Compound and its use, pharmaceutical composition, sterile container and method for preparing pharmac

专利摘要:
COMPOUND AND PHARMACEUTICAL COMPOSITION AND USES THEREOF, STERILE CONTAINER AND METHOD FOR PREPARING PHARMACEUTICAL COMPOSITION FOR ADMINISTRATION. Disclosed herein are compositions of antimicrobial compounds, pharmaceutical compositions, their use and their preparation. The invention relates to the cyclic boronic acid ester derivatives of the formula I and their use as therapeutic agents especially in the treatment of bacterial infections.
公开号:BR112013003045B1
申请号:R112013003045-3
申请日:2011-08-08
公开日:2021-08-31
发明作者:Gavin Hirst；Raja Reddy；Scott Hecker；Maxim Totrov；David C. Griffith；Olga Rodny；Michel N. Dudley；Serge Boyer
申请人:Rempex Pharmaceuticals, Inc.；
IPC主号:

专利说明:

DESCRIPTIVE REPORT RELATED ORDERS
[001] This Application claims the benefit of U.S. Provisional Applications Numbers 61/372,296, filed August 10, 2010 and 61/488,655, filed May 20, 2011, both of which are incorporated herein in their entirety by reference. FIELD OF THE INVENTION
[002] The present invention relates to antimicrobial compounds, compositions, their use and their preparation as therapeutic agents. Especially, the present invention relates to cyclic boronic acid ester compounds. FUNDAMENTALS OF THE INVENTION
[003] Antibiotics have been effective tools in the treatment of infectious diseases for the past fifty years. From the development of antibiotic therapy until the late 1980s, there was almost complete control over bacterial infections in developed countries. However, in response to the pressure of antibiotic use, multiple resistance mechanisms have become widespread and are threatening the clinical utility of antibacterial therapy. Increases in antibiotic-resistant strains have become especially common in major care centers and hospitals. Consequences of the increase in resistant strains include higher morbidity and mortality, longer patient hospitalization and an increase in treatment costs.
[004] Several bacteria have developed β-lactam deactivating enzymes, namely, β-lactamases, which impede the effectiveness of the various β-lactams. β-lactamases can be grouped into 4 classes based on their amino acid sequences, namely Ambler classes A, B, C and D. Enzymes in classes A, C and D include the active site serine β-lactamases and the enzymes of class B, which are found less frequently, are dependent on Zn. These enzymes catalyze the chemical degradation of β-lactam antibiotics, rendering them inactive. Some β-lactamases can be transferred within and between various bacterial species and strains. The rapid spread of bacterial resistance and the evolution of multiresistant strains greatly limits the available β-lactam treatment options.
[005] The increase in bacterial strains expressing class D β-lactamase such as Acinetobacter baumannii has become an emerging threat of multidrug resistance. Strains of A. baumannii express class A, C and D β-lactamases. Class D β-lactamases such as those from the OXA families are especially effective in destroying carbapenem-type β-lactam antibiotics, eg, imipenem, the active carbapenem component of Primaxin® from Merck (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 has imposed a pressing deterrent to the effective use of drugs in that category to treat and prevent bacterial infections. In fact, the number of cataloged serine-based β-lactamases has exploded from less than ten in the 1970s to more than 300 variants. These problems spurred the development of five “generations” of cephalosporins. When initially licensed into clinical practice, extended-spectrum cephalosporins resisted hydrolysis by the prevalent class A β-lactamases, TEM-1 and SHV-1. However, the development of resistant strains by the evolution of single amino acid substitutions in TEM-1 and SHV-1 resulted in the emergence of the extended-spectrum β-lactamase phenotype, ESBL.
[006] New β-lactamases that hydrolyze the carbapenem class of antimicrobials, including imipenem, biapenem, doripenem, meropenem and ertapenem, as well as other β-lactam antibiotics, have recently been developed. These carbapenemases belong to molecular classes A, B and D. KPC-type class A carbapenemases predominantly in Klebsiella pneumoniaes are now also reported in other Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii. Carbapenemase KPC was first described in 1996 in North Carolina, but has since been widely disseminated in the US. It has been especially problematic in the New York City area, where several reports of spread within major hospitals and patient morbidity have been reported. These enzymes have also recently been reported in France, Greece, Sweden, the UK and an outbreak in Germany has recently been reported. Treatment of resistant strains with carbapenems may be associated with unsatisfactory results.
[007] Another mechanism of β-lactamase-mediated resistance to carbapenems involves the combination of permeability or efflux mechanisms combined with the hyperproduction of betalactamases. One example is that the loss of a combined porin in beta-lactamase AmpC hyperproduction results in imipenem resistance in Pseudomonas aeruginosa. Efflux pump overexpression combined with overproduction of the β-lactamase AmpC can also result in resistance to a carbapenem such as meropenem.
[008] Because there are three major molecular classes of serine-based β-lactamases and each of these classes contain significant numbers of β-lactamase variants, inhibition of one or a small number of β-lactamases is of therapeutic value unlikely. Older β-lactamase inhibitors are predominantly ineffective against at least Class A carbapenemases, against plasmid-mediated Class C cephalosporins, and against many of the Class D oxacillinases. Therefore, there is a need for improved β-lactamase inhibitors. SUMMARY OF THE INVENTION
[009] The present invention relates to antimicrobial agents and their enhancers. Some modalities include compounds, compositions, pharmaceutical compositions, their use and their preparation. Especially, some embodiments refer to cyclic boronic acid ester derivatives.
[0010] Some modalities include compounds having the structure of formula I:
or a pharmaceutically acceptable salt thereof, wherein: Y is a 1-4 atom alkylene or 2-4 atom alkenylene linking group, optionally substituted with one or more substituents selected from the group consisting of Cl, F, CN, CF3, -R9, -OR9, -C(=O)NR9R10 and -C(=O)OR9, wherein said alkylene or alkenylene linking group is optionally fused to an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally heterocyclyl replaced; R1 is selected from the group consisting of -C1-9alkyl, -C2-9alkenyl, -C2-9alkynyl, -NR9R10, -C1-9alkyl-R11, -C2-9alkenyl-R11, -C2-9alkynyl-R11, -carbocyclyl-R11 , -CH(OH)C1-9alkyl-R9, -CH(OH)C2-9alkenyl-R9, -CH(OH)C2-9alkynyl-R9, -CH(OH)carbocyclyl-R9, -C(=O)R9 , -C(=O)C1-9alkyl-R9, -C(=O)C2-9alkenyl-R9, -C(=O)C2-9alkynyl-R9, -C(=O)C2-9carbocyclyl-R9, - C(=O)NR9R10, -N(R9)C(=O)R9, - N(R9)C(=O)NR9R10, -N(R9)C(=O)OR9, -N(R9)C( =O)C(=NR10)R9, - N(R9)C(=O)C(=CR9R10)R9, -N(R9)C(=O)C1-4alkyl-N(R9)C(=O) R9, -N(R9)C(=NR10)R9, -C(=NR10)NR9R10, -N=C(R9)NR9R10, -N(R9)SO2R9, -N(R9)SO2NR9R10, -N=CHR9, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl; R6 is selected from the group consisting of H, -C1-9alkyl, -C2-9alkenyl, -C2-9alkynyl, carbocyclyl, -C1-9alkyl-R11, -C2-9alkenyl-R11, -C2-9alkynyl-R11, carbocyclyl-R11, -C(=O)OR9, -C1-9alkyl-CO2R9, -C2-9alkenyl-CO2R9, -C2-9alkynyl-CO2R9e -carbocyclyl-CO2R9or alternatively: (i) R6e an R7are taken together with the atoms to which they are bonded to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl, (ii) R6 and a carbon atom in Y are taken together with intervening atoms to form substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl or (iii ) R6 is absent when the carbon to which it is attached is a ring atom in an aryl or heteroaryl ring; each R7 is independently selected from the group consisting of H, halo, -C1-9alkyl, -C2-9alkenyl, -C2-9alkynyl, -NR9R10, -OR9, -C1-9alkyl-CO2R9, -C2-9alkenyl-CO2R9, -C2 —9alkynyl-CO2R9e -carbocyclyl-CO2R9or independently: (i) R6and an R7are taken together with the atoms to which they are bonded to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl, (ii) R7and an R8are taken together with the atoms on which they are bonded to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl, (iii) an R7 and a carbon atom in Y are taken together with intervening atoms to form substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl, (iv) each of the following conditions are met: (a) Y is a 3-4 atom alkylene or 3-4 atom alkenylene linking group, (b) R6 is absent, (c) R7and a carbon atom in Y are taken together with intervening atoms to form substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, and (d) each R8 attached to a ring atom forming part of the substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl substituted formed by R7e Y is absent; each R8 is independently selected from the group consisting of H, halo, -C1-9alkyl, -C2-9alkenyl, -C2-9alkenyl, -NR9R10, -OR9, -C1-9alkyl-Cθ2R9, -C2-9alkenyl-Cθ2R9, -C2— 9alkynyl-Cθ2R9, -carbocyclyl-CO2R9or independently: (i) an R7and an R8are taken together with the atoms to which they are bonded to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl, (ii) a geminal R7 R7 and geminal R8 together form -C2-9 alkenylenyl-CO2R9, or (iii) each R8 attached to a ring atom forming part of a substituted or unsubstituted aryl is absent; each R9 is independently selected from the group consisting of H, -C1-9alkyl, C2-9alkenyl, -C2-9alkynyl, carbocyclyl, -C1-9alkyl-R11, -C2-9alkenyl-R11, -C2-9alkynyl-R11, -carbocyclyl- R11, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl; each R10 is independently selected from the group consisting of H, -C1-9alkyl, -OR9, -CH(=NH), -C(=O)OR9, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted carbocyclyl or unsubstituted and substituted or unsubstituted heterocyclyl; each R11 is independently selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl; X is selected from the group consisting of -CO2R12and carboxylic acid isosteres; R12 is selected from the group consisting of H, C1-9alkyl, -(CHa)o-3-R11, -C(R13)2OC(O)C1-9alkyl, -C(R13)2OC(O)R11, -C( R13)20C(0)0Ci-9 alkyl and -C(R13)2OC(O)OR11; each R13 is independently selected from the group consisting of H and C1-4alkyl; and em is independently zero or an integer from 1 to 2, where each C1-9alkyl, C2-9alkenyl and C2-9alkynyl is independently optionally substituted.
[0011] In some embodiments, the compound of formula I has the structure of formula II:
or a pharmaceutically acceptable salt thereof, wherein: the bond represented by a solid dashed line represents a bond selected from the group consisting of a single bond or a double bond with the proviso that the solid dashed line can only be a double bond when n is 1; R2and R4are independently selected from the group consisting of Cl, F, CN, CF3, -R9, -OR9, -C(=O)NR9R1o and -C(=O)OR9; or, alternatively, R2 and R4 are taken together with the atoms at which they are bonded to form a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl; R3and R5are independently selected from the group consisting of Cl, F, CN, CF3, -R9, -OR9, -C(=O)NR9R10 and -C(=O)OR9, with the proviso that if the bond is represented by a solid dashed line is a double bond, then R3 and R5 will be absent; en is independently zero or an integer from 1 to 2.
[0012] In some embodiments, the compound of formula I has the structure of formula IIIa or IIIb:
or a pharmaceutically acceptable salt thereof, wherein: the bond represented by a solid dashed line represents a bond selected from the group consisting of a single bond and a double bond; each R2and R4are independently selected from the group consisting of Cl, F, CN, CF3, -R9, -OR9, -C(=O)NR9R10and -C(=O)OR9; or, alternatively, an R2 and R4 are taken together with the atoms to which they are bonded to form a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl; each R3and R5are independently selected from the group consisting of Cl, F, CN, CF3, -R9, -OR9, -C(=O)NR9R10 and -C(=O)OR9, with the proviso that the bond is represented by a solid dashed line is a double bond, then R3 and R5 will be absent.
[0013] In some embodiments, the compound of formula I has the structure of formula IVa, IVb or IVc:
or a pharmaceutically acceptable salt thereof, wherein: the bond represented by a represents a bond selected from the group consisting of a single bond and a double bond; each R2and each R4 are independently selected from the group consisting of Cl, F, CN, CF3, -R9, -OR9, -C(=O)NR9R10 and -C(=O)OR9; or, alternatively, an R2 and an R4 are taken together with the atoms at which they are bonded to form a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl; each R3and each R5are independently selected from the group consisting of Cl, F, CN, CF3, -R9, -OR9, -C(=O)NR9R10e -C(=O)OR9, with the proviso that if the bond is represented by a solid dashed line is a double bond, then the R3and R5 bonded on the carbon atoms bonded in that bond will be absent.
Some embodiments include a pharmaceutical composition containing a therapeutically effective amount of any of the foregoing compounds and a pharmaceutically acceptable excipient.
Some embodiments include any of the foregoing compounds or compositions for use in treating or preventing a bacterial infection.
Some embodiments include methods of treating or preventing a bacterial infection comprising administering to a subject in need thereof, an effective amount of any of the foregoing compounds or compositions.
Some embodiments include the use of any of the foregoing compounds or compositions in the preparation of a medicament for treating or preventing a bacterial infection.
[0018] Some modalities additionally comprise administering an additional drug, either in a separate composition or in the same composition.
In some embodiments, the additional medicament includes an antibacterial agent, an antifungal agent, an antiviral agent, an antiinflammatory agent, or an antiallergic agent.
In some embodiments, the additional medicament comprises an antibacterial agent such as a β-lactam.
[0021] In some modalities, β-lactam includes Amoxicillin, Ampicillin (Pivampicillin, Hetacillin, Baccampicillin, Metampicillin, Talampicillin), Epicillin, Carbenicillin (Carindacillin), Ticarcillin, Temocillin, Azlocillin, Piperacillin, Mezlocillin (Mecillinam) , Benzyl-penicillin (G), Clomethocillin, Benzaine-benzyl-penicillin, Procaine-benzyl-penicillin, Azidocillin, Penamicillin, Phenoxy-methyl-penicillin (V), Propicillin, Benzatine-phenoxy-methyl-penicillin, Pheneticillin, Cloxacillin (Dicloxacillin , Flucloxacillin), Oxacillin, Methicillin, Nafcillin, Faropenem, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Panipenem, Tomopenem, Razupenem, Cefazolin, Cefacetril, Cephadroxil, Cephalexin, Cephaloglycin, Cephalodin, Cephalonium, Cephalonium Cefazaflur, Cephradine, Cefroxadine, Ceftezole, Cefaclor, Cefamandol, Cefminox, Cefonicide, Ceforanid, Cefotiam, Cefprozil, Cefbuperazone, Cefuroxime, Cefuzonam, Cefoxitin, Cefote tetanus, Cefmetazol, Loracarbef, Cefixime, Ceftazidime, Ceftriaxone, Cefcapene, Cefdaloxim, Cefdinir, Cefditoren, Cefetamet, Cefmenoxime, Ceftazidime, Cefoperazone, Cefotaxime, Cefpimizol, Cefpyramide, Cefthienoxoxime, Cefepime, Cefozopran, Cefpiroma, Cefquinome, Ceftobiprol, Ceftaroline, CXA-101, RWJ-54428, MC-04.546, ME1036, BAL30072, SYN 2416, Ceftiofur, Cefquinoma, Cefovecina, Aztreonam, Tigemonam, RWJ-54428, MC-04.546, ME1036, BAL30072, SYN 2416, Ceftiofur, Cefquinoma, Cefovecin, Aztreonam, Tigemonam, RWJ-4431, RWJumonam or RWJ-333442.
[0022] In some embodiments, β-lactam includes Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem or Panipenem.
[0023] In some modalities, β-lactam is selected from Aztreonam, Tigemonam, BAL30072, SYN 2416 or Carumonam.
[0024] In some embodiments, the β-lactam is Tigemonam, the composition is suitable for oral administration, X is -CO2R12 and R12 is selected from the group consisting of C1-9alkyl, -(CHajα-β-R11, -C(R13)2OC (O)C1-9alkyl, -C(R13)2OC(O)R11, C(R13)2OC(O)OC1-9alkyl and -C(R13)2OC(O)OR11.
[0025] In some embodiments, the infection that is treated or prevented comprises a bacterium that includes Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia, Emonas acidovorans, Emonas hydrophilia typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcesis, Providencia al. Providencia rettgeri, Providencia stuartii, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bornch ophilus influenzae , Haemophilus parainfluenzae , Haemophilus haemolyticus , Haemophilus parahaemolyticus , Haemophilus ducreyi , Pasteurella multocida , Pasteurella haemolytica , Branhamella catarrhalis , Helicobacter pylori , Campylobacter fetus , Campylobacter fetus , Campylobacter , Campylobacter , , , Campylobacter , Campylobacter , Campylobacter , . , Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella, Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis, homology group Bacteroides 3452A, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacterothus bacterium Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococ cus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis or Staphylococcus saccharolyticus.
In some embodiments, the infection that is treated or prevented comprises a bacterium that includes Pseudomonas fluorescens, Stenotrophomonas maltophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella dysenteriae sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia haemolyticus, Haemophilus, Haemophilus, Haemophilus, Haemophilus, Haemophilus, Haemophilus, Haemophilus, Haemophilus, Haemophilus, Haemophilus, influenzae Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella, Bacteroides fragilis, Bacteroides vulgatus ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii or Bacteroides splanchnicus.
[0027] Some embodiments include a sterile container, containing any of the foregoing compounds in solid form and an antibacterial agent in solid form. In some embodiments, the antimicrobial agent is one of the additional drugs described above. Some embodiments include a method of preparing a pharmaceutical composition for administration, comprising reconstituting the contents of the sterile container using a pharmaceutically diluent. In some embodiments, the reconstituted solution is administered intravenously to a patient. BRIEF DESCRIPTION OF THE DRAWINGS
[0028] FIG. 1 is a graph depicting the plasma concentration profile of a cyclic boronic acid ester derivative as a function of time after administration to Sprague Dawley rats.
[0029] FIG. 2 is a graph depicting the plasma concentration profile of a prodrug of the cyclic boronic acid ester derivative of Figure 1 as a function of time after administration to Sprague Dawley rats.
[0030] FIG. 3 is an X-ray powder diffraction of a crystalline form of a cyclic boronic acid ester derivative.
[0031] FIG. 4 is a graph representing an overlay of differential scanning calorimetry and thermogravimetry results for the crystal form of Figure 3. DETAILED DESCRIPTION
[0032] The present invention relates to antimicrobial agents and their enhancers. Some modalities include compounds, compositions, pharmaceutical compositions, their uses, including methods of preparation and methods of treatment. Especially, the present invention relates to cyclic boronic acid ester derivatives. In some embodiments, the cyclic boronic acid ester derivatives have the structure of formula I, II, IIIa, IIIb, IVa, IVb or IVc as described above.
[0033] Some embodiments of the compound of formula II have the defined 3,6-cis stereochemistry shown in formula IIa:
or a pharmaceutically acceptable salt thereof.
[0034] Some modalities of the compound of formula II the defined-3,6-trans stereochemistry shown in formula IIb:
or a pharmaceutically acceptable salt thereof.
[0035] In one embodiment of the compound of formula II: R1 is selected from the group consisting of -C1-9alkyl, -C2-9alkenyl, -C2-9alkenyl, -NR9R10, -C1-9alkyl-R11, -C2-9alkenyl-R11 , -C2-9alkynyl-R11, -CH(OH)C1-9alkyl-R9, -CH(OH)C2-9alkenyl-R9, -CH(OH)C2-9alkynyl-R9, -C(=O)R9, - C(=O)C1-9alkyl-R9, -C(=O)C2-9alkenyl-R9, -C(=O)C2-9alkynyl-R9, -C(=O)NR9R10, -N(R9)C( =O)R9, - N(R9)C(=O)NR9R10, -N(R9)C(=O)OR9, -N(R9)C(=O)C(=NR10)R9, - N(R9 )C(=O)C1-4alkyl-N(R9)C(=O)R9, N(R9)C(=NR10)R9, - C(=NR10)NR9R10, -N=C(R9)NR9R10, - N(R9)SO2R9, -N(R9)SO2NR9R10, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl; R6 is selected from the group consisting of H, -C1-9alkyl, C2-9alkenyl, -C2-9alkynyl, -C1-9alkyl-R11, -C2-9alkenyl-R11, -C2-9alkynyl-R11, -C(=O) OR9and -C1-9alkyl-CO2R9, -C2-9alkenyl-CO2R9and -C2-9alkynyl-CO2R9or alternatively R6and an R7are taken together with the atoms to which they are bonded to form a substituted or unsubstituted carbocyclyl or a substituted or unsubstituted heterocyclyl ; each R7 is independently selected from the group consisting of H, -NR9R10, -OR9e -C1-9alkyl-CO2R9, -C2-9alkenyl-CO2R9e -C2-9alkynyl-CO2R9or independently, R6and an R7or independently an R7and an R8are taken together with the atoms. which are linked to form a substituted or unsubstituted carbocyclyl or a substituted or unsubstituted heterocyclyl; each R8 is independently selected from the group consisting of H, -NR9R10, -OR9and -C1-9alkyl-CO2R9, -C2-9alkenyl-CO2R9and -C2-9alkynyl-CO2R9or independently, an R7and an R8are taken together with the atoms to which they are bonded to form a substituted or unsubstituted carbocyclyl or a substituted or unsubstituted heterocyclyl; each R9 is independently selected from the group consisting of H, -C1-9alkyl, C2-9alkenyl, -C2-9alkynyl, -C1-9alkyl-R11, -C2-9alkenyl-R11, -C2-9alkynyl-R11, substituted or unsubstituted aryl. substituted, substituted or unsubstituted heteroaryl, -(CH 2 ) 0 -3 substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl; each R10 is independently selected from the group consisting of H, -Ci-9alkyl, -OR9, -CH(=NH), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl - replaced; and X is selected from the group consisting of H, -CO2H and carboxylic acid isosters.
[0036] In some embodiments of compounds of formulas II, IIa or IIb, n is 1.
[0037] In some embodiments of compounds of formulas II, IIa or IIb, n is zero.
[0038] In some embodiments of compounds of formulas II, IIa or IIb, n is 2.
[0039] Some embodiments of the compounds of formula IIIa or IIIb have the 3,7-cis stereochemistry shown in formulas IIIc and IIId:
or a pharmaceutically acceptable salt thereof.
[0040] Some embodiments of the compounds of formula IIIa or IIIb have the 3,7-trans stereochemistry shown in formulas IIIe and IIIf:
or a pharmaceutically acceptable salt thereof.
[0041] Some modalities of compounds of formulas IVa, IVb or IVc have the 3,8-cis stereochemistry shown in formulas IVd, IVe and IVf:
or a pharmaceutically acceptable salt thereof.
[0042] Some modalities of compounds of formulas IVa, IVb or IVc have the 3,8-trans stereochemistry shown in formulas IVg, IVh and IVi:
or a pharmaceutically acceptable salt thereof.
[0043] In some embodiments of the compounds of formulas II, IIa, IIIa, IIIb, IIIc, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh and IVi, each R2, R3, R4 and R5 is hydrogen.
In some embodiments of the compounds of formulas II, IIa, IIIa, IIIb, IIIc, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh and IVi, at least one of R2 is substituted or unsubstituted aryl.
In some embodiments of the compounds of formulas II, IIa, IIIa, IIIb, IIIc, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh and IVi, at least one of R4 is substituted or unsubstituted aryl.
[0046] In some embodiments of the compounds of formulas II, IIa, IIIa, IIIb, IIIc, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh and IVi, at least one of R2 and R4 are considered together with the atoms in which are linked to form a substituted or unsubstituted aryl.
In some embodiments of the compounds of formulas II, IIa, IIIa, IIIb, IIIc, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh and IVi, the bond represented by a solid dashed line is a bond simple. In other embodiments, the bond represented by a solid dashed line is a double bond.
[0048] In some embodiments of the compounds of formulas I, II, IIa, IIIa, IIIb, IIIc, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh and IVi, R6e each R7 and R8 is hydrogen.
[0049] In some embodiments of the compounds of formulas I, II, IIa, IIIa, IIIb, IIIc, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh and IVi, R1 is -NHC(=O)Ci-9alkyl -R11. In some of these embodiments, R11 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. In some such embodiments, R11 is thien-2-yl.
[0050] In some embodiments of the compounds of formulas I, II, IIa, IIIa, IIIb, IIIc, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh and IVi, R1 is -NHC(=O)C(= NOR9)R9', in which R9' is selected from the group consisting of C1-9alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl.
[0051] In some embodiments of the compounds of formulas I, II, IIa, IIIa, IIIb, IIIc, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh and IVi, R1 is -NHC(=O)C1-9alkyl -R11. In some such embodiments, R11 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl.
[0052] In some embodiments of the compounds of formulas I, II, IIa, IIIa, IIIb, IIIc, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh and IVi, R1 is -NHC(=O)R9', in which R9' is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl.
In some embodiments of the compounds of formulas I, II, IIa, IIIa, IIIb, IIIc, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh and IVi, R1 is -NR9R10.
In some embodiments of the compounds of formulas I, II, IIa, IIIa, IIIb, IIIc, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh and IVi, R1 is -C1-9alkyl-R11.
[0055] In some embodiments of the compounds of formulas I, II, IIa, IIIa, IIIb, IIIc, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh and IVi, R1 is -CH(OH)C1-9alkyl- R9.
[0056] In some embodiments of the compounds of formulas I, II, IIa, IIIa, IIIb, IIIc, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh and IVi, R1 is -C(=O)C1-9alkyl -R9.
In some embodiments of the compounds of formulas I, II, IIa, IIIa, IIIb, IIIc, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh and IVi, R1 is -C(=O)NR9R10.
[0058] In some embodiments of the compounds of formulas I, II, IIa, IIIa, IIIb, IIIc, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh and IVi, R1 is -N(R8)C(=O )NR9R10.
[0059] In some embodiments of the compounds of formulas I, II, IIa, IIIa, IIIb, IIIc, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh and IVi, R1 is -N(R9)C(=O )OR9.
[0060] In some embodiments of the compounds of formulas I, II, IIa, IIIa, IIIb, IIIc, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh and IVi, R1 is -N(R9)C(=O )C1-4alkyalkyl-N(R9)C(=O)R9.
[0061] In some embodiments of the compounds of formulas I, II, IIa, IIIa, IIIb, IIIc, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh and IVi, R1 is -N(R9)C(=NR10 )R9.
In some embodiments of the compounds of formulas I, II, IIa, IIIa, IIIb, IIIc, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh and IVi, R1 is -C(=NR10)NR9R10.
In some embodiments of the compounds of formulas I, II, IIa, IIIa, IIIb, IIIc, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh and IVi, R1 is -N=C(R9)NR9R10.
[0064] In some embodiments of the compounds of formulas I, II, IIa, IIIa, IIIb, IIIc, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh and IVi, R1 is -C(=O)C(= NR10)R9.
In some embodiments of the compounds of formulas I, II, IIa, IIIa, IIIb, IIIc, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh and IVi, R1 is -N(R9)SO2R9.
In some embodiments of the compounds of formulas I, II, IIa, IIIa, IIIb, IIIc, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh and IVi, R1 is -N(R9)SO2NR9R10.
In some embodiments of the compounds of formulas I, II, IIa, IIIa, IIIb, IIIc, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh and IVi, X is -CO2H.
In some embodiments of the compounds of formulas I, II, IIa, IIIa, IIIb, IIIc, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh and IVi, X is a carboxylic acid isostere. In some such embodiments, the carboxylic acid isostere is selected from the group consisting of -P(O)(OR9)2, -P(O)(R9)(OR9), -P(O)(OR12')2, - P(O)(R9)(OR12'), -CON(R9)OH, -SO3H,
-SO2N(R9)OH, and HN N • where R12' is selected from the group consisting of H, R11, -C(R13)2OC(O)C1-9alkyl, -C(R13)2OC(O)R11, C (R13)2OC(O)OC1-9alkyl and -C(R13)2OC(O)OR11.
[0069] In some embodiments of the compounds of formulas I, II, IIa, IIIa, IIIb, IIIc, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh and IVi, m is 1.
In some embodiments of the compounds of formulas I, II, IIa, IIIa, IIIb, IIIc, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh and IVi, R6, R7and R8 are H.
In some embodiments of the compounds of formulas I, II, IIa, IIIa, IIIb, IIIc, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh and IVi, R7 is H; R8is -C1-9alkyl-CO2R9; and R9 is H.
[0072] Some modalities include a compound selected from the group consisting of:








