RU2815314C2 - Beta-lactamase inhibitors and their use - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to a method of treating a bacterial infection in a patient, including administering to a patient in need of such treatment a therapeutically effective amount of ethyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a β-lactam antibiotic, wherein the bacteria causing the bacterial infection produce β-lactamase and whereβ-lactam antibiotic is ceftibuten.

EFFECT: development of a treatment method based on a new compound or its pharmaceutically acceptable salt and β-lactam antibiotic, which can be used in medicine to effectively treat bacterial infections.

1 cl, 79 ex

Description

Field of technology to which the invention relates

The present disclosure relates to β-lactamase inhibitors and pharmaceutical compositions thereof and the use of β-lactamase inhibitors for the treatment of bacterial infections.

Prior Art

Overuse, misuse and agricultural use of antibiotics have led to the emergence of resistant bacteria that are resistant to killing by conventional anti-infectives such as β-lactam or fluoroquinoline-based agents. Worryingly, many of these resistant bacteria are responsible for common infections, including, for example, pneumonia, sepsis, etc.

The development of resistance to commonly used β-lactam anti-infectives is associated with the expression of β-lactamases by the target bacteria. β-lactamases usually hydrolyze the β-lactam ring, thus making the antibiotic ineffective against bacteria. Accordingly, inhibition of β-lactamases with a suitable substrate can prevent the degradation of the β-lactam antibiotic, thereby increasing the effectiveness of the administered antibiotic and reducing the emergence of resistance.

Avibactam is a known β-lactamase inhibitor that is currently marketed in combination with ceftazidime for the treatment of Gram-negative bacterial infections. Avibactam must be administered intravenously, which limits its use to expensive clinical settings.

Essence of the Invention

According to the present invention, the compounds have the structure of formula (1):

(1)

or a pharmaceutically acceptable salt thereof, wherein

each R ¹ is independently selected from C _1–6 alkyl, or each R ¹ and the geminal carbon atom to which they are bonded forms a C _3–6 cycloalkyl ring, a C _3–6 heterocycloalkyl ring, a substituted C _3–6 cycloalkyl ring, or a substituted C _3–6 heterocycloalkyl ring;

R ² is selected from single bond, C _1-6 alkanediyl, C _1-6 heteroalkanediyl, C _5-6 cycloalkanediyl, C _5-6 heterocycloalkanediyl, C ₆ arenediyl, C _5-6 heteroarendiyl, substituted C _1-6 alkanediyl, substituted C _1-6 heteroalkanediyl, substituted _C5-6 cycloalkanediyl, substituted _C5-6 heterocycloalkanediyl, substituted _C6 arenediyl and substituted _C5-6 heteroarendiyl;

R ³ is selected from C _1–6 alkyl, –O–C(O)–R ⁴ , –S–C(O)–R ⁴ , –NH–C(O)–R ⁴ , –O–C(O) –O–R ⁴ , –S–C(O)–O–R ⁴ , –NH–C(O)–O–R ⁴ , –C(O)–O–R ⁴ , –C(O)–S –R ⁴ , –C(O)–NH–R ⁴ , –O–C(O)–O–R ⁴ , –O–C(O)–S–R ⁴ , –O–C(O)–NH –R ⁴ , –S–S–R ⁴ , –S–R ⁴ , –NH–R ⁴ , –CH(–NH ₂ )(–R ⁴ ), C _5–6 heterocycloalkyl, C _5–6 heteroaryl, substituted C _5–6 cycloalkyl, substituted C _5–6 heterocycloalkyl, substituted C _5–6 aryl, substituted C _5–6 heteroaryl and –CH=C(R ⁴ ) ₂ ; wherein

R ⁴ is selected from hydrogen, C _1–8 alkyl, C _1–8 heteroalkyl, C _5–8 cycloalkyl, C _5–8 heterocycloalkyl, C _5–10 cycloalkylalkyl, C _5–10 heterocycloalkylalkyl, C _6–8 aryl, C _{5 –8} heteroaryl, C _7–10 arylalkyl, C _5–10 heteroarylalkyl, substituted C _1–8 alkyl, substituted C _1–8 heteroalkyl, substituted C _5–8 cycloalkyl, substituted C _5–8 heterocycloalkyl, substituted C _5–10 cycloalkylalkyl , substituted C _5-10 heterocycloalkylalkyl, substituted C _6-8 aryl, substituted C _5-8 heteroaryl, substituted C _7-10 arylalkyl and substituted C _5-10 heteroarylalkyl;

R ⁵ is selected from hydrogen, C _1-6 alkyl, C _5-8 cycloalkyl, C _6-12 cycloalkylalkyl, C _2-6 heteroalkyl, C _5-8 heterocycloalkyl, C _6-12 heterocycloalkylalkyl, substituted C _1-6 alkyl, substituted _C5-8 cycloalkyl, substituted _C6-12 cycloalkylalkyl, substituted _C2-6 heteroalkyl, substituted _C5-8 heterocycloalkyl and substituted _C6-12 heterocycloalkylalkyl;

R ⁶ is selected from hydrogen, C _1-6 alkyl, C _5-8 cycloalkyl, C _6-12 cycloalkylalkyl, C _2-6 heteroalkyl, C _5-8 heterocycloalkyl, C _6-12 heterocycloalkylalkyl, substituted C _1-6 alkyl, substituted _C5-8 cycloalkyl, substituted _C6-12 cycloalkylalkyl, substituted _C2-6 heteroalkyl, substituted _C5-8 heterocycloalkyl and substituted _C6-12 heterocycloalkylalkyl; And

A represents a single bond (–) and R ⁷ represents hydrogen, or A represents a double bond (=) and R ⁷ represents C _1–3 alkyl.

According to the present invention, pharmaceutical compositions contain a compound of the present invention and a pharmaceutically acceptable base.

According to the present invention, methods of treating a bacterial infection in a patient comprise administering to the patient in need of such treatment a therapeutically effective amount of a compound of the present invention.

According to the present invention, methods of treating a bacterial infection in a patient include administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition according to the present invention.

According to the present invention, methods of inhibiting β-lactamase in a patient include administering to the patient an effective amount of a compound of the present invention.

According to the present invention, methods of inhibiting β-lactamase in a patient include administering to the patient an effective amount of a pharmaceutical composition according to the present invention.

Reference is made below to some connections and methods. The disclosed embodiments are not intended to limit the claims. To the contrary, the claims are intended to cover all alternatives, modifications and equivalents.

Detailed description

A dash (“–”) that is not between two letters or symbols is used to indicate an attachment point for a fragment or substituent. For example, –CONH ₂ is added via a carbon atom.

"Alkyl" refers to a saturated or unsaturated monovalent hydrocarbon radical, branched or straight chain, obtained by removing one hydrogen atom from one carbon atom of a parent alkane, alkene or alkyne. Examples of alkyl groups include methyl; ethyls such as ethanyl, ethenyl and ethynyl; propyls, such as propan-1-yl, propan-2-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop –1-in-1-yl, prop-2-in-1-yl, etc.; butyls, such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, but-1-en-1-yl, but-1- en-2-yl, 2-methyl-prop-1-en-1-yl, buta-2-en-1-yl, buta-2-en-2-yl, buta-1,3-dien-1- yl, buta-1,3-dien-2-yl, but-1-in-1-yl, but-1-in-3-yl, but-3-in-1-yl, etc.; etc. The term "alkyl" is intended specifically to include groups having any degree or level of saturation, i.e. groups having exclusively carbon-carbon single bonds, groups having one or more carbon-carbon double bonds, groups having one or more carbon-carbon triple bonds, and groups having combinations of carbon-carbon single, double and triple bonds. When a specific level of saturation is assumed, the terms alkanyl, alkenyl and alkynyl are used. The alkyl group can be _C1-6 alkyl, _C1-5 alkyl, _C1-4 alkyl, _C1-3 alkyl, ethyl or methyl.

“Alkoxy” refers to the radical –OR, where R is alkyl as defined herein. Examples of alkoxy groups include methoxy, ethoxy, propoxy and butoxy. The alkoxy group can be _C1-6 alkoxy, _C1-5 alkoxy, _C1-4 alkoxy, _C1-3 alkoxy, ethoxy or methoxy.

"Aryl" by itself or as part of another substituent refers to a monovalent aromatic hydrocarbon radical obtained by removing one hydrogen atom from one carbon atom of the original aromatic ring system. Aryl covers 5- and 6-membered carbocyclic aromatic rings, for example, benzene; bicyclic ring systems in which at least one ring is carbocyclic and aromatic, for example, naphthalene, indan and tetraline; and tricyclic ring systems in which at least one ring is carbocyclic and aromatic, for example fluorene. Aryl encompasses a variety of ring systems having at least one carbocyclic aromatic ring fused to at least one carbocyclic aromatic ring, cycloalkyl ring, or heterocycloalkyl ring. For example, aryl contains a phenyl ring fused to a 5-7 membered heterocycloalkyl ring containing one or more heteroatoms selected from N, O and S. For such fused, bicyclic ring systems in which only one of the rings is a carbocyclic aromatic ring, the carbon atom of the radical may be in a carbocyclic aromatic ring or in a heterocycloalkyl ring. Examples of aryl groups include those derived from aceanthrylene, acenaphthylene, acephenanthrilene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, assim-indacene, sim-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, pentacene, pentaline, pentafene, perylene, phenalene, phenanthrene, picene, pleiaden, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene and the like. The aryl group can be _C6-10 aryl, _C6-9 aryl, _C6-8 aryl or phenyl. However, aryl does not in any way encompass or overlap with heteroaryl, as separately defined herein.

"Arilalkyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to the carbon atom is replaced by an aryl group. Examples of arylalkyl groups include benzyl, 2-phenylethan-1-yl, 2-phenylethane-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethane-1-yl, naphthobenzyl and 2-naphthophenylethan-1-yl. When specific alkyl moieties are contemplated, the terminology arylalkanyl, arylalkenyl or arylalkynyl is used. An arylalkyl group may be a _C7-16 arylalkyl, for example the alkanyl, alkenyl or alkynyl moiety of an arylalkyl group is _C1-6 and the aryl moiety is _C6-10 . An arylalkyl group may be a _C7-16 arylalkyl, for example the alkanyl, alkenyl or alkynyl moiety of an arylalkyl group is _C1-6 and the aryl moiety is _C6-10 . The arylalkyl group may be C _7-9 arylalkyl, in which the alkyl moiety is C _1-3 alkyl and the aryl moiety is phenyl. The arylalkyl group can be C _7-16 arylalkyl, C _7-14 arylalkyl, C _7-12 arylalkyl, C _7-10 arylalkyl, C _7-8 arylalkyl or benzyl.

“Bioavailability” refers to the rate and amount of a drug that reaches a patient's systemic circulation following administration of the drug or its prodrug to the patient, and can be determined by assessing, for example, the plasma or blood concentration-time profile of the drug. Parameters used to characterize the concentration-time curve in plasma or blood include the area under the curve (AUC), time to maximum concentration ( _Tmax ), and maximum drug concentration ( _Cmax ), where _Cmax is the maximum drug concentration in plasma or blood of a patient after administration of a dose of a drug or form of a drug to a patient, and T _max is the time to the maximum concentration (C _max ) of a drug in the plasma or blood of a patient after administration of a dose of a drug or form of a drug to a patient.

“Oral bioavailability” (F%) refers to the proportion of an administered oral drug that reaches the systemic circulation. Oral bioavailability is the product of the fraction absorbed, the fraction avoided elimination at the intestinal wall, and the fraction avoided hepatic elimination; and the factors that influence bioavailability can be divided into physiological, physicochemical and biopharmaceutical factors.

"Compounds" and moieties disclosed herein include any specific compounds within the scope of these formulas. Compounds can be identified either by their chemical structure and/or chemical name. Compounds are named using the terminology/structure program ChemBioDraw Ultra Version 14.0.0.117 (CambridgeSoft, Cambridge, MA). When there is a conflict between chemical structure and chemical name, the chemical structure is decisive for the identity of the compound. The compounds described herein may contain one or more stereogenic centers and/or double bonds and, therefore, may exist as stereoisomers, such as double-bonded isomers (ie, geometric isomers), enantiomers, diastereomers, or atropoisomers. Accordingly, any chemical structures within the scope of the foregoing description, in whole or in part, with relative configuration, embrace all possible enantiomers and stereoisomers of the illustrated compounds, including the stereoisomeric pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be separated into their constituent enantiomers or stereoisomers using separation methods or chiral synthesis methods well known to those skilled in the art.

The compounds and fragments disclosed herein include optical isomers of the compounds and fragments, racemates thereof, and other mixtures thereof. In such embodiments, the individual enantiomers or diastereomers can be obtained through asymmetric synthesis or through racemate resolution. Separation of racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a separating agent or chromatography using, for example, a chiral high pressure liquid chromatography (HPLC) column with chiral stationary phases. In addition, the compounds include the (Z) and (E) forms (or cis and trans forms) of compounds with double bonds, either as individual geometric isomers or mixtures thereof.

Compounds and fragments can also exist in several tautomeric forms, including the enol form, the keto form, and mixtures thereof. Accordingly, the chemical structures depicted herein cover all possible tautomeric forms of the compounds illustrated. The compounds may exist in unsolvated forms as well as solvated forms, including hydrated forms. Some compounds can exist in many crystalline, cocrystalline, or amorphous forms. The compounds include their pharmaceutically acceptable salts or pharmaceutically acceptable solvates in the free acid form of any of the above, as well as crystalline forms of any of the above.

"Cycloalkyl" refers to a saturated or partially saturated cyclic alkyl radical. The cycloalkyl group may be C _3-6 cycloalkyl, C _3-5 cycloalkyl, C _5-6 cycloalkyl, cyclopropyl, cyclopentyl or cyclohexyl. The cycloalkyl may be selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

“Cycloalkylalkyl” refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to the carbon atom is replaced by a cycloalkyl group as defined herein. When specific alkyl moieties are contemplated, the terminology cycloalkylalkyl, cycloalkylalkenyl or cycloalkylalkynyl is used. The cycloalkylalkyl group can be, for example, C _4-30 cycloalkylalkyl, the alkanyl, alkenyl or alkynyl moiety of the cycloalkylalkyl group is C _1-10 , and the cycloalkyl moiety of the cycloalkylalkyl moiety is C _3-20 . The cycloalkylalkyl group may be _C4-20 cycloalkylalkyl, for example the alkanyl, alkenyl or alkynyl moiety of a cycloalkylalkyl group is _C1-8 and the cycloalkyl moiety of a cycloalkylalkyl group is _C3-12 . The cycloalkylalkyl may be _C4-9 cycloalkylalkyl, in which the alkyl moiety of the cycloalkylalkyl group is _C1-3 alkyl and the cycloalkyl moiety of the cycloalkylalkyl group is _C3-6 cycloalkyl. The cycloalkylalkyl group may be _C4-12 cycloalkylalkyl, _C4-10 cycloalkylalkyl, _C4-8 cycloalkylalkyl and _C4-6 cycloalkylalkyl. The cycloalkylalkyl group can be cyclopropylmethyl (–CH ₂ –cyclo–C ₃ H ₅ ), cyclopentylmethyl (–CH ₂ –cyclo–C ₅ H ₉ ) or cyclohexylmethyl (–CH ₂ –cyclo–C ₆ H ₁₁ ). The cycloalkylalkyl group can be cyclopropylethenyl (–CH=CH–cyclo–C ₃ H ₅ ) or cyclopentylethynyl (–C≡C–cyclo–C ₅ H ₉ ).

"Cycloalkylheteroalkyl", by itself or as part of another substituent, refers to a heteroalkyl group in which one or more carbon atoms (and some associated hydrogen atoms) of the alkyl group are independently replaced by the same or different heteroatom group or groups and in which one of the atoms hydrogen bonded to the carbon atom is replaced by a cycloalkyl group. When specific alkyl moieties are contemplated, the terminology cycloalkylheteroalkanyl, cycloalkylheteroalkenyl, and cycloalkylheteroalkynyl is used. In cycloalkylheteroalkyl, the heteroatom group can be selected from –O–, –S–, –NH–, –N(–CH ₃ )–, –SO– and –SO ₂ –, or the heteroatom group can be selected from –O– and –NH– , or the heteroatomic group is –O– or –NH–.

“Cycloalkyloxy” refers to the radical –OR, where R represents cycloalkyl as defined herein. Examples of cycloalkyloxy groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy. The cycloalkyloxy group may be C _3-6 cycloalkyloxy, C _3-5 cycloalkyloxy, C _5-6 cycloalkyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy.

“Disease” refers to an illness, disorder, condition or symptom of any of the above.

"Fluoroalkyl" refers to an alkyl group as defined herein in which one or more hydrogen atoms are replaced by fluorine. The fluoroalkyl group may be C _1-6 fluoroalkyl, C _1-5 fluoroalkyl, C _1-4 fluoroalkyl or C _1-3 fluoroalkyl. The fluoroalkyl group can be pentafluoroethyl (–CF ₂ CF ₃ ) or trifluoromethyl (–CF ₃ ).

"Fluoroalkoxy" refers to an alkoxy group as defined herein in which one or more hydrogen atoms are replaced by fluorine. The fluoroalkoxy group may be C _1-6 fluoroalkoxy, C _1-5 fluoroalkoxy, C _1-4 fluoroalkoxy, C _1-3 fluoroalkoxy, –OCF ₂ CF ₃ or –OCF ₃ .

"Halogen" refers to the group of fluorine, chlorine, bromine or iodine.

"Heteroalkoxy" refers to an alkoxy group in which one or more carbon atoms are replaced by a heteroatom. The heteroalkoxy group may be C _1-6 heteroalkoxy, C _1-5 heteroalkoxy, C _1-4 heteroalkoxy or C _1-3 heteroalkoxy. In heteroalkoxy, the heteroatom group can be selected from –O–, –S–, –NH–, –NR–, –SO ₂ – and –SO ₂ –, or the heteroatom group can be selected from –O– and –NH–, or the heteroatom group represents –O– and –NH–. The heteroalkoxy group may be C _1-6 heteroalkoxy, C _1-5 heteroalkoxy, C _1-4 heteroalkoxy or C _1-3 heteroalkoxy.

“Heteroalkyl,” by itself or as part of another substituent, refers to an alkyl group in which one or more carbon atoms (and some associated hydrogen atoms) are independently replaced by the same or different heteroatom group or groups. Examples of heteroatomic groups include –O–, –S–, –NH–, –NR–, –O–O–, –S–S–, =N–N=, –N=N–, –N=N–NR –, –PR–, –P(O)OR–, –P(O)R–, –POR–, –SO–, –SO ₂ –, –Sn(R) ₂ – and the like, each R independently selected from hydrogen, C _1-6 alkyl, substituted C _1-6 alkyl, C _6-12 aryl, substituted C _6-12 aryl, C _7-18 arylalkyl, substituted C _7-18 arylalkyl, C _3-7 cycloalkyl, substituted C _3–7 cycloalkyl, C _3–7 heterocycloalkyl, substituted C _3–7 heterocycloalkyl, C _1–6 heteroalkyl, substituted C _1–6 heteroalkyl, C _6–12 heteroaryl, substituted C _6–12 heteroaryl, C _7–18 heteroarylalkyl and substituted C _7–18 heteroarylalkyl. Each R can be independently selected from hydrogen and C _1-3 alkyl. A reference to, for example, C _1-6 heteroalkyl means a C _1-6 alkyl group in which at least one of the carbon atoms (and some associated hydrogen atoms) is replaced by a heteroatom. For example, C _1-6 heteroalkyl includes groups having five carbon atoms and one heteroatom, groups having four carbon atoms and two heteroatoms, etc. In heteroalkyl, the heteroatom group can be selected from –O–, –S–, –NH–, –N(–CH ₃ )–, –SO– and –SO ₂ –, or the heteroatom group can be selected from –O– and –NH– , or the heteroatomic group can be –O– or –NH–. The heteroalkyl group may be C _1-6 heteroalkyl, C _1-5 heteroalkyl or C _1-4 heteroalkyl or C _1-3 heteroalkyl.

"Heteroaryl" by itself or as part of another substituent refers to a monovalent heteroaromatic radical obtained by removing one hydrogen atom from one atom of the parent heteroaromatic ring system. Heteroaryl encompasses a variety of ring systems having at least one heteroaromatic ring fused to at least one other ring, which may be aromatic or non-aromatic. For example, heteroaryl encompasses bicyclic rings in which one ring is heteroaromatic and the second ring is a heterocycloalkyl ring. For such fused, bicyclic heteroaryl ring systems in which only one of the rings contains one or more heteroatoms, the radical carbon may be on an aromatic ring or on a heterocycloalkyl ring. When the total number of N, S and O atoms in a heteroaryl group exceeds one, the heteroatoms may or may not be adjacent to each other. The total number of heteroatoms in the heteroaryl group is no more than two. In heteroaryl, the heteroatom group can be selected from –O–, –S–, –NH–, –N(–CH ₃ )–, –S(O)– and –SO ₂ –, or the heteroatom group can be selected from –O– and –NH–, or the heteroatomic group can be –O– or –NH–. The heteroaryl group can be selected from C _5-10 heteroaryl, C _5-9 heteroaryl, C _5-8 heteroaryl, C _5-7 heteroaryl, C _5-6 heteroaryl, C ₅ heteroaryl or C ₆ heteroaryl.

Examples of suitable heteroaryl groups include those derived from acridine, arsindole, carbazole, α-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolysine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole , naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinolysine, quinoxaline, tetrazole, thiadiazole, thiazole , thiophene, triazole, xanthene, thiazolidine, oxazolidine and the like. The heteroaryl group can be obtained from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole or pyrazine. For example, the heteroaryl may be C ₅ heteroaryl and may be selected from furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl or isoxazolyl. The heteroaryl may be C ₆ heteroaryl and may be selected from pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl.

"Heteroarylalkyl" refers to an arylalkyl group in which one of the carbon atoms (and some associated hydrogen atoms) is replaced by a heteroatom. The heteroarylalkyl group may be _C6-16 heteroarylalkyl, _C6-14 heteroarylalkyl, _C6-12 heteroarylalkyl, _C6-10 heteroarylalkyl, _C6-8 heteroarylalkyl or _C7 heteroarylalkyl or _C6 heteroarylalkyl. In heteroarylalkyl, the heteroatom group can be selected from –O–, –S–, –NH–, –N(–CH ₃ )–, –SO– and –SO ₂ –, or the heteroatom group can be selected from –O– and –NH– , or the heteroatomic group can be –O– or –NH–.

“Heterocycloalkyl,” by itself or as part of another substituent, refers to a saturated or unsaturated cyclic alkyl radical in which one or more carbon atoms (and some associated hydrogen atoms) are independently replaced by the same or another heteroatom; or to the original aromatic ring system in which one or more carbon atoms (and some associated hydrogen atoms) are independently replaced by the same or another heteroatom such that the ring system violates Hückel's rule. Examples of heteroatoms to replace carbon atom(s) include N, P, O, S and Si. Examples of heterocycloalkyl groups include those derived from epoxides, azirines, thiranes, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine and quinuclidine. The heterocycloalkyl may be C ₅ heterocycloalkyl and is selected from pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, doxolanyl and dithiolanyl. The heterocycloalkyl may be C ₆ heterocycloalkyl and may be selected from piperidinyl, tetrahydropyranyl, piperisinyl, oxazinyl, dithianyl and dioxanyl. The heterocycloalkyl group may be C _3-6 heterocycloalkyl, C _3-5 heterocycloalkyl, C _5-6 heterocycloalkyl, C ₅ heterocycloalkyl or C ₆ heterocycloalkyl. In heterocycloalkyl, the heteroatom group can be selected from –O–, –S–, –NH–, –N(–CH ₃ )–, –SO– and –SO ₂ –, or the heteroatom group can be selected from –O– and –NH– , or the heteroatomic group can be –O– or –NH–.

“Heterocycloalkylalkyl” refers to a cycloalkylalkyl group in which one or more carbon atoms (and some associated hydrogen atoms) of the cycloalkyl ring are independently replaced by the same or another heteroatom. Heterocycloalkylalkyl may be C _4-12 heterocycloalkylalkyl, C _4-10 heterocycloalkylalkyl, C _4-8 heterocycloalkylalkyl, C _4-6 heterocycloalkylalkyl, C _6-7 heterocycloalkylalkyl or C ₆ heterocycloalkylalkyl or C ₇ heterocycloalkylalkyl. In heterocycloalkylalkyl, the heteroatom group can be selected from –O–, –S–, –NH–, –N(–CH ₃ )–, –SO– and –SO ₂ –, or the heteroatom group can be selected from –O– and –NH– , or the heteroatomic group can be –O– or –NH–.

"Primary aromatic ring system" refers to an unsaturated cyclic or polycyclic ring system having a cyclic conjugate π(pi) electron system with 4n+2 electrons (Hückel's rule). Included in the definition of "original aromatic ring system" are fused ring systems in which one or more rings are aromatic and one or more rings are saturated or unsaturated, such as, for example, fluorene, indane, indene, phenalene, etc. Examples of parent aromatic ring systems include aceanthrylene, acenaphthylene, acephenanthrilene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, assim-indacene, simm-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, pentacene, pentaline, pentafene, perylene, phenalene, phenanthrene, picene, pleiadenum, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene and the like.

"Hydrates" refers to the inclusion of water in the crystal lattice of a compound described herein in stoichiometric proportions, resulting in the formation of an adduct. Methods for preparing hydrates include, but are not limited to, storage in an atmosphere containing steam, dosage forms that contain water, or conventional pharmaceutical processing steps such as, for example, crystallization (i.e., from water or mixed aqueous solvents), lyophilization, wet granulation, aqueous film coating or spray drying. Under certain circumstances, hydrates can also form from crystalline solvates when exposed to steam or when anhydrous material is suspended in water. Hydrates can also crystallize in more than one form, resulting in hydrate polymorphism.

"Metabolic intermediate" refers to a compound that is formed in vivo as a result of the metabolism of the parent compound and which is further reacted in vivo to release the active agent. The compounds of formula (1) are protected sulfonate nucleophilic prodrugs of non-β-lactam β-lactamase inhibitors that are metabolized in vivo to form corresponding metabolic intermediates such as avibactam ([2S,5R]-2-carbamoyl-7-oxo-1 ,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate). Metabolic intermediates undergo nucleophilic cyclization to release a non-β-lactam β-lactamase inhibitor such as avibactam and one or more reaction products. It is necessary that the reaction products or their metabolites be non-toxic.

