethyl isobutyrate can be chloromethyl isobutyrate. In other embodiments, the halomethyl isobutyrate can be bromomethyl isobutyrate.

[0062] In some embodiments, the iodide source can be an alkali metal iodide, for example, sodium iodide, potassium iodide, or cesium iodide.

[0063] The choice of base used in the reaction can affect the overall yield and purity of the final product. In some embodiments, the base can be sodium bicarbonate. In other embodiments, the base can be NaH2PO4. In still other embodiments, the base can be Na2B4O7. In some particular embodiments, the base can be anhydrous Na2B4O7. In some embodiments, 0.1 to 10 molar equivalents of base relative to Compound I can be used in the reaction. For example, the number of molar equivalents of base relative to Compound I can be 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, or 10.0, or can be within the ranges defined by the values ​​described above. In some particular embodiments, 0.5 to 2.0 molar equivalents of base relative to compound I may be used in the reaction.

[0064] The reaction for converting compound I' or a salt thereof to compound II' can be carried out in a variety of solvents. In some embodiments, the solvent can be a polar aprotic solvent. In some embodiments, the solvent can be acetonitrile, dimethylformamide, methylene chloride, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, N-methylpyrrolidinone, acetone, methyl ethyl ketone, or any combination of the aforementioned solvents. In some embodiments, the solvent can be anhydrous. In some embodiments, the solvent can be acetonitrile.

[0065] The reaction to convert compound I' or a salt thereof to compound II' can be carried out at a variety of temperatures. In some embodiments, the reaction temperature is from about 25°C to about 100°C, from about 30°C to about 90°C, from about 40°C to about 80°C, from about 50°C to about 80°C, from about 55°C to about 80°C, from about 60°C to about 80°C, from about 65°C to about 80°C, or from about 70°C to about 80°C. For example, in some embodiments, the reaction to convert compound I' or a salt thereof to compound II' can be carried out at 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, or higher. In some embodiments, the reaction may be heated at any of the above temperatures for 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or more.

[0066] Crystalline Form of Compound II' Disclosed herein are crystalline forms of Compound II'. Two forms, Form A and Form B, have been identified (described below).

[0067] Crystalline Form A of Compound II' Some embodiments comprise a crystalline form of Compound II', referred to herein as Crystalline Form A. The exact conditions for forming Crystalline Form A of Compound II' can be determined empirically, and it is only possible to list some methods that have been found to be suitable in practice.

[0068] Crystalline Form A of Compound II' was characterized using various techniques, which are described in more detail in the Experimental Methods section. Figure 1 shows the crystalline structure of Form A of Compound II' as determined by X-ray powder diffraction (XRPD). Crystalline Form B of Compound II', obtainable by the methods disclosed herein, exhibits prominent peaks at approximately 4.3, 7.0, 7.2, 8.3, 11.0, 12.5, 15.0, 16.7, 17.5, 18.2, 19.1, 20.3, 22.3, 22.7, and 25.6 degrees 2θ. Thus, in some embodiments, the crystalline form of Compound II' has at least one characteristic peak (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 characteristic peaks) selected from about 4.3, 7.0, 7.2, 8.3, 11.0, 12.5, 15.0, 16.7, 17.5, 18.2, 19.1, 20.3, 22.3, 22.7, and 25.6 degrees 2θ. In some embodiments, the crystalline form of Compound II' has at least three characteristic peaks selected from about 4.3, 7.0, 7.2, 8.3, 11.0, 12.5, 15.0, 16.7, 17.5, 18.2, 19.1, 20.3, 22.3, 22.7, and 25.6 degrees 2θ.

[0069] 2 shows the results obtained by differential scanning calorimetry (DSC) for crystalline Form A of Compound II'. The DSC results show a peak at a temperature of about 141°C, which indicates the melting point of the crystal. Thus, in some embodiments, crystalline Form B of Compound II' exhibits a melting point of about 138°C to about 144°C, about 139°C to about 143°C, or about 141°C.

[0070] Figure 3 shows the results obtained by thermogravimetric analysis (TGA) for crystalline form A of Compound II'. The TGA results indicate that crystalline form A of Compound II' exhibited a weight loss of approximately 1% when run from 25°C to 125°C. Meanwhile, Figure 4 shows the results of dynamic vapor sorption (DVS) of crystalline form A of Compound II', which showed slight water absorption, indicating that crystalline form A of Compound II' is slightly hygroscopic. Karl Fischer analysis showed that crystalline form A of Compound II' contains an average of 0.12% water, indicating that crystalline form A of Compound II' is not solvated. Elemental analysis of crystalline form A of Compound II' is consistent with an anhydrate.

[0071] 5 shows the results obtained by Fourier transform infrared (FTIR) spectroscopy for crystalline Form A of Compound II'. Crystalline Form A of Compound II' exhibits peaks at approximately 1758, 1706, 1600, 1584, 1469, 1426, 1389, 1366, and 1322 cm -1 Thus, in some embodiments, the crystalline form of Compound II' exhibits prominent peaks at about 1758, 1706, 1600, 1584, 1469, 1426, 1389, 1366, and 1322 cm -1 In some embodiments, the crystalline form of Compound II' has at least one characteristic FTIR peak (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9 characteristic peaks) selected from: 1758, 1706, 1600, 1584, 1469, 1426, 1389, 1366, and 1322 cm -1 In some embodiments, the peak positions described herein are within ±1 cm -1 Includes variations within.

[0072] Figure 6 shows the results obtained by Fourier transform Raman spectroscopy for crystalline form B of compound II'. Crystalline form A of compound II' exhibits peaks at approximately 1754, 1709, 1600, 1584, 1465, 1428, 1366, and 1340 cm -1Thus, in some embodiments, the crystalline form of Compound II' exhibits prominent peaks at about 1754, 1709, 1600, 1584, 1465, 1428, 1366, and 1340 cm -1 In some embodiments, the crystalline form of Compound II' has at least one characteristic FT Raman peak (e.g., 1, 2, 3, 4, 5, 6, 7, or 8 characteristic peaks) selected from: 1754, 1709, 1600, 1584, 1465, 1428, 1366, and 1340 cm -1 In some embodiments, the peak positions described herein are within ±2 cm -1 Includes variations within.

[0073] Thus, crystalline Form A of Compound II' can be characterized as a non-solvated, slightly hygroscopic solid. Crystalline Form A of Compound II' also exhibits good crystallinity, with needle-like crystals of various sizes (Figure 7) and a relatively high melting point (about 141°C).

[0074] Crystalline Form B of Compound II' Some embodiments comprise a crystalline form of Compound II', referred to herein as Crystalline Form B. The exact conditions for forming Crystalline Form B of Compound II' can be determined empirically, and it is only possible to list some methods that have been found to be suitable in practice.

[0075] Crystalline Form B of Compound II' was characterized using various techniques, which are described in more detail in the Experimental Methods section. Figure 8 shows the crystalline structure of Form B of Compound II' as determined by X-ray powder diffraction (XRPD). Crystalline Form B of Compound II', obtainable by the methods disclosed herein, exhibits prominent peaks at approximately 5.1, 7.0, 9.9, 11.0, 11.1, 14.1, 16.4, 17.1, 21.1, 22.3, 22.6, 26.9, and 28.3 degrees 2θ. Thus, in some embodiments, the crystalline form of Compound II' has at least one characteristic peak (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 characteristic peaks) selected from about 5.1, 7.0, 9.9, 11.0, 11.1, 14.1, 16.4, 17.1, 21.1, 22.3, 22.6, 26.9, and 28.3 degrees 2θ. In some embodiments, the crystalline form of Compound II' has at least three characteristic peaks selected from about 5.1, 7.0, 9.9, 11.0, 11.1, 14.1, 16.4, 17.1, 21.1, 22.3, 22.6, 26.9, and 28.3 degrees 2θ.

[0076] 9 shows the results obtained by differential scanning calorimetry (DSC) for crystalline Form B of Compound II'. The DSC results show a peak at a temperature of about 152°C, which indicates the melting point of the crystal. Thus, in some embodiments, crystalline Form B of Compound II' exhibits a melting point of about 149°C to about 155°C, about 150°C to about 154°C, or about 152°C.

[0077] FIG. 10 shows the results obtained by thermogravimetric analysis (TGA) for crystalline form B of Compound II'. The TGA results indicate that crystalline form B of Compound II' exhibited a weight loss of 0.18% when run from 25°C to 125°C. Meanwhile, FIG. 11 shows the results of dynamic vapor sorption (DVS) for crystalline form B of Compound II', which showed moderate water absorption, indicating that crystalline form B of Compound II' is moderately hygroscopic. Karl Fischer analysis indicates that crystalline form B of Compound II' contains an average of 7.29% water. However, this water is believed to be a decomposition product due to heating of the sample. Elemental analysis indicates that crystalline form B of Compound II' is a non-solvated material.

[0078] 12 shows the results obtained by Fourier transform infrared (FTIR) spectroscopy for crystalline Form B of Compound II'. Crystalline Form B of Compound II' exhibits peaks at approximately 1608, 1592, 1553, 1473, 1416, 1364, 1334, and 1277 cm -1 Thus, in some embodiments, the crystalline form of Compound II' exhibits prominent peaks at about 1608, 1592, 1553, 1473, 1416, 1364, 1334, and 1277 cm -1 In some embodiments, the crystalline form of Compound II' has at least one characteristic FTIR peak (e.g., 1, 2, 3, 4, 5, 6, 7, or 8 characteristic peaks) selected from: 1608, 1592, 1553, 1473, 1416, 1364, 1334, and 1277 cm -1 In some embodiments, the peak positions described herein are within ±1 cm -1 Includes variations within.