[0073] Some modalities include compounds selected from the group consisting of:

or a pharmaceutically acceptable salt thereof. Definitions
[0074] Terms and substituents are assigned their common meanings unless otherwise defined and may be defined when introduced and retain their definitions throughout unless otherwise described and retain their definitions either either alone or as part of another group unless otherwise described.
As used herein, "alkyl" means a branched or straight chain saturated chemical group containing only carbon and hydrogen, such as methyl, isopropyl, isobutyl, sec-butyl and pentyl. In various embodiments, alkyl groups can be either unsubstituted or substituted with one or more substituents, for example, halogen, hydroxyl, substituted hydroxyl, acyloxy, amino, substituted amino, amido, cyano, nitro, guanidino, amidino, mercapto, substituted mercapto, carboxyl, sulfonyloxy, carbonyl, benzyloxy, aryl, heteroaryl, carbocyclyl, heterocyclyl or other functionality which may be suitably blocked with a protecting group. Typically, alkyl groups will comprise 1 to 20 carbon atoms, 1 to 9 carbon atoms, preferably 1 to 6 and more preferably 1 to 5 carbon atoms.
[0076] As used herein, "alkenyl" means a straight or branched chain chemical group containing only carbon and hydrogen and containing at least one carbon-carbon double bond, such as 1-propenyl, 2-propenyl, 2-methyl-1 -propenyl, 1-butenyl, 2-butenyl and the like. In various embodiments, alkenyls can be either unsubstituted or substituted with one or more substituents, for example, halogen, hydroxyl, substituted hydroxyl, acyloxy, amino, substituted amino, amido, cyano, nitro, guanidino, amidino, mercapto , substituted mercapto, carboxyl, sulfonyloxy, carbonyl, benzyloxy, aryl, heteroaryl, carbocyclyl, heterocyclyl or other functionality which may be suitably blocked with a protecting group. Typically, alkenyl groups will contain 2 to 20 carbon atoms, 2 to 9 carbon atoms, preferably 2 to 6 and more preferably 2 to 5 carbon atoms.
As used herein, "alkynyl" means a straight or branched chain chemical group containing only carbon and hydrogen and containing at least one carbon-carbon triple bond, such as 1-propynyl, 1-butynyl, 2-butynyl and the like. In various embodiments, alkynyls can be either unsubstituted or substituted with one or more substituents, for example, halogen, hydroxyl, substituted hydroxyl, acyloxy, amino, substituted amino, amido, cyano, nitro, guanidino, amidino, mercapto , substituted mercapto, carboxyl, sulfonyloxy, carbonyl, benzyloxy, aryl, heteroaryl, carbocyclyl, heterocyclyl or other functionality which may be suitably blocked with a protecting group. Typically, alkynyl groups will contain 2 to 20 carbon atoms, 2 to 9 carbon atoms, preferably 2 to 6 and more preferably 2 to 5 carbon atoms.
[0078] As used herein, "carbocyclyl" means a non-aromatic cyclic ring(s) system containing only carbon atoms in the main structure of the ring system (rings), such as cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl and cyclohexenyl. Carbocyclyls can include multiple fused rings. Carbocyclyls can have any degree of saturation as long as at least one of the rings in the ring system is non-aromatic. In various embodiments, carbocyclyl groups can be either unsubstituted or substituted with one or more substituents, for example, halogen, alkoxy, acyloxy, amino, amido, cyano, nitro, hydroxy, mercapto, carboxyl, carbonyl, benzyloxy , aryl, heteroaryl, or other functionality that may be suitably blocked with a protecting group. Typically, carbocyclyl groups will contain 3 to 10 carbon atoms, preferably 3 to 6.
[0079] As used herein, "cycloalkyl" means a fully saturated cabocyclyl ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
[0080] As used herein, "cycloalkenyl" means a carbocyclyl ring system having at least one double bond. An example is cyclohexenyl.
[0081] As used herein, "lower alkyl" means a subset of alkyl and thus is a hydrocarbon substituent, which is linear or branched. Preferred lower alkyls are from 1 to about 4 carbons and can be branched or linear. Examples of lower alkyl include butyl, propyl, isopropyl, ethyl and methyl. Likewise, radicals using the terminology "lower" refer to radicals preferably having 1 to about 4 carbons in the alkyl portion of the radical.
[0082] As used herein, "aryl" means an aromatic radical having a single ring (eg phenyl) or multiple condensed rings (eg naphthyl or anthryl) with only carbon atoms present in the main ring structure. In various embodiments, aryl groups can be either unsubstituted or substituted with one or more substituents, for example, amino, cyano, hydroxyl, lower alkyl, halo-alkyl, alkoxyl, nitro, halo, mercapto, carboxyl, carbonyl, benzyl- oxy, aryl, heteroaryl and other substituents. Some embodiments include substitution with an alkoxy group, which may be further substituted with one or more substituents, for example, amino, cyano, hydroxy, lower alkyl, halo-alkyl, alkoxy, nitro, halo, mercapto and other substituents. A preferred aryl is phenyl.
[0083] As used herein, the term "heteroaryl" means an aromatic radical having one or more heteroatom(s) (eg N, O or S) in the main ring structure and may include a single ring (eg pyridine ) or multiple condensed rings (eg quinoline). In various embodiments, heteroaryl groups can be either unsubstituted or substituted with one or more substituents, for example, amino, cyano, hydroxyl, lower alkyl, halo-alkyl, alkoxyl, nitro, halo, mercapto, carboxyl, carbonyl, benzyl- oxy, aryl, heteroaryl and other substituents. Examples of heteroaryl include thienyl, pyridyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, quinolinyl, and others.
[0084] In these definitions it is considered that substitution in the aryl and heteroaryl rings are within the scope of certain modalities. Where substitution occurs, the radical is called a substituted aryl or substituted heteroaryl. Preferably one to three and more preferably one or two substituents occur on the aryl ring. While many substituents may be useful, preferred substituents include those commonly found on aryl compounds, such as alkyl, cycloalkyl, hydroxy, alkoxy, cyano, halo, halo-alkyl, mercapto, and the like.
[0085] As used herein, "amide" or "starch" includes both RNR'CO- (in the case of R' = alkyl, alkyl-amino-carbonyl-) and RCONR'- (in the case of R' = alkyl, alkyl - carbonyl-amino-). "Amide" or "starch" includes a group H-CON-, alkyl-CON-, carbocyclyl-CON-, aryl-CON-, heteroaryl-CON- or heterocyclyl-CON-, where the group is alkyl, carbocyclyl, aryl or heterocyclyl is as described herein
[0086] As used herein, the term "ester" includes both ROCO- (in the case of R = alkyl, alkoxy-carbonyl-) and RCOO- (in the case of R = alkyl, alkyl-carbonyl-oxy-).
As used herein, "acyl" means an H-CO-, alkyl-CO-, carbocyclyl-CO-, aryl-CO-, heteroaryl-CO- or heterocyclyl-CO- group wherein the alkyl group is carbocyclyl, aryl or heterocyclyl is as described herein. Preferred acyls contain a lower alkyl. Preferred alkyl acyl groups include formyl, acetyl, propanoyl, 2-methyl-propanoyl, t-butyl-acetyl, butanoyl and palmitoyl.
[0088] As used herein, "halo or halide" is a chlorine, bromine, fluorine or iodine atom radical. Chlorine and fluorine are preferred halides. The term "halo" also considers the terms sometimes called "halogen" or "halide".
[0089] As used herein, "heterocyclyl" means a non-aromatic cyclic ring(s) system containing at least one heteroatom in the main chain of the ring system (rings). Heterocyclyls can include multiple fused rings. Heterocyclyls can have any degree of saturation as long as at least one of the rings in the ring system is non-aromatic. The heteroatom(s) may be present in either a non-aromatic or aromatic ring in the ring system (rings). In various embodiments, heterocyclyls can be unsubstituted or substituted with one or more substituents, for example, halogen, alkoxy, acyloxy, amino, amido, cyano, nitro, hydroxyl, mercapto, carboxyl, carbonyl, benzyloxy, aryl , heteroaryl and other substituents and are linked into other groups via any available valence, preferably any available carbon or nitrogen. Preferred heterocycles are 5-7 membered. In six-membered monocyclic heterocycles, the heteroatom(s) is (are) selected from one to three of O, N or S and when the heterocycle is five-membered it preferably has one or two selected heteroatoms. of O, N or S. Examples of heterocyclyl include pyrrolidinyl, piperidinyl, azepanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tiepanyl, indolinyl and dihydro -benzofuranyl.
[0090] As used herein, "substituted amino" means an amino radical that is substituted with one or two alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl groups, wherein the alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl groups are as defined above.
As used herein, "substituted hydroxyl" means the RO- group in which R is an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group or a heterocyclyl group, wherein the alkyl is cycloalkyl , aryl, heteroaryl or heterocyclyl are as defined above.
[0092] As used herein, "substituted thiol" means the group RS- in which R is an alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group or a heterocyclyl group, wherein the alkyl is cycloalkyl , aryl, heteroaryl or heterocyclyl are as defined above.
As used herein, "sulfonyl" means an alkyl-SO2, aryl-SO2, heteroaryl-SO2, carbocyclyl-O2 or heterocyclyl-SO2 group in which alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl are as defined above.
[0094] As used herein, "sulfamido" means an alkyl-NS(O)2N-, aryl-NS(O)2N-, heteroaryl-NS(O)2N-, carbocyclyl-NS(O)2N or heterocyclyl- group NS(O)2N- in which the alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl group is as described herein.
[0095] As used herein, "sulfonamido" means an alkyl-S(O)2N-, aryl-S(O)2N-, heteroaryl-S(O)2N-, carbocyclyl-S(O)2N- or heterocyclyl group -S(O)2N- in which the alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl group is as described herein.
[0096] As used herein, "ureido" means an alkyl-NCON-, aryl-NCON-, heteroaryl-NCON-, carbocyclyl-NCON-, heterocyclyl-NCON- or heterocyclyl-CON- group in which the heterocyclyl group is attached by a ring nitrogen and in which the alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl group is as described herein.
[0097] As used herein, "guanidino" means an alkyl-NC(=NR')N-, aryl-NC(=NR')N-, heteroaryl-NC(=NR')N-, carbocyclyl-NC( =NR')N- or heterocyclyl-NC(=NR')N- in which R' is an H, substituted or unsubstituted hydroxyl group, CN, alkyl, aryl, heteroaryl or heterocyclyl, in which the alkyl group, carbocyclyl, aryl, heteroaryl or heterocyclyl is as described herein.
[0098] As used herein, a substituted group is derived from the unsubstituted parent group in which there has been an exchange of one or more hydrogen atoms for another atom or group. When substituted, the substituent group(s) is (are) substituted with one or more substituent(s) individually and independently selected from C1-C6 alkyl, C1-C6 [sic] alkenyl, C1-C6 [sic] alkynyl, C3-C7 carbocycle (optionally substituted with halo, alkyl, alkoxyl, carboxyl, halo-alkyl, CN, -SO2-alkyl, -CF3 and -OCF3), C1-C6 heteroalkyl, heterocyclyl 5-7 membered (eg tetrahydrofuryl) (optionally substituted with halo, alkyl, alkoxy, carboxy, CN, -SO2-alkyl, -CF3 and -OCF3), aryl (optionally substituted with halo, alkyl, aryl optionally substituted with C1-C6 alkyl, aryl-alkyl, alkoxy, carboxy, CN, -SO2-alkyl, -CF3 and -OCF3), aryl-alkyl (optionally substituted with halo, alkyl, alkoxy, aryl, carboxy, CN, -SO2-alkyl, -CF3 and -OCF3), heteroaryl (optionally substituted with halo, alkyl, alkoxy, aryl, aralkyl, carboxyl, CN, -SO2-alkyl, -CF3 and -OCF3), heteroaryl-alkyl (optionally sub substituted with halo, alkyl, alkoxy, aryl, carboxy, CN, -SO2-alkyl, -CF3 and -OCF3), halo (eg, chlorine, bromine, iodine and fluorine), cyano, hydroxyl, C1-C6 alkoxy, C1 -C6 alkoxy-alkyl (ie, ether), aryl-oxy, sulfhydryl (mercapto), halo(C1-C6)alkyl (eg -CF3), C1-C6 alkyl-thio, aryl-thio, amino (- NH2), mono- and di-(C1-C6)alkylamino, quaternary ammonium salts, amino(C1-C6)alkoxy (eg -O(CH2)4NH2), amino(C1-C6)alkoxy-alkyl ( for example, -CH2O(CH2)2NH2), hydroxy(C1-C6)alkyl-amino, amino(C1-C6)alkyl-thio (for example, -S(CH2)2NH2), cyano-amino, nitro, carbamyl, oxo (=O), carboxyl, glycolyl, glycyl, hydrazino, guanidinyl, sulfamyl, sulfonyl, sulfinyl, thiocarbonyl, thiocarboxyl, C-amide, N-amide, N-carbamate, O-carbamate and urea. Whenever a group is described as "optionally substituted" that group may be substituted with the above substituents.
[0099] In some embodiments, substituted group(s) is (are) substituted with one or more substituent(s) individually and independently selected from C1-C6 alkyl, C3-C7 carbocycle, amino (-NH2 ), amino(C1-C6)alkoxy, carboxyl, oxo (=O), C1-C6 alkylthio, amino(C1-C6)alkylthio, guanidinyl, aryl, 5-7 membered heterocyclyl, heteroaryl-alkyl, hydroxyl, halo, amino(C1-C6)alkoxy and amino(C1-C6)alkoxy-alkyl.
[00100] In some embodiments, substituted group(s) is (are) substituted with one or more substituent(s) individually and independently selected from C1-C6 alkyl, amino (-NH2), amino(C1 -C6)alkoxy, carboxyl, oxo (=O), C1-C6 alkylthio, amino(C1-C6)alkylthio, guanidinyl, hydroxyl, halo, amino(C1-C6)alkoxy and amino(C1-C6) alkoxy-alkyl.
[00101] In some embodiments, substituted group(s) is (are) substituted with one or more substituent(s) individually and independently selected from C1-C6 alkyl, amino (-NH2), carboxyl, oxo (=O), guanidinyl, hydroxyl and halo.
[00102] It should be understood that certain radical naming conventions may include either a mono-stem or a di-radical, depending on the context. For example, where a substituent requires two points of attachment on the remainder of the molecule, it is understood that the substituent is a diradical. For example, a substituent identified as alkyl requiring two points of attachment includes diradicals such as -CH2-, -CH2CH2-, -CH2CH(CH3)CH2- and the like. Other radical naming conventions clearly indicate that the stem is a diradical. For example, as used herein, "alkylene" means a branched or straight chain saturated diradical chemical group containing only carbon and hydrogen, such as methylene, isopropylene, isobutylene, sec-butylene and pentylene, which is attached to the remainder of the molecule via two connection points. As used herein, "alkenylene" means a straight or branched chain diradical chemical group containing only carbon and hydrogen and containing at least one carbon-carbon double bond, such as 1-propenylene, 2-propenylene, 2-methyl-1 -propenylene, 1-butenylene and 2-butenylene, which is attached to the rest of the molecule via two attachment points.
[00103] As used herein, "isosters" of a chemical group are other chemical groups that exhibit the same or similar properties. For example, tetrazole is a carboxylic acid isostere because it mimics the properties of carboxylic acid even though they both have very different molecular formulas. Tetrazol is one of many possible isosteric substitutions for carboxylic acid. Other considered carboxylic acid isosters include -SO3H, -SO2HNR9, -PO2(R9)2, -PO3(R9)2, -CONHNHSO2R9, -COHNSO2R9 and -CONR9CN, in which R9 is as defined above. In addition, carboxylic acid isosters can include 5-7 membered carbocycles or heterocycles containing any combination of CH2, O, S or N in any chemically stable oxidation state, where any of the atoms of said ring structure are optionally substituted on one or more positions. The following structures are non-limiting examples of considered carbocyclic and heterocyclic isosters. Atoms of said ring structure may optionally be substituted at one or more positions with R9 as defined above.

