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WO2023060369A1 - Novel carbimidate substituted bicyclic compounds and their use as beta-lactamase inhibitors - Google Patents

Novel carbimidate substituted bicyclic compounds and their use as beta-lactamase inhibitors Download PDF

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Publication number
WO2023060369A1
WO2023060369A1 PCT/CN2021/122965 CN2021122965W WO2023060369A1 WO 2023060369 A1 WO2023060369 A1 WO 2023060369A1 CN 2021122965 W CN2021122965 W CN 2021122965W WO 2023060369 A1 WO2023060369 A1 WO 2023060369A1
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Prior art keywords
oxo
diazabicyclo
sulfooxy
octane
carbimidate
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PCT/CN2021/122965
Other languages
French (fr)
Inventor
Zhixiang Yang
Lijuan ZHAI
Jian Sun
Haikang YANG
Jinbo JI
Jingwen JI
Lili He
Yuanyu GAO
Dong TANG
Zafar Iqbal
Yuanbai LIU
Yangxiu MU
Xueqin Ma
Jianqiang Yu
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Ningxia Academy Of Agriculture And Forestry Sciences
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Priority to PCT/CN2021/122965 priority Critical patent/WO2023060369A1/en
Publication of WO2023060369A1 publication Critical patent/WO2023060369A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D491/02—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 two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • 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
    • C07D491/02—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 two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • 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
    • C07D491/02—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 two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • 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
    • C07D495/02—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 two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • This invention relates to novel beta-lactamase inhibitors and their preparation and their use as antibacterial agents either alone or in combination with an antibiotic (or plural antibiotics) for the treatment of infections caused by ⁇ -lactamase-producing pathogenic bacteria. More particularly, the invention relates to compositions and methods for overcoming bacterial antibiotic resistance.
  • ⁇ -Lactam antibiotics commonly called ⁇ -lactams
  • ⁇ -lactams have been playing an important role for treatment of bacterial infections, but pathogens resistant to them have been increasing in many countries around world.
  • ⁇ -lactamases are enzymes that catalyze the hydrolysis of the ⁇ -lactam ring, which inactivate the antibacterial activity of the ⁇ -lactam antibiotic and allow the bacteria to become resistant.
  • the present invention relates to new diazabicyclic compounds (some of which have potent broad-spectrum ⁇ -lactamase inhibitory activity and others do not have such activity) that when used in combination with a ⁇ -lactam antibiotic or with other non ⁇ -lactam antibiotic enhance the activity of the antibiotic against class A, class B, class C, and class D enzyme producing organisms and thereby enhance the antibacterial properties.
  • the inventive compounds are therefore useful in the treatment of bacterial infections in humans or animals either alone or in combination with ⁇ -lactam antibiotics.
  • X is oxygen or sulfur
  • M is hydrogen or a pharmaceutically acceptable salt forming cation
  • a “pharmaceutically acceptable salt” refers to a salt of a compound, which salt possesses the desired pharmacological activity of the parent compound
  • specified compounds “modified in that they have been deuterated” refer to compounds prepared by modifying the specified compounds so that one or more hydrogen atoms in the compounds have been replaced with or converted to deuterium,
  • R is optionally substituted with one or two substituents independently selected from the following:
  • the compounds of the present invention are new and the structural features are significantly distinct from the compounds described in the prior art.
  • R is a radical selected from any of the following groups:
  • Heterocyclyl (C 1-6 ) alkyl wherein the said heterocycle containing at least one heteroatom selected from O, N and S wherein the said heterocycle is optionally substituted.
  • the ring S is optionally oxidized to S (O) or S (O) 2 and the free ring N atom may optionally take a substituent.
  • Non-limiting examples of such compounds are:
  • Examples of the groups for forming a pharmaceutically acceptable salt represented by M 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 such as sodium, potassium, and lithium and alkaline earth metals such as 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 hydrochloric, hydrobromic, phosphoric, sulphuric, citric, oxalic, maleic, fumaric, glycolic, mandelic, tartaric, aspartic, succinic, malic, formic, acetic, p-toluenesulfonic, trifluoroacetic, methanesulfonic, ethanesulfonic, trifluoromethanesulfonic, benzenesulfonic and the like.
  • Another aspect of the present invention is to include all possible isomers of formula (I) .
  • the term ‘isomers’ refers to different compounds that have the same molecular formula 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, diastereomers 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.
  • stereoisomers are stereoisomers that have at least two asymmetric carbon atoms but which are not mirror-images of each other.
  • stereochemistry at each chiral carbon may be specified by either R or S.
  • 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 “Protective Groups in Organic Synthesis” , (Theodora W. Greene and Peter G. M. Wuts, John Wiley &Sons. Inc., 3 rd , 1999) .
  • Representative amino protecting groups include, but are not limited to formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ) , tert-butoxycarbonyl (Boc) , trimethylsilyl (TMS) , 9-fluorenylmethyloxycarbonyl (FMOC) , nitro-veratryoxycarbonyl (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.
  • Lower alkyl including from one to six carbon atoms in any arrangement, e.g., methyl, ethyl, i-propyl or t-butyl,
  • Substituted amino such as -NHCH 3 , -N (CH 3 ) 2 , -NHCH 2 CH 3 , -NHPr i , -NHBu t ,
  • Alkoxy such as -OCH 3 , -OC 2 H 5 , -OPr i (i.e., isopropyloxy) , -OBu t (i.e., isobtutyloxy) ,
  • Hydroxyalkyl such as -CH 2 OH, -CH 2 CH 2 OH,
  • Halogen such as F, Cl, Br,
  • Alkoxycarbonyl such as -COOCH 3 , -COOC 2 H 5 , -COOPr i , and -COOBu t ,
  • Haloalkyl such as -CH 2 Cl, -CH 2 F,
  • Alkylamine such as -CH 2 NH 2 , -CH 2 CH 2 NH 2 ,
  • Substituted alkylamine such as -CH 2 CH 2 NHCH 3 , -CH 2 CH 2 N (CH 3 ) 2 , -CH 2 NHCH 3 , -CH 2 N (CH 3 ) 2 ,
  • Substituted sulfonamide such as -SO 2 NHCH 3 , -SO 2 NHPr i , -SO 2 NHBu t , -SO 2 NHCH 2 CH 3 ,
  • Oxo ( O) when oxygen is bonded through double bond to a carbon atom
  • a particular subject of the invention is those in which M is hydrogen or a pharmaceutically acceptable salt forming cation.
  • compositions comprising a compound of formula (I) of this invention as an active ingredient in combination with an antibiotic (e.g., a ⁇ -lactam antibiotic or some other non ⁇ -lactam antibiotic) and a suitable amount of pharmaceutically acceptable carrier or diluent, so as to provide a form for proper administration to a patient.
  • antibiotic e.g., a ⁇ -lactam antibiotic or some other non ⁇ -lactam antibiotic
  • suitable amount of pharmaceutically acceptable carrier or diluent so as to provide a form for proper administration to a patient.
  • Suitable pharmaceutical vehicles 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.
  • Other examples of suitable pharmaceutical vehicles have been described in the art (Remington’s Science and Practice of Pharmacy, 21 st Edition, 2006) .
  • Compositions of the present disclosure can also contain minor amounts of wetting, dispersing or emulsifying agents,
  • compositions can be formulated in a conventional manner. Proper formulation is dependent upon the route of administration chosen.
  • the present 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.
  • the present invention also provides for the use, in the manufacture of a medicament, of a compound within formula (I) above as an active ingredient in an antibacterial composition in admixture with a carrier.
  • the present invention also provides for the use, in the manufacture of a medicament, of a compound within formula (I) above as an active ingredient.
  • the present invention also provides for the use, in the manufacture of a medicament, of a compound within formula (I) above as an active ingredient, along with one or more ⁇ -lactam antibiotics (e.g., a ⁇ -lactam antibiotic or some other non ⁇ -lactam antibiotic) , in an antibacterial composition in admixture with a carrier.
  • ⁇ -lactam antibiotics e.g., a ⁇ -lactam antibiotic or some other non ⁇ -lactam antibiotic
  • the present invention also provides for the use, in the manufacture of a medicament, of a compound within formula (I) above as an active ingredient, along with one or more ⁇ -lactam antibiotics (e.g., a ⁇ -lactam antibiotic or some other non ⁇ -lactam antibiotic) .
  • ⁇ -lactam antibiotics e.g., a ⁇ -lactam antibiotic or some other non ⁇ -lactam antibiotic
  • compositions for oral delivery can be, for example, in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs.
  • Orally administered compositions can contain one or more optional agents, for example, sweetening agents such as fructose, aspartame, or saccharin, flavoring agents such as peppermint, oil of wintergreen, cherry, coloring agents, and preserving agents to provide a pharmaceutically palatable preparation.
  • sweetening agents such as fructose, aspartame, or saccharin
  • flavoring agents such as peppermint, oil of wintergreen, cherry, coloring agents
  • preserving agents to provide a pharmaceutically palatable preparation.
  • the compositions when in tablet form, can be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over an extended period of time.
  • Oral compositions can include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like.
  • suitable carriers, excipients, or diluents include water, saline, alkyleneglycols (e.g. propylene glycol) , polyalkylene glycols (e.g., polyethylene glycol) , oils, alcohols, slightly acidic buffers ranging from about pH 4 to about pH 6 (e.g., acetate, citrate, ascorbate ranging from about 5 mM to about 50 mM) , and the like.
  • slightly acidic buffers ranging from about pH 4 to about pH 6 (e.g., acetate, citrate, ascorbate ranging from about 5 mM to about 50 mM) , and the like.
  • flavoring agents, preservatives, coloring agents, bile salts, acylcarnitines, and the like can be added.
  • Topical delivery systems also include transdermal patches containing at least one compound of formula (I) to be administered.
  • 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: 30 to 30: 1, for example, 1: 25 to 25: 1, 1: 20 to 20: 1, 1: 15 to 15: 1, 1: 10 to 10: 1, 1: 5 to 5: 1, 1: 4 to 4: 1, 1: 3 to 3: 1, 1: 2 to 2: 1, or 1: 1.
  • the administered daily dose varies according to the illness treated, and the administration route.
  • an effective dose e.g., in some instances, ⁇ -lactamase inhibiting dose
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof will be a daily dose in the range from about 1 to about 500 mg per kilogram of body weight orally, and from about 1 to about 500 mg per kilogram of body weight parenterally.
  • the weight ratio of the compound of present invention to the antibiotic will normally be in the range from 1: 30 to 30: 1, for example, 1: 25 to 25: 1, 1: 20 to 20: 1, 1: 15 to 15: 1, 1: 10 to 10: 1, 1: 9 to 9: 1, 1: 8 to 8: 1, 1: 7 to 7: 1, 1: 6 to 6: 1, 1: 5 to 5: 1, 1: 4 to 4: 1, 1: 3 to 3: 1, 1: 2 to 2: 1, or 1: 1.
  • an additional object is to provide an improved method for the treatment of bacterial infections caused by ⁇ -lactamase producing bacteria in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of at least one compound chosen from formula (I) or a pharmaceutically acceptable salt thereof in combination with a known ⁇ -lactam antibiotic.
