WO2014141132A1 - NEW HETEROCYCLIC COMPOUNDS AND THEIR USE AS ANTIBACTERIAL AGENTS AND β-LACTAMASE INHIBITORS - Google Patents

NEW HETEROCYCLIC COMPOUNDS AND THEIR USE AS ANTIBACTERIAL AGENTS AND β-LACTAMASE INHIBITORS Download PDF

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WO2014141132A1
WO2014141132A1 PCT/IB2014/059736 IB2014059736W WO2014141132A1 WO 2014141132 A1 WO2014141132 A1 WO 2014141132A1 IB 2014059736 W IB2014059736 W IB 2014059736W WO 2014141132 A1 WO2014141132 A1 WO 2014141132A1
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oxo
sulfooxy
octane
carboxamide
diazabicyclo
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PCT/IB2014/059736
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French (fr)
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Samarendra Nath Maiti
Biswajeet Ganguli
Dai Quoc Nguyen
Jehangir Khan
Rong Ling
Chan Minh Ha
Vladimir Khlebnikov
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Naeja Pharmaceutical Inc.
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Publication of WO2014141132A1 publication Critical patent/WO2014141132A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/529—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/18—Bridged systems

Definitions

  • the present invention relates to chemical compounds for use in the treatment of bacterial infections in animals, such as humans, means for synthesizing such compounds, and methods of medical treatment and prevention using such compounds.
  • Microbial drug resistance is an unavoidable consequence resulting from abuse and overuse of antimicrobial agents.
  • the rate at which resistance arises among microbial populations is often dictated by the extent of use of particular agents in a given environment.
  • Given the degree of popularity of ⁇ -lactam antibiotics it is not surprising that the prevalence of ⁇ -lactamase producing strains is increasing worldwide. Such bacterial strains are characterized by varying degrees of resistance to ⁇ -lactam antibiotics.
  • Class-A enzymes preferentially hydrolyze penicillins
  • class-B enzymes hydrolyze all ⁇ -lactams including carbapenems
  • class-C ⁇ -lactamases have a substrate profile favoring cephalosporin hydrolysis
  • substrate preference for class D ⁇ -lactamases include oxacillin and cloxacillin.
  • 2013/0296292 US 2013/0296291 , US 2013/0289012, WO 2013/149121 .
  • the present invention relates to new heterocyclic compounds, their preparation, and their use as ⁇ -lactamase inhibitors, either alone or in combination with (i) another ⁇ -lactamase inhibitor and/or (ii) one or more antibiotics in the treatment of infections caused by bacteria, such as ⁇ -lactamase-producing bacteria. More particularly, the invention is concerned with methods for overcoming antibiotic resistance caused by ⁇ -lactamase producing bacteria, methods of preparation of the new compounds, pharmaceutical compositions containing the new compounds, methods of treatment or prevention using the new compounds, and other subject matter.
  • the present invention is directed to compounds of formula (I) :
  • Y H, -OR 1 or -NR 2 R 3 ;
  • R is -SO 3 M, -OSO 3 M, -OS0 2 NH 2 , -OPO 3 M, -OCH 2 COOM, -OCF 2 COOM,
  • a and B are:
  • one of A and B is a C 3 . 6 membered ring forming a spiro system, and the other of A and B is CH 2 ,
  • one of A and B is C 4 .
  • 6 membered heterocyclic ring form ing a spiro system containing O as a heteroatom and the other of A and B is CH 2 , or
  • the radical R 1 is optionally substituted with one or two substituents independently selected from the group consisting of lower alkyl, amino, substituted amino, alkoxy, hydroxyalkyl, halogen, hydroxy, carboxy, alkoxycarbonyl, haloalkyi, trifluoromethyl, trifluoromethyloxy, alkylamine, substituted alkylamine, carboxamide, thiocarboxamide, sulfonic acid, sulphate, acylamino, sulfonylamino, substituted or unsubstituted sulfonamide, substituted or unsubstituted urea, substituted or unsubstituted thiourea, oxo, hydroxamic acid, acyl, trifluoromethyl carbonyl, cyano, amidino, guanidino, aryloxy, heterocyclylalkyloxy, and heteroaryloxy.
  • substituents independently selected from the group consisting of lower alkyl, amino
  • R is -OS0 3 M where M is hydrogen or a pharmaceutically acceptable salt-forming cation.
  • the ring system is selected from the group consisting of a pyrazolo group, a thieno group, a methylpyrazolo group, a furano group, a thiazolo group, a pyridine group, an oxazolo group, an imidazole group, a benzo group, and an ethanoimidazo group.
  • the present invention is directed to pharmaceutical compositions comprising one or more compounds of the first embodiment, i.e., the compounds of formula (I) (e.g., the compounds provided in Tables 1 and 2), and a pharmaceutically acceptable carrier or diluent.
  • the pharmaceutical compositions further comprise one or more ⁇ -lactamase inhibitors, or one or more antibacterial agents, or both one or more ⁇ -lactamase inhibitors and one or more antibacterial agents.
  • the present invention is directed to methods of preventing or treating a bacterial infection in a subject comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of the first embodiment, i.e. , the compounds of formula (I) (e.g., the compounds provided in Tables 1 and 2).
  • the bacterial infection is caused by bacteria producing one or more ⁇ - lactamase enzymes.
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of (a) one or more compounds of the first embodiment, i.e., the compounds of formula (I) (e.g., the compounds provided in Tables 1 and 2), and (b) one or more ⁇ -lactamase inhibitor.
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of (a) one or more compounds of the first embodiment, i.e., the compounds of formula (I) (e.g., the compounds provided in Tables 1 and 2), and (b) one or more antibacterial agent.
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of (a) one or more compounds of the first embodiment, i.e., the compounds of formula (I) (e.g., the compounds provided in Tables 1 and 2), (b) one or more ⁇ -lactamase inhibitor, and (c) one or more antibacterial agent.
  • a) one or more compounds of the first embodiment i.e., the compounds of formula (I) (e.g., the compounds provided in Tables 1 and 2)
  • one or more ⁇ -lactamase inhibitor e.g., the compounds provided in Tables 1 and 2
  • one or more antibacterial agent e.g., antibacterial agent.
  • the present invention is directed to methods of preventing or treating a bacterial infection in a subject comprising administering to a subject in need thereof a therapeutically effective a pharmaceutical composition of the second embodiment, i.e. , one or more compounds of formula (I) and a pharmaceutically acceptable carrier or diluent.
  • the bacterial infection is caused by bacteria producing one or more ⁇ -lactamase enzymes.
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of (a) a pharmaceutical composition of the second embodiment, i.e. , one or more compounds of formula (I) and a pharmaceutically acceptable carrier or diluent, and (b) one or more ⁇ -lactamase inhibitor.
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of (a) a pharmaceutical composition of the second embodiment, i.e. , one or more compounds of formula (I) and a pharmaceutically acceptable carrier or diluent, and (b) one or more antibacterial agent.
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of (a) a pharmaceutical composition of the second embodiment, i.e. , one or more compounds of formula (I) and a pharmaceutically acceptable carrier or diluent, (b) one or more ⁇ -lactamase inhibitor, and (c) one or more antibacterial agent.
  • the ⁇ -lactamase inhibitors include, but are not limited to, sulbactam, tazobactam, and clavulanic acid, and pharmaceutically acceptable salts thereof.
  • the antibacterial agents include, but are not limited to, ⁇ -lactam antibiotics, salts of ⁇ -lactam antibiotics, hydrates of ⁇ -lactam antibiotics, and prodrugs of ⁇ -lactam antibiotics, and pharmaceutically acceptable salts thereof.
  • the antibacterial agent is a ⁇ -lactam antibiotic or a pharmaceutically acceptable salt thereof.
  • the antibacterial agents also include, but are not limited to, one or more members selected from the group consisting of aminoglycosides, ansamycins, carbacephems, cephalosporins, cephamycins, lincosamides, lipopeptides, macrolides, monobactams, nitrofurans, penems, penicillins, polypeptides, quinolones, sulphonamides, tetracyclines, and oxazolidinone, and pharmaceutically acceptable salts thereof.
  • the antibacterial agent is one or more members selected from the group consisting of penicillins, penems, carbapenems, cephalosporins, and monobactams, and pharmaceutically acceptable salts thereof.
  • the antibacterial agent is one or more cephalosporin antibiotics selected from the group consisting of cephalothin, cephaloridine, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cephradine, ceftizoxime, cefoxitin, cephacetrile, cefotiam, cefotaxime, cefsulodin, cefoperazone, ceftizoxime, cefmenoxime, cefmetazole, cephaloglycin, cefonicid, cefodizime, cefpirome, ceftobiprole, ceftolozane, ceftazidime, cefpiramide, cefbuperazone, cefozopran, cefepime, cefoselis, cefluprenam, cefuzonam, cefpimazole, cefclidin, cefixime, ceftibuten, cefdinir, cefpod
  • the antibacterial agent is one or more members selected from the group consisting of ceftazidime, cefepime, cefpirome, piperacillin, doripenem, meropenem, imipenem, ceftaroline, ceftobiprole, and ceftolozane, and pharmaceutically acceptable salts thereof.
  • the subject may be a human.
  • Novel low molecular weight heterocyclic compounds of formula (I) below are disclosed herein. These compounds of the invention can be used in combination with a ⁇ -lactam antibiotic or a non ⁇ -lactam antibiotic to enhance the activity of the antibiotic against class A, class B, class C, and class D ⁇ -lactamase enzyme producing organisms. Thus, the compounds of the invention can be used to enhance the antibacterial properties of antibiotics, both those now known and those yet to be developed. Furthermore, some of the compounds of the present invention also possess innate, potent antibacterial activity, particularly against Gram negative bacteria. The compounds of the present invention are therefore useful in the treatment of bacterial infections in humans or in animals, either alone or in combination with (i) ⁇ -lactam antibiotics and/or ⁇ - ⁇ -lactam antibiotics, (ii)
  • Y H, -OR 1 or -NR 2 R 3 ;
  • R is -SO 3 M, -OSO 3 M, -OS0 2 NH 2 , -OPO 3 M, -OCH 2 COOM, -OCF 2 COOM, - OCH(CH 3 )COOM, -OC(CH 3 ) 2 COOM, -OCF 3 , -OCH 2 S0 3 M, -OCH 2 P0 3 M 2 , where M is hydrogen or a pharmaceutically acceptable salt-forming cation; preferably R is -OS0 3 M where M is hydrogen or a pharmaceutically acceptable salt-forming cation ;
  • a and B are:
  • a and B together form an aromatic ring system or a heteroaromatic ring system, such as pyrazolo group, a thieno group, a methylpyrazolo group, a furano group, a thiazolo group, a pyridine group, an oxazolo group, an imidazole group, a benzo group, or an ethanoimidazo group,
  • one of A and B is C 3 . 6 membered ring forming a spiro system, and the other of A and B is CH 2 ,
  • one of A and B is C 4 . 6 membered heterocyclic ring forming a spiro system containing O as a hetero-atom, and the other of A and B is CH 2 , or
  • R 1 is a radical selected from one of the following groups:
  • R 2 and R 3 together form a ring system which is optionally substituted, and wherein the ring optionally contains another heteroatom selected from O, N, and S.
  • a "pharmaceutically acceptable salt” refers to a salt of a compound, which salt possesses the desired pharmacological activity of the parent compound (i.e., when M is a pharmaceutically acceptable salt-forming cation, the compound possesses the desired pharmacological activity that the compound would have if M were instead a hydrogen atom).
  • reference to specified compounds "modified in that they have been deuterated” refers to compounds obtained by modifying the specified compounds so that one or more hydrogen atoms in the compound have been replaced with or converted to deuterium.
  • a "pharmaceutically acceptable solvate” refers to a molecular complex of a compound with one or more solvent molecules in a stoichiometric or non- stoichiometric amount.
  • solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to recipient, e.g., water, ethanol, and the like.
  • a molecular complex of a compound or moiety of a compound and a solvent can be stabilized by non-covalent intra-molecular forces such as, for example, electrostatic forces, Van der Waals forces or hydrogen bonds.
  • the term hydrate refers to a complex where the one or more solvent molecules are water.
  • Examples of the groups for forming a pharmaceutically acceptable salt in the formula (I) include: inorganic base salts, ammonium salts, organic base salts, basic amino acid salts, inorganic acid addition salts, and organic acid addition salts.
  • Inorganic bases that can form the inorganic base salts include alkali metals (e.g., sodium, potassium, and lithium) and alkaline earth metals (e.g., calcium and magnesium).
  • Organic bases that can form the organic base salts include n-propylamine, n-butylamine, cyclohexylamine, benzylamine, octylamine, ethanolamine, diethanolamine, diethylamine, triethylamine, dicyclohexylamine, procaine, choline, N-methylglucamine, morpholine, pyrrolidine, piperidine, N-ethylpiperidine and N-methylmorpholine.
  • Basic amino acids that can form the basic amino acid salts include lysine, arginine, ornithine and histidine.
  • the compounds of formula (I) containing a basic nitrogen atom are capable of forming acid addition salts.
  • Such salts with pharmaceutically acceptable acids are included in the invention.
  • acids are hydrochloric, hydrobromic, phosphoric, sulphuric, citric, oxalic, maleic, fumaric, glycolic, mandelic, tartaric, aspartic, succinic, malic, formic, acetic, trifluoroacetic, methanesulfonic, ethanesulfonic, trifluoromethanesulfonic, benzenesulfonic, p-toluenesulfonic and the like.
  • some compounds of formula (I) when they contain a basic group such as NH, NH 2 or pyridine and the like may form an inner, zwitterionic salt with S0 3 H, OS0 3 H, CH 2 COOH; such inner salts are also included in this invention.
  • the present invention includes all possible isomers of formula (I).
  • the term 'isomers' refers to compounds that have the same molecular formula as a selected compound, but differ in arrangement and configuration of the atoms, such as geometrical isomers and optical isomers.
  • a substituent may be attached at a chiral center of a carbon atom. Therefore the invention includes enantiomers, diastereoisomers or racemates of the compound.
  • 'enantiomers' are a pair of stereoisomers that are non-superimposable mirror images of each other, and 1 :1 mixture of a pair of enantiomers is a racemic mixture.
  • 'diastereoisomers' are stereoisomers that have at least two asymmetric carbon atoms but which are not mirror-images of each other.
  • the stereochemistry at each chiral carbon may be specified by either R or S.
  • a variety of protecting groups conventionally used in the ⁇ -lactam field to protect a reactive functional group present in the molecule of formula (I) can be used.
  • 'Protecting group' refers to a group of atoms that when attached to a reactive functional group in a molecule masks, reduces or prevents reactivity of the functional group. Examples of protecting groups can be found in Green et al., "Protective Groups in Organic Chemistry", (Wiley, 2 nd , 1991 ) and Harrison et al., "Compendium of Synthetic Organic Methods," Vols. 1 - 8 (John Wiley and Sons, 1971 -1996).
  • Representative amino protecting groups include, but are not limited to formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ), tert- butoxycarbonyl (Boc), trimethylsilyl (TMS), 2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC), nitro- veratryloxycarbonyl (NVOC), and the like.
  • hydroxy protecting groups include, but are not limited to, those where the hydroxyl group is either acylated or alkylated such as benzyl, and trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers, and allyl ethers.
  • Optionally substituted refers to compounds of the invention that are unsubstituted or substituted. When the compounds are substituted, they may be substituted with one or two of the following substituents, each of which is independently selected from :
  • alkyl including from one to six carbon atoms in any arrangement, e.g., methyl, ethyl, i-propyl or t-butyl -Amino
  • -Substituted amino such as -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -NHPr', -NHBu',
  • -Alkoxy such as -OCH 3 , -OC 2 H 5 , -OPr 1 (i.e. , isopropyloxy), -OBu' (i.e., isobutyloxy)
  • -Hydroxyalkyl such as -CH 2 OH, -CH 2 CH 2 OH
  • -Alkoxycarbonyl such as -COOCH 3 , -COOC 2 H 5 , -COOPr 1 , and -COOBu'
  • -Haloalkyl such as -CH 2 CI, -CH 2 F
  • -Alkylamine such as -CH 2 NH 2 , -CH 2 CH 2 NH 2
  • -Substituted alkylamine such as -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 NHCH 3 ,
  • -Substituted sulfonamide such as -S0 2 NHCH 3 , -S0 2 NHCH 2 CH 3 , -SOsNHPr 1 , -S0 2 NHBu',
  • the present invention also provides pharmaceutical compositions comprising one or more compounds of formula (I) and a pharmaceutically acceptable carrier or diluent.
  • These pharmaceutical compositions can be formulated for administration to a subject by various routes. Depending on the identity of the components included in the compositions, suitable routes include, but are not limited to, oral, sublingual, intranasal, intraocular, rectal, transdermal, mucosal, topical or parenteral administration. Parenteral modes of
  • administration include without limitation, intradermal, subcutaneous (s.c, s.q., sub-Q, Hypo), intramuscular (i.m.), intravenous (i.v.), intraperitoneal (i.p.), intra-arterial, intramedulary, intracardiac, intra-articular (joint), intrasynovial (joint fluid area), intracranial, intraspinal, and intrathecal (spinal fluids). Any known device useful for parenteral injection or infusion of drug formulations can be used to effect such administration.
  • Suitable pharmaceutical carriers for use in the pharmaceutical compositions generally include excipients such as starch, glucose, lactose, sucrose, gelatin, gum arabic, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like.
  • excipients such as starch, glucose, lactose, sucrose, gelatin, gum arabic, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like.
  • excipients such as starch, glucose, lactose, sucrose, gelatin, gum arabic, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate,
  • Suitable pharmaceutical diluents generally include water, water-for- injection, saline (e.g., 0.9% saline), buffered saline, a 5% glucose solution, glycerol, ethanol, propylene glycol, polysorbate 80 (Tween-80TM), poly(ethylene)glycol 300 and 400 (PEG 300 and 400), PEGylated castor oil (e.g. Cremophor EL), poloxamer 407 and 188, and combinations thereof.
  • saline e.g. 0.9% saline
  • buffered saline e.g., 5% glucose solution
  • glycerol glycerol
  • ethanol ethanol
  • propylene glycol polysorbate 80
  • PEG 300 and 400 poly(ethylene)glycol 300 and 400
  • PEGylated castor oil e.g. Cremophor EL
  • poloxamer 407 and 188 poloxamer 407 and 188
  • compositions can also contain minor amounts of wetting, dispersing or emulsifying agents, or pH buffering agents, and preservatives.
  • auxiliary, stabilizing, thickening, lubricating, and coloring agents can be included.
  • compositions can be formulated in a conventional manner. Proper formulation is dependent upon the route of administration chosen and the identity of the compounds.
  • the pharmaceutical compositions can take the form of injectable preparations, suspensions, emulsions, sugar-coated tablets, pellets, gelatin-capsules, capsules containing liquids, powders, granules, sustained-release formulations, suppositories, aerosols, sprays, ointments, creams or any other form suitable for use.
  • Formulations for parenteral administration can be in the form of aqueous or nonaqueous isotonic sterile injection solutions, suspensions or fat emulsions. The parenteral form used for injection must be fluid to the extent that easy syringability exists. These solutions or suspensions can be prepared from sterile concentrated liquids, powders or granules.
  • Excipients used in parenteral preparations also include, without limitation, stabilizing agents (e.g. carbohydrates, amino acids and polysorbates, such as 5% dextrose), solubilizing agents (e.g. cetrimide, sodium docusate, glyceryl monooleate,
  • stabilizing agents e.g. carbohydrates, amino acids and polysorbates, such as 5% dextrose
  • solubilizing agents e.g. cetrimide, sodium docusate, glyceryl monooleate
  • PVP polyvinylpyrolidone
  • PEG polyethylene glycol
  • surfactants e.g. polysorbates, tocopherol PEG succinate, poloxamer and CremophorTM
  • buffers e.g. acetates, citrates, phosphates, tartrates, lactates, succinates, amino acids and the like
  • antioxidants and preservatives e.g.
  • BHA, BHT, gentisic acids vitamin E, ascorbic acid, sodium ascorbate and sulfur containing agents such as sulfites, bisulfites, metabisulfites, thioglycerols, thioglycolates and the like), tonicity agents (for adjusting physiological compatibility), suspending or viscosity agents, antibacterials (e.g. thimersol, benzethonium chloride, benzalkonium chloride, phenol, cresol and chlorobutanol), chelating agents, and
  • administration aids e.g. local anesthetics, anti-inflammatory agents, anti-clotting agents, vaso-constrictors for prolongation and agents that increase tissue permeability), and combinations thereof.
  • Parenteral formulations using hydrophobic carriers include, for example, fat emulsions and formulations containing lipids, lipospheres, vesicles, particles and liposomes.
  • Fat emulsions include in addition to the above-mentioned excipients, a lipid and an aqueous phase, and additives such as emulsifiers (e.g. phospholipids, poloxamers, polysorbates, and polyoxyethylene castor oil), and osmotic agents (e.g. sodium chloride, glycerol, sorbitol, xylitol and glucose).
  • emulsifiers e.g. phospholipids, poloxamers, polysorbates, and polyoxyethylene castor oil
  • osmotic agents e.g. sodium chloride, glycerol, sorbitol, xylitol and glucose.
  • Liposomes include natural or derived phospholipids and optionally stabilizing agents such as
  • the unit dosage of the compounds of the invention can be in a concentrated liquid, powder or granular form for ex tempore reconstitution in the appropriate pharmaceutically acceptable carrier, such as sterile water, at the time of delivery.
  • the appropriate pharmaceutically acceptable carrier such as sterile water
  • powder forms optionally include bulking agents (e.g. mannitol, glycine, lactose, sucrose, trehalose, dextran, hydroxyethyl starch, ficoll and gelatin), and cryo or lyoprotectants.
  • a sterile formulation of the pharmaceutical compositions of the present invention and optionally one or more additives, including solubilizers or surfactants, can be dissolved or suspended in any of the commonly used intravenous fluids and administered by infusion.
  • Intravenous fluids include, without limitation, physiological saline, phosphate buffered saline, 5% dextrose in water or Ringer'sTM solution.
  • compositions of the present invention can be dissolved and administered in a pharmaceutical diluent such as Water-for-lnjection (WFI), physiological saline or 5% dextrose in water.
  • a pharmaceutical diluent such as Water-for-lnjection (WFI), physiological saline or 5% dextrose in water.
  • WFI Water-for-lnjection
  • physiological saline physiological saline
  • dextrose 5% dextrose
  • aqueous base e.g. an aqueous base or a pharmaceutically acceptable oil base, e.g. an ester of a long chain fatty acid such as ethyl oleate
  • the oral pharmaceutical composition may be made in the form of a unit dosage containing a therapeutically-effective amount of the pharmaceutical compositions.
  • Solid formulations such as tablets and capsules are particularly useful. Sustained released or enterically coated preparations may also be devised. For pediatric and geriatric applications, suspension, syrups and chewable tablets are especially suitable.
  • excipient or additives include, but are not limited to inert diluents, fillers, disintegrating agents, binding agents, wetting agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservatives.
  • the tablets and capsules can contain, in addition to the compounds of the invention, conventional carriers such as inert diluents (e.g., sodium and calcium carbonate, sodium and calcium phosphate, and lactose), binding agents (e.g., acacia gum, starch, gelatin, sucrose, polyvinylpyrrolidone (Povidone), sorbitol, tragacanth methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and ethylcellulose), fillers (e.g., calcium phosphate, glycine, lactose, maize-starch, sorbitol, or sucrose), wetting agents, lubricating agents (e.g., metallic stearates, stearic acid, polyethylene glycol, waxes, oils, silica and colloical silica, silicon fluid or talc), disintegrating agents (e.g., potato starch, corn starch and alg
  • Carriers may also include coating excipients such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.
  • Topical delivery systems also include transdermal patches containing at least one compound of formula (I) to be administered. Delivery through the skin can be achieved by diffusion or by more active energy sources such as iontophoresis or electrotransport.
  • Formulations of a compound of the present invention, for topical use, such as in creams, ointments, and gels can include an oleaginous or water soluble ointment base, for example, topical compositions can include vegetable oils, animal fats, and in certain embodiments, semisolid hydrocarbons obtained from petroleum.
  • Topical compositions can further include white ointment, yellow ointment, cetyl esters wax, oleic acid, olive oil, paraffin, petrolatum, white petrolatum, spermaceti, starch glycerite, white wax, yellow wax, lanolin, and glyceryl monostearate.
  • Various water- soluble ointment bases can also be used, including glycol ethers and derivatives, polyethylene glycols, polyoxyl 40 stearate, and polysorbates.
  • the weight ratio of active ingredient to carrier will normally be in the range of 1 :20 to 20:1 .
  • the present invention provides for the use, in the manufacture of a medicament, of one or more compounds within formula (I) as an active ingredient in an antibacterial composition in admixture with a carrier or diluent.
  • the present invention provides for the use, in the manufacture of a medicament, of one or more compounds within formula (I) as an active ingredient.
  • the present invention provides for the use, in the manufacture of a medicament, of one or more compounds within formula (I) as an active ingredient, along with one or more antibiotics (e.g., a ⁇ -lactam antibiotic or a non ⁇ -lactam antibiotic), in an antibacterial composition in admixture with a carrier or diluent.
  • antibiotics e.g., a ⁇ -lactam antibiotic or a non ⁇ -lactam antibiotic
  • the present invention provides for the use, in the manufacture of a medicament, of one or more compounds within formula (I) as an active ingredient, along with one or more antibiotics (e.g., a ⁇ -lactam antibiotic or a non ⁇ -lactam antibiotic).
  • antibiotics e.g., a ⁇ -lactam antibiotic or a non ⁇ -lactam antibiotic.
  • the present invention provides for the use, in the manufacture of a medicament, of one or more compounds within formula (I) as an active ingredient, along with one or more ⁇ -lactamase inhibitors, in an antibacterial composition in admixture with a carrier or diluent.
  • the present invention provides for the use, in the manufacture of a medicament, of one or more compounds within formula (I) as an active ingredient, along with one or more ⁇ -lactamase inhibitors.
  • the present invention provides for the use, in the manufacture of a medicament, of one or more compounds within formula (I) as an active ingredient, along with (i) one or more antibiotics (e.g., a ⁇ -lactam antibiotic or a non ⁇ -lactam antibiotic) and (ii) one or more ⁇ -lactamase inhibitors, in an antibacterial composition in admixture with a carrier or diluent.