[00104] It is also considered that when chemical substituents are added to a carboxylic isostere, the compound retains the properties of a carboxylic isostere. It is considered that when a carboxylic isostere is optionally substituted with one or more selected groups of R9 as defined above, then the substitution and the position of substitution are selected such that it does not eliminate the carboxylic acid isosteric properties of the compound. Similarly, it is also contemplated that the placement of one or more R9 substituents on a carbocyclic or heterocyclic carboxylic acid isoster is not a substitution on one or more atom(s) that retain (maintain) or is/are integral to the isosteric properties of the carboxylic acid of the compound, if such substituent(s) would destroy the isosteric carboxylic acid properties of the compound.
[00105] Other carboxylic acid isosters not specifically exemplified in this Descriptive Report are also considered.
[00106] The skilled artisan will recognize that some structures described herein may be resonance forms or tautomers of compounds that may be conveniently represented by other chemical structures, even when kinetically; the technician recognizes that such structures are only a very small part of a sample of such compound(s). Such compound(s) is (are) considered within the scope of the structures presented, although such resonance forms or tautomers are not represented here.
[00107] In some embodiments, due to the easy exchange of boron esters, the compounds described herein may convert or exist in equilibrium with alternative forms. Accordingly, in some embodiments, the compounds described herein can exist in combination with one or more of these forms. For example, Compound 5 may exist in combination with one or more of open-chain form (5a), dimeric form (5b), cyclic dimer form (5c), trimeric form (5d), cyclic trimeric form (5e) and the like.

[00108] The compounds obtained herein may include various stereochemical forms. The compounds also include diastereoisomers as well as optical isomers, for example mixtures of enantiomers including racemic mixtures, as well as individual enantiomers and diastereoisomers, which occur due to a consequence of structural asymmetry in certain compounds. Separation of the individual isomers or selective synthesis of the individual isomers is accomplished by applying various methods that are well known to those skilled in the art.
[00109] The term "agent" or "test agent" includes any substance, molecule, element, compound, entity or a combination thereof. It includes, but is not limited to, for example, protein, polypeptide, peptide or mimetic, small organic molecule, polysaccharide, polynucleotide, and the like. It can be a natural product, a synthetic compound or a chemical compound or a combination of two or more substances. Unless otherwise indicated, the terms "agent", "substance" and "compound" are used interchangeably herein.
[00110] The term "analog" is used herein to refer to a molecule that structurally resembles a reference molecule but that has been modified in a selected or controlled manner, by replacing a specific substituent of the reference molecule with a alternative substituent. Compared to the reference molecule, it would be assumed by a person skilled in the art that an analog would be of equal, similar or improved utility. Analog synthesis and selection, to identify variants of known compounds having improved characteristics (such as higher binding affinity for a selected molecule) is an approach that is well known in pharmaceutical chemistry.
[00111] The term "mammal" is used in its usual biological sense. Thus, it specifically includes humans, cattle, horses, dogs, cats, rats and mice but it also includes many other species.
[00112] The term "microbial infection" refers to the invasion of the host organism, whether the organism is a vertebrate, invertebrate, fish, plant, bird or mammal, by pathogenic microbes. This includes the overgrowth of microbes that are normally present in or on the body of a mammal or other organism. More generally, a microbial infection can be any situation in which the presence of a microbial population(s) is harmful to a host mammal. Thus, a mammal is “suffering” from a microbial infection when excessive numbers of a microbial population are present in or on the mammal's body or when the effects of the presence of a microbial population(s) are harmful to cells or other tissue from a mammal. Specifically, this description applies to a bacterial infection. Note that the compounds of the preferred modalities are also useful in the treatment of contamination or microbial growth of cell cultures or other inanimate media or surfaces or objects and nothing here should limit the preferred modalities to the treatment of higher organisms only, except as explicitly stated in the Claims .
[00113] 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 to the extent that any conventional agent or medium is incompatible with the active ingredient, its use in therapeutic compositions is considered. Supplementary active ingredients can also be incorporated into the compositions. In addition, various adjuvants as commonly used in the art can be included. These and other such compounds are described in the literature, for example, in the "Merck Index", Merck & Company, Rahway, NJ. Considerations for including various components 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.
The term "pharmaceutically acceptable salt" refers to those salts which retain the biological properties and effectiveness of the compounds of the preferred embodiments and which are not biologically or otherwise undesirable. In many cases, compounds of preferred embodiments are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or similar groups therein. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids 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 the 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 base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, the bases sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum and the like; especially preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, substituted amines including naturally existing substituted amines, cyclic amines, basic ion exchange resins and the like, specifically such as isopropylamine, trimethylamine , diethylamine, triethylamine, tripropylamine and ethanolamine. Many such salts are known in the art, as described in WO 87/05297, Johnston et al., published September 11, 1987 (herein incorporated in its entirety by reference).
[00115] "Solvate" refers to the compound formed by the interaction of a solvent and an EPI, a metabolite or its salt. Suitable solvates are pharmaceutically acceptable solvates including hydrates.
[00116] "Subject" as used herein means a human or non-human mammal, for example, a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate. human or a bird, for example a chicken, as well as any other vertebrate or invertebrate.
[00117] A therapeutic effect relieves, to some extent, one or more of the symptoms of the infection and includes healing of an infection. “Cure” means that the symptoms of active infection are eliminated, including the elimination of excess limbs of viable microbe from those involved in the infection. However, certain permanent or long-lasting effects of the infection may exist even after a cure is obtained (such as extensive tissue data).
[00118] "Treat", "treatment" or "treating" as used herein refers to the administration of a pharmaceutical composition for prophylactic and/or therapeutic purposes. The term "prophylactic treatment" refers to the treatment of a patient who is not yet infected, but who is susceptible to, or is otherwise at risk of, a specific infection, whereby treatment reduces the possibility that the patient will develop an infection. The term "therapeutic treatment" refers to administering the treatment to a patient already suffering from an infection. Administration and pharmaceutical compositions
[00119] Some embodiments include pharmaceutical compositions containing: (a) a safe and therapeutically effective amount of the cyclic boronic acid ester derivative or its corresponding enantiomer, diastereoisomer or tautomer or pharmaceutically acceptable salt; and (b) a pharmaceutically acceptable carrier.
Cyclic boronic acid ester derivatives are administered in a therapeutically effective dosage, for example a dosage sufficient to provide treatment for the disease states previously described. Although human dosage levels have yet to be optimized for compounds of preferred modalities, generally, a daily dose for most cyclic boronic acid ester derivatives described herein is from about 0.25 mg/kg to about 120 mg/kg or more of body weight, from about 0.5 mg/kg or less to about 70 mg/kg, from about 1.0 mg/kg to about 50 mg/kg of body weight or from about from 1.5 mg/kg to about 10 mg/kg body weight. Thus, for administration to a 70 kg person, the dosage range would be from about 17 mg per day to about 8,000 mg per day, from about 35 mg per day or less to about 7,000 mg per day or more, from about 70 mg per day to about 6,000 mg per day, from about 100 mg per day to about 5,000 mg per day, or from about 200 mg to about 3,000 mg per day. It is obvious that the amount of active compound administered will depend on the subject and disease state being treated, the severity of the affliction, the manner and timing of administration, and the judgment of the prescribing physician.
[00121] Administration of the compounds disclosed herein or pharmaceutically acceptable salts thereof may be via any of the accepted modes of administration for agents serving similar utilities including, but not limited to, oral, subcutaneous, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal or intraocular. Oral and parenteral administrations are customary in treating the indications that are the subject of the preferred modalities.
The compounds useful as described above can be formulated into pharmaceutical compositions for use in treating these conditions. Standard pharmaceutical formulation techniques are used, such as those disclosed in "Remington's The Science and Practice of Pharmacy", 21stEd., Lippincott Williams & Wilkins (2005), incorporated herein in its entirety by reference.
[00123] In addition to the selected compound useful as described above, some embodiments include compositions containing a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier", as used herein, means one or more compatible liquid or solid encapsulating substances or diluents, which are suitable for administration to a mammal. The term "compatible", as used herein, means that the components of the composition are capable of being mixed with the subject compound and with each other, in a manner such that there is no interaction, which would substantially reduce the pharmaceutical effectiveness of the composition under situations of common use. It is obvious that acceptable carriers need to be of sufficiently high purity and sufficiently low toxicity to make them suitable for administration preferably to an animal, preferably mammal being treated.
[00124] Some examples of substances, which can serve as pharmaceutically acceptable carriers or their components, are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium-carboxy-methyl-cellulose, ethyl-cellulose, methyl-cellulose; powdered tragacanth, malt; dextrin; talc, solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and Theobroma oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol and poly(ethylene glycol); alginic acid; emulsifiers such as TWEENS; wetting agents such as sodium lauryl sulfate; coloring agents; tablet forming agents; stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline solution; and phosphate buffer solutions.
[00125] The choice of a pharmaceutically acceptable vehicle to be used in conjunction with the investigated compound is basically determined by means of the compound to be administered.
The compositions described herein are preferably obtained in unit dosage form. As used herein, a "unit dosage form" is a composition containing an amount of a compound that is suitable for administration to an animal, preferably a mammalian subject, in a single dose, in accordance with good medical practice. The preparation of a unitary or single dosage form, however, does not imply that the dosage form is administered once a day or once during the course of therapy. Such dosage forms are intended to be administered once, twice, three times or more per day and may be administered as an infusion over a period of time (eg, from about 30 minutes to about 2-6 hours) or given as a continuous infusion and may be given more than once during a course of therapy, although a single administration is not specifically excluded. The experienced practitioner will recognize that the formulation does not specifically consider the entire course of therapy and such decisions are left to those experienced in the technique of treatment rather than the formulation.
Compositions useful as described above may be in any of a variety of forms suitable for a variety of routes of administration, for example, for oral, nasal, rectal, topical (including transdermal), ocular, intracerebral routes of administration. , intracranial, intrathecal, intraarterial, intravenous, intramuscular, or other parenteral routes of administration. The skilled artisan will recognize that oral and nasal compositions comprise compositions that are administered by inhalation and made using available methodologies. Depending on the specific route of administration desired, a variety of pharmaceutically acceptable vehicles well known in the art can be used. Pharmaceutically acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropes, surface active agents and encapsulating substances. Optional pharmaceutically active materials which do not substantially interfere with the inhibitory activity of the compound may be included. The amount of carrier used in conjunction with the compound is sufficient to provide a practical amount of material for administration per unit dose of the compound. Techniques and compositions for preparing dosage forms useful in the methods described herein are described in the following references, all incorporated by reference herein: "Modern Pharmaceutics", 4thEd., 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).
[00128] Various oral dosage forms can be used, including such dosage forms as tablets, capsules, granules and bulk powders. These oral forms comprise a safe and effective amount, usually at least about 5%, with a maximum of about 90%, of the compound. Tablets can be tablets, small cylindrical tablets (tablet grinders), enteric coated, sugar coated, film coated or multiple coated, containing binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents and agents suitable fluxes. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or reconstituted suspensions of effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweetening agents, melting agents, coloring agents and flavoring agents.
The pharmaceutically acceptable carrier suitable for the preparation of unit dosage forms for peroral administration is well known in the art. Tablets typically contain conventional pharmaceutically compatible adjuvants such as inert diluents such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrating agents such as starch, alginic acid and croscarmellose; lubricants such as magnesium stearate, stearic acid and talc. Sliding agents such as silicon dioxide can be used to improve the flow characteristics of the powder mixture. Coloring agents, such as FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, fruit flavoring, are useful adjuvants for chewable tablets. Capsules typically contain one or more solid diluents disclosed above. The selection of vehicle components depends on secondary considerations such as taste, cost, storage stability, which are not critical and can readily be made by a person skilled in the art.
[00130] Peroral compositions also include solutions, emulsions, liquid suspensions and the like. Pharmaceutically acceptable carriers suitable for the preparation of such compositions are well known in the art. Typical vehicle components for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, poly(ethylene glycol), liquid sucrose, sorbitol and water. For a suspension, typical suspending agents include methyl cellulose, sodium carboxy methyl cellulose, AVICEL RC-591, tragacanth and sodium alginate; typical wetting agents include lecithin, polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate. Liquid peroral compositions can also contain one or more components such as the sweeteners, flavoring agents and colorants disclosed above.
[00131] Such compositions can also be coated by conventional methods, typically with pH- or time-dependent coatings, such that the investigated compound is released into the gastrointestinal tract in the vicinity of the desired topical application or at various times to prolong the desired action . Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, hydroxy-propyl-methyl-cellulose phthalate, poly(vinyl acetate phthalate), hydroxy-propyl-methyl-cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.
[00132] Compositions described herein may optionally include other active drug agents.
[00133] Other compositions useful to effect systemic delivery of the investigated compounds include sublingual, buccal and nasal dosage forms. Such compositions typically contain one or more soluble fillers such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxy-methyl-cellulose and hydroxy-propyl-methyl-cellulose. Sliding agents, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.
A liquid composition, which is formulated for ophthalmic use, is formulated in such a way that it can be administered topically to the eye. Comfort should be maximized as much as possible, although some formulation considerations (eg drug stability) may require less-than-optimal comfort. In the case where comfort cannot be maximized, the liquid should be formulated in such a way that the liquid is tolerable to the patient for topical ophthalmic use. Additionally, an ophthalmically acceptable liquid must either be packaged for single use or contain a preservative to prevent contamination during multiple uses.
[00135] For ophthalmic application, solutions or drugs are often prepared using a physiological saline solution as a primary vehicle. Ophthalmic solutions should preferably be maintained at a comfortable pH with an appropriate buffer system. The formulations can also contain conventional pharmaceutically acceptable preservatives, stabilizers and surfactants.
Preservatives that can be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chloro-butanol, thimerosal, phenyl mercuric acetate and phenyl mercuric nitrate. A useful surfactant is, for example, Tween 80. Also, various useful carriers can be used in the ophthalmic preparations disclosed herein. Such carriers include, but are not limited to, poly(vinyl alcohol), povidone, hydroxy-propyl-methyl-cellulose, poloxamers, carboxy-methyl-cellulose, hydroxy-ethyl-cellulose and purified water.
[00137] Tonicity adjusters can be added if necessary or convenient. They include, but are not limited to, salts, especially sodium chloride, potassium chloride, mannitol and glycerin or any other suitable ophthalmically acceptable tonicity adjuster.
[00138] Various buffering agents and means to adjust the pH can be used so long as the resulting preparation is ophthalmically acceptable. For many compositions the pH will be between 4 and 9. Consequently, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids and bases can be used to adjust the pH of these formulations as needed.
[00139] Similarly, an ophthalmically acceptable antioxidant includes, but is not limited to, sodium metabisulfite, sodium thiosulfate, acetyl-cysteine, butylated hydroxyanisole and butylated hydroxytoluene.
[00140] Other excipient components, which may be included in ophthalmic preparations, are chelating agents. A useful chelating agent is disodium edetate, although other chelating agents can also be used in place of or in conjunction with it.
[00141] For topical use, creams, ointments, gels, solutions or suspensions etc., containing the compound disclosed herein may be used. Topical formulations may generally contain a pharmaceutical carrier, co-solvent, emulsifier, penetration enhancer, preservative system and emollient.
For intravenous administration, the compounds and compositions described herein can be dissolved or dispersed in a pharmaceutically diluent, such as saline or dextrose solution. Suitable excipients can be included to achieve the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HCl and citric acid. 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-sulfoxylate, thiourea and EDTA. Other non-limiting examples of suitable excipients found in the final intravenous composition may include sodium or potassium phosphates, citric acid, tartaric acid, gelatin and carbohydrates such as dextrose, mannitol and dextran. Other suitable 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 in their entirety by reference. Antimicrobial agents may also be included to obtain a bacteriostatic or fungistatic solution, including but not limited to phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol and chloro-butanol.
The resulting composition can be infused into the patient over a period of temp. In several modalities, the infusion time varies from 5 minutes to continuous infusion, from 10 minutes to 8 hours, from 30 minutes to 4 hours and from 1 hour to 3 hours. In one modality, the drug is infused over a 3-hour period. The infusion may be repeated at the desired dose range, which may include, for example, 6 hours, 8 hours, 12 hours or 24 hours.
Compositions for intravenous administration may be provided by healthcare professionals in the form of one or more solids which are reconstituted with a suitable diluent such as sterile water, saline or dextrose in water immediately prior to administration. Reconstituted concentrated solutions can be further diluted into parenteral solutions having a volume of from about 25 ml to about 1000 ml, from about 30 ml to about 500 ml, or from about 50 ml to about 100 ml. In other embodiments, the compositions are provided in a solution ready for parenteral administration. In still other embodiments, the compositions are obtained in a solution which is then diluted prior to administration. In embodiments that include a combination of a compound described herein and another agent, the combination can be provided to healthcare professionals as a mixture or healthcare professionals can mix the two agents prior to administration or the two agents can be administered separately.
[00145] The actual dose of the active compounds described herein depends on the specific compound and condition to be treated; selection of the proper dose is well within the ability of the experienced technician. Intravenous administration kits
Some embodiments include a kit containing a compound described herein and an additional agent, such as an antimicrobial agent. In one embodiment, both components are provided in a single sterile container. In the case of solids for reconstitution, the agents can be premixed and added to the container simultaneously or the container can be filled with the agents in dry powder form in two separate steps. In some embodiments, solids are direct crystalline products. In other embodiments, solids are lyophilic. In one modality, both components are lyophilized together. Non-limiting examples of agents to aid in lyophilization include sodium or potassium phosphates, citric acid, tartaric acid, gelatin and carbohydrates such as dextrose, mannitol and dextran. One embodiment includes non-sterile solids that are irradiated either before or after introduction into a container.
[00147] In the case of a liquid, the agents can be dissolved or dispersed in a diluent ready for administration. In another embodiment, the solution or dispersion may be further diluted prior to administration. Some modalities include providing the fluid in an IV bag. Liquid can be frozen to improve stability.
[00148] In one embodiment, the container includes other ingredients such as a pH adjuster, a solubilizing agent or a dispersing agent. Non-limiting examples of pH adjusters include NaOH, sodium carbonate, sodium acetate, HCl and citric acid.
[00149] The molar ratio of compound described herein to additional agent (for example, antibacterial agent) may be about 10:1 to 1:10, 8:1 to 1:8, 5:1 to 1:5, 3 :1 to 1:3, 2:1 to 1:2 or about 1:1. In various embodiments, the amount of compound described herein can be from 100 mg to 5 g, 500 mg to 2 g, or about 1 g. Similarly, in various embodiments the amount of additional agent can be from 100 mg to 5 g, 500 mg to 2 g, or about 1 g.
[00150] In an alternative embodiment, the two components can be supplied in separate containers. Each container can include a solid, a solution or a dispersion. In such modalities, the two containers can be supplied in a single package or they can be supplied separately. In one embodiment, the compound described herein is provided as a solution while the additional agent (eg, antibacterial agent) is provided as a solid ready for reconstitution. In one such embodiment, the solution of the compound described herein is used as the diluent to reconstitute the other agent. Treatment Methods
Some embodiments of the present invention include methods of treating bacterial infections with the compounds and compositions containing cyclic boronic acid ester derivatives described herein. Some methods include administering a compound, a composition, a pharmaceutical composition described herein to a subject in need thereof. In some embodiments, a subject can be an animal, e.g., a mammal, a human. In some embodiments, the bacterial infection comprises a bacterium described herein. As will be recognized from the foregoing, methods of treating a bacterial infection include methods of preventing bacterial infection in a subject at risk of the same.
[00152] Other modalities include administering a combination of compounds to a subject in need thereof. A combination may include a compound, a composition, a pharmaceutical composition described herein with an additional medicament.
Some modalities include co-administration of a compound, a composition, and/or a pharmaceutical composition described herein, with an additional medicament. “Co-administration” means that two or more agents can be found in the patient's bloodstream at the same time, regardless of when or how they are actually administered. In one modality, agents are administered simultaneously. In another embodiment, combination administration is accomplished by combining the agents in a unit dosage form. When the agents are combined in a unit dosage form, they can be physically mixed (eg, by co-dissolving or dry mixing) or they can form an adduct or be covalently linked in such a way that they divide into two or more active ingredients. after administration to the patient. In another modality, agents are administered sequentially. In one modality agents are administered via the same route, such as orally. In another embodiment, agents are administered via different routes, such as one being administered orally and the other being administered i.v.
[00154] Examples of additional medications include an antibacterial agent, an antifungal agent, an antiviral agent, an antiinflammatory agent, and an antiallergic agent.
Some modalities include co-administration of a compound, composition or pharmaceutical composition described herein with an antibacterial agent such as a β-lactam. Examples of such β-lactams include Amoxicillin, Ampicillin (e.g. Pivampicillin, Hetacillin, Baccampicillin, Metampicillin, Talampicillin), Epicillin, Carbenicillin (Carindacillin), Ticarcillin, Temocillin, Azlocillin, Piperacillin, Mezlocillin, Sulmecillin (Pzillinam), penicillin (G), Clomethocillin, Benzaine-benzyl-penicillin, Procaine-benzyl-penicillin, Azidocillin, Penamecillin, Phenoxy-methyl-penicillin (V), Propicillin, Benzatine-phenoxy-methyl-penicillin, Phenethicillin, Cloxacillin (for example Dicloxacillin, Flucloxacillin), Oxacillin, Methicillin, Nafcillin, Faropenem, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Panipenem, Tomopenem, Razupenem, Cefazolin, Cefacetril, Cephadroxil, Cephalexin, Cephaloglycine, Cephaloglycine, Cephaloglycin , Cefazaflur, Cephradine, Cephroxadine, Ceftezole, Cefaclor, Cefamandol, Cefminox, Cefonicide, Ceforanide, Cefotiam, Cefprozil, Cefbuperazone, Cefuroxime, Cefuzonam, Cefoxit Ina, Cefotetan, Cefmetazol, Loracarbef, Cefixime, Ceftazidime, Ceftriaxone, Cefcapene, Cefdaloxim, Cefdinir, Cefditoren, Cefetamet, Cefmenoxime, Ceftazidime, Cefoperazone, Cefotaxime, Cefpimizol, Cefdaloxime, Cefdinex, Cefdinir Latamoxef, Cefepime, Cefozopran, Cefpiroma, Cefquinome, Ceftobiprol, Ceftaroline, CXA-101, RWJ-54428, MC-04.546, ME1036, BAL30072, SYN 2416, Ceftiofur, Cefquinome, Cefovecin, Aztreonam, RWJ-54428, - 333441 or RWJ-333442.
Preferred embodiments include β-lactams such as Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, ME1036, Tomopenem, Razupenem and Panipenem.
Some embodiments include co-administration of the compounds, compositions and/or pharmaceutical compositions described herein with an additional agent, the additional agent comprising a monobactam. Examples of monobactans include aztreonam, tigemonam, BAL 30072, SYN 2416 (BAL19764) and carumonam.
Some modalities include co-administration of the compounds, compositions and/or pharmaceutical compositions described herein with an additional agent, the additional agent comprising a Class A, B, C, or Beta-lactamase inhibitor D. 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)). Other examples of administered beta-lactamase inhibitors include clavulanic acid, tazobactam, sulbactam, avibactam (NXL-104), MK-7655 and BAL29880. MK-7655 has the following structure:
Indications
The compounds and compositions containing cyclic boronic acid ester derivatives described herein can be used to treat bacterial infections. Bacterial infections treatable with the compounds, compositions and methods described herein may contain a broad spectrum 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, Citrobacterillus, Bacylobacter , Bacteroides, Peptococcus, Clostridium, Salmonella, Shigella, Serratia, Haemophilus, Brucella and other organisms.
More examples of bacterial infections include Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonas hydrophilia, Escherichia enterella, Salphitymon, Salphitymon, Salphiter, Salphim , 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 acinater alcalifaciens Providencia acinater alcalifaciens calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae, H aemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia goobrolyserria, Nedisseriae pneumolyserria, Vibrossum, Vibrophyllium, Br. , Kingella, Moraxella, Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis, homology group Bacteroides 3452A, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides Myplanchnicus a bacterium, Clostricobacterium tuberculosis, intrabacterium tuberculosis Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcu are epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis or Staphylococcus saccharolyticus.
[00161] The following examples will further describe the present invention and are used for illustrative purposes only and should not be considered limiting. EXAMPLES General Procedures
[00162] Materials used in the preparation of cyclic boronic acid ester derivatives described herein can be prepared by known methods or are commercially available. It will be apparent to the skilled artisan that methods for preparing precursors and functionality related to the compounds claimed herein are generally described in the literature including, for example, procedures described in US7271186 and WO2009064414, each of which is incorporated herein in its entirety by reference. In these reactions, it is also possible to make use of variants which are themselves known to those persons commonly experienced in this technique, but are not mentioned in any further detail. The skilled artisan with the indicated literature and this disclosure is well qualified to prepare any of the compounds.
[00163] It is recognized that the skilled artisan in the art of organic chemistry can readily perform manipulations without further guidance, i.e. it is well within the scope and practice of the skilled artisan to perform these manipulations. These include reduction of carbonyl compounds to their corresponding alcohols, oxidations, acylations, substitutions into aromatics, both electrophilic and nucleophilic, etherifications, esterifications and saponification, and the like. These manipulations are discussed in standard texts such as "March Advanced Organic Chemistry (Wiley)", "Carey and Sundberg, Advanced Organic Chemistry" (herein incorporated in their entirety by references) and the like.
[00164] The experienced technician will readily recognize that certain reactions are best performed when other functionality is masked or protected in the molecule, thus avoiding any undesirable side reactions and/or increasing the reaction yield. Often the experienced technician uses protective groups to achieve such increased yields or to avoid unwanted reactions. These reactions are found in the literature and are also well within the scope of the experienced technician. Examples of many of these manipulations can be found for example in “T. Greene and P. Wuts Protecting Groups in Organic Synthesis,” 4th Ed., John Wiley & Sons (2007), incorporated herein in its entirety by reference.
The following exemplary schemes are provided to guide the reader and represent preferred methods for preparing the compounds exemplified herein. These methods are not limited and it will be apparent that other routes can be used to prepare these compounds. Such methods specifically include solid-phase based chemistry, including combinatorial chemistry. The skilled person is fully qualified to prepare these compounds by those methods indicated by this literature and this disclosure. The compound numberings used in the synthesis schemes shown below are designed for those specific schemes only and should not be interpreted or confused with the same numberings in other sections of the application.
[00166] Trademarks used herein are examples only and reflect the illustrative materials used at the time of the invention. The experienced technician will recognize that variations in batches, manufacturing processes and the like are anticipated. Accordingly the examples and trademarks used therein are not limiting and are not intended to be limiting, but are merely illustration of how an experienced artisan may choose to carry out one or more of the embodiments of the invention.
Nuclear magnetic resonance (1H) spectra (nuclear magnetic resonance, NMR) were measured in the indicated solvents either on a Bruker NMR spectrometer (Avance TM DRX500, 500 MHz for 1H) or on a Varian NMR spectrometer (Mercury 400BB , 400 MHz for 1H). Peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane. Peak multiplicities are denoted as follows, s, singlet; d, doublet; t, triplet; q, quartet; quin, quintet; sex, sextet; sep, septet; non, nonet; dd, doublet of doublets; td, doublet triplet; m, multiplet.
[00168] The following abbreviations have the indicated meanings:


[00169] The following exemplary schemes are provided for the reader's guidance and collectively represent an exemplary method for preparing the compounds provided herein. Furthermore, other methods for preparing the compounds described herein will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. Unless otherwise noted, all variables are as defined above.
[00170] Compounds of formula I in which R1 is an acyl-amino group and X is a carboxylic acid can be prepared as shown in Scheme 1.


[00171] The addition of enolates in α,β-unsaturated ketones and substituted aldehydes to form e-hydroxy-esters is a well known reaction (Scheme 1). Substituents R7and R8of formula 1 can be controlled by the use of the appropriate α-mono or di-substituted ester III. Similarly, substituents R2, R3 and R4 can be controlled by the use of the appropriate substituted α,β-unsaturated ketones or aldehydes analog II. Precursors of structure IV, in which R6and R7or R8are combined together, can be prepared following known procedures [J. Am. Chem. Soc. (1982), 104, 1735-7, Tetrahedron Lett. (2003), 44, 1259-62]. The β-hydroxy-ester of structure IV is protected with an acid-sensitive protecting group, giving V; this selection allows simultaneous deprotection of the boronane ester and the hydroxyl protecting group in the final step, resulting in a cyclized product. Pinacol VII boronate is formed from substituted V using iridium catalysts [Tetrahedron (2004), 60, 10695-700]. Transesterification was readily performed with optically active pinanediol VIII to result in IX [Tetrahedron: Asymmetry, (1997), 8, 1435-40]. Transesterification can also be performed from the catechol-ester analog of VII. Such catechol-esters can be prepared by the reaction of V with commercially available catechol-borane [Tetrahedron (1989), 45, 1859-85]. Homologation of IX to give chloromethylene addition product X with good stereocontrol can be carried out via the Matteson reaction conditions (W00946098). The chloro-derivative X can be used to introduce a substituted amine group at the C3-position of oxa-borinan-2-ol. Stereospecific substitution with hexamethyldisilazane gives the corresponding bis(trimethylsilyl)amide XI which can be reacted in situ with an acid chloride to directly result in analogs of structure XII. Such analogs of XII can also be prepared via coupling of the bis-TMS amine with commercially available carboxylic acids under typical amide coupling conditions (eg, carbodiimide or HATU coupling). Compounds of formula I wherein R1 is substituted with -N(R9)C(=O)C(=NOR9)R9 can be synthesized from the corresponding carboxylic acids via copulation of XI to XII as in Scheme 1. Such carboxylic acids can be prepared by the following procedures described in US Patent Number 5,888,998, US Patent Application Publication Number 2004/0019203 and US Patent Number 4,822,786, all of which are incorporated herein in their entirety by reference. Simultaneous deprotection of the pinane-ester, tert-butyl-dimethyl-silyl-oxyl group and tert-butyl-ester group and concomitant cyclization are carried out with dilute HCl, giving the desired oxa-borinane derivatives of structure XIII. This transformation can also be performed by treatment with BCl3 or BBr3. Alternatively, deprotection can be carried out via transesterification with isobutyl-boronic acid in the presence of dilute HCl (WO09064413). Scheme 2


[00172] Compounds of structure XVI in which R1 of formula I is an alkyl, aralkyl or amino-aryl group can be prepared from the brominated intermediate XIV as shown in Scheme 2 [J. Organometry Chem. (1992), 431, 255-70]. Such brominated derivatives can be prepared analogously to the chlorinated compounds of Scheme 1, using dibromomethane [J. Am. Chem. Soc. (1990), 112, 3964-969]. Displacement of the bromine group in XIV can be accomplished by α-alkoxy-substituted alkyl lithium agents [J. Am. Chem. Soc. (1989), 111, 4399-402; J. Am. Chem. Soc. (1988), 110, 842-53] or by organic magnesium reagents (WO0946098) or by the sodium salt of alkyl- or aryl-carbamate derivatives [J. Org. Chem. (1996), 61, 795154], resulting in XV. Cyclization of XV to give XVI can be carried out under the conditions described in Scheme 1 Scheme 3
Compounds of formula XIII and XVI are mixtures of 3,6-cis- and 3,6-trans-isomers. These analogs can be prepared in enantiomerically pure form by starting (as in Scheme 1) from a single enantiomer (XVII), as shown in Scheme 3. A variety of methods for preparing such enantiomerically pure e-hydroxy-esters are known in the literature. , for example via resolution [Org. Lett., (2008), 10, 3907-09] or stereoselective synthesis [Tetrahedron, (2000), 56, 917-47]. Such single isomers result in enantiomerically pure cis-compounds XIII or XVI when used in the sequences shown in Schemes 1 and 2. Scheme 4
[00174] The sequence shown in Scheme 1 also allows for varying ring sizes in formula I such as 7- and 8-membered rings. For example, a seven-membered analog XX in which n = 1 can be prepared by using the corresponding allylated intermediate (XIX) as a starting material (Scheme 4). Such allylated derivatives as XIX can be prepared using one of several well-known e-hydroxy-ester preparations [Tetrahedron (2007), 63, 8336-50]. Intermediate XIX where n = 2 can be prepared as described in Scheme 1 to give the corresponding 8-membered compound of structure XX starting from pent-4-ene-1-al [J. Med. Chem. (1998), 41(6), 965-972]. Scheme 5
[00175] Compounds of formula XXVI and XXVII can be prepared following the sequence shown in Scheme 5. Ring Closing Metathesis Reaction with boronated olefins (XXI) and β-hydroxy-substituted olefin-esters (XXII) results in cyclic boronanes of formula XXIII. Such cyclic boronanes (XXIII) undergo prompt esterification with (+)-pinanediol to give the required Matteson reaction precursors under deprotection of the resulting alcohol with groups such as t-butyl-dimethyl-silyl or benzyl or trityl. Matteson homologation followed by amide formation results in compounds of formula XXV with high stereoselectivity, as described above. Acid-mediated hydrolysis of XXV compounds under deprotection gives cyclic boronate (XXVI). Double bond substitution of XXVI can then be modified to other analogs such as saturated cyclic boronate (XXVII) by catalytic hydrogenation. The above sequence can be used to prepare 7- or 8-membered rings double bonded at a desired position by varying p and q of XXI and XXII. Scheme 6
Compounds of formula I in which R 2 and R 4 taken together form an aryl ring can be prepared from commercially available substituted aryl precursors as XXVIII. Replacement of the bromine atom with a boronate ester can be done under palladium catalyzed conditions [Tetrahedron (2002), 58, 9633-95]. The steps of hydroxy-ester formation, preparation and cyclization of α-amido-boronate can be carried out by synthetic steps analogous to those in Scheme 1 to give compounds XXIX. Scheme 7

[00177] Compounds of formula I in which R7 and R8 are substituted as maleate (XXXV) or succinate (XXXVI) can be prepared following the sequence shown in Scheme 7. Maleate intermediates such as XXXII can be transformed to analogues XXXV analogously to the steps in Scheme 1 Analogs of XXXV can then be converted to the corresponding succinic acids of structure XXXVI by catalytic hydrogenation. Intermediate maleate XXXII can be assembled from intermediate XXXI by successive deprotection of the TBS group, oxidation to aldehyde and addition of vinyl-Grignard and reprotection as TBS-ether. Intermediate XXXI can be formed from a protected propargyl alcohol XXX following methods known in the literature [Tetrahedron, (2002), 58, 6545-54]. Compounds of formula I in which X is a carboxylic acid isostere can be prepared following protocols described in the literature (see J. Med. Chem. 2011, 54, 2529-2591, which is incorporated herein in its entirety by reference). Examples of illustrative compounds
Synthesis of 2-((3R)-2-hydroxy-3-(2-(thiophen-2-yl)-acetamido)-1,2-oxa-borinan-6-yl)-acetic acid. An exemplary synthesis of 1 is shown in Scheme 8 and Example 1. Scheme 8

Example 1 Step 1
[00179] A round bottom flask loaded with [Ir(cod)Cl] 2 (350 mg, 0.52 mmol) and 1,4-bis(diphenyl-phosphanyl)-butane (446 mg, 1.04 mmol) was subjected to argon flow. DCM (60 mL), pinacol-borane (3 mL, 21 mmol) and tert-butyl-3-(tert-butyl-dimethyl-silyl-oxyl) pent-4-enoate XXXVII [J. Org. Chem., (1994), 59(17), 4760 - 4764] (5 g, 17.48 mmol) in 5 mL of DCM were added successively at room temperature. The mixture was then stirred at room temperature 16h. The reaction was quenched with MeOH (3 mL) and water (10 mL), the product was extracted with ether and dried. Chromatography on silica gel (100% DCM → 50% EtOAc / DCM gave 3-(tert-butyl-dimethyl-silyl-oxyl)-5-(4,4,5,5-tetramethyl-1,3,2- tert-butyl dioxaborolan-2-yl)pentanoate XXXVIII (5.5 g, 13.2 mmol, 75.5% yield). Step 2
[00180] In a solution of 3-(tert-butyl-dimethyl-silyl-oxyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pentanoate of tert- Butyl XXXVIII (5.4 g, 13 mmol) in THF (25 mL) was added (1S,2S,3R,5S)-2,6,6-trimethyl-bicyclo[3.1.1]heptane-2,3-diol (2.4 g, 14.3 mol) at room temperature. The reaction mixture was stirred for 16 h and then concentrated in vacuo. The residue was purified by column chromatography (100% hexane→40% EtOAc/hexane) over silica gel to give 1-(tert-butoxy)-3-[(tert-butyl-dimethyl-silyl)-oxy]-1- oxo-6-[(2S,6R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02.6]decan-4-yl]-hexan-3-yl XXXIX (5 .5 g, 11 mmol, 84.6% yield). Step 3
[00181] To a solution of DCM (1.5 mL, 23.6 mmol) in THF (30 mL) at -100°C was added 2.5 M n-butyllithium in hexane (5.19 mL, 12 .98 mmol) slowly under nitrogen and down the side wall of the flask while keeping the temperature below -90°C. The resulting white precipitate was stirred for 30 minutes before the addition of 1-(tert-butoxy)-3-[(tert-butyl-dimethyl-silyl)-oxy]-1-oxo-6-[(2S,6R)- 2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02.6]decan-4-yl]-hexan-3-yl XXXIX (5.5 g, 11 mmol) in THF (10 ml) at -90°C. Zinc chloride (23.6 mL, 0.5 M in diethyl ether, 11.86 mmol) was then added to the reaction mixture at -90°C and then the reaction was allowed to warm to room temperature at which she was shaken for 16 h. The reaction was quenched with a saturated ammonium chloride solution and the phases were separated. The aqueous phase was then extracted with diethyl ether (3 x 50 mL) and the combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The concentrated material was then chromatographed (100% hexane→50% EtOAc/hexane) to obtain 6-(tert-butoxy)-4-[(tert-butyl-dimethyl-silyl)-oxy]-1-chloro-6 -oxo-1-[(2S,6R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02.6]decan-4-yl]-hexyl XL (5.6 g , 10.5 mmol, 95.4% yield). Steps 4-5
Chlorinated Intermediate XL (1.2 g, 2.33 mmol) in THF (10 mL) was cooled to -78°C under nitrogen. A solution of LiHMDS (2.33 mL, 1.0 M in THF, 2.33 mmol) was added slowly and the reaction flask was then allowed to warm to room temperature where it was stirred for 16 h. Method A: The resulting product was cooled to -78°C and 5-thiophene-acetyl chloride was added and the solution was stirred at -78°C for 1.5 h. Then, the cooling bath was removed and the solution was stirred at room temperature for 1.5 h. The reaction was quenched with water and extracted twice with EtOAc. The organic layers were combined, washed with water, brine, dried (Na2SO4) and concentrated in vacuo to give a pale yellow solid as crude product. The residue was chromatographed on a silica column (100% DCM→40% EtOAc/DCM) to give 570 mg of 6-(tert-butoxy)-4-[(tert-butyl-dimethyl-silyl)-oxy]-6 -oxo-1-(thiophen-2-yl-acetamido)-1-[(2S,6R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02.6]decan- 4-yl]-hexalidine XLII as a white solid (570 mg, 0.92 mmol, 39.5% yield). Step 6
[00183] Method D: To a solution of amide XLII (250 mg, 0.40 mmol) in 1,4-dioxane (10 mL) was added 10 mL of 3N HCl. The mixture was heated to 110°C for 90°C min. The solution was cooled and diluted with 10 ml of water and extracted twice with 10 ml of diethyl ether. The aqueous layer was concentrated to give a sticky residue as crude product. The residue was washed with 5 ml of water, dissolved in 10% MeCN - water and lyophilized to give 2-((3R)-2-hydroxy-3-(2-(thiophen-2-yl)-acetamido)-1 acid ,2-oxa-borinan-6-yl)-acetic 1 as white powder (100 mg, 0.337 mmol, 84.1% yield). 1H NMR (CD3OD) δ ppm 0.94-1.35 (m, 1H), 1.35-1.54 (m, 1H), 1.54-1.68 (m, 1H), 1.68- 2.00 (m, 1H), 2.20-2.67 (m, 3H), 3.93 (s, 1H), 3.98 (s, 1H), 4.02-4.23 (m, 2H), 6.98-7.05 (m, 2H), 7.32-7.36 (m, 1H); ESIMS checked for C12H16BNO5S m/z 280 (100%) (M-H2O)+.
[00184] Alternative procedures for Steps 5 and 6 are shown in Scheme 9. Scheme 9
Step 5, Method B
To a solution of the acid (0.36 mmol) in DCM (10 mL) at 0°C under nitrogen were added EDCI (86 mg, 0.45 mmol) and HOBT (48 mg, 0.36 mmol). After stirring at 0°C for 30 minutes, a solution of the intermediate bis-silyl-amide XLI (0.3 mmol) in DCM (2 mL) followed by N-methyl-morpholine (65 µL, 0.6 mmol) was sequentially added. added at 0°C. The reaction flask was then allowed to warm to room temperature. After stirring at room temperature overnight, the reaction mixture was washed with water, then with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography to yield intermediate XLIII. Step 5, Method C
[00186] A solution of bis-silyl-amide XLI (0.5 mmol) and acid in dry DCM (10 mL) were cooled to 0°C. Then DIPEA (1.5 mmol) was added dropwise followed by HATU (0.75 mmol). The mixture was then allowed to warm to room temperature. After TLC indicated complete conversion (~3h) of starting materials, the reaction was diluted with additional DCM (20 mL). The reaction mixture was washed with water (3X5 mL), brine (10 mL) and dried over Na2SO4. After removing the solvent, the residue was subjected to flash column chromatography to produce intermediate XLIII. Step 6, Method E
A solution of amide (XLIII) (0.1 mmol) in dichloroethane (2 ml) at 0°C was treated with aq. 90% pre-cooled (4 mL) and stirred at room temperature for 3 h. The reaction mixture was evaporated in vacuo, azeotroped with MeCN (3X5ml) and the residue triturated with ether (5ml). The separated product was filtered, dissolved in dioxane-water mixture and freeze-dried to give the final product XLIV as a soft/loose solid.
[00188] The following compounds are prepared according to the procedure described in Example 1 above using methods A and D.

[00189] 2-((3R)-2-hydroxy-3-(2-phenyl-acetamido)-1,2-oxaborinan-6-yl)-acetic acid 2. 1H NMR (CD3OD) δ ppm 0, 82-1.33 (m, 1H), 1.33 1.51 (m, 1H), 1.51-1.68 (m, 1H), 1.69-2.00 (m, 1H), 2 1.14-2.34 (m, 1H), 2.34-2.69 (m, 2H), 3.74-3.76 (m, 2H), 3.98-4.20 (m, 1H) , 7.22-7.41 (m, 5H); ESIMS verified for C14H18BNO5 m/z 274 (100%) (M-H2O)+.

[00190] 2-((3R)-3-Acetamido-2-hydroxy-1,2-oxa-borinan-6-yl)-acetic acid 3.1H NMR (CD3OD) δ ppm 1.07-1.36 ( m, 1H), 1.36-1.59 (m, 1H), 1.59-1.73 (m, 1H), 1.73-2.09 (m, 1H), 2.15-2, 16 (d, 3H), 2.35-2.69 (m, 3H), 4.01-4.23 (m, 1H); ESIMS verified for C8H14BNO5 m/z 198 (100%) (M-H2O)+.