"Neopentyl" refers to a radical in which a methylene carbon is bonded to a carbon atom that is bonded to three non-hydrogen substituents. Examples of non-hydrogen substituents include carbon, oxygen, nitrogen and sulfur. Each of the three non-hydrogen substituents can be carbon. Two of the three non-hydrogen substituents may be carbon, and the third non-hydrogen substituent may be selected from oxygen and nitrogen. The neopentyl group may have the structure:

where each R ¹ is determined as for formula (1).

"Primary Aromatic Ring System" refers to an unsaturated cyclic or polycyclic ring system having a conjugated π electron system. The definition of "parent aromatic ring system" specifically includes fused ring systems in which one or more rings are aromatic and one or more rings are saturated or unsaturated, such as, for example, fluorene, indane, indene, phenalene, etc. Examples of parent aromatic ring systems include aceanthrylene, acenaphthylene, acephenanthrilene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, assim-indacene, simm-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentaline, pentafene, perylene, phenalene, phenanthrene, picene, pleiaden, pyrene, pyranthrene, rubicene, triphenylene and trinaphthalene.

"Primary heteroaromatic ring system" refers to an aromatic ring system in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced by the same or another heteroatom in such a way as to maintain a constant π-electron characteristic of the aromatic systems and the π number –electrons corresponding to Hückel’s rule (4n +2). Examples of heteroatoms to replace carbon atoms include N, P, O, S and Si, etc. The definition of "parent heteroaromatic ring systems" specifically includes fused ring systems in which one or more rings are aromatic and one or more rings are saturated or unsaturated, such as, for example, arsindole, benzodioxane, benzofuran, chromane, chromene, indole, indoline and xanthene. Examples of parent heteroaromatic ring systems include arsindole, carbazole, β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolysine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinolysine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, thiazolidine and oxazolidine.

"Patient" refers to a mammal, such as a human. The term "patient" is used interchangeably with "subject".

“Pharmaceutically acceptable” refers to approved or pending regulatory approval by the federal or state government or listed in the United States Pharmacopoeia or other generally accepted pharmacopoeia for use in animals and, in particular, in humans.

"Pharmaceutically acceptable salt" refers to a salt of a compound that has the desired pharmacological activity of the parent compound. Such salts include acid addition salts formed with inorganic acids and one or more protonatable functional groups, such as primary, secondary or tertiary amines in the parent compound. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. The salt can be formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2 –naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like. A salt can be formed when one or more acid protons present in the parent compound are replaced by a metal ion such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion or combinations thereof; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine and N-methylglucamine. The pharmaceutically acceptable salt may be a hydrochloride salt. The pharmaceutically acceptable salt may be a sodium salt. In compounds having two or more ionizable groups, the pharmaceutically acceptable salt may contain one or more counterions, such as a bisalt, such as a dihydrochloride salt.

The term "pharmaceutically acceptable salt" includes hydrates and other solvates, as well as salts in crystalline or non-crystalline form. By disclosing a specific pharmaceutically acceptable salt, it is intended that the specific salt, such as the hydrochloride salt, is an example of the salt, and that other salts can be prepared using techniques known to one skilled in the art. Additionally, using techniques generally known in the art, one of ordinary skill in the art will be able to convert the pharmaceutically acceptable salt to the corresponding compound, free base and/or free acid.

"Pharmaceutically acceptable vehicle" refers to a pharmaceutically acceptable diluent, a pharmaceutically acceptable adjuvant, a pharmaceutically acceptable adjuvant, a pharmaceutically acceptable carrier, or a combination of any of the above, with which a compound of the present disclosure can be administered to a patient and which does not interfere with its pharmacological activity and which is non-toxic when administered in doses sufficient to provide a therapeutically effective amount of the compound.

"Pharmaceutical composition" refers to a compound of formula (1) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable base with which the compound of formula (1) or a pharmaceutically acceptable salt thereof is administered to a patient. Pharmaceutically acceptable bases are known in the art.

“Prevention” or “avoidance” refers to reducing the risk of acquiring a disease or disorder (i.e., preventing at least one of the clinical symptoms of a disease from developing in a patient who may be susceptible or predisposed to the disease, but does not yet experience or shows symptoms of the disease). In some embodiments, “preventing” or “preventing” refers to reducing the symptoms of a disease by administering the compound in a prophylactic manner. The use of a therapeutic agent to prevent or prevent a disease or disorder is known as prophylaxis. The compounds provided in the present disclosure may provide superior prevention due to lower long-term side effects over long periods of time.

“Prodrug” refers to a derivative of a drug molecule that requires transformation in the body to release the active drug. Prodrugs are often, although not necessarily, pharmacologically inactive until converted to the parent drug.

"Profragment" refers to a group associated with a drug, typically a functional group of the drug, through bond(s) that can be cleaved under certain conditions of use. The bond(s) between the drug and the profragment can be cleaved by enzymatic or non-enzymatic means. Under conditions of use, such as after administration to a patient, the bond(s) between the drug and the profragment may be cleaved to release the parent drug. Cleavage of the profragment may occur spontaneously, for example by a hydrolysis reaction, or it may be catalyzed or induced by another means, for example by an enzyme, by light, by an acid, or by a change or manipulation of a physical or environmental parameter, such as change in temperature, pH, etc. The agent may be endogenous to the conditions of use, such as an enzyme present in the systemic circulation of the patient to whom the prodrug is administered, or the acidic environment of the stomach, or the agent may be administered exogenously. For example, for a compound of formula (1), the profragment may have the structure:

where R ¹ , R ² and R ³ correspond to the definition for formula (1).

“Single bond,” as in “R ² is selected from a single bond,” refers to a moiety in which R ² is a single bond. For example, in a fragment having the structure –C(R ¹ ) ₂ –R ² –R ³ , where R ² represents a single bond, –R ² corresponds to a single bond, “–”, and the fragment has the structure –C(R ¹ ) ₂ –R ³ .

"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 pharmaceuticals that are known to be harmless to the patient, such as water, ethanol and the like. The molecular complex of a compound or fragment of a compound and a solvent can be stabilized by non-covalent intramolecular forces, such as, for example, electrostatic forces, van der Waals forces or hydrogen bonds. The term "hydrate" refers to a solvate in which one or more solvent molecules is water.

"Solvates" refers to the incorporation of solvents into the crystal lattice of a compound described herein in stoichiometric proportions, resulting in the formation of an adduct. Methods for preparing solvates include, but are not limited to, storage in an atmosphere containing a solvent, dosage forms that include a solvent, or conventional pharmaceutical processing steps such as, for example, crystallization (ie, from a solvent or mixed solvents) and vapor diffusion. Solvates can also be formed under certain circumstances from other crystalline solvates or hydrates upon exposure to a solvent or when the material is suspended in a solvent. Solvates can crystallize in more than one form, resulting in solvate polymorphism.

"Substituted" refers to a group in which one or more hydrogen atoms are independently replaced by the same or different substituent(s). Each substituent can be independently selected from deuterium, halogen, –OH, –CN, –CF ₃ , –OCF ₃ , =O, –NO ₂ , C _1-6 alkoxy, C _1-6 alkyl, –COOR, –NR ₂ and –CONR ₂ ; wherein each R is independently selected from hydrogen and C _1-6 alkyl. Each substituent can be independently selected from deuterium, halogen, –NH ₂ , –OH, C _1-3 alkoxy and C _1-3 alkyl, trifluoromethoxy, and trifluoromethyl. Each substituent can be independently selected from deuterium, –OH, methyl, ethyl, trifluoromethyl, methoxy, ethoxy and trifluoromethoxy. Each substituent can be selected from deuterium, C _1-3 alkyl, =O, C _1-3 alkyl, C _1-3 alkoxy and phenyl. Each substituent can be selected from deuterium, –OH, –NH ₂ , C _1–3 alkyl and C _1–3 alkoxy.

"Therapy" or "treatment" of a disease refers to the relief or attenuation of a disease or at least one of the clinical symptoms of a disease or disorder, reducing the risk of acquiring a disease or at least one of the clinical symptoms of a disease, reducing the progression of a disease or at least one of the clinical symptoms of a disease or disorder. symptoms of the disease or reducing the risk of developing the disease or at least one of the clinical symptoms of the disease. “Therapy” or “treatment” also refers to inhibiting a disease, either physically (eg, stabilizing a discernible symptom), physiologically (eg, stabilizing a physical parameter), or both, and inhibiting at least one physical parameter or manifestation , which may or may not be noticeable to the patient. “Therapy” or “treatment” also refers to delaying the onset of a disease or at least one or more symptoms thereof in a patient who may be susceptible or predisposed to the disease or disorder, even if that patient is not yet experiencing or exhibiting symptoms of the disease.

A “therapeutically effective amount” refers to an amount of a compound that, when administered to a subject to treat a disease or at least one clinical symptom of a disease, is sufficient to effect such treatment of the disease or symptom thereof. The "therapeutically effective amount" may vary depending on, for example, the compound, the disease and/or symptoms of the disease, the severity of the disease and/or symptoms of the disease or disorder, the age, weight and/or health status of the patient being treated, and the judgment of the prescriber. The appropriate amount in any particular case can be determined by those skilled in the art or can be determined by routine experimentation.

"Therapeutically effective dose" refers to a dose that provides effective treatment of a disease or disorder in a patient. The therapeutically effective dose may vary from compound to compound and from patient to patient, and may depend on factors such as the patient's condition and the route of delivery. The therapeutically effective dose can be determined in accordance with conventional pharmacological techniques known to those skilled in the art.

“Therapeutically effective amount” means an amount of a compound that, when administered to a patient to treat a disease, is sufficient to effect such treatment of the disease. A "therapeutically effective amount" will vary, for example, depending on the compound, the disease and its severity, and the age, weight, absorption, distribution, metabolism and excretion of the patient being treated.

“Vehicle” refers to the diluent, adjuvant, or carrier with which the compound is administered to the subject. In some embodiments, the base is pharmaceutically acceptable.

Reference is made in detail to certain embodiments of the compounds, compositions and methods. The disclosed embodiments are not intended to limit the claims. To the contrary, the claims are intended to cover all alternatives, modifications and equivalents.

The compounds presented in this disclosure are prodrugs in the form of sulfonic acid esters of non-β-lactam β-lactamase inhibitors. In prodrugs of a non-β-lactam β-lactamase inhibitor, the nucleophilic fragment is located next to the hydrosulfate group. In vivo, the nucleophilic moiety reacts to release a non-β-lactam β-lactamase inhibitor. Examples of non-β-lactam β-lactamase inhibitors include avibactam ([2S,5R]-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate), relebactam ((1R,2S ,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate) and nacubactam (1R,2S,5R)-2-((2 –aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate and derivatives and analogs of any of the above. These compounds are inhibitors of class A, class C, and some class D β-lactamases, and they are useful in the treatment of bacterial infections when used in combination with β-lactam antibiotics.

The compounds provided in the present disclosure include compounds of formula (1):

(1)

or a pharmaceutically acceptable salt thereof, wherein

each R ¹ is independently selected from C _1–6 alkyl, or each R ¹ and the geminal carbon atom to which they are bonded forms a C _3–6 cycloalkyl ring, a C _3–6 heterocycloalkyl ring, a substituted C _3–6 cycloalkyl ring, or a substituted C _3–6 heterocycloalkyl ring;

R ² is selected from single bond, C _1-6 alkanediyl, C _1-6 heteroalkanediyl, C _5-6 cycloalkanediyl, C _5-6 heterocycloalkanediyl, C ₆ arenediyl, C _5-6 heteroarendiyl, substituted C _1-6 alkanediyl, substituted C _1-6 heteroalkanediyl, substituted _C5-6 cycloalkanediyl, substituted _C5-6 heterocycloalkanediyl, substituted _C6 arenediyl and substituted _C5-6 heteroarendiyl;

R ³ is selected from C _1–6 alkyl, –O–C(O)–R ⁴ , –S–C(O)–R ⁴ , –NH–C(O)–R ⁴ , –O–C(O) –O–R ⁴ , –S–C(O)–O–R ⁴ , –NH–C(O)–O–R ⁴ , –C(O)–O–R ⁴ , –C(O)–S –R ⁴ , –C(O)–NH–R ⁴ , –O–C(O)–O–R ⁴ , –O–C(O)–S–R ⁴ , –O–C(O)–NH –R ⁴ , –S–S–R ⁴ , –S–R ⁴ , –NH–R ⁴ , –CH(–NH ₂ )(–R ⁴ ), C _5–6 heterocycloalkyl, C _5–6 heteroaryl, substituted C _5–6 cycloalkyl, substituted C _5–6 heterocycloalkyl, substituted C _5–6 aryl, substituted C _5–6 heteroaryl and –CH=C(R ⁴ ) ₂ , in which

R ⁴ is selected from hydrogen, C _1–8 alkyl, C _1–8 heteroalkyl, C _5–8 cycloalkyl, C _5–8 heterocycloalkyl, C _5–10 cycloalkylalkyl, C _5–10 heterocycloalkylalkyl, C _6–8 aryl, C _{5 –8} heteroaryl, C _7–10 arylalkyl, C _5–10 heteroarylalkyl, substituted C _1–8 alkyl, substituted C _1–8 heteroalkyl, substituted C _5–8 cycloalkyl, substituted C _5–8 heterocycloalkyl, substituted C _5–10 cycloalkylalkyl , substituted C _5-10 heterocycloalkylalkyl, substituted C _6-8 aryl, substituted C _5-8 heteroaryl, substituted C _7-10 arylalkyl and substituted C _5-10 heteroarylalkyl;

R ⁵ is selected from hydrogen, C _1-6 alkyl, C _5-8 cycloalkyl, C _6-12 cycloalkylalkyl, C _2-6 heteroalkyl, C _5-8 heterocycloalkyl, C _6-12 heterocycloalkylalkyl, substituted C _1-6 alkyl, substituted _C5-8 cycloalkyl, substituted _C6-12 cycloalkylalkyl, substituted _C2-6 heteroalkyl, substituted _C5-8 heterocycloalkyl and substituted _C6-12 heterocycloalkylalkyl;

R ⁶ is selected from hydrogen, C _1-6 alkyl, C _5-8 cycloalkyl, C _6-12 cycloalkylalkyl, C _2-6 heteroalkyl, C _5-8 heterocycloalkyl, C _6-12 heterocycloalkylalkyl, substituted C _1-6 alkyl, substituted _C5-8 cycloalkyl, substituted _C6-12 cycloalkylalkyl, substituted _C2-6 heteroalkyl, substituted _C5-8 heterocycloalkyl and substituted _C6-12 heterocycloalkylalkyl; And

A represents a single bond (–) and R ⁷ represents hydrogen, or A represents a double bond (=) and R ⁷ represents C _1–3 alkyl.

In compounds of formula (1), each substituent can be independently selected from deuterium, –OH, –CN, –CF ₃ , –OCF ₃ , =O, –NO ₂ , C _1–6 alkoxy, C _1–6 alkyl, –COOR, –NR ₂ and –CONR ₂ ; wherein each R is independently selected from hydrogen and C _1-6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl or iso-butyl.

In compounds of formula (1), the substituent group may be a nucleophilic group. Nucleophilic groups are a functional group that has a reactive pair of electrons and has the ability to form a chemical bond by donating electrons. Examples of suitable nucleophilic groups include esters, carboxylates, sulfonates, substituted or unsubstituted amines, alcohols (hydroxyl), thiols, sulfides, hydroxylamines and imines. Other examples of suitable nucleophilic groups include –OH, –CF ₃ , –O–CF ₃ , –NO ₂ , –O–C(O)–R ⁴ , –S–C(O)–R ⁴ , –NH–C( O)–R ⁴ , –O–C(O)–O–R ⁴ , –S–C(O)–O–R ⁴ , –NH–C(O)–O–R ⁴ , –C(O) –O–R ⁴ , –C(O)–S–R ⁴ , –C(O)–NH–R ⁴ , –O–C(O)–O–R ⁴ , –O–C(O)–S –R ⁴ , –O–C(O)–NH–R ⁴ , –S–S–R ⁴ , –S–R ⁴ , –NH–R ⁴ , –CH(–NH ₂ )(–R ⁴ ), where each R ⁴ is independently selected from hydrogen, C _1-6 alkyl, C _1-6 heteroalkyl, C _5-8 cycloalkyl, C _5-8 heterocycloalkyl, C _5-10 cycloalkylalkyl, C _5-10 heterocycloalkylalkyl, C _6-8 aryl , C _6–8 heteroaryl, C _5–10 arylalkyl, C _5–10 heteroarylalkyl, substituted C _1–6 alkyl, substituted C _1–6 heteroalkyl, substituted C _5–8 cycloalkyl, substituted C _5–8 heterocycloalkyl, substituted C _{5 –10} cycloalkylalkyl, substituted _C5-10 heterocycloalkylalkyl, substituted _C6-8 aryl, substituted _C6-8 heteroaryl, substituted _C5-10 arylalkyl and substituted _C5-10 heteroarylalkyl.

In compounds of formula (1), each substituent can be independently selected from –OH, –CF ₃ , –O–CF ₃ , –NO ₂ , –O–C(O)–R ⁴ , –S–C(O)–R ⁴ , –NH–C(O)–R ⁴ , –O–C(O)–O–R ⁴ , –S–C(O)–O–R ⁴ , –NH–C(O)–O–R ⁴ , –C(O)–O–R ⁴ , –C(O)–S–R ⁴ , –C(O)–NH–R ⁴ , –O–C(O)–O–R ⁴ , –O– C(O)–S– ^R4 , –O–C(O)–NH– ^R4 , –S–S– ^R4 , –S– ^R4 , –NH– ^R4 , –CH( _–NH2 ) (–R ⁴ ), where each R ⁴ is selected from hydrogen, C _1–8 alkyl and C _1–8 heteroalkyl.

In compounds of formula (1), A may be a single bond (–), and ^R7 may be hydrogen.

In compounds of formula (1), A may have a double bond (=) and ^R7 may be a _C1-3 alkyl such as methyl, ethyl, n-propyl or isopropyl.

In compounds of formula (1), each of R ⁵ and R ⁶ may be hydrogen.

In compounds of formula (1) A there may be a single bond (–); R ⁷ may be hydrogen; and R ⁵ may be hydrogen.

In compounds of formula (1) A may be a double bond (=) and ^R7 may be a _C1-3 alkyl such as methyl, ethyl, n-propyl or isopropyl; and each of R ⁵ and R ⁶ may be hydrogen.

In compounds of formula (1), the compound may have the structure of formula (2):

(2)

In compounds of formula (1), the compound may have the structure of formula (2a):

(2a)

In compounds of formula (1), the compound may have the structure of formula (3):

(3)

In compounds of formula (1), the compound may have the structure of formula (3a):

(3a)

In compounds of formula (1), the compound may have the structure of formula (4):

(4)

In compounds of formula (1), the compound may have the structure of formula (5):

(5)

In compounds of formula (1), R ⁵ may be C _2-6 heteroalkyl containing a terminal amino group, and R ⁶ may be hydrogen. For example, R ⁵ can be –O–(CH ₂ ) ₂ –NH ₂ , –CH ₂ –O–CH ₂ –NH ₂ , –(CH ₂ ) ₂ –O–CH ₂ –NH ₂ or –CH ₂ –O –(CH ₂ ) ₂ –NH ₂ .

In compounds of formula (1), A can be a single bond (–), and R ⁷ can be hydrogen, R ⁵ can be –O–(CH ₂ ) ₂ –NH ₂ , and R ⁶ can be hydrogen.

In compounds of formula (1), R ⁵ may be C _4–6 heterocycloalkyl containing at least one –NH– moiety, and R ⁶ may be hydrogen. For example, ^R5 could be 2-yl-piperidine, 3-yl-piperidine or 4-yl-piperidine.

In compounds of formula (1), A can be a single bond (–), and R ⁷ can be hydrogen, R ⁵ can be 4-yl-piperidine, and R ⁶ can be hydrogen.

In compounds of formula (1)–(5), each R ¹ can independently be C _1–6 alkyl.

In compounds of formula (1)–(5), each R ¹ can independently be methyl, ethyl or n-propyl.

In compounds of formula (1)–(5), each R ¹ can be the same and represents methyl, ethyl or n-propyl.

In compounds of formula (1)–(5), each R1 is methyl.

In compounds of formula (1)–(5), each R ¹ together with the geminal carbon atom to which it is bonded can form a C _3–6 cycloalkyl ring or a substituted C _3–6 cycloalkyl ring.

In compounds of formula (1)–(5), each ^R1, together with the geminal carbon atom to which it is bonded, can form a _C3–6 cycloalkyl ring. For example, each R ¹ together with the geminal carbon atom to which they are bonded can form a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, or a cyclohexyl ring.

In compounds of formula (1)–(5), each R ¹ together with the geminal carbon atom to which they are bonded can form a C _3–6 heterocycloalkyl ring or a substituted C _3–6 heterocycloalkyl ring.

In compounds of formula (1)–(5), R ² can be selected from a single bond, C _1–2 alkanediyl and substituted C _1–2 alkanediyl.

In compounds of formula (1)–(5) R ² may have a single bond.

In compounds of formula (1)–(5) R ² may have a single bond; and R ³ may be C _1-6 alkyl.

In compounds of formula (1)–(5), R ² can be selected from C _1–2 alkanediyl and substituted C _1–2 alkanediyl.

In the compounds of formula (1)–(5), R ² may be methandiyl, ethanediyl, substituted methanediyl or substituted ethanediyl.

In compounds of formula (1)–(5) R ² may be substituted with C _1–2 alkanediyl, where the substituted group can be selected from –OH, –CN, –CF ₃ , –OCF ₃ , =O, –NO ₂ , C _{1 –6} alkoxy, C _1–6 alkyl, –COOR, –NR ₂ and –CONR ₂ ; wherein each R is independently selected from hydrogen and C _1-6 alkyl.

In compounds of formula (1)–(5), R ² may be a substituted C _1–2 alkanediyl, where the substituent group may be a nucleophilic group. For example, R ² may be substituted C _1–2 alkanediyl, where the substituent group can be selected from –OH, –CF ₃ , –O–CF ₃ , –NO ₂ , –O–C(O)–R ⁴ , –S– C(O) ^–R4 , –NH–C(O) ^–R4 , –O–C(O)–O– ^R4 , –S–C(O)–O– ^R4 , –NH–C( O)–O–R ⁴ , –C(O)–O–R ⁴ , –C(O)–S–R ⁴ , –C(O)–NH–R ⁴ , –O–C(O)–O –R ⁴ , –O–C(O)–S–R ⁴ , –O–C(O)–NH–R ⁴ , –S–S–R ⁴ , –S–R ⁴ , –NH–R ⁴ , –CH(–NH ₂ )(–R ⁴ ), where each R ⁴ is defined as for formula (1), or each R ⁴ is selected from hydrogen and C _1–8 alkyl.

In compounds of formula (1)–(5) R ² may be substituted with C _1–2 alkanediyl, where the substituent group is selected from –OH, –O–C(O)–R ⁴ , –S–C(O)–R ⁴ , –NH–C(O)–R ⁴ , –C(O)–O–R ⁴ , –C(O)–S–R ⁴ , –C(O)–NH–R ⁴ , –S–S– R ⁴ , –S–R ⁴ , –NH–R ⁴ , –CH(–NH ₂ )(–R ⁴ ), substituted C _5–6 aryl, –NHR ⁴ , –CH(–NH ₂ )(–R ⁴ ); and R ⁴ is determined as for formula (1), or each R ⁴ is selected from hydrogen and C _1-8 alkyl.

In compounds of formula (1)–(5) where ^R2 is a substituted _C1-6 alkanediyl, a substituted _C1-6 heteroalkanediyl, or a substituted _C5-6 arenediyl, the stereochemistry of the carbon atom to which the substituent group is bonded may be ( S) configuration.

In compounds of formula (1)–(5) where ^R2 is a substituted _C1-6 alkanediyl, a substituted _C1-6 heteroalkanediyl, or a substituted _C5-6 arenediyl, the stereochemistry of the carbon atom to which the substituent group is bonded may be ( R) configuration.

In compounds of formula (1)-(5), R ² is selected from C _5-6 cycloalkanediyl, C _5-6 heterocycloalkanediyl, C _5-6 arendyl and C _5-6 heterocycloalkanediyl.

In compounds of formula (1)–(5), R ² may be cyclopenta-1,3-diene-diyl, substituted cyclopenta-1,3-diene-diyl, benzene-diyl or substituted benzene-diyl. For example, R ² can be 1,2-benzene-diyl or substituted 1,2-benzene-diyl.

In compounds of formula (1)–(5), R ³ can be selected from –O–C(O)–R ⁴ , –S–C(O)–R ⁴ , –NH–C(O)–R ⁴ , –O –C(O)–O–R ⁴ , –S–C(O)–O–R ⁴ , –NH–C(O)–O–R ⁴ , –C(O)–O–R ⁴ , –C (O)–S–R ⁴ , –C(O)–NH–R ⁴ , –O–C(O)–O–R ⁴ , –O–C(O)–S–R ⁴ , –O–C (O)–NH– ^R4 , –S–S– ^R4 , –S– ^R4 , –NH– ^R4 , –CH( _–NH2 )(– ^R4 ); where R ⁴ is determined as for formula (1), or each R ⁴ is selected from hydrogen and C _1–8 alkyl.

In compounds of formula (1)–(5), R ³ can be selected from –O–C(O)–R ⁴ , –C(O)–O–R ⁴ , –S–C(O)–R ⁴ , –C (O)–S–R ⁴ , –S–S–R ⁴ , –NH–R ⁴ and –CH(–NH ₂ )(–R ⁴ ); where R ⁴ is determined as for formula (1), or each R ⁴ is selected from hydrogen and C _1–8 alkyl.

In compounds of formula (1)–(5), R ³ is –C(O)–O–R ⁴ ); where R ⁴ is determined as for formula (1), or each R ⁴ is selected from hydrogen and C _1–8 alkyl.