[0079] Figure 13 shows the results obtained by Fourier transform Raman spectroscopy for crystalline Form B of Compound II'. Crystalline Form B of Compound II' exhibits peaks at approximately 1611, 1591, 1574, 1472, 1426, and 1366 cm -1Thus, in some embodiments, the crystalline form of Compound II' exhibits prominent peaks at about 1611, 1591, 1574, 1472, 1426, and 1366 cm -1 In some embodiments, the crystalline form of Compound II' has at least one characteristic FT Raman peak (e.g., 1, 2, 3, 4, 5, or 6 characteristic peaks) selected from: 1611, 1591, 1574, 1472, 1426, and 1366 cm -1 In some embodiments, the peak positions described herein are within ±2 cm -1 Includes variations within.

[0080] Thus, crystalline Form B of Compound II' can be characterized as a non-solvated, moderately hygroscopic solid. Crystalline Form B of Compound II' also exhibits good crystallinity, with blade-shaped crystals of various sizes (Figure 14) and a relatively high melting point (about 152°C).

[0081] Method for crystallizing compound II' Methods for crystallizing Compound II' are disclosed. Crystalline forms of Compound II' can generally be obtained or produced by crystallizing the compound of Compound II' under controlled conditions. In some embodiments, the methods can produce non-solvated crystalline forms. In some embodiments, the methods can produce crystalline Form A of Compound II'. In some embodiments, the methods can produce crystalline Form B of Compound II'.

[0082] In some embodiments, the crystalline form of compound II' can be prepared by incorporating compound II' in a solvent to form a crystallization solution, optionally heating the first solution, and optionally adding a second solvent to the crystallization solution. In some embodiments, the first solvent can be isopropyl acetate. In other embodiments, the first solvent can be isopropyl alcohol. In other embodiments, the first solvent can be hexane. In still other embodiments, the first solvent can be heptane. In some embodiments, the first solvent can be ethyl acetate. In some embodiments, the first solvent can be any combination of isopropyl acetate, isopropyl alcohol, hexane, heptane, and / or ethyl acetate. In some particular embodiments, the first solvent can be a combination of isopropyl acetate and isopropyl alcohol. In other particular embodiments, the first solvent can be a combination of hexane and ethyl acetate.

[0083] In some embodiments, the crystallization solution may be heated to 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90° C., or within a range defined by any of the foregoing temperatures, as needed.

[0084] In some embodiments, the second solvent can be heptane. In other embodiments, the second solvent can be hexane.

[0085] In some embodiments, seeds of the desired crystalline form of Compound II' may be added to the crystallization solution, if desired, to promote crystallization.

[0086] In some embodiments, the crystallization solution may be cooled to 55, 50, 45, 40, 35, 30, 35, 20, 15, 10, 5, 0, -5, or -10°C, or within a range defined by any of the aforementioned temperatures. The crystallization solution may be cooled over a period of 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, or 72 hours, or within a range defined by any of the aforementioned times. Cooling may be accomplished with or without stirring or agitation.

[0087] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs.All patents, applications, published applications and other publications are incorporated by reference in their entirety.If there are multiple definitions for terms in this specification, the definition in this section shall prevail unless otherwise stated.

[0088] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of a compound and is not biologically or otherwise undesirable for pharmaceutical use. In many cases, the compounds disclosed herein are capable of forming acid and / or base salts due to the presence of amino and / or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable salts can also be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, bases containing sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc., with ammonium, potassium, sodium, calcium, and magnesium salts being particularly preferred. In some embodiments, treatment of a compound disclosed herein with an inorganic base results in the loss of a labile hydrogen from the compound, forming Li + , Na + , K. + , Mg 2+ and Ca 2+ Salt forms containing inorganic cations such as are obtained. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in International Publication No. 87 / 05297 to Johnston et al., published September 11, 1987 (hereby incorporated by reference in its entirety).

[0089] Administration and Pharmaceutical Compositions The compounds disclosed herein are administered in therapeutically effective dosages.For the compounds described herein, human dosage levels have not yet been optimized, but typically, the daily dose can be about 0.25mg / kg body weight to about 120mg / kg body weight or more, about 0.5mg / kg body weight or less to about 70mg / kg body weight, about 1.0mg / kg body weight to about 50mg / kg body weight, or about 1.5mg / kg body weight to about 10mg / kg body weight.Therefore, when administered to a 70kg person, the dosage range is about 17mg / day to about 8000mg / day, about 35mg / day or less to about 7000mg / day or more, about 70mg / day to about 6000mg / day, about 100mg / day to about 5000mg / day, or about 200mg to about 3000mg / day. The amount of active compound administered will, of course, be dependent on the subject and disease condition being treated, the severity of the disorder, the manner and scheduling of administration, and the judgment of the prescribing physician.

[0090] Administration of the compounds disclosed herein, or pharmaceutically acceptable salts thereof, can be by any of the accepted modes of administration for agents exhibiting similar utilities, including, but not limited to, oral, subcutaneous, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, pulmonary, vaginal, rectal, or ocular. Oral and parenteral administration are conventional in the treatment of the indications that are the subject of preferred embodiments.

[0091] The compounds useful as described above can be formulated into pharmaceutical compositions for use in treating these conditions. Standard pharmaceutical formulation techniques, such as those disclosed in Remington's The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005), the entire contents of which are incorporated herein by reference, are used. Thus, some embodiments include pharmaceutical compositions comprising (a) a safe and therapeutically effective amount of a compound described herein (including enantiomers, diastereoisomers, tautomers, polymorphs and solvates thereof) or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof.

[0092] In addition to the useful compounds selected as described above, some embodiments include compositions containing a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in therapeutic compositions is contemplated. In addition, various auxiliary substances commonly used in the art may be included. Considerations for including various ingredients in pharmaceutical compositions are described, for example, in Gilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, which is incorporated herein by reference in its entirety.

[0093] Some examples of substances which can function as pharmaceutically acceptable carriers or components thereof are sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose, and methylcellulose), powdered tragacanth, malt, gelatin, talc, solid lubricants (e.g., stearic acid and magnesium stearate), calcium sulfate, vegetable oils (e.g., peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and theobroma oil), polyols (e.g., propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol), alginic acid, emulsifiers (e.g., TWEENS), wetting agents (e.g., sodium lauryl sulfate), colorants, flavorings, tableting agents, stabilizers, antioxidants, preservatives, pyrogen-free water, isotonic saline, and phosphate buffer.

[0094] The choice of pharmaceutically acceptable carrier to be used in conjunction with the subject compounds will basically depend on the way the compound is to be administered.

[0095] The compositions described herein are preferably provided in unit dosage form. As used herein, a "unit dosage form" is a composition containing an amount of compound suitable for administration in a single dose to an animal, preferably a mammalian subject, in accordance with good medical practice. However, the preparation of a single or unit dosage form does not imply that the dosage form is administered once per day or once per course of treatment. Such dosage forms are contemplated for administration once, twice, three or more times per day, and may be administered as an infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours), or as a continuous infusion, and may be administered more than once during the course of treatment, although single administration is not specifically excluded. Those skilled in the art will understand that the formulations do not specifically contemplate an entire course of treatment, and such decisions are left to those skilled in the art of treatment, not formulation.

[0096] The compositions useful as described above can be in any of a variety of suitable forms for various routes of administration, such as oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intraarterial, intravenous, intramuscular, or other parenteral routes of administration. Those skilled in the art will understand that oral and nasal compositions include compositions administered by inhalation and prepared using available methods. Depending on the specific route of administration desired, various pharmaceutically acceptable carriers known in the art can be used. Pharmaceutically acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropes, surfactants, and encapsulating materials. Optional pharmaceutically active materials that do not substantially interfere with the inhibitory activity of the compound may be included. The amount of carrier used with the compound is sufficient to provide a practical amount of material for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods described herein are described in the following references: Modern Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004), all of which are incorporated herein by reference.

[0097] Various oral dosage forms can be used, including solid forms such as tablets, capsules, granules, and bulk powders. Tablets can be compressed, powder tablets, enteric-coated, sugar-coated, film-coated, or multi-compressed, and can contain suitable binders, lubricants, diluents, disintegrants, colorants, flavorings, flow-inducing agents, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, and contain suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, melting agents, colorants, and flavoring agents.

[0098] Pharmaceutically acceptable carriers suitable for preparing unit dosage forms for oral administration are well known in the art. Tablets typically contain conventional pharmaceutically compatible adjuvants such as inert diluents (e.g., calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose), binders (e.g., starch, gelatin, and sucrose), disintegrants (e.g., starch, alginic acid, and croscarmellose), and lubricants (e.g., magnesium stearate, stearic acid, and talc). Lubricants such as silicon dioxide can be used to improve the flow properties of powder mixtures. Coloring agents (e.g., FD&C dyes) can be added for appearance. Sweeteners and flavoring agents (e.g., aspartame, saccharin, menthol, peppermint, and fruit flavors) are useful adjuvants for chewable tablets. Capsules typically contain one or more solid diluents as disclosed above. The selection of carrier components will depend on secondary concerns such as taste, cost, and storage stability, but these are not critical and can be readily made by one skilled in the art.

[0099] Oral compositions also include liquid solutions, emulsions, suspensions, etc. Pharmaceutically acceptable carriers suitable for preparing such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions, and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol, and water. For suspensions, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, AVICEL RC-591, tragacanth, and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methylparaben and sodium benzoate. Oral liquid compositions may also contain one or more ingredients, such as the sweeteners, flavorings, and coloring agents disclosed above.

[0100] Such compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, so that the subject compounds are released in the gastrointestinal tract near the desired topical application or at various times to prolong the desired effect. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, ethylcellulose, Eudragit coating, wax, and shellac.

[0101] The compositions described herein may optionally contain other pharmaceutical active agents.

[0102] Other compositions useful for achieving systemic delivery of the subject compound include sublingual, buccal and nasal dosage forms.Such compositions typically contain one or more of soluble filler substances such as sucrose, sorbitol and mannitol, and binders such as acacia, microcrystalline cellulose, carboxymethylcellulose and hydroxypropylmethylcellulose.The lubricants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.