2-((3R)-3-(Cyclopropane-carboxamido)-2-hydroxy-1,2-oxaborinan-6-yl)-acetic acid 4.1H NMR (CD3OD) δ ppm 0.98- 1.32 (m, 5H), 1.32-1.67 (m, 2H), 1.67-2.06 (m, 2H), 2.27-2.66 (m, 3H), 3. 98-4.16 (m, 1H); ESIMS verified for C10H16BNO5 m/z 224 (100%) (M-H2O)+.
The following compounds were prepared starting from enantiomerically pure (R)-3-hydroxy-pent-4-enoate of tert-butyl (J. Am. Chem. Soc. 2007, 129, 4175-4177) according to procedure described in Example 1 above.

[00193] 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)-acetamido)-1,2-oxa-borinan-6-yl)-acetic acid 5.1H NMR (CD3OD) δ ppm 0.97-1.11 (q, 1H), 1.47-1.69 (m, 2H), 1.69-1.80 (m, 1H), 2.21-2 .33 (td, 1H), 2.33-2.41 (dd, 1H), 2.58-2.67 (m, 1H), 3.97 (s, 2H), 4.06-4.14 (m, 1H), 6.97-7.04 (m, 1H), 7.04-7.08 (m, 1H), 7.34-7.38 (dd, 1H); ESIMS checked for C12H16BNO5S m/z 280 (100%) (M-H2O)+.

2-((3R,6S)-2-hydroxy-3-(2-phenyl-acetamido)-1,2-oxaborinan-6-yl)-acetic acid 6.1H NMR (CD3OD) δ ppm 0.86-1.02 (m, 1H), 1.441.53 (dd, 1H), 1.53-1.66 (td, 1H), 1.68-1.78 (m, 1H), 2, 17-2.26 (dd, 1H), 2.26-2.36 (dd, 2H), 3.75 (s, 2H), 4.02-4.12 (m, 1H), 7.22- 7.40 (m, 5H); ESIMS verified for C14H18BNO5 m/z 274 (100%) (M-H2O)+.
The following compounds are prepared according to the procedure described in Example 1 above starting from enantiomerically pure (R)-3-hydroxy-pent-4-enoate of tert-butyl (J. Am. Chem. Soc. 2007, 2007). 129, 4175-4177) using methods B and D.

2-((3R,6S)-3-((S)-2-amino-2-phenyl-acetamido)-2-hydroxy-1,2-oxa-borinan-6-yl)-acetic acid 33 was isolated as the HCl salt. 1H NMR (CD3OD) δ ppm 1.24-1.27 (m, 1H), 1.51-1.72 (m, 3H), 2.45 2.50 (dd, J=5 Hz, J=5 Hz, 1H), 2.55-2.63 (dd, J=2 Hz, J=3 Hz, 1H), 3.66-3.71 (m, 1H), 4.38-4.53 (m , 1H), 4.99-5.09 (d, 1H), 7.48-7.56 (m, 5H); ESIMS verified for C14H19BN2O5 m/z 289 (M-H2O)+.

[00197] 2-((3R,6S)-3-(3-amino-propanamido)-2-hydroxy-1,2-oxa-borinan-6-yl)-acetic acid 34 was isolated as the HCl salt. 1H NMR (CD3OD) δ ppm 1.24-1.29 (td, J=13 Hz. J=3 Hz, 1H), 1.55-1.62 (td, J=14 Hz, J=4 Hz, 1H), 1.68-1.72 (m, 1H), 1.79-1.82 (m, 1H), 2.43-2.47 (dd, J=6Hz, J=6Hz, 2H ), 2.70-2.74 (m, 2H), 2.83-2.86 (t, J=7Hz, 2H), 3.263.29 (t, J=7Hz, 1H), 4.10 -4.16 (m, 1H); ESIMS verified for C9H17BN2O5 m/z 227 (M-H2O)+.

(S)-2-Amino-5-((3R,6S)-6-(carboxy-methyl)-2-hydroxy-1,2-oxa-borinan-3-yl-amino)-5- acid oxo-pentanoic 35 was isolated as the HCl salt. 1H NMR (CD3OD) δ ppm 1.50-1.66 (m, 2H), 1.66-1.84 (m, 2H), 2.10-2.20 (fri, J=8Hz 1H), 2.20-2.29 (m, 1H), 2.40-2.47 (m, 2H), 2.552.59 (q, J=7Hz 1H), 2.69-2.75 (m, 1H) ), 2.94-2.98 (td, J=9Hz, J=2Hz 1H), 3.99-4.12 (m, 2H); ESIMS verified for C11H19BN2O7 m/z 302.8 (M+H).

2-((3R,6S)-3-(2-Amino-4-(methyl-thio)-butanamido)-2-hydroxy-1,2-oxa-borinan-6-yl)-acetic acid 41 was isolated as the HCl salt. 1H NMR (CD3OD) δppm 1.45-1.65 (m, 1H), 1.65-1.75 (m, 1H), 1.75 1.86 (m, 1H), 1.86-2 .05 (m, 1H), 2.09-2.20 (m, 4H), 2.46-2.73 (m, 6H), 2.84-2.86 (t, J=6Hz, 1H ), 3.99-4.02 (t, J=7Hz, 1H), 4.38-4.46 (m, 1H); ESIMS verified for C11H21BN2O5S m/z 287 (M-H2O)+.

2-((3R,6S)-3-(2-(3,5-difluorophenyl)-acetamido)-2-hydroxy-1,2-oxa-borinan-6-yl)-acetic acid 66 was isolated as the HCl salt. 1H NMR (CD3OD) δ ppm 0.98-1.07 (q, J=13 Hz, 1H), 1.55-1.68 (m, 2H), 1.73-1.79 (dd, J= 6Hz, J=3Hz, 1H), 2.22-2.26 (dd, J=15Hz, J=6Hz, 1H), 2.33-2.38 (dd, J=13Hz, J =7Hz, 1H), 2.62-2.63 (m, 1H), 3.78 (s, 2H), 4.05-4.12 (m, 1H), 6.88-5.93 ( tt, J=5Hz, J=2Hz, 1H), 6.97-7.01 (dd, J=5Hz, J=2Hz, 2H); ESIMS verified for C14H16BF2NO5 m/z 310.1 (M-H2O)+.
The following compounds are prepared according to the procedure described in Example 1 above starting from enantiomerically pure tert-butyl (R)-3-hydroxy-pent-4-enoate (J. Am. Chem. Soc. 2007, 2007). 129, 4175-4177) using methods A and E.

2-((3R,6S)-3-benzamido-2-hydroxy-1,2-oxa-borinan-6-yl)-acetic acid 37. 1H NMR (CD3OD) δ ppm 1.10-1, 19 (q, J=11Hz, 1H), 1.60-1.65 (dd, J=14Hz, J=3Hz, 1H), 1.71-1.80 (td, J=9Hz, J=3Hz, 1H), 1.91-1.96 (d, J=14Hz, 1H), 2.32-2.38 (dd, J=15Hz, J=6Hz, 1H), 2 .44-2.49 (dd, J=15Hz, J=7Hz, 1H), 2.82-2.84 (d, J=4Hz, 1H), 4.10-4.17 (m, 1H), 7.57-7.60 (t, J=8 Hz, 2H), 7.70-7.73 (t, J=8 Hz, 1H), 8.00-8.02 (d, J =8 Hz 2H); ESIMS checked for C13H16BNO5 m/z 260 (M-H2O)+.
The following compounds are prepared according to the procedure described in Example 1 above starting from enantiomerically pure tert-butyl (R)-3-hydroxy-pent-4-enoate (J. Am. Chem. Soc. 2007, 2007). 129, 4175-4177) using methods B and E.

[00204] Acid 2-((Z)-1-(2-amino-thiazol-4-yl)-2-((3R,6S)-6-(carboxy-methyl)-2-hydroxy-1,2- oxa-borinan-3-yl-amino)-2-oxo-ethylidene-amino-oxy)-2-methyl-propanoic 36 was isolated as the TFA salt. 1H NMR (CD3OD) δ ppm 1.60 (s, 3H), 1.61 (s, 3H), 1.62-1.75 (m, 2H), 1.77-1.82 (m, 1H) , 1.86-1.91 (m, 1H), 2.55-2.58 (t, J=6Hz, 2H), 2.90-2.94 (t, J=6Hz, 2H), 4.37-4.42 (m, 1H), 7.11 (s, 1H); ESIMS verified for C15H21BN4O8S m/z 411 (M-H2O)+.

2-((3R,6S)-2-hydroxy-3-(3-phenyl-propanamido)-1,2-oxaborinan-6-yl)-acetic acid 38. 1H NMR (CD3OD) δ ppm 0.78-0.87 (q, J=13Hz, 1H), 1.40-1.46 (dd, J=10Hz, J=3Hz, 1H), 1.54-1.62 (dt , J=8 Hz, J=4 Hz, 1H), 1.63-1.70 (d, J=13 Hz, 1H), 2.24-2.29 (dd, J=15 Hz, J=6 Hz, 1H), 2.36-2.40 (dd, J=8 Hz, J=3 Hz, 1H), 2.53-2.56 (d, J=3.2 Hz, 1H), 2.742, 78 (t, J=7Hz, 2H), 2.98-3.01 (t, J=6Hz, 2H), 3.90-4.03 (m, 1H), 7.187.23 (m, 1H) ), 7.25-7.33 (m, 4H); ESIMS checked for C15H20BNO5 m/z 288 (M-H2O)+.

2-((3R,6S)-3-(2-(2-Amino-thiazol-4-yl)-acetamido)-2-hydroxy-1,2-oxa-borinan-6-yl)-acid acetic 39 was isolated as the TFA salt. 1H NMR (CD3OD) δ ppm 1.25-1.36 (m, 1H), 1.63-1.76 (m, 3H), 2.40 2.43 (d, J=6Hz 2H), 2 .68-2.70 (m, 1H), 3.72 (s, 2H), 4.17-4.21 (m, 1H), 6.69 (s, 1H); ESIMS verified for C11H16BN3O5S m/z 296.1 (M-H2O)+.

2-((3R,6S)-3-((Z)-2-(2-amino-thiazol-4-yl)-2-(methoxyimino)-acetamido)-2-hydroxy acid -1,2-oxa-borinan-6-yl)-acetic 40 was isolated as the TFA salt. 1H NMR (CD3OD) δ ppm 1.56-1.67 (m, 2H), 1.761.81 (m, 1H), 1.86-1.90 (m, 1H), 2.50-2.54 ( dd, J=17Hz, J=6Hz, 1H), 2.59-2.64 (dd, J=16Hz, J=7Hz, 1H), 2.86-2.90 (t, J= 7Hz, 1H), 4.22 (s, 3H), 4.34-4.37 (m, 1H), 7.86 (s, 1H); ESIMS verified for C12H17BN4O6S m/z 339.1 (M-H2O)+.

2-((3R,6S)-3-(2-Amino-3-(pyridin-3-yl)-propanamido)-2-hydroxy-1,2-oxa-borinan-6-yl)- acid 42 acetic was isolated as the TFA salt. 1H NMR (CD3OD/CF3O2D) δppm 1.43-1.56 (m, 2H), 1.72-1.83 (m, 2H), 2.37-2.42 (m, 1H), 2, 53-2.57 (t, J=6Hz, 1H), 2.89-2.93 (t, J=7Hz, 1H), 3.37-3.43 (m, 2H), 4.17 -4.21 (t, J=7Hz, 1H), 4.41-4.46 (m, 1H), 8.068.10 (dd, J=6Hz, J=3Hz, 1H), 8.53 -8.57 (t, J=17 Hz, 1H), 8.80-8.81 (brd, J=4 Hz, 1H), 8.84-8.87 (brd, J=6 Hz, 1H) ; ESIMS verified for C14H20BN3O= m/z 304.2 (M-H2O)+.

2-((3R,6S)-2-hydroxy-3-(2-(pyridin-3-yl)-acetamido)-1,2-oxa-borinan-6-yl)-acetic acid 43 was isolated as the TFA salt. 1H NMR (CD3OD) δ ppm 1.15-1.20 (m, 1H), 1.59-1.63 (m, 1H), 1.68-1.74 (m, 2H), 2.29- 2.34 (dd, J=15Hz, J=6Hz, 2H), 2.66-2.68 (m, 1H), 3.94 (s, 2H), 4.11-4.18 (m , 1H), 7.82-7.85 (dd, J=8Hz, J=6Hz, 1H), 8.30-8.32 (d, J=8Hz, 1H), 8.68-8 .70 (brd, J=5Hz, 1H), 8.72-8.75 (brs, 1H); ESIMS verified for C13H17BN2O5 m/z 275 (M-H2O)+.

2-((3R,6S)-2-hydroxy-3-((S)-piperidine-2-carboxamido)-1,2-oxa-borinan-6-yl)-acetic acid 45 was isolated as the salt of TFA. 1H NMR (CD3OD) δ ppm 1.44-1.51 (m, 1H), 1.54-1.80 (m, 5H), 1.80-1.91 (m, 2H), 1.91- 1.98 (brd, J=12 Hz, 1H), 2.16-2.21 (dd, J=13 Hz, J=2 Hz, 1H), 2.49-2.57 (non, J=7 Hz, 2H), 2.75-2.78 (t, J=6 Hz, 1H), 2.98-3.03 (dt, J=13 Hz, J=3 Hz, 1H), 3.36- 3.39 (d, J=13Hz, 1H), 3.79-3.82 (dd, J=12Hz, J=4Hz, 1H), 4.34-4.38 (m, 1H); ESIMS verified for C12H21BN2O5 m/z 267 (M-H2O)+.

2-((3R,6S)-2-hydroxy-3-((R)-1,2,3,4-tetrahydro-isoquinoline-3-carboxamido)-1,2-oxa acid -borinan-6-yl)-acetic 46 was isolated as the TFA salt. 1H NMR (CD3OD) δ ppm 1.43-1.51 (m, 1H), 1.56-1.63 (m, 1H), 1.75-1.83 (m, 1H), 1.86- 1.94 (m, 1H), 2.46-2.57 (dq, J=16Hz, J=6Hz, 2H), 2.82-2.86 (t, J=7Hz, 1H), 3.18-3.24 (dd, J=17 Hz, J=12 Hz, 1H), 3.36-3.41 (dd, J=17 Hz, J=5 Hz, 1H), 4.21- 4.24 (dd, J=18Hz, J=13Hz, 1H), 4.36-4.40 (m, 1H), 4.42 (s, 2H), 7.23-7.25 (m , 1H), 7.27-7.33 (m, 3H); ESIMS verified for C16H21BN2O5 m/z 315 (M-H2O)+.

[00212] Following Method E although the compound was still in 90% aqueous trifluoroacetic acid (10 mL), 10% Pd/C (50 mg) was added. The reaction mixture was stirred under hydrogen for 6 h, filtered through Celite and washed with dichloromethane (10 mL). The filtrate was concentrated in vacuo and azeotroped with dichloroethane (2x10ml). Trituration with ether resulted in a precipitate which was filtered and washed with ether (5 mL) and dried to give 2-((3R,6S)-3-((R)-2-amino-5-guanidino-pentanamido)- acid 2-hydroxy-1,2-oxa-borinan-6-yl)-acetic 47 as the TFA salt (50 mg) as an off-white solid. 'II NMR (CD3OD) δ ppm 1.39-1.46 (m, 1H), 1.52-1.58 (m, 1H), 1.66-1.77 (m, 2H), 1.77 -1.84 (m, 1H), 1.87-1.95 (m, 3H), 2.34-2.38 (dd, J=17 Hz, J=3 Hz, 1H), 2.63- 2.68 (dd, J=17 Hz, J=7 Hz, 1H), 2.94-2.97 (dd, J=10 Hz, J=6 Hz, 1H), 3.20-3.24 ( dt, J=7Hz, J=2Hz, 2H), 3.86-3.88 (t, J=6Hz, 1H), 4.27-4.31 (m, 1H); ESIMS verified for C12H24BN5O5 m/z 312.2 (M-H2O)+.

2-((3R,6S)-3-(2-(2-Amini-ethyl-thio)-acetamido)-2-hydroxy-1,2-oxa-borinan-6-yl)-acetic acid 48 was isolated as the TFA salt. 1H NMR (CD3OD) δppm 1.38-1.46 (m, 1H), 1.46-1.54 (m, 1H), 1.71-1.78 (m, 1H), 1.84- 1.92 (m, 1H), 2.30-2.34 (dd, J=16 Hz, J=4 Hz, 1H), 2.56-2.61 (dd, J=16 Hz, J=6 Hz, 1H), 2.80-2.83 (t, J=6 Hz, 1H), 2.89-2.97 (non, J=7 Hz, 2H), 3.17-3.24 (non , J=5Hz, 2H), 3.37 (s, 2H), 4.15-4.20 (m, 1H); ESIMS verified for C10H19BN2O5S m/z 273 (M-H2O)+.

2-((3R,6S)-2-hydroxy-3-(2-(pyridin-4-yl)-acetamido)-1,2-oxa-borinan-6-yl)-acetic acid 49 was isolated as the TFA salt. 1H NMR (CD3OD) δ ppm 1.17-1.27 (m, 1H), 1.60-1.67 (m, 1H), 1.67-1.76 (m, 2H), 2.32- 2.43 (m, 2H), 2.68-2.70 (t, J=4Hz, 2H), 3.22-3.26 (t, J=7Hz, 1H), 4.15-4 .21 (m, 1H), 7.94-7.96 (d, J=7Hz, 2H), 8.75-8.79 (d, J=6Hz, 2H); ESIMS verified for C13H17BN2O5 m/z 275.1 (M-H2O)+.

2-((3R,6S)-3-(2-(4-amino-cyclohexyl)-acetamido)-2-hydroxy-1,2-oxa-borinan-6-yl)-acetic acid 50 was isolated as the TFA salt. 1H NMR (CD3OD) δ ppm 1.15-1.25 (m, 1H), 1.44-1.88 (m, 10H), 2.052.13 (m, 1H), 2.19-2.21 ( d, J=8Hz, 1H), 2.30-2.36 (dd, J=6Hz, 1H), 2.38-2.47 (m, 3H), 2.61-2.63 (brd , J=3Hz, 1H), 3.18-3.22 (t, J=7Hz, 1H), 4.04-4.11 (m, 1H); ESIMS verified for C14H25BN2O5 m/z 295.1 (M-H2O)+.

2-((3R,6S)-3-(2-(1-amino-cyclohexyl)-acetamido)-2-hydroxy-1,2-oxa-borinan-6-yl)-acetic acid 51 was isolated as the TFA salt. 1H NMR (CD3OD) δ ppm 1.23-1.34 (m, 1H), 1.34-1.48 (m, 1H), 1.48 1.86 (m, 12H), 2.40-2 .50 (m, 2H), 2.65-2.83 (m, 2H), 3.22-3.26 (t, J=7Hz, 1H), 4.11-4.18 (m, 1H) ); ESIMS checked for C14H25BN2O5 m/z 295 (M-H2O)+.

[00217] 2-((3R,6S)-2-hydroxy-3-(2-((R)-piperidin-2-yl)-acetamido)-1,2-oxa-borinan-6-yl acid )-acetic 52 was isolated as the TFA salt. 1H NMR (CD3OD) δ ppm 1.27-1.37 (m, 1H), 1.49-1.80 (m, 7H), 1.86-2.00 (brdd, J=11 Hz, 3H) , 2.44-2.46 (d, J=6Hz, 2H), 2.61-2.65 (m, 1H), 2.72-2.73 (d, J=6Hz, 1H), 3.03-3.09 (t, J=13Hz, 1H), 3.41-3.45 (d, J=13Hz, 1H), 3.47-3.56 (m, 1H), 4 .15-4.21 (m, 1H); ESIMS verified for C13H23BN2O5 m/z 281 (M-H2O)+.

[00218] 2-((3R,6S)-2-hydroxy-3-(2-((S)-piperidin-2-yl)-acetamido)-1,2-oxa-borinan-6-yl acid )-acetic 53 was isolated as the TFA salt. 1H NMR (CD3OD) δ ppm 1.26-1.35 (m, 1H), 1.48-1.59 (m, 1H), 1.59-1.68 (m, 2H), 1.68- 1.81 (m, 3H), 1.87-2.00 (m, 3H), 2.45-2.47 (d, J=7Hz, 2H), 2.65-2.67 (t, J=4Hz, 1H), 2.74-2.76 (t, J=6Hz, 2H), 3.03-3.08 (dt, J=13Hz, J=3Hz, 1H), 3 .42-3.46 (brd, J=13 Hz, 1H), 3.47-3.55 (m, 1H), 4.12-4.19 (m, 1H); ESIMS verified for C13H23BN2O5 m/z 298.1 (M+H).

[00219] 2-((3R,6S)-2-hydroxy-3-(2-(2-phenyl-1H-imidazol-1-yl)-acetamido)-1,2-oxa-borinan-6-yl acid )-acetic 54 was isolated as the TFA salt. 1H NMR (CD3OD) δ ppm 1.36-1.44 (m, 1H), 1.44-1.54 (m, 1H), 1.66-1.80 (m, 2H), 2.15 ( s, 1H), 2.48-2.51 (m, J=6Hz, 1H), 2.72-2.75 (t, J=7Hz, 1H), 4.33-4.39 (m , 1H), 4.94-5.05 (m, 2H), 7.65-7.76 (m, 7H); ESIMS verified for C17H20BN3O5 m/z 358.2 (M+H).

2-((3R,6S)-2-hydroxy-3-(3-(2-methyl-1H-benzo[d]imidazol-1-yl)-propanamido)-1,2-oxa acid -borinan-6-yl)-acetic 55. 1H NMR (CD3OD) δ ppm 0.92-1.00 (m, 1H), 1.47-1.53 (m, 1H), 1.58-1, 62 (m, 2H), 2.31-2.33 (d, J=7Hz, 2H), 2.50-2.52 (t, J=4Hz, 1H), 2.97 (s, 3H ), 3.08-3.20 (m, 2H), 4.04-4.10 (m, 1H), 4.77-4.81 (t, J=6Hz, 2H), 7.617.68 ( m, 2H), 7.75-7.78 (d, J=7Hz, 1H), 7.93-7.95 (d, J=7Hz, 1H); ESIMS verified for C17H22BN3O5 m/z 342.2 (M-H2O)+.