In compounds of formula (1)–(5), R ⁴ can be selected from hydrogen, C _1–3 alkyl, C _5–6 cycloalkyl, C _5–6 heterocycloalkyl, C _5–6 aryl, substituted C _1–3 alkyl, substituted C _5–6 cycloalkyl, _C5–6 substituted heterocycloalkyl and _C5–6 substituted aryl.

In compounds of formula (1)–(5), R ⁴ can be selected from methyl, ethyl, phenyl and benzyl.

In compounds of formula (1)–(5), R ⁴ can be selected from hydrogen and C _1–8 alkyl.

In compounds of formula (1)–(5), R ⁴ can be selected from C _1–8 alkyl, C _1–8 heteroalkyl, C _7–9 arylalkyl, C _5–7 heterocycloalkyl, substituted C _1–8 alkyl, substituted C _{1– 8} heteroalkyl, substituted C _7–9 arylalkyl and substituted C _5–7 heterocycloalkyl.

In compounds of formula (1)-(5), R ⁴ can be selected from C _1-8 alkyl, C _1-8 heteroalkyl, C _7-9 arylalkyl and C _5-7 heterocycloalkyl.

In compounds of formula (1)–(5), R ⁴ can be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl isobutyl, tert-butyl, 2-methoxyethyl, methylbenzene, oxetane-3-oxy- yl, cyclopentyl, cyclohexyl and 2-pyrrolidinyl.

In compounds of formula (1)–(5) R ³ can be –C(O)–O–R ⁴ ; and R ⁴ can be selected from C _1-8 alkyl, C _1-8 heteroalkyl, C _5-7 cycloalkyl, C _5-7 heterocycloalkyl, C ₆ aryl, C _7-9 arylalkyl, substituted C _1-8 alkyl, substituted C _{1 –8} heteroalkyl, substituted C _5–6 cycloalkyl, substituted C _5–6 heterocycloalkyl, substituted C ₆ aryl and C _7–9 arylalkyl,

In compounds of formula (1)–(5) R ³ can be –C(O)–O–R ⁴ ; and R ⁴ can be selected from C _1-8 alkyl, C _1-8 heteroalkyl, C _7-9 arylalkyl, C _5-7 heterocycloalkyl, substituted C _1-8 alkyl, substituted C _1-8 heteroalkyl, substituted C _7-9 arylalkyl and substituted C _5–7 heterocycloalkyl.

In compounds of formula (1)–(5) R ³ can be –C(O)–O–R ⁴ ; and R ⁴ can be selected from C _1-8 alkyl, C _1-8 heteroalkyl, C _7-9 arylalkyl and C _5-7 heterocycloalkyl.

In compounds of formula (1)–(5), R ³ can be selected from –O–C(O)–CH ₃ , –O–C(O)–CH ₂ –CH ₃ , –O–C(O)–phenyl, –O–C(O)–CH ₂ –phenyl, –S–C(O)–CH ₃ , –S–C(O)–CH ₂ –CH ₃ , –S–C(O)–phenyl, –S –C(O)–CH ₂ –phenyl, –NH–C(O)–CH ₃ , –NH–C(O)–CH ₂ –CH ₃ , –NH–C(O)–phenyl, –NH–C (O)–CH ₂ –phenyl, –O–C(O)–O–CH ₃ , –O–C(O)–O–CH ₂ –CH ₃ , –O–C(O)–O–phenyl, –O–C(O)–O–CH ₂ –phenyl, –S–C(O)–O–CH ₃ , –S–C(O)–O–CH ₂ –CH ₃ , –S–C(O )–O–phenyl, –S–C(O)–O–CH ₂ –phenyl, –NH–C(O)–O–CH ₃ , –NH–C(O)–O–CH ₂ –CH ₃ , –NH–C(O)–O–phenyl, –NH–C(O)–O–CH ₂ –phenyl, –C(O)–O–CH ₃ , –C(O)–O–CH ₂ –CH ₃ , –C(O)–O–phenyl, –C(O)–O–CH ₂ –phenyl, –C(O)–S–CH ₃ , –C(O)–S–CH ₂ –CH ₃ , –C(O)–S–phenyl, –C(O)–S–CH ₂ –phenyl, –C(O)–NH–CH ₃ , –C(O)–NH–CH ₂ –CH ₃ , –C (O)–NH–phenyl, –C(O)–NH–CH ₂ –phenyl, –O–C(O)–O–CH ₃ , –O–C(O)–O–CH ₂ –CH ₃ , –O–C(O)–O–phenyl, –O–C(O)–O–CH ₂ –phenyl, –O–C(O)–S–CH ₃ , –O–C(O)–S– CH ₂ –CH ₃ , –O–C(O)–S–phenyl, –O–C(O)–S–CH ₂ –phenyl, –O–C(O)–NH–CH ₃ , –O–C (O)–NH–CH ₂ –CH ₃ , –O–C(O)–NH–phenyl, –O–C(O)–NH–CH ₂ –phenyl, –S–SH, –S–S–CH ₃ , –S–S–CH ₂ –CH ₃ , –S–S–phenyl, –S–S–CH ₂ –phenyl, –SH, –S–CH ₃ , –S–CH ₂ –CH ₃ , –S –phenyl, –S–CH ₂ –phenyl, –NH ₂ , –NH–CH ₃ , –NH–CH ₂ –CH ₃ , –NH–phenyl, –NH–CH ₂ –phenyl, –CH(–NH ₂ ) (–CH ₃ ), –CH(–NH ₂ )(–CH ₂ –CH ₃ ), –CH(–NH ₂ )(–phenyl) and –CH(–NH ₂ )(–CH ₂ –phenyl).

In compounds of formula (1)–(5), R ³ can be selected from C _5–6 cycloalkyl, C _5–6 heterocycloalkyl, C _5–6 aryl, C _5–6 heteroaryl, substituted C _5–6 cycloalkyl, substituted C _{5– 6} heterocycloalkyl, substituted C _5–6 aryl and substituted C _5–6 heteroaryl containing at least one nucleophilic group. For example, R ³ may have the structure of formula (4a) or formula (4b):

(4a) (4b)

In compounds of formula (1)–(5), R ⁴ can be selected from C _1–3 alkyl, C _5–6 cycloalkyl, C _5–6 heterocycloalkyl, C _5–6 aryl, substituted C _1–3 alkyl, substituted C _{5– 6} cycloalkyl, substituted C _5–6 heterocycloalkyl and substituted C _5–6 aryl.

In compounds of formula (1)–(5), each R ¹ together with the carbon atom to which they are bonded forms a C _4–6 heterocycloalkyl ring containing two adjacent S atoms, or a substituted C _4–6 heterocycloalkyl ring containing at least one heteroatom selected from O and S, and a carbonyl (=O) substituent group bonded to a carbon atom adjacent to at least one heteroatom.

In compounds of formula (1)–(5) R ² can be any bond; R ³ may be C _1-3 alkyl; and each R ¹ together with the carbon atom to which they are bonded form a C _4-6 heterocycloalkyl ring containing two adjacent S atoms, or a substituted C _4-6 heterocycloalkyl ring containing at least one heteroatom selected from O and S, and =O substituent group bonded to the carbon atom adjacent to the heteroatom.

In compounds of formula (1)–(5), the pro-fragment –CH ₂ –C(R ¹ ) ₂ –R ³ –R ⁴ can have any of the following structures, where R ³ can be C _1-6 alkyl, such as C _{1– 4} alkyl such as methyl or ethyl:

In compounds of formula (1)–(5) R ² may have a single bond; R ³ may be C _1-3 alkyl; and each R ¹ together with the carbon atom to which they are bonded can form a C _4–6 heterocycloalkyl ring or a substituted C _4–6 heterocycloalkyl ring.

In compounds of formula (1)–(5) R ² may have a single bond; R ³ may be C _1-3 alkyl; and each R ¹ together with the carbon atom to which they are bonded may form a C _4-6 heterocycloalkyl ring containing two adjacent S atoms, or a substituted C _4-6 heterocycloalkyl ring containing at least one heteroatom selected from O and S , and a carbonyl (=O) substituent group bonded to the carbon atom adjacent to the heteroatom.

In compounds of formula (1)–(5) R ² may have a single bond; R ³ may be C _1-3 alkyl; and each R ¹ together with the carbon atom to which they are bonded can form a 1,2-dithiolane, a 1,2-dithane ring, a thiethan-2-one ring, a dihydrothiophen-2(3H)-one ring, a tetrahydro-2H- tipiran-2-one ring, oxetan-2-one ring, dihydrofuran-2(3H)-one ring or tetrahydro-2H-pyran-2-one ring.

In compounds of formula (1)–(5)

each R ¹ may be methyl;

R ² can be selected from single bond, methandiyl, ethanediyl, –CH(–OH)–, –CH(–O–C(O)–CH ₂ CH ₃ )– and 1,2-benzene-diyl; And

R ³ can be selected from –O–C(O)–R ⁴ , –C(O)–O–R ⁴ , –S–C(O)–R ⁴ , –C(O)–S–R ⁴ , – S–S–R ⁴ , –NHR ⁴ and –CH(–NH ₂ )(–R ⁴ ), where R ⁴ can be selected from hydrogen, methyl, ethyl, cyclopentyl, cyclohexyl, phenyl, benzyl and 2-pyrrolidinyl.

In compounds of formula (1)–(5)

each R ¹ and the geminal carbon to which they are bonded can form a C _3–6 cycloalkyl ring;

R ² can be selected from any bond, methandiyl, ethanediyl, –CH(–OH)–, –CH(–O–C(O)–CH ₂ CH ₃ )– and 1,2-benzene-diyl; And

R ³ can be selected from –O–C(O)–R ⁴ , –C(O)–O–R ⁴ , –S–C(O)–R ⁴ , –C(O)–S–R ⁴ , – S–S–R ⁴ , –NHR ⁴ and –CH(–NH ₂ )(–R ⁴ ), where R ⁴ can be selected from hydrogen, methyl, ethyl, cyclopentyl, cyclohexyl, phenyl, benzyl and 2-pyrrolidinyl.

In compounds of formula (1)–(5)

R ² can be any connection;

R ³ may be C _1-3 alkyl; And

each R ¹ , together with the carbon atom to which they are bonded, can form a 1,2-dithiolane, 1,2-dithane ring, thiethan-2-one ring, dihydrothiophen-2(3H)-one ring, tetrahydro-2H-tipyran –2-one ring, oxetan-2-one ring, dihydrofuran-2(3H)-one ring, or tetrahydro-2H-pyran-2-one ring.

In compounds of formula (1)–(5), each R ¹ may be methyl;

R ² can be selected from single bond, methandiyl, ethanediyl, –CH(–OH)–, –CH(–O–C(O)–CH ₂ CH ₃ )– and 1,2-benzene-diyl; And

R ³ can be selected from –O–C(O)–R ⁴ , –C(O)–O–R ⁴ , –S–C(O)–R ⁴ , –C(O)–S–R ⁴ , – S–S–R ⁴ , –NHR ⁴ and –CH(–NH ₂ )(–R ⁴ );

wherein R ⁴ can be selected from C _1–8 alkyl, C _1–8 heteroalkyl, C _7–9 arylalkyl and C _5–7 heterocycloalkyl.

In compounds of formula (1)–(5)

each R ¹ may be methyl;

R ² can be selected from single bond, methandiyl, ethanediyl, –CH(–OH)–, –CH(–O–C(O)–CH ₂ CH ₃ )– and 1,2-benzene-diyl; And

R ³ can be –C(O)–O–R ⁴ ;

wherein R ⁴ can be selected from C _1–8 alkyl, C _1–8 heteroalkyl, C _7–9 arylalkyl and C _5–7 heterocycloalkyl.

In compounds of formula (1)–(5)

each R ¹ may be methyl;

R ² can be selected from single bond, methandiyl, ethanediyl, –CH(–OH)–, –CH(–O–C(O)–CH ₂ CH ₃ )– and 1,2-benzene-diyl; And

R ³ can be selected from –O–C(O)–R ⁴ , –C(O)–O–R ⁴ , –S–C(O)–R ⁴ , –C(O)–S–R ⁴ , – S–S–R ⁴ , –NHR ⁴ and –CH(–NH ₂ )(–R ⁴ );

in this case, R ⁴ can be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl isobutyl, tert-butyl, 2-methoxyethyl, methylbenzene, oxetan-3-oxy-yl, cyclopentyl, cyclohexyl and 2- pyrrolidinyl.

In compounds of formula (1)–(5)

each R ¹ may be methyl;

R ² can be selected from single bond, methandiyl, ethanediyl, –CH(–OH)–, –CH(–O–C(O)–CH ₂ CH ₃ )– and 1,2-benzene-diyl; And

R ³ can be –C(O)–O–R ⁴ ;

in this case, R ⁴ can be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl isobutyl, tert-butyl, 2-methoxyethyl, methylbenzene, oxetan-3-oxy-yl, cyclopentyl, cyclohexyl and 2- pyrrolidinyl.

In compounds of formula (1)–(5)

each R ¹ may be methyl;

R ² may be a single bond; And

R ³ can be –C(O)–O–R ⁴ ;

wherein R ⁴ can be selected from C _1–10 alkyl, C _1–10 heteroalkyl, C _7–10 alkylarene and C _5–10 heteroalkylcycloalkyl.

In compounds of formula (1)–(5)

each R ¹ may be methyl;

R ² may be a single bond;

R ³ can be –C(O)–O–R ⁴ ;

wherein R ⁴ can be selected from C _1–10 alkyl, C _1–10 heteroalkyl, C _7–10 alkylarene and C _5–10 heteroalkylcycloalkyl;

R ⁵ , R ⁶ and R ⁷ can each be hydrogen; And

A represents a single bond.

In compounds of formula (1)–(5), A may be a single bond, and ^R5 , ^R6 , and ^R7 may each be hydrogen.

In compounds of formula (1)–(5) A there may be a single bond; each R ¹ can be independently C _1–3 alkyl; each R ² can be a single bond; and each of R ⁵ , R ⁶ and R ⁷ can be hydrogen;

In the compounds of formula (1), the compound may be selected from:

3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl benzoate ( 2);

ethyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( 3);

benzyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( 4);

4-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl benzoate ( 6);

4-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl propionate ( 7);

benzyl (4-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl ) adipata (8);

6–(4–(((((2S,5R)–2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)–3,3– dimethylbutoxy)-6-oxohexanoic acid (9);

methyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( 10);

isopropyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( eleven);

hexyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( 12);

heptyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( 13);

tert-butyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2- dimethylpropanoate (14);

2-methoxyethyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2- dimethylpropanoate (15);

oxetan-3-yl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2, 2-dimethylpropanoate (16);

ethyl 1-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclohexanecarboxylate (17 );

ethyl 1-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclopropanecarboxylate (18 );

ethyl 1-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclobutanecarboxylate (19 );

(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl 1H-imidazol-1-sulfonate (34);

ethyl 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate ( 35);

hexyl 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate ( 36);

heptyl 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate ( 37);

2-methoxyethyl 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4- dimethyl pentanoate (38);

5–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–2,2,4,4 –tetramethylpentyl propionate (39);

5–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–2,2,4,4 –tetramethylpentyl benzoate (40);

5–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–2,2,4,4 –tetramethylpentyl 2,6-dimethylbenzoate (41);

(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl ((3-methyl-2-oxotetrahydrofuran-3-yl)methyl) sulfate (42);

3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl pivalate ( 43);

3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl 3- chloro-2,6-dimethoxybenzoate (44);

4–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–2,2,3,3 –tetramethylbutyl 2,6-dimethylbenzoate (45);

4–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–2,2,3,3 –tetramethylbutyl benzoate (46);

4–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–2,2,3,3 –tetramethylbutyl propionate (47);

(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl ((3-methyl-2-oxotetrahydro-2H-pyran-3-yl)methyl) sulfate (48);

2–(3–(((((2S,5R)–2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)–2,2– dimethylpropyl)phenylacetate (49);

2–(3–(((((2S,5R)–2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)–2,2– dimethylpropyl)phenyl pivalate (50);

S–(4–(((((2S,5R)–2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)–3,3– dimethylbutyl)ethanethioate (51);

S–(5–(((((2S,5R)–2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)–4,4– dimethylpentyl)ethanethioate (52);

S–(3–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–2,2– dimethylpropyl) ethanethiate (53);

3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl 2, 6-dimethylbenzoate (54);

3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl adamantane- 1-carboxylate (55);

diethyl 2-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonate (56);

propyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( 57);

butyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( 58);

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1] octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (59);

4-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl pivalate (60 );

ethyl 2-(((((2S,5R)–2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylbutanoate (61);

4-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl 2, 6-dimethylbenzoate (62);

4–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–3,3–dimethylbutyl adamantane– 1-carboxylate (63);

4-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl 2, 6-dimethoxybenzoate (64);

5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentyl benzoate ( 65);

5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentyl 2, 6-dimethoxybenzoate (66);

5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentyl 2, 6-dimethylbenzoate (67);

5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentyl 2- methyl benzoate (68);

4–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–2,2,3,3 –tetramethylbutyl 3-chloro-2,6-dimethoxybenzoate (69);

2-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylpropane- 1,3-diyl dibenzoate (70);

2-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylpropane- 1,3-diyl diacetate (71);

5–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–2,2,4,4 –tetramethylpentyl 2,6-dimethoxybenzoate (72);

ethyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylbutanoate ( 73);

(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl ((3,5,5-trimethyl-2-oxotetrahydrofuran-3-yl)methyl) sulfate (74);

a pharmaceutically acceptable salt of any of the above; And

combinations of any of the above.

In the compounds of formula (1), the compound may be selected from:

ethyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( 3);

benzyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( 4);

methyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( 10);

isopropyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( eleven);

hexyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( 12);

heptyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( 13);

tert-butyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2- dimethylpropanoate (14);

2-methoxyethyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2- dimethylpropanoate (15);

oxetan-3-yl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2, 2-dimethylpropanoate (16);

ethyl 1-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclohexanecarboxylate (17 );

ethyl 1-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclopropanecarboxylate (18 );

ethyl 1-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclobutanecarboxylate (19 );

hexyl 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate ( 36);

heptyl 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate ( 37);

(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl ((3-methyl-2-oxotetrahydrofuran-3-yl)methyl) sulfate (42);

S–(3–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–2,2– dimethylpropyl) ethanethiate (53);

propyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( 57);

butyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( 58);

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1] octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (59);

a pharmaceutically acceptable salt of any of the above; And

combinations of any of the above.

In the compounds of formula (1), the compound may be selected from:

ethyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( 3);

benzyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( 4);

methyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( 10);

isopropyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( eleven);

hexyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( 12);

heptyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( 13);

tert-butyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2- dimethylpropanoate (14);

2-methoxyethyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2- dimethylpropanoate (15);

oxetan-3-yl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2, 2-dimethylpropanoate (16);

ethyl 1-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclohexanecarboxylate (17 );

ethyl 1-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclopropanecarboxylate (18 );

ethyl 1-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclobutanecarboxylate (19 );

a pharmaceutically acceptable salt of any of the above; And

combinations of any of the above.

In the compounds of formula (1), the compound may be selected from:

hexyl 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate ( 36);

heptyl 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate ( 37);

(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl ((3-methyl-2-oxotetrahydrofuran-3-yl)methyl) sulfate (42);

S–(3–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–2,2– dimethylpropyl) ethanethiate (53);

propyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( 57);

butyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( 58);

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1] octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (59);

a pharmaceutically acceptable salt of any of the above; And

combinations of any of the above.

In a compound of formula (2a)

each R ¹ can be independently selected from C _1-3 alkyl, or each R ¹ together with the geminal carbon atom to which they are bonded form a C _3-6 cycloalkyl ring, a substituted C _3-6 cycloalkyl ring, a C _3-6 heterocycloalkyl ring or a substituted C _3–6 heterocycloalkyl ring;

R ² may be a single bond;

R ³ can be –C(O)–O–R ⁴ ; And

R ⁴ can be selected from C _1-8 alkyl, C _1-8 heteroalkyl, C _7-9 arylalkyl, C _5-7 heterocycloalkyl, substituted C _1-8 alkyl, substituted C _1-8 heteroalkyl, substituted C _7-9 arylalkyl and substituted C _5–7 heterocycloalkyl.

In a compound of formula (2a)

each R ¹ can be independently selected from C _1-3 alkyl, or each R ¹ together with the carbon atom to which they are bonded form a C _3-6 cycloalkyl ring;

R ² can be selected from single bond, methane-diyl and ethane-diyl; And

R ³ can be selected from –C(O)–O–R ⁴ and –S–C(O)–R ⁴ , in which R ⁴ can be selected from C _1–10 alkyl, C _1–10 heteroalkyl, C _5–10 arylalkyl, _C3-6 heterocycloalkyl and substituted _C4-10 heterocycloalkylalkyl.

In a compound of formula (2a)

each R ¹ can be independently selected from C _1-3 alkyl, or each R ¹ together with the carbon atom to which they are bonded form a C _3-6 cycloalkyl ring;

R ² may be a single bond; And

^R3 may be –C(O)–O– ^R4 , where ^R4 may be selected from _C1-10 alkyl, _C1-10 heteroalkyl, _C5-10 arylalkyl, _C3-6 heterocycloalkyl and substituted _C4-10 heterocycloalkylalkyl.

In a compound of formula (2a)

each R ¹ can be independently selected from C _1-3 alkyl, or each R ¹ together with the carbon atom to which they are bonded form a C _3-6 cycloalkyl ring;

R ² can be –(CH ₂ ) ₂ –; And

R ³ may be –C(O)–O–R ⁴ in which R ⁴ may be selected from C _1–10 alkyl, C _1–10 heteroalkyl, C _5–10 arylalkyl, C _3–6 heterocycloalkyl and substituted C _{4– 10} heterocycloalkylalkyl.

In a compound of formula (2a)

each R ¹ can be selected from C _1-3 alkyl, or each R ¹ together with the carbon atom to which they are bonded form a C _3-6 cycloalkyl ring;

R ² can be –CH ₂ –; And

R ³ can be –S–C(O)–R ⁴ , in which R ⁴ can be selected from C _1–10 alkyl, C _1–10 heteroalkyl, C _5–10 arylalkyl, C _3–6 heterocycloalkyl substituted with C _{4– 10} heterocycloalkylalkyl.

In a compound of formula (2a)

each R ¹ together with the carbon atom to which they are bonded form a C _3–6 cycloalkyl ring, a C _3–6 heterocycloalkyl ring, a C _3–6 cycloalkyl ring, or a C _3–6 heterocycloalkyl ring;

R ² may be a single bond; And

R ³ may be C _1-3 alkyl.

In a compound of formula (2a)

each R ¹ can be independently selected from C _1-3 alkyl;

R ² can be selected from single bond and methandiyl; And

R ³ can be selected from –O–C(O)–R ⁴ and –C(O)–O–R ⁴ , in which R ⁴ can be selected from C _1–10 alkyl and substituted phenyl.

In a compound of formula (2a)

each R ¹ can be independently selected from C _1-3 alkyl;

R ² may be a single bond;

R ³ may be –CH=C(R ⁴ ) ₂ , where each R ⁴ may be –C(O)–O–R ⁸ , or each R ⁴ together with the carbon atom to which they are bonded form a substituted heterocyclohexyl ring; And

each R ⁸ can be C _1-4 alkyl.

In a compound of formula (2a)

each R ¹ can be independently selected from C _1-3 alkyl;

R ² can be selected from single bond and methandiyl; And

R ³ may be substituted phenyl, in which one or more substituents can be independently selected from –CH ₂ –O–C(O)–R ⁴ and –O–C(O)–R ⁴ , in which R ⁴ can be selected from C _1–10 alkyl and phenyl.

In a compound of formula (2a)

each R ¹ can be independently selected from C _1-3 alkyl;

R ² can be selected from –C(R ⁸ ) ₂ – and –CH ₂ –C(R ⁸ ) ₂ –, where each R ⁸ can be independently selected from C _1-3 alkyl; And

R ³ can be selected from –C(O)–O–R ⁴ and –O–C(O)–R ⁴ , in which R ⁴ can be selected from C _1–10 alkyl, C _1–10 heteroalkyl, substituted C _{1– 10} alkyl, substituted C _1–10 heteroalkyl and 4(yl-methyl)-5-methyl-1,3-dioxol-2-one.

In a compound of formula (2a)

each R ¹ together with the carbon atom to which they are bonded form a substituted C _5–6 heterocyclic ring;

R ² may be a single bond; And

R ³ may be C _1-3 alkyl.

The compound of formula (1) may be a compound of subgroup (1A) or a pharmaceutically acceptable salt thereof, wherein

(1)

R ⁵ , R ⁶ and R ⁷ can each be hydrogen;

Or maybe a single bond;

each R ¹ can be independently selected from C _1-3 alkyl, or each R ¹ together with the carbon atom to which they are bonded form a C _3-6 cycloalkyl ring;

R ² can be selected from single bond, methane-diyl and ethane-diyl; And

R ³ can be selected from –C(O)–O–R ⁴ and –S–C(O)–R ⁴ , in which R ⁴ can be selected from C _1–10 alkyl, C _1–10 heteroalkyl, C _5–10 arylalkyl, _C3-6 heterocycloalkyl and substituted _C4-10 heterocycloalkylalkyl.

In compounds of subgroup (1A), each R ¹ can be independently selected from C _1-3 alkyl.

In compounds of subgroup (1A), each R ^1, together with the carbon atom to which it is bonded, forms a C _3–6 cycloalkyl ring.

In compounds of subgroup (1A) R ² is a single bond.

In compounds of subgroup (1A) R ² can be methane-diyl.

In compounds of subgroup (1A) R ² can be ethane-diyl.

In compounds of subgroup (1A), R ³ can be –C(O)–O–R ⁴ .

In compounds of subgroup (1A), R ³ can be –S–C(O)–R ⁴ .

In compounds of subgroup (1A), R ⁴ can be C _1–10 alkyl.

In compounds of subgroup (1A), R ⁴ may be C _1–10 heteroalkyl.

In compounds of subgroup (1A), R ⁴ may be C _5–10 arylalkyl.

In compounds of subgroup (1A), R ⁴ may be C _3–6 heterocycloalkyl.