  • the compounds 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.
  • said 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 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 treatment with the antibiotic.
  • Therapeutically effective amount refers to the amount of a compound that, when administered to a subject for treating a disease, or at least one of the clinical symptoms of a disease, is sufficient to affect such treatment of the disease, disorder, or symptom.
  • the therapeutically effective amount can vary depending, for example, on the compound, the disease, disorder, and/or symptoms of the disease, severity of the disease, disorder, and/or symptoms of the disease, the age, weight, and/or health of the patient to be treated, and the judgement of the prescribing physician.
  • ⁇ -lactam antibiotic refers to a compound with antibiotic property that contains a ⁇ -lactam functionality.
  • Examples of ⁇ -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.
  • Examples of ⁇ -lactam antibiotics which can be used in combination with the compounds of the present invention represented by formula (I) are commonly used 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
  • ⁇ -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
  • examples of antibiotics which can be used in combination with the compounds of the present invention (i.e., compounds of formula (I) above, salts thereof, solvates of such compounds and salts, and deuterated compounds of any such compounds) include aminoglycosides, quinolones, tetracyclines, glycylcyclines, glycopeptides, lipopeptides, macrolides, ketoliddes, lincosamides, streptogramin, oxazolidinones, polymyxins, and other compounds known to have antibacterial properties.
  • ‘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.
  • the present invention also relates to methods for the preparation of compounds of formula (I) .
  • the compounds of the present invention of formula (I) can be readily prepared by the following reaction Scheme 1 and examples using readily available starting materials, reagents and conventional synthesis procedures known to those of ordinary skill in this art.
  • the bicyclic intermediate amide (II) may be prepared following the literature (Org. Process Res. Dev. 2016, 20, 1799-1805) .
  • Compounds of the general of formula (I) can be prepared by converting amide (II) to the nitrile (III) in presence of a suitable reagents.
  • the suitable reagents used for carrying out this step include, but are not limited to trifluoroacetic anhydride (TFAA) and triethylamine (TEA) or diisopropylethylamine (DIPEA) , phosphoryl chloride (POCl 3 ) and TEA, and the like.
  • the organic solvents useful in the reaction are not particularly limited and include any of those which do not adversely affect the reaction. Typical solvents include dichlomethane, chloroform, tetrahydrofuran and the like.
  • the reaction is normally carried out at a temperature of from about 0 °C to 40 °C, and preferably at room temperature under nitrogen. After completion of the reaction the desired product can be easily separated by conventional methods such as column chromatography, crystallization or similar methods.
  • the intermediate amide (III) could be converted to the hydroxy compound (IV) under an atmosphere of hydrogen or hydrogen mixed with an inert diluent such as nitrogen or argon in the presence of a hydrogenation catalyst.
  • the catalysts used in this hydrogenation reaction are the type of agents known in the art for this kind of deprotection and typical examples are the noble metals, such as nickel, palladium, platinum and rhodium. Examples of the catalysts are platinum, platinum oxide, palladium, palladium oxide and the like.
  • the catalyst is usually present in the amount from about 1 to about 50 weight percent and preferably from about 5 to about 15 weight percent based on the compound of amide (III) . It is often convenient to suspend the catalyst on an inert support.
  • a particularly convenient catalyst is palladium suspended on an inert support such as carbon, e.g., 5%or 10 %by weight palladium on carbon.
  • This reaction may be conveniently effected at ambient temperature from 15 psi to 60 psi until reaction is complete (2 to 72 hours) .
  • Suitable solvents for this reaction are those which substantially dissolve the starting material of the formula (III) , after reaction, the suitable solvents are sufficiently volatile to be removed by evaporation and do not themselves suffer hydrogenation. Examples of such solvents include methanol, ethanol, dioxane, ethyl acetate, tetrahydrofuran or a mixture of these solvents.
  • the hydroxy intermediate (IV) can be purified by silica gel column chromatography or in many cases can be directly carried out to the next step without further purification.
  • the compound of formula (IV) can be converted to the key intermediate (V) by sulfation of the hydroxy intermediate (IV) using a sulfating reagent (e.g., pyridine-SO 3 complex, SO 3 -NMe 3 complex, SO 3 -triethylamine complex, DMF-SO 3 complex and ClSO 3 H) in an appropriate base (e.g., pyridine, triethylamine or 2-picoline) as described in the literature (WO2017155765A1, Org. Process Res. Dev. 2016, 20, 1799-1805) .
  • a sulfating reagent e.g., pyridine-SO 3 complex, SO 3 -NMe 3 complex, SO 3 -triethylamine complex, DMF-SO 3 complex and ClSO 3 H
  • an appropriate base e.g., pyridine, triethylamine or 2-picoline
  • pyridine-SO 3 complex or SO 3 -NMe 3 complex can be added to a solution of the hydroxy intermediate (IV) in a solvent in an excess amount, if desired, to force the reaction to completion.
  • the organic solvents useful for this transformation are not particularly limited and include those which do not adversely affect the reaction. Typical solvents include, but are not limited to pyridine, tertrahydrofuran, isopropyl alcohol, dimethyl formamide, dimethylacetamide, acetonitrile, or those solvents mixed with water.
  • the transformation can be carried out at from 0 °C to 40 °C, and preferably at room temperature.
  • the compound of formula (Ia or Ib) can be achieved by treatment of the key intermediate (V) with alcohol or thiol and an appropriate base in an suitable organic solvent.
  • suitable base used for carrying out this step include, but are not limited to sodium hydride (NaH) , potassium hydride (KH) , sodium tert-butoxide or potassium tert-butoxide, and the like.
  • suitable organic solvents useful in the reaction are not particularly limited and include any of those which do not adversely affect the reaction. Typical solvents include methanol, ethanol, dichlomethane, N, N-dimethylformamide, tetrahydrofuran and the like.
  • the reaction is normally carried out at a temperature of from about 0 °C to 40 °C, and preferably at room temperature under nitrogen.
  • R 1 when R 1 is methyl or ethyl group, the compound of formula (Ia) can be achieved by treatment of the key intermediate (V) directly with sodium methoxide or sodium ethoxide in an suitable organic solvent.
  • the compound of formula (Ia or Ib) also can be achieved by removing protecting group when the compound (Ia or Ib) containing protection group, such as Boc., and the like.
  • the treatment is suitably conducted at a temperature in a range from about -10 °C to room temperature and is typically conducted at a temperature in a range of from about 0 °C to about 35 °C.
  • Suitable purification methods for the final compound of formula (Ia or Ib) are a preparative HPLC, or HP20 chromatograph, or inon exchange resin and the like.
  • DIPEA N, N-diisopropylethylamine
  • Preparative HPLC was performed on an Agilent 1260 Infinity II System on Agilent 10 prep-C18 250 ⁇ 21.2 mm column, using an acetonitrile/aqueous 0.1%trifluoroacetic acid gradient, or an acetonitrile/aqueous 0.1%formic acid gradient at 22°C.
  • Mass spectra were performed on an Agilent 1260II-6125 Separation Module using either ES - or ES + ionization modes.
  • Step 1 Synthesis of (2S, 5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carbonitrile (A-2)
  • TFAA 0.3 g, 1.4 mmol
  • A-1 0.2 g, 0.7 mmol, prepared according to Org. Process Res. Dev. 2016, 20, 1799-1805
  • TEA 0.7 g, 7.0 mmol
  • DCM 5 mL
  • the resulting reaction mixture was heated at 35 °C for 3 hours, and then concentrated under reduced pressure.
  • the residue was extracted with ethyl acetate, washed with water, brine, dried over Na 2 SO 4 and filtrated.
  • Step 3 Synthesis of triethylamine (2S, 5R) -2-cyano-7-oxo-1, 6-diazabicyclo [3.2.1] octan-6-yl sulfate (B5_1)
  • Imipenem as a test antibiotic compound was dissolved in DMSO, and then diluted in microbial growth medium (Mueller-Hinton Broth II, cation adjusted) resulting in a final concention range of 0.125-64 mg/L in serial two-fold dilution. In all cases the filnal DMSO concentraion was less than 0.5%.
  • Bacteria were added to 96-well microtitre plates containing the serial two-fold dilutions of the compounds; the final cell density was appoximately 5x10 5 colony forming units/mL (CFU/mL) . Plates were incubated at 37 °C for 18-24 hours and read visually. The MIC, i.e.
  • test compound that inhibited visible growth of the bacteria.
  • the same assay conditions were used when the compounds of present invention alone, avibactam (as a control) alone, and as a combination with test imipenem was tested for minmum inhibitory concentration (MIC, mg/L) . While test imipenem was serially diluted as descrribed above, a constant concentration of both avibactam and the present invention of 4 mg/L was used.
  • Bacterial strains that were used to evaluate the antimicrobial activity using the MIC determination included but were not limited to E. coli clinical isolate (strain 1) , E. coli 8739 (strain 2) , K. pneumoniae clinical isolate (strain 3) , K. pneumoniae 700603 (strain 4) , E. cloacae clinical isolate (strain 5) , E. cloacae 700323 (strain 6) , A. baumannii clinical isolate (strain 7) , A. baumannii 19606 (strain 8) , P. aeruginosa clinical isolate (strain 9) , P. aeruginosa 9027 (strain 10) .
  • Table 2 Synergy of the inhibitor example 1 to example 14 (4 mg/L) in combination with imipenem (IMI, AVI and Ex. 1 to Ex. 4, MIC, mg/L)
  • Table 3 Antibacterial activity of example 1 to example 14 (AVI and Ex. 1 to Ex. 7, MIC, mg/L)
  • 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 (1991) ] .
  • the concentration of inhibitor (IC 50 ) which inhibits by 50%the reaction of hydrolysis of nitrocefin by the enzyme is determined.
  • Efficacy of the ⁇ -lactamase inhibitors can be evaluated in combination with ceftazidime aztreonam, meropenem, imipenem and other class of carbapenems and cephalosporins in murine infection models such as septicemia, pneumonia and thigh infection models (Ref: Andrea Endimiani et. al. Antimicrobial Agents and Chemotherapy, January 2011, page 82-85) .
  • murine acute lethal septicemia model mice were infected by the intraperitoneal injection of the clinical strains resulting in death of the untreated controls within 24-48 hours.
  • a single subcutaneous dose of meropenem with and without ⁇ -lactamase inhibitor was initiated and the survival ratio monitored for 5 days twice daily.
  • the dosing regimen used are meropenem alone (doses of 512, 1024 &2048 mg/kg of body weight) and meropenem plus ⁇ -lactamase inhibitor at ratio of 2: 1, 4: 1, 8: 1, 16: 1 &32: 1 (meropenem doses were 4, 8, 16, 32 &64 mg/kg for each ratio) .
  • the median effective dose for 50%protective dose (ED 50 ) of animals was determined by a computerized program of Probit analysis. Survival rates stratified for different dosing regimen were also obtained.
  • ED 50 50%protective dose
  • mice were used and intratracheally infected with Klebsiella pneumoniae strains. Mice in this model developed bacteraemia pneumoniae and fatal disease within 2 to 4 days with lung bacterial burden at 16-18 hours post infection of 10 11 to 10 13 CFU/gm lung.