[00221] 2-((3R,6S)-3-(4-((1H-Tetrazol-1-yl)-methyl)-benzamido)-2-hydroxy-1,2-oxa-borinan-6-yl acid )-acetic 56. 1H NMR (CD3OD) δ ppm 1.101.21 (m, 1H), 1.58-1.64 (m, 1H), 1.70-1.79 (m, 1H), 1.89 -1.96 (m, 1H), 2.31-2.36 (dd, J=15Hz, J=6Hz, 1H), 2.41-2.47 (m, 1H), 2.80- 2.83 (brd, J=4Hz, 1H), 4.11-4.17 (m, 1H), 5.83 (s, 2H), 7.53-7.55 (d, J=8Hz , 2H), 8.02-8.05 (d, J=8 Hz, 2H), 9.30 (s, 1H); ESIMS verified for C15H18BN5O5 m/z 342.0 (M-H2O)+.

2-((3R,6S)-2-hydroxy-3-(2-(pyridin-2-yl)-acetamido)-1,2-oxa-borinan-6-yl)-acetic acid 57 was isolated as the TFA salt. 1H NMR (CD3OD) δ ppm 1.21-1.32 (m, 1H), 1.59-1.67 (m, 2H), 1.67-1.75 (m, 2H), 2.29- 2.40 (m, 3H), 2.67-2.72 (m, 1H), 4.14-4.21 (m, 1H), 7.62-7.66 (t, J=6Hz, 1H), 7.70-7.73 (d, J=8Hz, 1H), 8.14-8.18 (t, J=8Hz, 1H), 8.65-8.67 (d, J =5Hz, 1H); ESIMS verified for C13H17BN2O5 m/z 275.1 (M-H2O)+.
[00223] The following compounds are prepared according to the procedure described in Example 1 above using methods C and E.

[00224] Acid 2-((3R,6S)-3-(1-Cyclo-propyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-1,4-dihydro- quinoline-3-carboxamido)-2-hydroxy-1,2-oxa-borinan-6-yl)-acetic 58 was isolated as the TFA salt. 1H NMR (CD3OD) δ ppm 1.14-1.29 (m, 3H), 1.39-1.44 (brd, J=7 Hz, 2H), 1.56-1.63 (dd, J= 14Hz, J=3Hz, 1H), 1.70-1.80 (m, 1H), 1.92-1.99 (d, J=14Hz, 1H), 2.33-2.38 ( dd, J=15 Hz, J=6 Hz, 1H), 2.43-2.48 (dd, J=15 Hz, J=7 Hz, 1H), 2.85-2.86 (d, J= 3Hz, 1H), 3.46-3.52 (m, 4H), 3.59-3.64 (m, 4H), 3.73-3.79 (m, 1H), 4.08-4 .15 (m, 1H), 7.66-7.67 (d, J=7Hz, 1H), 8.008.03 (d, J=13Hz, 1H), 8.81 (s, 1H); ESIMS verified for C23H28BFN4O6 m/z 469.2 (M-H2O)+.

2-[(3R,6S)-2-hydroxy-3-[(2S,3S,5R)-3-methyl-4,4,7-trioxo-3-(1H-1,2) acid ,3-triazol-1-yl methyl)-4A6-thia-1-azabicyclo[3.2.0]heptane-2-amido]-1,2-oxa-borinan-6-yl]-acetic 59.1H NMR (CD3OD) δ ppm 1.43 (s, 3H), 1.49-1.57 (m, 1H), 1.72-1.81 (m, 3H), 2.51-2.56 dd, J=15 Hz, J=6Hz, 1H), 2.62-2.67 (dd, J=15Hz, J=8Hz, 1H), 2.80-2.84 (m, 1H), 3.41- 3.44 (dd, J=17 Hz, J=2 Hz, 1H), 3.63-3.67 (dd, J=16 Hz, J=5 Hz, 1H), 4.37-4.44 ( m, 1H), 4.61 (s, 1H), 4.90-4.94 (dd, J=5Hz, J=2Hz, 1H), 5.16-5.19 (d, J=15 Hz, 1H), 5.25-5.28 (d, J=15 Hz, 1H), 7.77 (s, 1H), 8.07 (s, 1H); ESIMS verified for C16H22BN5O8S m/z 438 (M-H2O)+.

2-((3R,6S)-2-hydroxy-3-(3-(5-phenyl-1,3,4-oxadiazol-2-yl)-propanamido)-1,2-oxa-borinan acid -6-yl)-acetic 60. 1H NMR (CD3OD) δ ppm 1.10-1.21 (m, 1H), 1.50-1.58 (dd, J=14 Hz, J=3 Hz, 1H ), 1.59-1.68 (dt, J=11 Hz, J=5 Hz, 1H), 1.74-1.81 (brd, J=13 Hz, 1H), 2.22-2.26 (dd, J=15 Hz, J=6 Hz, 1H), 2.30-2.34 (dd, J=15 Hz, J=7 Hz, 1H), 2.63-2.64 (d, J =4 Hz, 1H), 3.01-3.12 (fri, J=7 Hz, 2H), 3.33-3.43 (fri, J=7 Hz, 2H), 4.03-4.09 (m, 1H), 7.54-7.62 (m, 3H), 8.03-8.05 (d, J=8 Hz, 2H); ESIMS verified for C17H20BN3O6 m/z 356.1 (M-H2O)+.

[00227] 2-((3R,6S)-3-(2-(2-amino-pyridin-4-yl)-acetamido)-2-hydroxy-1,2-oxa-borinan-6-yl)- acid 61 acetic was isolated as the TFA salt. 1H NMR (CD3OD) δ ppm 1.58-1.66 (m, 1H), 1.67-1.78 (m, 3H), 2.31 2.36 (dd, J=15 Hz, J=6 Hz, 1H), 2.39-2.44 (dd, J=15 Hz, J=7 Hz, 1H), 2.65-2.68 (t, J=4 Hz, 1H), 4.12- 4.19 (m, 1H), 6.85-6.87 (d, J =7Hz, 1H), 6.99 (s, 1H), 7.81-7.82 (d, J=7Hz , 1H); ESIMS verified for C13H18BN3O5 m/z 290.1 (M-H2O)+.

Following Method E, the reaction mixture was evaporated in vacuo, azeotroped with MeCN (3*5ml) and the residue triturated with ether (5ml). The precipitate was filtered, dissolved in dioxane-water mixture and freeze-dried to give 2-((3R)-3-((Z)-2-(2-amino-thiazol-4-yl)-2-(acid (1,5-dihydroxy-4-oxo-1,4-dihydropyridin-2-yl)-methoxyimino)-acetamido)-2-hydroxy-1,2-oxa-borinan-6- il)-acetic 62 as the TFA salt (25 mg) as a loose/fluffy solid. ESIMS verified for C17H20BN5O9S m/z 464.0 (M-H2O)+.
[00229] Synthesis of 2-((3R)-3-amino-2-hydroxy-1,2-oxa-borinan-6-yl)-acetic acid hydrochloride 7. An exemplary synthesis of 7 is shown in Scheme 10 and Example 2. Scheme 10
Example 2 Step 1
[00230] 6-(tert-butoxy)-4-[(tert-butyl-dimethyl-silyl)-oxy]-1-chloro-6-oxo-1-[(2S,6R)-2,9,9- trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02.6]decan-4-yl]-hexane XLI (515 mg, 0.97 mmol) in THF (5 mL) was cooled to -78°C under nitrogen. A solution of LiHMDS (1 mL, 1.0 M in THF, 1 mmol, 1.0 eq) was added slowly and the reaction flask was allowed to warm to room temperature where it was stirred for 16 h. The yellow solution was concentrated under reduced pressure to give an oil. Upon addition of hexane (10 ml) to the oil, a precipitate was formed. This was then filtered through Celite and the filtrate was concentrated under reduced pressure to give 1-[bis(trimethyl-silyl)amino]-6-(tert-butoxy)-4-[(tert-butyl-dimethyl-silyl) )-oxy]-6-oxo-1-[(2S,6R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02.6]decan-4-yl]-hexyl XLII. Step 2
The procedure is identical to that found in Example 1 Method D. Compound 7 was isolated as a white powder (120 mg, 0.573 mmol, 59.1% yield). 1H NMR (CD3OD) δ ppm 1.43-1.66 (m, 1H), 1.66-1.79 (m, 1H), 1.79-1.97 (m, 1H), 1.97- 2.30 (m, 1H), 2.40-2.71 (m, 3H), 4.34-4.54 (m, 1H); ESIMS verified for C6H12BNO4 m/z 174 (63%) (M+H).
Synthesis of 2-((3R)-2-hydroxy-3-(2-(thiophen-2-yl)-acetamido)-1,2-oxaborepan-7-yl)-acetic acid 63. An exemplary synthesis of 63 is shown in Scheme 11 and Example 3. Scheme 11
Example 3 Step 1
To a solution of tert-butyl 3-hydroxy-pent-4-enoate, XLVI (674 mg, 3.92 mmol) in DCM (15 mL) was added allyl diisopropyl boronate XLV (2 g, 11 .76 mmol) via syringe. First generation Grubb catalyst (260 mg, 0.31 mmol, 7.5 mol%) was then added to the mixture and the vessel was purged with argon. The reaction was heated at 65°C under nitrogen for 18h. The mixture was concentrated in vacuo and the residue was purified by flash column chromatography (100% hexane→30% EtOAc/hexane) to give 2-(2-hydroxy-3,6-dihydro-2H-1,2- tert-butyl oxaborinin-6-yl)-acetate XLVII (770 mg, 3.63 mmol, 92.7% yield). Step 2
In a solution of tert-butyl 2-(2-hydroxy-3,6-dihydro-2H-1,2-oxaborinin-6-yl)-acetate XLVII (670 mg, 3.16 mmol) in EtOAc (45 mL) was added 10% Pd/C (135 mg). The vessel was evacuated by applying a vacuum and subjected to a flow of hydrogen gas. The reaction was stirred under hydrogen for 2 h. The mixture was filtered through a pad of Celite which was washed with additional EtOAc (15 mL). Concentration of the filtrate gave pure 2-(2-hydroxy-1,2-oxa-borinan-6-yl)-tert-butyl acetate XLVIII (641 mg, 3.00 mmol, 94.8% yield). Step 3
[00235] Into a solution of 2-(2-hydroxy-1,2-oxa-borinan-6-yl)-tert-butyl acetate XLVIII (641 mg, 3.00 mmol) in THF (20 mL) was added (1S,2S,3R,5S)-2,6,6-trimethyl-bicyclo[3.1.1]heptane-2,3-diol (509 mg, 3 mol) at room temperature. The reaction mixture was stirred for 16 h and concentrated in vacuo. The residue was purified by column chromatography (100% hexane→40% EtOAc/hexane) over silica gel to give 3-hydroxy-6-[(1R,2R,6S,8R)-6,9.9-trimethyl-3 tert-butyl XLIX ,5-dioxa-4-boratricyclo[6.1.1.02.6]decan-4-yl]hexanoate (790 mg, 2.16 mmol, 71.9% yield). Step 4
[00236] To a solution of alcohol XLIX (790 mg, 2.16 mmol) in DMF (7.5 mL) was added imidazole (548 mg, 8.06 mmol) followed by TBDMSCl (580 mg, 3.87 mol) . The reaction mixture was stirred at room temperature for 16 h and concentrated in vacuo. The white slurry was dissolved in 100 mL of EtOAc and washed with saturated NaHCOa solution (20 mL), water (2 x10 mL) and dried (Na2SO4). The organic extract was concentrated in vacuo and the residue was purified by column chromatography (100% hexane→30% EtOAc/hexane) over silica gel to give 3-[(tert-butyl-dimethyl-silyl)-oxy]-6- [(1R,2R,6S,8R)-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02.6]decan-4-yl]-hexanoate tert-butyl L (1 g, 2.08 mmol, 96.3% yield). Step 5
[00237] To a solution of DCM (0.26 mL, 4.16 mmol) in THF (5 mL) at -100°C was added 2.5 M n-butyllithium in hexane (1 mL, 2.5 mmol) slowly under nitrogen and down the side wall of the flask while keeping the temperature below -90°C. The resulting white precipitate was stirred for 30 minutes before adding L (1 g, 2.08 mmol) in THF (3 mL) at -90°C. Zinc chloride (5ml, 0.5M in THF, 2.5mmol) was then added to the reaction mixture at -90°C and then the reaction was allowed to warm to room temperature at which it was stirred for 16 h. The reaction was quenched with a saturated ammonium chloride solution and the phases were separated. The aqueous phase was then extracted with diethyl ether (2 x 10 mL) and the combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The concentrated material was then chromatographed (100% hexane→20% EtOAc-hexane) to obtain (7S)-3-[(tert-butyl-dimethyl-silyl)-oxy]-7-chloro-7-[(1R LI,2R,6S,8R)-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02.6]decan-4-yl]heptanoate (740 mg, 1 .40 mmol, 67.2% yield). Step 6
[00238] Chlorinated intermediate LI (727 mg, 1.37 mmol) in THF (7 mL) was cooled to -78°C under nitrogen. A solution of 1M LiHMDS in THF (1.37 mL, 1.37 mmol) was added slowly at -78°C. Upon completion of the addition, the reaction flask was allowed to warm to room temperature. After stirring at room temperature for 16 h, the reaction mixture was concentrated in vacuo and hexane (20 mL) was added. Precipitated lithium salts were filtered through a pad of Celite, washed with additional hexane and the combined filtrates were concentrated in vacuo to give (7S)-7-[bis(trimethyl-silyl)amino]-3-[(tert- butyl-dimethyl-silyl)-oxy]-7-[(1R,2R,6S,8R)-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02.6]decan-4 crude tert-butyl -yl]-heptanoate LII. Step 7
[00239] To a stirred solution of 2-thiophene-acetic acid (232 mg, 1.64 mmol) in DCM (45 mL) at 0°C under nitrogen were added EDCI (391 mg, 2.05 mmol) and HOBT ( 221mg, 1.64mmol). After stirring at 0°C for 30 minutes, a solution of the bis-silyl-amide intermediate LII (1.37 mmol) in DCM (10 mL) followed by N-methyl-morpholine (0.3 mL, 2.74 mmol) ) were sequentially added at 0°C. Upon completion of the addition, the reaction flask was allowed to warm to room temperature. After stirring at room temperature overnight, the reaction mixture was washed with water, dried and concentrated in vacuo. The residue was purified by column chromatography (100% DCM → 50% EtOAc / DCM) to give (7S)-3-[(tert-butyl-dimethyl-silyl)-oxy]-7-[2-(thiophen-2 -yl)-acetamido]-7-[(1R,2R,6S,8R)-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02.6]decan-4-yl] - tert -butyl heptanoate LIII (340 mg, 0.54 mmol, 39.4% yield for 2 steps). Step 8
To a solution of amide LIII (300 mg, 0.47 mmol) in 1,4-dioxane (9 mL) was added 9 mL of 3N HCl. The reaction mixture was heated under reflux for 90 minutes. The cooled reaction mixture was then diluted with water (10ml) and extracted with diethyl ether (2x10ml). The aqueous layer was concentrated to give a sticky solid which was azeotroped with MeCN (3 x 10 mL). The residue was dissolved in 40% dioxane-water and lyophilized to give 2-((3R)-2-hydroxy-3-(2-(thiophen-2-yl)-acetamido)-1,2-oxaborepan-7- acid il)-acetic 63 as an off-white solid (100 mg, 32.1 mmol, 68.4% yield). 1H NMR (CD3OD) δ ppm 1.21-1.38 (m, 2H), 1.42-1.60 (m, 2H), 1.60-1.72 (m, 1H), 1.80- 1.94 (m, 1H), 2.32-2.47 (m, 2H), 2.54-2.58 (dd, J=15Hz, J=6Hz, 1H), 3.97-3 .98 (d, J=8Hz, 1H), 4.05 (s, 2H), 6.977.01 (m, 1H), 7.02-7.10 (m, 1H), 7.33-7, 37 (m, 1H); ESIMS verified for C13H18BNO5S m/z 294.0 (M-H2O)+.
[00241] Synthesis of 2-((3R)-2-hydroxy-3-(2-(thiophen-2-yl)-acetamido)-2,3,4,7-tetrahydro-1,2-oxaborepin acid -7-yl)-acetic 64. An exemplary synthesis of 64 is shown in Scheme 12 and Example 4. Scheme 12
Example 4 Step 1
[00242] In a stirred solution of tert-butyl 2-(2-hydroxy-3,6-dihydro-2H-1,2-oxaborinin-6-yl)-acetate XLVII (770 mg, 4.58 mmol) in THF (25 mL) was added (1S,2S,3R,5S)-2,6,6-trimethyl-bicyclo[3.1.1]-heptane-2,3-diol (980 mg, 4.58 mmol) at the temperature environment. The reaction mixture was stirred for 16 h and concentrated in vacuo. The residue was purified by column chromatography (100% hexane→30% EtOAc/hexane) over silica gel to give (4Z)-3-hydroxy-6-[(1R,2R,6S,8R)-6.9.9 tert-butyl LIV -trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02.6]decan-4-yl]-hex-4-enoate (1 g, 2.75 mmol, 59.9% of Yield). Step 2
[00243] To a solution of alcohol LIV (650 mg, 1.78 mmol) in DMF (10 mL) was added imidazole (484 mg, 7.12 mmol) followed by TBDMSCl (534 mg, 3.56 mol). The reaction mixture was stirred at room temperature for 16 h and concentrated in vacuo. The white slurry was dissolved in 100 mL of EtOAc and washed with water (2 x10 mL), brine and dried (Na2SO4). The organic extract was concentrated in vacuo and the residue was purified by column chromatography (100% hexane→20% EtOAc/hexane) over silica gel to give (4Z)-3-[(tert-butyl-dimethyl-silyl)-oxy ]-6-[(1R,2R,6S,8R)-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02.6]decan-4-yl]-hex-4- tert-butyl enoate LV (800 mg, 1.67 mmol, 93.9% yield). Step 3
[00244] To a solution of DCM (0.3 mL, 4.68 mmol) in THF (8 mL) at -100°C was added 2.5 M n-butyllithium in hexane (1.12 mL, 2 .8 mmol) slowly under nitrogen and down the side wall of the flask while keeping the temperature below -90°C. The resulting white precipitate was stirred for 30 minutes before the addition of LV (1.12 g, 2.34 mmol) in THF (3 mL) at -90°C and the reaction was allowed to warm to room temperature at which it was stirred for 16 h. The reaction was quenched with a saturated ammonium chloride solution and the phases were separated. The aqueous phase was then extracted with diethyl ether (2 x 10 mL) and the combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The concentrated material was then chromatographed (100% hexane→20% EtOAc/hexane) to obtain (4Z,7S)-3-[(tert-butyl-dimethyl-silyl)-oxy]-7-chloro-7-[ (1R,2R,6S,8R)-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02.6]decan-4-yl]-hept-4-enoate tert-butyl LVI (820 mg, 1.56 mmol, 66.5% yield). Step 4
Chlorinated intermediate LVI (790 mg, 1.49 mmol) in THF (10 mL) was cooled to -78°C under nitrogen. A solution of 1M LiHMDS in THF (1.5 mL, 1.5 mmol) was added slowly at -78°C. Upon completion of the addition, the reaction flask was allowed to warm to room temperature. After stirring at room temperature for 16 h, the reaction mixture was concentrated in vacuo and hexane (20 mL) was added. Precipitated lithium salts were filtered through a pad of Celite, washed with additional hexane and the combined filtrates were concentrated in vacuo to give (4Z,7S)-7-bis(trimethylsilyl)amino]-3-[(tert. -butyl-dimethyl-silyl)-oxy]-1-[(1R,2R,6S,8R)-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02.6] crude tert-butyl decan-4-yl]-hept-4-enoate LVII. Step 5
[00246] To a stirred solution of 2-thiophene-acetic acid (252 mg, 1.78 mmol) in DCM (35 mL) at 0°C under nitrogen were added EDCI (426 mg, 2.23 mmol) and HOBT ( 240mg, 1.78mmol). After stirring at 0°C for 30 minutes, a solution of crude bis-silyl-amide intermediate LVII in DCM (10 mL) followed by N-methyl-morpholine (0.32 mL, 3 mmol) were sequentially added at 0° Ç. Upon completion of the addition, the reaction flask was allowed to warm to room temperature. After stirring at room temperature overnight, the reaction mixture was washed with water, dried and concentrated in vacuo. The residue was purified by column chromatography (100% DCM→25% EtOAc / DCM) to give (4Z,7S)-3-[(tert-butyl-dimethyl-silyl)-oxy]-7-[2-(thiophene) -2-yl)-acetamido]-7-[(1R,2R,6S,8R)-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02.6]decan- tert-butyl 4-yl]-hept-4-enoate LVIII (600 mg, 0.95 mmol, 63.7% yield for 2 steps). Step 6
A solution of amide LVIII (100mg, 0.15mmol) in anisole (5ml) at 0°C was treated with pre-cooled 90% aqueous trifluoroacetic acid (10ml). The reaction mixture was warmed to room temperature and stirred for 16 h. The mixture was evaporated in vacuo, azeotroped with MeCN (3*5ml). The residue was sonicated in water (10ml) and ether (10ml). The aqueous phase was separated, washed with ether (2 X 5 mL) and freeze-dried to give 2-((3R)-2-hydroxy-3-(2-(thiophen-2-yl)-acetamido)-2 acid Fluffy solid ,3,4,7-tetrahydro-1,2-oxaborepin-7-yl)-acetic 64 (15 mg, 0.05 mmol, 32.3% yield). 1H NMR (CD3OD) δppm 2.23-2.35 (m, 2H), 2.40-2.61 (m, 2H), 2.76-2.83 (m, 1H), 3.96- 4.03 (m, 1H), 4.10 (s, 2H), 5.34-5.40 (m, 1H), 5.53-5.74 (m, 1H), 6.97-7, 08 (m, 2H), 7.32-7.39 (m, 1H); ESIMS verified for C13H16BNO5S m/z 292 (M-H2O)+.
[00248] Synthesis of 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)-acetamido)-1,2-oxa-borinan-6-yl)-acetate of ethyl 65. An exemplary synthesis of 65 is shown in Scheme 13 and Example 5. Scheme 13
Example 5 Step 1
[00249] To a solution of 5 (400 mg, 1.35 mmol) in 4 mL of absolute ethanol was added 1M anhydrous HCl in EtOAc (4 mL, 4 mmol). The reaction was stirred at room temperature for 16 h. The mixture was then concentrated and azeotroped with acetonitrile (3X10 mL) to give a sticky solid. Ether (10 mL) was added to the azeotrope-transformed sticky solid and the resulting precipitated product filtered. The filtered solid was washed with additional ether (5 mL) and dried to give 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)-acetamido)-1,2-oxa -borinan-6-yl)-ethyl acetate 65 (300 mg, 0.92 mmol, 68.5% yield). 1H NMR (CD3OD) δ ppm 0.98-1.09 (q, J=14 Hz, 1H), 1.23-1.26 (t, J=7 Hz, 3H), 1.49-1.54 (dd, J=14 Hz, J=3 Hz, 1H), 1.57-1.64 (dt, J=11 Hz, J=2 Hz, 1H), 1.72-1.78 (brd, J =14Hz, 1H), 2.24-2.28 (dd, J=15Hz, J=6Hz, 1H), 2.34-2.39 (dd, J=15Hz, J=8Hz, 1H), 2.63 (brs, 1H), 3.99 (s, 2H), 4.07-4.13 (q, J=4Hz, 3H), 6.99-7.01 (t, J =4Hz, 1H), 7.05-7.06 (d, J=3Hz, 1H), 7.35-7.36 (dd, J=5Hz, J=1.3Hz, 1H); ESIMS verified for C14H20BNO5S m/z 308.1 (M-H2O)+.
Synthesis of 2-((3R,7R)-2-hydroxy-3-(2-(thiophen-2-yl)-acetamido)-2,3,4,7-tetrahydro-1 acid ,2-oxaborepin-7-yl)-acetic 67. An exemplary synthesis of 67 is shown in Scheme 14 and Example 6. Scheme 14
Example 6 Step 1
[00251] Prepared starting from enantiomerically pure (R)-3-hydroxy-pent-4-enoate [J. Am. Chem. Soc. (2007), 129, 4175-4177] according to the procedure described in Step 1 of Example 3 above. Steps 2-7
[00252] Prepared according to the procedure described in Steps 1-6 of Example 4 above.
[00253] Fluffy white solid (23 mg, 0.074 mmol, 47% yield). 1H NMR (CD3OD) δ ppm 2.29-2.31 (m, 1H), 2.40-2.68 (m, 4H), 4.10 (m, 2H), 4.74-4.82 ( m, 1H), 5.35-5.38 (m, 1H), 5.53-5.58 (m, 1H), 6.98-7.05 (m, 2H), 7.32-7, 36 (m, 1H); ESIMS verified for C13H16BNO5S m/z 292 (M-H2O)+.
Synthesis of 2-((3R,7S)-2-hydroxy-3-(2-(thiophen-2-yl)-acetamido)-2,3,4,7-tetrahydro-1,2 acid -oxaborepin-7-yl)-acetic 68. An exemplary synthesis of 68 is shown in Scheme 15 and Example 7. Scheme 15
Example 7 Step 1
Prepared starting from enantiomerically pure (S)-tert-butyl 3-hydroxy-pent-4-enoate [J. Med. Chem., (2010), 53, 4654 4667] according to the procedure described in Step 1 of Example 3 above. Steps 2-7
[00256] Prepared according to the procedures described in Steps 1-6 of Example 4 above.
[00257] Fluffy white solid (45 mg, 0.146 mmol, 39% yield). 1H NMR (CD3OD) δ ppm 2.15-2.18 (m, 1H), 2.29-2.38 (m, 2H), 2.66-2.72 (m, 2H), 3.88- 3.91 (m, 1H) 4.00 (s, 2H), 5.24-5.27 (m, 1H), 5.57-5.63 (m, 1H), 6.87-6.96 (m, 2H), 7.24-7.28 (m, 1H); ESIMS verified for C13H16BNO5S m/z 292 (M-H2O)+.
Synthesis of 2-((3R,6S)-3-(Benzyl-oxy-carbonyl-amino)-2-hydroxy-1,2-oxa-borinan-6-yl)-acetic acid 69. An exemplary synthesis of 69 is shown in Scheme 16 and Example 8. Scheme 16
Example 8 Step 1
[00259] A solution of bis-silyl-amide XLI (0.2 mmol) in DCM (5 mL) was cooled to 0°C and benzyl chloroformate (0.056 mL, 0.4 mmol) was added. Then, the cooling bath was removed and the solution was stirred at room temperature for 16 h. The reaction was quenched with water and extracted twice with EtOAc. The organic layers were combined, washed with water, brine, dried (Na2SO4) and concentrated in vacuo to give a pale yellow oil as crude product. The residue was chromatographed on a silica column (100% DCM→40% EtOAc/DCM) to give carbamate LXIII (90 mg, 0.143 mmol, 71.5% yield). Step 2
A solution of LXIII carbamate (70 mg, 0.11 mmol) in anisole (5 mL) at 0°C was treated with pre-cooled 90% aqueous trifluoroacetic acid (10 mL). The reaction mixture was warmed to room temperature and stirred for 16 h. The mixture was evaporated in vacuo, azeotroped with MeCN (3*5ml). The residue was sonicated in water (10ml) and ether (10ml). The aqueous phase was separated, washed with ether (2 x 5 mL) and freeze-dried to give 2-((3R,6S,)-3-(benzyl-oxy-carbonyl-amino)-2-hydroxy-1, acid. 2-oxa-borinan-6-yl)-acetic 69 as a fluffy solid (10 mg, 0.033 mmol, 29.6% yield). ESIMS verified for C14H18BNO6S m/z 289.9 (M-H2O)+.
[00261] The following compound is prepared according to the procedure described in Example 8 above.