  • antibiotics e.g., a ⁇ -lactam antibiotic or a non ⁇ -lactam antibiotic
  • ⁇ -lactamase inhibitors e.g., ⁇ -lactamase inhibitors
  • the present invention provides for the use, in the manufacture of a medicament, of one or more compounds within formula (I) as an active ingredient, along with (i) one or more antibiotics (e.g., a ⁇ -lactam antibiotic or a non ⁇ -lactam antibiotic) and (ii) one or more ⁇ -lactamases inhibitors.
  • antibiotics e.g., a ⁇ -lactam antibiotic or a non ⁇ -lactam antibiotic
  • the pharmaceutical compositions of the invention can be supplemented to include one or more antibiotic agents (e.g., ⁇ -lactam antibiotics and/or non ⁇ -lactam antibiotics). In certain other aspects, the pharmaceutical compositions of the invention can be supplemented to include one or more ⁇ -lactamase inhibitors. In certain further aspects, the pharmaceutical compositions of the invention can be supplemented to include both (i) one or more antibiotic agents and (ii) one or more ⁇ -lactamase inhibitors.
  • antibiotic agents e.g., ⁇ -lactam antibiotics and/or non ⁇ -lactam antibiotics
  • the pharmaceutical compositions of the invention can be supplemented to include one or more ⁇ -lactamase inhibitors.
  • ' ⁇ -lactam antibiotic' refers to a compound with antibiotic property that contains a ⁇ -lactam functionality.
  • ⁇ -lactam antibiotics which can be used in combination with the compounds of the present invention represented by formula (I) are commonly marketed penicillins, cephalosporins, penems, carbapenems and monobactams.
  • ⁇ -lactam antibiotics included, but are not limited to, penicillins, such as amoxicillin, ampicillin, azlocillin, mezlocillin, apalcillin, hetacillin, bacampicillin, carbenicillin, sulbenicillin, ticarcillin, piperacillin, methicillin, ciclacillin, talampicillin, oxacillin, cloxacillin, dicloxacillin and commonly used cephalosporins such as cephalothin, cephaloridine, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cephradine, cephapirin, cefuroxime, cefoxitin, cephacetrile, cefotiam, cefotaxime, cefatriazine, cefsulodin, cefoperazone, ceftizoxime, cefmenoxime, cefmetazole, cephalog
  • ⁇ -lactam antibiotics such as imipenem, meropenem, panipenem, biapenem, doripenem, ertapenem and the like could be used.
  • monobactam class of ⁇ -lactam antibiotics such as aztreonam, carumonam, tigemonam, and the like could be used as the combination partner of antibiotic.
  • antibiotics which are not ⁇ -lactam antibiotics and which can be used in combination with the compounds of the present invention include, but are not limited to, aminoglycosides, quinolones, tetracyclines, glycylcyclines, glycopeptides, lipopeptides, macrolides, ketolides, lincosamides, streptogramin, oxazolidinones, polymyxins, and other compounds known to have antibacterial properties.
  • Examples of ⁇ -lactamase inhibitors which can be used in combination with the compounds of the present invention represented by formula (I) are sulbactam, tazobactam, and clavulanic acid, and pharmaceutically acceptable salts thereof.
  • the present invention also provides methods for the prevention or treatment of bacterial infections in a subject.
  • the invention includes methods of preventing or treating a bacterial infection in a subject comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of formula (I) (e.g., compounds provided in Tables 1 and 2), thereby preventing or treating a bacterial infection in a subject.
  • compounds of formula (I) e.g., compounds provided in Tables 1 and 2
  • the methods of the invention may also be practiced by administering to a subject in need thereof a therapeutically effective amount of (a) one or more compounds of formula (I), and (b) one or more ⁇ -lactamase inhibitor.
  • the methods of the invention may also be practiced by administering to a subject in need thereof a therapeutically effective amount of (a) one or more compounds of formula (I), and (b) one or more antibacterial agent.
  • the methods of the invention may further be practiced by administering to a subject in need thereof a therapeutically effective amount of (a) one or more compounds of formula (I), (b) one or more ⁇ -lactamase inhibitor, and (c) one or more antibacterial agent.
  • the bacterial infections that may be prevented or treated are caused by bacteria producing one or more ⁇ -lactamase enzymes and a ⁇ -lactam antibiotic is administered as the antibacterial agent to the subject along with one or more compounds of formula (I).
  • the compounds of the invention increase the antibacterial effectiveness of ⁇ -lactamase susceptible ⁇ -lactam antibiotics, that is, they increase the effectiveness of the antibiotic against infections caused by ⁇ -lactamase producing microorganisms in mammalian subjects, particularly in human.
  • this makes the compounds of formula (I) and pharmaceutically acceptable salts thereof, valuable for co-administration with ⁇ -lactam antibiotics.
  • the compounds of formula (I) or a pharmaceutically salt thereof can be mixed with the ⁇ -lactam antibiotic, and the two agents thereby administered simultaneously.
  • the combination of the compound of the invention and the antibiotic can provide a synergistic effect.
  • the term 'synergystic effect' refers to the effect produced when two or more agents are co-administered and the resulting antibacterial effect is greater than the effect produced when the agents are administered individually.
  • the compound of formula (I) or a salt thereof can be administered as a separate agent during a course of prevention or treatment with the antibiotic.
  • the compounds of the invention can be used in methods of prevention or treatment, where they are administered before, concurrently with, or after administration of an antibiotic to the subject.
  • Suitable ⁇ -lactamase inhibitors include, but are not limited to, sulbactam, tazobactam, and clavulanic acid, and pharmaceutically acceptable salts thereof.
  • Suitable antibacterial agents included, but are not limited to, ⁇ -lactam antibiotics, salts of ⁇ -lactam antibiotics, hydrates of ⁇ -lactam antibiotics, prodrugs of ⁇ -lactam antibiotics, and pharmaceutically acceptable salts thereof.
  • Suitable antibacterial agents include aminoglycosides, ansamycins, carbacephems, cephalosporins, cephamycins, lincosamides, lipopeptides, macrolides, monobactams, nitrofurans, penems, penicillins, polypeptides, quinolones, sulphonamides, tetracyclines, oxazolidinone, and pharmaceutically acceptable salts thereof.
  • the methods of the present invention will generally be practiced by administering the compounds of the invention to a subject as a pharmaceutical composition, as defined herein. However, it should be understood that each of the methods of the invention may be practiced by directly administering the compounds of the invention to a subject.
  • the present invention includes in vitro and ex vivo methods of killing or inhibiting the growth of a bacterial population by contacting a population of bacteria with an effective amount of one or more of the compounds of the invention. Such methods may also be practiced by contacting a population of bacteria with an effective amount of (a) one or more compounds of the invention and (b) one or more ⁇ -lactamase inhibitor; (a) one or more compounds of the invention and (b) one or more antibacterial agent; and (a) one or more compounds of the invention, (b) one or more ⁇ -lactamase inhibitor, and (c) one or more antibacterial agent.
  • the in vitro methods are exemplified, but not limited to, methods performed in a laboratory setting, such as in a cell culture, as well as methods performed on inert objects such as laboratory or hospital equipment and devices, surfaces such as countertops and bench tops.
  • the ex vivo methods are exemplified, but not limited to, methods performed on the surface of the human body, such as on the hands.
  • the therapeutically effective amount of the compounds of the present invention and the amounts sufficient to achieve the stated goals of the methods disclosed herein vary depending upon the physical characteristics of the subject, the severity of the subject's symptoms, the formulation and the means used to administer the compounds, and the method being practiced.
  • the specific dose for a given subject is usually set by the judgment of the attending physician.
  • a therapeutically effective and/or sufficient amount of the compounds of the present invention is typically between about 1 mg/kg body weight to 500 mg/kg body weight, and may be between 1 to 100 mg/kg, 5 to 200 mg/kg, 10 to 300 mg/kg, 1 to 50 mg/kg, and 5 to 50 mg/kg, regardless of the formulation.
  • Specific doses include about 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34 or 35 mg/kg body weight, regardless of the formulation. In some situations, a dose less than 1 mg/kg body weight or greater than 500 mg/kg body weight may be effective.
  • the weight ratio of the compound of present invention and an antibiotic and/or ⁇ -lactamase inhibitor if the compound is being administered with an antibiotic or ⁇ -lactamase inhibitor will normally be in the range from 1 :20 to 20:1 .
  • dose refers to physically discrete units that contain a predetermined quantity of active ingredient calculated to produce a desired therapeutic effect. These terms are synonymous with the therapeutically effective amounts and amounts sufficient to achieve the stated goals of the methods disclosed herein.
  • Suitable frequencies of administration may vary based on whether administration is for the purposes of treatment or prevention. However, administration frequencies of doses for the treatment or prevention of a bacterial infection will include 4, 3, 2 or once daily, every other day, every third day, every fourth day, every fifth day, every sixth day, once weekly, every eight days, every nine days, every ten days, bi-weekly, monthly and bi-monthly.
  • the dosage may be administered all at once, such as with an oral formulation in a capsule, or slowly over a period of time, such as with an intravenous administration.
  • the administering period can be a matter of minutes, such as about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 1 10, 1 15, 120 or more minutes, or a period of hours, such as about 0.5, 1 , 1 .5, 2, 2.5, 3, 3.5, 4, 4.5, 5 or more hours.
  • the terms “inhibit”, “inhibiting” and “inhibition” have their ordinary and customary meanings, and include one or more of inhibiting growth of bacteria, inhibiting a function of bacteria, and inhibiting propagation of bacteria.
  • Such inhibition is an inhibition of about 1 % to about 100% of the particular activity versus the activity in a subject to which a compound of the present invention has not been administered.
  • the inhibition is an inhibition of about 100%, 99%, 98%, 97%, 96%, 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5% or 1 % of the activity versus a subject to which a compound of the invention has not been administered.
  • the terms “treating” and “treatment” mean at least the mitigation of a disease condition or symptom associated with a bacterial infection in a subject that is achieved by a reduction of growth, replication, and/or propagation, or death or destruction of bacteria, on or in the subject.
  • the terms “treating” and “treatment” include curing, healing, inhibiting, relieving from, improving and/or alleviating, in whole or in part, the disease condition.
  • the mitigation of a disease condition or symptom may be about 100%, 99%, 98%, 97%, 96%, 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5% or 1 % in the subject, versus a subject to which a compound of the invention has not been administered.
  • treating means reducing the population of bacteria causing the infection in the subject to an undetectable level, where detection is by any conventional means, such culturing a sample in the laboratory.
  • treating means complete healing of the infection, shown by an absence of clinical symptoms associated with the infection.
  • treating means the mitigation of a disease condition or symptom by at least about 90% in the subject.
  • treating means the mitigation of a disease condition or symptom by at least about 95% in the subject.
  • the terms "preventing” and “prevention” have their ordinary and customary meanings, and includes one or more of preventing colonization of bacteria in a subject, preventing development of a disease caused by bacteria in a subject, and preventing symptoms of a disease caused by bacteria in a subject. As used herein, the prevention lasts at least about 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 45, 50 or more days after administration of a compound of the present invention.
  • the term "contacting” is meant to broadly refer to bringing a bacterial cell and a molecule of a compound of the present invention into sufficient proximity that the compound can exert an effect on the bacterial cell.
  • the compound may be transported to the location of the bacterial cell, or the compound may be situated in a location to which the bacterial cell travels or is brought into contact.
  • the skilled artisan will understand that the term “contacting” includes physical interaction between a compound of the invention and a bacterial cell, as well as interactions that do not require physical interaction.
  • a "subject" refers to an animal, such as a mammalian or an avian species, including a human, an ape, a horse, a cow, a sheep, a goat, a dog, and a cat.
  • the subject may have a bacterial infection, may be at risk for developing a bacterial infection, or may be at greater risk than the general population for developing a bacterial infection.
  • subjects having a higher risk for bacterial infection include patients undergoing treatment for bacterial infections whereby normal gut flora is inhibited by antimicrobial therapy, patients with impaired immune function (e.g., immunoglobulin deficiency, splenic dysfunction, splenectomy, HIV infection, impaired leukocyte function, hemoglobinopathies), the elderly (Loo et al., 2005. NEJM 353:2442), people with certain malignancies (e.
  • impaired immune function e.g., immunoglobulin deficiency, splenic dysfunction, splenectomy, HIV infection, impaired leukocyte function, hemoglobinopathies
  • the elderly Lio et al., 2005. NEJM 353:2442
  • people with certain malignancies e.
  • multiple myeloma, chronic lympocytic leukemia, lymphoma people at increased occupational risk (e.g., public services workers, such a fire, water, sanitary, police, medical, and laboratory workers, hospital workers), people in closed populations (e.g., prisons, military, nursing homes) and others that have immunological deficiencies that might enhance their susceptibility to bacterial infection.
  • occupational risk e.g., public services workers, such a fire, water, sanitary, police, medical, and laboratory workers, hospital workers
  • closed populations e.g., prisons, military, nursing homes
  • DIAD diisopropyl azodicarboxylate
  • DIPEA diisopropyl ethyl amine
  • FAB fast atom bombardment g: gram(s) h: hour(s)
  • HOBt A -hydroxybenzotriazole HATU : 2-(7-aza-1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate
  • LiBu' ferf-butyl lithium
  • LHMDS lithium hexamethyl disilazane m : multiplet mL: milliliter(s) mmol: millimole(s)
  • NFSi N-fluorobenzenesulfonamide
  • NaBH(OAc) 3 sodium triacetoxyborohydride
  • PhSeBr phenyl selenium bromide
  • Step 1 6-Benzyl 5-fert-butyl (6S)-4-oxo-5-azaspiro[2.4]heptane-5,6-dicarboxylate (2):
  • DMSO (10 mL) was added to a mixture of trimethylsulfoxonium iodide (1 .60 g, 7.31 mmol) and potassium tert-butoxide (0.74 g, 7.00 mmol) in tetrahydrofuran (8 mL) at room temperature. The mixture was stirred for 0.5 h and cooled to - 12 °C. A solution of 6-benzyl 5-terf-butyl (6S)-4-oxo-5-azaspiro[2.4]heptane-5,6-dicarboxylate 2 (from Step 1 , 2.2 g, 6.37 mmol) in tetrahydrofuran (7 mL) was added slowly.
  • Step 3 Benzyl (5S)-8-[(benzyloxy)imino]-6-azaspiro[2.5]octane-5-carboxylate (5):
  • Step 4 Benzyl (5S)-8-[(benzyloxy)amino]-6-azaspiro[2.5]octane-5-carboxylate (6):
  • Step 5 Benzyl (1 S,4/?)-7-(benzyloxy)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1 '- cyclopropane]-4-carboxylate (7A):
  • Step 6 (1 S,4fi)-7-(Benzyloxy)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1 '- cyclopropane]-4-carboxylic acid (8):
  • the aqueous phase was isolated and the organic phase was extracted with water (2 x 5 mL).
  • the extracts and aqueous phase were combined, washed with a mixture of isopropyl ether-ethyl acetate (8/2 vol./vol., 6 mL), acidified with saturated NaH 2 P0 4 and extracted with ethyl acetate (3 x 20 mL).
  • Step 7 fert-Butyl 3-[(2- ⁇ [(1 S,4fi)-7-(benzyloxy)-6-oxo-5,7- diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropan]-4- yl]carbonyl ⁇ hydrazinyl)carbonyl]azetidine-1-carboxylate (10):
  • Step 8 fert-Butyl 3-[(2- ⁇ [(1S,4fi)-7-hydroxy-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane- 2,1'-cyclopropan]-4-yl]carbonyl ⁇ hydrazinyl)carbonyl]azetidine-1-carboxylate (11):
  • Step 9 fert-Butyl 3-[(2- ⁇ [(1 S,4fi)-6-oxo-7-(sulfooxy)-5,7- diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropan]-4- yl]carbonyl ⁇ hydrazinyl)carbonyl]azetidine-1-carboxylate (12):
  • Step 10 (1 S,4fi)-W-(Azetidin-3-ylcarbonyl)-6-oxo-7-(sulfooxy)-5,7- diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropane]-4-carbohydrazide (Compound 62, Table 2):
  • Step 1 fert-butyl (3S)-3-[( ⁇ [(1 /?,4S)-7-(benzyloxy)-6-oxo-5,7- diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropan]-4- yl]carbonyl ⁇ amino)oxy]pyrrolidine-1 -carboxylate (3):
  • Step 2 fert-butyl (3S)-3-[( ⁇ [(1/?,4S)-7-hydroxy-6-oxo-5,7- diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropan]-4- yl]carbonyl ⁇ amino)oxy]pyrrolidine-1-carboxylate (4):
  • Step 3 fert-butyl (3S)-3-[( ⁇ [(1 /?,4S)-6-oxo-7-(sulfooxy)-5,7- diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropan]-4- yl]carbonyl ⁇ amino)oxy]pyrrolidine-1 -carboxylate (5):
  • Step 4 (1 /?,4S)-6-oxo-A/-[(3S)-pyrrolidin-3-yloxy]-7-(sulfooxy)-5,7- diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropane]-4-carboxamide (Compound 151 , Table 1 ):
  • Step 1 (ferf-butyl ⁇ 2-[( ⁇ [(1 R,4S)-7-(benzyloxy)-6-oxo-5,7- diazaspiro[bicyclo[3.2.1 joctane-2,1 '-cyclopropan]-4- yl]carbonyl ⁇ amino)oxy]ethyl ⁇ carbamate (3):
  • Step 2 ferf-butyl ⁇ 2-[( ⁇ [(1/?,4S)-7-hydroxy-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane- 2,1'-cyclopropan]-4-yl]carbonyl ⁇ amino)oxy]ethyl ⁇ carbamate (4):
  • Step 4 (1 /?,4S)-A/-(2-aminoethoxy)-6-oxo-7-(sulfooxy)-5,7- diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropane]-4-carboxamide (Compound 61 , Table 1 ):
  • reaction mixture was concentrated under vacuo, washed with ether (2 x) and trituarated with a mixture of methanol-ether (1 :5, 6 x) to provide (1 fl,4S)-/V-(2-aminoethoxy)-6-oxo-7- (sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropane]-4-carboxamide
  • Step 1 (1 /?,4S)-W-acetyl-7-(benzyloxy)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1 '- cyclopropane]-4-carbohydrazide (3):
  • Step 2 (1 /?,4S)-W-acetyl-7-hydroxy-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1 '- cyclopropane]-4-carbohydrazide (4):
  • Step 3 (1 /?,4S)-W-acetyl-6-oxo-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '- cyclopropane]-4-carbohydrazide (Compound 55, Table 2):
  • Step 1 (1 S,2S,5fi)-3-(ferf-Butoxycarbonyl)-4-oxo-3-azabicyclo[3.1.0]hexane-2- carboxylic acid (2):
  • the reaction was quenched by addition of isopropanol (250 mL) and slow addition of saturated NaHC0 3 (100 mL) at 0 °C.
  • the volatiles were removed under reduced pressure and the resultant mixture was diluted with water (150 mL) and ethyl acetate (340 mL).
  • the solution was then extracted with ether (3 x 200 mL) and the aqueous layer was acidified with 0.1 N HCI to pH 3 at 0 °C.
  • the acidifed solution was extracted with ethyl acetate (3 x 200 mL).
  • Step 2 2-Benzyl 3-fert-butyl (1 S,2S,5fi)-4-oxo-3-azabicyclo[3.1.0]hexane-2,3- dicarboxylate (3):
  • DMSO (12 ml_) was added to a mixture of trimethylsulfoxonium iodide (1 .74 g, 7.97 mmol) and potassium fert-butoxide (0.81 g, 7.63 mmol) in tetrahydrofuran (9 ml_) at room temperature. The mixture was stirred for 0.5 h and cooled to - 12 °C. A solution of 2-benzyl 3-terf-butyl (1 S,2S,5ft)-4-oxo-3-azabicyclo[3.1 .0]hexane-2,3-dicarboxylate 3 (2.3 g, 6.94 mmol) in tetrahydrofuran (8 ml_) was added slowly.
  • Step 4 Benzyl (1 S,2S,5Z,6fi)-5-[(benzyloxy)imino]-3-azabicyclo[4.1.0]heptane-2- carboxylate (6):
  • Step 5 Benzyl (1 S,2S,6/3 ⁇ 4-5-[(benzyloxy)amino]-3-azabicyclo[4.1.0]heptane-2- carboxylate (7):
  • Step 6 Benzyl (1 S,2S,4/?,5/?)-8-(benzyloxy)-7-oxo-6,8-diazatricyclo[4.2.1.0 2 ' 4 ]nonane-5- carboxylate (8):
  • Step 7 (1 S,2S,4/?,5fi)-8-(Benzyloxy)-7-oxo-6,8-diazatricyclo[4.2.1.0 2,4 ]nonane-5- carboxylic acid (9):
  • the aqueous phase was separated out and the organic phase was extracted with water (2 x 5 mL).
  • the extracts and aqueous phase were combined, washed with a mixture of isopropyl ether-ethyl acetate (8/2 vol./vol., 6 mL), acidified with saturated NaH 2 P0 4 and extracted with ethyl acetate (3 x 20 mL).
  • Step 8 fert-Butyl ⁇ 2-[( ⁇ [(1S,2S,4/?,5/?)-8-(benzyloxy)-7-oxo-6,8- diazatricyclo[4.2.1.0 2 ' 4 ]non-5-yl]carbonyl ⁇ amino)oxy]ethyl ⁇ carbamate (11):
  • Step 9 fert-butyl ⁇ 2-[( ⁇ [(1 S,2S,4/?,5/?)-8-hydroxy-7-oxo-6,8-diazatricyclo[4.2.1.0 2 ' 4 ]non- 5-yl]carbonyl ⁇ amino)oxy]ethyl ⁇ carbamate (12):
  • Step 10 fert-butyl ⁇ 2-[( ⁇ [(1 S,2S,4/?,5/?)-7-oxo-8-(sulfooxy)-6,8- diazatricyclo[4.2.1.0 2 ' 4 ]non-5-yl]carbonyl ⁇ amino)oxy]ethyl ⁇ carbamate (13):
  • Step 11 (1 S,2S,4/?,5fi)-A/-(2-aminoethoxy)-7-oxo-8-(sulfooxy)-6,8- diazatricyclo[4.2.1.0 2 >onane-5-carboxamide (Compound 93, Table 1):
  • Table 3 Synergistic activity of test compounds in combination with Ceftazidime against enterobacteriacae
  • Organism Enzyme(s) CAZ (Compd 62, (Compd 151, (Compd 61, (Compd 55,
  • K. pneumoniae KPC-2 >64 ⁇ 0.12 64 ⁇ 0.12
  • Efficacy of the ⁇ -lactamase inhibitors can be evaluated in combination with ceftazidime (CAZ), aztreonam (AZT), meropenem (MER) and other class of cephalosporins and carbapenems in murine infection models such as septicemia, pneumoniae and thigh infection models (Ref: Andrea Endimiani et. ai. Antimicrob. Agents and Chemother an 201 1 , pp-82-85).
  • CAZ ceftazidime
  • AZT aztreonam
  • MER meropenem
  • CAZ colony forming units
  • the survival ratio is monitored for 5 days twice daily.
  • the dosing regimen used are CAZ alone (doses of 512, 1024 & 2048 mg/kg of body weight) and CAZ plus ⁇ -lactamase inhibitor at ratio of 2:1 , 4:1 , 8:1 & 16:1 (CAZ doses are 4, 8, 16, 32 & 64 mg/kg for each ratio).
  • the median effective dose for 50% (ED 50 ) of animals is determined by a computerized program of Probit analysis. Survival rates stratified for different dosing regimen are also obtained.
  • ED 50 The median effective dose for 50% (ED 50 ) of animals is determined by a computerized program of Probit analysis. Survival rates stratified for different dosing regimen are also obtained.
  • For experimental pneumoniae model immunocompromised mice are used and intratracheal ⁇ infected with Klebsiella pneumoniae strains. Mice in this model develop bacteraemia pneumoniae and fatal disease within 2 to 4 days with lung bacterial burden at 16-18 hrs post infection of 10 11 to 10 13 cfu/gm lung.
  • Treatment with CAZ and inhibitor at a ratio of 2/1 & 4/1 demonstrate efficacy with significant 3 to 6 log reduction in lung counts compared to CAZ alone and is relevant to the clinical situation.
  • Human testing of the ⁇ -lactamase inhibitor can be conducted in combination with partner antibiotic at a set ratio utilizing standard clinical development practice.

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Abstract

The present invention relates to new heterocyclic compounds, their preparation and their use as β−lactamase inhibitors in combination with one or more antibiotics for the treatment of infections caused by β−lactamase-producing pathogenic bacteria.

Description

NEW HETEROCYCLIC COMPOUNDS AND THEIR USE AS ANTIBACTERIAL AGENTS AND β-LACTAMASE INHIBITORS
Field of the invention
[0001 ] The present invention relates to chemical compounds for use in the treatment of bacterial infections in animals, such as humans, means for synthesizing such compounds, and methods of medical treatment and prevention using such compounds.
Background of the invention
[0002] Microbial drug resistance is an unavoidable consequence resulting from abuse and overuse of antimicrobial agents. The rate at which resistance arises among microbial populations is often dictated by the extent of use of particular agents in a given environment. Given the degree of popularity of β-lactam antibiotics, it is not surprising that the prevalence of β-lactamase producing strains is increasing worldwide. Such bacterial strains are characterized by varying degrees of resistance to β-lactam antibiotics. The most significant known mechanism related to the development of bacterial resistance to the β-lactam antibiotics is bacterial production of class-A, class-B, class-C and class-D β-lactamases, resulting in bacteria that are able to hydrolyze the β-lactam antibiotics and thus lose susceptibility to the antibacterial activity of this class of drugs. Class-A enzymes preferentially hydrolyze penicillins, class-B enzymes hydrolyze all β-lactams including carbapenems, class-C β-lactamases have a substrate profile favoring cephalosporin hydrolysis, whereas substrate preference for class D β-lactamases include oxacillin and cloxacillin.