In compounds of subgroup (1A), R ⁴ may be substituted with C _4–10 heterocycloalkylalkyl.

The compound of formula (1) may be a compound of subgroup (1B) or a pharmaceutically acceptable salt thereof, wherein

(1)

R ⁵ , R ⁶ and R ⁷ can each be hydrogen;

Or maybe a single bond;

each R ¹ can be independently selected from C _1-3 alkyl, or each R ¹ together with the carbon atom to which they are bonded form a C _3-6 cycloalkyl ring;

R ² may be a single bond; And

^R3 may be –C(O)–O– ^R4 , where ^R4 may be selected from _C1-10 alkyl, _C1-10 heteroalkyl, _C5-10 arylalkyl, _C3-6 heterocycloalkyl and substituted _C4-10 heterocycloalkylalkyl.

In compounds of subgroup (1B), each R ¹ can be independently selected from C _1-3 alkyl.

In compounds of subgroup (1B), each R ^1, together with the carbon atom to which it is bonded, forms a C _3–6 cycloalkyl ring.

In compounds of subgroup (1B), R ⁴ can be selected from C _1–7 alkyl, C _1–10 heteroalkyl, in which one or more heteroatoms may be oxygen, –CH ₂ –C _4–6 cycloalkyl, –(CH ₂ ) ₂ – C _4–6 cycloalkyl, C _3–6 heterocycloalkyl, in which one or more heteroatoms may be oxygen, and –CH ₂ –C _3–6 substituted heterocycloalkyl and –(CH ₂ ) ₂ –C _3–6 substituted heterocycloalkyl.

In compounds of subgroup (1B), in a substituted C _3-6 heterocycloalkyl, one or more heteroatoms may be oxygen, and one or more substituents may be independently selected from C _1-3 alkyl and =O.

In compounds of subgroup (1B), each R ¹ may be methyl, or each R ¹ together with the carbon atom to which they are bonded form a cyclohexyl ring or a cyclopentyl ring.

In compounds of subgroup (1B), R ⁴ can be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, n-hexyl, n-heptyl, –CH ₂ –CH ₂ –O–CH ₃ , benzyl, 3-oxetanyl and methyl-5-methyl-1,3-dioxol-2-one.

In subgroup compounds (1B)

R ⁵ , R ⁶ and R ⁷ can each be hydrogen;

Or maybe a single bond;

each R ¹ may be methyl, or each R ¹ together with the carbon atom to which they are bonded form a cyclohexyl ring or a cyclopentyl ring;

R ² may be a single bond; And

R ³ can be –C(O)–O–R ⁴ , in which R ⁴ can be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, n-hexyl, n-heptyl, –CH ₂ –CH ₂ –O–CH ₃ , –CH ₂ –phenyl (benzyl), 3-oxetanyl and methyl-5-methyl-1,3-dioxol-2-one.

The compound of formula (1) may be a compound of subgroup (1C) or a pharmaceutically acceptable salt thereof, wherein

(1)

R ⁵ , R ⁶ and R ⁷ can each be hydrogen;

Or maybe a single bond;

each R ¹ can be independently selected from C _1-3 alkyl, or each R ¹ together with the carbon atom to which they are bonded form a C _3-6 cycloalkyl ring;

R ² can be –(CH ₂ ) ₂ –; And

R ³ may be –C(O)–O–R ⁴ in which R ⁴ may be selected from C _1–10 alkyl, C _1–10 heteroalkyl, C _5–10 arylalkyl, C _3–6 heterocycloalkyl and substituted C _{4– 10} heterocycloalkylalkyl.

In compounds of subgroup (1C), each R ¹ can be independently selected from C _1–3 alkyl.

In compounds of subgroup (1C), each ^R1 , together with the carbon atom to which it is bonded, forms a _C3–6 cycloalkyl ring.

In compounds of subgroup (1C), R ⁴ can be selected from C _1–7 alkyl, C _1–10 heteroalkyl, in which one or more heteroatoms may be oxygen, –CH ₂ –C _4–6 cycloalkyl, –(CH ₂ ) ₂ – C _4–6 cycloalkyl, C _3–6 heterocycloalkyl, in which one or more heteroatoms may be oxygen, –CH ₂ –C _3–6 substituted heterocycloalkyl and –(CH ₂ ) ₂ –C _3–6 substituted heterocycloalkyl.

In compounds of subgroup (1C) in a substituted C _3-6 heterocycloalkyl, one or more heteroatoms may be oxygen, and one or more substituents may be independently selected from C _1-3 alkyl and =O.

In compounds of subgroup (1C), R ⁴ can be C _1–10 alkyl.

In subgroup compounds (1C)

R ⁵ , R ⁶ and R ⁷ can each be hydrogen;

Or maybe a single bond;

each R ¹ may be methyl;

R ² can be –(CH ₂ ) ₂ –; And

R ³ can be –C(O)–O–R ⁴ , in which R ⁴ can be selected from n-hexyl and n-heptyl.

The compound of formula (1) may be a compound of subgroup (1D) or a pharmaceutically acceptable salt thereof, wherein

(1)

R ⁵ , R ⁶ and R ⁷ can each be hydrogen;

Or maybe a single bond;

each R ¹ can be selected from C _1-3 alkyl, or each R ¹ together with the carbon atom to which they are bonded form a C _3-6 cycloalkyl ring;

R ² can be –CH ₂ –; And

R ³ can be –S–C(O)–R ⁴ , in which R ⁴ can be selected from C _1–10 C _1–1 alkyl, C _1–10 heteroalkyl, C _5–10 arylalkyl, C _3–6 heterocycloalkyl, substituted C _4–10 heterocycloalkylalkyl.

In compounds of subgroup (1D), each R ¹ can be independently selected from C _1-3 alkyl.

In subgroup (1D) compounds, each ^R1, together with the carbon atom to which it is bonded, forms a _C3–6 cycloalkyl ring.

In compounds of subgroup (1D), R ⁴ can be selected from C _1–7 alkyl, C _1–10 heteroalkyl, in which one or more heteroatoms may be oxygen, –CH ₂ –C _4–6 cycloalkyl, –(CH ₂ ) ₂ – C _4–6 cycloalkyl, C _3–6 heterocycloalkyl, in which one or more heteroatoms may be oxygen, –CH ₂ –C _3–6 substituted heterocycloalkyl, –(CH ₂ ) ₂ –C _3–6 substituted heterocycloalkyl.

In compounds of subgroup (1D), in a substituted C _3-6 heterocycloalkyl, one or more heteroatoms may be oxygen, and one or more substituents may be independently selected from C _1-3 alkyl and =O.

In compounds of subgroup (1D), R ⁴ can be C _1–10 alkyl.

In subgroup connections (1D)

R ⁵ , R ⁶ and R ⁷ can each be hydrogen;

Or maybe a single bond;

each R ¹ may be methyl;

R ² can be –CH ₂ –; And

^R3 may be –S–C(O) ^–R4 , in which ^R4 may be methyl.

The compound of formula (1) may be a compound of subgroup (1E) or a pharmaceutically acceptable salt thereof, wherein

(1)

R ⁵ , R ⁶ and R ⁷ can each be hydrogen;

Or maybe a single bond;

each R ¹ together with the carbon atom to which they are bonded form a C _3–6 cycloalkyl ring, a C _3–6 heterocycloalkyl ring, a C _3–6 cycloalkyl ring, or a C _3–6 heterocycloalkyl ring;

R ² may be a single bond; And

R ³ may be C _1-3 alkyl.

In compounds of subgroup (1E), each R ¹ together with the carbon atom to which it is bonded forms a C _3–6 heterocycloalkyl ring or a C _3–6 heterocycloalkyl ring;

In compounds of subgroup (1E), one or more heteroatoms may be oxygen, and one or more substituents may be =O.

In subgroup compounds (1E)

each R ¹ together with the carbon atom to which they are bonded form a dihydrofuran–2(3H)–one ring;

R ² may be a single bond; And

R ³ may be methyl.

The compound of formula (1) may be a compound of subgroup (1F) or a pharmaceutically acceptable salt thereof, wherein

(1)

R ⁵ , R ⁶ and R ⁷ can each be hydrogen;

Or maybe a single bond;

each R ¹ can be independently selected from C _1-3 alkyl;

R ² can be selected from single bond and methandiyl; And

R ³ can be selected from –O–C(O)–R ⁴ and –C(O)–O–R ⁴ , in which R ⁴ can be selected from C _1–10 alkyl and substituted phenyl.

In compounds of subgroup (1F) R ² there may be a single bond.

In compounds of subgroup (1F), R ² may be methandiyl.

In compounds of subgroup (1F), R ³ can be –O–C(O)–R ⁴ .

In compounds of subgroup (1F), R ² may be methandiyl; and R ³ can be –O–C(O)–R ⁴ .

In compounds of subgroup (1F), R ³ can be –C(O)–O–R ⁴ .

In compounds of subgroup (1F) R ² may have a single bond; and R ³ can be –C(O)–O–R ⁴ .

In compounds of subgroup (1E) R ² may have a single bond; R ³ can be –C(O)–O–R ⁴ ; and R ⁴ may be C _1-3 alkyl.

In compounds of subgroup (1F), R ⁴ can be C _1–10 alkyl.

In compounds of subgroup (1F), R ⁴ can be C _1–4 alkyl.

In compounds of subgroup (1F), R ⁴ may be substituted phenyl.

In compounds of subgroup (1F), R ² may be methandiyl; R ³ can be –O–C(O)–R ⁴ ; and R ⁴ may be substituted phenyl.

In compounds of subgroup (1F), one or more substituents can be independently selected from halogen, C _1-3 alkyl and C _1-3 alkoxy.

In compounds of subgroup (1F), the substituted phenyl may be 2,6-substituted phenyl.

In compounds of subgroup (1F), each of the substituents can be selected from C _1–3 alkyl and C _1–3 alkoxy.

In compounds of subgroup (1F), the substituted phenyl may be 2,5,6-substituted phenyl.

In compounds of subgroup (1F), each of the substituents in positions 2 and 6 can be independently selected from C _1–3 alkyl and C _1–3 alkoxy; and the substituent at the 5th position may be halogen.

The compound of formula (1) may be a compound of subgroup (1G) or a pharmaceutically acceptable salt thereof, wherein

(1)

R ⁵ , R ⁶ and R ⁷ can each be hydrogen;

Or maybe a single bond;

each R ¹ can be independently selected from C _1-3 alkyl;

R ² may be a single bond; And

R ³ may be –CH=C(R ⁴ ) ₂ , where each R ⁴ may be –C(O)–O–R ⁸ , or each R ⁴ together with the carbon atom to which they are bonded form a substituted heterocyclohexyl ring; And

each R ⁸ can be C _1-4 alkyl.

In compounds of subgroup (1G), each ^R4 can be –C(O)–O– ^R8 .

In compounds of subgroup (1G), each ^R4 can be –C(O)–O– ^R8 , or each ^R4 together with the carbon atom to which they are bonded form a substituted heterocyclohexyl ring.

In compounds of subgroup (1G), one or more heteroatoms in the substituted heterocyclohexyl ring may be oxygen.

In compounds of subgroup (1G) on the substituted heterocyclohexyl ring, one or more substituents can be independently selected from C _1–3 alkyl and =O.

In compounds of subgroup (1G), the substituted heterocycloalkyl ring may be 2,2-dimethyl-5-yl-1,3-dioxane-4,6-dione.

The compound of formula (1) may be a compound of subgroup (1H) or a pharmaceutically acceptable salt thereof, wherein

(1)

R ⁵ , R ⁶ and R ⁷ can each be hydrogen;

Or maybe a single bond;

each R ¹ can be independently selected from C _1-3 alkyl;

R ² can be selected from single bond and methandiyl; And

R ³ may be substituted phenyl, in which one or more substituents can be independently selected from –CH ₂ –O–C(O)–R ⁴ and –O–C(O)–R ⁴ , in which R ⁴ can be selected from C _1–10 alkyl and phenyl.

In compounds of subgroup (1H) R ² there may be a single bond.

In compounds of subgroup (1H) R ² there may be 2-substituted phenyl.

In compounds of subgroup (1H), one or more substituents may be –CH ₂ –O–C(O)–R ⁴ .

In compounds of subgroup (1H), one or more substituents may be –O–C(O)–R ⁴ .

In compounds of subgroup (1H), R ⁴ can be C _1–10 alkyl.

In subgroup (1H) compounds, R ⁴ can be selected from methyl, ethyl, isopropyl, pivalolyl and phenyl.

The compound of formula (1) may be a compound of subgroup (1I) or a pharmaceutically acceptable salt thereof, wherein

(1)

R ⁵ , R ⁶ and R ⁷ can each be hydrogen;

Or maybe a single bond;

each R ¹ can be independently selected from C _1-3 alkyl;

R ² can be selected from –C(R ⁸ ) ₂ – and –CH ₂ –C(R ⁸ ) ₂ –, where each R ⁸ can be independently selected from C _1-3 alkyl; And

R ³ can be selected from –C(O)–O–R ⁴ and –O–C(O)–R ⁴ , in which R ⁴ can be selected from C _1–10 alkyl, C _1–10 heteroalkyl, substituted C _{1– 10} alkyl, substituted C _1–10 heteroalkyl and 4(yl-methyl)-5-methyl-1,3-dioxol-2-one.

In compounds of subgroup (1I), each R ¹ may be methyl.

In compounds of subgroup (1I) R ² can be –C(R ⁸ ) ₂ –.

In compounds of subgroup (1I) R ² can be –CH ₂ –C(R ⁸ ) ₂ –.

In compounds of subgroup (1I), each R ⁸ may be methyl.

In compounds of subgroup (1I), each R ¹ may be methyl; and each R ⁸ may be methyl.

In compounds of subgroup (1I), R ³ can be –C(O)–O–R ⁴ .

In compounds of subgroup (1I), R ³ can be –O–C(O)–R ⁴ .

The compound of formula (1) may be a compound of subgroup (1J) or a pharmaceutically acceptable salt thereof, wherein

(1)

R ⁵ , R ⁶ and R ⁷ can each be hydrogen;

Or maybe a single bond;

each R ¹ together with the carbon atom to which they are bonded form a substituted C _5–6 heterocyclic ring;

R ² may be a single bond; And

R ³ may be C _1-3 alkyl.

In compounds of subgroup (1J) in the substituted C _5–6 heterocyclic ring, one or more heteroatoms may be oxygen; and one or more substituents may be independently selected from C _1-3 alkyl and =O.

In compounds of subgroup (1J), each R ^1, together with the carbon atom to which it is bonded, forms a tetrahydro-2H-pyran-2-one ring.

In subgroup compounds (1J)

R ⁵ , R ⁶ and R ⁷ can each be hydrogen;

Or maybe a single bond;

each R ¹ can be independently selected from C _1-3 alkyl;

R ² can be selected from C _2-4 alkanediyl; And

R ³ may be substituted C _5-6 heterocycloalkyl, in which one or more heteroatoms may be independently selected from N and O; and one or more substituents may be independently selected from C _1-3 alkyl and =O.

In compounds of subgroup (1J), R ³ may have the structure of formula (6):

(6)

in which R ⁹ can be selected from hydrogen, C _1-6 alkyl, C _4-6 cycloalkyl, C _1-6 heteroalkyl, C _4-6 heterocycloalkyl, substituted C _1-6 alkyl, substituted C _4-6 cycloalkyl, substituted C _{1 –6} heteroalkyl and substituted C _4–6 heterocycloalkyl.

In subgroup (1J) compounds, R ⁹ can be selected from hydrogen and C _1-6 alkyl, such as C _1-4 alkyl, such as methyl or ethyl.

The compound of formula (4) may be a compound of subgroup (4A) or a pharmaceutically acceptable salt thereof, wherein

(4)

^R5 , ^R6 and R7 can each be hydrogen;

Or maybe a single bond;

each R ¹ can be independently selected from C _1-3 alkyl, or each R ¹ together with the carbon atom to which they are bonded form a C _3-6 cycloalkyl ring;

R ² may be a single bond; And

R ³ may be –C(O)–O–R ⁴ in which R ⁴ may be selected from C _1–10 alkyl, C _1–10 heteroalkyl, C _5–10 arylalkyl, C _3–6 heterocycloalkyl and substituted C _{4– 10} heterocycloalkylalkyl.

In compounds of subgroup (4A), each R ¹ can be independently selected from C _1-3 alkyl.

In compounds of subgroup (4A), each R ^1, together with the carbon atom to which it is bonded, forms a C _3–6 cycloalkyl ring.

In compounds of subgroup (4A), R ⁴ can be selected from C _1–7 alkyl, C _1–10 heteroalkyl, in which one or more heteroatoms may be oxygen, –CH ₂ –C _4–6 cycloalkyl, –(CH ₂ ) ₂ – C _4–6 cycloalkyl, C _3–6 heterocycloalkyl, in which one or more heteroatoms may be oxygen, –CH ₂ –C _3–6 substituted heterocycloalkyl and –(CH ₂ ) ₂ –C _3–6 substituted heterocycloalkyl.

In compounds of subgroup (4A) in a substituted C _3-6 heterocycloalkyl, one or more heteroatoms may be oxygen, and one or more substituents may be independently selected from C _1-3 alkyl and =O.

In compounds of subgroup (4A), each R ¹ may be methyl, or each R ¹ together with the carbon atom to which they are bonded form a cyclohexyl ring or a cyclopentyl ring.

In compounds of subgroup (4A), R ⁴ can be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, n-hexyl, n-heptyl, –CH ₂ –CH ₂ –O–CH ₃ , benzyl, 3-oxetanyl and methyl-5-methyl-1,3-dioxol-2-one.

In connections of subgroup (4A)

R ⁵ , R ⁶ and R ⁷ can each be hydrogen;

Or maybe a single bond;

R ² may be a single bond; And

R ³ may be –C(O)–O–R ⁴ in which R ⁴ may be C _1–10 alkyl.

The compound of formula (4) can be selected from:

ethyl 2,2-dimethyl-3-(((((2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy )sulfonyl)oxy)propanoate (20);

2-methoxyethyl 2,2-dimethyl-3-(((((2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl )oxy)sulfonyl)oxy)propanoate (21);

4–((2S,5R)–6–(((3–(hexyloxy)–2,2–dimethyl–3–oxopropoxy)sulfonyl)oxy)–7–oxo–1,6–diazabicyclo[3.2.1]octane –2-carboxamido)piperidine-1-ium 2,2,2-trifluoroacetate (22);

4–((2S,5R)–6–(((3–(heptyloxy)–2,2–dimethyl–3–oxopropoxy)sulfonyl)oxy)–7–oxo–1,6–diazabicyclo[3.2.1]octane –2-carboxamido)piperidine-1-ium 2,2,2-trifluoroacetate (23);

4–((2S,5R)–6–((((1–(ethoxycarbonyl)cyclohexyl)methoxy)sulfonyl)oxy)–7–oxo–1,6–diazabicyclo[3.2.1]octane–2–carboxamido)piperidine –1-ium 2,2,2-trifluoroacetate (24);

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2,2-dimethyl-3-(((((2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl )-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)propanoate (25);

a pharmaceutically acceptable salt of any of the above; And

combinations of any of the above.

The compound of formula (4) can be selected from:

ethyl 2,2-dimethyl-3-(((((2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy )sulfonyl)oxy)propanoate (20);

4–((2S,5R)–6–(((3–(hexyloxy)–2,2–dimethyl–3–oxopropoxy)sulfonyl)oxy)–7–oxo–1,6–diazabicyclo[3.2.1]octane –2-carboxamido)piperidine-1-ium 2,2,2-trifluoroacetate (22);

4–((2S,5R)–6–(((3–(heptyloxy)–2,2–dimethyl–3–oxopropoxy)sulfonyl)oxy)–7–oxo–1,6–diazabicyclo[3.2.1]octane –2-carboxamido)piperidine-1-ium 2,2,2-trifluoroacetate (23);

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2,2-dimethyl-3-(((((2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl )-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)propanoate (25);

a pharmaceutically acceptable salt of any of the above; And

combinations of any of the above.

The compound of formula (5) can be selected from:

ethyl 3–(((((2S,5R)–2–((2–aminoethoxy)carbamoyl)–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy) –2,2-dimethylpropanoate (27);

2-methoxyethyl 3-(((((2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl) oxy)-2,2-dimethylpropanoate (28);

TFA salts (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 3-(((((2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1 ,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (29);

TFA salts hexyl 3–(((((2S,5R)–2–((2-aminoethoxy)carbamoyl)–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl) hydroxy)-2,2-dimethylpropanoate (30);

TFA salts heptyl 3–(((((2S,5R)–2–((2-aminoethoxy)carbamoyl)–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl) oxy)-2,2-dimethylpropanoate (31);

TFA salts ethyl-1-(((((2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy) sulfonyl)oxy)methyl)cyclohexanecarboxylate (32);

a pharmaceutically acceptable salt of any of the above; And

combinations of any of the above.

The compound of formula (1)-(5) may be a solvate, a pharmaceutically acceptable salt, or a combination thereof.

In the compounds of formula (1) to (5), the pharmaceutically acceptable salt may be a hydrochloride salt.

In the compounds of formula (1) to (5), the pharmaceutically acceptable salt may be a dihydrochloride salt.

The compound of formula (1)-(5) may be a pharmaceutically acceptable salt of the compound of formula (1)-(5), a hydrate thereof, or a solvate of any of the above.

The compound described herein can be synthesized using methods known in the art. The synthesis of the various diazabicyclo[3.2.1]octane structures described herein is conventional and well known to those skilled in the art (Tandiparthi et al. PCT International Application Publication No. WO 2016/116788; Lampilas et al. US Patent No. 7112592; King et al., ACS Chemical Biology 2016;11, 864; and Bush et al., Cold Spring Harb Perspect Med 2016;6:a025247). The formation of sulfuric acid esters is also well known in the art (Simpson et al. J. Am. Chem. Soc. 2006, 128, 1605; Li et al. US Application Publication No. 2009/0099253; Jandeleit et al. PCT International Application Publication No. WO 2009/033054; Jandeleit et al. PCT International Application Publication No. WO 2009/033079; and Jandeleit et al. PCT International Application Publication No. WO 2011/150380).

Sulfuric acid monoester analogues of sulfate-containing compounds can be prepared by reacting the hydroxyl-substituted sulfate-containing compound with chlorosulfonic acid monoesters to form the corresponding sulfuric acid monoester analogue. The methods can be used in the preparation of prodrugs of sulfate-containing pharmaceutical compounds.

Prodrugs are derivatized forms of drugs that, after administration, are converted or metabolized into the active form of the parent drug in vivo. Prodrugs are used to modify one or more aspects of the pharmacokinetics of a drug so as to enhance the therapeutic efficacy of the parent drug. For example, prodrugs are often used to increase the oral bioavailability of a drug. For therapeutic effectiveness, drugs exhibiting poor oral bioavailability may require frequent dosing, large administered doses, or may require administration other than the oral route, such as intravenously. In particular, many drugs with sulfate groups exhibit poor oral bioavailability.

Intramolecular cyclization prodrug strategies have been used to alter drug pharmacokinetics. Intramolecular cyclization-release prodrug strategies have been applied to drugs containing sulfonic acid functional groups. For example, US Pat. No. 7,994,218 and US Pat. No. 8,168,617 disclose, for example, prodrugs containing a substituted neopentyl sulfonic acid ester derivative in which the neopentyl group is removed in vivo by masking the nucleophilic heteroatom associated with the substituted neopentyl moiety, followed by intramolecular cyclization to produce the parent drug in the form of a sulfonic acid or a salt of a sulfonic acid. In such prodrugs, the nucleophilic heteroatom may be nitrogen or oxygen, and the nucleophilic nitrogen or oxygen may be masked by an amine or alcohol protecting group, respectively, which can be deprotected in vivo.

Sulfuric acid monoester analogs of a sulfate-containing compound can be prepared by reacting a hydroxyl-substituted sulfate-containing compound analog with a chlorosulfonic acid monoester under alkaline conditions to form the corresponding sulfuric acid monoester analog. Chlorosulfonic acid monoesters can be prepared by reacting sulfuryl chloride with an alcohol having the desired profragment. Neopentyl alcohols having neopentyl pro-moieties can be prepared using standard synthetic methods, such as those described in US Pat. Nos. 7,994,218 and 8,168,617.

For example, the avibactam monosulfuric acid ester analogs provided in this disclosure can be synthesized by reacting (2S,5R)–6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide with monoesters of chlorosulfonic acid having the desired profragment to form the corresponding (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl monoesters of sulfuric acid.

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide can be prepared by hydrogenation of (2S,5R)-6-(benzyloxy)-7-oxo-1 ,6-diazabicyclo[3.2.1]octane-2-carboxamide using methods described, for example, in US patent No. 8772490; 9035062; and 9284273.

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide can be reacted with chlorosulfonic acid monoesters in the presence of a base to form the corresponding avibactam sulfuric acid monoester analog . Suitable methods are disclosed, for example, in J. Am. Chem. Soc. 2006, 128, 1605–1610.

Similar methods can be adapted to produce analogues of the sulfuric acid monoesters of relebactam and nacubactam. For example, the tert-butyl carboxylate-protected 6-hydroxyl analog of relebactam can be reacted with chlorosulfonic acid monoesters in the presence of a base to form the corresponding tert-butyl carboxylate-protected sulfuric acid monoester analog of relebactam. The compound can then be deprotected in the presence of an acid to yield the relebactam sulfuric acid monoester analogue. To prepare the nacubactam sulfuric acid monoester analogues, methods similar to those used to prepare the relebactam sulfuric acid monoester analogues can be used.