  • Treatment with meropenem and inhibitor at a ratio of 2/1 &4/1 demonstrated efficacy with significant 3 to 6 log reduction in lung counts compared to meropenem alone and was 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 disclosure provides novel β-lactamase inhibitors, for the treatment of bacterial infections in combination with β-lactam antibiotics, including infection caused by drug resistant organisms and especially multi-drug resistant organisms. Specifically, the present disclosure provides compounds according to formula (I) or pharmaceutically acceptable salts thereof, wherein M, X and R are as defined herein.

Description

NOVEL CARBIMIDATE SUBSTITUTED BICYCLIC COMPOUNDS AND THEIR USE AS BETA-LACTAMASE INHIBITORS Field of the invention
This invention relates to novel beta-lactamase inhibitors and their preparation and their use as antibacterial agents either alone or in combination with an antibiotic (or plural antibiotics) for the treatment of infections caused by β-lactamase-producing pathogenic bacteria. More particularly, the invention relates to compositions and methods for overcoming bacterial antibiotic resistance.
Background of the invention
β-Lactam antibiotics commonly called β-lactams, have been playing an important role for treatment of bacterial infections, but pathogens resistant to them have been increasing in many countries around world. The key microbial drug resistance to β-lactam antibiotics, especially in Gram-negative bacterial, is most commonly mediated by β-lactamases. β-lactamases are enzymes that catalyze the hydrolysis of the β-lactam ring, which inactivate the antibacterial activity of the β-lactam antibiotic and allow the bacteria to become resistant. Inhibition of the β-lactamase with a β-lactamases inhibitor slows or prevents degradation of the β-lactam antibiotic and restores β-lactam antibiotic susceptibility to β-lactamase producing bacteria. Many of these β-lactamases are not effectively inhibited by β-lactamase inhibitors currently on the market rendering the β-lactam antibiotics ineffective in treating bacteria that produce these β-lactamases. There is an urgent need for novel β-lactamase inhibitors that inhibit β-lactamases that are not effectively inhibited by the current clinical β-lactamases (e.g. KPC, class C and class D β-lactamases) and that could be used in combination with β-lactam antibiotics to treat infection caused by β-lactam resistant bacteria.
Recently, certain diazabicyclic compounds have been disclosed in WO 2009/091856 which is hereby incorporated by reference in its entirety. In addition, a number of diazabicyclic heterocycles have been disclosed in the following patents or applications as β-lactamase inhibitors: US 2003/0199541 A1, US 2004/0157826 A1, US 2004/0097490 A1, US 2005/0020572 A1, US 2006/7112592 B2, US 2006/0189652 A1, US 2008/7439253 B2, US 2009/0018329 A1, EP 1307457 B1, EP 1537117 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, WO 2013/038330 A1, US 2015/0031666 A1, US 2015/0239840 A1, US 2016/0297817 A1, US2016/0002235 A1, WO 2017037607 A1, WO 2018053057 A2, WO 2018053215  A1, WO2018060481A1, WO2018060484A1, WO2018208769A1, WO2018141991A1, WO20133030735.
Detailed description of the invention
In one aspect, the present invention relates to new diazabicyclic compounds (some of which have potent broad-spectrum β-lactamase inhibitory activity and others do not have such activity) that when used in combination with a β-lactam antibiotic or with other non β-lactam antibiotic enhance the activity of the antibiotic against class A, class B, class C, and class D enzyme producing organisms and thereby enhance the antibacterial properties. The inventive compounds are therefore useful in the treatment of bacterial infections in humans or animals either alone or in combination with β-lactam antibiotics.
In accordance with the present invention, there are provided (A) new compounds of general formula (I) , (B) pharmaceutically acceptable salts of the compounds of formula (I) , and (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 the compounds of formula (I) modified in that they have been deuterated, (iii) pharmaceutically acceptable solvates of the compounds of formula (I) and of their salts modified in that they have been deuterated) :
Figure PCTCN2021122965-appb-000001
wherein:
X is oxygen or sulfur,
M is hydrogen or a pharmaceutically acceptable salt forming cation,
a “pharmaceutically acceptable salt” refers to a salt of a compound, which salt possesses the desired pharmacological activity of the parent compound,
specified compounds “modified in that they have been deuterated” refer to compounds prepared by modifying the specified compounds so that one or more hydrogen atoms in the compounds have been replaced with or converted to deuterium,
R is optionally substituted with one or two substituents independently selected from the following:
Lower alkyl, amino, substituted amino, alkoxy, hydroxyalkyl, halogen, hydroxy, carboxy, alkoxycarbonyl, haloalkyl, trifluoromethyl, trifluoromethyloxy, alkylamine, substituted alkylamine, carboxamide, thiocarboxamide, sulfonic acid, sulphate, acylamino, sulfonylamino, substituted or unsubstituted sulfonamide, substituted or unsubstituted urea, substituted or unsubstituted thiourea, oxyimino, hydroxamic acid, acyl, trifluoromethyl carbonyl, cyano, amidino, guanidino, aryloxy, heterocyclylalkyloxy, and heteroaryloxy.
The compounds of the present invention are new and the structural features are significantly distinct from the compounds described in the prior art.
In the formula (I) , R is a radical selected from any of the following groups:
(1) C 1-6 straight, or branched chain which is optionally substituted. Non-limiting examples of such compounds are:
Figure PCTCN2021122965-appb-000002
(2) Heterocyclyl (C 1-6) alkyl, wherein the said heterocycle containing at least one heteroatom selected from O, N and S wherein the said heterocycle is optionally substituted. Furthermore the ring S is optionally oxidized to S (O) or S (O)  2 and the free ring N atom may optionally take a substituent. Non-limiting examples of such compounds are:
Figure PCTCN2021122965-appb-000003
(3) C 5-6 membered heteroarylalkyl which is optionally substituted. Non-limiting examples of such compounds are:
Figure PCTCN2021122965-appb-000004
Examples of the groups for forming a pharmaceutically acceptable salt represented by M 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 such as sodium, potassium, and lithium and alkaline earth metals such as 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, p-toluenesulfonic, trifluoroacetic, methanesulfonic, ethanesulfonic, trifluoromethanesulfonic, benzenesulfonic and the like.
Moreover, 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 OSO 3H, such inner salts are also included in this invention.
Another aspect of the present invention is to include all possible isomers of formula (I) . As used herein, the term ‘isomers’ refers to different compounds that have the same molecular formula 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, diastereomers 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.
A variety of protecting groups conventionally used in the β-lactam field to protect a reactive functional group present in the compound 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 “Protective Groups in Organic Synthesis” , (Theodora W. Greene and Peter G. M. Wuts, John Wiley &Sons. Inc., 3 rd, 1999) . Representative amino protecting groups include, but are not limited to formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ) , tert-butoxycarbonyl (Boc) , trimethylsilyl (TMS) , 9-fluorenylmethyloxycarbonyl (FMOC) , nitro-veratryoxycarbonyl (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.
The term ‘optionally substituted’ refers to unsubstituted or 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 -NHCH 3, -N (CH 3)  2, -NHCH 2CH 3, -NHPr i, -NHBu t,
Alkoxy such as -OCH 3, -OC 2H 5, -OPr i (i.e., isopropyloxy) , -OBu t (i.e., isobtutyloxy) ,
Hydroxyalkyl such as -CH 2OH, -CH 2CH 2OH,
Halogen such as F, Cl, Br,
Hydroxy,
Carboxy,
Alkoxycarbonyl such as -COOCH 3, -COOC 2H 5, -COOPr i, and -COOBu t,
Haloalkyl such as -CH 2Cl, -CH 2F,
Trifluoromethyl,
Trifluoromethyloxy,
Alkylamine such as -CH 2NH 2, -CH 2CH 2NH 2,
Substituted alkylamine such as -CH 2CH 2NHCH 3, -CH 2CH 2N (CH 3)  2, -CH 2NHCH 3, -CH 2N (CH 3)  2,
Carboxamide,
Thiocarboxamide,
Sulfonic acid,
Sulfate,
Acylamino,
Sulfonylamino,
Sulfonamide,
Substituted sulfonamide such as -SO 2NHCH 3, -SO 2NHPr i, -SO 2NHBu t, -SO 2NHCH 2CH 3,
Urea (-NHCONH 2) which may be optionally substituted,
Thiourea (-NHCSNH 2) , optionally substituted,
Sulfonylurea (-NHSO 2NH 2) , optionally substituted,
Oxo (=O) when oxygen is bonded through double bond to a carbon atom,
Oxyimino (=N-O-A) where the nitrogen is bonded through double bond to a carbon atom which is attached to the rest of the molecule and A can be hydrogen, or  optionally substituted straight or branched lower alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl,
Hydroxamic acid (-CONHOH) ,
Acyl (-COCH 3) ,
Trifluoromethyl carbonyl (-COCF 3) ,
Cyano (-CN) ,
Amidino -C (=NH) NH 2 which may be optionally substituted,
Guanidino -NHC (=NH) NH 2 which may be optionally substituted,
Aryloxy,
Heterocyclyl,
Heteroaryl,
Heterocyclyloxy,
Heteroaryloxy,
Heterocyclyalkyloxy,
Trialkylammonium,
The substituent mentioned above could be substituted at the carbon atom or at the free N-atom of the molecule as appropriate.
Among the compounds of formula (I) , a particular subject of the invention is those in which M is hydrogen or a pharmaceutically acceptable salt forming cation.
A group of preferred examples of formula (I) are from the following Table 1
Figure PCTCN2021122965-appb-000005
*= point of attachment with X (X is oxygen or sulphur)
Table 1. List of compounds
Figure PCTCN2021122965-appb-000006
Figure PCTCN2021122965-appb-000007
Figure PCTCN2021122965-appb-000008
Figure PCTCN2021122965-appb-000009
Figure PCTCN2021122965-appb-000010
It is also an object of this invention to provide a combination of a compound of general formula (I) having antibacterial activity with another existing antibacterial agent, thus causing synergistic effect and the use of the same as drugs for the treatment of bacterial infections.
It is another object of the invention to provide methods for preparing the compounds of the invention of formula (I) .
It is a further object of the invention to provide pharmaceutical compositions comprising a compound of formula (I) of this invention as an active ingredient in combination with an antibiotic (e.g., a β-lactam antibiotic or some other non β-lactam antibiotic) and a suitable amount of pharmaceutically acceptable carrier or diluent, so as to provide a form for proper administration to a patient. These compositions can be administered by parenteral, in particular intramascular route, oral, sublingual, rectal, aerosol or by local route in a topical application on the skin and the mucous membranes. Suitable pharmaceutical vehicles 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 vehicles have been described in the art (Remington’s Science and Practice of Pharmacy, 21 st Edition, 2006) . Compositions of the present disclosure, 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. The present 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.
In another aspect, the present invention also provides for the use, in the manufacture of a medicament, of a compound within formula (I) above as an active ingredient in an antibacterial composition in admixture with a carrier.
In another aspect, the present invention also provides for the use, in the manufacture of a medicament, of a compound within formula (I) above as an active ingredient.