[0003] The possibility of rescuing individual β-lactam antibiotics by combination with a β-lactamase inhibitor that inactivates the β-lactamase enzyme before it can hydrolyze the β-lactam antibiotic has been demonstrated with clinically useful combination between penicillins such as amoxicillin, ampicillin, piperacillin and ticarcillin and β-lactamase inhibitors such as clavulanic acid, sulbactam and tazobactam. Further potential combinations have been described involving various β-lactam antibiotics and newly reported β-lactamase inhibitors including bicyclic monobactams, exomethylene penems and 7-oxo-6- diazabicyclo[3.2.1 ]octane-2-carboxamide derivatives (NXL-104, also called avibactam). Recently, certain diazabicyclic compounds have been disclosed as β-lactamase inhibitors in WO 2009/091856. In addition, a number of diazabicyclic heterocydes have been disclosed in the following patents and patent application publications as β-lactamase inhibitors: US 2003/0199541 A1 , US 2004/0157826 A1 , US 2004/0097490 A1 , US 2005/0020572 A1 , US 2006/71 12592 B2, US 2006/0189652 A1 , US 2008/7439253 B2, US 2009/0018329 A1 , EP 1307457 B1 , EP 15371 17 B1 , WO 2002/100860 A2, WO 2002/10172 A1 , WO 2003/063864 A2, WO 2004/052891 A1 , WO 2004/022563 A1 , WO 2008/142285 A1 , WO 2009/090320 A1 , US 2010/0092443 A1 , WO 2010/126820 A2, US 2012/0165533 A1 , WO 2012/172368, WO 2013/180197, WO 2013/030735, WO 2013/038330, WO 2013/030733, US 2013/0345190, US 2013/0296555, US 2013/0296293, US 2013/0303504, US 2013/0296290, US
2013/0296292, US 2013/0296291 , US 2013/0289012, WO 2013/149121 .
[0004] As a result of point mutations and plasmid transfer, the diversity of β-lactamases is increasing constantly. The current commercially available β-lactamase inhibitors are insufficient to counter these new β-lactamases - they are particularly ineffective against class C producing organisms, newly emerged extended-spectrum β-lactamases (ESBLs) and carbapenemases like IMP, VIM, OXA, KPC, and NDM. Thus there is a need for broad- spectrum β-lactamase inhibitors to combat over 1000 β-lactamases including the newly emerged β-lactamases. Brief Summary
[0005] The present invention relates to new heterocyclic compounds, their preparation, and their use as β-lactamase inhibitors, either alone or in combination with (i) another β-lactamase inhibitor and/or (ii) one or more antibiotics in the treatment of infections caused by bacteria, such as β-lactamase-producing bacteria. More particularly, the invention is concerned with methods for overcoming antibiotic resistance caused by β-lactamase producing bacteria, methods of preparation of the new compounds, pharmaceutical compositions containing the new compounds, methods of treatment or prevention using the new compounds, and other subject matter.
[0006] The compounds of the present invention are new and the structural features are significantly distinct from compounds described to date.
[0007] In a first embodiment, the present invention is directed to compounds of formula (I) :
Figure imgf000004_0001
wherein:
Y = H, -OR1 or -NR2R3;
R is -SO3M, -OSO3M, -OS02NH2, -OPO3M, -OCH2COOM, -OCF2COOM,
-OCH(CH3)COOM, -OC(CH3)2COOM, -OCF3, -OCH2S03M, or -OCH2P03M2, where M is hydrogen or a pharmaceutically acceptable salt-forming cation;
A and B are:
(1 ) different from each other and each is independently selected from CH2, CF2 and C(CH3)2, (2) A and B together form an aromatic ring system or a heteroaromatic ring system,
(3) one of A and B is a C3.6 membered ring forming a spiro system, and the other of A and B is CH2,
(4) one of A and B is C4.6 membered heterocyclic ring form ing a spiro system containing O as a heteroatom and the other of A and B is CH2, or
(5) A and B together form a cyclopropyl ring ; wherein when Y = -OR1 , R1 is a radical selected from one of the following groups:
(1 ) Ci-6 straight or branched chain alkyl which is optionally substituted,
(2) C3.7 cycloalkyl which is optionally substituted,
(3) C4-7 saturated heterocycle containing at least one heteroatom selected from O, N and S, wherein the heterocycle is optionally substituted, the ring S is optionally oxidized to S(O) or S(0)2, and the free ring N atom may optionally take a substituent,
(4) heterocyclyl (d-6) alkyl containing at least one heteroatom selected from O, N and S, wherein the heterocycle is optionally substituted, the ring S is optionally oxidized to S(O) or S(0)2, and the free ring N atom may optionally take a substituent, and
(5) unsubstituted C3.7 cycloalkyl which is optionally fused with a C5.7 membered saturated heterocycle to form a bicyclic ring system , wherein the bicyclic ring is optionally substituted; wherein when Y = -NR2R3, R2 is hydrogen and R3 is a radical selected from one of the following groups:
(1 ) C1-6 straight or branched chain alkyl which is optionally substituted,
(2) C3.7 cycloalkyl which is optionally substituted, (3) C4-7 saturated heterocycle containing at least one heteroatom selected from O, N and S, wherein the heterocycle is optionally substituted, the ring S is optionally oxidized to S(O) or S(0)2, and the free ring N atom may optionally take a substituent,
(4) C1-6 straight or branched chain alkyl carbonyl which is optionally substituted,
(5) C3.7 cycloalkyl carbonyl which is optionally substituted,
(6) C4-7 membered saturated heterocyclyl carbonyl containing at least one heteroatom selected from O, N and S, wherein the heterocycle is optionally substituted, the ring S is optionally oxidized to S(O) or S(0)2, and the free ring N atom may optionally take a substituent,
(7) C3.7 membered saturated heterocyclyl (Ci-6) alkyl carbonyl containing at least one heteroatom selected from O, N and S, wherein the heterocycle is optionally substituted, the ring S is optionally oxidized to S(O) or S(0)2, and the free ring N atom may optionally take a substituent,
(8) C6-io aryl carbonyl which is optionally substituted,
(9) C6.10 aryl (Ci-6) alkyl carbonyl which is optionally substituted,
(10) C5-6 membered heteroaryl carbonyl containing at least one heteroatom selected from O, N and S, and wherein the heteroaryl is optionally substituted,
(1 1 ) C5-6 membered heteroaryl (Ci-6) alkyl carbonyl containing at least one heteroatom selected from O, N and S, and wherein the heteroaryl is optionally substituted,
(12) CF3CO-, CH3S02-, NH2CO-, or NH2S02-,
(13) C6-io aryl which is optionally substituted,
(14) C5-6 membered heteroaryl which is optionally substituted, and (15) R2 and R3 together form a ring system which is optionally substituted, and wherein the ring optionally contains another heteroatom selected from O, N, and S; or a deuterated compound of any such compound.
[0008] In certain aspects of this embodiment, the radical R1 is optionally substituted with one or two substituents independently selected from the group consisting of lower alkyl, amino, substituted amino, alkoxy, hydroxyalkyl, halogen, hydroxy, carboxy, alkoxycarbonyl, haloalkyi, trifluoromethyl, trifluoromethyloxy, alkylamine, substituted alkylamine, carboxamide, thiocarboxamide, sulfonic acid, sulphate, acylamino, sulfonylamino, substituted or unsubstituted sulfonamide, substituted or unsubstituted urea, substituted or unsubstituted thiourea, oxo, hydroxamic acid, acyl, trifluoromethyl carbonyl, cyano, amidino, guanidino, aryloxy, heterocyclylalkyloxy, and heteroaryloxy.
[0009] In certain aspects of this embodiment, R is -OS03M where M is hydrogen or a pharmaceutically acceptable salt-forming cation.
[0010] In certain aspects of this embodiment, when A and B together form an aromatic ring system or a heteroaromatic ring system, the ring system is selected from the group consisting of a pyrazolo group, a thieno group, a methylpyrazolo group, a furano group, a thiazolo group, a pyridine group, an oxazolo group, an imidazole group, a benzo group, and an ethanoimidazo group.
[0011 ] Specific examples of compounds encompassed by this embodiment include, but are not limited to, those compounds provided in Tables 1 and 2 herein.
[0012] In a second embodiment, the present invention is directed to pharmaceutical compositions comprising one or more compounds of the first embodiment, i.e., the compounds of formula (I) (e.g., the compounds provided in Tables 1 and 2), and a pharmaceutically acceptable carrier or diluent. In certain aspects of this embodiment, the pharmaceutical compositions further comprise one or more β-lactamase inhibitors, or one or more antibacterial agents, or both one or more β-lactamase inhibitors and one or more antibacterial agents.
[0013] In a third embodiment, the present invention is directed to methods of preventing or treating a bacterial infection in a subject comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of the first embodiment, i.e. , the compounds of formula (I) (e.g., the compounds provided in Tables 1 and 2). In certain aspects, the bacterial infection is caused by bacteria producing one or more β- lactamase enzymes.
[0014] In certain aspects of this embodiment, the method comprises administering to a subject in need thereof a therapeutically effective amount of (a) one or more compounds of the first embodiment, i.e., the compounds of formula (I) (e.g., the compounds provided in Tables 1 and 2), and (b) one or more β-lactamase inhibitor.
[0015] In certain aspects of this embodiment, the method comprises administering to a subject in need thereof a therapeutically effective amount of (a) one or more compounds of the first embodiment, i.e., the compounds of formula (I) (e.g., the compounds provided in Tables 1 and 2), and (b) one or more antibacterial agent.
[0016] In certain aspects of this embodiment, the method comprises administering to a subject in need thereof a therapeutically effective amount of (a) one or more compounds of the first embodiment, i.e., the compounds of formula (I) (e.g., the compounds provided in Tables 1 and 2), (b) one or more β-lactamase inhibitor, and (c) one or more antibacterial agent.
[0017] In a fourth embodiment, the present invention is directed to methods of preventing or treating a bacterial infection in a subject comprising administering to a subject in need thereof a therapeutically effective a pharmaceutical composition of the second embodiment, i.e. , one or more compounds of formula (I) and a pharmaceutically acceptable carrier or diluent. In certain aspects, the bacterial infection is caused by bacteria producing one or more β-lactamase enzymes. [0018] In certain aspects of this embodiment, the method comprises administering to a subject in need thereof a therapeutically effective amount of (a) a pharmaceutical composition of the second embodiment, i.e. , one or more compounds of formula (I) and a pharmaceutically acceptable carrier or diluent, and (b) one or more β-lactamase inhibitor.
[0019] In certain aspects of this embodiment, the method comprises administering to a subject in need thereof a therapeutically effective amount of (a) a pharmaceutical composition of the second embodiment, i.e. , one or more compounds of formula (I) and a pharmaceutically acceptable carrier or diluent, and (b) one or more antibacterial agent.
[0020] In certain aspects of this embodiment, the method comprises administering to a subject in need thereof a therapeutically effective amount of (a) a pharmaceutical composition of the second embodiment, i.e. , one or more compounds of formula (I) and a pharmaceutically acceptable carrier or diluent, (b) one or more β-lactamase inhibitor, and (c) one or more antibacterial agent.
[0021 ] In the noted embodiments, the β-lactamase inhibitors include, but are not limited to, sulbactam, tazobactam, and clavulanic acid, and pharmaceutically acceptable salts thereof.
[0022] In the noted embodiments, the antibacterial agents include, but are not limited to, β-lactam antibiotics, salts of β-lactam antibiotics, hydrates of β-lactam antibiotics, and prodrugs of β-lactam antibiotics, and pharmaceutically acceptable salts thereof. In a preferred aspects, the antibacterial agent is a β-lactam antibiotic or a pharmaceutically acceptable salt thereof. The antibacterial agents also include, but are not limited to, one or more members selected from the group consisting of aminoglycosides, ansamycins, carbacephems, cephalosporins, cephamycins, lincosamides, lipopeptides, macrolides, monobactams, nitrofurans, penems, penicillins, polypeptides, quinolones, sulphonamides, tetracyclines, and oxazolidinone, and pharmaceutically acceptable salts thereof. In certain preferred aspects, the antibacterial agent is one or more members selected from the group consisting of penicillins, penems, carbapenems, cephalosporins, and monobactams, and pharmaceutically acceptable salts thereof. In other aspects, the antibacterial agent is one or more cephalosporin antibiotics selected from the group consisting of cephalothin, cephaloridine, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cephradine, ceftizoxime, cefoxitin, cephacetrile, cefotiam, cefotaxime, cefsulodin, cefoperazone, ceftizoxime, cefmenoxime, cefmetazole, cephaloglycin, cefonicid, cefodizime, cefpirome, ceftobiprole, ceftolozane, ceftazidime, cefpiramide, cefbuperazone, cefozopran, cefepime, cefoselis, cefluprenam, cefuzonam, cefpimazole, cefclidin, cefixime, ceftibuten, cefdinir, cefpodoxime axetil, cefpodoxime proxetil, cefteram pivoxil, cefetamet pivoxil, cefcapene pivoxil or cefditoren pivoxil, cefuroxime, cefuroxime axetil, loracarbacef, ceftaroline, and latamoxef, and pharmaceutically acceptable salts thereof. In preferred aspects, the antibacterial agent is one or more members selected from the group consisting of ceftazidime, cefepime, cefpirome, piperacillin, doripenem, meropenem, imipenem, ceftaroline, ceftobiprole, and ceftolozane, and pharmaceutically acceptable salts thereof.
[0023] In each of the embodiments and aspects of the invention related to methods of preventing or treating, the subject may be a human.
Detailed Description
[0024] Novel low molecular weight heterocyclic compounds of formula (I) below are disclosed herein. These compounds of the invention can be used in combination with a β-lactam antibiotic or a non β-lactam antibiotic to enhance the activity of the antibiotic against class A, class B, class C, and class D β-lactamase enzyme producing organisms. Thus, the compounds of the invention can be used to enhance the antibacterial properties of antibiotics, both those now known and those yet to be developed. Furthermore, some of the compounds of the present invention also possess innate, potent antibacterial activity, particularly against Gram negative bacteria. The compounds of the present invention are therefore useful in the treatment of bacterial infections in humans or in animals, either alone or in combination with (i) β-lactam antibiotics and/or ηοη-β-lactam antibiotics, (ii)
β-lactamase inhibitors, or (iii) both antibiotics and β-lactamase inhibitors. [0025] In accordance with the present invention, there are provided (A) compounds of general formula (I), (B) pharmaceutically acceptable salts of the compounds of formula (I), (C) pharmaceutically acceptable solvates of the compounds of formula (I) and of their salts, and (D) deuterated compounds of compounds of (A), (B) and (C), namely, (i) compounds of formula (I) modified in that they have been deuterated, (ii) pharmaceutically acceptable salts of compounds of formula (I) modified in that they have been deuterated, and (iii) pharmaceutically solvates of compounds of formula (I) and of their salts modified in that they have been deuterated. Collectively, these compounds are termed herein "compounds of the invention" and "compounds of the present invention".
[0026] The compounds of formula (I) are as follows:
Figure imgf000011_0001
wherein:
Y = H, -OR1 or -NR2R3;
R is -SO3M, -OSO3M, -OS02NH2, -OPO3M, -OCH2COOM, -OCF2COOM, - OCH(CH3)COOM, -OC(CH3)2COOM, -OCF3, -OCH2S03M, -OCH2P03M2, where M is hydrogen or a pharmaceutically acceptable salt-forming cation; preferably R is -OS03M where M is hydrogen or a pharmaceutically acceptable salt-forming cation ;
A and B are:
(1 ) different from each other and each is independently selected from CH2, CF2, and C(CH3)2,
(2) A and B together form an aromatic ring system or a heteroaromatic ring system, such as pyrazolo group, a thieno group, a methylpyrazolo group, a furano group, a thiazolo group, a pyridine group, an oxazolo group, an imidazole group, a benzo group, or an ethanoimidazo group,
(3) one of A and B is C3.6 membered ring forming a spiro system, and the other of A and B is CH2,
(4) one of A and B is C4.6 membered heterocyclic ring forming a spiro system containing O as a hetero-atom, and the other of A and B is CH2, or
(5) A and B together for a cyclopropyl ring.
[0027] In formula (I), when Y = -OR1 , R1 is a radical selected from one of the following groups:
(1 ) Ci-6 straight or branched chain alkyl which is optionally substituted,
(2) C3.7 cycloalkyl which is optionally substituted,
(3) C4-7 saturated heterocycle containing at least one heteroatom selected from O, N and S, wherein the heterocycle is optionally substituted, the ring S is optionally oxidized to S(O) or S(0)2, and the free ring N atom may optionally take a substituent,
(4) heterocyclyl (Ci-6) alkyl containing at least one heteroatom selected from O, N and S, wherein the heterocycle is optionally substituted, the ring S is optionally oxidized to S(O) or S(0)2, and the free ring N atom may optionally take a substituent, and
(5) unsubstituted C3.7 cycloalkyl which is optionally fused with a C5.7 membered saturated heterocycle to form a bicyclic ring system, wherein, the bicyclic ring is optionally substituted.
[0028] Several non-limiting examples of the compounds of the present invention and of formula (I) when Y = -OR1 as described above are mentioned in Table 1 :
Figure imgf000013_0001
Y = OR1 , R = OSO3H
Figure imgf000013_0002
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
[0029] In formula (I), when Y = -NR2R3, R2 is hydrogen and R3 is a radical selected from one of the following groups:
(1 ) Ci-6 straight or branched chain alkyl which is optionally substituted,
(2) C3.7 cycloalkyl which is optionally substituted,
(3) C4-7 saturated heterocycle containing at least one heteroatom selected from O, N and S, wherein the heterocycle is optionally substituted, the ring S is optionally oxidized to S(O) or S(0)2, and the free ring N atom may optionally take a substituent,
(4) C1-6 straight or branched chain alkyl carbonyl which is optionally substituted,
(5) C3.7 cycloalkyl carbonyl which is optionally substituted,
(6) C4-7 membered saturated heterocyclyl carbonyl containing at least one heteroatom selected from O, N and S, wherein the heterocycle is optionally substituted, the ring S is optionally oxidized to S(O) or S(0)2, and the free ring N atom may optionally take a substituent, (7) C3.7 membered saturated heterocyclyl (C^) alkyl carbonyl containing at least one heteroatom selected from O, N and S, wherein the heterocycle is optionally substituted, the ring S is optionally oxidized to S(O) or S(0)2, and the free ring N atom may optionally take a substituent,
(8) C6-io aryl carbonyl which is optionally substituted,
(9) C6.10 aryl (C^) alkyl carbonyl which is optionally substituted,
(10) C5-6 membered heteroaryl carbonyl containing at least one heteroatom selected from O, N and S, and wherein the heteroaryl is optionally substituted,
(1 1 ) C5-6 membered heteroaryl (d.6) alkyl carbonyl containing at least one heteroatom selected from O, N and S, and wherein the heteroaryl is optionally substituted,
(12) CF3CO-, CH3SO2-, NH2CO-, or NH2S02-,
(13) C6-io aryl which is optionally substituted,
(14) C5-6 membered heteroaryl which is optionally substituted, and
(15) R2 and R3 together form a ring system which is optionally substituted, and wherein the ring optionally contains another heteroatom selected from O, N, and S.
[0030] Several non-limiting examples of the compounds of the present invention and of formula (I) when Y = -NR2R3 as described above are mentioned in Table 2:
Figure imgf000033_0001
Y = NR2R3 , R OSO3H Table 2
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
[0031] As used herein, a "pharmaceutically acceptable salt" refers to a salt of a compound, which salt possesses the desired pharmacological activity of the parent compound (i.e., when M is a pharmaceutically acceptable salt-forming cation, the compound possesses the desired pharmacological activity that the compound would have if M were instead a hydrogen atom). As used herein, reference to specified compounds "modified in that they have been deuterated" refers to compounds obtained by modifying the specified compounds so that one or more hydrogen atoms in the compound have been replaced with or converted to deuterium.
[0032] As used herein, a "pharmaceutically acceptable solvate" refers to a molecular complex of a compound with one or more solvent molecules in a stoichiometric or non- stoichiometric amount. Such solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to recipient, e.g., water, ethanol, and the like. A molecular complex of a compound or moiety of a compound and a solvent can be stabilized by non-covalent intra-molecular forces such as, for example, electrostatic forces, Van der Waals forces or hydrogen bonds. The term hydrate refers to a complex where the one or more solvent molecules are water.
[0033] Examples of the groups for forming a pharmaceutically acceptable salt in the formula (I) include: inorganic base salts, ammonium salts, organic base salts, basic amino acid salts, inorganic acid addition salts, and organic acid addition salts. Inorganic bases that can form the inorganic base salts include alkali metals (e.g., sodium, potassium, and lithium) and alkaline earth metals (e.g., calcium and magnesium). Organic bases that can form the organic base salts include n-propylamine, n-butylamine, cyclohexylamine, benzylamine, octylamine, ethanolamine, diethanolamine, diethylamine, triethylamine, dicyclohexylamine, procaine, choline, N-methylglucamine, morpholine, pyrrolidine, piperidine, N-ethylpiperidine and N-methylmorpholine. Basic amino acids that can form the basic amino acid salts include lysine, arginine, ornithine and histidine. As will be appreciated by one skilled in the art, the compounds of formula (I) containing a basic nitrogen atom are capable of forming acid addition salts. Such salts with pharmaceutically acceptable acids are included in the invention. Examples of such acids are hydrochloric, hydrobromic, phosphoric, sulphuric, citric, oxalic, maleic, fumaric, glycolic, mandelic, tartaric, aspartic, succinic, malic, formic, acetic, trifluoroacetic, methanesulfonic, ethanesulfonic, trifluoromethanesulfonic, benzenesulfonic, p-toluenesulfonic and the like.
[0034] Moreover, some compounds of formula (I) when they contain a basic group such as NH, NH2 or pyridine and the like may form an inner, zwitterionic salt with S03H, OS03H, CH2COOH; such inner salts are also included in this invention.
[0035] The present invention includes all possible isomers of formula (I). As used herein, the term 'isomers' refers to compounds that have the same molecular formula as a selected compound, but differ in arrangement and configuration of the atoms, such as geometrical isomers and optical isomers. For a given compound of the present invention, it is understood that a substituent may be attached at a chiral center of a carbon atom. Therefore the invention includes enantiomers, diastereoisomers or racemates of the compound. By definition 'enantiomers' are a pair of stereoisomers that are non-superimposable mirror images of each other, and 1 :1 mixture of a pair of enantiomers is a racemic mixture. By definition, 'diastereoisomers' are stereoisomers that have at least two asymmetric carbon atoms but which are not mirror-images of each other. When a compound of formula (I) is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S.
[0036] Compounds may also exist in several tautomeric forms including the enol form, the keto form, and mixtures of any of the foregoing. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated compounds.
[0037] A variety of protecting groups conventionally used in the β-lactam field to protect a reactive functional group present in the molecule of formula (I) can be used. 'Protecting group' refers to a group of atoms that when attached to a reactive functional group in a molecule masks, reduces or prevents reactivity of the functional group. Examples of protecting groups can be found in Green et al., "Protective Groups in Organic Chemistry", (Wiley, 2nd, 1991 ) and Harrison et al., "Compendium of Synthetic Organic Methods," Vols. 1 - 8 (John Wiley and Sons, 1971 -1996). Representative amino protecting groups include, but are not limited to formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ), tert- butoxycarbonyl (Boc), trimethylsilyl (TMS), 2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC), nitro- veratryloxycarbonyl (NVOC), and the like. Examples of hydroxy protecting groups include, but are not limited to, those where the hydroxyl group is either acylated or alkylated such as benzyl, and trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers, and allyl ethers.
[0038] The term Optionally substituted' refers to compounds of the invention that are unsubstituted or substituted. When the compounds are substituted, they may be substituted with one or two of the following substituents, each of which is independently selected from :
-Lower alkyl including from one to six carbon atoms in any arrangement, e.g., methyl, ethyl, i-propyl or t-butyl -Amino
-Substituted amino such as -NHCH3, -N(CH3)2 , -NHCH2CH3, -NHPr', -NHBu',
Figure imgf000048_0001
-Alkoxy such as -OCH3, -OC2H5 , -OPr1 (i.e. , isopropyloxy), -OBu' (i.e., isobutyloxy)
-Hydroxyalkyl such as -CH2OH, -CH2CH2OH
-Halogen such as F, CI, Br
-Hydroxy
-Carboxy
-Alkoxycarbonyl such as -COOCH3, -COOC2H5, -COOPr1, and -COOBu'
-Haloalkyl such as -CH2CI, -CH2F
-Trifluoromethyl
-Trifluoromethyloxy
-Alkylamine such as -CH2NH2, -CH2CH2NH2
-Substituted alkylamine such as -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3,
-CH2CH2N(CH3)2, N' -Carboxamide
-Thiocarboxamide
-Sulfonic acid
-Sulfate
-Acylamino
-Sulfonylamino
-Sulfonamide
-Substituted sulfonamide such as -S02NHCH3, -S02NHCH2CH3, -SOsNHPr1, -S02NHBu',
-Urea (-NHCONH2) which may be optionally substituted -Thiourea (-NHCSNH2) which may be optionally substituted -Sulfonylurea (-NHS02NH2) which may be optionally substituted -Oxo (=0) when oxygen is bonded through double bond to a carbon atom -Hydroxamic acid (-CONHOH) -Acyl (-COCH3)
-Trifluoromethyl carbonyl (-COCF3) -Cyano (-CN)
-Amidino -C(=NH)NH2 which may be optionally substituted
-Guanidino -NHC(=NH)NH2 which may be optionally substituted
-Aryloxy
-Heterocyclyl
-Heteroaryl
-Heterocyclyloxy
-Heteroaryloxy
-Heterocyclylalkyloxy
-T alkylammonium
[0039] The substituent mentioned above could be substituted at the carbon atom or at the free N-atom of the molecule as appropriate.
Pharmaceutical Compositions
[0040] The present invention also provides pharmaceutical compositions comprising one or more compounds of formula (I) and a pharmaceutically acceptable carrier or diluent. These pharmaceutical compositions can be formulated for administration to a subject by various routes. Depending on the identity of the components included in the compositions, suitable routes include, but are not limited to, oral, sublingual, intranasal, intraocular, rectal, transdermal, mucosal, topical or parenteral administration. Parenteral modes of
administration include without limitation, intradermal, subcutaneous (s.c, s.q., sub-Q, Hypo), intramuscular (i.m.), intravenous (i.v.), intraperitoneal (i.p.), intra-arterial, intramedulary, intracardiac, intra-articular (joint), intrasynovial (joint fluid area), intracranial, intraspinal, and intrathecal (spinal fluids). Any known device useful for parenteral injection or infusion of drug formulations can be used to effect such administration.
[0041 ] Suitable pharmaceutical carriers for use in the pharmaceutical compositions generally include excipients such as starch, glucose, lactose, sucrose, gelatin, gum arabic, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. Other examples of suitable pharmaceutical carriers have been described in the art (Remington's Science and Practice of Pharmacy, 21 s' Edition, 2006). Suitable pharmaceutical diluents generally include water, water-for- injection, saline (e.g., 0.9% saline), buffered saline, a 5% glucose solution, glycerol, ethanol, propylene glycol, polysorbate 80 (Tween-80™), poly(ethylene)glycol 300 and 400 (PEG 300 and 400), PEGylated castor oil (e.g. Cremophor EL), poloxamer 407 and 188, and combinations thereof.