For example, a sulfuric acid monoester analogue of formula (80a) can be synthesized by reacting cyclic hydroxamic acid of formula (80b) with a chlorosulfonate monoester of formula (80c) under basic conditions:

(80a) (80b)

(80c)

Where

R is selected from C _1-8 alkyl, C _1-8 heteroalkyl, C _5-8 cycloalkyl, C _5-8 heterocycloalkyl, C _5-10 cycloalkylalkyl, C _5-10 heterocycloalkylalkyl, C _6-8 aryl, C _5-8 heteroaryl , C _7–10 arylalkyl, C _5–10 heteroarylalkyl, substituted C _1–8 alkyl, substituted C _1–8 heteroalkyl, substituted C _5–8 cycloalkyl, substituted C _5–8 heterocycloalkyl, substituted C _5–10 cycloalkylalkyl, substituted C _5-10 heterocycloalkylalkyl, substituted _C6-8 aryl, substituted _C5-8 heteroaryl, substituted _C7-10 arylalkyl and substituted _C5-10 heteroarylalkyl;

R ⁵ is selected from hydrogen, C _1-6 alkyl, C _5-8 cycloalkyl, C _6-12 cycloalkylalkyl, C _2-6 heteroalkyl, C _5-8 heterocycloalkyl, C _6-12 heterocycloalkylalkyl, substituted C _1-6 alkyl, substituted _C5-8 cycloalkyl, substituted _C6-12 cycloalkylalkyl, substituted _C2-6 heteroalkyl, substituted _C5-8 heterocycloalkyl and substituted _C6-12 heterocycloalkylalkyl;

R ⁶ is selected from hydrogen, C _1-6 alkyl, C _5-8 cycloalkyl, C _6-12 cycloalkylalkyl, C _2-6 heteroalkyl, C _5-8 heterocycloalkyl, C _6-12 heterocycloalkylalkyl, substituted C _1-6 alkyl, substituted _C5-8 cycloalkyl, substituted _C6-12 cycloalkylalkyl, substituted _C2-6 heteroalkyl, substituted _C5-8 heterocycloalkyl and substituted _C6-12 heterocycloalkylalkyl; And

A represents a single bond (–) and R ⁷ represents hydrogen, or A represents a double bond (=) and R ⁷ represents C _1–3 alkyl.

The chlorosulfonic acid monoesters may contain a neopentyl chlorosulfonic acid ester, such as a neopentyl chlorosulfonic acid ester of formula (81):

(81)

in which

each R ¹ is independently selected from C _1–6 alkyl, or each R ¹ and the geminal carbon atom to which they are bonded forms a C _3–6 cycloalkyl ring, a C _3–6 heterocycloalkyl ring, a substituted C _3–6 cycloalkyl ring, or a substituted C _3–6 heterocycloalkyl ring;

R ² is selected from single bond, C _1-6 alkanediyl, C _1-6 heteroalkanediyl, C _5-6 cycloalkanediyl, C _5-6 heterocycloalkanediyl, C ₆ arenediyl, C _5-6 heteroarendiyl, substituted C _1-6 alkanediyl, substituted C _1-6 heteroalkanediyl, substituted _C5-6 cycloalkanediyl, substituted _C5-6 heterocycloalkanediyl, substituted _C6 arenediyl and substituted _C5-6 heteroarendiyl; And

R ³ is selected from C _1–6 alkyl, –O–C(O)–R ⁴ , –S–C(O)–R ⁴ , –NH–C(O)–R ⁴ , –O–C(O) –O–R ⁴ , –S–C(O)–O–R ⁴ , –NH–C(O)–O–R ⁴ , –C(O)–O–R ⁴ , –C(O)–S –R ⁴ , –C(O)–NH–R ⁴ , –O–C(O)–O–R ⁴ , –O–C(O)–S–R ⁴ , –O–C(O)–NH –R ⁴ , –S–S–R ⁴ , –S–R ⁴ , –NH–R ⁴ , –CH(–NH ₂ )(–R ⁴ ), C _5–6 heterocycloalkyl, C _5–6 heteroaryl, substituted C _5–6 cycloalkyl, substituted C _5–6 heterocycloalkyl, substituted C _5–6 aryl, substituted C _5–6 heteroaryl and –CH=C(R ⁴ ) ₂ , in which

R ⁴ is selected from hydrogen, C _1–8 alkyl, C _1–8 heteroalkyl, C _5–8 cycloalkyl, C _5–8 heterocycloalkyl, C _5–10 cycloalkylalkyl, C _5–10 heterocycloalkylalkyl, C _6–8 aryl, C _{5 –8} heteroaryl, C _7–10 arylalkyl, C _5–10 heteroarylalkyl, substituted C _1–8 alkyl, substituted C _1–8 heteroalkyl, substituted C _5–8 cycloalkyl, substituted C _5–8 heterocycloalkyl, substituted C _5–10 cycloalkylalkyl , substituted C _5–10 heterocycloalkylalkyl, substituted C _6–8 aryl, substituted C _5–8 heteroaryl, substituted C _7–10 arylalkyl and substituted C _5–10 heteroarylalkyl.

Chlorosulfonic acid monoesters can be synthesized by reacting an alcohol such as neopentyl alcohol with sulfuryl chloride.

The method can be used to couple any suitable chlorosulfonic acid ester with cyclic hydroxamic acid, such as, for example, a chlorosulfonic acid ester of formula (82) and cyclic hydroxamic acid of formula (83) to form the corresponding monosulfuric acid ester analogue of formula (84):

(82) (83) (84)

Where

R can be selected from C _1-8 alkyl, C _1-8 heteroalkyl, C _5-8 cycloalkyl, C _5-8 heterocycloalkyl, C _5-10 cycloalkylalkyl, C _5-10 heterocycloalkylalkyl, C _6-8 aryl, C _5-8 heteroaryl, C _7–10 arylalkyl, C _5–10 heteroarylalkyl, substituted C _1–8 alkyl, substituted C _1–8 heteroalkyl, substituted C _5–8 cycloalkyl, substituted C _5–8 heterocycloalkyl, substituted C _5–10 cycloalkylalkyl, substituted _C5-10 heterocycloalkylalkyl, substituted _C6-8 aryl, substituted _C5-8 heteroaryl, substituted _C7-10 arylalkyl and substituted _C5-10 heteroarylalkyl;

n can be an integer from 1 to 6;

each A can be independently selected from –(CH ₂ )–, –(CHR)–, –(CR ₂ )–, –NH–, –NR–, O and S, where R is independently selected from hydrogen, C _1-8 alkyl , C _1–8 heteroalkyl, C _5–8 cycloalkyl, C _5–8 heterocycloalkyl, C _5–10 cycloalkylalkyl, C _5–10 heterocycloalkylalkyl, C _6–8 aryl, C _5–8 heteroaryl, C _7–10 arylalkyl, C _5–10 heteroarylalkyl, substituted C _1–8 alkyl, substituted C _1–8 heteroalkyl, substituted C _5–8 cycloalkyl, substituted C _5–8 heterocycloalkyl, substituted C _5–10 cycloalkylalkyl, substituted C _5–10 heterocycloalkylalkyl, substituted C _{6 –8} aryl, substituted C _5–8 heteroaryl, substituted C _7–10 arylalkyl and substituted C _5–10 heteroarylalkyl; or one A is linked to another A through a –L– group, where L is selected from C _1-8 alkyl, C _1-8 heteroalkyl, substituted C _1-8 alkyl and substituted C _1-8 heteroalkyl.

R may further comprise any of the profragments disclosed herein, such as a profragment having the structure:

where R ¹ , R ² and R ³ correspond to the definition of formula (1).

The compositions provided herein contain therapeutically effective amounts of one or more compounds provided herein that are useful for preventing, treating, or ameliorating one or more symptoms of the diseases or disorders described herein, and a base. Vehicles suitable for administration of the compounds provided herein include any such carriers known to those skilled in the art suitable for the particular mode of administration. In addition, the compounds may be formulated as the sole active ingredient in a composition or may be combined with other active ingredients.

The compositions contain one or more of the compounds provided herein. In some embodiments, the compounds are formulated into suitable formulations, such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs, for oral administration or in sterile solutions or suspensions for parenteral administration, and topical administration, transdermal administration and oral inhalation via nebulizers, metered dose inhalers and powder inhalers. In some embodiments, the compounds described above are formulated using technologies and techniques well known in the art (See, for example, Ansel, Introduction to Pharmaceutical Dosage Forms, Seventh Edition (1999)).

In the compositions, effective concentrations of one or more compounds or derivatives thereof are mixed with a suitable base. The compounds can be derivatized as the corresponding salts, esters, enol esters or esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, solvates, ion pairs, hydrates or prodrugs before obtaining the finished forms as described above. The concentrations of the compounds in the compositions are effective for delivery when administered in an amount that treats, leads to the prevention or improvement of one or more symptoms of the diseases or disorders described herein. In some embodiments, the compositions are formulated for single dosage administration. To formulate the composition, a weight fraction of the compound is dissolved, suspended, dispersed or otherwise mixed in a selected vehicle at an effective concentration so as to alleviate, prevent the condition being treated, or improve one or more symptoms.

The active compound is included in the base in an amount sufficient to provide a therapeutically beneficial effect in the absence of undesirable side effects on the patient receiving treatment. The therapeutically effective concentration can be empirically predicted by testing compounds in in vitro and in vivo systems well known to those skilled in the art, and then extrapolate dosages for humans from them. Doses for humans are then typically fine-tuned in clinical trials and titrated to response.

The concentration of the active compound in the composition will depend on the rate of absorption, inactivation and elimination of the active compound, the physicochemical characteristics of the compound, the dosage regimen and amount administered, as well as other factors known to those skilled in the art. For example, the amount delivered is sufficient to reduce one or more symptoms of diseases or disorders that are described herein.

In cases where compounds exhibit insufficient solubility, methods for solubilizing compounds can be used, such as the use of liposomes, prodrugs, complexation/chelation, nanoparticles or emulsions or tertiary templates. Such methods are known to those skilled in the art and include, but are not limited to, the use of co-solvents such as dimethyl sulfoxide (DMSO), the use of surfactants or surface modifiers such as TWEEN®, complexing agents such as cyclodextrin or enhanced ionization dissolution ( i.e. dissolution in aqueous sodium bicarbonate). Derivatives of the compounds, such as prodrugs of the compounds, can also be used in formulating effective compositions.

When the compound(s) are mixed or added, the resulting mixture may be a solution, suspension, emulsion, or the like. The form of the resulting mixture depends on a number of factors, including the intended mode of administration and the solubility of the compound in the chosen vehicle. An effective concentration is sufficient to reduce the symptoms of the disease, disorder or condition being treated, and can be determined empirically.

The compositions are intended for administration to humans and animals in the appropriate dosage forms shown, such as dry powder inhalers (DPIs), metered dose inhalers (pMDIs), nebulizers, tablets, capsules, pills, sublingual strips/biodegradable strips, tablets or capsules, powders, granules, lozenges, lotions, ointments, suppositories, quick melts, transdermal patches or other devices/preparations for transdermal use, sterile parenteral solutions or suspensions and oral solutions or suspensions, and oil-in-water emulsions containing suitable amounts of the compounds or derivatives thereof. In some embodiments, therapeutically active compounds and derivatives thereof are formulated and administered in single dosage forms or multiple dosage forms. As used herein, unit dosage forms refer to physically discrete units suitable for use in humans and animals and individually packaged as is known in the art. Each unit dose contains a predetermined amount of a therapeutically active compound sufficient to produce the desired therapeutic effect, in combination with the required vehicle. Examples of unit dosage forms include ampoules and syringes and individually packaged tablets or capsules. Unit dosage forms can be administered in fractions or multiples thereof. A multiple dosage form is a plurality of identical unit dosage forms packaged in a single container for administration as separate unit dosage forms. Examples of multiple dosage forms include vials, tablet or capsule bottles, or pint or gallon bottles. Therefore, a multiple dosage form is a plurality of unit doses that are not separated within the package.

Liquid compositions can be prepared, for example, by dissolving, dispersing or otherwise mixing the active compound as defined above and optional excipients in a base such as, for example, water, saline, aqueous dextrose, glycerin, glycols, ethanol and the like, thereby forming a solution or suspension, colloidal dispersion, emulsion or liposomal formulation. If desired, the administration composition may also contain minor amounts of non-toxic auxiliary agents such as wetting agents, emulsifying agents, solubilizing agents, pH buffers and the like, for example sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, sodium triethanolamine acetate, triethanolamine oleate and other similar agents.

Current methods for preparing such dosage forms are known or will be apparent to those skilled in the art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th Edition, 1975 or later editions.

Dosage forms or compositions can be prepared containing the active ingredient in the range from 0.005% to 100% with the remainder consisting of a base or carrier. Methods for preparing these compositions are known to those skilled in the art. Contemplated compositions may contain 0.001%-100% of the active ingredient, in one embodiment 0.1-95%, in another embodiment 0.4-10%.

The compositions may be lactose-free compositions containing auxiliaries that are well known in the art and are listed, for example, in United States Pharmacopeia (USP) 25 NF ₂ 0 (2002). Typically, lactose-free compositions contain active ingredients, a binder/excipient and a lubricant in compatible amounts. Specific lactose-free dosage forms contain the active ingredients microcrystalline cellulose, pregelatinized starch and magnesium stearate.

In addition, anhydrous compositions and dosage forms containing active ingredients are provided, since water may promote the degradation of some compounds. For example, the addition of water (e.g., 5%) is widely accepted as a means of simulating long-term storage to determine characteristics such as shelf life or stability of finished forms over time. See, for example, Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379–80. In fact, water and heat speed up the decomposition of some compounds. Thus, the effect of water on the finished mold can be significant since moisture and/or humidity is typically present during the manufacture, processing, packaging, storage, transportation and use of finished molds.

The anhydrous compositions and dosage forms provided herein can be prepared using anhydrous or low-moisture ingredients and low-moisture or low-humidity conditions.

The anhydrous composition should be prepared and stored in such a manner as to maintain its anhydrous nature. Accordingly, anhydrous compositions are typically packaged using materials known to prevent exposure to water so that they can be included in suitable formulation kits. Examples of suitable packaging include, but are not limited to, sealed foil, plastics, unit dose containers (eg, vials), blister packs, and tape packs.

Oral dosage forms are either solid, gel or liquid. Solid dosage forms are tablets, capsules, granules and bulk powders. Types of oral tablets include compressed chewable lozenges and tablets, which may be enteric-coated, sugar-coated, or film-coated. Capsules may be hard or soft gelatin capsules, while granules and powders may be provided in non-effervescent or effervescent form in combination with other ingredients known to those skilled in the art.

The finished forms may be solid dosage forms, such as, for example, capsules or tablets. Tablets, pills, capsules, lozenges and the like may contain one or more of the following ingredients or compounds of a similar nature: a binder; lubricant; diluent; glidant; disintegrant; coloring agent; sweetener; flavoring agent; wetting agent; enteric coating; a film coating agent; and a release modifying agent. Examples of binders include microcrystalline cellulose, methylparaben, polyalkylene oxides, gum tragacanth, glucose solution, acacia mucilage extract, gelatin solution, molasses, polyvinylpyrrolidine, povidone, crospovidones, sucrose and starch and starch derivatives. Lubricants include talc, starch, magnesium/calcium stearate, lycopodium and stearic acid. Diluents include, for example, lactose, sucrose, trehalose, lysine, leucine, lecithin, starch, kaolin, salt, mannitol and dicalcium phosphate. Glidants include, but are not limited to, colloidal silica. Disintegrants include croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose. Colorants include, for example, any of the approved certified water-soluble dyes FD and C, mixtures thereof; and water-insoluble FD and C dyes suspended in alumina hydrate, and improved coloring or anti-counterfeiting coloring/opalescent additives known to those skilled in the art. Sweeteners include sucrose, lactose, mannitol and artificial sweeteners such as saccharin and any number of spray-dried flavors. Flavoring agents include natural flavors extracted from plants, such as fruits, and synthetic mixtures of compounds that produce a pleasant sensation or mask an unpleasant taste, such as, but not limited to, peppermint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Enteric coatings include fatty acids, greases, waxes, shellac, ammoniated shellac and cellulose acetate phthalates. Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Release modifiers include polymers such as the Eudragit® series and cellulose esters.

The compound or a derivative thereof may be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition may be formulated as an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition may also be formulated in combination with an antacid or other such ingredient.

When the unit dosage form is a capsule, it may contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, unit dosage forms may contain various other materials that modify the physical form of the unit dose, such as coatings of sugar and other enteric agents. The compounds may also be administered as a component of an elixir, suspension, syrup, wafer, sprinkle, chewing gum, or the like. In addition to the active compounds, syrup may contain sucrose as a sweetener and certain preservatives, dyes, coloring agents and flavorings.

The active materials can also be mixed with other active materials that do not impair the desired effect, or with materials that are additive to the desired effect, such as antacids, H ₂ blockers and diuretics. The active ingredient is a compound or derivative thereof that is described herein. Higher concentrations of up to about 98% by weight of active ingredient may be included.

In all embodiments, tablet and capsule formulations may be coated as known to those skilled in the art to modify or maintain dissolution of the active ingredient. For example, they can be coated with conventional enteric coatings such as phenyl salicylate, waxes and cellulose acetate phthalate.

Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules. Aqueous solutions include, for example, elixirs and syrups. Emulsions are oil in water or water in oil.

Elixirs are clear, sweetened, hydroalcoholic preparations. Bases used in elixirs include solvents. Syrups are concentrated aqueous solutions of sugar, such as sucrose, and may contain a preservative. An emulsion is a two-phase system in which one liquid is dispersed in the form of small beads in another liquid. The carriers used in emulsions are non-aqueous liquids, emulsifying agents and preservatives. Suspensions use suspending agents and preservatives. Suitable substances used in non-effervescent granules to be reconstituted into a liquid oral dosage form include diluents, sweeteners and wetting agents. Suitable substances used in effervescent granules to be reconstituted into a liquid oral dosage form include organic acids and a source of carbon dioxide. Coloring and flavoring agents are used in all of the above dosage forms.

Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examples of preservatives include glycerin, methyl and propylparaben, benzoic acid, sodium benzoate and alcohol. Examples of non-aqueous liquids used in emulsions include mineral oil and cottonseed oil. Examples of emulsifying agents include gelatin, acacia, tragacanth, bentonite and surfactants such as polyoxyethylene sorbitan monooleate. Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, veegum and acacia. Sweeteners include sucrose, syrups, glycerin and artificial sweeteners such as saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Organic acids include citric and tartaric acids. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate. Colorants include any of the approved certified water soluble dyes FD and C and mixtures thereof. Flavoring agents include natural flavors extracted from plants such as fruits and synthetic mixtures of compounds that produce a pleasant taste sensation.

For a solid dosage form, the solution or suspension, for example, in propylene carbonate, vegetable oils, or triglycerides, is in some embodiments enclosed in a gelatin capsule. Such solutions, as well as their preparation and encapsulation, are disclosed in US Pat. Nos. 4,328,245; 4409239; and 4410545. For a liquid dosage form, a solution, for example, in polyethylene glycol, can be diluted with a sufficient amount of liquid base, such as water, so that it can be easily measured for administration.

Alternatively, liquid or semi-solid oral formulations can be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (eg, propylene carbonate) and other such vehicles and encapsulating these solutions or suspensions in hard or soft gelatin capsules shells. Other formulations used include the formulations set forth in US Patent Nos. RE28819 and 4358603. In brief, such formulations include, but are not limited to, formulations that contain a compound provided herein, a dialkylated mono- or polyalkylene glycol, including but not limited to limitations, 1,2-dimethoxyethane, diglyme, triglyme, tetraglyme, polyethylene glycol dimethyl ether 350, polyethylene glycol dimethyl ether 550, polyethylene glycol dimethyl ether 750, where 350, 550 and 750 refer to the approximate average molecular weight of polyethylene glycol, and one or more antioxidants such such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters and dithiocarbamates.

Other prepared forms include, but are not limited to, aqueous-alcoholic solutions, including acetal. The alcohols used in these formulations are any water-miscible solvents having one or more hydroxyl groups, including, but not limited to, propylene glycol and ethanol. Acetals include, but are not limited to, di(lower alkyl) acetals of lower alkyl aldehydes such as acetaldehyde diethyl acetal.

In some embodiments characterized by subcutaneous, intramuscular, or intravenous injection, parenteral administration is also contemplated herein. Injectable preparations can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid before injection, or as emulsions. Injectable preparations, solutions and emulsions also contain one or more excipients. Suitable excipients are, for example, water, saline, dextrose, glycerol or ethanol. In addition, if desired, the administration compositions may also contain minor amounts of non-toxic auxiliary agents such as wetting or emulsifying agents, pH buffers, stabilizers, solubility enhancers and the like, such as, for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins.

Also contemplated herein is the implementation of a slow release or sustained release system so as to maintain a constant dosage level (see, for example, US Pat. No. 3,710,795). Briefly, the compound provided herein is dispersed in a solid internal matrix, for example, polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers ta, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as acrylic and methacrylic acid ester hydrogels, collagen, crosslinked polyvinyl alcohol and crosslinked partially hydrolyzed polyvinyl acetate, which is surrounded by an outer polymer membrane such as polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, polyethylene terephthalate ionomer, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/terpolymer vinyl alcohol and ethylene/vinyloxyethanol copolymer, which is insoluble in body fluids. The compound diffuses through the outer polymer membrane in a rate-controlled release step. The percentage of active compound contained in such parenteral compositions depends greatly on its specific nature, as well as on the activity of the compound and the needs of the patient.

Parenteral administration of the compositions includes intravenous, subcutaneous and intramuscular administration. Formulations for parenteral administration include sterile solutions, ready for injection, sterile dry soluble products, such as lyophilized powders, ready for combination with a solvent immediately before use, including tablets for subcutaneous injection, sterile suspensions, ready for injection, sterile dry insoluble products, prepared for connection with the base immediately before use, and sterile emulsions. Solutions may be aqueous or non-aqueous.

For intravenous administration, suitable carriers include physiological saline or phosphate buffered saline (PBS) and solutions containing thickening and solubilizing agents such as glucose, polyethylene glycol and polypropylene glycol, and mixtures thereof.

Bases used in parenteral formulations include aqueous bases, non-aqueous bases, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents, and other agents.

Examples of aqueous bases include sodium chloride injection, Ringer's solution for injection, isotonic dextrose injection, sterile water for injection, dextrose solution and lactated Ringer's injection. Non-aqueous parenteral bases include vegetable fatty oils, cottonseed oil, corn oil, sesame oil, and peanut oil. For parenteral products packaged in multiple-use containers, antimicrobial agents must be added at bacteriostatic or fungistatic concentrations, which include phenols or cresols, mercury, benzyl alcohol, chlorobutanol, methyl and propyl hydroxybenzoic acid esters, thimerosal, benzalkonium chloride, and benzethonium chloride. Isotonic agents include sodium chloride and dextrose. Buffers include phosphate and citrate. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. Emulsifying agents include polysorbate 80 (Tween® 80). The metal ion sequestering or chelating agent includes EDTA. Carriers also include ethyl alcohol, polyethylene glycol and propylene glycol for water-miscible bases; and sodium hydroxide, hydrochloric acid, citric acid or lactic acid to adjust the pH.

The concentration of the compound is adjusted so that the injection provides an effective amount to produce the desired pharmacological effect. As is known in the art, the exact dose depends on the age, weight, body surface area and condition of the patient or animal.

A single dose of parenteral drugs is packaged in an ampoule, vial or syringe with a needle. All preparations for parenteral administration must be sterile as is known and practiced in the art.

Illustratively, intravenous or intra-arterial infusion of a sterile aqueous solution containing the active compound is an effective route of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing the active material administered as needed to obtain the desired pharmacological effect.

Injectable preparations are intended for local and systemic use. In some embodiments, a therapeutically effective dosage is formulated to contain a concentration of at least 0.01 wt% to 90 wt% or more, for example, more than 0.1 wt% of active compound per treated tissue(s).

The compound may be suspended in micronized or other suitable form, or may be derivatized to provide a more soluble active product or to produce a prodrug. The form of the resulting mixture depends on a number of factors, including the intended route of administration and the solubility of the compound in the chosen vehicle or base. The effective concentration is sufficient to reduce the symptoms of the condition and can be determined empirically.

The active ingredients provided herein can be administered via controlled release or delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in US Pat. Nos.: 3,845,770; 3916899; 3536809; 3598123; 4008719; 5674533; 5059595; 5591767; 5120548; 5073543; 5639476; 5354556; 5639480; 5733566; 5739108; 5891474; 5922356; 5972891; 5980945; 5993855; 6045830; 6087324; 6113943; 6197350; 6248363; 6264970; 6267981; 6376461; 6419961; 6589548; 6613358; 6699500 and 6740634. Such dosage forms can be used to provide slow or controlled release of one or more active ingredients using, for example, hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof to obtain the desired release profile in various proportions. Suitable controlled release formulations known to those of ordinary skill in the art, including the formulations described herein, can be readily selected for use with the active ingredients disclosed herein.

All controlled-release products have the common goal of improving drug therapy beyond what is achieved by their non-regulated counterparts. Ideally, the use of an optimally formulated controlled-release drug in treatment is characterized by the minimum amount of drug used to treat or manage the condition in the minimum amount of time. Advantages of controlled-release formulations include enhanced drug activity, reduced dosing frequency, and increased patient compliance. In addition, controlled release compositions can be used to influence the time of onset of action or other characteristics, such as drug levels in the blood, and thus can influence the occurrence of side (eg, adverse) effects.

Most controlled-release formulations are designed to initially release an amount of drug (active ingredient) that rapidly produces the desired therapeutic effect, and gradually and continuously release other amounts of drug to maintain that level of therapeutic or prophylactic effect over an extended period of time. To maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug that is metabolized and eliminated from the body. The controlled release of the active ingredient can be stimulated by various conditions, including, but not limited to, pH, temperature, enzymes, water or other physiological conditions or compounds.

The agent can be administered using intravenous infusion, implantable osmotic pump, transdermal patch, liposomes, or other routes of administration. In some embodiments, a pump can be used (see Sefton, CRC Crit. Ref. Biomed. Eng. 14: 201 (1987); Buchwald et al., Surgery 88: 507 (1980); Saudek et al., N. Engl. J Med 321: 574 (1989)). In other embodiments, polymeric materials can be used. In other embodiments, the controlled release system can be placed in close proximity to the therapeutic target, thus requiring only a fraction of the systemic dose (see, for example, Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115138 ( 1984)). In some embodiments, the controlled release device is administered to a patient near a site of unnecessary immune activation or tumor. Other controlled release systems are discussed in a review by Langer (Science 249: 1527 1533 (1990)). The active ingredient can be dispersed in a solid internal matrix, for example, polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubbers ukah, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as acrylic and methacrylic acid ester hydrogels, collagen, cross-linked polyvinyl alcohol and cross-linked partially hydrolyzed polyvinyl acetate, which is surrounded by an outer polymer membrane such as polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/ vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubbers, chlorinated polyethylene, polyvinyl chloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, polyethylene terephthalate ionomer, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer a, ethylene/vinyl acetate/vinyl alcohol terpolymer and ethylene copolymer /vinyloxyethanol, which is insoluble in body fluids. The active ingredient then diffuses through the outer polymer membrane in a rate-controlled release step. The percentage of active ingredient contained in such parenteral compositions depends greatly on its specific nature as well as the needs of the patient.