[0103] The liquid composition formulated for topical ophthalmic use is formulated so that it can be administered locally to the eye.Comfort should be maximized as much as possible, but formulation considerations (such as drug stability) may force suboptimal comfort.If comfort cannot be maximized, the liquid should be formulated so that it can be tolerated by patients for topical ophthalmic use.In addition, ophthalmologically acceptable liquid should be packaged for single use or contain a preservative to prevent contamination over multiple uses.

[0104] For ophthalmic use, solutions or drugs are often prepared using saline as the main vehicle. Ophthalmic solutions should preferably be maintained at a comfortable pH using an appropriate buffer system. Preparations may also contain conventional pharmaceutically acceptable preservatives, stabilizers and surfactants.

[0105] Preservatives that can be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate. A useful surfactant is, for example, Tween® 80. Similarly, various useful vehicles can be used in the ophthalmic preparations disclosed herein. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropylmethylcellulose, poloxamer, carboxymethylcellulose, hydroxyethylcellulose, and purified water.

[0106] Tonicity adjusting agents may be added as necessary or convenient, including, but not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjusting agent.

[0107] Various buffers and pH adjusting means can be used as long as the resulting preparation is ophthalmologically acceptable. For many compositions, the pH is 4 to 9. Therefore, buffers include acetate buffer, citrate buffer, phosphate buffer, and borate buffer. Acids or bases can be used to adjust the pH of these formulations as needed.

[0108] Along similar lines, ophthalmically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.

[0109] Another excipient component that may be included in the ophthalmic preparation is a chelating agent. A useful chelating agent is edetate disodium, although other chelating agents may be used instead or in combination therewith.

[0110] For topical use, creams, ointments, gels, solutions, or suspensions, etc., containing the compounds disclosed herein are used. Topical formulations may generally be comprised of a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.

[0111] For intravenous administration, the compounds and compositions described herein can be dissolved or dispersed in a pharmaceutically acceptable diluent, such as saline or dextrose solution. To achieve the desired pH, suitable excipients, such as, but not limited to, NaOH, sodium carbonate, sodium acetate, HCl, and citric acid, can be included. In various embodiments, the pH of the final composition ranges from 2 to 8, or preferably from 4 to 7. Antioxidant excipients can include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylates, thiourea, and EDTA. Other non-limiting examples of suitable excipients found in the final intravenous composition can include sodium or potassium phosphate, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran. Additional acceptable excipients are described in Powell et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-311, and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332, both of which are incorporated herein by reference in their entireties. Antimicrobial agents may also be included to provide a bacteriostatic or fungistatic solution, including, but not limited to, phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.

[0112] Compositions for intravenous administration may be provided to the caregiver in one or more solid forms that are reconstituted with a suitable diluent, such as sterile water, saline, or aqueous dextrose, immediately prior to administration. In other embodiments, the compositions are provided in a solution that is ready for parenteral administration. In still other embodiments, the compositions are provided in the form of a solution that is further diluted before administration. In embodiments involving administration of a combination of a compound described herein and another agent, the combination may be provided to the caregiver as a mixture, or the caregiver may mix the two agents prior to administration, or the two agents may be administered separately.

[0113] The actual dose of the active compounds described herein will depend on the particular compound and the condition being treated, and the selection of an appropriate dose is well within the knowledge of one of ordinary skill in the art.

[0114] Treatment method Some embodiments of the present invention include methods of treating bacterial infections with the compounds and compositions comprising the compounds described herein. Some methods include administering a compound, composition, or pharmaceutical composition described herein to a subject in need thereof. In some embodiments, the subject can be an animal, e.g., a mammal (including a human). In some embodiments, the bacterial infection comprises a bacterium described herein. As will be understood from the foregoing, methods of treating a bacterial infection include methods of preventing a bacterial infection in a subject at risk thereof.

[0115] In some embodiments, the subject is a human.

[0116] Further embodiments include administering a combination of compounds to a subject in need thereof. The combination can include a compound, composition, pharmaceutical composition described herein and an additional agent.

[0117] Some embodiments include co-administering the compounds, compositions, and / or pharmaceutical compositions described herein with additional agents. "Co-administration" means that two or more agents may be found in a patient's bloodstream at the same time, regardless of when or how they are actually administered. In one embodiment, the agents are administered simultaneously. In one such embodiment, combined administration is achieved by combining the agents in a single dosage form. In another embodiment, the agents are administered sequentially. In one embodiment, the agents are administered via the same route, such as orally. In another embodiment, the agents are administered via different routes, such as one being administered orally and the other being administered intravenously (iv).

[0118] Examples of additional agents include antibacterial agents, antifungal agents, antiviral agents, anti-inflammatory agents, and anti-allergic agents.

[0119] Preferred embodiments include combinations of the compounds, compositions, or pharmaceutical compositions described herein with antibacterial agents, such as β-lactams. Examples of such β-lactams include amoxicillin, ampicillin (e.g., pivampicillin, hetacillin, bacampicillin, metampicillin, talampicillin), epicillin, carbenicillin (carindacillin), ticarcillin, temocillin, azlocillin, piperacillin, mezlocillin, mecillinam (pivmecillinam), sulbenicillin, benzylpenicillin (G), clometocillin, benzathine benzylpenicillin, procaine benzylpenicillin, azidocillin, Penamecillin, phenoxymethylpenicillin (V), propicillin, benzathine phenoxymethylpenicillin, phenethicillin, cloxacillin (e.g., dicloxacillin, flucloxacillin), oxacillin, methicillin, nafcillin, faropenem, biapenem, doripenem, ertapenem, imipenem, meropenem, panipenem, cefazolin, cephacetrile, cefadroxil, cephalexin, cephaloglycin, cephalonium, cephaloridine, cephalothin cephapirin, cefatrizine, cefazedone, cefazaflour, cephradine, cefroxadine, ceftezole, cefaclor, cefamandole, cefminox, cefonicid, ceforanide, cefotiam, cefprozil, cefbuperazone, cefuroxime, cefuzonam, cefoxitin, cefotetan, cefmetazole, loracarbef, cefixime, ceftazidime, ceftriaxone, cefcapene, cefdaloxime, cefdinir, cefidericor, cefditoren , cefetamet, cefmenoxime, cefodizime, cefoperazone, cefotaxime, cefpimizole, cefpiramide, cefpodoxime, cefpodoxime proxetil, cefsulodin, cefteram, ceftibuten, ceftiolene, ceftizoxime, flomoxef, latamoxef, cefepime, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftaroline, ceftiofur, cefquinome, cefovecin, aztreonam, tigemonam, and carumonam.

[0120] Preferred embodiments include β-lactams such as ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, tebipenem, tebipenem pivoxil, apapenem, and panipenem.

[0121] Further preferred embodiments include β-lactams such as aztreonam, tigemonam and carumonam.

[0122] Further preferred embodiments include a β-lactam antibacterial agent such as tebipenem pivoxil.

[0123] A further preferred embodiment includes a β-lactam antibacterial agent such as ceftibuten.

[0124] Some embodiments include a combination of a compound, composition, and / or pharmaceutical composition described herein with an additional agent, wherein the additional agent comprises a monobactam. Examples of monobactams include aztreonam, tigemonam, nocardicin A, carumonam, and tabtoxin. In some such embodiments, the compound, composition, and / or pharmaceutical composition comprises a class A, C, or D beta-lactamase inhibitor. Some embodiments include co-administering a compound, composition, or pharmaceutical composition described herein with one or more additional agents.

[0125] Some embodiments include a combination of a compound, composition, and / or pharmaceutical composition described herein with an additional agent, wherein the additional agent comprises a Class B beta-lactamase inhibitor. An example of a Class B beta-lactamase inhibitor includes ME1071 (Yoshikazu Ishii et al., "In Vitro Potentiation of Carbapenems with ME1071, a Novel Metallo-β-Lactamase Inhibitor, Against Metallo-β-lactamase Producing Pseudomonas aeruginosa Clinical Isolates." Antimicrob. Agents Chemother. doi:10.1128 / AAC.01397-09 (July 2010)). Some embodiments include co-administering a compound, composition, or pharmaceutical composition described herein with one or more additional agents.

[0126] Some embodiments include combinations of the compounds, compositions and / or pharmaceutical compositions described herein with additional agents, where the additional agents include one or more agents including beta-lactamase inhibitors of class A, B, C, or D. Some embodiments include co-administering the compounds, compositions or pharmaceutical compositions described herein with one or more additional agents.

[0127] Indications The compounds and compositions containing the compounds described herein can be used to treat bacterial infections.The bacterial infections that can be treated with the compounds, compositions, and methods described herein can include a wide range of bacteria.Examples of organisms include gram-positive bacteria, gram-negative bacteria, aerobic and anaerobic bacteria, such as Staphylococcus, Lactobacillus, Streptococcus, Sarcina, Escherichia, Enterobacter, Klebsiella, Pseudomonas, Acinetobacter, Mycobacterium, Proteus, Campylobacter, Citrobacter, Nisseria, Bacillus, Bacteroides, Peptococcus, Clostridium, Salmonella, Shigella, Serratia, Haemophilus, Brucella, and other organisms.

[0128] Further examples of bacterial infections include Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonas hydrophilia, 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, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticusHaemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella, Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A 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, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, StaphylococcusExamples include Staphylococcus haemolyticus, Staphylococcus hominis, or Staphylococcus saccharolyticus.