[00262] 2-((3R,6S)-2-hydroxy-3-(isobutoxy-carbonyl-amino)-1,2-oxa-borinan-6-yl)-acetic acid 70 as an off white solid (20 mg, 0.073 mmol, 27% yield). 1H NMR (CD3OD) δ ppm 0.95 (d, J=7Hz, 6H), 1.62-1.67 (m, 1H), 1.70-1.75 (m, 2H), 1.87 -1.90 (m, 2H), 2.422.60 (m, 3H), 3.77-3.86 (m, 2H), 4.35-4.38 (m, 1H); ESIMS checked for C11H20BNO6S m/z 256 (M-H2O)+.
Synthesis of 2-((3R,6S)-2-hydroxy-3-(phenylsulfonamido)-1,2-oxa-borinan-6-yl)-acetic acid 71. An exemplary synthesis of 71 is shown in Scheme 17 and Example 9. Scheme 17
Example 9 Steps 1-2
[00264] Prepared according to the procedure described in Steps 1-2 of Example 8 above.
Off-white solid (30 mg, 0.096 mmol, 43% yield). 1H NMR (CD3OD) δ ppm 1.57-1.83 (m series, 4H), 2.49-2.71 (m series, 3H), 4.35-4.89 (m, 1H) , 7.51-7.59 (m, 3H), 7.85-7.89 (m, 2H); ESIMS verified for C12H16BNO6S m/z 296.1 (M-H2O)+.
[00266] Synthesis of 2-((3R,6S)-2-hydroxy-3-(3-phenylureido)-1,2-oxa-borinan-6-yl)-acetic acid 72. An exemplary synthesis of 72 is shown in Scheme 18 and Example 10. Scheme 18
Example 10 Step 1
[00267] To a solution of bis-silyl-amide XLI (0.2 mmol) in DCM (5 mL) at 0°C was added a solution of TFA in hexane (0.6 mmol). The reaction was stirred at 0°C for 20 min before addition of phenyl-isocyanate (0.04 mL, 0.4 mmol) followed by N,N-diisopropyl-ethyl-amine (0.18 mL, 1 mmol). The cooling bath was then removed and the solution stirred at room temperature for 16 h. The reaction was quenched with water and extracted twice with EtOAc. The organic layers were combined, washed with water, brine, dried (Na2SO4) and concentrated in vacuo to give a pale yellow oil as crude product. The residue was chromatographed on a silica column (100% DCM→25% EtOAc / DCM) to give the pure urea (50 mg, 0.081 mmol, 40.7% yield). Step 2
[00268] Deprotection was carried out following the procedure described above in Step 2 of Example 8 to give 2-((3R,6S)-2-hydroxy-3-(3-phenylureido)-1,2-oxa-borinan-6 acid -yl)-acetic 72 as a white solid (20 mg, 0.068 mmol, 86% yield). 1H NMR (CD3OD) δ ppm 1.24-1.31 (m, 1H), 1.56-1.64 (m, 2H) 1.78-1.81 (m, 1H), 2.36-2 .40 (dd, J=15 Hz, J=6 Hz, 1H), 2.46-2.58 (dd, J=13 Hz, J=7 Hz, 1H), 2.68-2.71 (m , 1H), 4.07-4.12 (m, 1H), 7.15-7.18 (m, 1H), 7.34-7.37 (m, 4H); ESIMS verified for C13H17BN2O5 m/z 275.1 (M-H2O)+.
[00269] Illustrative compounds of formula (I) are shown in Table 1. Some structures are shown with defined configurations at selected stereocenters but the stereochemistry shown is not meant to be limiting and all possible stereoisomers of the structures shown are to be considered here. Compounds of any absolute and relative configurations at the stereocenters as well as mixtures of enantiomers and diastereoisomers of any given structure are also included herein. TABLE 1










Example 11
[00270] The potency and spectrum of β-lactamase inhibitors were determined by evaluating their antibiotic potentiating activity.
[00271] The potentiating effect is observed by reducing the minimal inhibitory concentration of β-lactam antibiotics in the presence of β-lactamase inhibitors (β-lactamase inhibitors, BLIs). The activity of BLIs in combination with ceftazidime or biapenem is assessed by the checkerboard assay (“Antimicrobial Combinations.” In “Antibiotics in Laboratory Medicine”, Ed. Victor Lorian, MD, fourth edition, 1996, pp 333-338 ) using the broth microdilution method performed as recommended by the NCCLS ("National Committee for Clinical Laboratory Standards" (NCCLS). 1997. "Methods for Dilution of Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically" - Fourth Edition; "Approved Standard" "NCCLS Document M7-A4", Vol 17 No. 2). In this assay, multiple dilutions of two drugs, namely BLI and β-lactam (ceftazidime or biapenem), are tested, alone and in combination, in concentrations equal to, above or below their respective minimal inhibitory concentrations (minimal inhibitory concentrations. MICs). BLIs are solubilized in 10% DMSO at 10 mg/ml. Stock solutions are then diluted, as needed for the specific assay, into Mueler Hinton Broth (Mueller Hinton Broth, MHB). Stock solutions can be stored at -80°C.
[00272] The checkerboard assay (checkerboard, CB) is performed in microtiter plates. Ceftazidime or biapenem are diluted on the x-axis, each column containing a single concentration of antibiotic. BLIs are diluted on the y-axis, each row containing an equal concentration of BLI. The result of these manipulations is that each well of the microtiter plate contains a unique combination of concentrations of the two agents. The assay is performed in MHB with a final bacterial inoculum of 5 x 105CFU/ml (from the initial log phase of the culture). Microtiter plates are incubated for 20 h at 35°C and are read using a microtiter plate reader (Molecular Devices) at 650 nm as well as visual observation using a microtiter plate reading mirror. MIC is defined as the lowest concentration of antibiotics within the combination at which visible organism growth is completely inhibited. Activity of BLIs is reported at MPC8 or the minimal potentiating concentration to reduce 8-fold antibiotic MIC.
[00273] The potentiation of ceftazidime is studied in strains of various bacteria that are resistant to ceftazidime due to the expression of β-lactamase hydrolyzing enzymes. The strain panel used in checker plate experiments contains β-lactamases that belong to all known classes of these enzymes: A, B, C and D. Activity of Compound 1 is tested at a maximum concentration of 40 μg/mL. At this concentration no growth inhibition of any bacteria tested is shown, however at a concentration as low as 0.6 μg/mL it reduces 8-fold MICs for ceftazidime in some bacteria (Table 2). Based on the results in CB, 1 has broad-spectrum β-lactam potentiating activity against strains expressing β-lactamases. Compound 1 was the most potent against strains expressing KPCs and other class A enzymes (CTX-M-3) and some class C (MIR-1, CMY-2) and class D (OXA-2) enzymes. TABLE 2



[00274] Next, ceftazidime potentiating activity of various cyclic boronic acid ester derivatives was tested using a larger panel of strains expressing β-lactamase hydrolyzing enzymes. MICs of ceftazidime were determined alone and in the presence of fixed concentrations of various cyclic boronic acid ester derivatives. Most compounds were tested at 10 μg/ml. Cyclic boronic acid ester derivatives were able to reduce ceftazidime MICs 4 by >64-fold depending on the β-lactamase (Table 3). TABLE 3




[00275] Biapenem is a β-lactam carbapenem; only selected β-lactamases confer resistance to this class of antibiotics. Among them are serine carbapenemases that belong to class A and class D. The potentiation of biapenem is studied in strains expressing several carbapenemases from these classes using assays in CB. Several cyclic boronic acid ester derivatives showed significant potentiation of biapenem against strains expressing class A carbapenemases: MPC8 (minimum potentiating concentration (μg/mL) to reduce 8-fold MIC of Biapenem) ranging from 0.02 μg/mL at 0.16 µg/ml (Table 4). Cyclic boronic acid ester derivatives were able to reduce biapenem MICs up to 1000-fold (Table 4). TABLE 4



Example 12
[00276] The ability of β-lactamase inhibitors to inhibit the hydrolysis of ceftazidime and biapenem has been studied. Lysates were prepared from bacteria expressing various β-lactamases as an enzyme source. Bacterial lysates were prepared as follows. A single colony from the new overnight plate was transferred to 5 mL of LB broth and grown to OD600 = 0.6-0.8. Next, this culture was transferred to 500 ml of LB and grown to OD600 = 0.7-0.9. Cells were pelleted by centrifugation at 5,000 RPM (JA-14 rotor) for 15 minutes at room temperature. The pellet was resuspended in 10 ml PBS. Five freeze-thaw-freeze cycles were then performed by exposing the cells to -20°C and thawing them to room temperature. After the last thawing step, the cells were centrifuged at 18K for 30 minutes and the supernatant was collected. This lysate was stored at -20°C.
[00277] Next, the activity of bacterial lysates was optimized for cleavage of ceftazidime and biapenem as follows. 50 µl of buffer A (50 mM Sodium Phosphate pH=7; 0.5% glucose, 1 mM MgCl 2 ) was added to each well of the 96-well UV-clear plate. 50 μL of lysate was vertically titrated in a 96-well plate column to generate double lysate dilutions. 100 μL of buffer A was added to each well, left in a plate reader at 37°C and incubated for 15 minutes. 50 μL of 50 μg/mL solutions of ceftazidime or biapenem in buffer A (pre-incubated at 37°C for 15 minutes) were added to each well. Hydrolysis of ceftazidime and biapenem was measured at 250 nm and 296 nm, respectively. This experiment was used to determine the optimal lysate dilution that produced a linear curve relative to the UV signal that decreased to approximately OD=0.3-0.5 over 1 hour.
[00278] Finally, the potency of cyclic boronic acid ester derivative to inhibit the cleavage of ceftazidime and biapenem by bacterial lysates was determined. 100 µl of buffer A (50 mM Sodium Phosphate pH=7; 0.5% glucose, 1 mM MgCl 2 ) was added to each well of the 96-well UV-clear plate. 50 μL of 6 x cyclic boronic acid ester derivative solution in buffer A were titrated vertically in 96-well plate column to generate triple dilutions. 50 μL of lysate diluted in buffer A (optimal dilution is determined in the above experiment) was added and the plate was incubated in the plate reader at 37°C for 15 minutes. 50 μL of 50 μg/mL solutions of ceftazidime or biapenem in buffer A (pre-incubated at 37°C for 15 minutes) were then added to each well and hydrolysis of ceftazidime or biapenem was recorded at 250 nm and 296 nm, respectively. Inhibition EC50 was determined by plotting the cleavage rate of ceftazidime or biapenem versus the concentration of cyclic boronic acid ester derivative.
[00279] The results of these experiments are presented in Table 5 and Table 6. These experiments demonstrate that the compounds described are inhibitors with a broad spectrum activity against various β-lactamases. TABLE 5


TABLE 6


[00280] The potency and spectrum of β-lactamase inhibitors are also determined by evaluating their potentiating activity of aztreonam in a dose titration potentiation assay using strains of various bacteria that are resistant to aztreonam due to the expression of various β -lactamases. Aztreonam is a monobactam antibiotic and, similar to ceftazidime, is hydrolyzed by most beta-lactamases that belong to class A, C or D (but not class B). The potentiating effect is observed as the ability of BLI compounds to inhibit growth in the presence of sub-inhibitory concentration of aztreonam. MIC of test strains ranges from 32 μg/mL to > 128 μg/mL. Aztreonam is present in the test medium at 4 µg/ml. Compounds were tested at the highest concentration of 40 μg/mL. In this assay the potency of compounds is determined as a concentration of BLIs to inhibit bacterial growth in the presence of 4 µg/ml aztreonam (MPC<4). Tables 7, 8 and 9 summarize the potency of aztreonam potentiating activity BLI (MPC@4) for various strains overexpressing class A (ESBLs), class A (KPCs) and class C and class D beta-lactamases, respectively. Aztreonam MIC for each strain is also shown. Table 7 summarizes the activity of BLIs to potentiate aztreonam against strains expressing class A ESBLs. Table 8 summarizes the activity of BLIs to potentiate aztreonam against strains expressing class A KPCs. Table 9 summarizes the activity of BLIs to potentiate aztreonam against strains expressing class C and D enzymes. TABLE 7


TABLE 8

TABLE 9


[00281] The potency and spectrum of β-lactamase inhibitors are also determined by evaluating their biapenem potentiating activity in a dose-titration potentiation assay using strains expressing serine-carbapenemases (such as KPC). The potentiating effect is observed as the ability of BLI compounds to inhibit growth in the presence of sub-inhibitory concentration of biapenem. MIC of test strains ranges from 4 μg/mL to > 1 μg/mL. Biapenem is present in the test medium at 1 μg/ml. Compounds were tested at the highest concentration of 40 μg/mL. In this assay the potency of compounds is determined as a concentration of BLIs to inhibit bacterial growth in the presence of 1 µg/ml biapenem (MPC@1). Table 10 summarizes the potency of BLI of biapenem enhancing capacity (MPC@1). Biapenem MIC for each strain is also shown. TABLE 10


[00282] Some bacterial lysates have also been optimized for cleavage of aztreonam and nitrocefin. Inhibition EC50 was determined by plotting the cleavage rate of aztreonam or nitrocefin versus BLI concentration. The results of these experiments are shown in Table 11. These experiments confirmed that the compounds described are inhibitors with a broad spectrum activity against various β-lactamases. TABLE 11

Example 13
[00283] Selected β-lactamase inhibitors have also been tested for their ability to potentiate the monobactam tigemonam. The potentiating effect is observed as the ability of BLI compounds to inhibit growth in the presence of sub-inhibitory concentration of tigemonam. MIC of test strains ranges from 8 μg/mL to > 128 μg/mL. Tigemonam is present in the test medium at 4 µg/ml. Compounds were tested at the highest concentration of 40 μg/mL. In this assay the potency of compounds is determined as the concentration of BLIs to inhibit bacterial growth in the presence of 4 µg/ml aztreonam (MPC<4). Tables 12 and 13 summarize the potency of tigemonam potentiating BLI (MPC@4) for various strains overexpressing class A beta-lactamases (ESBLs), class C, and class D beta, respectively. Tigemonam MIC for each strain is also shown. Table 12 summarizes the activities of BLIs to potentiate tigemonam against strains expressing class A ESBLs. Table 13 summarizes the activity of BLIs to potentiate aztreonam against strains expressing class C and D enzymes. TABLE 12
TABLE 13
Example 14
Checkerboard assays were used to assess the ability of Compound 5 to potentiate various carbapenems (biapenem, doripenem, ertapenem, imipenem and meropenem) against strains expressing only KPC or in combination with other additional beta-lactamases. The highest concentration of Compound 5 was 10 mg/L. The results are shown in Table 14. Compound 5 was able to significantly potentiate multiple carbapenems. TABLE 14