In this case, lyophilized powders are also of interest, which can be reconstituted for administration in the form of solutions, emulsions and other mixtures. They can also be reconstituted and formulated as solids or gels.

A sterile lyophilized powder is prepared by dissolving a compound provided herein, or a derivative thereof, in a suitable solvent. The solvent may contain an adjuvant that improves stability or another pharmacological component of the powder or powder-derived reconstituted solution. Excipients that can be used include, but are not limited to, antioxidant, buffer and bulking agent. In some embodiments, the adjuvant is selected from dextrose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose, and other suitable agents. The solvent may contain a buffer such as citrate, sodium or potassium phosphate, or other such buffer known to those skilled in the art at a neutral pH. The desired finished form is obtained by subsequent sterile filtration of the solution followed by lyophilization under standard conditions known to those skilled in the art. In some embodiments, the resulting solution should be distributed into vials for lyophilization. Each vial will contain one dose or multiple doses of the compound. The lyophilized powder can be stored under appropriate conditions, for example at 4°C to room temperature.

Reconstitution of this lyophilized powder with water for injection provides a ready-made form for use in parenteral administration. For reconstitution, the lyophilized powder is added to sterile water or other suitable vehicle. The exact amount depends on the selected compound. This amount can be determined experimentally.

Topical mixtures are prepared as described for local and systemic administration. The resulting mixture may be a solution, suspension, emulsion or the like, and is formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, irrigations, sprays, suppositories, dressings , skin patches or any other prepared forms suitable for topical use.

The compounds or derivatives thereof can be formulated into aerosols for topical administration, for example, by inhalation (see, for example, US Patent Nos. 4044126, 4414209 and 4364923, which describe aerosols for the delivery of a steroid used to treat inflammatory diseases, in particular asthma ). These respiratory formulations may be in the form of an aerosol or nebulizer solution or as a fine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, in some embodiments, the finished shaped particles will have mass average geometric diameters of less than 5 microns, in other embodiments, less than 10 microns.

Formulations for oral inhalation of compounds or derivatives suitable for inhalation include metered-dose inhalers, powder inhalers, and liquid preparations for administration from a nebulizer or metered-dose system. For both metered dose inhalers and powder inhalers, the crystalline form of the compounds or derivatives is the preferred physical form of the drug to provide greater product stability.

In addition to particle size reduction techniques known to those skilled in the art, crystalline particles of compounds or derivatives can be prepared using supercritical fluid processing, which provides significant advantages in preparing such particles for inhalation delivery by producing respirable particles of the desired size in a single step ( for example, PCT International Publication No. WO 2005/025506). The controlled particle size for the microcrystals can be selected to ensure that a significant portion of the compounds or derivatives are retained in the lungs. In some embodiments, these particles have a mass average aerodynamic diameter from 0.1 microns to 10 microns, in other embodiments from 1 micron to 5 microns, and in other embodiments from 1.2 microns to 3 microns.

Inert and non-flammable HFA propellants are selected from HFA 134a (1,1,1,2 tetrafluoroethane) and HFA 227e (1,1,1,2,3,3,3 heptafluoropropane) and are provided individually or in a ratio corresponding to the density of the crystalline particles compounds or derivatives. The ratio is also chosen to ensure that harmful sedimentation of the product or cream suspension (which could cause irreversible agglomeration) is prevented and instead promotes the formation of a weakly flocculated system that is easily dispersed by shaking. Low oscillating systems are believed to provide optimal stability for pMDI boxes. As a result of the properties of the finished form, the finished form was free of ethanol and surfactants/stabilizers.

The compounds can be formulated for topical or topical use, such as topical application to the skin and mucous membranes, for example, in the eye, in the form of gels, creams and lotions and for application to the eye or for intracisternal or intraspinal application. Topical administration is intended for transdermal delivery, as well as for ocular or mucosal administration or for inhalation therapy. Nasal solutions of the active compound may also be administered alone or in combination with other excipients.

For nasal administration, the preparation may contain an esterified phosphonate compound dissolved or suspended in a liquid carrier, in particular an aqueous vehicle, for aerosol administration. The carrier may contain solubilizing or suspending agents such as propylene glycol, surfactants, absorption enhancers such as lecithin or cyclodextrin, or preservatives.

Solutions, especially solutions intended for ophthalmic use, can be formulated as isotonic solutions of 0.01–10%, pH 5–7.4, with appropriate salts.

Other routes of administration such as transdermal patches, including iontophoretic and electrophoretic devices and rectal administration are also contemplated herein.

Transdermal patches, including iontophoretic and electrophoretic devices, are well known to those skilled in the art. For example, such patches are disclosed in US Patent Nos. 6,267,983, 6,261,595, 6,256,533, 6,167,301, 6,024,975, 6,010,715, 5,985,317, 5,983,134, 5,948,433, and 5,860,957.

For example, dosage forms for rectal administration are rectal suppositories, capsules and tablets for systemic action. Rectal suppositories, as used herein, mean solid bodies for insertion into the rectum that melt or soften at body temperature, releasing one or more pharmacologically or therapeutically active ingredients. The substances used in rectal suppositories are bases or carriers and agents for increasing the melting point. Examples of bases include cocoa butter (oil from the theobroma plant), gelatin-glycerin, Carbowax (polyoxyethylene glycol) and appropriate mixtures of mono-, di- and triglycerides of fatty acids. Combinations of different bases can be used. Agents for increasing the melting point of suppositories include spermaceti and wax. Rectal suppositories can be prepared by compressed or molded methods. In one embodiment, the weight of the rectal suppository is from 2 g to 3 g. Tablets and capsules for rectal administration are manufactured using the same substance and by the same methods as for formulations for oral administration.

The compounds provided herein, or derivatives thereof, may also be formulated to target a specific tissue, receptor, or other area of the body of the subject being treated. Many such targeting methods are well known to those skilled in the art. All such targeting methods are provided herein for use in the present compositions. For non-limiting examples of targeting methods, see, for example, US Patent Nos. 6316652, 6274552, 6271359, 6253872, 6139865, 6131570, 6120751, 6071495, 6060082, 6048736, 6039975, 6 004534, 5985307, 5972366, 5900252, 5840674, 5759542 and 5709874 .

In some embodiments, liposome suspensions may also be suitable as carriers, including tissue-targeted liposomes, such as tumor-targeted liposomes. They can be prepared in accordance with methods known to those skilled in the art. For example, liposome formulations can be prepared as described in US Pat. No. 4,522,811. Briefly, liposomes such as multilayer vesicles (MLVs) can be prepared by drying phosphatidylcholine and phosphatidylserine (7:3 molar ratio) inside a flask. A solution of the compound provided herein in phosphate buffered saline free of divalent cations (PBS) is added and the flask is shaken until the lipid film is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS.

The compounds or derivatives may be packaged as articles containing the packaging material, compound or derivative thereof provided herein that is effective for treating, preventing, or alleviating one or more symptoms of the diseases or disorders above in the packaging material, and a label that indicates that the compound or composition or a derivative thereof is used for the treatment, prevention or alleviation of one or more symptoms of the diseases or disorders above.

The finished products presented herein contain packaging materials. Packaging materials for use in packaging products are well known to those skilled in the art. See, for example, US Pat. Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, pouches, vials, containers, syringes, bottles, and any packaging material suitable for the selected finished form and intended method of administration and processing. A wide range of formulations of the compounds and compositions provided herein are provided, as well as various methods of treating any disease or disorder described herein.

For use in the treatment or prevention of an infectious disease, the compounds or compositions described herein or pharmaceutical compositions thereof can be administered or used in a therapeutically effective amount. When treating a person, the physician will determine a treatment regimen that is most appropriate in accordance with the prophylactic or therapeutic treatment and in accordance with the age, weight, stage of the disease and other factors specific to the subject being treated. The amount of active ingredient in the formulations provided herein that will be effective in preventing or treating an infectious disease will vary depending on the nature and severity of the disease or condition and route of administration of the active ingredient. Frequency and dosage will also vary depending on factors specific to each subject, depending on the specific therapy prescribed (eg, therapeutic or prophylactic agents), severity of infection, route of administration, and age, body weight, body weight, response, and previous subject's medical history.

Exemplary drug doses include the amount of active compound in milligrams or micrograms per kilogram of the subject (for example, from 1 microgram per kilogram to 50 milligrams per kilogram, from 10 micrograms per kilogram to 30 milligrams per kilogram, from 100 micrograms per kilogram to 10 milligrams per kilogram, or 100 micrograms per kilogram to 5 milligrams per kilogram).

In some embodiments, a therapeutically effective dosage will produce a serum concentration of the active ingredient from 0.001 ng/ml to 50 μg/ml to 200 μg/ml. In other embodiments, the compositions should provide a dosage of from 0.0001 to 70 mg of compound per kilogram of body weight per day. Unit dosage forms are formulated to provide 0.01 to 0.1 mg, 1 to 500 mg, or 1000 to 5000 mg, and in some embodiments, 10 to 500 mg of active ingredient or combination of essential ingredients per unit dosage form.

The active ingredient may be administered all at once or may be divided into several smaller doses administered at regular intervals. It is understood that the exact dosage and duration of treatment are a function of the disease being treated and can be determined empirically using known testing protocols or by extrapolation from data from in vivo or in vitro testing or subsequent clinical testing. It should be noted that concentrations and dosage values may also vary depending on the severity of the condition being treated. In addition, it should be understood that for any particular subject, specific treatment regimens must be adjusted over time according to individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are merely illustrative and are not intended to to limit the scope or practical use of the claimed compositions.

As will be apparent to those skilled in the art, in some cases it may be necessary to use dosages of the active ingredient beyond those disclosed herein. Additionally, it should be noted that the physician or prescriber should know how and when to interrupt, adjust, or discontinue therapy based on the subject's response.

For systemic administration, the therapeutically effective dose can initially be estimated from in vitro assays. For example, the dose can be formulated in animal models to achieve a range of circulating concentrations that includes IC ₅₀ as determined in cell culture (i.e., the concentration of test compound that is lethal to 50% of the cell culture), MIC as determined in cell culture (that is, is the minimum growth inhibitory concentration) or IC ₁₀₀ as determined in cell culture (ie, the concentration of an antimicrobial sulfonamide derivative that is lethal to 100% of the cell culture). Such information can be used to more accurately determine appropriate doses in humans.

Initial doses can also be estimated from in vivo data (eg, animal models) using techniques that are well known in the art. One skilled in the art can easily optimize administration to humans based on animal data.

Alternatively, initial doses can be determined from the administered dosages of known antimicrobial agents by comparing the IC ₅₀ , MIC and/or I ₁₀₀ of a particular compound disclosed herein with the dosage of a known antimicrobial agent, and adjusting the initial doses accordingly. The optimal dosage can be obtained from these initial values by conventional optimization.

In cases of local administration or selective absorption, the effective local concentration of the compound used may not be related to the plasma concentration. One skilled in the art will be able to optimize therapeutically effective local dosages without undue experimentation.

Ideally, a therapeutically effective dose of the compounds described herein will provide therapeutic benefit without causing significant toxicity. The toxicity of compounds can be determined using standard pharmaceutical procedures for cell cultures or experimental animals, for example, by determining the LD ₅₀ (dose lethal to 50% of the population) or LD ₁₀₀ (dose lethal to 100% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic indicator. Compounds that exhibit high therapeutic properties are preferred. Data obtained from these cell culture assays and animal studies can be used to formulate dosage ranges that are nontoxic for use in subjects. The dosage of the compounds described herein is preferably within a range of circulating concentrations that include an effective dose with little or no toxicity. The dosage may vary within this range depending on the dosage form used and the route of administration used. The exact formulation, route of administration and dosage may be selected by the individual physician based on the patient's condition (see, eg, Fingl et al., 1975, In: The Pharmacological Basis of Therapeutics, Ch. 1, p. 1).

Treatment can be repeated periodically as long as infections are detected, or even when they are not detected. Administration of the same composition provided herein may be repeated, and administration may be divided into at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months or 6 months.

The compound of formula (1) and/or the pharmaceutical composition thereof can generally be used in an amount effective to achieve the intended purpose. For use in treating a disease such as a bacterial infection, a compound of formula (1) and/or pharmaceutical compositions thereof can be administered or used in a therapeutically effective amount.

The amount of a compound of Formula (1) and/or a pharmaceutical composition thereof that will be effective in treating a particular disorder or condition disclosed herein will depend in part on the nature of the disorder or condition and can be determined using standard clinical techniques known in the art. In addition, in vitro or in vivo assays can be used to help determine optimal dose ranges. The amount of the compound of formula (1) and/or the pharmaceutical composition thereof administered will depend, among other factors, on the subject being treated, the weight of the patient, the severity of the disease, the route of administration and the judgment of the prescribing physician.

The compound of formula (1) can be assayed in vitro and in vivo for desired therapeutic activity prior to use in humans. For example, in vitro assays can be used to determine whether administration of a particular compound or combination of compounds is preferred. The compounds can also be demonstrated to be effective and safe using animal model systems.

A therapeutically effective dose of a compound of formula (1) and/or a pharmaceutical composition thereof will provide therapeutic benefit without causing significant toxicity. The toxicity of the compounds of formula (1) and/or pharmaceutical compositions thereof can be determined using standard pharmaceutical techniques and can be easily determined by one skilled in the art. The dose ratio between toxic and therapeutic effects is the therapeutic indicator. The compound of formula (1) and/or the pharmaceutical composition thereof exhibits a particularly high therapeutic index in the treatment of diseases and disorders. The dose of a compound of formula (1) and/or a pharmaceutical composition thereof will be within a range of concentrations in the bloodstream that includes an effective dose with minimal toxicity.

The compound of formula (1), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any of the foregoing can be included in a kit that can be used to administer the compound to a patient for therapeutic purposes. The kit may include a pharmaceutical composition containing a compound of formula (1) suitable for administration to a patient, and instructions for administering the pharmaceutical composition to the patient. The kit for use in the treatment of a bacterial infection in a patient contains a compound of formula (1) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable vehicle for administering the compound, and instructions for administering the compound to the patient. The instructions included with the kit may be printed and/or provided, for example, in the form of an electronically readable medium, videotape, audiotape, flash memory device, or may be published on an Internet website or distributed to patients and/or health care providers in in the form of an electronic message.

The amount of a compound of formula (1) that will be effective in treating a bacterial infection will depend, at least in part, on the nature of the disease and can be determined by standard clinical methods known in the art. In addition, in vitro or in vivo assays can be used to assist in determining optimal dosage ranges. Treatment regimens and dosage intervals can also be determined using methods known to those skilled in the art. The amount of compound of formula (1) administered may depend, among other factors, on the subject being treated, the weight of the subject, the severity of the disease, the route of administration, and the discretion of the prescribing physician.

For systemic administration, the therapeutically effective dose can be initially estimated from in vitro assays. Initial doses can also be estimated from in vivo data, for example, in animal models using techniques known in the art. Such information can be used to more accurately determine the applicable doses for humans. One skilled in the art can optimize administration to humans based on animal data.

The dosage of the compound of Formula (1) and appropriate dosing intervals may be selected to maintain a sustained therapeutically effective concentration of the compound of formula (1) in the patient's blood, and in some embodiments, without exceeding a minimum unfavorable concentration.

Pharmaceutical compositions containing a compound of formula (1) may be administered once daily, twice daily, or at intervals greater than once daily. The medication may be administered alone or in combination with other medications and may be continued for as long as required to effectively treat the disease. The medication can also be administered using continuous or semi-continuous administration over a period of time. Administration of a medication involves administering the pharmaceutical composition to a mammal, such as a human, in a fed or fasted state.

The pharmaceutical composition can be administered in a single dose form or in a multi-dose form or in a continuous or cumulative dose over a period of time. When using a multi-dose form, the amount of the compound of formula (1) contained in each of the multi-dose forms may be the same or different.

Suitable daily dosage ranges for administration may be from 2 μg to 20 mg of the compound of formula (1) per kilogram of body weight.

Suitable daily dosage ranges for administration may be from 1 μg to 50 mg of the compound of formula (1) per square meter (m ² ) of body surface.

A compound of formula (1) can be administered to treat a bacterial infection in a patient in an amount of 1 mg to 2000 mg per day, 100 μg to 1500 mg per day, 20 μg to 1000 mg per day, or any other suitable daily dose.

A pharmaceutical composition containing a compound of formula (1) may be administered to treat a bacterial infection in a subject to provide a therapeutically effective concentration of the compound of formula (1) in the blood or plasma of the subject. The therapeutically effective concentration of the compound of formula (1) in the blood or plasma of the subject is from 1 μg/ml to 60 μg/ml, from 2 μg/ml to 50 μg/ml, from 5 μg/ml to 40 μg/ml, from 5 μg /ml to 20 µg/ml or from 5 µg/ml to 10 µg/ml. The therapeutically effective concentration of a compound of formula (1) in the blood or plasma of a subject is at least 2 μg/ml, at least 5 μg/ml, at least 10 μg/ml, at least 15 μg/ml, at least 25 µg/ml or at least 30 µg/ml. A therapeutically effective concentration of a compound of formula (1) in the blood or plasma of a subject is less than an amount that causes unacceptable adverse effects, including adverse effects on homeostasis. A therapeutically effective concentration of a compound of formula (1) in the blood or plasma of a subject is an amount sufficient to restore and/or maintain homeostasis in the subject.

A pharmaceutical composition containing a compound of formula (1) may be administered to treat a bacterial infection in a patient to provide a therapeutically effective concentration of the compound of formula (1) in the blood or plasma of the subject for an extended period of time, for example, for at least 4 hours, for at least 6 hours, for at least 8 hours, for at least 10 hours, or for at least 12 hours.

The amount of compound of formula (1) administered may vary during the treatment regimen.

In addition to the compound of formula (1), the pharmaceutical compositions provided herein may further contain one or more pharmaceutically active compounds. Such compounds may be provided for the treatment of a bacterial infection treated with a compound of formula (1), or for the treatment of a disease, disorder or condition other than the bacterial infection treated with a compound of formula (1).

The compounds and compositions described herein can be used for a wide range of uses to treat infectious diseases in a subject. The methods typically involve administering to a subject a therapeutically effective amount of a compound of formula (1) or a pharmaceutical composition thereof, or administering to a subject a therapeutically effective amount of a compound of formula (1) and an antibiotic or a pharmaceutical composition thereof.

The compounds presented herein are prodrugs of β-lactamase inhibitors. The compounds and compositions provided herein can be used to treat a disease in which the etiology of the disease is related to the expression of β-lactamases. For example, some bacterial infections are resistant to β-lactamase antibiotics because β-lactamases produced by bacteria hydrolyze the β-lactam ring of the β-lactam antibiotic.

The compounds and compositions provided by the present disclosure can be used to treat a bacterial disease in a patient.

The compounds and compositions provided in the present disclosure can be used to treat a bacterial infection. For example, the compounds and composition provided by the present disclosure can be used to treat a bacterial infection associated with bacteria such as obligate aerobic bacteria, obligate anaerobic bacteria, facultative anaerobic bacteria and microaerophilic bacteria.

Examples of obligate aerobic bacteria include gram-negative cocci such as Moraxella catarrhalis, Neisseria gonorrhoeae and N. meningitidi; gram-positive bacilli such as Corynebacterium jeikeium; acid-fast bacilli such as Mycobacterium avium complex, M. kansasii, M. leprae, M. tuberculosis and Nocardia spp.; non-enzymatic, non-enterobacterial, such as Acinetobacter calcoaceticus, Elizabethkingia meningoseptica (formerly Flavobacterium meningosepticum), Pseudomonas aeruginosa, P. alcaligenes, other Pseudomonas species and Stenotrophomonas maltophilia; gram-negative coccobacilli and bacilli with complex nutritional requirements, such as Brucella, Bordetella, Francisella and Legionella species; and treponemataceae (spiral bacteria), such as Leptospira spp.

Examples of obligate anaerobic bacteria include gram-negative bacteria such as Bacteroides fragilis, other Bacteroides spp., and Fusobacterium spp., Prevotella spp.; gram-negative cocci such as Veillonella species; gram-positive cocci such as Peptococcus niger and Peptostreptococcus species; non-spore forming gram-positive bacilli such as Clostridium botulinum, C. perfringens, C. tetani, other Clostridium species; and endospore-forming gram-positive bacilli such as Clostridium botulinum, C. perfringens, C. tetani and other Clostridium species.

Examples of facultative anaerobic bacteria include gram-positive, catalase-positive cocci such as Staphylococcus aureus (coagulase-positive), S. epidermidis (coagulase-negative) and other coagulase-negative staphylococci; gram-positive cocci, catalase-negative, such as Enterococcus faecalis, E. faecium, Streptococcus agalactiae (group B streptococci), S. bovis, S. pneumoniae, S. pyogenes (group A streptococci), viridans group streptococci (S. mutans, S. mitis , S. salivarius, S. sanguis), S. anginosus group (S. anginosus, S. milleri, S. constellatus) and Gemella morbillorum; gram-positive bacilli such as Bacillus anthracis, Erysipelothrix rhusiopathiae and Gardnerella vaginalis (gram-variable); gram-negative bacilli such as Enterobacteriaceae (Citrobacter spp., Enterobacter aerogenes, Escherichia coli, Klebsiella spp., Morganella morganii, Proteus spp., Plesiomonas shigelloides, Providencia rettgeri, Salmonella typhi, other Salmonella spp., Serratia marcescens and Shigella spp., Yersinia enterocolitica, Y. pestis ); fermentative non-Enterobacteriaceae such as Aeromonas hydrophila, Chromobacterium violaceum and Pasteurella multocida; gram-negative coccobacilli and bacilli with complex nutritional requirements, such as Actinobacillus actinomycetemcomitans, Bartonella bacilliformis, B. henselae, B. quintana, Eikenella corrodens, Haemophilus influenzae and other Haemophilus species; mycoplasma such as Mycoplasma pneumoniae; and Treponemataceae (spiral bacteria) such as Borrelia burgdorferi and Treponema pallidum.

Examples of microaerophilic bacteria include curved bacteria such as Campylobacter jejuni, Helicobacter pylori, Vibrio cholerae and V. vulnificus; obligate intracellular parasites; chlamydiaceae such as Chlamydia trachomatis, Chlamydophila pneumoniae and C. psittaci; coxiellaceae such as Coxiella burnetii; and rickettsiales such as Rickettsia prowazekii, R. rickettsii, R. typhi, R. tsutsugamushi, Ehrlichia chaffeensis and Anaplasma phagocytophilum.

The compounds and compositions provided herein can be used to treat a bacterial disease in which the bacteria produce β-lactamase. Examples of bacteria that produce β-lactamase include Mycobacterium tuberculosis, methicillin-resistant Staphylococcus aureus, Staphyloccus, Enterobacteriaceae, Pseudomonas aeruginosa, Haemophilus influenzae, Klebsiella pneumoniae, Citrobacter and Morganella.

The compounds and compositions provided herein can be used to treat a bacterial disease in which a β-lactamase inhibitor is effective in treating the bacterial disease such as a bacterial infection.

The infectious disease may be a bacterial infection. The bacterial infection may be an infection of gram-positive bacteria. The bacterial infection may be an infection of gram-negative bacteria. Examples of Gram-negative bacteria include Acinetobacter, Aeromonas, Bacteroides, Burkholderia, Citrobacter, Enterobacter, Escherichia, Fusobacterium, Haemophilus, Klebsiella, Moraxella, Morganella, Mycoplasma, Neisseria, Pantoea, Pasteurella, Plesiomonas, Porphyromonas, Prevotella, Proteus, Providencia, Pseudomonas, Salmonella, Serratia, Shigella, Spirillum, Stenotrophomonas, Streptobacillus, Treponema or Yersinia. Examples of Gram-negative bacteria include Acinetobacter baumannii, Aeromonas hydrophila, Arizona hinshawii, Bacteroides fragilis, Branhamella catarrhalis, Burkholderia cepacia, Citrobacter diversus, Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Fusobacterium nucleatum, Haemophilus influenzae, Haemophilus parainfluenza e, Klebsiella oxytoca, Klebsiella pneumoniae, Moraxella catarrhalis, Morganella morganii, Neisseria gonorrhoeae, Neisseria meningitidis, Pantoea agglomerans, Pasteurella multocida, Plesiomonas shigelloides, Prevotella melaninogenica, Proteus mirabilis, Proteus rettgeri, Proteus vulgaris, Pseudomonas aeruginosa, Pseudomonas diminuta, Pseu domonas fluorescens, Pseudomonas stutzeri, Salmonella enterica, Salmonella enteritidis, Salmonella typhi, Serratia marcescens, Spirillum minus, Stenotrophomonas maltophilia, Streptobacillus moniliformis, Treponema pallidum or Yersinia enterocolitica.

The development of antibiotic resistance continues to grow as a problem facing patients and physicians. Accordingly, the US Food and Drug Administration has identified the following pathogens as potentially hazardous to public health: Acinetobacter spp., Aspergillus spp., Burkholderia cepacia complex, Campylobacter spp., Candida spp., Clostridium difficile, Coccidioides spp., Cryptococcus spp., Enterobacteriaceae ( eg Klebsiella pneumoniae), Enterococcus spp., Helicobacter pylori, Mycobacterium tuberculosis complex, Neisseria gonorrhoeae, N. meningitidis, non-tuberculous mycobacteria spp., Pseudomonas spp., Staphylococcus aureus, Streptococcus agalactiae, S. pneumoniae, S. pyogenes and Vibrio cholerae. The Food and Drug Administration has designated these organisms as “qualified pathogens” for purposes of the Making Antibiotic Investment Now (GAIN) Act, designed to encourage the development of new antibacterial and antifungal drugs to treat serious or life-threatening infections. Other types of bacteria may be added or subtracted from the list of “qualified pathogens,” and the methods provided in this disclosure cover any newly added bacteria. The compounds, compositions, methods and kits disclosed herein are useful for treating diseases, infections, etc. also caused by many of these organisms.