[0129] The following examples are included to further illustrate the present invention. Of course, these examples should not be construed as specifically limiting the present invention. Variations of these examples within the scope of the claims are within the purview of those skilled in the art and are considered to be within the scope of the invention described and claimed herein. The reader will understand that one skilled in the art, armed with this disclosure and the skills of the art, can prepare and use the present invention without exhaustive examples. The following examples further illustrate the present invention and are used for illustrative purposes only and should not be considered limiting. [Example]

[0130] Example X-ray powder diffraction (XRPD) The Rigaku Smart-Lab X-ray diffraction system was configured for reflection Bragg-Brentano geometry using a line X-ray beam. The X-ray source was a Cu long fine-focus tube operating at 40 kV and 44 mA. The source provided the sample with an incident beam profile that varied from a narrow line at high angles to a wide rectangle at low angles. Beam-adjusting slits were used on the line X-ray source to ensure that the maximum beam size was less than 10 mm along the line and perpendicular to the line. The Bragg-Brentano geometry is a parafocusing geometry controlled by passive divergence and acceptance slits, with the sample itself acting as the focusing component of the optical system. The intrinsic resolution of the Bragg-Brentano geometry is governed, in part, by the radius of the diffractometer used and the width of the acceptance slit. The Rigaku Smart-Lab is typically operated to achieve peak widths of 0.1° 2θ or less. The axial divergence of the X-ray beam was controlled by 5.0-degree Soller slits in both the incident and diffracted beam paths. The equipment was qualified using ASTM silicon standards on the same day of analysis.

[0131] Powder samples were prepared in a low-background silicon holder by applying light finger pressure to keep the sample surface flat and level with the reference plane of the sample holder. Each sample was analyzed from 2 to 40° 2θ using a continuous scan of 6° 2θ / min with an effective step size of 0.02° 2θ.

[0132] Differential scanning calorimetry (DSC) DSC analyses were performed using a TA Instruments Q2500 Discovery Series instrument. Indium was used for instrument temperature calibration. For each analysis, the DSC cell was maintained under a nitrogen purge of approximately 50 mL per minute. Samples were placed in standard crimped aluminum pans and heated from approximately 25°C to 350°C at a rate of 10°C per minute.

[0133] Melting point (MP) analysis Melting point analyses were performed using a Stuart SMP3 melting point apparatus. Samples were placed in glass capillaries and heated at 10°C / min.

[0134] Thermogravimetric (TG) analysis TG analyses were performed using a TA Instruments Q5500 Discovery Series instrument. The instrument balance was calibrated using a Class M weight, and temperature calibration was performed using Alumel. The nitrogen purge was approximately 40 mL / min for the balance and approximately 60 mL / min for the furnace. Each sample was placed in a tared platinum pan and heated from approximately 25°C to 350°C at a rate of 10°C / min.

[0135] Dynamic Vapor Sorption (DVS) Analysis DVS analysis was performed using a TA Instruments Q5000 Dynamic Vapor Sorption Analyzer. The instrument was calibrated to standard weight and humidity with a sodium bromide standard. Approximately 20 mg of sample was placed in a metal-clad quartz pan for analysis. Samples were analyzed at 25°C in 10% relative humidity (RH) steps from 5 to 95% RH (adsorption cycle) and from 95 to 5% RH (desorption cycle) with a maximum equilibration time of 1 hour. Transfer from one step to the next occurred either after meeting an equilibrium criterion of 0.01% weight change or after 1 hour if the equilibrium criterion was not met. Percent weight change values ​​were calculated using Microsoft Excel. The temperature of the DVS analysis may affect the outcome of the results.

[0136] Karl Fischer (KF) analysis Karl Fischer analysis was performed using a Mettler-Toledo C20 coulometric KF titrator with an oven attachment heated to 175°C. The instrument was calibrated using a hydranal water standard containing 1% water. The titrant was a hydranal methanol solution. Samples were analyzed in triplicate.

[0137] optical microscopy Light microscopy experiments were performed on a Leica DM 2500P compound microscope equipped with a 10x magnification eyepiece and a 10x magnification objective, for a total magnification of 100x. Images were captured using a QImaging MicroPublisher 3.3 RTV camera.

[0138] Infrared (IR) spectroscopy IR spectra were obtained using a Thermo Nicolet model 6700 Fourier transform (FT) IR spectrophotometer equipped with a deuterated triglycine sulfate (DTGS) detector, a potassium bromide (KBr) beam splitter, and an electronic temperature controlled (ETC) Ever-Glo® IR source. The instrument was configured with a SMART iTR diamond attenuated total reflectance (ATR) sampling accessory. Single-beam scans of the background (air) and sample were performed over the spectral range 4000–400 cm. -1 2cm across -1 The data were collected with 128 signal-averaged scans at a resolution of 100 kHz. Final sample spectra were calculated automatically and presented in Log1 / R units. Wavelength calibration was verified using certified polystyrene standards. Data collection and processing were performed using Omnic 9.7.46 software.

[0139] Raman spectroscopy Fourier transform (FT) Raman spectra were acquired on a Nicolet model 6700 spectrometer interfaced with a Nexus Raman accessory module. The instrument consists of a Nd:YAG laser operating at 1024 nm, a CaF2 beam splitter, and an indium gallium arsenide detector. OMNIC 8.1 software was used to control data acquisition and process the spectra. Samples were loaded into 3-inch glass NMR tubes for analysis.

[0140] Low-frequency Raman spectroscopy Raman spectroscopy is a complementary technique to infrared (IR) spectroscopy, and both techniques provide a complete vibrational analysis of the entity being studied. Commercially available Raman instruments typically filter out Rayleigh scattering and provide a vibrational analysis of the spectrum at approximately 100 cm. -1 A notch filter is used, which allows obtaining only good quality Raman spectra up to approximately 500 cm, depending on the type of filter. -1 50cm from -1The spectral region at or below this is called the low-frequency Raman spectral region. In this region, vibrational modes originate from the crystal lattice of organic compounds or from heavy atoms, such as those incorporated into organometallic or inorganic molecules. The characteristic vibrational frequencies of the crystal lattice are called phonon modes. Phonon modes arise from the basic structure, i.e., the specific crystal lattice, of the particular compound being studied. Different crystal forms typically display unique crystal lattices, and therefore, unique phonon modes will be displayed for each different crystal form.

[0141] New filter designs have enabled the access of low-frequency (LF) Raman spectra, and it has been demonstrated that this region allows the identification / distinguishing of different crystalline forms (see Roy, S., Chamberlin, B., and Matzger, AJ, “Polymorph Discrimination Using Low Wavenumber Raman Spectroscopy,” Org. Process Res. Dev. 2013, 17, 976-980). LF Raman spectroscopy utilizes the 2200 cm wavelength band. -1 From 0cm -1 Stokes region of 0cm -1 From -900cm -1 LF Raman spectroscopy allows for the acquisition of spectra in the Raman spectral region, including the anti-Stokes region. LF Raman spectroscopy allows the observation of phonon modes (the characteristic vibrational frequencies of a crystal lattice), which can be used to distinguish between crystalline forms. The same "mirror-image" signals corresponding to phonon modes are visible in both the Stokes and anti-Stokes regions, but the Stokes signal is typically used to distinguish between crystalline forms because it is more intense than the anti-Stokes signal.

[0142] LF-Raman spectra were acquired using a Renishaw Raman equipped with an ONDAX THz Raman system (excitation laser 853 nm, notch filter). Solid samples were analyzed with a 10-second exposure time and 32 accumulations. Solid samples were spread on gold slides and analyzed with an ONDAX TR-probe (Marqme TriX) in contact with the solid sample. LF-Raman was calibrated using a sulfur reference standard prior to sample analysis.

[0143] 13 C nuclear magnetic resonance (NMR) spectroscopy solid 13 C cross-polarization magic-angle spinning (CPMAS) experiments were performed on a Bruker Avance II 400 spectrometer. Each sample (approximately 200 mg) was loaded into a 4 mm zirconia rotor closed with a Kel-F end cap for subsequent data acquisition. Adamantane was set at 29.5 ppm and used as an external standard. The acquisition and processing parameters used are listed in the table below. [Table 1A]

[0144] Example 1 Synthesis of (isobutyryloxy)methyl (1aR,7bS)-5-fluoro-2-hydroxy-1,1a,2,7b-tetrahydrobenzo[e]cyclopropa[c][1,2]oxaborinin-4-carboxylate (II') To a heterogeneous mixture of Compound (I) (5.0 g, 17.6 mmol), sodium bicarbonate (5.92 g, 70.4 mmol), and sodium iodide (1.62 g, 8.8 mmol) in acetonitrile (ACN) (25 mL) was added chloromethyl isobutyrate (8.9 mL, 70.4 mmol) at room temperature. The heterogeneous mixture was heated at 55 °C. After stirring at 55 °C for 16 h, HPLC showed 93.6% conversion. The reaction mixture was cooled to 0 °C. Ice water (50 mL) was added, and after stirring at 0 °C for 1 min, MTBE (50 mL) was added. The layers were separated. The organic layer was washed several times with 20 mM NaHCO3 (3 x 50 mL) and filtered through a 0.7 μm GMF syringe filter. The filtrate was concentrated to a few mL. ACN (25 mL) was added, and the solution was concentrated to near dryness at 25 °C. The residual oil was taken up in ACN (25 mL) and cooled to -5°C. Water (25 mL) was added, and the cloudy solution was cooled to -6°C. While maintaining the temperature below -5°C, 2N NaOH (7.1 mL) was slowly added until the pH reached 9, resulting in a biphasic mixture. The layers were separated (the aqueous layer was kept). The aqueous layer was extracted with heptane (25 mL, the aqueous layer was kept). The colorless aqueous layer was saturated with solid NaCl at room temperature to yield a biphasic mixture. The layers were separated. The aqueous layer was back-extracted with ACN (25 mL). The combined organic layers were concentrated to a few mL. ACN (25 mL) was added, and the heterogeneous mixture was concentrated to a few mL. Isopropyl acetate (25 mL) was added, and the heterogeneous solution was filtered through a 0.45 μm PTFE syringe filter to remove residual salts. The clear filtrate was concentrated to dryness to yield a colorless oily gel, which was crystallized as described herein to yield the sodium salt of Compound (II) (i.e., Compound (II')).