[0042] Pharmaceutical compositions, if desired, can also contain minor amounts of wetting, dispersing or emulsifying agents, or pH buffering agents, and preservatives. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be included.
Pharmaceutical compositions can be formulated in a conventional manner. Proper formulation is dependent upon the route of administration chosen and the identity of the compounds. The pharmaceutical compositions can take the form of injectable preparations, suspensions, emulsions, sugar-coated tablets, pellets, gelatin-capsules, capsules containing liquids, powders, granules, sustained-release formulations, suppositories, aerosols, sprays, ointments, creams or any other form suitable for use. [0043] Formulations for parenteral administration can be in the form of aqueous or nonaqueous isotonic sterile injection solutions, suspensions or fat emulsions. The parenteral form used for injection must be fluid to the extent that easy syringability exists. These solutions or suspensions can be prepared from sterile concentrated liquids, powders or granules.
[0044] Excipients used in parenteral preparations also include, without limitation, stabilizing agents (e.g. carbohydrates, amino acids and polysorbates, such as 5% dextrose), solubilizing agents (e.g. cetrimide, sodium docusate, glyceryl monooleate,
polyvinylpyrolidone (PVP) and polyethylene glycol (PEG)), surfactants (e.g. polysorbates, tocopherol PEG succinate, poloxamer and Cremophor™), buffers (e.g. acetates, citrates, phosphates, tartrates, lactates, succinates, amino acids and the like), antioxidants and preservatives (e.g. BHA, BHT, gentisic acids, vitamin E, ascorbic acid, sodium ascorbate and sulfur containing agents such as sulfites, bisulfites, metabisulfites, thioglycerols, thioglycolates and the like), tonicity agents (for adjusting physiological compatibility), suspending or viscosity agents, antibacterials (e.g. thimersol, benzethonium chloride, benzalkonium chloride, phenol, cresol and chlorobutanol), chelating agents, and
administration aids (e.g. local anesthetics, anti-inflammatory agents, anti-clotting agents, vaso-constrictors for prolongation and agents that increase tissue permeability), and combinations thereof.
[0045] Parenteral formulations using hydrophobic carriers include, for example, fat emulsions and formulations containing lipids, lipospheres, vesicles, particles and liposomes. Fat emulsions include in addition to the above-mentioned excipients, a lipid and an aqueous phase, and additives such as emulsifiers (e.g. phospholipids, poloxamers, polysorbates, and polyoxyethylene castor oil), and osmotic agents (e.g. sodium chloride, glycerol, sorbitol, xylitol and glucose). Liposomes include natural or derived phospholipids and optionally stabilizing agents such as cholesterol. [0046] In another embodiment, the parenteral unit dosage form of the compounds of the invention can be a ready-to-use solution of the compound in a suitable carrier in sterile, hermetically sealed ampoules or in sterile pre-loaded syringes. The suitable carrier optionally comprises any of the above-mentioned excipients.
[0047] Alternatively, the unit dosage of the compounds of the invention can be in a concentrated liquid, powder or granular form for ex tempore reconstitution in the appropriate pharmaceutically acceptable carrier, such as sterile water, at the time of delivery. In addition to the above-mentioned excipients, powder forms optionally include bulking agents (e.g. mannitol, glycine, lactose, sucrose, trehalose, dextran, hydroxyethyl starch, ficoll and gelatin), and cryo or lyoprotectants.
[0048] In intravenous (IV) use, a sterile formulation of the pharmaceutical compositions of the present invention and optionally one or more additives, including solubilizers or surfactants, can be dissolved or suspended in any of the commonly used intravenous fluids and administered by infusion. Intravenous fluids include, without limitation, physiological saline, phosphate buffered saline, 5% dextrose in water or Ringer's™ solution.
[0049] In intramuscular preparations, a sterile formulation of the pharmaceutical
compositions of the present invention can be dissolved and administered in a pharmaceutical diluent such as Water-for-lnjection (WFI), physiological saline or 5% dextrose in water. A suitable insoluble form of the pharmaceutical compositions may be prepared and
administered as a suspension in an aqueous base or a pharmaceutically acceptable oil base, e.g. an ester of a long chain fatty acid such as ethyl oleate
[0050] For oral use, the oral pharmaceutical composition may be made in the form of a unit dosage containing a therapeutically-effective amount of the pharmaceutical compositions. Solid formulations such as tablets and capsules are particularly useful. Sustained released or enterically coated preparations may also be devised. For pediatric and geriatric applications, suspension, syrups and chewable tablets are especially suitable. For general oral administration, excipient or additives include, but are not limited to inert diluents, fillers, disintegrating agents, binding agents, wetting agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservatives.
[0051 ] For therapeutic purposes, the tablets and capsules can contain, in addition to the compounds of the invention, conventional carriers such as inert diluents (e.g., sodium and calcium carbonate, sodium and calcium phosphate, and lactose), binding agents (e.g., acacia gum, starch, gelatin, sucrose, polyvinylpyrrolidone (Povidone), sorbitol, tragacanth methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and ethylcellulose), fillers (e.g., calcium phosphate, glycine, lactose, maize-starch, sorbitol, or sucrose), wetting agents, lubricating agents (e.g., metallic stearates, stearic acid, polyethylene glycol, waxes, oils, silica and colloical silica, silicon fluid or talc), disintegrating agents (e.g., potato starch, corn starch and alginic acid), flavouring (e.g. peppermint, oil of wintergreen, fruit flavoring, cherry, grape, bubblegum, and the like), and coloring agents. Carriers may also include coating excipients such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.
[0052] For topical formulations of compounds of the present invention, creams, gels, ointments or viscous lotions can be used as appropriate delivery forms. Topical delivery systems also include transdermal patches containing at least one compound of formula (I) to be administered. Delivery through the skin can be achieved by diffusion or by more active energy sources such as iontophoresis or electrotransport. Formulations of a compound of the present invention, for topical use, such as in creams, ointments, and gels, can include an oleaginous or water soluble ointment base, for example, topical compositions can include vegetable oils, animal fats, and in certain embodiments, semisolid hydrocarbons obtained from petroleum. Topical compositions can further include white ointment, yellow ointment, cetyl esters wax, oleic acid, olive oil, paraffin, petrolatum, white petrolatum, spermaceti, starch glycerite, white wax, yellow wax, lanolin, and glyceryl monostearate. Various water- soluble ointment bases can also be used, including glycol ethers and derivatives, polyethylene glycols, polyoxyl 40 stearate, and polysorbates. [0053] In a pharmaceutical composition containing a compound of this invention, the weight ratio of active ingredient to carrier will normally be in the range of 1 :20 to 20:1 .
[0054] In another aspect, the present invention provides for the use, in the manufacture of a medicament, of one or more compounds within formula (I) as an active ingredient in an antibacterial composition in admixture with a carrier or diluent.
[0055] In another aspect, the present invention provides for the use, in the manufacture of a medicament, of one or more compounds within formula (I) as an active ingredient.
[0056] In another aspect, the present invention provides for the use, in the manufacture of a medicament, of one or more compounds within formula (I) as an active ingredient, along with one or more antibiotics (e.g., a β-lactam antibiotic or a non β-lactam antibiotic), in an antibacterial composition in admixture with a carrier or diluent.
[0057] In another aspect, the present invention provides for the use, in the manufacture of a medicament, of one or more compounds within formula (I) as an active ingredient, along with one or more antibiotics (e.g., a β-lactam antibiotic or a non β-lactam antibiotic).
[0058] In another aspect, the present invention provides for the use, in the manufacture of a medicament, of one or more compounds within formula (I) as an active ingredient, along with one or more β-lactamase inhibitors, in an antibacterial composition in admixture with a carrier or diluent.
[0059] In another aspect, the present invention provides for the use, in the manufacture of a medicament, of one or more compounds within formula (I) as an active ingredient, along with one or more β-lactamase inhibitors.
[0060] In another aspect, the present invention provides for the use, in the manufacture of a medicament, of one or more compounds within formula (I) as an active ingredient, along with (i) one or more antibiotics (e.g., a β-lactam antibiotic or a non β-lactam antibiotic) and (ii) one or more β-lactamase inhibitors, in an antibacterial composition in admixture with a carrier or diluent. [0061 ] In another aspect, the present invention provides for the use, in the manufacture of a medicament, of one or more compounds within formula (I) as an active ingredient, along with (i) one or more antibiotics (e.g., a β-lactam antibiotic or a non β-lactam antibiotic) and (ii) one or more β-lactamases inhibitors.
Pharmaceutical Compositions Comprising Other Agents
[0062] In certain aspects, the pharmaceutical compositions of the invention can be supplemented to include one or more antibiotic agents (e.g., β-lactam antibiotics and/or non β-lactam antibiotics). In certain other aspects, the pharmaceutical compositions of the invention can be supplemented to include one or more β-lactamase inhibitors. In certain further aspects, the pharmaceutical compositions of the invention can be supplemented to include both (i) one or more antibiotic agents and (ii) one or more β-lactamase inhibitors.
[0063] The term 'β-lactam antibiotic' refers to a compound with antibiotic property that contains a β-lactam functionality. Examples of β-lactam antibiotics which can be used in combination with the compounds of the present invention represented by formula (I) are commonly marketed penicillins, cephalosporins, penems, carbapenems and monobactams.
[0064] Particular examples of β-lactam antibiotics included, but are not limited to, penicillins, such as amoxicillin, ampicillin, azlocillin, mezlocillin, apalcillin, hetacillin, bacampicillin, carbenicillin, sulbenicillin, ticarcillin, piperacillin, methicillin, ciclacillin, talampicillin, oxacillin, cloxacillin, dicloxacillin and commonly used cephalosporins such as cephalothin, cephaloridine, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cephradine, cephapirin, cefuroxime, cefoxitin, cephacetrile, cefotiam, cefotaxime, cefatriazine, cefsulodin, cefoperazone, ceftizoxime, cefmenoxime, cefmetazole, cephaloglycin, cefonicid, cefodizime, cefpirome, cefepime, ceftazidime, cefpiramide, ceftriaxone, cefbuperazone, cefprozil, cefixime, ceftobiprole, ceftaroline, cefalonium, cefminox, ceforanide, cefuzonam, cefoxitin, cefotetan, loracarbef, cefdinir, cefditoren, cefetamet, cefcapene, cefdaloxime, ceftibuten, cefroxadine, latamoxef (moxalactam), and CXA-101 . From the carbapenem class of β-lactam antibiotics such as imipenem, meropenem, panipenem, biapenem, doripenem, ertapenem and the like could be used. From monobactam class of β-lactam antibiotics such as aztreonam, carumonam, tigemonam, and the like could be used as the combination partner of antibiotic.
[0065] Examples of antibiotics which are not β-lactam antibiotics and which can be used in combination with the compounds of the present invention include, but are not limited to, aminoglycosides, quinolones, tetracyclines, glycylcyclines, glycopeptides, lipopeptides, macrolides, ketolides, lincosamides, streptogramin, oxazolidinones, polymyxins, and other compounds known to have antibacterial properties.
[0066] Examples of β-lactamase inhibitors which can be used in combination with the compounds of the present invention represented by formula (I) are sulbactam, tazobactam, and clavulanic acid, and pharmaceutically acceptable salts thereof.
Methods of Preventing and Treating
[0067] The present invention also provides methods for the prevention or treatment of bacterial infections in a subject. The invention includes methods of preventing or treating a bacterial infection in a subject comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of formula (I) (e.g., compounds provided in Tables 1 and 2), thereby preventing or treating a bacterial infection in a subject.
[0068] The methods of the invention may also be practiced by administering to a subject in need thereof a therapeutically effective amount of (a) one or more compounds of formula (I), and (b) one or more β-lactamase inhibitor.
[0069] The methods of the invention may also be practiced by administering to a subject in need thereof a therapeutically effective amount of (a) one or more compounds of formula (I), and (b) one or more antibacterial agent. [0070] The methods of the invention may further be practiced by administering to a subject in need thereof a therapeutically effective amount of (a) one or more compounds of formula (I), (b) one or more β-lactamase inhibitor, and (c) one or more antibacterial agent.
[0071 ] In certain aspects, the bacterial infections that may be prevented or treated are caused by bacteria producing one or more β-lactamase enzymes and a β-lactam antibiotic is administered as the antibacterial agent to the subject along with one or more compounds of formula (I). In such aspects, the compounds of the invention increase the antibacterial effectiveness of β-lactamase susceptible β-lactam antibiotics, that is, they increase the effectiveness of the antibiotic against infections caused by β-lactamase producing microorganisms in mammalian subjects, particularly in human. In these aspects of the present invention, this makes the compounds of formula (I) and pharmaceutically acceptable salts thereof, valuable for co-administration with β-lactam antibiotics. In the prevention or treatment of a bacterial infection in such aspects of the invention, the compounds of formula (I) or a pharmaceutically salt thereof can be mixed with the β-lactam antibiotic, and the two agents thereby administered simultaneously. When co-administered with a β-lactam antibiotic in such aspects of the present invention, the combination of the compound of the invention and the antibiotic can provide a synergistic effect. The term 'synergystic effect' refers to the effect produced when two or more agents are co-administered and the resulting antibacterial effect is greater than the effect produced when the agents are administered individually. Alternatively, the compound of formula (I) or a salt thereof can be administered as a separate agent during a course of prevention or treatment with the antibiotic. Thus, the compounds of the invention can be used in methods of prevention or treatment, where they are administered before, concurrently with, or after administration of an antibiotic to the subject.
[0072] Suitable β-lactamase inhibitors include, but are not limited to, sulbactam, tazobactam, and clavulanic acid, and pharmaceutically acceptable salts thereof. [0073] Suitable antibacterial agents included, but are not limited to, β-lactam antibiotics, salts of β-lactam antibiotics, hydrates of β-lactam antibiotics, prodrugs of β-lactam antibiotics, and pharmaceutically acceptable salts thereof. Other suitable antibacterial agents include aminoglycosides, ansamycins, carbacephems, cephalosporins, cephamycins, lincosamides, lipopeptides, macrolides, monobactams, nitrofurans, penems, penicillins, polypeptides, quinolones, sulphonamides, tetracyclines, oxazolidinone, and pharmaceutically acceptable salts thereof.
[0074] The methods of the present invention will generally be practiced by administering the compounds of the invention to a subject as a pharmaceutical composition, as defined herein. However, it should be understood that each of the methods of the invention may be practiced by directly administering the compounds of the invention to a subject.
[0075] In a further embodiment, the present invention includes in vitro and ex vivo methods of killing or inhibiting the growth of a bacterial population by contacting a population of bacteria with an effective amount of one or more of the compounds of the invention. Such methods may also be practiced by contacting a population of bacteria with an effective amount of (a) one or more compounds of the invention and (b) one or more β-lactamase inhibitor; (a) one or more compounds of the invention and (b) one or more antibacterial agent; and (a) one or more compounds of the invention, (b) one or more β-lactamase inhibitor, and (c) one or more antibacterial agent. The in vitro methods are exemplified, but not limited to, methods performed in a laboratory setting, such as in a cell culture, as well as methods performed on inert objects such as laboratory or hospital equipment and devices, surfaces such as countertops and bench tops. The ex vivo methods are exemplified, but not limited to, methods performed on the surface of the human body, such as on the hands.
[0076] The therapeutically effective amount of the compounds of the present invention and the amounts sufficient to achieve the stated goals of the methods disclosed herein vary depending upon the physical characteristics of the subject, the severity of the subject's symptoms, the formulation and the means used to administer the compounds, and the method being practiced. The specific dose for a given subject is usually set by the judgment of the attending physician. However, a therapeutically effective and/or sufficient amount of the compounds of the present invention is typically between about 1 mg/kg body weight to 500 mg/kg body weight, and may be between 1 to 100 mg/kg, 5 to 200 mg/kg, 10 to 300 mg/kg, 1 to 50 mg/kg, and 5 to 50 mg/kg, regardless of the formulation. Specific doses include about 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34 or 35 mg/kg body weight, regardless of the formulation. In some situations, a dose less than 1 mg/kg body weight or greater than 500 mg/kg body weight may be effective. The weight ratio of the compound of present invention and an antibiotic and/or β-lactamase inhibitor (if the compound is being administered with an antibiotic or β-lactamase inhibitor) will normally be in the range from 1 :20 to 20:1 .
[0077] The terms "dose", "unit dose", "unit dosage", or "effective dose" refer to physically discrete units that contain a predetermined quantity of active ingredient calculated to produce a desired therapeutic effect. These terms are synonymous with the therapeutically effective amounts and amounts sufficient to achieve the stated goals of the methods disclosed herein.
[0078] Suitable frequencies of administration may vary based on whether administration is for the purposes of treatment or prevention. However, administration frequencies of doses for the treatment or prevention of a bacterial infection will include 4, 3, 2 or once daily, every other day, every third day, every fourth day, every fifth day, every sixth day, once weekly, every eight days, every nine days, every ten days, bi-weekly, monthly and bi-monthly.
[0079] Depending on the means of administration, the dosage may be administered all at once, such as with an oral formulation in a capsule, or slowly over a period of time, such as with an intravenous administration. For slower means of administration, the administering period can be a matter of minutes, such as about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 1 10, 1 15, 120 or more minutes, or a period of hours, such as about 0.5, 1 , 1 .5, 2, 2.5, 3, 3.5, 4, 4.5, 5 or more hours. [0080] As used herein, the terms "inhibit", "inhibiting" and "inhibition" have their ordinary and customary meanings, and include one or more of inhibiting growth of bacteria, inhibiting a function of bacteria, and inhibiting propagation of bacteria. Such inhibition is an inhibition of about 1 % to about 100% of the particular activity versus the activity in a subject to which a compound of the present invention has not been administered. Preferably, the inhibition is an inhibition of about 100%, 99%, 98%, 97%, 96%, 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5% or 1 % of the activity versus a subject to which a compound of the invention has not been administered.
[0081 ] As used herein, the terms "treating" and "treatment" mean at least the mitigation of a disease condition or symptom associated with a bacterial infection in a subject that is achieved by a reduction of growth, replication, and/or propagation, or death or destruction of bacteria, on or in the subject. The terms "treating" and "treatment" include curing, healing, inhibiting, relieving from, improving and/or alleviating, in whole or in part, the disease condition. The mitigation of a disease condition or symptom may be about 100%, 99%, 98%, 97%, 96%, 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5% or 1 % in the subject, versus a subject to which a compound of the invention has not been administered. In one aspect, treating means reducing the population of bacteria causing the infection in the subject to an undetectable level, where detection is by any conventional means, such culturing a sample in the laboratory. In another aspect, treating means complete healing of the infection, shown by an absence of clinical symptoms associated with the infection. In further aspect of the invention, treating means the mitigation of a disease condition or symptom by at least about 90% in the subject. In an additional aspect, treating means the mitigation of a disease condition or symptom by at least about 95% in the subject.
[0082] As used herein, the terms "preventing" and "prevention" have their ordinary and customary meanings, and includes one or more of preventing colonization of bacteria in a subject, preventing development of a disease caused by bacteria in a subject, and preventing symptoms of a disease caused by bacteria in a subject. As used herein, the prevention lasts at least about 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 45, 50 or more days after administration of a compound of the present invention.
[0083] As used herein, the term "contacting" is meant to broadly refer to bringing a bacterial cell and a molecule of a compound of the present invention into sufficient proximity that the compound can exert an effect on the bacterial cell. The compound may be transported to the location of the bacterial cell, or the compound may be situated in a location to which the bacterial cell travels or is brought into contact. The skilled artisan will understand that the term "contacting" includes physical interaction between a compound of the invention and a bacterial cell, as well as interactions that do not require physical interaction.
[0084] As used herein, a "subject" refers to an animal, such as a mammalian or an avian species, including a human, an ape, a horse, a cow, a sheep, a goat, a dog, and a cat. The subject may have a bacterial infection, may be at risk for developing a bacterial infection, or may be at greater risk than the general population for developing a bacterial infection. Examples of subjects having a higher risk for bacterial infection include patients undergoing treatment for bacterial infections whereby normal gut flora is inhibited by antimicrobial therapy, patients with impaired immune function (e.g., immunoglobulin deficiency, splenic dysfunction, splenectomy, HIV infection, impaired leukocyte function, hemoglobinopathies), the elderly (Loo et al., 2005. NEJM 353:2442), people with certain malignancies (e. g., multiple myeloma, chronic lympocytic leukemia, lymphoma), people at increased occupational risk (e.g., public services workers, such a fire, water, sanitary, police, medical, and laboratory workers, hospital workers), people in closed populations (e.g., prisons, military, nursing homes) and others that have immunological deficiencies that might enhance their susceptibility to bacterial infection.
Examples
[0085] In the examples, the following abbreviations will be used: Bn: benzyl
BnONH2: benzyl hydroxyl amine Boc: N-fert-butoxycarbonyl br s: broad singlet CDCI3: deuterated chloroform CD3OD: deuterated methanol CH20: formaldehyde CH2N2: diazomethane
(CH2=NMe2)+l" :Eschenmoser's salt, dimethylmethyleneiminium iodide d: doublet
D20: deuterium oxide
DCC: Λ/,Λ/'-dicyclohexylcarbodiimide
DCM: dichloromethane
DMP: 2,2-dimethoxy propane
DIAD: diisopropyl azodicarboxylate
DIPEA: diisopropyl ethyl amine
DMAP: 4-dimethylaminopyridine
DMSO: dimethyl sulfoxide
EDCI: 1 -(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride
El : electron impact
ES: electron spray
FAB: fast atom bombardment g: gram(s) h: hour(s)
HOBt: A -hydroxybenzotriazole HATU : 2-(7-aza-1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate
HPLC: high-performance liquid chromatography H202: hydrogen peroxide Hz: Hertz
J: coupling constant
KO'Bu: potassium ferf-butoxide
LDA: lithium diisopropyl amide
LiOH: lithium hydroxide
LiBu': ferf-butyl lithium
LHMDS: lithium hexamethyl disilazane m : multiplet mL: milliliter(s) mmol: millimole(s)
Mel : methyl iodide
MeNHNH2: methyl hydrazine
(MeO)2CHN(Me)2 : Ν,Ν-Dimethylformamide dimethyl acetal Me3SOI : trimethyl sulfoxonium iodide
MSA: methane sulfonic acid
MHz: megahertz
MS: mass spectrometry m/z: mass-to-charge ratio
NFSi : N-fluorobenzenesulfonamide NaBH(OAc)3 :sodium triacetoxyborohydride
NMR: nuclear magnetic resonance
PhSeBr: phenyl selenium bromide
Pd/C: palladium on carbon
Pd(OAc)2: palladium acetate
PyBop: (benzotriazol-1 -yloxy)tripyrrolidinophosphonium hexafluorophosphate s: singlet
t: triplet
TBS-CI: ferf-butyldimethylsilyl chloride
TFA: trifluoroacetic acid
THF: tertrahydrofuran
TsOH: p-toluene sufonic acid
p-TsCI: p-toluene sulfonyl chloride
δ: chemical shift in parts per million (ppm) by frequency
[0086] The compounds of the present invention of formula (I) where Y = OR1 or Y = NR can be readily prepared by the following reaction Schemes 1 -6.
Scheme 1
Figure imgf000065_0001
Boc20
DMAP
Figure imgf000065_0002
(Y=H, OR',NR2R3) Scheme 2
Figure imgf000066_0001
DIPEA, triphosgene
DCM
Figure imgf000066_0002
Scheme 3
Figure imgf000067_0001
Scheme 4
Figure imgf000068_0001
Scheme 5
Figure imgf000069_0001
KOBu'
Figure imgf000069_0002
Y NH2
EDCI, HOBt (Y= H, OR1, NR2R3)
Figure imgf000069_0003
Scheme 6
Figure imgf000070_0001
13 14
[0087] Compounds of general formula (I) where Y = OR1 or NR2R3 and R = OS03H can be prepared by coupling an appropriately substituted hydroxylamine or the substituted hydrazine with the intermediate acid as described in US 2013/0225554 which is incorporated herein by reference in its entirety.
Example 1 (Compound 62, Table 2)
(1 S,4fi)-W-(Azetidin-3-ylcarbonyl)-6-oxo-7-(sulfooxy)-5,7- diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropane]-4-carbohydrazide:
Figure imgf000071_0001
Compound 62, Table 2
Step 1 : 6-Benzyl 5-fert-butyl (6S)-4-oxo-5-azaspiro[2.4]heptane-5,6-dicarboxylate (2):
Figure imgf000071_0002
2
[0088] To a solution of Pd(OAc)2 (0.3 g, 1 .4 mmol) and 2-benzyl 1 -terf-butyl (2S)-4- methylidene-5-oxopyrrolidine-1 ,2-dicarboxylate 1 (2.5 g, 7.54 mmol) in diethyl ether (45 mL) was added a solution of CH2N2 in diethyl ether (75 mL) at - 10 °C over 20 min. and the reaction mixture was further stirred as it was allowed to warm to room temperature overnight. The resulting suspension was filtered through Celite and the filtrate was concentrated in vacuo to give an oily residue which was purified by column chromatography on silica gel (EtOAc/hexane, 1 :4) to give 6-benzyl 5-fert-butyl (6S)-4-oxo-5-azaspiro[2.4]heptane-5,6- dicarboxylate 2 (2.2 g, 85%) as a clear thick oil. 1 H NMR (400 MHz, CDCI3): δ 0.74-0.82 (2H, m), 1.17 (1 H, m), 1 .28 (1 H, m), 1 .45 (9H, s), 1 .88 (1 H, m), 2.52 (1 H, m), 4.70 (1 H, m), 5.21 (2H, m), 7.35 (5H,m).
Figure imgf000072_0001
2 3 4
[0089] DMSO (10 mL) was added to a mixture of trimethylsulfoxonium iodide (1 .60 g, 7.31 mmol) and potassium tert-butoxide (0.74 g, 7.00 mmol) in tetrahydrofuran (8 mL) at room temperature. The mixture was stirred for 0.5 h and cooled to - 12 °C. A solution of 6-benzyl 5-terf-butyl (6S)-4-oxo-5-azaspiro[2.4]heptane-5,6-dicarboxylate 2 (from Step 1 , 2.2 g, 6.37 mmol) in tetrahydrofuran (7 mL) was added slowly. The mixture was stirred at - 12 °C for 4 h. The reaction was quenched by the addition of saturated aqueous ammonium chloride (10 mL) and water (7 mL). The product was extracted with ethyl acetate (30 mL) and the resulting organic solution was washed with brine, dried over Na2S04 and evaporated to give a residue. To a solution of this residue in ethyl acetate (20 mL) was added O- benzylhydroxylamine hydrochloride (1 .07 g, 6.68 mmol). The mixture was stirred at reflux overnight. The mixture was cooled and washed with water and brine. The organic layer was concentrated in vacuo to give benzyl 3-{1 -[/V-(benzyloxy)-2-chloroethanimidoyl]cyclopropyl}- /V-(ferf-butoxycarbonyl)-L-alaninate 4 (2.90 g, 90%) as a yellow oil which was used in the next step without purification.