Example 15
[00285] An in vivo model can be used to evaluate the single-dose pharmacokinetic properties and absolute oral bioavailability of a test compound. As described more specifically below, a test compound is administered to Sprague-Dawley (SD) rats either intravenously or orally in a crossover study design and the resulting pharmacokinetic properties and oral bioavailability are measured.
For intravenous administration, male rats received for 30 minutes an intravenous infusion dose of 20 or 50 mg/kg of Compound 5 via femoral vein cannula. Plasma samples (0.3 mL) were collected from the jugular vein cannula at 0.17, 0.33, 0.47, 0.58, 0.68, 0.75, 1, 2, 3, 4 and 6 h after dosing. For oral administration, male rats received 50 mg/kg of Compound 5 (in saline) or Compound 62 (in 100% ethanol) orally using an oral gavage probe tip. Plasma samples were collected from each rat at 0.08, 0.17, 0.25, 0.33, 0.50, 0.75, 1, 2, 3, 4 and 6 h after dosing.
[00287] Plasma concentrations of compounds were tested using the LC/MS/MS method with a lower limit of 10 ng/mL for Compound 5 and 100 ng/mL for Compound 62. Extraction: 50 μL volumes of sample plasma and standards were extracted using 200 µl methanol with 100 mM ammonium acetate, 2 µg/ml gatifloxacin (internal standard for Compound 62) and 2 µg/ml Compound 38 (internal standard for Compound 5). Samples were mixed and centrifuged for 30min at 3000 x g. 150 μL of supernatant was removed and added to 450 μL of water.
[00288] HPLC - mass spectrometry: an Agilent 1100HPLC pump, an HTC PAL autosampler and a Sciex 3200Q mass spectrometer were used for separation and quantification. Compound 62 and its internal pattern were detected using +ESI. Compound 5 and its internal pattern were detected using -ESI. LC/MS/MS: 1) Column: Chromolith FastGradient RP-18e, 50mmx 2mm; 2) Mobile phase A: Aqueous, Water with 0.1% TFA, Organic phase B: Acetonitrile with 0.1% TFA; Flow rate: 600 µL/min; Injection Volume: 10μL; HPLC gradient: 5% B 0% B, 0.01 ^ 1.5 min; 60% B, 1.5 x 1.6 min; 60% B 5% B, 1.6 ^ 1.7 min; 5% B, 1.7 2.7 min.
[00289] Plasma concentrations were modeled using WinNonlin® (Pharsight Corp, Mountain View, CA).
In this experiment, three male Sprague Dawley rats received Compound 5 by the intravenous or oral route. At designated time points, bloods were collected and analyzed. As shown in Table 15 and Figure 1 above, Compound 5 has a PK (pharmacokinetics) in rats. However, Compound 5 is not absorbed orally. TABLE 15

[00291] In this experiment, three male Sprague Dawley rats received Compound 5 intravenously or Compound 62 orally (prodrug for Compound 5). Plasma samples were collected at designated time points and analyzed for the presence of Compound 5. This study was designed to determine the oral bioavailability of Compound 62 a prodrug of Compound 5. Male rats (not fasting) were orally administered with 50 mg/kg of Compound 62 prodrug. As shown in Figure 2, Compound 5 prodrug has oral bioavailability of greater than 80%.
[00292] Polymorphs can be detected, identified and characterized using well known techniques such as, but not limited to, differential scanning calorimetry (DSC), thermogravimetry (TGA) and powder X-ray diffraction (powder). X-ray diffractometry, PXRD). Example 16
[00293] The crystal structure of Compound 5 was analyzed using X-ray powder diffraction (“PXRD”). X-ray diffraction data were collected at room temperature using a PANalytical X'Pert Pro diffractometer (Cu Kα calibration) equipped with an automatic sample modifier, a theta-theta goniometer, automatic beam divergence slits, a monochromator secondary and a flicker counter. Samples were prepared for analysis by packing the powder into a 12 mm diameter, 0.25 mm deep cavity that had been cut into a zero background Si wafer specimen assembly. The sample was spun while irradiated with copper K-alpha 1 X-rays (wavelength = 1.5406 Angstrom) with an X-ray tube operated at 45kV/40mA. Analyzes were performed with the goniometer operating in continuous setting for a count of 5 seconds per 0.02° step over a two-theta range from 2° to 55°. The illustrative PXRD pattern for Compound 5 is shown in Figure 3.
[00294] It will be recognized by the experienced crystallography technician that the relative intensities of the various peaks reported in Figure 3 may vary due to numerous factors such as crystal orientation effects in the X-ray beam or the purity of the material being analyzed or the degree of crystallinity of the sample. Peak positions may also shift due to variations in sample height but also peak positions will remain substantially as defined in Figure 3. The experienced crystallography technician will also recognize that measurements using a different wavelength will result in different shifts according to the Bragg equation - nA = 2d sin θ. Such other PXRD patterns generated by the use of alternative wavelengths are considered to be alternative representations of the PXRD patterns of the crystalline materials of the present invention and as such are within the scope of the present invention.
[00295] Table 16 lists the peak positions and relative intensities for the PXRD pattern of Figure 3. Consequently, some modalities include a crystalline form of Compound 5 having three or more, four or more, five or more, six or more , seven or more, eight or more, nine or more, or ten or more characteristic PXRD peaks (wavelength = 1.5406 Â) selected from 9.0°, 15.7°, 17.3°, 17.6 °, 18.1°, 21.3°, 22.4°, 23.5°, 24.9°, 27.2°, 27.4°, 28.1°, 29.1°, 31.2 ° and 35.7° 2θ. Some embodiments include a crystalline form of Compound 5 having three or more, four or more, five or more, or six or more characteristic PXRD peaks (wavelength = 1.5406 Â) selected from 9.0°, 17.3° , 17.6°, 18.1°, 22.4° and 27.2° 2θ. Some embodiments include a crystalline form of Compound 5 having peaks characteristic of PXRD (wavelength = 1.5406 Â) at 9.1°, 17.3°, 17.6° and 18.1° 2θ. TABLE 16


[00296] As is well understood in the art, because of experimental variability when X-ray diffraction patterns are measured on different instruments, the peak positions are assumed to be equal if the values of two theta (2θ) are within 0, 2° (ie ± 0.2°). For example, the "United States Pharmacopeia" states that if the angular fit of the 10 strongest diffraction peaks are within ±0.2° with that of a reference material and the relative peak intensities do not vary by more than 20 %, the identity is confirmed. Consequently, peak positions within 0.2° of the positions cited herein are assumed to be identical. Example 17
[00297] DSC measures thermal transition temperatures at which a crystal form absorbs or releases heat when its crystal structure changes or melts. TGA is used to measure the thermal stability and fraction of volatile components of a sample by monitoring the change in weight as the sample is heated. If infrared spectroscopy is conducted on the volatile components released as gases during TGA analysis of a pseudo-polymorph (TGA-IR), then the molecular composition of the pseudo-polymorph can be determined. These techniques are therefore useful for characterizing existing solid state forms as solvates and/or hydrate.
[00298] Compound 5 was analyzed using differential scanning calorimetry (DSC). A TA Instruments Q100 differential scanning colorimeter equipped with an autosampler and a refrigerated cooling system under a 40 mL/min N2 purge was used to perform the analysis. Each sample was heated from 25°C to 300°C at 15°C per minute in an aluminum crucible with a lid positioned over the top, with a nitrogen purge gas. Data from DSC analyzes is dependent on several factors, including heating rate, sample purity, crystal size, and sample size. The DSC thermogram obtained for the Compound 5 sample is shown in Figure 4 overlaid with the TGA thermogram. These data reveal a single endothermic transition at 155°C.
[00299] Thermogravimetric-infrared analysis (Thermogravimetric-infrared, TG-IR) was performed on a TA Instruments Q5000 thermogravimetric analyzer interfaced with a Nicolet 6700 FT-IR (Thermo Electron) infrared spectrophotometer. External TGA-IR with a gas flow cell and a DTGS detector. FT-IR wavelength verification was performed using polystyrene and TG calibration standards were nickel and Alumel™. The sample was placed inside a platinum or aluminum crucible and the crucible was inserted into the TG oven. The TG instrument was started first, immediately followed by the FT-IR instrument. The TG instrument was operated under helium flow at 90 and 10 cm3/min for purge and equilibrium, respectively. The oven was heated under nitrogen at a speed of 15°C/minute to a final temperature of 230°C. IR spectra were collected approximately every 32 seconds for approximately 13 minutes. Each IR spectrum used 32 co-added scans collected at a spectral resolution of 4 cm-1. The TGA thermogram obtained for the Compound 5 sample is shown in Figure 4 overlaid with the DSC thermogram. This TGA data with IR analysis of the released gas indicates that the starting material is not solvated but loses a water equivalent between 135°C and 181°C.
[00300] All references cited herein, including but not limited to references to published and unpublished applications, published and unpublished patents, and literature, are hereby incorporated in their entirety and form a part of this Descriptive Report. To the extent publications and patents or patent applications incorporated as references contradict the disclosure contained in the Descriptive Report, the Descriptive Report is intended to replace and/or take precedence over any such contradictory material.
[00301] The term "comprise" as used herein is synonymous with "include", "contain" or "characterized by" and is inclusive or unlimited and does not exclude additional, unnamed elements or method steps.
[00302] All numbers expressing amounts of ingredients, reaction conditions etc. in the Descriptive Report are to be understood as being modified in all situations by the term “about”. Consequently, unless otherwise indicated, the numerical parameters presented herein are approximations which may vary depending on the desired properties desired to be obtained. At the very least, and not as an attempt to limit the application of the equivalents doctrine to the scope of any Claims in any application claiming priority for the present application, each numerical parameter should be interpreted in light of the number of significant digits and common rounding approaches.
[00303] The above description reveals methods and materials that are susceptible to modifications, as well as changes in manufacturing methods and equipment. Such modifications will become apparent to those skilled in the art from a consideration of this disclosure or practice of the methods disclosed herein. Accordingly, it is not intended that this invention be limited to the specific embodiments disclosed herein, but that it encompass all modifications and alternatives that fall within the true scope and spirit of the invention.

权利要求:
Claims (12)
[0001]
1. Compound, characterized in that it has the structure of formula I:
[0002]
Compound according to Claim 1, characterized in that it has the structure of formula II:
[0003]
Compound according to Claim 1, characterized in that it has the structure of formula IIIa or IIIb:
[0004]
A compound according to Claim 1, characterized in that it has the structure of formula IVa, IVb or IVc:
[0005]
A compound according to any one of Claims 2 to 4, characterized in that each R 2 , R 3 , R 4 and R 5 is hydrogen; and/or wherein the bond represented by a dashed solid line is a single bond; and/or wherein the bond represented by a dashed solid line is a double bond.
[0006]
Compound according to any one of Claims 1 to 5, characterized in that R6 and each R7 and R8 are hydrogen; and/or wherein R1 is -NHC(=O)C1‒9alkyl‒R11; and/or wherein R11 is aryl or heteroaryl; and/or wherein R11 is thien-2-yl; and/or wherein R1 is 'NHC(=O)C(=NOR9)R9', wherein R9' is selected from a group consisting of C1'9alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl -substituted, substituted or unsubstituted carbocyclyl and substituted or unsubstituted heterocyclyl; and/or wherein X is -CO2H; and/or wherein X is a carboxylic acid isostere; and/or wherein the carboxylic acid isostere is selected from a group consisting of -P(O)(OR9)2, -P(O)(R9)(OR9), -P(O)(OR12' )2, L/N. -P(O)(R9)(OR12'), -CON(R9)OH, -SO3H, -SO2N(R9)OH, and HN-N , where R12' is selected from a group consisting of H , R11, -C(R13)2OC(O)C1-9alkyl, -C(R13)2OC(O)R11, -C(R13)2OC(O)OC1-9alkyl and -C(R13)2OC(O)OR11 ; and/or where m is 1; and/or where R6, R7and R8 are H.
[0007]
7. Compound according to Claim 1, characterized in that it has a structure selected from the group consisting of:
[0008]
8. Compound according to Claim 1, characterized in that it has a structure selected from the group consisting of:
[0009]
A pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of a compound as defined in any one of Claims 1 to 8 and a pharmaceutically acceptable excipient thereof; and/or an additional drug; and/or wherein the additional medicament is selected from an antibacterial agent, an antifungal agent, an antiviral agent, an antiinflammatory agent or an antiallergic agent; and/or wherein the additional medicament is a β-lactam antibacterial agent; and/or wherein the β-lactam is selected from Amoxicillin, Ampicillin (Pivampicillin, Hetacillin, Bacampicillin, Metampicillin, Thalampicillin), Epicillin, Carbenicillin (Carindacillin), Ticarcillin, Temocillin, Azlocillin, Piperacillin, Mezlocillin (Mecillin) , Sulbenicillin, Benzyl-penicillin (G), Clomethocillin, Benzaine-benzyl-penicillin, Procaine-benzyl-penicillin, Azidocillin, Penamicillin, Phenoxy-methyl-penicillin (V), Propicillin, Benzathine-phenoxy-methyl-penicillin, Pheneticillin, Cloxacillin (Dicloxacillin, Flucloxacillin), Oxacillin, Methicillin, Nafcillin, Faropenem, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Panipenem, Tomopenem, Razupenem, Cefazolin, Cefacetril, Cephadroxil, Cephalexin, Cephalonium, Cephaloglycin, Cefazedone, Cefazaflur, Cephradine, Cephroxadine, Ceftezole, Cefaclor, Cefamandol, Cefminox, Cefonicide, Ceforanide, Cefotiam, Cefprozil, Cefbuperazone, Cefuroxime, Cefuzonam, Cefoxitin, Cefote tetanus, Cefmetazol, Loracarbef, Cefixime, Ceftazidime, Ceftriaxone, Cefcapene, Cefdaloxim, Cefdinir, Cefditoren, Cefetamet, Cefmenoxime, Ceftazidime, Cefoperazone, Cefotaxime, Cefpimizol, Cefpyramide, Cefthienoxoxime, Cefepime, Cefozopran, Cefpiroma, Cefquinome, Ceftobiprol, Ceftaroline, CXA-101, RWJ-54428, MC-04.546, ME1036, BAL30072, SYN 2416, Ceftiofur, Cefquinoma, Cefovecin, Aztreonam, Tigemonam, RWJ-54428, MC-04.546, ME1036, BAL30072, SYN 2416, Ceftiofur, Cefquinoma, Cefovecin, Aztreonam, Tigemonam, RWJ-4431, RWJumonam or RWJ-333442; and/or wherein the β-lactam is selected from Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem or Panipenem; and/or wherein the β-lactam is selected from Aztreonam, Tigemonam, BAL30072, SYN 2416 or Carumonam; and/or wherein: the β-lactam is Tigemonam; the composition is suitable for oral administration; X is -CO2R12; and R12 is selected from the group consisting of C1-9alkyl, -(CH2)0-3-R11, -C(R13)2OC(O)C1-9alkyl, -C(R13)2OC(O)R11, - C(R13)2OC(O)OC1-9alkyl and -C(R13)2OC(O)OR11.
[0010]
Use of Compound as defined in any one of Claims 1 to 8, characterized in that it is in the preparation of a medicament for the treatment or prevention of a bacterial infection; and/or for use in combination with an additional medicine; and/or wherein the additional medicament is selected from an antibacterial agent, an antifungal agent, an antiviral agent, an antiinflammatory agent or an antiallergic agent; and/or wherein the additional medicament comprises a β-lactam antibacterial agent; and/or wherein the β-lactam is selected from Amoxicillin, Ampicillin (Pivampicillin, Hetacillin, Bacampicillin, Metampicillin, Thalampicillin), Epicillin, Carbenicillin (Carindacillin), Ticarcillin, Temocillin, Azlocillin, Piperacillin, Mezlocillin (Mecillin) , Sulbenicillin, Benzyl-penicillin (G), Clomethocillin, Benzathine-benzyl-penicillin, Procaine-benzyl-penicillin, Azidocillin, Penamicillin, Phenoxy-methyl-penicillin (V), Propicillin, Benzathine-phenoxy-methyl-penicillin, Pheneticillin, Cloxacillin (Dicloxacillin, Flucloxacillin), Oxacillin, Methicillin, Nafcillin, Faropenem, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Panipenem, Tomopenem, Razupenem, Cefazolin, Cefacetril, Cephadroxil, Cephalexin, Cephalonium, Cephaloglycin, Cefazedone, Cefazaflur, Cephradine, Cephroxadine, Ceftezole, Cefaclor, Cefamandol, Cefminox, Cefonicide, Ceforanide, Cefotiam, Cefprozil, Cefbuperazone, Cefuroxime, Cefuzonam, Cefoxitin, Cefot ethane, Cefmetazol, Loracarbef, Cefixime, Ceftazidime, Ceftriaxone, Cefcapene, Cefdaloxim, Cefdinir, Cefditoren, Cefetamet, Cefmenoxime, Ceftazidime, Cefoperazone, Cefotaxime, Cefpimizol, Cefpyramide, Cefthienoxidine, Cefepime, Cefozopran, Cefpiroma, Cefquinome, Ceftobiprol, Ceftaroline, CXA-101, RWJ-54428, MC-04.546, ME1036, BAL30072, SYN 2416, Ceftiofur, Cefquinoma, Cefovecin, Aztreonam, Tigemonam, RWJ-54428, MC-04.546, ME1036, BAL30072, SYN 2416, Ceftiofur, Cefquinoma, Cefovecin, Aztreonam, Tigemonam, RWJ-4431, RWJumonam or RWJ-333442; and/or wherein the β-lactam is selected from Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem or Panipenem; and/or wherein the β-lactam is selected from Aztreonam, Tigemonam, BAL30072, SYN 2416 or Carumonam; and/or where the subject is a mammal; and/or where the mammal is a human person; and/or in which the infection comprises a bacterium selected from Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonas hydrophilia, Eschemurella, Salphirichia, Eschemur, coli, Eschemur, colity Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Francisella tularensis, Morganella morganter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Francisella tularensis, Morganella morganii, Providencia al Providenti, Providencia al Providenti, Proteus vulgarii, Providencia al. , Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus influenzae arainfluenzae , Haemophilus haemolyticus , Haemophilus parahaemolyticus , Haemophilus ducreyi , Pasteurella multocida , Pasteurella haemolytica , Branhamella catarrhalis , Helicobacter pylori , Campylobacter fetus , Campylobacter jejuni , Campylobacter jejuni , Campylobacter jejuni , Campylobacter , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , B , B , B , B . Neisseria meningitidis, Kingella, Moraxella, Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis, homology group of Bacteroides 3452A, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides eggerthii, Bacteroides difcobacterium tuberculosis, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus au reus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis or Staphylococcus saccharolyticus; and/or wherein the infection comprises a bacterium selected from Pseudomonas aeruginosa, Pseudomonas fluorescens, Stenotrophomonas maltophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella para dystyphi, Salmonella Shiellagentei, sogella Enterobacter cloacae, aerogenes Enterobacter, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, pseudotuberculosis Yersinia intermedia Yersinia, Haemophilus influenzae, Haemophilus parainfluenzae, haemolyticus Haemophilus, 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 acteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii or Bacteroides splanchnicus.
[0011]
A Sterile Container, characterized in that it contains: a compound as defined in any one of Claims 1 to 8 in solid form; and an antibacterial agent in solid form; and/or wherein the antibacterial agent is a β-lactam; and/or wherein the β-lactam is selected from Amoxicillin, Ampicillin (Pivampicillin, Hetacillin, Bacampicillin, Metampicillin, Thalampicillin), Epicillin, Carbenicillin (Carindacillin), Ticarcillin, Temocillin, Azlocillin, Piperacillin, Mezlocillin (Mecillin) , Sulbenicillin, Benzyl-penicillin (G), Clomethocillin, Benzathine-benzyl-penicillin, Procaine-benzyl-penicillin, Azidocillin, Penamicillin, Phenoxy-methyl-penicillin (V), Propicillin, Benzathine-phenoxy-methyl-penicillin, Pheneticillin, Cloxacillin (Dicloxacillin, Flucloxacillin), Oxacillin, Methicillin, Nafcillin, Faropenem, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Panipenem, Tomopenem, Razupenem, Cefazolin, Cefacetril, Cephadroxil, Cephalexin, Cephalonium, Cephaloglycin, Cefazedone, Cefazaflur, Cephradine, Cephroxadine, Ceftezole, Cefaclor, Cefamandol, Cefminox, Cefonicide, Ceforanide, Cefotiam, Cefprozil, Cefbuperazone, Cefuroxime, Cefuzonam, Cefoxitin, Cefot ethane, Cefmetazol, Loracarbef, Cefixime, Ceftazidime, Ceftriaxone, Cefcapene, Cefdaloxim, Cefdinir, Cefditoren, Cefetamet, Cefmenoxime, Ceftazidime, Cefoperazone, Cefotaxime, Cefpimizol, Cefpyramide, Cefthienoxidine, Cefepime, Cefozopran, Cefpiroma, Cefquinome, Ceftobiprol, Ceftaroline, CXA-101, RWJ-54428, MC-04,546, ME1036, BAL30072, SYN 2416, Ceftiofur, Cefquinoma, Cefovecina, Aztreonam, Tigemonam, RWJ-54428, MC-04,546, ME1036, BAL30072, SYN 2416, Ceftiofur, Cefquinoma, Cefovecina, Aztreonam, Tigemonam, RWJ-4431, RWJumonam or RWJ-333442; and/or wherein the β-lactam is selected from Ceftazidime, Biapenem, Tomopenem, Doripenem, Ertapenem, Imipenem, Meropenem or Panipenem; and/or wherein the β-lactam is selected from Aztreonam, Tigemonam, BAL30072, SYN 2416 or Carumonam; and/or wherein the compound and antibacterial agent are mixed and/or wherein the compound and antibacterial agent are not mixed; and/or wherein the compound is in crystalline form; and/or wherein the antibacterial agent is in crystalline form; and/or wherein the compound and the antimicrobial agent are lyophilic; and/or wherein the molar ratio of compound to antibacterial agent is from 1:8 to 8:1; and/or wherein the molar ratio of compound to antibacterial agent is from 1:2 to 2:1; and/or wherein the molar ratio of compound to antibacterial agent is 1:1; and/or which additionally contain a pH adjusting agent; and/or wherein the pH adjusting agent comprises NaOH; and/or wherein the pH adjusting agent comprises citric acid.
[0012]
A Method of Preparing Pharmaceutical Composition for Administration, characterized in that it comprises reconstituting the contents of the sterile container as defined in Claim 11 using a pharmaceutically acceptable diluent therefor; and/or wherein the diluent comprises saline solution; and/or wherein the diluent comprises a dextrose solution; and/or where it is in the manufacture of a medicament for the treatment or prevention of bacterial infections.

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法律状态:
2018-05-29| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

---

2018-12-26| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

---

2020-04-28| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

---

2020-06-09| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

---

2021-04-06| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

---

2021-07-20| B25G| Requested change of headquarter approved|Owner name: REMPEX PHARMACEUTICALS, INC. (US) |

---

2021-08-31| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 08/08/2011, OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME ADI 5.529/DF, QUE DETERMINA A ALTERACAO DO PRAZO DE CONCESSAO. |

优先权:

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