[0145] Example 2 Alternative synthesis of (isobutyloxy)methyl (1aR,7bS)-5-fluoro-2-hydroxy-1,1a,2,7b-tetrahydrobenzo[e]cyclopropa[c][1,2]oxaborinin-4-carboxylate (II') To a heterogeneous mixture of compound (I) (5 g, 17.6 mmol), NaI (1.32 g, 8.8 mol, 0.5 equiv.), and ground anhydrous Na2B4O7 (5.31 g, 26.4 mmol, 1.5 equiv.) in anhydrous acetonitrile (25 mL) was added chloromethyl isobutyrate (5.6 mL, 44 mmol, 2.5 equiv.) at room temperature. The reaction mixture was heated to 60 °C. After stirring at 60 °C for 16 h and at room temperature for 2 days, the conversion was 97.5% by HPLC. The reaction mixture was cooled to room temperature, diluted with methyl tert-butyl ether (MTBE) (25 mL), and cooled to 0 °C. Ice water (25 mL) was added at 0 °C. After stirring at 0 °C for 5 min, the biphasic heterogeneous mixture was filtered through Celite, and the salt and pad were rinsed with MTBE. The clear biphasic filtrate was partitioned, and the organic layer was washed with water containing 20% ​​brine (2 x 25 mL) followed by brine (25 mL). The organic layer was concentrated to dryness. The residual oil was dissolved in ACN (25 mL) and cooled to 0 °C. Cold water (15 mL) was added, and the mixture was cooled to 0 °C. 2 M Na2CO3 was added while maintaining the temperature below 5 °C (pH = 7.6). 2 N NaOH was then added until the pH reached 10.5 (7.6 mL). The slightly heterogeneous mixture was extracted with heptane (2 x 25 mL). The aqueous layer was saturated with solid NaCl, and the layers were separated. The aqueous layer was back-extracted with ACN (25 mL). The combined organic extracts were concentrated to dryness. The residual oil was dissolved in ACN (25 mL) and concentrated to near dryness. The residual oil was dissolved in isopropyl acetate (iPAc) (25 mL) and polish-filtered through a 0.45 um syringe filter. The filtrate was concentrated to dryness. The residual oil was dissolved in iPAc (3 mL), IPA (1 mL), and heptane (25 mL) to obtain a clear solution. After seeding, heptane (25 mL) was further added. After stirring at room temperature for 30 minutes, a white slurry was obtained. After stirring at room temperature overnight, the solid was collected by filtration, rinsed with 17 / 3 heptane / IPAc (20 mL), air-dried, and then dried under high vacuum to obtain compound (II') as a white powder (4.601 g, 72.2% yield, 99.67% purity, mp = 145.4 °C, Form B).

[0146] Example 3 Effect of base on the formation of compound (II') The effect of base was studied when preparing compound (II') according to the methods of Examples 1 and 2. Changing the base from NaHCO3 to NaH2PO4 improved the conversion of compound (I). Furthermore, the use of Na2B4O7 resulted in 96% conversion even when only 0.5 equivalents of base were used. Changing the base to either NaH2PO4 or Na2B4O7 significantly reduced the formation of the impurity isobutyryloxymethyl isobutyrate (IBOIB). The data are shown in the table below. [Table 1B]

[0147] Example 4 Serum activation: Compounds 1, 2, or II were solubilized in water and added to rat, dog, monkey, and human serum at a concentration of 50 μg / mL. Samples were incubated at room temperature for 1 hour and then assayed for "active" drug content using an LC / MS / MS assay. Microsomal activation: Compounds 1, 2, or II were solubilized in water and added to rat, dog, monkey, and human liver microsomes at a concentration of 1 μM. Samples were incubated at room temperature for 1 hour and then assayed for "active" drug content using an LC / MS / MS assay. [Table 1]

[0148] Example 5 Animals (rats, dogs, or monkeys) were administered Compound 1, 2, or II formulated in water by oral gavage. Blood samples were collected at various time points into EDTA-containing tubes. After centrifugation, plasma samples were analyzed for Compound 1, 2, or II and "active" drug content by LC / MS / MS. Bioavailability was determined by comparing the clearance of "active" drug after intravenous administration with the clearance of "active" drug after oral administration of Compound 1, 2, or II. [Table 2]

[0149] The oral bioavailability of Compound 2 at 100 mg / kg was 46%, while the oral bioavailability of Compound 1 and Compound II was both 100%. Furthermore, Compound 2 is not crystalline, which may affect its stability. Compound 1 has significantly slower human microsomal activation than either Compound 2 or Compound II. Compound II has the best overall profile of the microsomal-activated prodrugs.

[0150] Example 6 Preparation of Crystalline Form A of Compound (II') At room temperature, dissolve compound (II') in a mixture of isopropyl acetate and isopropanol (volume ratio 1:0.2, or 2 mL of isopropyl acetate per 1 g of compound (II') and 0.4 mL of isopropanol per 1 g of compound (II')). After complete dissolution, rapidly add n-heptane (10 mL per 1 g of compound (II')) over a period of no more than 1 hour. After the addition of n-heptane is complete, stir the resulting slurry for an additional 8 to 12 hours. Filter the slurry, wash the filter cake with a mixture of n-heptane and isopropyl acetate (volume ratio 9:1, 2 mL per 1 g of compound (II')), and dry.

[0151] Example 7 Alternative Preparation of Crystalline Form A of Compound (II') Compound II' was dissolved in isopropyl acetate (5 mL), and the solution was heated to 50°C. Heptane (10 mL) was added, followed by seeds (approximately 10 mg), and the mixture was stirred at 50°C. Over 30 minutes, the mixture went from a clear solution to an opaque, slightly heterogeneous, thick slurry as the seeds were stirred. Heptane (10 mL) was added for better stirring. After stirring at 50°C for 2 hours, heptane (10 mL) was added for better stirring, and the slurry was cooled to room temperature. After stirring at room temperature for 2 hours, heptane (10 mL) was added for better stirring. After stirring at room temperature over the weekend, the solid was collected by filtration, rinsed with 6 / 1 heptane / isopropyl acetate (2 x 10 mL), air-dried, and then dried under high vacuum to give a white powder (4.24 g, 66.6% yield).

[0152] Example 8 Alternative Preparation of Crystalline Form A of Compound (II') Compound II' was dissolved in hexane and heated to 60-65°C. Ethyl acetate was added to a hexane:ethyl acetate ratio of 85 / 15 (v / v). The mixture was cooled to 50°C and stirred at 50°C for 1 day. The mixture was slowly cooled to room temperature and allowed to stand at room temperature for 3 days to obtain crystalline form A of compound II'.

[0153] Example 9 Preparation of Crystalline Form B of Compound (II') At room temperature, compound (II') is dissolved in a mixture of isopropyl acetate and isopropanol (volume ratio 1:0.2, or 2 mL of isopropyl acetate per gram of compound (II') and 0.4 mL of isopropanol per gram of compound (II')). After complete dissolution, n-heptane (10 mL per gram of compound (II')) is slowly added over a period of at least 8 to 12 hours. After the addition of n-heptane is complete, the resulting slurry is stirred for an additional 8 to 12 hours. The slurry is filtered, and the filter cake is washed with a mixture of n-heptane and isopropyl acetate (volume ratio 9:1, 2 mL per gram of compound (II')) and dried.

[0154] Example 10 Alternative Preparation of Crystalline Form B of Compound (II') At room temperature, Compound (II') is dissolved in a mixture of isopropyl acetate and isopropanol (volume ratio 1:0.2, or 2 mL of isopropyl acetate per 1 g of Compound (II') and 0.4 mL of isopropanol per 1 g of Compound (II')). After complete dissolution, n-heptane (4 mL per 1 g of Compound (II')) is added. The solution remains clear. Seed crystals of Form B of Compound (II') are added (10 mg per 1 g of Compound (II')). Then, n-heptane (5 mL per 1 g of Compound (II')) is slowly added over at least 7 hours. After the addition of n-heptane is complete, the resulting slurry is stirred for an additional 8 to 12 hours. The slurry is filtered, and the filter cake is washed with a mixture of n-heptane and isopropyl acetate (volume ratio 9:1, 2 mL per 1 g of Compound (II')) and dried.

[0155] Example 11 Alternative Preparation of Crystalline Form B of Compound (II') Compound II' (5 g scale) was dissolved in isopropyl acetate (2.5 mL) and isopropanol (2.5 mL). Heptane (15 mL) was added, followed by seeds (approximately 10 mg), and the mixture was stirred at room temperature. Over 30 minutes, the mixture went from a clear solution to an opaque, slightly heterogeneous, thick slurry as the seeds were stirred. To improve stirring, heptane (3 x 5 mL) was added over 1 hour. After stirring at room temperature for 16 hours, the solid was collected by filtration, rinsed with 10 / 1 / 1 heptane / isopropyl acetate / isopropanol (2 x 10 mL), air-dried, and then dried under high vacuum to give a white powder (4.24 g, 56.6% yield).