Step 3: Benzyl (5S)-8-[(benzyloxy)imino]-6-azaspiro[2.5]octane-5-carboxylate (5):
Figure imgf000072_0002
4
[0090] To a solution of benzyl 3-{1 -[/V-(benzyloxy)-2-chloroethanimidoyl]cyclopropyl}-/V-(fert- butoxycarbonyl)-L-alaninate 4 (from Step 2, 2.90 g, 5.79 mmol) in ethyl acetate (8 mL) was added methanesulfonic acid (1 .23 mL, 19.13 mmol). The solution was stirred at 42 °C for 3 h and added to a solution of potassium bicarbonate (3.17 g, 31.83 mmol) in water (10 mL) and the resulting mixture was stirred vigorously at 52 °C for 2 h. The organic layer was washed with brine, dried over Na2S04 and concentrated to give benzyl (5S)-8-[(benzyloxy)imino]-6- azaspiro[2.5]octane-5-carboxylate 5 (1 .31 g, 62.5%) as a brown oil which was used in the next step without purification.
Step 4: Benzyl (5S)-8-[(benzyloxy)amino]-6-azaspiro[2.5]octane-5-carboxylate (6):
Figure imgf000073_0001
[0091 ] Propanoic acid (2.62 mL, 35.00 mmol) was added to a suspension of sodium borohydride (0.47 g, 12.71 mmol) in ethyl acetate (13 mL) and stirred for 0.5 h. The resulting solution was added to a solution of benzyl (5S)-8-[(benzyloxy)imino]-6-azaspiro[2.5]octane-5- carboxylate 5 (from Step 3, 1 .31 g, 3.59 mmol) in ethyl acetate (13 mL) and concentrated sulfuric acid (1.70 mL) at - 20 °C and stirred for 2 h. The reaction was quenched by the addition of water (26 mL), then neutralized with aqueous ammonia solution. The organic layer was washed with water, dried over Na2S04 and concentrated. The residue was purified by column chromatography using EtOAc/MeOH (96:4) as eluent to give benzyl (5S)-8- [(benzyloxy)amino]-6-azaspiro[2.5]octane-5-carboxylate 6 (0.72 g, 54.5%) as a brown oil.
Step 5: Benzyl (1 S,4/?)-7-(benzyloxy)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1 '- cyclopropane]-4-carboxylate (7A):
Figure imgf000073_0002
[0092] To a mixture of benzyl (5S)-8-[(benzyloxy)amino]-6-azaspiro[2.5]octane-5-carboxylate 6 (from Step 4, 0.72 g, 1.96 mmol) and diisopropylethylamine (1.63 mL) in dichloromethane (30 mL) was added dropwise a solution of triphosgene (0.48 g, 1.60 mmol) in
dichloromethane (20 mL) at room temperature. After 30 min, a dilute phosphoric acid solution (20 mL) was added, and the mixture was continued to stir overnight. The phases were separated and the organic phase was then dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography using
hexane:chloroform:ethyl acetate (7:2:1) as eluent to give benzyl (1 S,4R)-7-(benzyloxy)-6- oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1'-cyclopropane]-4-carboxylate 7A (0.27 g, 35%) as a thick clear oil.1H NMR (400 MHz, CDCI3): 50.02 (1H, m), 0.37 (2H, m), 0.48 (1H, m),1.51 (1H, d, J= 15.2 Hz), 2.33 (1H, s), 2.50 (1H, m), 3.04 (2H, m), 4.22 (1H, d, J= 8.4 Hz ), 4.85 (1H, d, J= 11.2 Hz), 5.01 (1H, d, J = 11.2 Hz), 5.17 (2H, m), 7.39 (10H, m).
[0093] And benzyl (1S,4R)-7-(benzyloxy)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1'- cyclopropane]-4-carboxylate 7B (0.046 g, 6%) as a clear thick oil.1H NMR (400 MHz, CDCI3): δ 0.05 (1H, m), 0.37 (1H, m), 0.56 (2H, m), 1.26 (1H, d, J= 15.2 Hz), 2.38 (1H, s), 2.60 (1H, m), 2.91 (1H, d, J= 11.2 Hz), 3.35 (1H, m), 3.80 (1H, m), 4.87 (1H, d, J= 11.2 Hz), 5.01 (1H, d, J = 11.2 Hz), 5.24 (2H, s), 7.39 (10H, m).
Step 6: (1 S,4fi)-7-(Benzyloxy)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1 '- cyclopropane]-4-carboxylic acid (8):
Figure imgf000074_0001
8
[0094] A solution of lithium hydroxide (20.00 mg, 0.84 mmol) in water (5 mL) was added dropwise to a solution of benzyl (1 S,4R)-7-(benzyloxy)-6-oxo-5,7- diazaspiro[bicyclo[3.2.1]octane-2,1'-cyclopropane]-4-carboxylate 7A (0.27 g, 0.69 mmol) in tetrahydrofuran (5 mL) at 0 °C. The reaction mixture was stirred at the same temperature for 2 h before adding a mixture isopropyl ether-ethyl acetate (8/2 vol./vol., 6 mL). The aqueous phase was isolated and the organic phase was extracted with water (2 x 5 mL). The extracts and aqueous phase were combined, washed with a mixture of isopropyl ether-ethyl acetate (8/2 vol./vol., 6 mL), acidified with saturated NaH2P04 and extracted with ethyl acetate (3 x 20 mL). The organic phases were combined, dried over sodium sulfate, filtered and evaporated to give (1 S,4R)-7-(benzyloxy)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2, 1 '- cyclopropane]-4-carboxylic acid 8 (0.15 g, 72%) as a white solid. 1 H NMR (400 MHz, CDCI3): δ 0.10 (1 H, m), 0.43 (1 H, m), 0.53 (2H, m), 1 .25 (1 H, s), 1 .66 (1 H, d, J= 15.2 Hz), 2.39 (1 H, s), 2.43 (1 H, m), 3.01 (1 H, d, J= 1 1 .2 Hz), 3.14 (1 H, m), 4.20 (1 H, d, J= 8.0 Hz ), 4.87 (1 H, d, J= 1 1 .2 Hz), 5.03 (1 H, d, J = 1 1 .2 Hz), 7.38 (5H, m).
Step 7: fert-Butyl 3-[(2-{[(1 S,4fi)-7-(benzyloxy)-6-oxo-5,7- diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropan]-4- yl]carbonyl}hydrazinyl)carbonyl]azetidine-1-carboxylate (10):
Figure imgf000075_0001
8 10
[0095] To a solution of (1 S,4R)-7-(benzyloxy)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '- cyclopropane]-4-carboxylic acid 8 (0.19 g, 0.63 mmol) in dry dichloromethane (20 mL) were added fert-butyl 3-(hydrazinylcarbonyl)azetidine-1 -carboxylate 9 (0.20 g, 0.95 mmol), 1 - hydroxybenzotriazole (0.133 g, 0.95 mmol), 1 -ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.182 g, 0.95 mmol) and 4-(dimethylamino)pyridine (0.112 g, 0.95 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, and then concentrated under vacuum. The residue was purified by column chromatography to give fert-butyl 3-[(2-{[(1 S,4R)-7-(benzyloxy)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '- cyclopropan]-4-yl]carbonyl}hydrazinyl)carbonyl]azetidine-1 -carboxylate 10 (0.19 g, 60%) as a white solid.1H NMR (400 MHz, CDCI3): δ 0.11(1H, m), 0.42 (1H, m), 0.51 (2H, m), 1.40 (9H, s), 1.75 (1H, d, J= 15.2 Hz), 2.28 (1H, m), 2.39 (1H, s), 3.10 (1H, m), 3.29 (2H, m), 4.07 (5H, m), 4.87 (1 H, d, J = 11.6 Hz), 5.01 (1 H, d, J = 11.6 Hz), 7.38 (5H, m), 8.72 (2H, br s).
Step 8: fert-Butyl 3-[(2-{[(1S,4fi)-7-hydroxy-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane- 2,1'-cyclopropan]-4-yl]carbonyl}hydrazinyl)carbonyl]azetidine-1-carboxylate (11):
Figure imgf000076_0001
10 11
[0096] To a solution of fert-butyl 3-[(2-{[(1 S,4R)-7-(benzyloxy)-6-oxo-5,7- diazaspiro[bicyclo[3.2.1]octane-2,1'-cyclopropan]-4-yl]carbonyl}hydrazinyl)carbonyl]azetidine- 1-carboxylate 10 (0.19 g, 0.38 mml) in methanol (10 ml_) was added 5% Pd/C (0.20 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 2 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give tert- butyl 3-[(2-{[(1 S,4R)-7-hydroxy-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1'-cyclopropan]- 4-yl]carbonyl}hydrazinyl)carbonyl]azetidine-1-carboxylate 11 (0.125 g, 87%) as a white solid. 1H NMR (400 MHz, CD3OD): δ 0.01 (1 H, m), 0.11(1H, m), 0.23 (1H, m), 0.38 (1H, m), 1.14 (9H, s), 1.46 (1H, d, J= 14.8Hz), 1.98 (1H, m), 2.64 (1H, m), 2.92 (1H, m), 3.08 (2H, m), 3.76 (5H, m), 3 protons were not observed in CD3OD.
Step 9: fert-Butyl 3-[(2-{[(1 S,4fi)-6-oxo-7-(sulfooxy)-5,7- diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropan]-4- yl]carbonyl}hydrazinyl)carbonyl]azetidine-1-carboxylate (12):
Figure imgf000077_0001
11 12
[0097] To a solution of fert-butyl 3-[(2-{[(1 S,4R)-7-hydroxy-6-oxo-5,7- diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropan]-4-yl]carbonyl}hydrazinyl)carbonyl]azetidine- 1 -carboxylate 11 (0.125 g, 0.305 mmol) in dry pyridine (6 ml_) under nitrogen atmosphere was added sulfur trioxide pyridine complex (0.31 g, 1 .96 mmol). The mixture was stirred at room temperature for 20 h, filtered and evaporated. The residue was purified by column chromatography using DCM: EtOAc: MeOH (20:30:50) as eluent to give fert-butyl 3-[(2- {[(1 S,4R)-6-oxo-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropan]-4- yl]carbonyl}hydrazinyl)carbonyl]azetidine-1 -carboxylate 12 (0.12 g, 80%) as a white solid. 1 H NMR (400 MHz, CD3OD): δ 0.31 (1 H, m), 0.42 (1 H, m), 0.52 (1 H, m), 0.77 (1 H, m), 1 .44 (9H, s), 1 .77 (1 H, d, J= 15.6 Hz), 2.27 (1 H, m), 3.77 (4H, m), 4.08 (5H, m), 3 protons were not observed in CD3OD.
Step 10: (1 S,4fi)-W-(Azetidin-3-ylcarbonyl)-6-oxo-7-(sulfooxy)-5,7- diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropane]-4-carbohydrazide (Compound 62, Table 2):
Figure imgf000077_0002
12 Compound 62, Table 2 [0098] To a solution terf-butyl 3-[(2-{[(1 S,4R)-6-oxo-7-(sulfooxy)-5,7- diazaspiro[bicyclo[3.2.1 ]octane-2 '-cyclopropan]-4-yl]carbonyl}hydrazinyl)carbonyl]azetidine- 1 -carboxylate 12 (0.12 g, 0.245 mmol) in dichloromethane (2.5 mL) was added trifluoroacetic acid (1 .00 mL) dropwise at 0 °C. The reaction mixture was stirred for 1 h, then evaporated. Ether was added to the residue and the resulting white precipitate was collected by centrifugation. The solid was triturated with a mixture of MeOH :ether (1 :5, 6 X) and the white solid was collected by centrifugation to give (1 S,4fi)-/V-(azetidin-3-ylcarbonyl)-6-oxo-7- (sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropane]-4-carbohydrazide
Compound 62 (Table 2) (0.05 g, 52.6%) as a white solid. 1 H NMR (400 MHz, D20): δ 0.01 (1 H, m), 0.09 (2H, m), 0.33 (1 H, m), 1 .33 (1 H, d, J= 15.6 Hz), 1 .87 (1 H, m), 2.95 (2H, m), 3.06 (1 H, m), 3.41 (1 H, m), 3.88 (5H, m), 4 protons were not observed in D20. MS (negative eletrospray) m/z: [M] = 388. HPLC 97.9%
Example 2 (Compound 151 , Table 1 )
Figure imgf000078_0001
Step 1 : fert-butyl (3S)-3-[({[(1 /?,4S)-7-(benzyloxy)-6-oxo-5,7- diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropan]-4- yl]carbonyl}amino)oxy]pyrrolidine-1 -carboxylate (3):
Figure imgf000078_0002
[0099] To a mixture of (1 R,4S)-7-(benzyloxy)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '- cyclopropane]-4-carboxylic acid 1 (0.203 g, 0.672 mmol) in dichloromethane (10.0 mL) were added fert-butyl (3S)-3-(aminooxy)pyrrolidine-1 -carboxylate 2 (0.204 g, 1 .008 mmol), 1 - hydroxybenzotriazole (0.136 g, 1.008 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.193 g, 1.008 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with dichloromethane, washed with water, brine, dried over sodium sulfate and concentrated to provide a residue, which was subjected to chromatography (silica gel, DCM: EtOAc: MeOH = 70: 27: 3) to give tert- butyl (3S)-3-[({[(1R,4S)-7-(benzyloxy)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1'- cyclopropan]-4-yl]carbonyl}amino)oxy]pyrrolidine-1-carboxylate 3 (0.280 g, 86 %) as a white foam.1H NMR (400 MHz, CDCI3): 50.07 (1H, m), 0.46-0.60 (3H, m), 1.46 (9H, s), 1.79-2.37 (6H, m), 2.88 (1H, d, J= 11.6 Hz), 3.06 (1H, m), 3.38-3.68 (3H, m), 4.07-4.11 (1H, m), 4.62 (1H, m), 4.89 (1H, d, J= 11.6 Hz), 5.04 (1H, d, J= 11.6 Hz), 7.40 (5H, m), 9.00 (1H, br s). MS (ES+) m/z: [M+H]+ calcd for C25H34N406: 486.25. Found: 487.1.
Step 2: fert-butyl (3S)-3-[({[(1/?,4S)-7-hydroxy-6-oxo-5,7- diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropan]-4- yl]carbonyl}amino)oxy]pyrrolidine-1-carboxylate (4):
Figure imgf000079_0001
[0100] A mixture of fert-butyl (3S)-3-[({[(1 R,4S)-7-(benzyloxy)-6-oxo-5,7- diazaspiro[bicyclo[3.2.1]octane-2,1'-cyclopropan]-4-yl]carbonyl}amino)oxy]pyrrolidine-1- carboxylate 3 (0.280 g, 0.48 mmol) and Pd/C (0.070 g) in methanol (15 mL) was hydrogenated at 35 psi at room temperature for 1.5 h. The mixture was filtered through celite pad and concentrated to provide fert-butyl (3S)-3-[({[(1R,4S)-7-hydroxy-6-oxo-5,7- diazaspiro[bicyclo[3.2.1]octane-2,1'-cyclopropan]-4-yl]carbonyl}amino)oxy]pyrrolidine-1- carboxylate 4 (0.226 g, quant, yield) as a light yellow foam.1H NMR (400 MHz, CD3OD): δ 0.33 (1H, m), 0.40 (1H, m), 0.57 (1H, m), 0.70 (1H, m), 1.28 (1H, m), 1.46 (9H, s), 1.72 (1H, d, J= 14.8 Hz), 1.85 (1H, d, J= 11.6 Hz), 2.01 (1H, m), 2.18-2.31 (2H, m), 2.95 (1H, d, J = 4.0 Hz), 3.12 (1 H, d, J = 11 .6 Hz), 3.24 (1 H, m), 3.35-3.50 (2H, m), 3.63 (1 H, d, J
4.00 (1 H, d, J = 8.0 Hz), 4.59 (1 H, m). 1 proton was not observed in CD3OD.
Step 3: fert-butyl (3S)-3-[({[(1 /?,4S)-6-oxo-7-(sulfooxy)-5,7- diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropan]-4- yl]carbonyl}amino)oxy]pyrrolidine-1 -carboxylate (5):
Figure imgf000080_0001
4 5
[0101 ] To a mixture of fert-butyl (3S)-3-[({[(1 R,4S)-7-hydroxy-6-oxo-5,7- diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropan]-4-yl]carbonyl}amino)oxy]pyrrolidine-1 - carboxylate 4 (0.224 g, 0.57 mmol) in pyridine (5.0 mL) was added sulfur trioxide pyridine complex (0.267 g, 1 .71 mmol). The mixture was stirred at room temperature for 16 h and concentrated to provide a residue which was subjected to chromatography (silica gel, DCM: EtOAc: MeOH = 5: 4: 1 ) to give fert-butyl (3S)-3-[({[(1 R,4S)-6-oxo-7-(sulfooxy)-5,7- diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropan]-4-yl]carbonyl}amino)oxy]pyrrolidine-1 - carboxylate 5 (0.107 g, 40 %) as a white solid. 1 H NMR (400 MHz, CD3OD): δ 0.35 (1 H, m), 0.44 (1 H, m), 0.57 (1 H, m), 0.79 (1 H, m), 1 .24 (1 H, t, J = 7.2 Hz), 1.47 (9H, s), 1 .74 (1 H, d, J = 15.2 Hz), 2.00 (1 H, m), 2.23 (2H, m), 3.15 (1 H, d, J = 11 .2 Hz), 3.35-3.47 (4H, m), 3.63 (1 H, m), 4.10 (1 H, m), 4.60 (1 H, s). 2 protons were not observed in CD3OD.
Step 4: (1 /?,4S)-6-oxo-A/-[(3S)-pyrrolidin-3-yloxy]-7-(sulfooxy)-5,7- diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropane]-4-carboxamide (Compound 151 , Table 1 ):
Figure imgf000080_0002
ble 1 [0102] To a mixture of ferf-butyl (3S)-3-[({[(1 R,4S)-6-oxo-7-(sulfooxy)-5,7- diazaspiro[bicyclo[3.2.1 ]octane-2 '-cyclopropan]-4-yl]carbonyl}amino)oxy]pyrrolidine-1 - carboxylate 5 (0.096 g, 0.2016 mmol) in dichloromethane (5.0 ml_) was added trifluoroacetic acid (2.0 ml_) at 0 °C. The mixture was stirred at 0 °C for 1 h, concentrated and washed with ether. The white solid was collected by centrifugation. The crude product was triturated with a mixture of MeOH-Ether (1 :5, 6x) to provide (1 ft,4S)-6-oxo-/V-[(3S)-pyrrolidin-3-yloxy]-7- (sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropane]-4-carboxamide
(Compound 151 , Table 1) (0. 042 g, 55 %) as a white solid. 1 H NMR (400 MHz, D20): δ 0.02 (2H, m), 0.16 (1 H, m), 0.27 (1 H, m), 1 .20 (1 H, d, J = 16.0 Hz), 1 .73-1 .83 (4H, m), 2.86-3.13 (6H, m), 3.61 (1 H, d, J = 8.0 Hz), 4.31 (1 H, m). 3 protons were not observed in D20. HPLC: 93.26 %, Rt = 6.097 min. MS (ES ) m/z: [M+H]+ calcd for C13H20N4O7S: 376.11. Found: 376.9.
Example 3 (Compound 61 , Table 1)
Figure imgf000081_0001
Step 1 : (ferf-butyl {2-[({[(1 R,4S)-7-(benzyloxy)-6-oxo-5,7- diazaspiro[bicyclo[3.2.1 joctane-2,1 '-cyclopropan]-4- yl]carbonyl}amino)oxy]ethyl}carbamate (3):
Figure imgf000081_0002
1 3
[0103] To a mixture of (1 R,4S)-7-(benzyloxy)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '- cyclopropane]-4-carboxylic acid 1 (0.201 g, 0.665 mmol) in dichloromethane (15.0 ml_) were added ferf-butyl [2-(aminooxy)ethyl]carbamate 2 (0.176 g, 1 .0 mmol), 1 -hydroxybenzotriazole (0.135 g, 1 .0 mmol), and 1 -ethyl-(3-dimethylamino propyl) carbodiimide hydrochloride (0.192 g, 1.0 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM, washed with water, brine, dried over sodium sulfate and concentrated to provide a residue which was subjected to chromatography (silica gel, DCM: EtOAc: MeOH = 70: 27: 3) to give ferf-butyl {2-[({[(1 R,4S)-7-(benzyloxy)-6-oxo-5,7- diazaspiro[bicyclo[3.2.1]octane-2,1'-cyclopropan]-4-yl]carbonyl}amino)oxy]ethyl}carbamate 3 (0.255 g, 83 %) as a white foam.1H NMR (400 MHz, CDCI3): δ 0.09 (1H, m), 0.42-0.62 (3H, m), 1.44 (9H, s), 1.80 (1H, d, J= 15.2 Hz), 2.27-2.32 (1H, m), 2.39 (1H, d, J=4.0 Hz), 2.92 (1H, d, J= 11.6 Hz), 3.07 (1H, m), 3.26-3.40 (2H, m), 3.92 (2H, m), 4.06 (1H, d, J= 7.6 Hz), 4.87 (1H, d, J= 11.2 Hz), 5.02 (1H, d, J= 11.6 Hz), 5.55 (1H, br s), 7.36-7.39 (5H, m), 9.69 (1H, br s). MS (ES) m/z: [M-H]" calcd for C16H26N406: 460.23. Found: 458.9.
Step 2: ferf-butyl {2-[({[(1/?,4S)-7-hydroxy-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane- 2,1'-cyclopropan]-4-yl]carbonyl}amino)oxy]ethyl}carbamate (4):
Figure imgf000082_0001
[0104] A mixture of ferf-butyl {2-[({[(1 R,4S)-7-(benzyloxy)-6-oxo-5,7- diazaspiro[bicyclo[3.2.1]octane-2,1'-cyclopropan]-4-yl]carbonyl}amino)oxy]ethyl}carbamate 3 (0.255 g, 0.554 mmol) and Pd/C (0.050 g) in methanol (15 ml_) was hydrogenated at 35 psi at room temperature for 2 h. The mixture was filtered through celite pad and concentrated to provide (ferf-butyl {2-[({[(1 R,4S)-7-hydroxy-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1'- cyclopropan]-4-yl]carbonyl}amino)oxy]ethyl}carbamate 4 (0.205 g, quant, yield) as a white foam.1H NMR (400 MHz, CD3OD): δ 0.32 (1H, m), 0.43 (1H, m), 0.56 (1H, m), 0.70 (1H, m), 1.27 (1H, m), 1.44 (9H, s), 1.75 (1H, d, J= 15.2 Hz), 2.25-2.31 (1H, m), 2.94 (1H, d, J=3.2 Hz), 3.10 (1H, m), 3.24 (1H, m), 3.34 (1H, m ), 3.88 (2H, m), 3.98 (1H, d, J= 8.0 Hz).3 protons were not observed in CD3OD. MS (ES ) m/z: [M-H]" calcd for C16H26N406: 370.19. Found: 369.0. Step 3: fert-butyl {2-[({[(1 /?,4S)-6-oxo-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1]octane- 2,1 '-cyclopropan]-4-yl]carbonyl}amino)oxy]ethyl}carbamate (5):
Figure imgf000083_0001
[0105] To a mixture of fert-butyl {2-[({[(1 ft,4S)-7-hydroxy-6-oxo-5,7- diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropan]-4-yl]carbonyl}amino)oxy]ethyl}carbamate 4 (0.205 g, 0.554 mmol) in pyridine (7.0 mL) was added sulfur trioxide pyridine complex (0.440 g, 2.817 mmol). The mixture was stirred at room temperature for 24 h and concentrated to provide a residue which was subjected to chromatography (silica gel, DCM: EtOAc: MeOH = 5: 4:1 ) to give fert-butyl {2-[({[(1 R,4S)-6-oxo-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane- 2,1 '-cyclopropan]-4-yl]carbonyl}amino)oxy]ethyl}carbamate 5 (0.200 g, 80 %) as a white solid. 1 H NMR (400 MHz, CD3OD): δ 0.35 (1 H, m), 0.44 (1 H, m), 0.57 (1 H, m), 0.76 (1 H, m), 1 .24 (1 H, m), 1 .44 (9H, s), 1 .77 (1 H, d, J = 14.0 Hz), 2.27 (1 H, m), 3.17-3.40 (4H, m), 3.89 (2H, m), 4.05 (1 H, m). 3 protons were not observed in CD3OD.
Step 4: (1 /?,4S)-A/-(2-aminoethoxy)-6-oxo-7-(sulfooxy)-5,7- diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropane]-4-carboxamide (Compound 61 , Table 1 ):
Figure imgf000083_0002
5
[0106] To a mixture of fert-butyl {2-[({[(1 R,4S)-6-oxo-7-(sulfooxy)-5,7- diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropan]-4-yl]carbonyl}amino)oxy]ethyl}carbamate 5 (0.200 g, 0.4443 mmol) in dichloromethane (11 .0 mL) was added trifluoroacetic acid (4.4 mL) at 0 °C. The mixture was stirred at 0 °C for 5 min. and at room temperature for 1 h. The reaction mixture was concentrated under vacuo, washed with ether (2 x) and trituarated with a mixture of methanol-ether (1 :5, 6 x) to provide (1 fl,4S)-/V-(2-aminoethoxy)-6-oxo-7- (sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropane]-4-carboxamide
(Compound 61 , Table 1) (0.036 g) as a white solid. 1 H NMR (400 MHz, D20): δ 0.06-0.17 (3H, m), 0.33 (1 H, m), 1 .30 (1 H, d, J = 16.0 Hz), 1 .83-1 .89 (1 H, m), 2.82-3.05 (5H, m), 3.77- 3.82 (3H, m). 4 protons were not observed in D20. HPLC: 92.75 %, Rt = 6.472 min. MS (ES~) m/z: [M-H]" calcd for Cii H18N407S: 350.09. Found: 348.8.