The compounds and compositions described herein can be used for the treatment or prevention of various diseases caused by the above bacteria. These include, but are not limited to, sexually transmitted diseases, pneumonia, complicated urinary tract infections, urinary tract infections, complicated intra-abdominal infections, and intra-abdominal infections.

The methods provided herein can also be used to inhibit β-lactamase in a patient. The compounds and compositions of the present invention can be administered to a patient to inhibit any suitable type of β-lactamase. Examples of types of β-lactamases include extended spectrum β-lactamases such as TEM β-lactamases (Class A), SHV β-lactamases (Class A), CTX-M β-lactamases (Class A), OXA β-lactamases (Class D ) and other extended spectrum beta-lactamases, such as PER, VEB, GES and IBC beta-lactamases; resistant to β-lactamase inhibitor; AmpC-type β-lactamases (class C); carbapenemases, such as IMP-type carbapenemases (metallo-β-lactamases) (class B), VIM (integron-encoded metallo-β-lactamase from Verona (class B), OXA (oxcillinase) group of β-lactamases (class D), KPC ( K. pneumoniae carbapenemase) (class A), CMY (class C), SME, IMI, NMC and CcrA and NDM-1 (New Delhi metallo-β-lactamase) (class B).

Examples of types of β-lactamases include cephalosporinases, penicillinases, cephalosporinases, broad-spectrum β-lactamases, extended-spectrum β-lactamases, inhibitor-resistant β-lactamases, carbenicillinase, cloxicillinases, oxacillinases, carbapenemases, and metalloenzymes.

Types of β-lactamases include class A, class B, class C and class D β-lactamases.

The compounds and compositions provided herein can be administered orally.

The compounds of the present invention, when administered orally, provide increased oral bioavailability of the β-lactamase inhibitor compared to the oral bioavailability of the parent β-lactamase inhibitor. For example, compounds of formula (1) may exhibit an oral bioavailability (%F) of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or at least 60% .

The pharmaceutical compositions provided herein may further include one or more pharmaceutically active compounds in addition to the compound of formula (1). Such compounds may be provided for the treatment of a bacterial infection treated with a compound of formula (1), or for the treatment of a disease, disorder or condition other than the bacterial infection treated with a compound of formula (1).

The compound of formula (1) can be used in combination with at least one other therapeutic agent. The compound of formula (1) can be administered to a patient together with another compound to treat a bacterial infection in the patient. The at least one other therapeutic agent may be another compound of formula (1). The compound of formula (1) and at least one other therapeutic agent may act additively or synergistically. The at least one additional therapeutic agent may be included in the same pharmaceutical composition or base containing the compound of formula (1), or may be in a separate pharmaceutical composition or base. Accordingly, the methods provided in the present disclosure further include, in addition to administering a compound of formula (1), administering one or more therapeutic agents effective for treating a bacterial infection or a disease, disorder or condition other than a bacterial infection. The methods provided herein include administration of a compound of formula (1) and one or more other therapeutic agents, provided that the combination administration does not inhibit the therapeutic efficacy of the compound of formula (1) and/or does not result in an adverse combination of effects.

Pharmaceutical compositions containing a compound of formula (1) may be administered concomitantly with the administration of another therapeutic agent, which may be part of the same pharmaceutical composition as a pharmaceutical composition other than that containing the compound of formula (1). The compound of formula (1) can be administered before or after the administration of another therapeutic agent. In some embodiments of the combination therapy, the combination therapy may include alternating administration of a compound of formula (1) and a composition containing another therapeutic agent, for example, to minimize adverse drug effects associated with a particular drug. When a compound of formula (1) is administered concomitantly with another therapeutic agent that has the potential to cause adverse drug effects, including, for example, toxicity, the other therapeutic agent may be administered at a dose that falls below the threshold at which an adverse drug reaction occurs.

Pharmaceutical compositions containing a compound of formula (1) can be administered with one or more substances to enhance, modulate and/or control the release, bioavailability, therapeutic efficacy, therapeutic efficacy, stability, and the like of the compound of formula (1). For example, to enhance the therapeutic efficacy of a compound of formula (1), a compound of formula (1) or a pharmaceutical composition containing a compound of formula (1) may be co-administered with one or more active agents to enhance the absorption or diffusion of the compound of formula (1) from the gastrointestinal tract. intestinal tract into the systemic circulation or to inhibit the breakdown of a compound of formula (1) in the blood of a subject. A pharmaceutical composition containing a compound of formula (1) may be co-administered with an active agent having a pharmacological effect that enhances the therapeutic efficacy of the compound of formula (1).

The compound of formula (1) can be administered together with another therapeutic compound, where the compound of formula (1) enhances the effectiveness of the other therapeutic compound. For example, the other therapeutic compound may be an antibiotic, such as a β-lactam antibiotic, and the compound of formula (1), which provides a systemic β-lactamase inhibitor, may enhance the effectiveness of the β-lactam antibiotic by inhibiting the hydrolysis of the β-lactam ring by β-lactamases.

The compounds and compositions provided in the present invention can be administered in combination with an antibiotic, such as a β-lactam antibiotic.

Antibiotics include, for example, aminoglycosides such as amikacin, gentamicin, neomycin, streptomycin and tobramycin; β-lactams (first generation cephalosporins), such as cefadroxil, cefazolin, cephalexin; β-lactams (second generation cephalosporins), such as cefaclor, cefotetan, cefoxitin, cefprozil and cefuroxime; β-lactams (third generation cephalosporins), such as cefotaxime, cefpodoxime, ceftazidime, ceftibuten and ceftriaxone; β-lactams (sixth generation cephalosporins), such as cefepime; β-lactams (fifth generation cephalosporins), such as ceftaroline; β-lactams (penicillins), such as amoxicillin, ampicillin, dicloxacillin, nafcillin and oxacillin, penicillin G, penicillin G benzathine, penicillin G procaine, piperacillin and ticarcillin; β-lactam monobactams such as aztreonam; β-lactam carbapenems such as ertapenem, imipenem, meropenem and doripenem; fluoroquiniolones such as ciprofloxacin, gemifloxacin, levofloxacin, moxifloxacin, norfloxacin and ofloxacin; macrolides such as azithromycin, clarithromycin, erythromycin, fidaxomicin, lactobionate, gluceptate and telithromycin; sulfonamides such as sulfisoxazole, sulfamethizole, sulfamethoxazole and trimethoprim; tetracyclines such as doxycycline, minocycline, tetracycline and tigecycline; and other antibiotics such as clindamycin, chloramphenicol, colistin (polymyxin E), dalbavancin, daptomycin, fosfomycin, linezolid, metronidazole, nitrofurantoin, oritavancin, quinupristin, dalfoprizin, rifampin, rifapentine, tedizolid, telavancin, and vancomycin. An antibiotic may be ceftazidime.

Other examples of antibiotics include penicillins, such as aminopenicillins, including amoxicillin and ampicillin, antipseudomonal penicillins, including carbenicillin, peperacillin and ticarcillin, β-lactamase inhibitors, including amoxicillin, ampicillin, piperacillin and clavulanate, natural penicillins, including penicillin g benzathine, penicillin v ka Leah and procaine penicillin and penicillinase-resistant penicillin, including oxacillin, dicloxacillin and nafcillin; tetracyclines; cephalosporins such as avibactam, tazobactam, cefadroxil, defazolin, cephalexin and cefazolin; quinolones such as lomefloxacin, ofloxacin, norfloxacin, gatifloxacin, ciprofloxacin, moxifloxacin, levofloxacin, gemifloxacin, delafoxacin, cinoxacin, nalidixic acid, trovafloxacin and sparfloxacin; lincomycins such as lincomycin and clindamycin; macrolides such as detolides, including telithromycin, and macrolides such as erythromycin, azithromycin, clarithromycin and fidaxomicin; sulfonamides such as sulfamethoxazole/trimethoprim, sulfisoxazole; glycopeptides; aminoglycosides such as paromomycin, tobramycin, gentamicin, amikacin, kanamycin and neomycin; and carbapenems such as doripenem, meropenem, ertapenem and cilastatin/imipenem. Examples of suitable β-lactam antibiotics include penams, such as β-lactamase-sensitive penams such as benzathine penicillin, benzylpenicillin, phenoxymethyl penicillin and procaine penicillin; β-lactamase-resistant penams such as cloxacillin, dicloxacillin, flucloxacillin, methicillin, nafcillin, oxacillin and temocillin; broad spectrum penams such as amoxicillin and ampicillin; extended spectrum penams such as mecillanam; carboxypenicillins such as carbenicillin and ticarcillin, and ureidopenicillins such as azlocillin, mezlocillin and peperacillin.

Examples of suitable β-lactam antibiotics include cephams, such as first generation cephams, including cefazolin, cephalexin, cephalosporin C, cephalothin; second-generation cephams such as cefaclor, cefamoandol, cefuroxime, cefotetan and cefoxitin; third generation cephams such as cefixime, cefotaxime, cefpodoxime, ceflazidime and ceftriaxone; fourth generation cephams such as cefipime and cefpirome; and fifth-generation cephams such as ceftaroline.

Examples of suitable β-lactam antibiotics include carbapenems and penems such as biapenem, doripenem, ertapenem, faropenem, imipenem, meropenem, panipernem, razupenem, tebipenem and thienamycin.

Examples of suitable β-lactam antibiotics include monobactams such as aztreonam, tigemonam, nocardicin A and tabtoxin β-lactam.

The compounds and pharmaceutical compositions provided in the present invention can be administered with β-lactamase inhibitors and/or carbapenemase inhibitors or pharmaceutical compositions thereof. Examples of suitable β-lactamase inhibitors and/or carbapenemase inhibitors include clavulanic acid, sulbactam, avibactam, tazobactam, relebactam, vaborbactam, ETX 2514, RG6068 (ie OP0565) (Livermore et al., J AntiMicrob Chemother 2015, 70: 3032 ) and RPX7009 (Hecker et al., J Med Chem 2015 58: 3682 3692).

The compounds and compositions provided by this disclosure should be used in combination with one or more other active ingredients. The compound can be administered in combination or sequentially with another therapeutic agent. Such other therapeutic agents include those known to treat, prevent, or alleviate infectious disease.

It should be understood that any suitable combination of the compounds and pharmaceutical compositions provided herein with one or more of the above therapeutic agents and, optionally, one or more other pharmacologically active substances is considered to be included within the scope of the present invention. In some embodiments, the compounds and pharmaceutical compositions provided herein are administered before or after the administration of one or more additional active ingredients.

ASPECTS OF THE INVENTION

Aspect 1. Compound of Formula (1):

(1)

in which

each R ¹ is independently selected from C _1–6 alkyl, or each R ¹ and the geminal carbon atom to which they are bonded forms a C _3–6 cycloalkyl ring, a C _3–6 heterocycloalkyl ring, a substituted C _3–6 cycloalkyl ring, or a substituted C _3–6 heterocycloalkyl ring;

R ² is selected from single bond, C _1-6 alkanediyl, C _1-6 heteroalkanediyl, C _5-6 cycloalkanediyl, C _5-6 heterocycloalkanediyl, C ₆ arenediyl, C _5-6 heteroarendiyl, substituted C _1-6 alkanediyl, substituted C _1-6 heteroalkanediyl, substituted _C5-6 cycloalkanediyl, substituted _C5-6 heterocycloalkanediyl, substituted _C6 arenediyl and substituted _C5-6 heteroarendiyl;

R ³ is selected from C _1–6 alkyl, –O–C(O)–R ⁴ , –S–C(O)–R ⁴ , –NH–C(O)–R ⁴ , –O–C(O) –O–R ⁴ , –S–C(O)–O–R ⁴ , –NH–C(O)–O–R ⁴ , –C(O)–O–R ⁴ , –C(O)–S –R ⁴ , –C(O)–NH–R ⁴ , –O–C(O)–O–R ⁴ , –O–C(O)–S–R ⁴ , –O–C(O)–NH –R ⁴ , –S–S–R ⁴ , –S–R ⁴ , –NH–R ⁴ , –CH(–NH ₂ )(–R ⁴ ), C _5–6 heterocycloalkyl, C _5–6 heteroaryl, substituted C _5–6 cycloalkyl, substituted C _5–6 heterocycloalkyl, substituted C _5–6 aryl, substituted C _5–6 heteroaryl and –CH=C(R ⁴ ) ₂ , in which

R ⁴ is selected from hydrogen, C _1–8 alkyl, C _1–8 heteroalkyl, C _5–8 cycloalkyl, C _5–8 heterocycloalkyl, C _5–10 cycloalkylalkyl, C _5–10 heterocycloalkylalkyl, C _6–8 aryl, C _{5 –8} heteroaryl, C _7–10 arylalkyl, C _5–10 heteroarylalkyl, substituted C _1–8 alkyl, substituted C _1–8 heteroalkyl, substituted C _5–8 cycloalkyl, substituted C _5–8 heterocycloalkyl, substituted C _5–10 cycloalkylalkyl , substituted C _5-10 heterocycloalkylalkyl, substituted C _6-8 aryl, substituted C _5-8 heteroaryl, substituted C _7-10 arylalkyl and substituted C _5-10 heteroarylalkyl;

R ⁵ is selected from hydrogen, C _1-6 alkyl, C _5-8 cycloalkyl, C _6-12 cycloalkylalkyl, C _2-6 heteroalkyl, C _5-8 heterocycloalkyl, C _6-12 heterocycloalkylalkyl, substituted C _1-6 alkyl, substituted _C5-8 cycloalkyl, substituted _C6-12 cycloalkylalkyl, substituted _C2-6 heteroalkyl, substituted _C5-8 heterocycloalkyl and substituted _C6-12 heterocycloalkylalkyl;

R ⁶ is selected from hydrogen, C _1-6 alkyl, C _5-8 cycloalkyl, C _6-12 cycloalkylalkyl, C _2-6 heteroalkyl, C _5-8 heterocycloalkyl, C _6-12 heterocycloalkylalkyl, substituted C _1-6 alkyl, substituted _C5-8 cycloalkyl, substituted _C6-12 cycloalkylalkyl, substituted _C2-6 heteroalkyl, substituted _C5-8 heterocycloalkyl and substituted _C6-12 heterocycloalkylalkyl; And

A represents a single bond (–) and R ⁷ represents hydrogen, or A represents a double bond (=) and R ⁷ represents C _1–3 alkyl.

Aspect 2. A compound according to aspect 1, wherein each substituent is independently selected from –OH, –CN, –CF ₃ , –OCF ₃ , =O, –NO ₂ , C _1-6 alkoxy, C _1-6 alkyl, –COOR, –NR ₂ and –CONR ₂ ; wherein each R is independently selected from hydrogen and C _1-6 alkyl.

Aspect 3. A compound according to any of aspects 1-2, wherein each substituent is independently selected from –OH, –CF ₃ , –O–CF ₃ , –NO ₂ , –O–C(O)–R ⁴ , –S–C (O) ^–R4 , –NH–C(O) ^–R4 , –O–C(O)–O– ^R4 , –S–C(O)–O– ^R4 , –NH–C(O )–O–R ⁴ , –C(O)–O–R ⁴ , –C(O)–S–R ⁴ , –C(O)–NH–R ⁴ , –O–C(O)–O– ^R4 , –O–C(O)–S– ^R4 , –O–C(O)–NH– ^R4 , –S–S– ^R4 , –S– ^R4 , –NH– ^R4 , – CH(–NH ₂ )(–R ⁴ ), where each R ⁴ is selected from hydrogen, C _1–8 alkyl and C _1–8 heteroalkyl.

Aspect 4. A compound according to any of aspects 1-3, wherein A is a single bond (-) and R ⁷ is hydrogen.

Aspect 5. A compound according to any of aspects 1-4, wherein A is a double bond (=) and R ⁷ is C _1-3 alkyl.

Aspect 6. A compound according to any one of aspects 1 to 5, wherein the compound has the structure of formula (2):

(2)

Aspect 7. A compound according to any one of aspects 1 to 5, wherein the compound has the structure of formula (2a):

(2a)

Aspect 8. A compound according to any one of aspects 1 to 5, wherein the compound has the structure of formula (3):

(3)

Aspect 9. A compound according to any one of aspects 1 to 5, wherein the compound has the structure of formula (3a):

(3a)

Aspect 10. A compound according to any one of aspects 1 to 5, wherein the compound has the structure of formula (4):

(4)

Aspect 11. A compound according to any one of aspects 1 to 5, wherein the compound has the structure of formula (5):

(5)

Aspect 12. A compound according to any one of aspects 1 to 11, wherein R ⁵ is hydrogen; and R ⁶ represents hydrogen.

Aspect 13. A compound according to any of aspects 1-12, wherein R ⁵ is a C _2-6 heteroalkyl containing an amino terminal group; and R ⁶ represents hydrogen.

Aspect 14. A compound according to any of aspects 1 to 13, wherein R ⁵ is –O–(CH ₂ ) ₂ –NH ₂ ; and R ⁶ represents hydrogen.

Aspect 15. A compound according to any of aspects 1-14, wherein R ⁵ is a C _4-6 heterocycloalkyl containing at least one –NH– moiety; and R ⁶ represents hydrogen.

Aspect 16. A compound according to any of aspects 1-15, wherein R ⁵ is 4-yl-piperidine; and R ⁶ represents hydrogen.

Aspect 17. A compound according to any of aspects 1-16, wherein A is a single bond; R ⁵ is selected from hydrogen, –O–(CH ₂ ) ₂ –NH ₂ and 4-yl-piperidine; R ⁶ represents hydrogen; and R ⁷ is hydrogen.

Aspect 18. A compound according to any of aspects 1-17, wherein each R ¹ independently represents C _1-6 alkyl.

Aspect 19. A compound according to any of aspects 1 to 18, wherein each R ¹ is methyl.

Aspect 20. A compound according to any of aspects 1-19, wherein each R ¹ together with the geminal carbon atom to which it is bonded forms a C _3-6 cycloalkyl ring or a substituted C _3-6 cycloalkyl ring.

Aspect 21. A compound according to any of aspects 1-20, wherein each R ¹ together with the geminal carbon atom to which it is bonded forms a C _3-6 cycloalkyl ring.

Aspect 22. A compound according to any of aspects 1 to 21, wherein each R ¹ together with the geminal carbon atom to which it is bonded forms a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, or a cyclohexyl ring.

Aspect 23. A compound according to any of aspects 1-22, wherein each R ¹ together with the geminal carbon atom to which it is bonded forms a C _3-6 heterocycloalkyl ring or a substituted C _3-6 heterocycloalkyl ring.

Aspect 24. A compound according to any of aspects 1-23, wherein R ² is a single bond.

Aspect 25. A compound according to any one of aspects 1-24, wherein R ² represents a single bond; and R ³ is C _1-6 alkyl.

Aspect 26. A compound according to any of aspects 1-25, wherein R ² is selected from C _1-2 alkanediyl and substituted C _1-2 alkanediyl.

Aspect 27. The compound of aspect 26, wherein the substituent group is selected from –OH, –CN, –CF ₃ , –OCF ₃ , =O, –NO ₂ , C _1-6 alkoxy, C _1-6 alkyl, –COOR, –NR ₂ and –CONR ₂ ; wherein each R is independently selected from hydrogen and C _1-6 alkyl.

Aspect 28. The compound according to aspect 26, wherein the substituent group is selected from –OH, –O–C(O) ^–R4 , –S–C(O) ^–R4 , –NH–C(O) ^–R4 , –C(O)–O–R ⁴ , –C(O)–S–R ⁴ , –C(O)–NH–R ⁴ , –S–S–R ⁴ , –S–R ⁴ , –NH– ^R4 , –CH( _–NH2 )(– ^R4 ) and –CH( _–NH2 )(– ^R4 ); and R ⁴ is selected from hydrogen and C _1-6 alkyl.

Aspect 29. A compound according to any of aspects 26-28, wherein R ² is a substituted C _1-2 alkanediyl; and the stereochemistry of the carbon atom to which the substituent group is bonded is the (S) configuration.

Aspect 30. A compound according to any of aspects 26-28, wherein R ² is a substituted C _1-2 alkanediyl; and the stereochemistry of the carbon atom to which the substituent group is bonded is the (R) configuration.

Aspect 31. A compound according to any one of aspects 1-30, wherein R ² is selected from C _5-6 cycloalkanediyl, C _5-6 heterocycloalkanediyl, C ₆ arendiyl and C _5-6 heterocycloalkanediyl.

Aspect 32. A compound according to any one of aspects 1 to 31, wherein R ³ is selected from –O–C(O)–R ⁴ , –C(O)–O–R ⁴ , –S–C(O)–R ⁴ , –C(O)–S–R ⁴ , –S–S–R ⁴ , –NH–R ⁴ and –CH(–NH ₂ )(–R ⁴ ).

Aspect 33. A compound according to any of aspects 1 to 32, wherein R ³ is –C(O)–O–R ⁴ .

Aspect 34. A compound according to any of aspects 1-33, wherein R ⁴ is selected from C _1-8 alkyl, C _1-8 heteroalkyl, C _5-7 cycloalkyl, C _5-7 heterocycloalkyl, C ₆ aryl, C _7-9 arylalkyl, substituted _C1-8 alkyl, substituted _C1-8 heteroalkyl, substituted _C5-6 cycloalkyl, substituted _C5-6 heterocycloalkyl, substituted _C6 aryl and _C7-9 arylalkyl.

Aspect 35. A compound according to any of aspects 1-34, wherein R ⁴ is selected from C _1-8 alkyl, C _1-8 heteroalkyl, C _7-9 arylalkyl, C _5-7 heterocycloalkyl, substituted C _1-8 alkyl, substituted _C1-8 heteroalkyl, substituted _C7-9 arylalkyl and substituted _C5-7 heterocycloalkyl.

Aspect 36. A compound according to any of aspects 1-35, wherein R ⁴ is selected from C _1-8 alkyl, C _1-8 heteroalkyl, C _7-9 arylalkyl and C _5-7 heterocycloalkyl.

Aspect 37. A compound according to any of aspects 1-36, wherein R ⁴ is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl isobutyl, tert-butyl, 2-methoxyethyl, methylbenzene, oxetane-3 -oxy-yl, cyclopentyl, cyclohexyl and 2-pyrrolidinyl.

Aspect 38. A compound according to any of aspects 1 to 37, wherein R ³ is –C(O)–O–R ⁴ ; and R ⁴ is selected from C _1–8 alkyl, C _1–8 heteroalkyl, C _5–7 cycloalkyl, C _5–7 heterocycloalkyl, C ₆ aryl, C _7–9 arylalkyl, substituted C _1–8 alkyl, substituted C _{1– 8} heteroalkyl, substituted C _5–6 cycloalkyl, substituted C _5–6 heterocycloalkyl, substituted C ₆ aryl and C _7–9 arylalkyl.

Aspect 39. A compound according to any of aspects 1 to 38, wherein R ³ is –C(O)–O–R ⁴ ; and R ⁴ is selected from C _1-8 alkyl, C _1-8 heteroalkyl, C _7-9 arylalkyl, C _5-7 heterocycloalkyl, substituted C _1-8 alkyl, substituted C _1-8 heteroalkyl, substituted C _7-9 arylalkyl and substituted C _5–7 heterocycloalkyl.

Aspect 40. A compound according to any of aspects 1 to 39, wherein R ³ is –C(O)–O–R ⁴ ; and R ⁴ is selected from C _1-8 alkyl, C _1-8 heteroalkyl, C _7-9 arylalkyl and C _5-7 heterocycloalkyl.

Aspect 41. A compound according to any of aspects 1-40, wherein each R ¹ together with the carbon atom to which it is bonded forms a C _4-6 heterocycloalkyl ring containing two adjacent S atoms, or a substituted C _4-6 heterocycloalkyl ring containing at least one heteroatom selected from O and S, and a =O substituent group bonded to a carbon atom adjacent to the at least one heteroatom.

Aspect 42. A compound according to any one of aspects 1 to 41, wherein R ² represents a single bond; R ³ represents C _1–3 alkyl; and each R ¹ together with the carbon atom to which they are bonded form a C _4–6 heterocycloalkyl ring or a substituted C _4–6 heterocycloalkyl ring.

Aspect 43. A compound according to any one of aspects 1 to 42, wherein R ² represents a single bond; R ³ represents C _1–3 alkyl; and each R ¹ together with the carbon atom to which they are bonded form a C _4-6 heterocycloalkyl ring containing two adjacent S atoms, or a substituted C _4-6 heterocycloalkyl ring containing at least one heteroatom selected from O and S, and =O substituent group bonded to the carbon atom adjacent to the heteroatom.

Aspect 44. A compound according to any one of aspects 1 to 43, wherein R ² is a single bond; R ³ represents C _1–3 alkyl; and each R ¹ together with the carbon atom to which they are bonded form a 1,2-dithiolane, 1,2-dithane ring, thiethan-2-one ring, dihydrothiophen-2(3H)-one ring, tetrahydro-2H-tipyran –2-one ring, oxetan-2-one ring, dihydrofuran-2(3H)-one ring, or tetrahydro-2H-pyran-2-one ring.

Aspect 45. A compound according to any one of aspects 1 to 44, wherein each R ¹ is methyl; R ² is selected from single bond, methandiyl, ethanediyl, –CH(–OH)–, –CH(–O–C(O)–CH ₂ CH ₃ )– and 1,2-benzene-diyl; and R ³ is selected from –O–C(O)–R ⁴ , –C(O)–O–R ⁴ , –S–C(O)–R ⁴ , –C(O)–S–R ⁴ , – S–S–R ⁴ , –NHR ⁴ and –CH(–NH ₂ )(–R ⁴ ); wherein R ⁴ is selected from C _1-8 alkyl, C _1-8 heteroalkyl, C _7-9 arylalkyl and C _5-7 heterocycloalkyl.