[0156] Example 12 Alternative Preparation of Crystalline Form B of Compound (II') Compound II' (200 mg scale) was dissolved in isopropanol (0.3 mL) and heated to 50 °C to form a nearly clear solution. After an additional 5-10 minutes of heating at 50 °C, a solid began to precipitate. The solution was slowly cooled to room temperature, and the slurry was allowed to stand at room temperature for 1 day. The solid was collected, suspended in hexane, and isolated by vacuum filtration to obtain crystalline Form B of Compound II'. In one embodiment, for example, the following items are provided: (Item 1) Compound II': [ka] or a crystalline form of a solvate thereof. (Item 2) 2. The crystalline form of claim 1, wherein the crystalline form exhibits a powder X-ray diffraction pattern comprising at least one characteristic peak, the characteristic peak being selected from the group consisting of about 4.3 degrees, about 7.0 degrees, about 7.2 degrees, about 8.3 degrees, about 11.0 degrees, about 12.5 degrees, about 15.0 degrees, about 16.7 degrees, about 17.5 degrees, about 18.2 degrees, about 19.1 degrees, about 20.3 degrees, about 22.3 degrees, about 22.7 degrees, and about 25.6 degrees 2θ. (Item 3) 3. The crystalline form of claim 2, wherein the crystalline form exhibits an X-ray powder diffraction pattern comprising at least three characteristic peaks, the characteristic peaks being selected from the group consisting of 4.3 degrees, 7.0 degrees, 7.2 degrees, 8.3 degrees, 11.0 degrees, 12.5 degrees, 15.0 degrees, 16.7 degrees, 17.5 degrees, 18.2 degrees, 19.1 degrees, 20.3 degrees, 22.3 degrees, 22.7 degrees, and 25.6 degrees 2θ. (Item 4) 4. The crystalline form of any one of items 1 to 3, wherein the crystalline form has an endotherm at about 141° C. (Item 5) 2. The crystalline form of claim 1, wherein the crystalline form exhibits a powder X-ray diffraction pattern comprising at least one characteristic peak, wherein the characteristic peak is selected from the group consisting of about 5.1 degrees, about 7.0 degrees, about 9.9 degrees, about 11.0 degrees, about 11.1 degrees, about 14.1 degrees, about 16.4 degrees, about 17.1 degrees, about 21.1 degrees, about 22.3 degrees, about 22.6 degrees, about 26.9 degrees, and about 28.3 degrees 2θ. (Item 6) 7. The crystalline form of claim 6, wherein the crystalline form exhibits a powder X-ray diffraction pattern comprising at least three characteristic peaks, the characteristic peaks being selected from the group consisting of 5.1 degrees, 7.0 degrees, 9.9 degrees, 11.0 degrees, 11.1 degrees, 14.1 degrees, 16.4 degrees, 17.1 degrees, 21.1 degrees, 22.3 degrees, 22.6 degrees, 26.9 degrees, and 28.3 degrees 2θ. (Item 7) 7. The crystalline form of any one of items 1, 5, or 6, wherein the crystalline form has an endotherm at about 152°C. (Item 8) 8. The crystalline form according to any one of items 1 to 7, wherein the crystalline form is non-solvated. (Item 9) [ka] or a pharmaceutically acceptable salt of any of the foregoing. (Item 10) Anhydrous compounds [ka] or a pharmaceutically acceptable salt thereof. (Item 11) 11. The compound according to item 9 or item 10, wherein the pharmaceutically acceptable salt is a sodium salt. (Item 12) 12. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of items 1 to 11 and a pharmaceutically acceptable excipient. (Item 13) 13. The pharmaceutical composition according to item 12, further comprising an additional agent. (Item 14) Item 14. The pharmaceutical composition according to item 13, wherein the additional agent is selected from the group consisting of an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, and an antiallergic agent. (Item 15) 15. The pharmaceutical composition of claim 14, wherein the additional agent is a β-lactam antibacterial agent. (Item 16) The β-lactam antibacterial agent is selected from the group consisting of amoxicillin, ampicillin (pivanpicillin, hetacillin, bacampicillin, metampicillin, talampicillin), epicillin, carbenicillin (carindacillin), ticarcillin, temocillin, azlocillin, piperacillin, mezlocillin, mecillinam (pivmecillinam), sulbenicillin, benzylpenicillin (G), clometocillin, benzathine benzylpenicillin, procaine benzylpenicillin, azidocillin, penamecillin, and phenoxymethylpenicillin. Cirrhosis (V), propicillin, benzathine phenoxymethylpenicillin, phenethicillin, cloxacillin (dicloxacillin, flucloxacillin), oxacillin, methicillin, nafcillin, faropenem, tomopenem, raspenem, cefazolin, cephacetrile, cefadroxil, cephalexin, cephaloglycin, cephalonium, cephaloridine, cephalothin, cephapirin, cefatrizine, cefazedone, cefazaflour, cephradine, cefroxadine, ceftezole, Cefaclor, cefamandole, cefminox, cefonicid, ceforanide, cefotiam, cefprozil, cefbuperazone, cefuroxime, cefuzonam, cefoxitin, cefotetan, cefmetazole, loracarbef, cefixime, ceftriaxone, cefcapene, cefdaloxime, cefdinir, cefidericor, cefditoren, cefetamet, cefmenoxime, cefodizime, cefoperazone, cefotaxime, cefpimizole, cefpiramide, cefpodoxime, cefpodoxime 16. The pharmaceutical composition of item 15, wherein the compound is selected from the group consisting of protexil, cefsulodin, cefteram, ceftibuten, ceftiolene, ceftizoxime, flomoxef, latamoxef, cefepime, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftaroline, ceftolozane (CXA-101), RWJ-54428, MC-04,546, ME1036, ceftiofur, cefquinome, cefovecin, RWJ-442831, RWJ-333441, and RWJ-333442. (Item 17) 16. The pharmaceutical composition of item 15, wherein the beta-lactam antibacterial agent is selected from the group consisting of ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, tebipenem, tebipenem pivoxil, apapenem, and panipenem. (Item 18) 16. The pharmaceutical composition of claim 15, wherein the beta-lactam antibacterial agent is selected from the group consisting of aztreonam, tigemonam, BAL30072, SYN 2416, and carumonam. (Item 19) 16. The pharmaceutical composition of item 15, wherein the β-lactam antibacterial agent is tebipenem pivoxil. (Item 20) 16. The pharmaceutical composition of item 15, wherein the β-lactam antibacterial agent is ceftibuten. (Item 21) 12. A method of treating a bacterial infection, comprising administering a compound according to any one of items 1 to 11 to a subject in need thereof. (Item 22) 22. The method of claim 21, further comprising administering an additional agent to the subject. (Item 23) 23. The method of claim 22, wherein the additional agent is an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, or an antiallergic agent. (Item 24) 24. The method of claim 23, wherein the additional agent is a β-lactam antibacterial agent. (Item 25) The β-lactam antibacterial agent is selected from the group consisting of amoxicillin, ampicillin (pivanpicillin, hetacillin, bacampicillin, metampicillin, talampicillin), epicillin, carbenicillin (carindacillin), ticarcillin, temocillin, azlocillin, piperacillin, mezlocillin, mecillinam (pivmecillinam), sulbenicillin, benzylpenicillin (G), clometocillin, benzathine benzylpenicillin, procaine benzylpenicillin, azidocillin, penamecillin, and phenoxymethylpenicillin. Cirrhosis (V), propicillin, benzathine phenoxymethylpenicillin, phenethicillin, cloxacillin (dicloxacillin, flucloxacillin), oxacillin, methicillin, nafcillin, faropenem, tomopenem, rasppenem, cefazolin, cephacetrile, cefadroxil, cephalexin, cephaloglycin, cephalonium, cephaloridine, cephalothin, cephapirin, cefatrizine, cefazedone, cefazaflour, cephradine, cefroxadine, ceftezole , cefaclor, cefamandole, cefminox, cefonicid, ceforanide, cefotiam, cefprozil, cefbuperazone, cefuroxime, cefuzonam, cefoxitin, cefotetan, cefmetazole, loracarbef, cefixime, ceftriaxone, cefcapene, cefdaloxime, cefdinir, cefidericol, cefditoren, cefetamet, cefmenoxime, cefodizime, cefoperazone, cefotaxime, cefpimizole, cefpiramide, cefpodoxime, cefpodoxine 25. The method of item 24, wherein the anti-inflammatory drug is selected from the group consisting of simprotexil, cefsulodin, cefteram, ceftibuten, ceftiolene, ceftizoxime, flomoxef, latamoxef, cefepime, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftaroline, ceftolozane (CXA-101), RWJ-54428, MC-04,546, ME1036, ceftiofur, cefquinome, cefovecin, RWJ-442831, RWJ-333441, and RWJ-333442. (Item 26) 25. The method of claim 24, wherein the beta-lactam antibacterial agent is selected from the group consisting of ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, tebipenem, tebipenem pivoxil, apapenem, and panipenem. (Item 27) 25. The method of claim 24, wherein the beta-lactam antibacterial agent is selected from the group consisting of aztreonam, tigemonam, BAL30072, SYN 2416, and carumonam. (Item 28) 25. The method of claim 24, wherein the β-lactam antibacterial agent is tebipenem pivoxil. (Item 29) 25. The method of claim 24, wherein the beta-lactam antibacterial agent is ceftibuten. (Item 30) 30. The method of any one of items 21 to 29, wherein the subject is a mammal. (Item 31) 31. The method of claim 30, wherein the mammal is a human. (Item 32) The aforementioned infections are caused by Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Burkholderia cepacia, Aeromonas hydrophilia, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter baumannii, Bordetella pertussis, Bordetella para pertussis, Bordetella bronchiseptica, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Borrelia burgdorferi, Kingella, Gardnerella vaginalis, Bacteroides distasonis, Bacteroides 3452A homology group, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis、Enterococcus faecium、Staphylococcus aureus、Staphylococcus epidermidis、Staphylococcus saprophyticus、Staphylococcus intermedius、Staphylococcus hyicus subsp.32. The method of any one of items 21 to 31, comprising a bacterium selected from the group consisting of Staphylococcus hyicus, Staphylococcus haemolyticus, Staphylococcus hominis, and Staphylococcus saccharolyticus. (Item 33) where the infectious disease is Pseudomonas aeruginosa, Pseudomonas fluorescens, Stenotrophomonas maltophilia, 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, 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 coli, 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, and Bacteroides32. The method of any one of items 21 to 31, comprising a bacterium selected from the group consisting of: Bacillus subtilis, Bacillus anthracis, Bacillus subtilis, Bacillus splanchnicus, Bacillus subtilis ... (Item 34) 1. A method for preparing crystalline form A of compound II′, said method comprising: (a) dissolving Compound II' in a solvent system to form a crystallization solution, wherein the solvent system comprises isopropyl acetate; (b) heating the crystallization solution; (c) adding heptane to the crystallization solution; (d) adding seed crystals of crystalline Form A of Compound II' to the crystallization solution; A method comprising: (Item 35) 35. The method of claim 34, wherein the crystallization solution is heated to a temperature of from 30°C to 80°C. (Item 36) 36. The method of claim 35, wherein the crystallization solution is heated to a temperature of 40°C to 70°C. (Item 37) 38. The method according to any one of items 35 to 37, wherein the crystallization solution is heated to a temperature of 50°C. (Item 38) 1. A method for preparing crystalline form B of compound II′, said method comprising: (a) dissolving Compound II' in a solvent system to form a crystallization solution, wherein the solvent system consists of isopropyl acetate and isopropanol; (b) adding heptane to the crystallization solution; (c) adding seed crystals of crystalline Form B of Compound II' to the crystallization solution; A method comprising: (Item 39) 39. The method of claim 38, wherein the solvent system consists of isopropyl acetate and isopropanol in a 1:1 (v / v) ratio. (Item 40) 1. A method for preparing crystalline form A of compound II′, said method comprising: (a) dissolving compound II' in a solvent system to form a crystallization solution, wherein the solvent system consists of hexane and ethyl acetate; (b) heating the crystallization solution; (c) initially cooling the crystallization solution; (d) stirring the crystallization solution; (e) further cooling the crystallization solution to room temperature; (f) allowing the crystallization mixture to stand at room temperature; A method comprising: (Item 41) 41. The method of claim 40, wherein the crystallization solution is heated to a temperature of from 30°C to 80°C. (Item 42) 42. The method of claim 41, wherein the crystallization solution is heated to a temperature of 50°C to 70°C. (Item 43) 43. The method of any one of items 40 to 42, wherein the crystallization solution is heated to a temperature of 65°C. (Item 44) 44. The method according to any one of items 40 to 43, wherein the crystallization solution is first cooled to a temperature of from 30°C to 50°C. (Item 45) Item 45. The method of item 44, wherein the crystallization solution is first cooled to a temperature of 50°C. (Item 46) 46. ​​The method of any one of items 40 to 45, wherein the crystallization solution of step (d) is stirred for 12 to 36 hours. (Item 47) Item 47. The method of item 46, wherein the crystallization solution of step (d) is stirred for 24 hours. (Item 48) 48. The method according to any one of items 40 to 47, wherein the crystallization solution of step (f) is allowed to stand at room temperature for 72 hours. (Item 49) 1. A method for preparing crystalline form A of compound II′, said method comprising: (a) dissolving compound II' in isopropanol to form a crystallization solution; (b) heating the crystallization solution; (c) cooling the crystallization solution to room temperature; A method comprising: (Item 50) A method for preparing compound II', comprising: combining Compound I or a salt thereof, a halomethyl isobutyrate, and a base in a polar organic solvent to form a reaction mixture; heating the reaction mixture to a temperature of about 50° C. to about 80° C. for 0.5 hours to 24 hours; A method comprising: (Item 51) 51. The method of claim 50, wherein the reaction mixture further comprises an iodide source. (Item 52) 52. The method of claim 51, wherein the iodide source is sodium iodide, potassium iodide, or cesium iodide. (Item 53) The base is NaH 2 PO 4 53. The method of any one of items 50 to 52, wherein (Item 54) The base is Na 2 B 4 O 7 53. The method of any one of items 50 to 52, wherein (Item 55) 55. The method of any one of items 50 to 54, wherein the molar ratio of base to compound I is from about 0.5 to about 2.0. (Item 56) Item 56. The method according to item 55, wherein the molar ratio of base to compound I is 1.0. (Item 57) Item 56. The method according to item 55, wherein the molar ratio of base to compound I is 1.5. (Item 58) 58. The method of any one of items 50 to 57, wherein the solvent is acetonitrile. (Item 59) 59. The method of claim 58, wherein the acetonitrile is anhydrous. (Item 60) 60. The method of any one of items 50 to 59, wherein the halomethyl isobutyrate is chloromethyl isobutyrate. (Item 61) 61. The method of any one of items 50 to 60, wherein the reaction mixture is heated to a temperature of about 50°C to about 80°C. (Item 62) 62. The method of claim 61, wherein the reaction mixture is heated to a temperature of 60°C. (Item 63) 62. The method of claim 61, wherein the reaction mixture is heated to a temperature of 70°C. (Item 64) 62. The method of claim 61, wherein the reaction mixture is heated to a temperature of 80°C. (Item 65) 65. The method of any one of items 50 to 64, wherein the reaction mixture is heated for about 0.5 hours to about 24 hours. (Item 66) Item 66. The method of item 65, wherein the reaction mixture is heated for about 4 hours to about 18 hours. (Item 67) Item 67. The method of item 66, wherein the reaction mixture is heated for 6 hours. (Item 68) Item 67. The method of item 66, wherein the reaction mixture is heated for 8 hours. (Item 69) Item 67. The method of item 66, wherein the reaction mixture is heated for 16 hours.