Example 4 (compound 55, Tabl
Figure imgf000084_0001
Step 1 : (1 /?,4S)-W-acetyl-7-(benzyloxy)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1 '- cyclopropane]-4-carbohydrazide (3):
Figure imgf000084_0002
1 3
[0107] To a mixture of (1 R,4S)-7-(benzyloxy)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '- cyclopropane]-4-carboxylic acid 1 (0.203 g, 0.6719 mmol) in dichloromethane (10.0 ml_) were added acetohydrazide 2 (0.074 g, 1 .0 mmol), 1 -hydroxybenzotriazole (0.135 g, 1 .0 mmol), and 1 -ethyl-(3-dimethylamino propyl) carbodiimide hydrochloride (0.192 g, 1 .0 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM, washed with water, brine, dried over sodium sulfate and concentrated to provide a residue, which was subjected to chromatography (silica gel, DCM: EtOAc: MeOH = 70: 27: 3) to give (1 R,4S)-/V-acetyl-7-(benzyloxy)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1 ]octane- 2,1 '-cyclopropane]-4-carbohydrazide 3 (0.135 g, 56 %) as a white foam. 1 H NMR (400 MHz, CDCI3): δ 0.88 (1 H, m), 0.46-0.51 (3H, m), 1 .78 (1 H, d, J = 15.2 Hz), 2.04 (3H, s), 2.28-2.40 (2H, m), 3.12 (1 H, m), 3.28 (1 H, d, J = 11 .6 Hz), 4.09 (1 H, d, J = 7.6 Hz), 4.88 (1 H, d, J = 11 .2 Hz), 5.03 (1 H, d, J = 11 .6 Hz), 7.36-7.40 (5H, m), 8.50 (1 H, s), 8.71 (1 H, s). MS (ES ) m/z: [M-H]" calcd for C18H22N404: 358.16. Found: 356.9.
Step 2: (1 /?,4S)-W-acetyl-7-hydroxy-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1 '- cyclopropane]-4-carbohydrazide (4):
Figure imgf000085_0001
3 4
[0108] A mixture of (1 R,4S)-/V-acetyl-7-(benzyloxy)-6-oxo-5,7- diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropane]-4-carbohydrazide 3 (0.135 g, 0.3769 mmol) and Pd/C (0.030 g) in methanol (10 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through celite pad and concentrated to provide(1 R,4S)-/V-acetyl-7-hydroxy-6-oxo-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '- cyclopropane]-4-carbohydrazide 4 (0.101 g, quant, yield) as a white foam. 1H NMR (400 MHz, CD3OD): δ 0.29 (1 H, s), 0.42 (1 H, m), 0.53 (1 H, m), 0.67 (1 H, m), 1 .77 (1 H, d, J = 14.8 Hz), 1 .96 (3H, s), 2.28-2.33 (1 H, m), 2.94 (1 H, d, J = 3.6 Hz), 3.23 (1 H, m), 3.40 (1 H, d, J = 11 .6 Hz), 4.06 (1 H, d, J = 8.0 Hz). 3 protons were not observed in CD3OD. MS (ES ) m/z: [M- H]- calcd for Cn H^N^: 268.27. Found: 266.9.
Step 3: (1 /?,4S)-W-acetyl-6-oxo-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '- cyclopropane]-4-carbohydrazide (Compound 55, Table 2):
Figure imgf000085_0002
[0109] To a mixture of (1 R,4S)-/V-acetyl-7-hydroxy-6-oxo-5,7- diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropane]-4-carbohydrazide 4 (0.101 g, 0.3764 mmol) in pyridine (7.0 mL) was added sulfur trioxide pyridine complex (0.352 g, 2.2584 mmol). The mixture was stirred at room temperature for 16 h and concentrated to provide a residue which was co-evaporated with DCM (3 x) and purified by chromatography (silica gel, DCM: EtOAc: MeOH = 5: 4: 1 ) to give (1 ft,4S)-/V-acetyl-6-oxo-7-(sulfooxy)-5,7- diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropane]-4-carbohydrazide (Compound 55, Table 2) (0.025 g) as a white solid. 1 H NMR (400 MHz, CD3OD): δ 0.04 (1 H, s), 0.13 (1 H, m), 0.22 (1 H, m), 0.38 (1 H, m), 1 .40 (1 H, d, J = 15.6 Hz), 1 .74 (3H, s), 1.97 (1 H, m), 2.80 (1 H, d, J = 4.0 Hz), 2.93-3.02 (2H, m), 3.84 (1 H, d, J = 7.6 Hz). 3 protons were not observed in CD3OD. MS (ES ) m/z: [M-H]- calcd for Cn
Figure imgf000086_0001
348.07. Found: 346.7. HPLC: 95.69 %, Rt = 7.738 min.
Example 5 (compound 93, Table 1)
(1 S,2S,4/?,5fi)-A/-(2-aminoethoxy)-7-oxo-8-(sulfooxy)-6,8- diazatricyclo[4.2.1.02 4]nonane-5-carboxamide:
Figure imgf000086_0002
Compound 93, Table 1
Step 1 : (1 S,2S,5fi)-3-(ferf-Butoxycarbonyl)-4-oxo-3-azabicyclo[3.1.0]hexane-2- carboxylic acid (2):
Figure imgf000086_0003
[0110] To a solution of fert-butyl (1 S,2S,5R)-2-({[fert-butyl(dimethyl)silyl]oxy}methyl)-4-oxo-3- azabicyclo[3.1 .0]hexane-3-carboxylate 1 (4.2 g, 12.30 mmol) in acetone (88 mL) at 0 °C was added Jones reagent (8.82 mL) which has been cooled to 0 °C. The solution became bright orange and after 10 minutes a precipitate had formed and the solution had turned amber in color. The reaction mixture was stirred for 30 minutes at 0 °C and 1 hour at room temperature. The reaction was quenched by addition of isopropanol (250 mL) and slow addition of saturated NaHC03 (100 mL) at 0 °C. The volatiles were removed under reduced pressure and the resultant mixture was diluted with water (150 mL) and ethyl acetate (340 mL). The solution was then extracted with ether (3 x 200 mL) and the aqueous layer was acidified with 0.1 N HCI to pH 3 at 0 °C. The acidifed solution was extracted with ethyl acetate (3 x 200 mL). The combined organic extracts were dried over Na2S04 and evaporated to give (1 S,2S,5R)-3-(fert-butoxycarbonyl)-4-oxo-3-azabicyclo[3.1 .0]hexane-2- carboxylic acid 2 (2.22 g, 75%) as a white solid. 1H NMR (400 MHz, CDCI3): δ 0.94 (1 H, m), 1 .26 (1 H, m), 1 .46 (9H, s), 2.09(2H, m), 4.58 (1 H, m), 12.09 (1 H, br s).
Step 2: 2-Benzyl 3-fert-butyl (1 S,2S,5fi)-4-oxo-3-azabicyclo[3.1.0]hexane-2,3- dicarboxylate (3):
Figure imgf000087_0001
2
[0111 ] To a stirred solution of (1 S,2S,5ft)-3-(ferf-butoxycarbonyl)-4-oxo-3- azabicyclo[3.1 .0]hexane-2-carboxylic acid 2 (2.22 g, 9.20 mmol) and diisopropylethylamine (2.00 mL, 1 1.76 mmol) in dichloromethane (70 mL) was added benzyl bromide (1 .50 mL, 12.60 mmol) at room temperature. The mixture was heated at reflux overnight, cooled to room temperature, washed with aqueous Na H2P04 (0.2 M, 2 x 15 mL), brine (15 mL), dried over Na2S04 and evaporated. The residue was purified by column chromatography using hexanes/ ethyl acetate (1 :1 ) as eluent to give 2-benzyl 3-fert-butyl (1 S,2S,5R)-4-oxo-3- azabicyclo[3.1 .0]hexane-2,3-dicarboxylate 3 (2.40 g, 80%) as a clear thick oil. 1 H NMR (400 MHz, CDCI3): δ 0.85 (1 H, m), 1 .25 (1 H, m), 1.38 (9H, s), 1 .95 (1 H, m), 2.06(1 H, m), 4.55 (1 H, m), 5.18 (1 H, d, J= 12.0 Hz), 5.30 (1 H, J= 12.0 Hz), 7.38 (5H, m). Step 3: Benzyl (2S)-{(1 S,2fi)-2-[(1Z)-W-(benzyloxy)-2- chloroethanimidoyl]cyclopropyl}[(ferf-butoxycarbonyl)amino]ethanoate (5):
Figure imgf000088_0001
[0112] DMSO (12 ml_) was added to a mixture of trimethylsulfoxonium iodide (1 .74 g, 7.97 mmol) and potassium fert-butoxide (0.81 g, 7.63 mmol) in tetrahydrofuran (9 ml_) at room temperature. The mixture was stirred for 0.5 h and cooled to - 12 °C. A solution of 2-benzyl 3-terf-butyl (1 S,2S,5ft)-4-oxo-3-azabicyclo[3.1 .0]hexane-2,3-dicarboxylate 3 (2.3 g, 6.94 mmol) in tetrahydrofuran (8 ml_) was added slowly. The mixture was stirred at - 12 °C for 4 h. The reaction was quenched by the addition of saturated aqueous ammonium chloride (12 ml_) and water (8 ml_). The product was extracted with ethyl acetate (40 ml_) and the resulting organic solution was washed with brine, dried over Na2S04 and evaporated to give a residue. To the solution of this residue in ethyl acetate (25 ml_) was added O- benzylhydroxylamine hydrochloride (1 .17 g,7.28 mmol). The mixture was stirred at reflux overnight. The mixture was cooled and washed with water and brine. The organic layer was concentrated in vacuo to give benzyl (2S)-{(1 S,2R)-2-[(1 Z)-/V-(benzyloxy)-2- chloroethanimidoyl]cyclopropyl}[(fert-butoxycarbonyl)amino]ethanoate 5 (2.60 g, 77%) as yellow oil which was used in the next step without purification.
Step 4: Benzyl (1 S,2S,5Z,6fi)-5-[(benzyloxy)imino]-3-azabicyclo[4.1.0]heptane-2- carboxylate (6):
Figure imgf000088_0002
5
[0113] To a solution of benzyl (2S)-{(1 S,2R)-2-[(1 Z)-/V-(benzyloxy)-2- chloroethanimidoyl]cyclopropyl}[(fert-butoxycarbonyl)amino]ethanoate 5 (2.60 g, 5.34 mmol) in ethyl acetate (9 mL) was added methanesulfonic acid (1 .35 mL, 17.62 mmol). The solution was stirred at 42 °C for 3 h and added to a solution of potassium bicarbonate (3.17 g, 31 .83 mmol) in water (10 mL) and the resulting mixture was stirred vigorously at 52 °C for 2 h. The organic layer was washed with brine, dried over Na2S04 and concentrated to give benzyl (1 S,2S,5Z,6R)-5-[(benzyloxy)imino]-3-azabicyclo[4.1 .0]heptane-2-carboxylate 6 (1 .73 g, 92%) as a brown oil which was used in the next step without purification.
Step 5: Benzyl (1 S,2S,6/¾-5-[(benzyloxy)amino]-3-azabicyclo[4.1.0]heptane-2- carboxylate (7):
Figure imgf000089_0001
[0114] Propanoic acid (3.61 mL, 48.17 mmol) was added to a suspension of sodium borohydride (0.65 g, 17.29 mmol) in ethyl acetate (18 mL) and stirred for 0.5 h. The resulting solution was added to a solution of benzyl (1 S,2S,5Z,6R)-5-[(benzyloxy)imino]-3- azabicyclo[4.1 .0]heptane-2-carboxylate 6 (1 .73 g, 4.94 mmol) in ethyl acetate (18 mL) and concentrated sulfuric acid (2.35 mL) at - 20 °C and was stirred for 2 h. The reaction mixture was quenched by the addition of water (30 mL), and neutralized with aqueous ammonia solution. The organic layer was washed with water, dried over Na2S04 and concentrated. The residue was purified by column chromatography using EtOAc/MeOH (96:4) as eluent to give benzyl (1 S,2S,6R)-5-[(benzyloxy)amino]-3-azabicyclo[4.1 .0]heptane-2-carboxylate 7 (0.68 g, 39%) as a brown oil.
Step 6: Benzyl (1 S,2S,4/?,5/?)-8-(benzyloxy)-7-oxo-6,8-diazatricyclo[4.2.1.02'4]nonane-5- carboxylate (8):
Figure imgf000089_0002
[0115] To a mixture of benzyl (1 S,2S,6R)-5-[(benzyloxy)amino]-3-azabicyclo[4.1 .0]heptane- 2-carboxylate 7 (0.68 g, 1 .93 mmol) and diisopropylethylamine (1 .50 mL) in dichloromethane (40 mL) was added dropwise triphosgene (0.43 g, 1 .45 mmol) in dichloromethane (20 mL) at room temperature. After 30 min, a dilute phosphoric acid solution (20 mL) was added, and the mixture was continued to stir overnight. The phases were separated and the organic phase was then dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography using hexane:chloroform:ethyl acetate (7:2:1 ) as eluent to give benzyl (1 S,2S,4fl,5fl)-8-(benzyloxy)-7-oxo-6,8-diazatricyclo[4.2.1 .02,4]nonane-5-carboxylate 8 (0.09 g, 12%) as a thick clear oil. 1 H NMR (400 MHz, CDCI3): 5 0.95 (2 H, m), 1.12 (1 H, m), 1 .71 (1 H, m),3.06 (2H, m), 3.57 (1 H, d, J= 6.8 Hz), 4.38 (1 H, s), 4.71 (2H, s ), 4.82 (1 H, d, J= 11 .2 Hz), 4.97 (1 H, d, J = 1 1.6 Hz), 7.36 (10H, m).
Step 7: (1 S,2S,4/?,5fi)-8-(Benzyloxy)-7-oxo-6,8-diazatricyclo[4.2.1.02,4]nonane-5- carboxylic acid (9):
Figure imgf000090_0001
9
8
[0116] A solution of lithium hydroxide (16.85 mg, 0.71 mmol) in water (4.5 mL) was added dropwise to a solution of benzyl (1 S,2S,4R,5/:?)-8-(benzyloxy)-7-oxo-6,8- diazatricyclo[4.2.1 .02,4]nonane-5-carboxylate 8 (0.213 g, 0.56 mmol) in tetrahydrofuran (4.5 mL) at 0 °C. The reaction mixture was stirred at same temperature for 2 h before adding a mixture isopropyl ether-ethyl acetate (8/2 vol./vol., 6 mL). The aqueous phase was separated out and the organic phase was extracted with water (2 x 5 mL). The extracts and aqueous phase were combined, washed with a mixture of isopropyl ether-ethyl acetate (8/2 vol./vol., 6 mL), acidified with saturated NaH2P04 and extracted with ethyl acetate (3 x 20 mL). The organic phases were combined, dried over sodium sulfate, filtered and evaporated to give (1 S,2S,4R,5R)-8-(benzyloxy)-7-oxo-6,8-diazatricyclo[4.2.1 .02'4]nonane-5-carboxylic acid 9 (0.08 g, 50%) as a white solid.1H NMR (400 MHz, CDCI3): 50.89 (1H, m), 0.98 (1H, m), 1.18 (1H, m), 1.35 (1H, m), 2.78 (1H, d, J= 10.8 Hz), 3.08 (1H,m), 3.65 (1H, m), 4.26 (1H, s), 4.71 (1 H, s ), 4.84 (1 H, d, J= 12.0 Hz), 4.98 (1 H, d, J = 11.2 Hz), 7.38 (5H, m).
Step 8: fert-Butyl {2-[({[(1S,2S,4/?,5/?)-8-(benzyloxy)-7-oxo-6,8- diazatricyclo[4.2.1.02'4]non-5-yl]carbonyl}amino)oxy]ethyl}carbamate (11):
Figure imgf000091_0001
11
[0117] To a solution of (1 S,2S,4R,5R)-8-(benzyloxy)-7-oxo-6,8- diazatricyclo[4.2.1.02,4]nonane-5-carboxylic acid 9 (0.08 g, 0.28 mmol) in dry
dichloromethane (15 mL) were added fert-butyl [2-(aminooxy)ethyl]carbamate 10 (0.084 g, 0.48 mmol), 1-hydroxybenzotriazole (0.057 g, 0.42 mmol), 1-ethyl-(3- dimethylaminopropyl)carbodiimide hydrochloride (0.08 g, 0.42 mmol) and 4- (dimethylamino)pyridine (0.05 g, 0.42 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, and then concentrated under vacuum. The residue was purified by column chromatography to give fert-butyl {2-[({[(1 S^S^R.S^-S-ibenzyloxy)- 7-0X0-6, 8-diazatricyclo[4.2.1.02'4]non-5-yl]carbonyl}amino)oxy]ethyl}carbamate 11 (0.09 g, 72%) as a white solid.1H NMR (400 MHz, CDCI3): δ 0.89 (1H, m), 0.96 (1H, m), 1.36 (1H, m), 1.44 (10H, m), 2.70 (1H, d, J= 10.8 Hz), 3.03 (1H, m), 3.33 (2H, m), 3.64 (1H, m), 3.90 (2H, m), 4.19 (1H, s), 4.84 (1H, d, J= 12.0 Hz), 4.98 (1H, d, J = 11.6 Hz), 5.50 (1H, br s), 7.40 (5H, m), 9.57 (1H, brs). Step 9: fert-butyl {2-[({[(1 S,2S,4/?,5/?)-8-hydroxy-7-oxo-6,8-diazatricyclo[4.2.1.02'4]non- 5-yl]carbonyl}amino)oxy]ethyl}carbamate (12):
Figure imgf000092_0001
12
1 1
[0118] To a solution of fert-butyl {2-[({[(1 S,2S,4R,5R)-8-(benzyloxy)-7-oxo-6,8- diazatricyclo[4.2.1 .02,4]non-5-yl]carbonyl}amino)oxy]ethyl}carbamate 11 (0. 09 g, 0.20 mml) in methanol (10 mL) was added 10% Pd/C (0.20 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 2 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give fert-butyl {2-[({[(1 S,2S,4R,5R)-8-hydroxy-7- oxo-6,8-diazatricyclo[4.2.1 .02,4]non-5-yl]carbonyl}amino)oxy]ethyl}carbamate 12 (0.07 g, 98%) as a white solid. 1 H NMR (400 MHz, CD3OD): 5 0.77 (1 H, m), 0.95 (1 H, m), 1.33 (2H, m), 1.44 (9H, s), 3.04 (1 H, d, J= 10.8 Hz), 3.19 (1 H, m), 3.30 (3H, m), 3.87 (2H, m), 4.02 (1 H, s), 3 protons were not observed in CD3OD.
Step 10: fert-butyl {2-[({[(1 S,2S,4/?,5/?)-7-oxo-8-(sulfooxy)-6,8- diazatricyclo[4.2.1.02'4]non-5-yl]carbonyl}amino)oxy]ethyl}carbamate (13):
Figure imgf000092_0002
[0119] To a solution of fert-butyl {2-[({[(1 S,2S,4R,5R)-8-hydroxy-7-oxo-6,8- diazatricyclo[4.2.1 .02,4]non-5-yl]carbonyl}amino)oxy]ethyl}carbamate 12 (0.07 g, 0.20 mmol) in dry pyridine (3 mL) under nitrogen atmosphere was added sulfur trioxide pyridine complex (0.1 g, 0.6 mmol). The mixture was stirred at room temperature for 20 h, filtered and evaporated. The residue was purified by column chromatography using DCM: EtOAc: MeOH (20:30:50) as eluent to give ferf-butyl {2-[({[(1 S,2S,4ft,5ft)-7-oxo-8-(sulfooxy)-6,8- diazatricyclo[4.2.1 .02,4]non-5-l]carbonyl}amino)oxy] ethyljcarbamate 13 (0.06 g, 69%) as a white solid. 1 H NMR (400 MHz, CD3OD) : δ 0.76 (1 H, m), 0.97 (1 H, m), 1 .35 (2H, m), 1 .44 (9H, s), 3.06 (1 H, d, J= 10.8 Hz), 3.30 (3H, m), 3.88 (2H, m), 4.1 1 (1 H, s), 4.47 (1 H, m), 3 protons were not observed in CD3OD.
Step 11 : (1 S,2S,4/?,5fi)-A/-(2-aminoethoxy)-7-oxo-8-(sulfooxy)-6,8- diazatricyclo[4.2.1.02>onane-5-carboxamide (Compound 93, Table 1):
Figure imgf000093_0001
13 Compound 93, Table 1
[0120] To a solution ferf-butyl {2-[({[(1 S,2S,4R,5R)-7-oxo-8-(sulfooxy)-6,8- diazatricyclo[4.2.1 .02,4]non-5-yl]carbonyl}amino)oxy]ethyl}carbamate 13 (0.06 g, 0.14 mmol) in dichloromethane (2.5 mL) was added trifluoroacetic acid (1 .00 mL) dropwise at 0 °C. The reaction mixture was stirred for 1 h then evaporated. Ether was added to the residue and the resulting white precipitate was collected by centrifugation. The solid was triturated with a mixture of MeOH :ether (1 :5, 6X) and the white solid was collected by centrifugation to give (1 S,2S,4R,5R)-/V-(2-aminoethoxy)-7-oxo-8-(sulfooxy)-6,8-diazatricyclo[4.2.1 .02'4]nonane-5- carboxamide, Compound 93, Table 1 (0.02 g, 42.5%) as a white solid. 1 H NMR (400 MHz, D20): δ 0.46 (1 H, m), 0.94 (1 H, m), 1 .12 (1 H, m), 1 .29 (1 H, m), 3.06 (1 H, d, J = 1 1 .2 Hz), 3.14 (2H, m), 3.22 (1 H, m), 4.03 (2H, m), 4.13 (1 H, s), 4.39 (1 H, m), 4 protons were not observed in D20. MS (negative eletrospray) m/z: [M]" = 335. HPLC: 92.46% Antibacterial activity and synergistic activity:
[0121 ] Compounds of the present invention alone, ceftazidime alone, meropenem alone, and as a combination with these antibiotics are tested for minimum inhibitory concentration (MIC, μς/πΊί.) against bacteria listed in Tables 3-5.
Table 3: Synergistic activity of test compounds in combination with Ceftazidime against enterobacteriacae
Example 1 Example 2 Example 3 Example4
Organism Enzyme(s) CAZ (Compd 62, (Compd 151, (Compd 61, (Compd 55,
Table 2) Table 1) Table 1) Table2)
E. coli TEM-10 >64 8 8 4 >64
E. coli CMY-2 <0.12 1 0.5 32
K. pneumoniae CTX-M-14 2 <0.12 0.25 0.5 2
K. pneumoniae KPC-3, VIM-1 64 0.5 1 0.5 32
E. cloacae P99 8 0.25 1 0.25 >64
Table 4: Synergistic activity of test compounds in combination with Meropenem against enterobacteriacae
MER:Compd 62, MER:Compd 151,! MER:Compd 61,
Organism Enzyme MER
Table 2 Table 1 Table 1 |
E. coli KPC-2,TEM-1, CMY-type 16 0.25 1 8
E. coli KPC-2 64 <0.12 2 <0.12
K. pneumoniae KPC-3, TEM-1, SHV-11 8 <0.12 0.25 0.25
K. pneumoniae KPC-3, TEM-1, SHV-12, SHV141 ! 16 <0.12 0.25 <0.12
K. pneumoniae KPC-2, TEM-1, SHV-11 16 0.25 0.25 <0.12
K. pneumoniae ! KPC-3, TEM-166, SHV-12, SHV141 \ 16 0.25 0.25 <0.12
K. pneumoniae KPC-2 >64 <0.12 64 <0.12
K. pneumoniae KPC-3, VIM-1 32 0.25 1 32
K. pneumoniae KPC-3, VIM-1 16 <0.12 0.25 <0.12
Table 5: Antibacterial activity of test compounds
! Compd 62, Compd 61,
; Ta bl e 2 \ Ta bl e l
Orga ni s m Enzyme(s)
E. coli CTX-M15 2 >16
E. coli CTX-M14, TEM-1 1 >16
E. coli CTX-M15, OXA-1 1 >16
E. coli CTX-M15, OXA-1, TEM-1 1 >16
E. coli CTX-M15, FOX-5 2 >16
K. pneumoniae SHV-1, SHV-12 4 >16
K. pneumoniae KPC-3, VI M-1 16 2
E. coli CMY-2 2 2
E. cloacae P99 4 4
K. pneumoniae multi-drug R ATCC 51503 32 4
K. pneumoniae multi -drug R ATCC 700603 32 4
Test for β-lactamase Inhibitory Activity:
[0122] The inhibitory activities of present compounds against various enzymes are measured by spectrophotometric assay using 490 nM and using nitrocefin as a substrate [J. Antimicrob. Chemother., 28, pp 775-776 (1 991 )] . The concentration of inhibitor (IC50) which inhibits by 50% the reaction of hydrolysis of nitrocefin by the enzyme is determined. Table 6 shows the results.
Figure imgf000097_0001
[0123] Efficacy of the β-lactamase inhibitors can be evaluated in combination with ceftazidime (CAZ), aztreonam (AZT), meropenem (MER) and other class of cephalosporins and carbapenems in murine infection models such as septicemia, pneumoniae and thigh infection models (Ref: Andrea Endimiani et. ai. Antimicrob. Agents and Chemother an 201 1 , pp-82-85). For murine acute lethal septicemia model, mice are infected by the intraperitoneal injection of the clinical strains resulting in death of the untreated controls within 24-48 hrs. In particular, a fresh predetermined bacterial inoculum of approximately 3.3 x 105 to 3.6 x 105 CFU (colony forming units) in 5% hog gastric mucin grown overnight. Thirty minutes post infection, a single subcutaneous dose of CAZ with and without β-lactamase inhibitor is initiated and the survival ratio is monitored for 5 days twice daily. For each strain tested, the dosing regimen used are CAZ alone ( doses of 512, 1024 & 2048 mg/kg of body weight) and CAZ plus β-lactamase inhibitor at ratio of 2:1 , 4:1 , 8:1 & 16:1 (CAZ doses are 4, 8, 16, 32 & 64 mg/kg for each ratio). The median effective dose for 50% (ED50) of animals is determined by a computerized program of Probit analysis. Survival rates stratified for different dosing regimen are also obtained. For experimental pneumoniae model, immunocompromised mice are used and intratracheal^ infected with Klebsiella pneumoniae strains. Mice in this model develop bacteraemia pneumoniae and fatal disease within 2 to 4 days with lung bacterial burden at 16-18 hrs post infection of 1011 to 1013 cfu/gm lung. Treatment with CAZ and inhibitor at a ratio of 2/1 & 4/1 demonstrate efficacy with significant 3 to 6 log reduction in lung counts compared to CAZ alone and is relevant to the clinical situation. Human testing of the β-lactamase inhibitor can be conducted in combination with partner antibiotic at a set ratio utilizing standard clinical development practice.