In another aspect, the present invention also provides for the use, in the manufacture of a medicament, of a compound within formula (I) above as an active ingredient, along with one or more β-lactam antibiotics (e.g., a β-lactam antibiotic or some other non β-lactam antibiotic) , in an antibacterial composition in admixture with a carrier.
In another aspect, the present invention also provides for the use, in the manufacture of a medicament, of a compound within formula (I) above as an active ingredient, along with one or more β-lactam antibiotics (e.g., a β-lactam antibiotic or some other non β-lactam antibiotic) .
For the parenteral administration which includes intramuscular, intraperitonial, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared and the pH of the solutions are suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to render the preparation isotonic. Suitable solvents include saline solution (e.g., 0.9%NaCl solution) and apyrogenic sterile water. Pharmaceutical compositions for oral delivery can be, for example, in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs. Orally administered compositions can contain one or more optional agents, for example, sweetening agents such as fructose, aspartame, or saccharin, flavoring agents such as peppermint, oil of wintergreen, cherry, coloring agents, and preserving agents to provide a pharmaceutically palatable preparation. Moreover, when in tablet form, the compositions can be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over an extended period of time. Oral compositions can include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. For oral liquid preparations, for example, suspensions, elixirs, and solutions, suitable carriers, excipients, or diluents include water, saline, alkyleneglycols (e.g. propylene glycol) , polyalkylene glycols (e.g., polyethylene glycol) , oils, alcohols, slightly acidic buffers ranging from about pH 4 to about pH 6 (e.g., acetate, citrate, ascorbate ranging from about 5 mM to about 50 mM) , and the like. Additionally, flavoring agents, preservatives, coloring agents, bile salts, acylcarnitines, and the like can be added.
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.
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: 30 to 30: 1, for example, 1: 25 to 25: 1, 1: 20 to 20: 1, 1: 15 to 15: 1, 1: 10 to 10: 1, 1: 5 to 5: 1, 1: 4 to 4: 1, 1: 3 to 3: 1, 1: 2 to 2: 1, or 1: 1. The administered daily dose varies according to the illness treated, and the administration route. However in most instances, an effective dose (e.g., in some instances, β-lactamase inhibiting dose) of a compound of formula (I) or a pharmaceutically acceptable salt thereof will be a daily dose in the range from about 1 to about 500 mg per kilogram of body weight orally, and from about 1 to about 500 mg per kilogram of body weight parenterally. The weight ratio of the compound of present invention to the antibiotic (if it is being administered with an antibiotic) will normally be in the range from 1: 30 to 30: 1, for example, 1: 25 to 25: 1, 1: 20 to 20: 1, 1: 15 to 15: 1, 1: 10 to 10: 1, 1: 9 to 9: 1, 1: 8 to 8: 1, 1: 7 to 7: 1, 1: 6 to 6: 1, 1: 5 to 5: 1, 1: 4 to 4: 1, 1: 3 to 3: 1, 1: 2 to 2: 1, or 1: 1.
In some aspects of the present invention, an additional object is to provide an improved method for the treatment of bacterial infections caused by β-lactamase producing bacteria in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of at least one compound chosen from formula (I) or a pharmaceutically acceptable salt thereof in combination with a known β-lactam antibiotic. In such an aspect of the present invention, the compounds 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 treatment of a bacterial infection in such an aspect of the present invention, said 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 an aspect 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 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 treatment with the antibiotic.
‘Therapeutically effective amount’ refers to the amount of a compound that, when administered to a subject for treating a disease, or at least one of the clinical symptoms of a disease, is sufficient to affect such treatment of the disease, disorder, or symptom. The therapeutically effective amount can vary depending, for example, on the compound, the disease, disorder, and/or symptoms of the disease, severity of the disease, disorder, and/or symptoms of the disease, the age, weight, and/or health of the patient to be treated, and the judgement of the prescribing physician.
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.
Examples of β-lactam antibiotics which can be used in combination with the compounds of the present invention represented by formula (I) are commonly used 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 and latamoxef (moxalactam) . 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.
Examples of antibiotics (which are not β-lactam antibiotics) which can be used in combination with the compounds of the present invention (i.e., compounds of formula (I) above, salts thereof, solvates of such compounds and salts, and deuterated compounds of  any such compounds) include aminoglycosides, quinolones, tetracyclines, glycylcyclines, glycopeptides, lipopeptides, macrolides, ketoliddes, lincosamides, streptogramin, oxazolidinones, polymyxins, and other compounds known to have antibacterial properties.
‘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.
Among the compounds of formula (I) , a particular subject of the invention is the compounds with the following names. The following examples illustrate the invention, and are not intended to be limiting of its scope. To the contrary, the claims are intended to cover alternatives, modifications, and equivalents.
The non-limiting examples of the compounds of the present invention are:
Methyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
Ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidothioate,
3, 3, 3-Trifluoropropyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
Ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2-Acetamidoethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
Isobutyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2-Aminoethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2-Hydroxyethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
3-Hydroxypropyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2-Ureidoethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
3- (Imino ( (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octan-2-yl) methoxy) propanoic acid,
2-Methoxyethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2-Aminopropyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
3-Amino-3-oxopropyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
3-Methoxypropyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2-Guanidinoethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (Guanidinooxy) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2-Amino-2-oxoethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidothioate,
2- (Pyrrolidin-3-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (1-Acetylpiperidin-3-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (1-Methylpiperidin-4-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (Piperidin-2-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (1, 3-Oxazinan-2-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (Piperazin-2-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (1- (Methylsulfonyl) piperidin-3-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (Tetrahydrofuran-2-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (4-Methylpiperidin-4-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (Piperazin-1-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (1- (Methylsulfonyl) piperidin-4-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
(1-Methylpiperidin-4-yl) methyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (4-Methylpiperazin-1-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (3-Acetyltetrahydropyrimidin-1 (2H) -yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (1-Methylpiperidin-4-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (1-Acetylpiperidin-4-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (1-Methylpyrrolidin-3-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
( (R) -1-Methylpiperidin-3-yl) methyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (Tetrahydro-2H-pyran-4-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (Pyrrolidin-1-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (1, 1-Dioxidotetrahydro-2H-thiopyran-4-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (1-Acetylpyrrolidin-3-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (Piperidin-1-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
( (R) -1-Methylpyrrolidin-3-yl) methyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
Pyridin-3-ylmethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
Pyridin-4-ylmethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (Pyrimidin-5-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (Pyridin-4-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (1 H-Imidazol-2-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (1 H-Imidazol-1-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (1-Methyl-1 H-imidazol-2-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (2-Methyl-1 H-imidazol-4-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (1-Methyl-1 H-pyrazol-3-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (1 H-Pyrazol-3-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (1-Acetyl-1 H-imidazol-2-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (1-Methyl-1 H-imidazol-5-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (2-Aminothiazol-4-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (Oxazol-4-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (Thiazol-4-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (1 H-Imidazol-4-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (1-Methyl-1 H-imidazol-4-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
2- (1 H-1, 2, 4-Triazol-3-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate.
The present invention also relates to methods for the preparation of compounds of formula (I) . The compounds of the present invention of formula (I) can be readily prepared by the following reaction Scheme 1 and examples using readily available starting materials, reagents and conventional synthesis procedures known to those of ordinary skill in this art.
SCHEME 1
Figure PCTCN2021122965-appb-000011
The bicyclic intermediate amide (II) may be prepared following the literature (Org. Process Res. Dev. 2016, 20, 1799-1805) .
Compounds of the general of formula (I) can be prepared by converting amide (II) to the nitrile (III) in presence of a suitable reagents. The suitable reagents used for carrying out this step include, but are not limited to trifluoroacetic anhydride (TFAA) and triethylamine (TEA) or diisopropylethylamine (DIPEA) , phosphoryl chloride (POCl 3) and TEA, and the like. The organic solvents useful in the reaction are not particularly limited and include any of those which do not adversely affect the reaction. Typical solvents include dichlomethane, chloroform, tetrahydrofuran and the like. The reaction is normally carried out at a temperature of from about 0 ℃ to 40 ℃, and preferably at room temperature under nitrogen. After completion of the reaction the desired product can be easily separated by conventional methods such as column chromatography, crystallization or similar methods.
the intermediate amide (III) could be converted to the hydroxy compound (IV) under an atmosphere of hydrogen or hydrogen mixed with an inert diluent such as nitrogen or argon in the presence of a hydrogenation catalyst. The catalysts used in this hydrogenation reaction are the type of agents known in the art for this kind of deprotection and typical examples are the noble metals, such as nickel, palladium, platinum and rhodium. Examples of the catalysts are platinum, platinum oxide, palladium, palladium oxide and the like. The catalyst is usually  present in the amount from about 1 to about 50 weight percent and preferably from about 5 to about 15 weight percent based on the compound of amide (III) . It is often convenient to suspend the catalyst on an inert support. A particularly convenient catalyst is palladium suspended on an inert support such as carbon, e.g., 5%or 10 %by weight palladium on carbon. This reaction may be conveniently effected at ambient temperature from 15 psi to 60 psi until reaction is complete (2 to 72 hours) . Suitable solvents for this reaction are those which substantially dissolve the starting material of the formula (III) , after reaction, the suitable solvents are sufficiently volatile to be removed by evaporation and do not themselves suffer hydrogenation. Examples of such solvents include methanol, ethanol, dioxane, ethyl acetate, tetrahydrofuran or a mixture of these solvents. Upon completion, the hydroxy intermediate (IV) can be purified by silica gel column chromatography or in many cases can be directly carried out to the next step without further purification.
In the following step, the compound of formula (IV) can be converted to the key intermediate (V) by sulfation of the hydroxy intermediate (IV) using a sulfating reagent (e.g., pyridine-SO 3 complex, SO 3-NMe 3 complex, SO 3-triethylamine complex, DMF-SO 3 complex and ClSO 3H) in an appropriate base (e.g., pyridine, triethylamine or 2-picoline) as described in the literature (WO2017155765A1, Org. Process Res. Dev. 2016, 20, 1799-1805) . Thus, pyridine-SO 3 complex or SO 3-NMe 3 complex can be added to a solution of the hydroxy intermediate (IV) in a solvent in an excess amount, if desired, to force the reaction to completion. The organic solvents useful for this transformation are not particularly limited and include those which do not adversely affect the reaction. Typical solvents include, but are not limited to pyridine, tertrahydrofuran, isopropyl alcohol, dimethyl formamide, dimethylacetamide, acetonitrile, or those solvents mixed with water. The transformation can be carried out at from 0 ℃ to 40 ℃, and preferably at room temperature.
Finally, the compound of formula (Ia or Ib) can be achieved by treatment of the key intermediate (V) with alcohol or thiol and an appropriate base in an suitable organic solvent. The suitable base used for carrying out this step include, but are not limited to sodium hydride (NaH) , potassium hydride (KH) , sodium tert-butoxide or potassium tert-butoxide, and the like. The suitable organic solvents useful in the reaction are not particularly limited and include any of those which do not adversely affect the reaction. Typical solvents include methanol, ethanol, dichlomethane, N, N-dimethylformamide, tetrahydrofuran and the like. The reaction is normally carried out at a temperature of from about 0 ℃ to 40 ℃, and preferably at room temperature under nitrogen. In the case of R 1 when R 1 is methyl or ethyl group, the compound of formula (Ia) can be achieved by treatment of the key intermediate (V) directly with sodium methoxide or sodium ethoxide in an suitable organic solvent.