Claims

1. Compound II': 【Transformation 7】 or a crystal of a solvate thereof.

2. 2. The crystal of claim 1, wherein the crystal exhibits a powder X-ray diffraction pattern comprising at least eight characteristic peaks, the characteristic peaks being selected from the group consisting of 4.3 degrees, 7.0 degrees, 7.2 degrees, 8.3 degrees, 11.0 degrees, 12.5 degrees, 15.0 degrees, 16.7 degrees, 17.5 degrees, 18.2 degrees, 19.1 degrees, 20.3 degrees, 22.3 degrees, 22.7 degrees, and 25.6 degrees 2θ.

3. 3. The crystal of claim 2, wherein the crystal exhibits a powder X-ray diffraction pattern including the following characteristic peaks at 2θ: 4.3 degrees, 7.0 degrees, 7.2 degrees, 8.3 degrees, 11.0 degrees, 12.5 degrees, 15.0 degrees, 16.7 degrees, 17.5 degrees, 18.2 degrees, 19.1 degrees, 20.3 degrees, 22.3 degrees, 22.7 degrees, and 25.6 degrees.

4. The crystal according to any one of claims 1 to 3, wherein the crystal has an endotherm at 141°C.

5. 2. The crystal of claim 1, wherein the crystal exhibits a powder X-ray diffraction pattern comprising at least eight characteristic peaks, the characteristic peaks being selected from the group consisting of 5.1 degrees, 7.0 degrees, 9.9 degrees, 11.0 degrees, 11.1 degrees, 14.1 degrees, 16.4 degrees, 17.1 degrees, 21.1 degrees, 22.3 degrees, 22.6 degrees, 26.9 degrees, and 28.3 degrees 2θ.

6. 6. The crystal of claim 5, wherein the crystal exhibits a powder X-ray diffraction pattern including the following characteristic peaks at 2θ degrees: 5.1 degrees, 7.0 degrees, 9.9 degrees, 11.0 degrees, 11.1 degrees, 14.1 degrees, 16.4 degrees, 17.1 degrees, 21.1 degrees, 22.3 degrees, 22.6 degrees, 26.9 degrees, and 28.3 degrees.

7. 7. The crystal of claim 1, 5, or 6, wherein the crystal has an endotherm at 152°C.

8. 8. The crystal of any one of claims 1 to 7, wherein the crystal is non-solvated. 【Request Item 9】 【Transformation 8】 or a pharmaceutically acceptable salt of any of the foregoing.

10. Anhydrous compounds 【Chemistry 9】 or a pharmaceutically acceptable salt thereof.

11. 11. The compound of claim 9 or claim 10, wherein the pharmaceutically acceptable salt is a sodium salt.

12. A pharmaceutical composition comprising a therapeutically effective amount of a crystal of any one of claims 1 to 8 or a compound of any one of claims 9 to 11, and a pharmaceutically acceptable excipient.

13. 13. The pharmaceutical composition of claim 12, further comprising an additional agent.

14. 14. The pharmaceutical composition of claim 13, wherein the additional agent is selected from the group consisting of an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, and an antiallergic agent.

15. 15. The pharmaceutical composition of claim 14, wherein the additional agent is a β-lactam antibacterial agent.

16. The β-lactam antibacterial agent is amoxicillin, ampicillin (pivanpicillin, hetacillin, bacampicillin, metampicillin, talampicillin), epicillin, carbenicillin (carindacillin), ticarcillin, temocillin, azlocillin, piperacillin, mezlocillin, mecillinam (pivmecillinam), sulbenicillin, benzylpenicillin (G), clometocillin, benzathine benzylpenicillin, procaine benzylpenicillin, azidocillin, penamecillin, phenoxymethylpenicillin, Phosphate (V), propicillin, benzathine phenoxymethylpenicillin, phenethicillin, cloxacillin (dicloxacillin, flucloxacillin), oxacillin, methicillin, nafcillin, faropenem, tomopenem, rasppenem, cefazolin, cephacetrile, cefadroxil, cephalexin, cephaloglycin, cephalonium, cephaloridine, cephalothin, cephapirin, cefatrizine, cefazedone, cefazaflour, cephradine, cefroxadine, ceftezole, Fachlor, cefamandole, cefminox, cefonicid, ceforanide, cefotiam, cefprozil, cefbuperazone, cefuroxime, cefuzonam, cefoxitin, cefotetan, cefmetazole, loracarbef, cefixime, ceftriaxone, cefcapene, cefdaloxime, cefdinir, cefidericol, cefditoren, cefetamet, cefmenoxime, cefodizime, cefoperazone, cefotaxime, cefpimizole, cefpiramide, cefpodoxime, cefpodoxime 16. The pharmaceutical composition of claim 15, wherein the compound is selected from the group consisting of lotexil, cefsulodin, cefteram, ceftibuten, ceftiolene, ceftizoxime, flomoxef, latamoxef, cefepime, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftaroline, ceftolozane (CXA-101), RWJ-54428, MC-04,546, ME1036, ceftiofur, cefquinome, cefovecin, RWJ-442831, RWJ-333441, and RWJ-333442.

17. 16. The pharmaceutical composition of claim 15, wherein the β-lactam antibacterial agent is selected from the group consisting of ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, tebipenem, tebipenem pivoxil, apapenem, and panipenem.

18. The β-lactam antibacterial agent is aztreonam, tigemonam, BAL30072, SYN 2416, and carumonum.

19. 16. The pharmaceutical composition of claim 15, wherein the β-lactam antibacterial agent is tebipenem pivoxil.

20. 16. The pharmaceutical composition of claim 15, wherein the β-lactam antibacterial agent is ceftibuten.