[0124] All patents and publications mentioned in this specification are indicative of the level of those skilled in the art to which the invention pertains. All patents and publications cited herein are incorporated by reference in its entirety to the same extent as if each individual patent or publication was specifically and individually indicated as having been incorporated by reference in its entirety.

Claims

What we claim is:
1 . A compound of formula (I):
Figure imgf000099_0001
wherein:
Y = H, -OR1 or -NR2R3;
R is -SO3M, -OSO3M, -OS02NH2, -OPO3M, -OCH2COOM, -OCF2COOM,
-OCH(CH3)COOM, -OC(CH3)2COOM, -OCF3, -OCH2S03M, or -OCH2P03M2, where M is hydrogen or a pharmaceutically acceptable salt-forming cation;
A and B are:
(1 ) different from each other and each is independently selected from CH2, CF2 and C(CH3)2,
(2) A and B together form an aromatic ring system or a heteroaromatic ring system,
(3) one of A and B is a C3.6 membered ring forming a spiro system, and the other of A and B is CH2,
(4) one of A and B is C4.6 membered heterocyclic ring forming a spiro system containing O as a heteroatom and the other of A and B is CH2, or
(5) A and B together form a cyclopropyl ring;
wherein when Y = -OR1 , R1 is a radical selected from one of the following groups:
(1 ) C1 -6 straight or branched chain alkyl which is optionally substituted, (2) C3.7 cycloalkyl which is optionally substituted,
(3) C4-7 saturated heterocycle containing at least one heteroatom selected from O, N and S, wherein the heterocycle is optionally substituted, the ring S is optionally oxidized to S(O) or S(0)2, and the free ring N atom may optionally take a substituent,
(4) heterocyclyl (C^) alkyl containing at least one heteroatom selected from O, N and S, wherein the heterocycle is optionally substituted, the ring S is optionally oxidized to S(O) or S(0)2, and the free ring N atom may optionally take a substituent, and
(5) unsubstituted C3-7 cycloalkyl which is optionally fused with a C5-7 membered saturated heterocycle to form a bicyclic ring system , wherein the bicyclic ring is optionally substituted; wherein when Y = -NR2R3, R2 is hydrogen and R3 is a radical selected from one of the following groups:
(1 ) C1-6 straight or branched chain alkyl which is optionally substituted,
(2) C3.7 cycloalkyl which is optionally substituted,
(3) C4-7 saturated heterocycle containing at least one heteroatom selected from O, N and S, wherein the heterocycle is optionally substituted, the ring S is optionally oxidized to S(O) or S(0)2, and the free ring N atom may optionally take a substituent,
(4) C1-6 straight or branched chain alkyl carbonyl which is optionally substituted,
(5) C3.7 cycloalkyl carbonyl which is optionally substituted,
(6) C4-7 membered saturated heterocyclyl carbonyl containing at least one heteroatom selected from O, N and S, wherein the heterocycle is optionally substituted, the ring S is optionally oxidized to S(O) or S(0)2, and the free ring N atom may optionally take a substituent,
(7) C3.7 membered saturated heterocyclyl (Ci-6) alkyl carbonyl containing at least one heteroatom selected from O, N and S, wherein the heterocycle is optionally substituted, the ring S is optionally oxidized to S(O) or S(0)2, and the free ring N atom may optionally take a substituent,
(8) C6-io aryl carbonyl which is optionally substituted,
(9) C6.10 aryl (Ci-6) alkyl carbonyl which is optionally substituted,
(10) C5-6 membered heteroaryl carbonyl containing at least one heteroatom selected from O, N and S, and wherein the heteroaryl is optionally substituted,
(1 1 ) C5-6 membered heteroaryl (Ci-6) alkyl carbonyl containing at least one heteroatom selected from O, N and S, and wherein the heteroaryl is optionally substituted,
(12) CF3CO-, CH3S02-, NH2CO-, or NH2S02-,
(13) C6-io aryl which is optionally substituted,
(14) C5-6 membered heteroaryl which is optionally substituted, and
(15) R2 and R3 together form a ring system which is optionally substituted, and wherein the ring optionally contains another heteroatom selected from O, N, and S; or a deuterated compound of any such compound.
2. A compound as recited in claim 1 , wherein the radical R1 is optionally substituted with one or two substituents independently selected from the group consisting of lower alkyl, amino, substituted amino, alkoxy, hydroxyalkyi, halogen, hydroxy, carboxy, alkoxycarbonyl, haloalkyi, trifluoromethyl, trifluoromethyloxy, alkylamine, substituted alkylamine, carboxamide, thiocarboxamide, sulfonic acid, sulphate, acylamino, sulfonylamino, substituted or unsubstituted sulfonamide, substituted or unsubstituted urea, substituted or unsubstituted thiourea, oxo, hydroxamic acid, acyl, trifluoromethyl carbonyl, cyano, amidino, guanidino, aryloxy, heterocyclylalkyloxy, and heteroaryloxy.
3. A compound as recited in claim 1 , wherein R is -OS03M where M is hydrogen or a pharmaceutically acceptable salt-forming cation.
4. A compound as recited in claim 1 , wherein when A and B together form an aromatic ring system or a heteroaromatic ring system, the ring system is selected from the group consisting of a pyrazolo group, a thieno group, a methylpyrazolo group, a furano group, a thiazolo group, a pyridine group, an oxazolo group, an imidazole group, a benzo group, and an ethanoimidazo group.
5. A compound of formula (I) as defined in claim 1 , wherein the compound is selected from the group consisting of:
(2S,5S)-N-(2-aminoethoxy)-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carboxamide
(2S,5S)-N-(3-aminopropoxy)-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carboxamide
(2S,5S)-4,4-difluoro-N-[2-(methylamino)ethoxy]-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane- 2-carboxamide
(2S,5S)-4,4-difluoro-N-[3-(methylamino)propoxy]-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane- 2-carboxamide
(2S,5S)-N-(2-aminopropoxy)-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carboxamide
(2S,5S)-4,4-difluoro-N-[2-(methylamino)propoxy]-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane- 2-carboxamide
(2S,5S)-N-(2-amino-2-methylpropoxy)-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-4,4-difluoro-N-[2-methyl-2-(methylamino)propoxy]-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-N-[(1 -aminocyclopropyl)methoxy]-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-4,4-difluoro-N-{[1 -(methylamino)cyclopropyl]methoxy}-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-N-(2-aminobutoxy)-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carboxamide
(2S,5S)-4^-difluoro-N-[2-(methylamino)butoxy]-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane- 2-carboxamide
(2S,5S)-N-(2-amino-3-methylbutoxy)-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-4,4-difluoro-N-[3-methyl-2-(methylamino)butoxy]-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-N-(2-amino-3,3-dimethylbutoxy)-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-N-[3,3-dimethyl-2-(methylamino)butoxy]-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-N-{[1 -(aminomethyl)cyclopropyl]methoxy}-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-4,4-difluoro-N-({1 -[(methylamino)methyl]cyclopropyl}methoxy)-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-4,4-difluoro-7-oxo-N-[2-(propan-2-ylamino)propoxy]-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-N-[(2-aminocyclopropyl)oxy]-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-4,4-difluoro-N-{[2-(methylamino)cyclopropyl]oxy}-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-N-[(2-aminocyclobutyl)oxy]-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane- 2-carboxamide
(2S,5S)-4,4-difluoro-N-{[2-(methylamino)cyclobutyl]oxy}-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-N-[(2-aminocyclopentyl)oxy]-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane- 2-carboxamide
(2S,5S)-4,4-difluoro-N-{[2-(methylamino)cyclopentyl]oxy}-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-N-(2-amino-2-cyclopropylethoxy)-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-N-(2-amino-2-cyclobutylethoxy)-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-N-(2-amino-2-cyclopentylethoxy)-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-N-(2-amino-2-cyclohexylethoxy)-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-N-[2-amino-2-(tetrahydro-2H-pyran-4-yl)ethoxy]-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-N-[2-amino-2-(piperidin-4-yl)ethoxy]-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-N-[2-amino-2-(1 ,1 -dioxidotetrahydro-2H-thiopyran-4-yl)ethoxy]-4,4-difluoro-7-oxo-6- (sulfooxy)-l ,6-diazabicyclo[3.2.1]octane-2-carboxamide
(2S,5S)-N-[(3-aminopyrrolidin-3-yl)methoxy]-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-N-[(3-aminooxetan-3-yl)methoxy]-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-N-[(3-aminotetrahydrofuran-3-yl)methoxy]-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-N-(2-amino-2-phenylethoxy)-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-N-[2-amino-2-(pyridin-2-yl)ethoxy]-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-N-[2-amino-2-(pyridin-3-yl)ethoxy]-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-N-[2-amino-2-(thiophen-2-yl)ethoxy]-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-N-[2-amino-2-(furan-2-yl)ethoxy]-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-N-[2-amino-2-(1 ,3-thiazol-2-yl)ethoxy]-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-N-[2-amino-2-(1 ,3-thiazol-2-yl)ethoxy]-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-N-[2-amino-2-(1 -methyl-1 H-imidazol-2-yl)ethoxy]-4,4-difluoro-7-oxo-6-(sulfooxy)-1 , 6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-N-[2-amino-2-(1 -methyl-1 H-imidazol-5-yl)ethoxy]-4,4-difluoro-7-oxo-6-(sulfooxy)-1 , 6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5R)-N-(2-aminoethoxy)-4,4-dimethyl-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carboxamide
(2S,5R)-N-(3-aminopropoxy)-4,4-dimethyl-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carboxamide
(2S,5R)-4,4-dimethyl-N-[2-(methylamino)ethoxy]-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octan 2-carboxamide
(2S,5R)-4,4-dimethyl-N-[3-(methylamino)propoxy]-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5R)-N-[(2-aminocyclopropyl)oxy]-4,4-dimethyl-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5R)-4,4-dimethyl-N-{[2-(methylamino)cyclopropyl]oxy}-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5R)-N-[(2-aminocyclobutyl)oxy]-4^-dimethyl-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane- 2-carboxamide
(2S,5R)-4,4-dimethyl-N-{[2-(methylamino)cyclobutyl]oxy}-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5R)-N-[(2-aminocyclopentyl)oxy]-4,4-dimethyl-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5R)-4,4-dimethyl-N-{[2-(methylamino)cyclopentyl]oxy}-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5R)-N-(2-amino-2-cyclopropylethoxy)-4,4-dimethyl-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5R)-N-[(3-aminopyrrolidin-3-yl)methoxy]-4,4-dimethyl-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5R)-N-(2-amino-2-phenylethoxy)-4,4-dimethyl-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5R)-N-[2-amino-2-(pyridin-3-yl)ethoxy]-4,4-dimethyl-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5R)-N-[2-amino-2-(thiophen-2-yl)ethoxy]-4^-dimethyl-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5R)-N-[2-amino-2-(furan-2-yl)ethoxy]-4,4-dimethyl-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(1 R,4S)-N-(2-aminoethoxy)-6-oxo-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '- cyclopropane]-4-carboxamide
(1 R,4S)-N-(3-aminopropoxy)-6-oxo-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '- cyclopropane]-4-carboxamide
(1 R^S)-N-[2-(methylamino)ethoxy]-6-oxo-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1 '- cyclopropane]-4-carboxamide
(1 R^S)-N-[3-(methylamino)propoxy]-6-oxo-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '- cyclopropane]-4-carboxamide
(1 R,4S)-N-[(2-aminocyclopropyl)oxy]-6-oxo-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '- cyclopropane]-4-carboxamide
(1 R,4S)-N-{[2-(methylamino)cyclopropyl]oxy}-6-oxo-7-(sulfooxy)-5,7- diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropane]-4-carboxamide
(1 R,4S)-N-[(2-aminocyclobutyl)oxy]-6-oxo-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '- cyclopropane]-4-carboxamide
(1 R,4S)-N-{[2-(methylamino)cyclobutyl]oxy}-6-oxo-7-(sulfooxy)-5,7- diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropane]-4-carboxamide
(1 R,4S)-N-[(2-aminocyclopentyl)oxy]-6-oxo-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '- cyclopropane]-4-carboxamide
(1 R,4S)-N-{[2-(methylamino)cyclopentyl]oxy}-6-oxo-7-(sulfooxy)-5,7- diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropane]-4-carboxamide
(1 R,4S)-N-(2-amino-2-cyclopropylethoxy)-6-oxo-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane- 2,1 '-cyclopropane]-4-carboxamide
(1 R,4S)-N-[(3-aminopyrrolidin-3-yl)methoxy]-6-oxo-7-(sulfooxy)-5,7- diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropane]-4-carboxamide
(1 R,4S)-N-(2-amino-2-phenylethoxy)-6-oxo-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '- cyclopropane]-4-carboxamide
(1 R^S)-N-[2-amino-2-(pyridin-3-yl)ethoxy]-6-oxo-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane- 2,1 '-cyclopropane]-4-carboxamide
(1 R,4S)-N-[2-amino-2-(thiophen-2-yl)ethoxy]-6-oxo-7-(sulfooxy)-5,7- diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropane]-4-carboxamide
(1 R^S)-N-[2-amino-2-(furan-2-yl)ethoxy]-6-oxo-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane- 2,1 '-cyclopropane]-4-carboxamide
(1 R,4S)-N-(2-aminoethoxy)-6-oxo-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1 ]octane-2,3'-oxetane]-4- carboxamide
(1 R,4S)-N-(3-aminopropoxy)-6-oxo-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1 ]octane-2,3'-oxetane]- 4-carboxamide
(1 R^S)-N-[2-(methylamino)ethoxy]-6-oxo-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1]octane-2,3'- oxetane]-4-carboxam ide
(1 R^S)-N-[3-(methylamino)propoxy]-6-oxo-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1 ]octane-2,3'- oxetane]-4-carboxam ide
(1 R,4S)-N-[(2-aminocyclopropyl)oxy]-6-oxo-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1 ]octane-2,3'- oxetane]-4-carboxam ide
(1 R,4S)-N-{[2-(methylamino)cyclopropyl]oxy}-6-oxo-7-(sulfooxy)spiro[5,7- diazabicyclo[3.2.1 ]octane-2,3'-oxetane]-4-carboxamide
(1 R,4S)-N-[(2-aminocyclobutyl)oxy]-6-oxo-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1 ]octane-2,3'- oxetane]-4-carboxam ide
(1 R^S)-N-{[2-(methylamino)cyclobutyl]oxy}-6-oxo-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1 ]octane- 2,3'-oxetane]-4-carboxamide
(1 R,4S)-N-[(2-aminocyclopentyl)oxy]-6-oxo-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1 ]octane-2,3'- oxetane]-4-carboxam ide
(1 R,4S)-N-{[2-(methylamino)cyclopentyl]oxy}-6-oxo-7-(sulfooxy)spiro[5,7- diazabicyclo[3.2.1 ]octane-2,3'-oxetane]-4-carboxamide
(1 R,4S)-N-(2-amino-2-cyclopropylethoxy)-6-oxo-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1 ]octane- 2,3'-oxetane]-4-carboxamide
(1 R,4S)-N-[(3-aminopyrrolidin-3-yl)methoxy]-6-oxo-7-(sulfooxy)spiro[5,7- diazabicyclo[3.2.1 ]octane-2,3'-oxetane]-4-carboxamide
(1 R,4S)-N-(2-amino-2-phenylethoxy)-6-oxo-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1 ]octane-2,3'- oxetane]-4-carboxam ide
(1 R^S)-N-[2-amino-2-(pyridin-3-yl)ethoxy]-6-oxo-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1 ]octane- 2,3'-oxetane]-4-carboxamide
(1 R,4S)-N-[2-amino-2-(thiophen-2-yl)ethoxy]-6-oxo-7-(sulfooxy)spiro[5,7- diazabicyclo[3.2.1 ]octane-2,3'-oxetane]-4-carboxamide
(1 R,4S)-N-[2-amino-2-(furan-2-yl)ethoxy]-6-oxo-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1 ]octane- 2,3'-oxetane]-4-carboxamide
(1 R,5S)-N-(2-aminoethoxy)-7-oxo-8-(sulfooxy)-6,8-diazatricyclo[4.2.1 .02,4]nonane-5-carboxamide
(1 R,5S)-N-(3-aminopropoxy)-7-oxo-8-(sulfooxy)-6,8-diazatricyclo[4.2.1 .02,4]nonane-5- carboxamide
(1 R,5S)-N-[2-(methylamino)ethoxy]-7-oxo-8-(sulfooxy)-6,8-diazatricyclo[4.2.1 .02,4]nonane-5- carboxamide
(1 R,5S)-N-[3-(methylamino)propoxy]-7-oxo-8-(sulfooxy)-6,8-diazatricyclo[4.2.1 .02,4]nonane-5- carboxamide
(1 R,5S)-N-[(2-aminocyclopropyl)oxy]-7-oxo-8-(sulfooxy)-6,8-diazatricyclo[4.2.1 .02,4]nonane-5- carboxamide
(1 R,5S)-N-{[2-(methylamino)cyclopropyl]oxy}-7-oxo-8-(sulfooxy)-6,8- diazatricyclo[4.2.1 .02,4]nonane-5-carboxamide
(1 R,5S)-N-[(2-aminocyclobutyl)oxy]-7-oxo-8-(sulfooxy)-6,8-diazatricyclo[4.2.1 .02,4]nonane-5- carboxamide
(1 R,5S)-N-{[2-(methylamino)cyclobutyl]oxy}-7-oxo-8-(sulfooxy)-6,8- diazatricyclo[4.2.1 .02,4]nonane-5-carboxamide
(1 R,5S)-N-[(2-aminocyclopentyl)oxy]-7-oxo-8-(sulfooxy)-6,8-diazatricyclo[4.2.1 .02,4]nonane-5- carboxamide
(1 R,5S)-N-{[2-(methylamino)cyclopentyl]oxy}-7-oxo-8-(sulfooxy)-6,8- diazatricyclo[4.2.1 .02,4]nonane-5-carboxamide
(1 R,5S)-N-(2-amino-2-cyclopropylethoxy)-7-oxo-8-(sulfooxy)-6,8-diazatricyclo[4.2.1 .02,4]nonane- 5-carboxamide
(1 R,5S)-N-[(3-aminopyrrolidin-3-yl)methoxy]-7-oxo-8-(sulfooxy)-6,8- diazatricyclo[4.2.1 .02,4]nonane-5-carboxamide
(1 R,5S)-N-(2-amino-2-phenylethoxy)-7-oxo-8-(sulfooxy)-6,8-diazatricyclo[4.2.1 .02,4]nonane-5- carboxamide
(1 R,5S)-N-[2-amino-2-(pyridin-3-yl)ethoxy]-7-oxo-8-(sulfooxy)-6,8-diazatricyclo[4.2.1 .02,4]nonane- 5-carboxamide
(1 R,5S)-N-[2-amino-2-(thiophen-2-yl)ethoxy]-7-oxo-8-(sulfooxy)-6,8- diazatricyclo[4.2.1 .02,4]nonane-5-carboxamide
(1 R,5S)-N-[2-amino-2-(furan-2-yl)ethoxy]-7-oxo-8-(sulfooxy)-6,8-diazatricyclo[4.2.1 .02,4]nonane- 5-carboxamide
(4R,8S)-N-(2-aminoethoxy)-1 -methyl-6-oxo-5-(sulfooxy)-4,5,6,8-tetrahydro-1 H-4,7- methanopyrazolo[3,4-e][1 ,3]diazepine-8-carboxamide
(4R,8R)-N-(3-aminopropoxy)-6-oxo-5-(sulfooxy)-4,5,6,8-tetrahydro-4,7-methanothieno[2,3- e][1 ,3]diazepine-8-carboxamide
(4R,8S)-1 -methyl-N-[2-(methylamino)ethoxy]-6-oxo-5-(sulfooxy)-4,5,6,8-tetrahydro-1 H-4,7- methanopyrazolo[3,4-e][1 ,3]diazepine-8-carboxamide
(4R,8S)-N-[3-(methylamino)propoxy]-6-oxo-5-(sulfooxy)-4,5,6,8-tetrahydro-4,7-methanofuro[2,3- e][1 ,3]diazepine-8-carboxamide
(4R,8S)-N-[(2-aminocyclopropyl)oxy]-1 -methyl-6-oxo-5-(sulfooxy)-4,5,6,8-tetrahydro-1 H-4,7- methanopyrazolo[3,4-e][1 ,3]diazepine-8-carboxamide
(4R,8S)-N-[(2-aminocyclobutyl)oxy]-1 -methyl-6-oxo-5-(sulfooxy)-4,5,6,8-tetrahydro-1 H-4,7- methanopyrazolo[3,4-e][1 ,3]diazepine-8-carboxamide
(5R,9S)-N-(2-aminoethoxy)-7-oxo-6-(sulfooxy)-5,6,7,9-tetrahydro-5,8-methanopyrido[2,3- e][1 ,3]diazepine-9-carboxamide
(1 R,5S)-N-(3-aminopropoxy)-3-oxo-2-(sulfooxy)-1 ,2,3,5-tetrahydro-1 ,4-methano-2,4- benzodiazepine-5-carboxamide
(4S,8S)-N-(2-aminoethoxy)-1 -ethyl-6-oxo-5-(sulfooxy)-4,5,6,8-tetrahydro-1 H-4,7- methanoimidazo[4,5-e][1 ,3]diazepine-8-carboxamide
(5R,9S)-2-amino-N-(3-aminopropoxy)-7-oxo-6-(sulfooxy)-5,6,7,9-tetrahydro-5,8- methanopyrimido[4,5-e][1 ,3]diazepine-9-carboxamide
(2S,5S)-N-(azetidin-3-yloxy)-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carboxamide
(2S,5S)-4,4-difluoro-7-oxo-N-(pyrrolidin-3-yloxy)-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carboxamide
(2S,5S)-4,4-difluoro-7-oxo-N-(piperidin-3-yloxy)-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane-2- carboxamide
(2S,5S)-4,4-difluoro-7-oxo-N-(piperidin-4-yloxy)-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane-2- carboxamide
(2S,5S)-4,4-difluoro-N-[(1 -methylazetidin-3-yl)oxy]-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-4,4-difluoro-N-[(1 -methylpyrrolidin-3-yl)oxy]-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-4,4-difluoro-N-[(1 -methylpiperidin-3-yl)oxy]-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-4,4-difluoro-7-oxo-N-(pyrrolidin-2-ylmethoxy)-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carboxamide
(2S,5S)-4^-difluoro-7-oxo-N-(piperidin-2-ylmethoxy)-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carboxamide
(2S,5S)-4^-difluoro-7-oxo-N-(piperidin-3-ylmethoxy)-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carboxamide
(2S,5S)-4^-difluoro-N-[(1 -methylpyrrolidin-2-yl)methoxy]-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-N-[(5-carbamoylpyrrolidin-3-yl)oxy]-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-4,4-difluoro-N-[(5-methylpyrrolidin-3-yl)oxy]-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-N-(3-azabicyclo[3.1 .0]hex-6-yloxy)-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5S)-4,4-difluoro-N-(1 ,2-oxazolidin-4-yloxy)-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carboxamide
(2S,5S)-4,4-difluoro-7-oxo-N-(pyrazolidin-4-yloxy)-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carboxamide
(2S,5S)-4,4-difluoro-N-(morpholin-3-ylmethoxy)-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane- 2-carboxamide
(2S,5S)-4,4-difluoro-7-oxo-N-(piperazin-2-ylmethoxy)-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carboxamide
(2S,5S)-4,4-difluoro-7-oxo-6-(sulfooxy)-N-(thiomorpholin-3-ylmethoxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5R)-N-(azetidin-3-yloxy)-4,4-dimethyl-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carboxamide
(2S,5R)-4,4-dimethyl-7-oxo-N-(pyrrolidin-3-yloxy)-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carboxamide
(2S,5R)-4,4-dimethyl-7-oxo-N-(piperidin-3-yloxy)-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carboxamide
(2S,5R)-4,4-dimethyl-7-oxo-N-(piperidin-4-yloxy)-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carboxamide
(2S,5R)-4,4-dimethyl-N-[(1 -methylazetidin-3-yl)oxy]-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5R)-4,4-dimethyl-N-[(1 -methylpyrrolidin-3-yl)oxy]-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5R)-4,4-dimethyl-7-oxo-N-(pyrrolidin-2-ylmethoxy)-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane- 2-carboxamide
(2S,5R)-4,4-dimethyl-7-oxo-N-(piperidin-2-ylmethoxy)-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane- 2-carboxamide
(2S,5R)-4,4-dimethyl-7-oxo-N-(piperidin-3-ylmethoxy)-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane- 2-carboxamide
(2S,5R)-4,4-dimethyl-N-[(1 -methylpyrrolidin-2-yl)methoxy]-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5R)-N-[(5-carbamoylpyrrolidin-3-yl)methoxy]-4,4-dimethyl-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5R)-4,4-dimethyl-N-[(5-methylpyrrolidin-3-yl)methoxy]-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carboxamide
(1 R,4S)-N-(azetidin-3-yloxy)-6-oxo-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '- cyclopropane]-4-carboxamide
(1 R,4S)-6-oxo-N-(pyrrolidin-3-yloxy)-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '- cyclopropane]-4-carboxamide
(1 R,4S)-6-oxo-N-(piperidin-3-yloxy)-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '- cyclopropane]-4-carboxamide
(1 R,4S)-6-oxo-N-(piperidin-4-yloxy)-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '- cyclopropane]-4-carboxamide
(1 R,4S)-N-[(1 -methylazetidin-3-yl)oxy]-6-oxo-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2, 1 '- cyclopropane]-4-carboxamide
(1 R,4S)-N-[(1 -methylpyrrolidin-3-yl)oxy]-6-oxo-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane- 2,1 '-cyclopropane]-4-carboxamide
(1 R,4S)-6-oxo-N-(pyrrolidin-2-ylmethoxy)-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '- cyclopropane]-4-carboxamide
(1 R^S)-6-oxo-N-(piperidin-2-ylmethoxy)-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '- cyclopropane]-4-carboxamide
(1 R^S)-6-oxo-N-(piperidin-3-ylmethoxy)-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '- cyclopropane]-4-carboxamide
(1 R,4S)-N-[(1 -methylpyrrolidin-2-yl)methoxy]-6-oxo-7-(sulfooxy)-5,7- diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropane]-4-carboxamide