The compound of formula (Ia or Ib) also can be achieved by removing protecting group when the compound (Ia or Ib) containing protection group, such as Boc., and the like. The treatment is suitably conducted at a temperature in a range from about -10 ℃ to room temperature and is typically conducted at a temperature in a range of from about 0 ℃ to about 35 ℃.
Suitable purification methods for the final compound of formula (Ia or Ib) are a preparative HPLC, or HP20 chromatograph, or inon exchange resin and the like.
Examples
Abbreviations
In the experiments the following abbreviations have been used:
δ: chemical shift in parts per million (ppm) by frequency
br s: broad single in NMR
d: doublet in NMR
dd: doublet of doublet in NMR
t: triplet in NMR
q: quartet in NMR
m: multiplet in NMR
J: coupling constant in NMR
Hz: hertz
MHz: megahertz
NMR: nuclear magnetic resonance
ES -: negative ion mode in electrospray ionization mass spectrometry
ES +: positive ion mode in electrospray ionization mass spectrometry
MS: mass spectrum
HPLC: high performance liquid chromatography
g: gram (s)
mg: milligram (s)
mmol: millimole (s)
L: liter (s)
mL: milliliter (s)
M: molarity
h: hour (s)
min: minute (s)
Pd/C: palladium on carbon
TEA: triethylamine
DIPEA: N, N-diisopropylethylamine
TFAA: trifluoroacetic anhydride
DCM: dichloromethane
DMF: N, N-dimethylformamide
DMSO: dimethyl sulfoxide
EtOAc: ethyl acetate
TFA: trifluoroacetic acid
THF: tertrahydrofuran
TLC: thin layer chromatography
TMS: tetramethylsilane
CDCl 3: deuterated chloroform
CD 3OD: deuterated methanol
D 2O: deuterium oxide
DMSO-d 6: deuterium dimethyl sulfoxide
pH: the negative logarithm of the hydrogen ion concentration
Boc: N-tert-butoxycarbonyl
Analytical Methods
All  1H and  19F NMR spectra were recorded on a Bruker AVANCE NEO 400 NMR operating at 400 MHz for  1H, and 376 MHz for  19F respectively. NMR data was recorded in chemical shifts relative to tetramethylsilane (TMS) as internal standard. NMR spectra were run either in CDCl 3 containing 0.05%TMS, CD 3OD containing 0.05%TMS, D 2O or DMSO-d 6 containing 0.03%TMS.
Preparative HPLC was performed on an Agilent 1260 Infinity II System on Agilent 10 prep-C18 250×21.2 mm column, using an acetonitrile/aqueous 0.1%trifluoroacetic acid gradient, or an acetonitrile/aqueous 0.1%formic acid gradient at 22℃.
Mass spectra were performed on an Agilent 1260II-6125 Separation Module using either ES - or ES + ionization modes.
Column Chromatography was performed with using Qingdao Inc. Silica Gel: CC Grade (230 –400 Mesh) .
Commercial solvents and reagents were generally used without further purification. All products were dried before characterisation and use in subsequent synthetic steps.
1. General Synthetic Methods
1.1 Synthesis of triethylamine (2S, 5R) -2-cyano-7-oxo-1, 6-diazabicyclo [3.2.1] octan-6-yl sulfate (B5_1)
Figure PCTCN2021122965-appb-000012
Step 1: Synthesis of (2S, 5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carbonitrile (A-2)
TFAA (0.3 g, 1.4 mmol) was added to a mixture of A-1 (0.2 g, 0.7 mmol, prepared according to Org. Process Res. Dev. 2016, 20, 1799-1805) and TEA (0.7 g, 7.0 mmol) in DCM (5 mL) at 0 ℃. The resulting reaction mixture was heated at 35 ℃ for 3 hours, and then concentrated under reduced pressure. The residue was extracted with ethyl acetate, washed with water, brine, dried over Na 2SO 4 and filtrated. The filtrate was concentrated to give a residue, which was further purified by column chromatography eluting with 30%ethyl acetate in hexane to give the title compound A-2 (0.17 g, 64%) as a brown solid.  1H NMR (400 MHz, DMSO-d 6) : δ 1.81-1.91 (m, 2H) , 1.92-2.00 (m, 2H) , 3.10 (d, J = 11.7 Hz, 1H) , 3.21 (d, J = 12.3 Hz, 1H) , 3.74 (s, 1H) , 4.58 (d, J = 6.6 Hz, 1H) , 4.93 (d, J = 11.6 Hz, 1H) , 4.96 (d, J = 11.6 Hz, 1H) , 7.36-7.43 (m, 3H) , 7.44-7.48 (m, 2H) . LC-MS [M+H]  + m/z 258.1 (calcd for C 14H 15N 3O 2, 257.12) .
Step 2: Synthesis of (2S, 5R) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carbonitrile (A-3)
Wet 5%Pd/C (400 mg) was added to a solution of compound A-2 (2.57 g, 10.0 mmol) in EtOAc (45 mL) , and then hydrogenated at room temperature under atmospheric pressure for 4 hours. After completion of reaction, the catalyst was removed by celite filtration and washed with EtOAc. The filtrate was concentrated to obtain the pale yellow compound A-3 (1.66 g, 99.4%) as a crude oily product, which was used for further reaction without further  purification.  1H NMR (400 MHz, DMSO-d 6) : δ 1.80-1.89 (m, 2H) , 1.95-2.08 (m, 2H) , 3.18 (s, 2H) , 3.70 (s, 1H) , 4.51 (d, J = 6.9 Hz, 1H) , 9.99 (br s, 1H) . LC-MS [M+H]  + m/z 168.1 (calcd for C 7H 9N 3O 2, 167.07) .
Step 3: Synthesis of triethylamine (2S, 5R) -2-cyano-7-oxo-1, 6-diazabicyclo [3.2.1] octan-6-yl sulfate (B5_1)
A mixture of compound A-3 (1.39 mg, 8.3 mmol) , SO 3-NMe 3 (1.66 g, 1.4 mmol) and TEA (1.24 mL, 9.6 mmol) in THF/water (6/3 mL) was stirred at room temperature overnight. The reaction mixture was concentrated to dryness under reduced pressure to give a residue, which was purified by column chromatography using 5%MeOH in DCM to give the title compound B5_1 (1.21 g, 41.8%) as a white solid.  1H NMR (400 MHz, CDCl 3) δ 1.34 (t, J =7.4 Hz, 9H) , 1.87-1.97 (m, 2H) , 2.17-2.29 (m, 2H) , 3.19 (q, J = 7.4 Hz, 6H) , 3.37 (d, J = 12.3 Hz, 1H) , 3.40-3.45 (m, 1H) , 4.28 (t, J = 3.3 Hz, 1H) , 4.43 (d, J = 7.1 Hz, 1H) , 8.62 (br s, 1H) . LC-MS [M-H]  -m/z 246.0 (calcd for C 7H 9N 3O 5S, 247.03) .
1.2 Synthesis of (S) - (1-methylpiperidin-3-yl) methanol (B5_2)
Figure PCTCN2021122965-appb-000013
Pd/C (10%, dry, 52 mg) was added to a solution of compound (S) -piperidin-3-ylmethanol (B-1, 0.51 g, 3.9 mmol) and paraformaldehyde (0.72 g, 8.0 mmol) in MeOH (10 mL) , and then hydrogenated at room temperature under atmospheric pressure overnight. After completion of reaction, the catalyst was removed by celite filtration and washed with EtOAc. The filtrate was concentrated to obtain a residue, which was purified by preparative HPLC on an Agilent 10 prep-C18 250×21.2 mm column and lyophilized to give B5_2 (0.37 g, 71.7%) as a colorless oil.  1H NMR (400 MHz, CDCl 3) : δ 1.04-1.14 (m, 1H) , 1.56-1.63 (m, 1H) , 1.66-2.10 (s, 6H) , 2.26 (s, 3H) , 2.58-2.66 (m, 1H) , 2.77-2.83 (m, 1H) , 3.50-3.56 (m, 1H) , 3.60-3.65 (m, 1H) . LC-MS [M+H]  + m/z 130.1 (calcd for C 7H 15NO, 129.12) .
1.3 Synthesis of (S) - (1-methylpyrrolidin-3-yl) methanol (B5_3)
Figure PCTCN2021122965-appb-000014
Pd/C (10%, dry, 50 mg) was added to a solution of compound (S) -pyrrolidin-3-ylmethanol (C-1, 0.30 g, 2.97 mmol) and paraformaldehyde (0.54 g, 6.0 mmol) in MeOH (15 mL) , and then hydrogenated at room temperature under atmospheric pressure overnight. After completion of reaction, the catalyst was removed by celite filtration and washed with  EtOAc. The filtrate was concentrated to obtain a residue, which was purified by preparative HPLC on an Agilent 10 prep-C18 250×21.2 mm column and lyophilized to give B5_3 (0.32 g, 95.1%) as a colorless oil.  1H NMR (400 MHz, DMSO-d 6) : δ 1.29-1.37 (m, 1H) , 1.72-1.81 (m, 1H) , 2.13-2.18 (m, 1H) , 2.19 (s, 3H) , 2.19-2.22 (m, 1H) , 2.28-2.44 (m, 3H) , 3.25 (d, J = 2.5 Hz, 1H) , 3.26 (d, J = 1.6 Hz, 1H) , 4.53 (br s, 1H) . LC-MS [M+H]  + m/z 116.1 (calcd for C 6H 13NO, 115.10) .
1.4 Synthesis of pyridin-3-ylmethanol (B5_4)
Figure PCTCN2021122965-appb-000015
NaBH 4 (0.56 g, 14.6 mmol) was added to a solution of methyl nicotinate (D-1, 1.0 g, 7.3 mmol) in dry MeOH (10 mL) at room temperature for 3 hours. The reaction was quenched by adding excess MeOH, and concentrated under reduce pressure to give a residue. The residue was extracted with CH 2Cl 2, the combined organic layers dried over Na 2SO 4, filtered. The filtrate was concentrated to produce the title compound B5_4 (0.67 g, 84.2%) as a colorless oil.  1H NMR (400 MHz, CDCl 3) : δ 3.09 (br s, 1H) , 4.73 (s, 2H) , 7.29 (dd, J = 7.8, 4.9 Hz, 1H) , 7.73 (dt, J = 7.8, 1.6 Hz, 1H) , 8.49 (dd, J = 4.9, 1.6 Hz, 1H) , 8.54 (d, J =1.6 Hz, 1H) . LC-MS [M+H]  + m/z 110.1 (calcd for C 6H 7NO, 109.05) .