21. A composition for treating a bacterial infection in a subject in need thereof, comprising a crystal described in any one of claims 1 to 8 or a compound described in any one of claims 9 to 11.

22. 22. The composition of claim 21, wherein the composition is administered to the subject in combination with an additional agent.

23. 23. The composition of claim 22, wherein the additional agent is an antibacterial, antifungal, antiviral, anti-inflammatory, or antiallergic agent.

24. 24. The composition of claim 23, wherein the additional agent is a β-lactam antibacterial agent.

25. The β-lactam antibacterial agent is amoxicillin, ampicillin (pivampicillin, hetacillin, bacampicillin, metampicillin, talampicillin), epicillin, carbenicillin (carindacillin), ticarcillin, temocillin, azlocillin, piperacillin, mezlocillin, mecillinam (pivmecillinam), sulbenicillin, benzylpenicillin (G), clometocillin, benzathine benzylpenicillin, procaine benzylpenicillin, azidocillin, penamecillin, phenoxymethylpenicillin, Cirrhosis (V), propicillin, benzathine phenoxymethylpenicillin, phenethicillin, cloxacillin (dicloxacillin, flucloxacillin), oxacillin, methicillin, nafcillin, faropenem, tomopenem, rasppenem, cefazolin, cephacetrile, cefadroxil, cephalexin, cephaloglycin, cephalonium, cephaloridine, cephalothin, cephapirin, cefatrizine, cefazedone, cefazaflour, cephradine, cefroxadine, ceftezole, Cefaclor, cefamandole, cefminox, cefonicid, ceforanide, cefotiam, cefprozil, cefbuperazone, cefuroxime, cefuzonam, cefoxitin, cefotetan, cefmetazole, loracarbef, cefixime, ceftriaxone, cefcapene, cefdaloxime, cefdinir, cefidericol, cefditoren, cefetamet, cefmenoxime, cefodizime, cefoperazone, cefotaxime, cefpimizole, cefpiramide, cefpodoxime, cefpodoxime 25. The composition of claim 24, wherein the anti-inflammatory drug is selected from the group consisting of muprotexil, cefsulodin, cefteram, ceftibuten, ceftiolene, ceftizoxime, flomoxef, latamoxef, cefepime, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftaroline, ceftolozane (CXA-101), RWJ-54428, MC-04,546, ME1036, ceftiofur, cefquinome, cefovecin, RWJ-442831, RWJ-333441, and RWJ-333442.

26. 25. The composition of claim 24, wherein the beta-lactam antibacterial agent is selected from the group consisting of ceftazidime, biapenem, doripenem, ertapenem, imipenem, meropenem, tebipenem, tebipenem pivoxil, apapenem, and panipenem.

27. The β-lactam antibacterial agent is aztreonam, tigemonam, BAL30072, SYN 25. The composition of claim 24, wherein the compound is selected from the group consisting of: 2416, and carumonum.

28. 25. The composition of claim 24, wherein the β-lactam antibacterial agent is tebipenem pivoxil.

29. 25. The composition of claim 24, wherein the beta-lactam antibacterial agent is ceftibuten.

30. 30. The composition of any one of claims 21 to 29, wherein the subject is a mammal.

31. 31. The composition of claim 30, wherein the mammal is a human.

32. The above-mentioned infections tularensis、Mrrganellamrganii、Proteus mrabilis、rerulgaris、rovidentia alkalifaciens、rovidencia rettgerirr stuartii、Acinetobacter baumannii、Bordetella pertussis、Bordetella para pertussis、Bordetella bronchiseptica、Haemophilus ducrey, Pasteurella multocida, Pasteurella haemolytica, Ranhamella catarrhalis, Orrelia burgdorferi, Kingella, Gardnerella vaginalis, Bacteroides distasonis, Bacteroides 3452A-group, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus Pneumonia, Streptococcus agalactiae、ｳtrrptococcus pyogenes、Enterococcus faecalis、Enterococcuss I aureus、ｳtaphylococcus epidermidiss saprophyticus、3 intermedius、ttaphylococcus hyicuuu subsp(hyicuss haemolyticus、3taphylococcus hominis、、《よびttaphylococcus sacccharolltticcus 21, 31, 100,000,000,000,000,000,000,000. 【33】 Read more aeruginosa、Pseudomon fluorescenss maltophiliaa coli、Citrobacter freundii、 cf. 、aalmonellaa enteritidiss dysenteriae、ｳhigella flexnerri、3 、snterobacterr cloacae、Enterobacter aerogenes、ｫlebsiella pneumoniaae、llebsiella oxytoca、3 marcescens、｡cinetobacter calcoaceticuss｡ haemolyticus、ersinia enterocoliticaaaersinia pestiis、yeiii pseudotuberculosis、errsini intermedia influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria 32. The composition of any one of claims 21 to 31, comprising a bacterium selected from the group consisting of Bacteroides gonorrhoeae, Neisseria meningitidis, Moraxella, Bacteroides fragilis, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, and Bacteroides splanchnicus.

34. 4. A method for preparing the crystal of claim 2 or 3, said method comprising: (a) dissolving Compound II' in a solvent system to form a crystallization solution, wherein the solvent system comprises isopropyl acetate; (b) heating the crystallization solution; (c) adding heptane to the crystallization solution; (d) adding seed crystals of the crystals according to claim 2 or 3 to the crystallization solution; A method comprising:

35. 35. The method of claim 34, wherein the crystallization solution is heated to a temperature of from 30°C to 80°C.

36. 36. The method of claim 35, wherein the crystallization solution is heated to a temperature of from 40°C to 70°C.

37. 37. The method of any one of claims 34 to 36, wherein the crystallization solution is heated to a temperature of 50°C.

38. 7. A method for preparing the crystal of claim 5 or 6, said method comprising: (a) dissolving Compound II' in a solvent system to form a crystallization solution, wherein the solvent system consists of isopropyl acetate and isopropanol; (b) adding heptane to the crystallization solution; (c) adding seed crystals of the crystals according to claim 5 or 6 to the crystallization solution; A method comprising:

39. 39. The method of claim 38, wherein the solvent system consists of isopropyl acetate and isopropanol in a 1:1 (v / v) ratio.

40. 4. A method for preparing the crystal of claim 2 or 3, said method comprising: (a) dissolving Compound II' in a solvent system to form a crystallization solution, wherein the solvent system consists of hexane and ethyl acetate; (b) heating the crystallization solution; (c) initially cooling the crystallization solution; (d) stirring the crystallization solution; (e) further cooling the crystallization solution to room temperature; (f) allowing the crystallization mixture to stand at room temperature; A method comprising:

41. 41. The method of claim 40, wherein the crystallization solution is heated to a temperature of from 30°C to 80°C.

42. 42. The method of claim 41, wherein the crystallization solution is heated to a temperature of from 50°C to 70°C.

43. 43. The method of any one of claims 40 to 42, wherein the crystallization solution is heated to a temperature of 65°C.

44. 44. The method of any one of claims 40 to 43, wherein the crystallization solution is first cooled to a temperature of from 30°C to 50°C.

45. 45. The method of claim 44, wherein the crystallization solution is first cooled to a temperature of 50°C.

46. 46. ​​The method of any one of claims 40 to 45, wherein the crystallization solution of step (d) is stirred for 12 to 36 hours.

47. 47. The method of claim 46, wherein the crystallization solution of step (d) is stirred for 24 hours.

48. 48. The method of any one of claims 40 to 47, wherein the crystallization solution of step (f) is allowed to stand at room temperature for 72 hours.

49. 4. A method for preparing the crystal of claim 2 or 3, said method comprising: (a) dissolving Compound II' in isopropanol to form a crystallization solution; (b) heating the crystallization solution; (c) cooling the crystallization solution to room temperature; A method comprising:

50. Compound II': 【Chemistry 10】 1. A method for preparing Compound I: 【Chemistry 11】 or a salt thereof, a halomethyl isobutyrate, and a base in a polar organic solvent to form a reaction mixture; heating the reaction mixture to a temperature of 50° C. to 80° C. for 0.5 hours to 24 hours; A method comprising:

51. 51. The method of claim 50, wherein the reaction mixture further comprises an iodide source.

52. 52. The method of claim 51, wherein the iodide source is sodium iodide, potassium iodide, or cesium iodide.

53. The base is NaH ２ P.O. ４ 53. The method of any one of claims 50 to 52, wherein

54. The base is Na ２ B ４ O ７ 53. The method of any one of claims 50 to 52, wherein

55. 55. The method of any one of claims 50 to 54, wherein the molar ratio of base to compound I is from 0.5 to 2.

0.

56. 56. The method of claim 55, wherein the molar ratio of base to compound I is 1.

0.

57. 56. The method of claim 55, wherein the molar ratio of base to compound I is 1.

5.

58. 58. The method of any one of claims 50 to 57, wherein the solvent is acetonitrile.

59. 59. The method of claim 58, wherein the acetonitrile is anhydrous.

60. 60. The method of any one of claims 50 to 59, wherein the halomethyl isobutyrate is chloromethyl isobutyrate.

61. 61. The method of any one of claims 50 to 60, wherein the reaction mixture is heated to a temperature of from 50°C to 80°C.

62. 62. The method of claim 61, wherein the reaction mixture is heated to a temperature of 60°C.

63. 62. The method of claim 61, wherein the reaction mixture is heated to a temperature of 70°C.

64. 62. The method of claim 61, wherein the reaction mixture is heated to a temperature of 80°C.

65. 65. The method of any one of claims 50 to 64, wherein the reaction mixture is heated for 0.5 hours to 24 hours.

66. 66. The method of claim 65, wherein the reaction mixture is heated for 4 to 18 hours.

67. 67. The method of claim 66, wherein the reaction mixture is heated for 6 hours.

68. 67. The method of claim 66, wherein the reaction mixture is heated for 8 hours.

69. 67. The method of claim 66, wherein the reaction mixture is heated for 16 hours.

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