(1 R,4S)-N-[(5-carbamoylpyrrolidin-3-yl)oxy]-6-oxo-7-(sulfooxy)-5,7- diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropane]-4-carboxamide
(1 R,4S)-N-[(5-methylpyrrolidin-3-yl)oxy]-6-oxo-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane- 2,1 '-cyclopropane]-4-carboxamide
(1 R,4S)-N-(azetidin-3-yloxy)-6-oxo-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1 ]octane-2,3'-oxetane]- 4-carboxamide
(1 R,4S)-6-oxo-N-(pyrrolidin-3-yloxy)-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1 ]octane-2,3'-oxetane]- 4-carboxamide
(1 R,4S)-6-oxo-N-(piperidin-3-yloxy)-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1 ]octane-2,3'-oxetane]- 4-carboxamide
(1 R,4S)-N-[(1 -methylazetidin-3-yl)oxy]-6-oxo-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1 ]octane-2,3'- oxetane]-4-carboxam ide
(1 R,4S)-N-[(1 -methylpyrrolidin-3-yl)oxy]-6-oxo-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1 ]octane-2,3'- oxetane]-4-carboxam ide
(1 R,4S)-6-oxo-N-(pyrrolidin-2-ylmethoxy)-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1 ]octane-2,3'- oxetane]-4-carboxam ide
(1 R,4S)-N-[(1 -methylpyrrolidin-2-yl)methoxy]-6-oxo-7-(sulfooxy)spiro[5,7- diazabicyclo[3.2.1 ]octane-2,3'-oxetane]-4-carboxamide
(1 R,4S)-N-[(5-carbamoylpyrrolidin-3-yl)oxy]-6-oxo-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1 ]octane- 2,3'-oxetane]-4-carboxamide
(1 R,4S)-N-[(5-methylpyrrolidin-3-yl)oxy]-6-oxo-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1 ]octane-2,3'- oxetane]-4-carboxam ide
(4R,8S)-N-(azetidin-3-yloxy)-1 -methyl-6-oxo-5-(sulfooxy)-4,5,6,8-tetrahydro-1 H-4,7- methanopyrazolo[3,4-e][1 ,3]diazepine-8-carboxamide
(4R,8S)-1 -methyl-6-oxo-N-(pyrrolidin-3-yloxy)-5-(sulfooxy)-4,5,6,8-tetrahydro-1 H-4,7- methanopyrazolo[3,4-e][1 ,3]diazepine-8-carboxamide
(4R,8S)-6-oxo-N-(piperidin-4-yloxy)-5-(sulfooxy)-4,5,6,8-tetrahydro-4,7-methanofuro[2,3- e][1 ,3]diazepine-8-carboxamide
(4R,8S)-1 -methyl-6-oxo-N-(piperidin-3-yloxy)-5-(sulfooxy)-4,5,6,8-tetrahydro-1 H-4,7- methanopyrazolo[3,4-e][1 ,3]diazepine-8-carboxamide
(4R,8R)-N-[(1 -methylazetidin-3-yl)oxy]-6-oxo-5-(sulfooxy)-4,5,6,8-tetrahydro-4,7- methanothieno[2,3-e][1 ,3]diazepine-8-carboxamide
(4R,8S)-1 -methyl-N-[(1 -methylpyrrolidin-3-yl)oxy]-6-oxo-5-(sulfooxy)-4,5,6,8-tetrahydro-1 H-4,7- methanopyrazolo[3,4-e][1 ,3]diazepine-8-carboxamide
(5R,9S)-7-oxo-N-(pyrrolidin-2-ylmethoxy)-6-(sulfooxy)-5,67,9-tetrahydro-5,8-methanopyrido[2,3- e][1 ,3]diazepine-9-carboxamide
(1 R,5S)-3-oxo-N-(piperidin-2-ylmethoxy)-2-(sulfooxy)-1 ,2,3,5-tetrahydro-1 ,4-methano-2,4- benzodiazepine-5-carboxamide
(4S,8S)-1 -ethyl-6-oxo-N-(piperidin-3-ylmethoxy)-5-(sulfooxy)-4,5,6,8-tetrahydro-1 H-4,7- methanoimidazo[4,5-e][1 ,3]diazepine-8-carboxamide
(2S,5S)-4^-difluoro-N'-methyl-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2-carbohydrazide
(2S,5S)-4,4-difluoro-7-oxo-N'-(propan-2-yl)-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carbohydrazide
(2S,5S)-N'-cyclopropyl-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carbohydrazide
(2S,5S)-N'-acetyl-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2-carbohydrazide
(2S,5S)-4,4-difluoro-7-oxo-N'-propanoyl-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carbohydrazide
(2S,5S)-4,4-difluoro-N'-(2-methylpropanoyl)-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carbohydrazide
(2S,5S)-N'-butanoyl-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carbohydrazide
(2S,5S)-4,4-difluoro-N'-(2-methylbutanoyl)-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carbohydrazide
(2S,5S)-N'-(2-aminopropanoyl)-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carbohydrazide
(2S,5S)-4,4-difluoro-7-oxo-6-(sulfooxy)-N'-(trifluoroacetyl)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carbohydrazide
(2S,5S)-N'-(cyclopropylcarbonyl)-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carbohydrazide (2S,5S)-N'-[(2,2-dimethylcyclopropyl)carbonyl]-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carbohydrazide
(2S,5S)-N'-[(2,2-difluorocyclopropyl)carbonyl]-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carbohydrazide
(2S,5S)-N'-(cyclopentylcarbonyl)-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carbohydrazide
(2S,5S)-N'-(azetidin-3-ylcarbonyl)-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carbohydrazide
(2S,5S)-4,4-difluoro-7-oxo-N'-(pyrrolidin-2-ylcarbonyl)-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane- 2-carbohydrazide
(2S,5S)-4,4-difluoro-7-oxo-N'-(pyrrolidin-3-ylcarbonyl)-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane- 2-carbohydrazide
(2S,5S)-4,4-difluoro-7-oxo-N'-(piperidin-4-ylcarbonyl)-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carbohydrazide
(2S,5S)-N'-[(2-aminocyclopentyl)carbonyl]-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carbohydrazide
(2S,5S)-4,4-difluoro-7-oxo-N'-(pyrrolidin-2-ylacetyl)-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carbohydrazide
(2S,5S)-4,4-difluoro-7-oxo-N'-(phenylcarbonyl)-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carbohydrazide
(2S,5S)-4,4-difluoro-7-oxo-N'-(pyridin-2-ylcarbonyl)-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carbohydrazide
(2S,5S)-N'-[(2-amino-1 ,3-thiazol-4-yl)carbonyl]-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carbohydrazide
(2S,5S)-4,4-difluoro-7-oxo-N'-(pyridin-3-ylcarbonyl)-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carbohydrazide
(2S,5S)-4,4-difluoro-7-oxo-N-(piperidin-1 -yl)-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carboxamide
(2S,5S)-4,4-difluoro-N-(morpholin-4-yl)-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carboxamide
(2S,5S)-N-(3-aminopyrrolidin-1 -yl)-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carboxamide
(2S,5R)-N',4,4-trimethyl-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2-carbohydrazide
(2S,5R)-4,4-dimethyl-7-oxo-N'-(propan-2-yl)-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carbohydrazide
(2S,5R)-N'-cyclopropyl-4,4-dimethyl-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carbohydrazide
(2S,5R)-N'-acetyl-4,4-dimethyl-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2-carbohydrazide
(2S,5R)-4,4-dimethyl-7-oxo-N'-propanoyl-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carbohydrazide
(2S,5R)-4^-dimethyl-N'-(2-methylpropanoyl)-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carbohydrazide
(2S,5R)-4,4-dimethyl-7-oxo-6-(sulfooxy)-N'-(trifluoroacetyl)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carbohydrazide
(2S,5R)-N'-(cyclopropylcarbonyl)-4,4-dimethyl-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carbohydrazide
(2S,5R)-N'-[(2,2-difluorocyclopropyl)carbonyl]-4,4-dimethyl-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carbohydrazide
(2S,5R)-N'-(cyclobutylcarbonyl)-4,4-dimethyl-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carbohydrazide
(2S,5R)-N'-(azetidin-3-ylcarbonyl)-4,4-dimethyl-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane- 2-carbohydrazide
(2S,5R)-N'-(azetidin-2-ylcarbonyl)-4,4-dimethyl-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane- 2-carbohydrazide
(2S,5R)-4,4-dimethyl-7-oxo-N'-(pyrrolidin-2-ylcarbonyl)-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane- 2-carbohydrazide
(2S,5R)-4,4-dimethyl-7-oxo-N'-(pyrrolidin-3-ylcarbonyl)-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane- 2-carbohydrazide
(2S,5R)-4,4-dimethyl-7-oxo-N'-(piperidin-4-ylcarbonyl)-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane- 2-carbohydrazide
(2S,5R)-N'-[(2-aminocyclopentyl)carbonyl]-4,4-dimethyl-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carbohydrazide
(2S,5R)-4,4-dimethyl-7-oxo-N'-(pyrrolidin-2-ylacetyl)-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carbohydrazide
(2S,5R)-N'-benzoyl-4,4-dimethyl-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carbohydrazide
(2S,5R)-4,4-dimethyl-7-oxo-N'-(pyridin-2-ylcarbonyl)-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carbohydrazide
(2S,5R)-N'-[(2-amino-1 ,3-thiazol-4-yl)carbonyl]-4,4-dimethyl-7-oxo-6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1 ]octane-2-carbohydrazide
(2S,5R)-4,4-dimethyl-7-oxo-N'-(pyridin-3-ylacetyl)-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carbohydrazide
(2S,5R)-4^-dimethyl-7-oxo-N-(piperidin-1 -yl)-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carboxamide
(2S,5R)-4,4-dimethyl-N-(morpholin-4-yl)-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carboxamide
(2S,5R)-N-(3-aminopyrrolidin-1 -yl)-4^-dimethyl-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octan 2-carboxamide
(1 R,4S)-N'-methyl-6-oxo-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropane]-4- carbohydrazide
(1 R,4S)-6-oxo-N'-(propan-2-yl)-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '- cyclopropane]-4-carbohydrazide
(1 R,4S)-N'-cyclopropyl-6-oxo-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropane]- 4-carbohydrazide
(1 R,4S)-N'-acetyl-6-oxo-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropane]-4- carbohydrazide
(1 R,4S)-6-oxo-N'-propanoyl-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropane]-4- carbohydrazide
(1 R,4S)-N'-(2-methylpropanoyl)-6-oxo-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '- cyclopropane]-4-carbohydrazide
(1 R,4S)-6-oxo-7-(sulfooxy)-N'-(trifluoroacetyl)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '- cyclopropane]-4-carbohydrazide
(1 R,4S)-N'-(cyclopropylcarbonyl)-6-oxo-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '- cyclopropane]-4-carbohydrazide
(1 R,4S)-N'-[(2,2-difluorocyclopropyl)carbonyl]-6-oxo-7-(sulfooxy)-5,7- diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropane]-4-carbohydrazide
(1 R,4S)-N'-(cyclobutylcarbonyl)-6-oxo-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '- cyclopropane]-4-carbohydrazide
(1 R,4S)-N'-(azetidin-3-ylcarbonyl)-6-oxo-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '- cyclopropane]-4-carbohydrazide
(1 R,4S)-N'-(azetidin-2-ylcarbonyl)-6-oxo-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '- cyclopropane]-4-carbohydrazide
(1 R,4S)-6-oxo-N'-(pyrrolidin-2-ylcarbonyl)-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '- cyclopropane]-4-carbohydrazide (non-preferred name)
(1 R,4S)-6-oxo-N'-(pyrrolidin-3-ylcarbonyl)-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '- cyclopropane]-4-carbohydrazide
(1 R,4S)-6-oxo-N'-(piperidin-4-ylcarbonyl)-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1 '- cyclopropane]-4-carbohydrazide
(1 R^S)-N'-[(2-aminocyclopentyl)carbonyl]-6-oxo-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane- 2,1 '-cyclopropane]-4-carbohydrazide
(1 R,4S)-6-oxo-N'-(pyrrolidin-2-ylacetyl)-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1 '- cyclopropane]-4-carbohydrazide
(1 R,4S)-N'-benzoyl-6-oxo-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1 '-cyclopropane]-4- carbohydrazide
(1 R,4S)-6-oxo-N'-(pyridin-2-ylcarbonyl)-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1 '- cyclopropane]-4-carbohydrazide
(1 R,4S)-N'-[(2-amino-1 ,3-thiazol-4-yl)carbonyl]-6-oxo-7-(sulfooxy)-5,7- diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropane]-4-carbohydrazide
(1 R,4S)-6-oxo-N'-(pyridin-3-ylacetyl)-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '- cyclopropane]-4-carbohydrazide
(1 R,4S)-6-oxo-N-(piperidin-1 -yl)-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '- cyclopropane]-4-carboxamide
(2S,5R)-4,4-dimethyl-N-(morpholin-4-yl)-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2- carboxamide
(1 R^S)-N-(3-aminopyrrolidin-1 -yl)-6-oxo-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '- cyclopropane]-4-carboxamide
(1 R,4S)-N'-methyl-6-oxo-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1 ]octane-2,3'-oxetane]-4- carbohydrazide
(1 R,4S)-N'-cyclopropyl-6-oxo-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1 ]octane-2,3'-oxetane]-4- carbohydrazide
(1 R,4S)-N'-acetyl-6-oxo-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1 ]octane-2,3'-oxetane]-4- carbohydrazide
(1 R,4S)-6-oxo-N'-propanoyl-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1 ]octane-2,3'-oxetane]-4- carbohydrazide
(1 R,4S)-6-oxo-7-(sulfooxy)-N'-(trifluoroacetyl)spiro[5,7-diazabicyclo[3.2.1 ]octane-2,3'-oxetane]-4- carbohydrazide
(1 R,4S)-N'-(cyclopropylcarbonyl)-6-oxo-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1 ]octane-2,3'- oxetane]-4-carbohydrazide
(1 R,4S)-N'-[(2,2-dimethylcyclopropyl)carbonyl]-6-oxo-7-(sulfooxy)spiro[5,7- diazabicyclo[3.2.1 ]octane-2,3'-oxetane]-4-carbohydrazide
(1 R,4S)-N'-(cyclobutylcarbonyl)-6-oxo-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1 ]octane-2,3'- oxetane]-4-carbohydrazide
(1 R,4S)-N'-(azetidin-3-ylcarbonyl)-6-oxo-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1 ]octane-2,3'- oxetane]-4-carbohydrazide
(1 R,4S)-6-oxo-N'-(pyrrolidin-2-ylcarbonyl)-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1 ]octane-2,3'- oxetane]-4-carbohydrazide
(1 R,4S)-6-oxo-N'-(pyrrolidin-3-ylcarbonyl)-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1 ]octane-2,3'- oxetane]-4-carbohydrazide
(1 R,4S)-N'-[(2-aminocyclopentyl)carbonyl]-6-oxo-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1 ]octane- 2,3'-oxetane]-4-carbohydrazide
(1 R,4S)-6-oxo-N'-(pyrrolidin-2-ylacetyl)-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1]octane-2,3'- oxetane]-4-carbohydrazide
(1 R,4S)-N'-benzoyl-6-oxo-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1 ]octane-2,3'-oxetane]-4- carbohydrazide
(1 R,4S)-6-oxo-N'-(pyridin-2-ylcarbonyl)-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1 ]octane-2,3'- oxetane]-4-carbohydrazide
(1 R,4S)-6-oxo-N-(piperidin-1 -yl)-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1 ]octane-2,3'-oxetane]-4- carboxamide
(1 R,4S)-N-(morpholin-4-yl)-6-oxo-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1 ]octane-2,3'-oxetane]-4- carboxamide
(1 R^S)-N-(3-aminopyrrolidin-1 -yl)-6-oxo-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1 ]octane-2,3'- oxetane]-4-carboxam ide
(4R,8S)-N'-acetyl-1 -methyl-6-oxo-5-(sulfooxy)-4,5,6,8-tetrahydro-1 H-47-methanopyrazolo[3,4- e][1 ,3]diazepine-8-carbohydrazide
(4R,8S)-1 -methyl-6-oxo-5-(sulfooxy)-N'-(trifluoroacetyl)-4,5,6,8-tetrahydro-1 H-4,7- methanopyrazolo[3,4-e][1 ,3]diazepine-8-carbohydrazide
(4R,8S)-6-oxo-N'-propanoyl-5-(sulfooxy)-4,5,6,8-tetrahydro-4,7-methanofuro[2,3-e][1 ,3]diazepine- 8-carbohydrazide
(4R,8R)-N'-(2-methylpropanoyl)-6-oxo-5-(sulfooxy)-4,5,6,8-tetrahydro-4J-methanothieno[2,3- e][1 ,3]diazepine-8-carbohydrazide
(1 R,5S)-N'-(cyclopropylcarbonyl)-3-oxo-2-(sulfooxy)-1 ,2,3,5-tetrahydro-1 ,4-methano-2,4- benzodiazepine-5-carbohydrazide
(5R,9S)-N'-[(2,2-difluorocyclopropyl)carbonyl]-7-oxo-6-(sulfooxy)-5,6,7,9-tetrahydro-5,8- methanopyrido[2,3-e][1 ,3]diazepine-9-carbohydrazide
(4R,8S)-N'-(azetidin-3-ylcarbonyl)-1 -methyl-6-oxo-5-(sulfooxy)-4,5,6,8-tetrahydro-1 H-4,7- methanopyrazolo[3,4-e][1 ,3]diazepine-8-carbohydrazide
(4R,8S)-1 -methyl-6-oxo-N'-(pyrrolidin-3-ylcarbonyl)-5-(sulfooxy)-4,5,6,8-tetrahydro-1 H-4,7- methanopyrazolo[3,4-e][1 ,3]diazepine-8-carbohydrazide
(4R,8S)-1 -methyl-6-oxo-N'-(piperidin-4-ylcarbonyl)-5-(sulfooxy)-4,5,6,8-tetrahydro-1 H-4,7- methanopyrazolo[3,4-e][1 ,3]diazepine-8-carbohydrazide
(4R,8S)-6-oxo-N'-(pyrrolidin-2-ylacetyl)-5-(sulfooxy)-4,5,6,8-tetrahydro-4,7-methanofuro[2,3- e][1 ,3]diazepine-8-carbohydrazide
(4R,8R)-N'-[(2-aminocyclopentyl)carbonyl]-6-oxo-5-(sulfooxy)-4,5,6,8-tetrahydro-4,7- methanothieno[2,3-e][1 ,3]diazepine-8-carbohydrazide
(4R,8S)-N'-benzoyl-6-oxo-5-(sulfooxy)-4,5,6,8-tetrahydro-4,7-methanofuro[2,3-e][1 ,3]diazepine-8- carbohydrazide
(4R,8R)-6-oxo-N'-(pyridin-2-ylcarbonyl)-5-(sulfooxy)-4,5,6,8-tetrahydro-47-methanothieno[^ e][1 ,3]diazepine-8-carbohydrazide
(4R,8S)-N'-[(2-amino-1 ,3-thiazol-4-yl)carbonyl]-1 -methyl-6-oxo-5-(sulfooxy)-4,5,6,8-tetrahydro-1 H- 4,7-methanopyrazolo[3,4-e][1 ,3]diazepine-8-carbohydrazide
(4R,8S)-1 -methyl-6-oxo-N'-(pyridin-3-ylacetyl)-5-(sulfooxy)-4,5,6,8-tetrahydro-1 H-4,7- methanopyrazolo[3,4-e][1 ,3]diazepine-8-carbohydrazide
(4R,8S)-1 -methyl-6-oxo-N-(piperidin-1 -yl)-5-(sulfooxy)-4,5,6,8-tetrahydro-1 H-4,7- methanopyrazolo[3,4-e][1 ,3]diazepine-8-carboxamide
(4S,8S)-1 -ethyl-N-(morpholin-4-yl)-6-oxo-5-(sulfooxy)-4,5,6,8-tetrahydro-1 H-4,7- methanoimidazo[4,5-e][1 ,3]diazepine-8-carboxamide
(4S,8S)-N-(3-aminopyrrolidin-1 -yl)-1 -ethyl-6-oxo-5-(sulfooxy)-4,5,6,8-tetrahydro-1 H-4,7- methanoimidazo[4,5-e][1 ,3]diazepine-8-carboxamide
(2S,5S)-4,4-difluoro-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2-carboxamide
(2S,5R)-4,4-dimethyl-7-oxo-6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane-2-carboxamide
(1 R,4S)-6-oxo-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '-cyclopropane]-4-carboxamide
(1 R,4S)-6-oxo-7-(sulfooxy)spiro[5,7-diazabicyclo[3.2.1]octane-2,3'-oxetane]-4-carboxamide
(1 R,5S)-7-oxo-8-(sulfooxy)-6,8-diazatricyclo[4.2.1 .02,4]nonane-5-carboxamide
(4R,8S)-1 -methyl-6-oxo-5-(sulfooxy)-4,5,6,8-tetrahydro-1 H-4,7-methanopyrazolo[3,4- e][1 ,3]diazepine-8-carboxamide
or a pharmaceutically acceptable salt thereof or a deuterated compound of any such compound.
6. A pharmaceutical composition comprising one or more compounds of any one of claims 1 -5 and a pharmaceutically acceptable carrier or diluent.
7. The pharmaceutical composition according to claim 6, further comprising one or more β-lactamase inhibitor selected from the group consisting of sulbactam, tazobactam, and clavulanic acid, and a pharmaceutically acceptable salt thereof.
8. The pharmaceutical composition according to claim 6 or 7, further comprising one or more antibacterial agent or a pharmaceutically acceptable salt thereof.
9. The pharmaceutical composition according to claim 8, wherein the one or more antibacterial agent is selected from the group consisting of a β-lactam antibiotic, a salt of a β-lactam antibiotic, a hydrate of a β-lactam antibiotic, and a prodrug of a β-lactam antibiotic, or a pharmaceutically acceptable salt thereof.
10. The pharmaceutical composition according to claim 8, wherein the one or more antibacterial agent is a β-lactam antibiotic or a pharmaceutically acceptable salt thereof.
1 1 . The pharmaceutical composition according to claim 8, wherein the one or more antibacterial agent is selected from the group consisting of aminoglycosides, ansamycins, carbacephems, cephalosporins, cephamycins, lincosamides, lipopeptides, macrolides, monobactams, nitrofurans, penems, penicillins, polypeptides, quinolones, sulphonamides, tetracyclines, and oxazolidinone, or a pharmaceutically acceptable salt thereof.
12. The pharmaceutical composition according to claim 8, wherein the one or more antibacterial agent is selected from the group consisting of penicillins, penems, carbapenems, cephalosporins, and monobactams, or a pharmaceutically acceptable salt thereof.
13. The pharmaceutical composition according to claim 8, wherein the one or more antibacterial agent is a cephalosporin antibiotic selected from the group consisting of cephalothin, cephaloridine, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cephradine, ceftizoxime, cefoxitin, cephacetrile, cefotiam, cefotaxime, cefsulodin, cefoperazone, ceftizoxime, cefmenoxime, cefmetazole, cephaloglycin, cefonicid, cefodizime, cefpirome, ceftobiprole, ceftolozane, ceftazidime, cefpiramide, cefbuperazone, cefozopran, cefepime, cefoselis, cefluprenam, cefuzonam, cefpimazole, cefclidin, cefixime, ceftibuten, cefdinir, cefpodoxime axetil, cefpodoxime proxetil, cefteram pivoxil, cefetamet pivoxil, cefcapene pivoxil or cefditoren pivoxil, cefuroxime, cefuroxime axetil, loracarbacef, ceftaroline, and latamoxef, or a pharmaceutically acceptable salt thereof.
14. The pharmaceutical composition according to claim 8, wherein the one or more antibacterial agent is selected from the group consisting of ceftazidime, cefepime, cefpirome, piperacillin, doripenem, meropenem, imipenem, ceftaroline, ceftobiprole, and ceftolozane, or a pharmaceutically acceptable salt thereof.
15. A method of preventing or treating a bacterial infection in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as recited in any one of claims 1 -5.
16. The method of preventing or treating a bacterial infection in a subject of claim 15, wherein the bacterial infection is caused by bacteria producing one or more β-lactamase enzymes.
17. A method of preventing or treating a bacterial infection in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition as recited in any one of claims 6-14.
18. A method of preventing or treating a bacterial infection in a subject of claim 17, wherein the bacterial infection is caused by bacteria producing one or more β-lactamase enzymes.
19. A method of preventing or treating a bacterial infection in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of (a) a pharmaceutical composition of claim 6, and (b) one or more β-lactamase inhibitor selected from the group consisting of sulbactam, tazobactam, and clavulanic acid, or a pharmaceutically acceptable salt thereof.
20. A method of preventing or treating a bacterial infection in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of (a) a pharmaceutical composition of claim 6, and (b) one or more antibacterial agent selected from the group consisting of a β-lactam antibiotic, a salt of a β-lactam antibiotic, a hydrate of a β-lactam antibiotic, and a prodrug of a β-lactam antibiotic, or a pharmaceutically acceptable salt thereof.
21 . A method of preventing or treating a bacterial infection in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of (a) a pharmaceutical composition of claim 6, and (b) one or more antibacterial agent selected from the group consisting of aminoglycosides, ansamycins, carbacephems, cephalosporins, cephamycins, lincosamides, lipopeptides, macrolides, monobactams, nitrofurans, penems, penicillins, polypeptides, quinolones, sulphonamides, tetracyclines, and oxazolidinone, or a pharmaceutically acceptable salt thereof.
22. A method of preventing or treating a bacterial infection in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of (a) a pharmaceutical composition of claim 6, (b) one or more β-lactamase inhibitor selected from the group consisting of sulbactam, tazobactam, and clavulanic acid, or a
pharmaceutically acceptable salt thereof, (c) one or more antibacterial agent selected from the group consisting of a β-lactam antibiotic, a salt of a β-lactam antibiotic, a hydrate of a β-lactam antibiotic, and a prodrug of a β-lactam antibiotic, or a pharmaceutically acceptable salt thereof.
23. A method of preventing or treating a bacterial infection in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of (a) a pharmaceutical composition of claim 6, (b) one or more β-lactamase inhibitor selected from the group consisting of sulbactam, tazobactam, and clavulanic acid, or a
pharmaceutically acceptable salt thereof, and (c) one or more antibacterial agent selected from the group consisting of aminoglycosides, ansamycins, carbacephems, cephalosporins, cephamycins, lincosamides, lipopeptides, macrolides, monobactams, nitrofurans, penems, penicillins, polypeptides, quinolones, sulphonamides, tetracyclines, and oxazolidinone, or a pharmaceutically acceptable salt thereof.
24. The method of any one of claims 15-23, wherein the subject is a human.
25. The method of any one of claims 19-21 , wherein (a) and (b) are administered concurrently or sequentially, in any order.
26. The method of claim 22 or 23, wherein (a), (b) and (c) are administered concurrently or sequentially, in any order.
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