2. Synthesis of the final compound
Example 1
Sodium (2S, 5R) -2- (imino (methoxy) methyl) -7-oxo-1, 6-diazabicyclo [3.2.1] octan-6-yl sulfate (compound 1 in table 1)
Figure PCTCN2021122965-appb-000016
NaOMe (40.5 mg, 0.7 mmol) was added to a solution of B5_1 (173 mg, 0.5 mmol) in dry MeOH (10 mL) at 0 ℃, and stirred for 20 minutes at 0 ℃. The reaction mixture was concentrated to give a residue, which was purified by preparative HPLC on an Agilent 10 prep-C18 250×21.2 mm column and lyophilized, followed by Dowex-50wx Na + resin exchange using water as an eluent to give example 1 (15 mg, 9.9%) as a white solid.  1H NMR (400 MHz, D 2O) δ 1.76-1.82 (m, 1H) , 1.87-2.08 (m, 3H) , 3.18 (d, J = 15.1 Hz, 1H) , 3.42  (br s, 1H) , 3.68 (s, 3H) , 4.16 (d, J = 15.1 Hz, 1H) , 5.35 (d, J = 4.6 Hz, 1H) . LC-MS [M-Na]  -m/z 278.0 (calcd for C 8H 12N 3NaO 6S, 301.03) .
Example 2
Sodium (2S, 5R) -2- (ethoxy (imino) methyl) -7-oxo-1, 6-diazabicyclo [3.2.1] octan-6-yl sulfate (compound 4 in table 1)
Figure PCTCN2021122965-appb-000017
NaOEt (30 mg, 0.8 mmol) was added to a solution of B5_1 (100 mg, 0.4 mmol) in dry EtOH (10 mL) at room temperature, and stirred overnight at room temperature. The reaction mixture was concentrated to give a residue, which was purified by preparative HPLC on an Agilent 10 prep-C18 250×21.2 mm column and lyophilized, followed by Dowex-50wx Na + resin exchange using water as an eluent to give example 2 (6 mg, 4.7%) as a white solid.  1H NMR (400 MHz, D 2O) : δ 1.19 (t, J = 7.1 Hz, 3H) , 1.72-1.79 (m, 1H) , 1.81-1.96 (m, 2H) , 1.97-2.08 (m, 1H) , 3.15 (d, J = 14.5 Hz, 1H) , 3.39 (s1H) , 4.10 (d, J = 7.1 Hz, 2H) , 4.13-4.25 (m, 1H) , 5.35 (s, 1H) . LC-MS [M-Na]  -m/z 292.0 (calcd for C 9H 14N 3NaO 6S, 315.05) .
Example 3
Sodium (2S, 5R) -2- ( (2-acetamidoethoxy) (imino) methyl) -7-oxo-1, 6-diazabicyclo [3.2.1] octan-6-yl sulfate (compound 5 in table 1)
Figure PCTCN2021122965-appb-000018
NaH (36 mg, 1.6 mmol) was added to a solution of B5_1 (139 mg, 0.4 mmol) and N- (2-hydroxyethyl) acetamide (74 μL, 0.8 mmol) in dry DMF (2 mL) at room temperature, and stirred for 20 minutes at room temperature. The reaction mixture was filtered, the filtrate was directly purified by preparative HPLC on an Agilent 10 prep-C18 250×21.2 mm column and lyophilized, followed by Dowex-50wx Na + resin exchange using water as an eluent to give example 3 (6 mg, 4.7%) as a white solid.  1H NMR (400 MHz, D 2O) δ 1.67-1.72 (m, 1H) , 1.97-2.00 (m, 6H) , 3.09 (d, J = 14.5 Hz, 1H) , 3.30-3.35 (m, 3H) , 4.04-4.13 (m, 3H) , 5.23 (br s, 1H) . LC-MS [M-Na]  -m/z 349.0 (calcd for C 11H 17N 4NaO 7S, 372.07) .
Example 4
Sodium (2S, 5R) -2- (imino (pyridin-4-ylmethoxy) methyl) -7-oxo-1, 6-diazabicyclo [3.2.1] octan-6-yl sulfate (compound 44 in table 1)
Figure PCTCN2021122965-appb-000019
NaH (48 mg, 2.0 mmol) was added to a solution of B5_1 (139 mg, 0.4 mmol) and pyridin-4-ylmethanol (87 mg, 0.8 mmol) in dry THF/CH 2Cl 2 (6/3 mL) at room temperature, and stirred for 30 minutes at room temperature. The reaction mixture was filtered, the filtrate was concentrated to give a residue, which was purified by preparative HPLC on an Agilent 10 prep-C18 250×21.2 mm column and lyophilized, followed by Dowex-50wx Na + resin exchange using water as an eluent to give example 4 (3.8 mg, 4.7%) as a white solid.  1H NMR (400 MHz, D 2O) δ 1.78-1.84 (m, 1H) , 1.91-1.97 (m, 2H) , 2.03-2.13 (m, 1H) , 3.23-3.31 (m, 1H) , 3.43-3.46 (m, 1H) , 4.36 (br s, 1H) , 5.19 (d, J = 14.6 Hz, 1H) , 5.27 (d, J = 14.6 Hz, 1H) , 5.36 (br s, 1H) , 7.50 (s, 2H) , 8.49 (d, J = 6.2 Hz, 2H) . LC-MS [M-Na]  -m/z 355.1 (calcd for C 13H 15N 4NaO 6S, 378.06) .
Example 5
Sodium (2S, 5R) -2- (imino ( (1-methylpiperidin-4-yl) methoxy) methyl) -7-oxo-1, 6-diazabicyclo [3.2.1] octan-6-yl sulfate (compound 30 in table 1)
Figure PCTCN2021122965-appb-000020
NaH (48 mg, 2.0 mmol) was added to a solution of B5_1 (139 mg, 0.4 mmol) and (1-methylpiperidin-4-yl) methanol (0.1 mL, 2.0 mmol) in dry DMF (3 mL) at room temperature, and stirred for 30 minutes at room temperature. The reaction mixture was filtered, the filtrate was directly purified by preparative HPLC on an Agilent 10 prep-C18 250×21.2 mm column and lyophilized, followed by Dowex-50wx Na + resin exchange using water as an eluent to give example 5 (35 mg, 21.9%) as a white solid.  1H NMR (400 MHz, D 2O) δ 1.43-1.57 (m, 2H) , 1.76-2.01 (m, 6H) , 2.02-2.09 (m, 1H) , 2.71 (s, 3H) , 2.76-2.92 (m, 3H) , 3.07-3.21 (m, 1H) ,  3.33-3.43 (m, 2H) , 3.93-4.09 (m, 2H) , 4.32-4.40 (m, 1H) , 5.33 (s, 1H) . LC-MS [M-Na]  -m/z 375.2 (calcd for C 14H 23N 4NaO 6S, 398.12) .
Example 6
Sodium (2S, 5R) -2- (imino (2- (4-methylpiperazin-1-yl) ethoxy) methyl) -7-oxo-1, 6-diazabicyclo [3.2.1] octan-6-yl sulfate (compound 31 in table 1)
Figure PCTCN2021122965-appb-000021
NaH (96 mg, 4.0 mmol) was added to a solution of B5_1 (278 mg, 0.8 mmol) and 2- (4-methylpiperazin-1-yl) ethan-1-ol (231 mg, 1.6 mmol) in dry DMF (1.5 mL) at room temperature, and stirred for 30 minutes at room temperature. The reaction mixture was filtered, the filtrate was directly purified by preparative HPLC on an Agilent 10 prep-C18 250×21.2 mm column and lyophilized, followed by Dowex-50wx Na + resin exchange using water as an eluent to give example 6 (17 mg, 5.1%) as a white solid.  1H NMR (400 MHz, D 2O) δ 1.42-1.52 (m, 1H) , 1.82-1.96 (m, 2H) , 2.04-2.11 (m, 1H) , 2.71 (s, 3H) , 2.73-3.18 (m, 12H) , 4.22-4.28 (m, 2H) , 4.37 (d, J = 12.5 Hz, 1H) , 5.35 (s, 1H) . LC-MS [M-Na]  -m/z 390.1 (calcd for C 14H 24N 5NaO 6S, 413.13) .
Example 7
2- (1H-imidazol-1-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate (compound 48 in table 1)
Figure PCTCN2021122965-appb-000022
NaH (60 mg, 2.5 mmol) was added to a solution of B5_1 (173 mg, 0.5 mmol) and 2- (1H-imidazol-1-yl) ethan-1-ol (112 mg, 1.0 mmol) in dry DMF (1.5 mL) at room temperature, and stirred for 30 minutes at room temperature. The reaction mixture was filtered, the filtrate was directly purified by preparative HPLC on an Agilent 10 prep-C18 250×21.2 mm column and lyophilized to give example 7 (17 mg, 9.4%) as a white solid.  1H NMR (400 MHz, D 2O) δ 1.31-1.41 (m, 1H) , 1.64-1.75 (m, 1H) , 1.79-1.86 (m, 1H) , 1.91-1.97 (m, 1H) , 2.63-2.73 (m,  1H) , 2.93-3.01 (m, 1H) , 4.16-4.25 (m, 3H) , 4.26-4.34 (m, 2H) , 5.14 (d, J = 5.1 Hz, 1H) , 6.89 (s, 1H) , 7.07 (s1H) , 7.61 (s, 1H) . LC-MS [M-H]  -m/z 358.1 (calcd for C 12H 17N 5O 6S, 359.09) .
Example 8
( (R) -1-Methylpyrrolidin-3-yl) methyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate (compound 42 in table 1)
Figure PCTCN2021122965-appb-000023
NaH (72 mg, 3.0 mmol) was added to a solution of B5_1 (208 mg, 0.6 mmol) and (R) - (1-methylpyrrolidin-3-yl) methanol (B5_3, 138 mg, 1.2 mmol) in dry DMF (1.5 mL) at room temperature, and stirred for 30 minutes at room temperature. The reaction mixture was filtered, the filtrate was directly purified by preparative HPLC on an Agilent 10 prep-C18 250×21.2 mm column and lyophilized to give example 8 (39 mg, 17.9%) as a white solid.  1H NMR (400 MHz, D 2O) δ 1.74-2.03 (m, 5H) , 2.14-2.24 (m, 2H) , 2.80-2.83 (m, 1H) , 2.84 (s, 3H) , 3.13-3.15 (m, 1H) , 3.17-3.19 (m, 1H) , 3.36-3.40 (m, 2H) , 4.04-4.10 (m, 2H) , 4.17-4.24 (m, 2H) , 5.19-5.32 (m, 1H) . LC-MS [M-H]  -m/z 361.1 (calcd for C 13H 22N 4O 6S, 362.13) .
Example 9
Sodium (2S, 5R) -2- (imino (pyridin-3-ylmethoxy) methyl) -7-oxo-1, 6-diazabicyclo [3.2.1] octan-6-yl sulfate (compound 43 in table 1)
Figure PCTCN2021122965-appb-000024
NaH (35 mg, 1.2 mmol) was added to a solution of B5_1 (139 mg, 0.4 mmol) and pyridin-3-ylmethanol (B5_4, 87 mg, 0.8 mmol) in dry DMF (2.2 mL) at room temperature, and stirred for 30 minutes at room temperature. The reaction mixture was filtered, the filtrate was directly purified by preparative HPLC on an Agilent 10 prep-C18 250×21.2 mm column and lyophilized, followed by Dowex-50wx Na + resin exchange using water as an eluent to give example 9 (24 mg, 15.8%) as a white solid.  1H NMR (400 MHz, D 2O) δ 1.37-1.48 (m, 1H) , 1.73-1.83 (m, 1H) , 1.85-1.92 (m, 1H) , 1.96-2.03 (m, 1H) , 2.77 (br s, 1H) , 3.01-3.10 (m, 1H) ,  4.31 (br s, 1H) , 5.11 (s, 2H) , 5.30 (br s, 1H) , 7.35 (dd, J = 7.8, 5.0 Hz, 1H) , 7.77 (dt, J = 7.8, 1.8 Hz, 1H) , 8.37 (dd, J = 5.0, 1.4 Hz, 1H) , 8.42 (d, J = 1.8 Hz, 1H) . LC-MS [M-Na]  -m/z 355.1 (calcd for C 13H 15N 4NaO 6S, 378.06) .
Example 10
Sodium (2S, 5R) -2- (imino ( ( (R) -1-methylpiperidin-3-yl) methoxy) methyl) -7-oxo-1, 6-diazabicyclo [3.2.1] octan-6-yl sulfate (compound 36 in table 1)
Figure PCTCN2021122965-appb-000025
NaH (29 mg, 1.2 mmol) was added to a solution of B5_1 (139 mg, 0.4 mmol) and (R) - (1-methylpiperidin-3-yl) methanol (103 mg, 0.8 mmol) in dry DMF (1.5 mL) at room temperature, and stirred for 30 minutes at room temperature. The reaction mixture was filterated, the filtrate was directly purified preparative HPLC on an Agilent 10 prep-C18 250×21.2 mm column and lyophilized, followed by Dowex-50wx Na + resin exchange using water as an eluent to give example 10 (11 mg, 6.9%) as a white solid.  1H NMR (400 MHz, D 2O) δ 1.02-1.17 (m, 1H) , 1.43-1.56 (m, 1H) , 1.67-1.98 (m, 7H) , 2.29-2.50 (m, 5H) , 2.95-3.15 (m, 3H) , 3.33 (s, 1H) , 3.77-3.85 (m, 1H) , 4.01-4.09 (m, 1H) , 4.13-4.23 (m, 1H) , 5.25 (br s, 1H) . LC-MS [M-Na]  -m/z 375.1 (calcd for C 14H 23N 4NaO 6S, 398.12) .
Example 11
Sodium (2S, 5R) -2- (imino (2- (pyrrolidin-1-yl) ethoxy) methyl) -7-oxo-1, 6-diazabicyclo [3.2.1] octan-6-yl sulfate (compound 38 in table 1)
Figure PCTCN2021122965-appb-000026
NaH (60 mg, 2.5 mmol) was added to a solution of B5_1 (173 mg, 0.5 mmol) and 2- (pyrrolidin-1-yl) ethan-1-ol (150 mg, 1.0 mmol) in dry DMF (1.5 mL) at room temperature, and stirred for 30 minutes at room temperature. The reaction mixture was filtered, the filtrate was directly purified preparative HPLC on an Agilent 10 prep-C18 250×21.2 mm column and lyophilized, followed by Dowex-50wx Na + resin exchange using water as an eluent to give  example 11 (13 mg, 6.7%) as a white solid.  1H NMR (400 MHz, D 2O) δ 1.73-1.91 (m, 3H) , 1.94-2.02 (m, 5H) , 3.15 (d, J = 14.8 Hz, 1H) , 3.29-3.39 (m, 5H) , 3.44-3.49 (m, 2H) , 4.20-4.28 (m, 1H) , 4.34-4.38 (m, 1H) , 4.41-4.49 (m, 1H) , 5.29 (br s, 1H) . LC-MS [M-Na]  -m/z 361.1 (calcd for C 13H 21N 4NaO 6S, 384.11) .
Example 12
Sodium (2S, 5R) -2- ( (3-amino-3-oxopropoxy) (imino) methyl) -7-oxo-1, 6-diazabicyclo [3.2.1] octan-6-yl sulfate (compound 14 in table 1)
Figure PCTCN2021122965-appb-000027
NaH (30 mg, 1.3 mmol) was added to a solution of B5_1 (174 mg, 0.5 mmol) and 3-hydroxypropanamide (122 mg, 1.1 mmol) in dry DMF (2.5 mL) at room temperature, and stirred for 30 minutes at room temperature. The reaction mixture was filtered, the filtrate was directly purified by preparative HPLC on an Agilent 10 prep-C18 250×21.2 mm column and lyophilized, followed by Dowex-50wx Na + resin exchange using water as an eluent to give example 12 (13 mg, 7.2%) as a white solid.  1H NMR (400 MHz, D 2O) δ 1.71-1.78 (m, 1H) , 1.83-1.92 (m, 2H) , 1.95-2.04 (m, 1H) , 2.55 (t, J = 5.7 Hz, 2H) , 3.14 (d, J = 14.4 Hz, 1H) , 3.38 (s, 1H) , 4.13 (d, J = 14.4 Hz, 1H) , 4.22-4.34 (m, 2H) , 5.28 (d, J = 4.0 Hz, 1H) . LC-MS [M-Na]  - m/z 335.1 (calcd for C 10H 15N 4NaO 7S, 358.06) .
Example 13
2-Hydroxyethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate (compound 8 in table 1)
Figure PCTCN2021122965-appb-000028
NaH (30 mg, 1.3 mmol) was added to a solution of B5_1 (174 mg, 0.5 mmol) and ethane-1, 2-diol (62 mg, 1.1 mmol) in dry DMF (2 mL) at room temperature, and stirred for 30 minutes at room temperature. The reaction mixture was filtered, the filtrate was directly purified by preparative HPLC on an Agilent 10 prep-C18 250×21.2 mm column and lyophilized to give example 13 (19 mg, 12.2%) as a white solid.  1H NMR (400 MHz, D 2O) δ  1.71-1.78 (m, 1H) , 1.88-1.91 (m, 2H) , 1.97-2.05 (m, 1H) , 3.16 (d, J = 14.3 Hz, 1H) , 3.38 (s, 1H) , 3.71 (dd, J = 5.3, 3.8 Hz, 2H) , 4.10-4.18 (m, 3H) , 5.33 (br s, 1H) . LC-MS [M-H]  -m/z 308.1 (calcd for C 9H 15N 3O 7S, 309.06) .
Example 14
Sodium (2S, 5R) -2- ( (ethylthio) (imino) methyl) -7-oxo-1, 6-diazabicyclo [3.2.1] octan-6-yl sulfate (compound 2 in table 1)
Figure PCTCN2021122965-appb-000029
NaH (60 mg, 2.5 mmol) was added to a solution of B5_1 (174 mg, 0.5 mmol) and ethanethiol (62 mg, 1.0 mmol) in dry DMF (2.5 mL) at room temperature, and stirred for 30 minutes at room temperature. The reaction mixture was filtered, the filtrate was directly purified by preparative HPLC on an Agilent 10 prep-C18 250×21.2 mm column and lyophilized, followed by Dowex-50wx Na + resin exchange using water as an eluent to give example 14 (43 mg, 25.9%) as a white solid.  1H NMR (400 MHz, D 2O) δ 1.15 (t, J = 7.4 Hz, 3H) , 1.75-1.86 (m, 1H) , 1.88-2.07 (m, 3H) , 2.82 (q, J = 7.4 Hz, 2H) , 3.06-3.14 (m, 1H) , 3.41-3.44 (m, 1H) , 4.27 (s, 1H) , 5.53 (s, 1H) . LC-MS [M-Na]  -m/z 308.1 (calcd for C 9H 14N 3NaO 5S 2, 331.03) .
Pharmacological Methods
Antibacterial activity and synergistic activity:
Compounds of the present invention alone, avibactam (AVI) alone, imipenem (IMI) alone, and as a combination with test antibiotic (imipenem) were tested for antimicrobial activity by determing minimum inhibitory concentration (MIC, mg/L) using the broth microdilution method according to the guidelines of the Clinical Laboratories and Stansards Insitute ( “Methods for Dilution Antimicrobial Suscetibility Tests for Bacterial that Grow Aerobiclly” , Approved standard, 7th ed., Clinical and Laboratories Stanards Institute (CLSI) Document M7-A8, Wayne, Pa., USA, 2009) . Imipenem as a test antibiotic compound was dissolved in DMSO, and then diluted in microbial growth medium (Mueller-Hinton Broth II, cation adjusted) resulting in a final concention range of 0.125-64 mg/L in serial two-fold dilution. In all cases the filnal DMSO concentraion was less than 0.5%. Bacteria were added to 96-well microtitre plates containing the serial two-fold dilutions of the compounds; the final cell density was appoximately 5x10 5 colony forming units/mL (CFU/mL) . Plates were  incubated at 37 ℃ for 18-24 hours and read visually. The MIC, i.e. the lowest concentration of the test compound that inhibited visible growth of the bacteria, was recorded. The same assay conditions were used when the compounds of present invention alone, avibactam (as a control) alone, and as a combination with test imipenem was tested for minmum inhibitory concentration (MIC, mg/L) . While test imipenem was serially diluted as descrribed above, a constant concentration of both avibactam and the present invention of 4 mg/L was used.
The antimicrobial activity by determing minmum inhibitory concentration (MIC, mg/L) against bacteria listed in Table 2 and Table 3.
Bacterial strains that were used to evaluate the antimicrobial activity using the MIC determination included but were not limited to E. coli clinical isolate (strain 1) , E. coli 8739 (strain 2) , K. pneumoniae clinical isolate (strain 3) , K. pneumoniae 700603 (strain 4) , E. cloacae clinical isolate (strain 5) , E. cloacae 700323 (strain 6) , A. baumannii clinical isolate (strain 7) , A. baumannii 19606 (strain 8) , P. aeruginosa clinical isolate (strain 9) , P. aeruginosa 9027 (strain 10) .
Table 2: Synergy of the inhibitor example 1 to example 14 (4 mg/L) in combination with imipenem (IMI, AVI and Ex. 1 to Ex. 4, MIC, mg/L)
Figure PCTCN2021122965-appb-000030
Table 2-continued: Synergy of the inhibitor example 1 to example 14 (4 mg/L) in combination with imipenem (Ex. 5 to Ex. 10, MIC, mg/L)
Figure PCTCN2021122965-appb-000031
Table 2-continued: Synergy of the inhibitor example 1 to example 14 (4 mg/L) in combination with imipenem (Ex. 11 to Ex. 14, MIC, mg/L)
Figure PCTCN2021122965-appb-000032
Table 3: Antibacterial activity of example 1 to example 14 (AVI and Ex. 1 to Ex. 7, MIC, mg/L)
Figure PCTCN2021122965-appb-000033
Table 3-continued: Antibacterial activity of example 1 to example 14 (Ex. 8 to Ex. 14, MIC, mg/L)
Figure PCTCN2021122965-appb-000034
Test for lactamase Inhibitory activity:
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 (1991) ] . The concentration of inhibitor (IC 50) which inhibits by 50%the reaction of hydrolysis of nitrocefin by the enzyme is determined.
In light of the data described herein, persons of skill in the art would expect that all of the compounds within the scope of formula (I) , salts of such compounds, solvates of such compounds and salts thereof, and deuterated compounds of all such compounds, salts and solvates (i.e., compounds of formula (I) modified in that they have been deuterated, salts of compounds of formula (I) modified in that they have been deuterated, and solvates of compounds of formula (I) modified in that they have been deuterated) would be effective on their own as antibacterial compounds, and in combination with β-lactam antibiotics.
Efficacy of the β-lactamase inhibitors can be evaluated in combination with ceftazidime aztreonam, meropenem, imipenem and other class of carbapenems and cephalosporins in murine infection models such as septicemia, pneumonia and thigh infection models (Ref: Andrea Endimiani et. al. Antimicrobial Agents and Chemotherapy, January 2011, page 82-85) . For murine acute lethal septicemia model, mice were infected by the intraperitoneal injection of the clinical strains resulting in death of the untreated controls within 24-48 hours. In particular, a fresh predetermined bacterial inoculum of approximately 3.3x10 5 to 3.6x10 5 CFU in 5%hog gastric mucin grown overnight. Thirty minutes post infection, a single subcutaneous dose of meropenem with and without β-lactamase inhibitor was initiated and the survival ratio monitored for 5 days twice daily. For each strain tested, the dosing regimen used are meropenem alone (doses of 512, 1024 &2048 mg/kg of body weight) and meropenem plus β-lactamase inhibitor at ratio of 2: 1, 4: 1, 8: 1, 16: 1 &32: 1 (meropenem doses were 4, 8, 16, 32 &64 mg/kg for each ratio) . The median effective dose for 50%protective dose (ED 50) of animals was determined by a computerized program of Probit analysis. Survival rates stratified for different dosing regimen were also obtained. For experimental pneumoniae model, immunocompromised mice were used and intratracheally infected with Klebsiella pneumoniae strains. Mice in this model developed bacteraemia pneumoniae and fatal disease within 2 to 4 days with lung bacterial burden at 16-18 hours post infection of 10 11 to 10 13 CFU/gm lung. Treatment with meropenem and inhibitor at a ratio of 2/1 &4/1 demonstrated efficacy with significant 3 to 6 log reduction in lung counts compared to meropenem alone and was 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.

Claims (18)

  1. A compound of formula (I) :
    Figure PCTCN2021122965-appb-100001
    wherein:
    X is oxygen or sulfur,
    M is hydrogen or a pharmaceutically acceptable salt forming cation,
    R is a radical selected from any of the following groups:
    (1) C 1-6 straight, or branched chain which is optionally substituted;
    (2) Heterocyclyl (C 1-6) alkyl, wherein the said heterocycle containing at least one heteroatom selected from O, N and S wherein the said heterocycle is optionally substituted, and furthermore the ring S is optionally oxidized to S (O) or S (O)  2 and the free ring N atom may optionally take a substituent;
    (3) C 5-6 membered heteroarylalkyl which is optionally substituted;
    or its pharmaceutically acceptable salt of such compound, or a deuterated compound of any such compound or salt.
  2. The compound as recited in claim 1, wherein R is substituted with one or two substituents independently selected from the following:
    Lower alkyl, amino, substituted amino, alkoxy, hydroxyalkyl, halogen, hydroxy, carboxy, alkoxycarbonyl, haloalkyl, trifluoromethyl, trifluoromethyloxy, alkylamine, substituted alkylamine, carboxamide, thiocarboxamide, sulfonic acid, sulphate, acylamino, sulfonylamino, substituted or unsubstituted sulfonamide, substituted or unsubstituted urea, substituted or unsubstituted thiourea, oxyimino, hydroxamic acid, acyl, trifluoromethyl carbonyl, cyano, amidino, guanidino, aryloxy, heterocyclylalkyloxy, and heteroaryloxy.
  3. The compound as recited in claim 1, which is selected from the following group of compounds:
    Figure PCTCN2021122965-appb-100002
    Figure PCTCN2021122965-appb-100003
    or a pharmaceutically acceptable salt of such compound, or a deuterated compound of such compound or salt.
  4. The compound as defined in claim 1, wherein the compound is selected from the group consisting of:
    Methyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    Ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidothioate,
    3, 3, 3-Trifluoropropyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    Ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2-Acetamidoethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate, Isobutyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2-Aminoethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2-Hydroxyethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    3-Hydroxypropyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2-Ureidoethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    3- (Imino ( (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octan-2-yl) methoxy) propanoic acid,
    2-Methoxyethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2-Aminopropyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    3-Amino-3-oxopropyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    3-Methoxypropyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2-Guanidinoethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (Guanidinooxy) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2-Amino-2-oxoethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidothioate,
    2- (Pyrrolidin-3-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (1-Acetylpiperidin-3-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (1-Methylpiperidin-4-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (Piperidin-2-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (1, 3-Oxazinan-2-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (Piperazin-2-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (1- (Methylsulfonyl) piperidin-3-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (Tetrahydrofuran-2-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (4-Methylpiperidin-4-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (Piperazin-1-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (1- (methylsulfonyl) piperidin-4-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    (1-Methylpiperidin-4-yl) methyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (4-Methylpiperazin-1-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (3-Acetyltetrahydropyrimidin-1 (2H) -yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (1-Methylpiperidin-4-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (1-Acetylpiperidin-4-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (1-Methylpyrrolidin-3-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    ( (R) -1-Methylpiperidin-3-yl) methyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (Tetrahydro-2H-pyran-4-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (Pyrrolidin-1-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (1, 1-Dioxidotetrahydro-2H-thiopyran-4-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (1-Acetylpyrrolidin-3-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (Piperidin-1-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    ( (R) -1-Methylpyrrolidin-3-yl) methyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    Pyridin-3-ylmethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    Pyridin-4-ylmethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (Pyrimidin-5-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (Pyridin-4-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (1H-Imidazol-2-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (1H-Imidazol-1-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (1-Methyl-1H-imidazol-2-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (2-Methyl-1H-imidazol-4-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (1-Methyl-1H-pyrazol-3-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (1H-Pyrazol-3-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (1-Acetyl-1H-imidazol-2-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (1-Methyl-1H-imidazol-5-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (2-Aminothiazol-4-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (Oxazol-4-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (Thiazol-4-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (1H-Imidazol-4-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (1-Methyl-1H-imidazol-4-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate,
    2- (1H-1, 2, 4-Triazol-3-yl) ethyl (2S, 5R) -7-oxo-6- (sulfooxy) -1, 6-diazabicyclo [3.2.1] octane-2-carbimidate.
    or pharmaceutically acceptable salts of such compounds, and deuterated compounds of such compounds and salts.
  5. A method of treating a bacterial infection comprising administering to a mammal in need thereof an antibacterially effective amount of a compound as recited in anyone of claims 1-4.
  6. A pharmaceutical composition containing, as an active ingredient, at least one compound as recited in anyone of claims 1-4.
  7. A pharmaceutical composition containing, as an active ingredient, (i) at least one compound as recited in anyone of claims 1-4 and (ii) at least one β-lactam antibiotic, at least one salt of a β-lactam antibiotic, at least one hydrate of a β-lactam antibiotic or at least one prodrug of a β-lactam antibiotic.
  8. The pharmaceutical composition of claim 7, wherein a ratio of the weight of (i) the compound of formula (I) to the weight of (ii) at least one β-lactam antibiotic, at least one salt of a β-lactam antibiotic, at least one hydrate of a β-lactam antibiotic or at least one prodrug of a β-lactam antibiotic, is in the range of 1: 30 to 30: 1.
  9. A pharmaceutical composition containing, as an active ingredient, (i) at least one compound as recited in anyone of claims 1-4 and (ii) at least one antibiotic, at least one salt of an antibiotic, at least one hydrate of an antibiotic or at least one prodrug of an antibiotic.
  10. The pharmaceutical composition of claim 9, wherein a ratio of the weight of (i) the compound of formula (I) to the weight of (ii) at least one antibiotic, at least one salt of an antibiotic, at least one hydrate of an antibiotic or at least one prodrug of an antibiotic, is in the range of 1: 30 to 30: 1.
  11. The pharmaceutical composition of anyone of claims 7-10, further comprising a pharmaceutically acceptable carrier.
  12. A method of treating a bacterial infection, comprising administering to a mammal in need thereof a combination of (i) an effective amount of a compound as recited in anyone of claims 1-4 and (ii) an effective amount of at least one β-lactam antibiotic, at least one salt of a β-lactam antibiotic, at least one hydrate of a β-lactam antibiotic or at least one prodrug of a β-lactam antibiotic.
  13. The method of claim 12, wherein a ratio of the weight of (i) the compound of formula (I) to the weight of (ii) at least one β-lactam antibiotic, at least one salt of a β-lactam antibiotic, at least one hydrate of a β-lactam antibiotic or at least one prodrug of a β-lactam antibiotic, is in the range of 1: 30 to 30: 1.
  14. A method of treating a bacterial infection, comprising administering to a mammal in need thereof a combination of (i) an effective amount of a compound as recited in anyone of claims 1-4 and (ii) an effective amount of at least one antibiotic, at least one salt of an antibiotic, at least one hydrate of an antibiotic or at least one prodrug of an antibiotic.
  15. The method of claim 14, wherein a ratio of the weight of (i) the compound of formula (I) to the weight of (ii) at least one antibiotic, at least one salt of an antibiotic, at least one hydrate of an antibiotic or at least one prodrug of an antibiotic, is in the range of 1: 30 to 30: 1.
  16. A molecular complex comprising a compound as recited in anyone of claims 1-4 and at least one solvent wherein the solvent comprises water.
  17. Use of a compound as recited in anyone of claims 1-4 in preparation of a medicament for treating bacterial infections in mammals.
  18. A process for preparing a compound recited in claim 1, wherein the process comprises:
    step A, removing the protecting group (PG) of the intermediate (C-1) to provide deprotection compound (C-2) , which could be converted to the key intermediate (C-3) by sulfation reagents;
    Figure PCTCN2021122965-appb-100004
    step B, contacting compound (C-3) with alcohol or thiol in the presence of a appropriate base to obtain the compound of formula (I) after removal of protection group only when R containing a protecting group.
    Figure PCTCN2021122965-appb-100005
    wherein M, R and X are recited as in claim 1.
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* Cited by examiner, † Cited by third party
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CN1655781A (en) * 2002-01-28 2005-08-17 安万特医药股份有限公司 Novel heterocyclic compounds which are active as inhibitors of beta-lactamases
US20140288051A1 (en) * 2011-12-02 2014-09-25 Naeja Pharmaceutical Inc. Bicyclic compounds and their use as antibacterial agents and beta-lactamase inhibitors
CN104334559A (en) * 2012-05-30 2015-02-04 明治制果药业株式会社 Novel beta-lactamase inhibitor and method for producing same
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