Aspect 46. A compound according to any one of aspects 1 to 45, wherein each R ¹ is methyl; R ² is selected from single bond, methandiyl, ethanediyl, –CH(–OH)–, –CH(–O–C(O)–CH ₂ CH ₃ )– and 1,2-benzene-diyl; and R ³ is selected from –C(O)–O–R ⁴ ; wherein R ⁴ is selected from C _1-8 alkyl, C _1-8 heteroalkyl, C _7-9 arylalkyl and C _5-7 heterocycloalkyl.

Aspect 47. A compound according to any one of aspects 1 to 46, wherein each R ¹ is methyl; R ² is selected from single bond, methandiyl, ethanediyl, –CH(–OH)–, –CH(–O–C(O)–CH ₂ CH ₃ )– and 1,2-benzene-diyl; and R ³ is selected from –O–C(O)–R ⁴ , –C(O)–O–R ⁴ , –S–C(O)–R ⁴ , –C(O)–S–R ⁴ , – S–S–R ⁴ , –NHR ⁴ and –CH(–NH ₂ )(–R ⁴ ); wherein R ⁴ is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl isobutyl, tert-butyl, 2-methoxyethyl, methylbenzene, oxetan-3-oxy-yl, cyclopentyl, cyclohexyl and 2-pyrrolidinyl.

Aspect 48. A compound according to any one of aspects 1 to 47, wherein each R ¹ is methyl; R ² is selected from single bond, methandiyl, ethanediyl, –CH(–OH)–, –CH(–O–C(O)–CH ₂ CH ₃ )– and 1,2-benzene-diyl; and R ³ is selected from –C(O)–O–R ⁴ ; wherein R ⁴ is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl isobutyl, tert-butyl, 2-methoxyethyl, methylbenzene, oxetan-3-oxy-yl, cyclopentyl, cyclohexyl and 2-pyrrolidinyl.

Aspect 49. A compound according to any of aspects 1-48, wherein A is a single bond and ^R5 , ^R6 and ^R7 are each hydrogen.

Aspect 50. A compound according to any of aspects 1-49, wherein A is a single bond; each R ¹ is independently C _1-3 alkyl; each R ² represents a single bond; and each of R ⁵ , R ⁶ and R ⁷ is hydrogen.

Aspect 51. A compound according to any one of aspects 1 to 50, wherein each R ¹ is methyl; R ² represents a single bond; and R ³ can be –C(O)–O–R ⁴ ; wherein R ⁴ is selected from C _1-10 alkyl, C _1-10 heteroalkyl, C _7-10 alkylarene and C _5-10 heteroalkylcycloalkyl.

Aspect 52. A compound according to any one of aspects 1 to 51, wherein each R ¹ is methyl; R ² represents a single bond; R ³ can be –C(O)–O–R ⁴ ; wherein R ⁴ is selected from C _1-10 alkyl, C _1-10 heteroalkyl, C _7-10 alkylarene and C _5-10 heteroalkylcycloalkyl; R ⁵ , R ⁶ and R ⁷ are each hydrogen; and represents a single bond.

Aspect 53. The connection according to aspect 1, wherein the connection is selected from:

3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl benzoate ( 2);

ethyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( 3);

benzyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( 4);

4-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl benzoate ( 6);

4-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl propionate ( 7);

benzyl (4-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl ) adipata (8);

6–(4–(((((2S,5R)–2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)–3,3– dimethylbutoxy)-6-oxohexanoic acid (9);

methyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( 10);

isopropyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( eleven);

hexyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( 12);

heptyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( 13);

tert-butyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2- dimethylpropanoate (14);

2-methoxyethyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2- dimethylpropanoate (15);

oxetan-3-yl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2, 2-dimethylpropanoate (16);

ethyl 1-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclohexanecarboxylate (17 );

ethyl 1-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclopropanecarboxylate (18 );

ethyl 1-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclobutanecarboxylate (19 );

(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl 1H-imidazol-1-sulfonate (34);

ethyl 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate ( 35);

hexyl 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate ( 36);

heptyl 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate ( 37);

2-methoxyethyl 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4- dimethyl pentanoate (38);

5–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–2,2,4,4 –tetramethylpentyl propionate (39);

5–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–2,2,4,4 –tetramethylpentyl benzoate (40);

5–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–2,2,4,4 –tetramethylpentyl 2,6-dimethylbenzoate (41);

(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl ((3-methyl-2-oxotetrahydrofuran-3-yl)methyl) sulfate (42);

3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl pivalate ( 43);

3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl 3- chloro-2,6-dimethoxybenzoate (44);

4–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–2,2,3,3 –tetramethylbutyl 2,6-dimethylbenzoate (45);

4–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–2,2,3,3 –tetramethylbutyl benzoate (46);

4–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–2,2,3,3 –tetramethylbutyl propionate (47);

(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl ((3-methyl-2-oxotetrahydro-2H-pyran-3-yl)methyl) sulfate (48);

2–(3–(((((2S,5R)–2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)–2,2– dimethylpropyl)phenylacetate (49);

2–(3–(((((2S,5R)–2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)–2,2– dimethylpropyl)phenyl pivalate (50);

S–(4–(((((2S,5R)–2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)–3,3– dimethylbutyl)ethanethioate (51);

S–(5–(((((2S,5R)–2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)–4,4– dimethylpentyl)ethanethioate (52);

S–(3–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–2,2– dimethylpropyl) ethanethiate (53);

3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl 2, 6-dimethylbenzoate (54);

3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl adamantane- 1-carboxylate (55);

diethyl 2-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonate (56);

propyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( 57);

butyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( 58);

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1] octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (59);

4-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl pivalate (60 );

ethyl 2-(((((2S,5R)–2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylbutanoate (61);

4-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl 2, 6-dimethylbenzoate (62);

4–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–3,3–dimethylbutyl adamantane– 1-carboxylate (63);

4-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl 2, 6-dimethoxybenzoate (64);

5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentyl benzoate ( 65);

5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentyl 2, 6-dimethoxybenzoate (66);

5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentyl 2, 6-dimethylbenzoate (67);

5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentyl 2- methyl benzoate (68);

4–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–2,2,3,3 –tetramethylbutyl 3-chloro-2,6-dimethoxybenzoate (69);

2–(((((2S,5R)–2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylpropane- 1,3-diyl dibenzoate (70);

2–(((((2S,5R)–2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylpropane- 1,3-diyl diacetate (71);

5–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–2,2,4,4 –tetramethylpentyl 2,6-dimethoxybenzoate (72);

ethyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylbutanoate ( 73);

(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl ((3,5,5-trimethyl-2-oxotetrahydrofuran-3-yl)methyl) sulfate (74); a pharmaceutically acceptable salt of any of the above; And

combinations of any of the above.

Aspect 54. A pharmaceutical composition comprising a compound according to any of aspects 1 to 53 and a pharmaceutically acceptable base.

Aspect 55. The pharmaceutical composition according to aspect 54, further containing an antibiotic.

Aspect 56. The pharmaceutical composition according to aspect 55, wherein the antibiotic is a β-lactam antibiotic.

Aspect 57. The pharmaceutical composition according to any one of aspects 54 to 56, wherein the pharmaceutical composition is in an oral dosage form.

Aspect 58. The pharmaceutical composition according to any one of aspects 54-57, wherein the pharmaceutical composition is in an oral dosage form.

Aspect 59. A pharmaceutical composition according to any one of aspects 54-58, comprising an amount of a compound according to claim 1 effective for treating a bacterial infection in a patient.

Aspect 60. A method of treating a bacterial infection in a patient, comprising administering to the patient in need of such treatment a therapeutically effective amount of a compound according to any one of aspects 1-53.

Aspect 61. The method of aspect 60, wherein administration comprises oral administration.

Aspect 62. The method of any one of aspects 60-61, wherein administration comprises administering an oral dosage form.

Aspect 63. A method according to any one of aspects 60-62, further comprising administering an antibiotic to a patient.

Aspect 64. The method of any one of aspects 60-63, wherein the antibiotic is a β-lactam antibiotic.

Aspect 65. A method of treating a bacterial infection in a patient, comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition according to any one of aspects 54-59.

Aspect 66. The method of aspect 65, wherein administration comprises oral administration.

Aspect 67. The method of any one of aspects 65-66, wherein administration comprises administering an oral dosage form.

Aspect 68. A method according to any one of aspects 65-67, further comprising administering an antibiotic to a patient.

Aspect 69. The method of Aspect 66, wherein the antibiotic is a β-lactam antibiotic.

Aspect 70. A method of inhibiting β-lactamase in a patient comprising administering to the patient an effective amount of a compound according to any one of aspects 1-53.

Aspect 71. The method of aspect 70, wherein administration comprises oral administration.

Aspect 72. According to any one of aspects 70 to 71, wherein administration includes administration of an oral dosage form.

Aspect 73. A method of inhibiting β-lactamase in a patient, comprising administering to the patient an effective amount of a pharmaceutical composition according to any one of aspects 54-59.

Aspect 74. The method of aspect 73, wherein administration comprises oral administration.

Aspect 75. A method according to any one of aspects 73 to 74, wherein administration includes administration of an oral dosage form.

Aspect 76. Compound of Formula (1):

(1)

or a pharmaceutically acceptable salt thereof, wherein

R ⁵ , R ⁶ and R ⁷ are each hydrogen;

A represents a single bond;

each R ¹ is independently selected from C _1-3 alkyl, or each R ¹ together with the carbon atom to which they are bonded form a C _3-6 cycloalkyl ring;

R ² is selected from single bond, methane-diyl and ethane-diyl; And

R ³ is selected from –C(O)–O–R ⁴ and –S–C(O)–R ⁴ , in which R ⁴ is selected from C _1–10 alkyl, C _1–10 heteroalkyl, C _5–10 arylalkyl, C _3–6 heterocycloalkyl and substituted C _4–10 heterocycloalkylalkyl.

Aspect 77. The compound of Aspect 76, wherein each R ¹ is independently selected from C _1-3 alkyl.

Aspect 78. The compound of Aspect 76, wherein each R ¹ together with the carbon atom to which it is bonded forms a C _3-6 cycloalkyl ring.

Aspect 79. The connection according to aspect 76, wherein R ² is a single bond.

Aspect 80. A compound according to any of aspects 76-79, wherein R ² is methane-diyl.

Aspect 81. A compound according to any of aspects 76-79, wherein R ² is ethane-diyl.

Aspect 82. A compound according to any one of aspects 76-81, wherein R ³ is –C(O)–O–R ⁴ .

Aspect 83. A compound according to any of aspects 76-81, wherein R ³ is –S–C(O)–R ⁴ .

Aspect 84. A compound according to any of aspects 76-83, wherein R ⁴ is C _1-10 alkyl.

Aspect 85. A compound according to any of aspects 76-83, wherein R ⁴ is C _1-10 heteroalkyl.

Aspect 86. A compound according to any of aspects 76-83, wherein R ⁴ is C _5-10 arylalkyl.

Aspect 87. A compound according to any of aspects 76-83, wherein R ⁴ is C _3-6 heterocycloalkyl.

Aspect 88. A compound according to any of aspects 76-83, wherein R ⁴ is substituted C _4-10 heterocycloalkylalkyl.

Aspect 89. Compound of Formula (1):

(1)

or a pharmaceutically acceptable salt thereof, wherein

R ⁵ , R ⁶ and R ⁷ are each hydrogen;

A represents a single bond;

each R ¹ is independently selected from C _1-3 alkyl, or each R ¹ together with the carbon atom to which they are bonded form a C _3-6 cycloalkyl ring;

R ² represents a single bond; And

R ³ is –C(O)–O–R ⁴ where R ⁴ is selected from C _1-10 alkyl, C _1-10 heteroalkyl, C _5-10 arylalkyl, C _3-6 heterocycloalkyl and substituted C _4-10 heterocycloalkylalkyl .

Aspect 90. The compound of aspect 89, wherein each R ¹ is independently selected from C _1-3 alkyl.

Aspect 91. The compound of Aspect 89, wherein each R ¹ together with the carbon atom to which it is bonded forms a C _3-6 cycloalkyl ring.

Aspect 92. A compound according to any one of aspects 89-91, wherein R ⁴ is selected from C _1-7 alkyl, C _1-10 heteroalkyl in which one or more heteroatoms is oxygen, –CH ₂ –C _4-6 cycloalkyl, – (CH ₂ ) ₂ –C _4–6 cycloalkyl, C _3–6 heterocycloalkyl, in which one or more heteroatoms is oxygen, and –CH ₂ –C _3–6 substituted heterocycloalkyl and –(CH ₂ ) ₂ –C _3–6 substituted heterocycloalkyl.

Aspect 93. The compound of Aspect 92, wherein in the substituted C _3-6 heterocycloalkyl, one or more heteroatoms is oxygen and one or more substituents are independently selected from C _1-3 alkyl and =O.

Aspect 94. A compound according to any of aspects 89-94, wherein each R ¹ is methyl, or each R ¹ together with the carbon atom to which they are bonded form a cyclohexyl ring or a cyclopentyl ring.

Aspect 95. A compound according to any of aspects 89-95, wherein R ⁴ is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, n-hexyl, n-heptyl, –CH ₂ –CH ₂ –O–CH ₃ , benzyl, 3-oxetanyl and methyl-5-methyl-1,3-dioxol-2-one.

Aspect 96. Connection according to aspect 89, while

R ⁵ , R ⁶ and R ⁷ are each hydrogen;

A represents a single bond;

each R ¹ represents methyl, or each R ¹ together with the carbon atom to which they are bonded form a cyclohexyl ring or a cyclopentyl ring;

R ² represents a single bond; And

R ³ represents –C(O)–O–R ⁴ , in which R ⁴ is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, n-hexyl, n-heptyl, –CH ₂ –CH ₂ – O–CH ₃ , –CH ₂ –phenyl (benzyl), 3-oxetanyl and methyl-5-methyl-1,3-dioxol-2-one.

Aspect 97. Compound of Formula (1):

(1)

or a pharmaceutically acceptable salt thereof, wherein

R ⁵ , R ⁶ and R ⁷ are each hydrogen;

A represents a single bond;

each R ¹ is independently selected from C _1-3 alkyl, or each R ¹ together with the carbon atom to which they are bonded form a C _3-6 cycloalkyl ring;

R ² represents –(CH ₂ ) ₂ –; And

R ³ is –C(O)–O–R ⁴ in which R ⁴ is selected from C _1-10 alkyl, C _1-10 heteroalkyl, C _5-10 arylalkyl, C _3-6 heterocycloalkyl and substituted C _4-10 heterocycloalkylalkyl.

Aspect 98. The compound of Aspect 97, wherein each R ¹ is independently selected from C _1-3 alkyl.

Aspect 99. The compound of Aspect 97, wherein each R ¹ together with the carbon atom to which it is bonded forms a C _3-6 cycloalkyl ring.

Aspect 100. A compound according to any of aspects 97-99, wherein R ⁴ is selected from C _1-7 alkyl, C _1-10 heteroalkyl in which one or more heteroatoms is oxygen, –CH ₂ –C _4-6 cycloalkyl, – (CH ₂ ) ₂ –C _4–6 cycloalkyl, C _3–6 heterocycloalkyl, in which one or more heteroatoms is oxygen, –CH ₂ –C _3–6 substituted heterocycloalkyl and –(CH ₂ ) ₂ –C _3–6 substituted heterocycloalkyl.

Aspect 101. A compound according to Aspect 100, wherein in the substituted C _3-6 heterocycloalkyl, one or more heteroatoms is oxygen and one or more substituents are independently selected from C _1-3 alkyl and =O.

Aspect 102. A compound according to any of aspects 97-99, wherein R ⁴ is C _1-10 alkyl.

Aspect 103. Connection according to aspect 97, while

R ⁵ , R ⁶ and R ⁷ are each hydrogen;

A represents a single bond;

each R ¹ represents methyl;

R ² represents –(CH ₂ ) ₂ –; And

R ³ is –C(O)–O–R ⁴ , where R ⁴ is selected from n-hexyl and n-heptyl.

Aspect 104. Compound of Formula (1):

(1)

or a pharmaceutically acceptable salt thereof, wherein

R ⁵ , R ⁶ and R ⁷ are each hydrogen;

A represents a single bond;

each R ¹ is selected from C _1-3 alkyl, or each R ¹ together with the carbon atom to which they are bonded form a C _3-6 cycloalkyl ring;

R ² represents –CH ₂ –; And

R ³ is –S–C(O)–R ⁴ in which R ⁴ is selected from C _1–10 alkyl, C _1–10 heteroalkyl, C _5–10 arylalkyl, C _3–6 heterocycloalkyl substituted with C _4–10 heterocycloalkylalkyl.

Aspect 105. The compound of Aspect 104, wherein each R ¹ is independently selected from C _1-3 alkyl.

Aspect 106. The compound of Aspect 104, wherein each R ¹ together with the carbon atom to which it is bonded forms a C _3-6 cycloalkyl ring.

Aspect 107. A compound according to any of aspects 104-106, wherein R ⁴ is selected from C _1-7 alkyl, C _1-10 heteroalkyl in which one or more heteroatoms is oxygen, –CH ₂ CH ₂ –C _4-6 cycloalkyl , –(CH ₂ ) ₂ –C _4–6 cycloalkyl, C _3–6 heterocycloalkyl, in which one or more heteroatoms is oxygen, –CH ₂ –C _3–6 substituted heterocycloalkyl, –(CH ₂ ) ₂ –C _{3– 6} substituted heterocycloalkyl.

Aspect 108. The compound of Aspect 107, wherein, in the substituted C _3-6 heterocycloalkyl, one or more heteroatoms is oxygen and one or more substituents are independently selected from C _1-3 alkyl and =O.

Aspect 109. A compound according to any one of aspects 104-106, wherein R ⁴ is C _1-10 alkyl.

Aspect 110. The connection according to aspect 104, wherein

R ⁵ , R ⁶ and R ⁷ are each hydrogen;

A represents a single bond;

each R ¹ represents methyl;

R ² represents –CH ₂ CH ₂ –; And

^R3 is –S–C(O) ^–R4 , in which ^R4 is methyl

Aspect 111. Compound of Formula (1):

(1)

or a pharmaceutically acceptable salt thereof, wherein

R ⁵ , R ⁶ and R ⁷ are each hydrogen;

A represents a single bond;

each R ¹ together with the carbon atom to which they are bonded form a C _3–6 cycloalkyl ring, a C _3–6 heterocycloalkyl ring, a C _3–6 cycloalkyl ring, or a C _3–6 heterocycloalkyl ring;

R ² represents a single bond; And

R ³ represents C _1-3 alkyl.

Aspect 112. The compound of aspect 111, wherein each R1, together with the carbon atom to which it is bonded, forms a C _3-6 heterocycloalkyl ring or a C _3-6 heterocycloalkyl ring;

Aspect 113. The compound of Aspect 112, wherein one or more heteroatoms is oxygen and one or more substituents are =O.

Aspect 114. Connection according to Aspect 111, wherein

each R ¹ together with the carbon atom to which they are bonded form a dihydrofuran–2(3H)–one ring;

R ² represents a single bond; And

R ³ represents methyl.

Aspect 115. Compound of Formula (1):

(1)

or a pharmaceutically acceptable salt thereof, wherein

R ⁵ , R ⁶ and R ⁷ are each hydrogen;

A represents a single bond;

each R ¹ is independently selected from C _1-3 alkyl;

R ² is selected from single bond and methandiyl; And

R ³ is selected from –O–C(O)–R ⁴ and –C(O)–O–R ⁴ , in which R ⁴ is selected from C _1–10 alkyl and substituted phenyl.

Aspect 116. The connection according to aspect 115, wherein R ² is a single bond.

Aspect 117. The compound of aspect 115, wherein R ² is methandiyl.

Aspect 118. A compound according to any one of aspects 115-117, wherein R ³ is –O–C(O)–R ⁴ .

Aspect 119. A compound according to any one of aspects 115-117, wherein R ² is methandiyl; and R ³ is –O–C(O)–R ⁴ .

Aspect 120. A compound according to any one of aspects 115-117, wherein R ³ is –C(O)–O–R ⁴ .

Aspect 121. A compound according to any one of aspects 115-117, wherein R ² is a single bond; and R ³ is –C(O)–O–R ⁴ .

Aspect 122. The connection according to aspect 115, wherein R ² represents a single bond; R ³ represents –C(O)–O–R ⁴ ; and R ⁴ is C _1-3 alkyl.

Aspect 123. A compound according to any of aspects 115-122, wherein R ⁴ is C _1-10 alkyl.

Aspect 124. A compound according to any of aspects 115-122, wherein R ⁴ is C _1-4 alkyl.

Aspect 125. A compound according to any of aspects 115-122, wherein R ⁴ is substituted phenyl.

Aspect 126. The compound of aspect 115, wherein R ² is methandiyl; R ³ is –O–C(O)–R ⁴ ; and R ⁴ is substituted phenyl.

Aspect 127. The compound of Aspect 126, wherein one or more substituents are independently selected from halogen, _C1-3 alkyl, and _C1-3 alkoxy.

Aspect 128. The compound of Aspect 126, wherein the substituted phenyl is a 2,6-substituted phenyl.

Aspect 129. The compound of Aspect 128, wherein each of the substituents is selected from _C1-3 alkyl and _C1-3 alkoxy.

Aspect 130. The compound of Aspect 126, wherein the substituted phenyl is a 2,5,6-substituted phenyl.

Aspect 131. The compound of Aspect 130, wherein each of the substituents at positions 2 and 6 is independently selected from _C1-3 alkyl and _C1-3 alkoxy; and the substituent at position 5 is halogen.

Aspect 132. Compound of Formula (1):

(1)

or a pharmaceutically acceptable salt thereof, wherein

R ⁵ , R ⁶ and R ⁷ are each hydrogen;

A represents a single bond;

each R ¹ is independently selected from C _1-3 alkyl;

R ² represents a single bond; And

R ³ is –CH=C(R ⁴ ) ₂ , where each R ⁴ is –C(O)–O–R ⁸ , or each R ⁴ together with the carbon atom to which they are bonded form a substituted heterocyclohexyl ring; And

each R ⁸ is C _1-4 alkyl.

Aspect 133. The compound of aspect 132, each R ⁴ is –C(O)–O–R ⁸ .

Aspect 134. The compound of aspect 132, each R ⁴ is –C(O)–O–R ⁸ , or each R ⁴ together with the carbon atom to which they are bonded form a substituted heterocyclohexyl ring.

Aspect 135. The compound of Aspect 133, wherein on the substituted heterocyclohexyl ring one or more heteroatoms are oxygen.

Aspect 136. A compound according to any of aspects 134-135, wherein on the substituted heterocyclohexyl ring one or more substituents are independently selected from C _1-3 alkyl and =O.

Aspect 137. The compound of Aspect 134, wherein the substituted heterocycloalkyl ring is 2,2-dimethyl-5-yl-1,3-dioxane-4,6-dione.

Aspect 138. Compound of Formula (1):

(1)

or a pharmaceutically acceptable salt thereof, wherein

R ⁵ , R ⁶ and R ⁷ are each hydrogen;

A represents a single bond;

each R ¹ is independently selected from C _1-3 alkyl;

R ² is selected from single bond and methandiyl; And

R ³ is a substituted phenyl in which one or more substituents are independently selected from –CH ₂ –O–C(O)–R ⁴ and –O–C(O)–R ⁴ in which R ⁴ is selected from C _{1– 10} alkyl and phenyl.

Aspect 139. The connection according to aspect 138, wherein R ² is a single bond.

Aspect 140. The compound of aspect 138, wherein R ² is methandiyl;

Aspect 141. The compound according to aspect 138, wherein R ² represents 2-substituted phenyl.

Aspect 142. A compound according to any of aspects 138-141, wherein one or more substituents is –CH ₂ –O–C(O)–R ⁴ .

Aspect 143. A compound according to any of aspects 138-141, wherein one or more substituents is –O–C(O)–R ⁴ .

Aspect 144. A compound according to any of aspects 138-143, wherein R ⁴ is C _1-10 alkyl.

Aspect 145. A compound according to any of aspects 138-143, wherein R ⁴ is selected from methyl, ethyl, isopropyl, pivalolyl and phenyl.

Aspect 146. Compound of Formula (1):

(1)

or a pharmaceutically acceptable salt thereof, wherein

R ⁵ , R ⁶ and R ⁷ are each hydrogen;

A represents a single bond;

each R ¹ is independently selected from C _1-3 alkyl;

R ² is selected from –C(R ⁸ ) ₂ – and –CH ₂ –C(R ⁸ ) ₂ –, where each R ⁸ is independently selected from C _1-3 alkyl; And

R3 is selected from –C(O)–O– ^R4 and –O–C(O) ^–R4 , in which ^R4 is selected from _C1-10 alkyl, _C1-10 heteroalkyl, substituted _C1-10 alkyl, substituted C _1–10 heteroalkyl and 4(yl-methyl)-5-methyl-1,3-dioxol-2-one.

Aspect 147. The compound of aspect 146, wherein each R ¹ is methyl.

Aspect 148. A compound according to any one of aspects 146-147, wherein R ² is –C(R ⁸ ) ₂ –.

Aspect 149. A compound according to any one of aspects 146-147, wherein R ² is –CH ₂ –C(R ⁸ ) ₂ –.

Aspect 150. A compound according to any one of aspects 146-149, wherein each ^R8 is methyl.

Aspect 151. A compound according to any one of aspects 146-149, wherein each R ¹ is methyl; and each R ⁸ is methyl.

Aspect 152. A compound according to any one of aspects 146-151, wherein R ³ is –C(O)–O–R ⁴ .

Aspect 153. A compound according to any of aspects 146-151, wherein R ³ is –O–C(O)–R ⁴ .

Aspect 154. Compound of Formula (1):

(1)

or a pharmaceutically acceptable salt thereof, wherein

R ⁵ , R ⁶ and R ⁷ are each hydrogen;

A represents a single bond;

each R ¹ together with the carbon atom to which they are bonded form a substituted C _5–6 heterocyclic ring;

R ² represents a single bond; And

R ³ represents C _1-3 alkyl.

Aspect 155. A compound according to Aspect 155, wherein on the substituted C _5-6 heterocyclic ring, one or more heteroatoms is oxygen, and one or more substituents are independently selected from C _1-3 alkyl and =O.

Aspect 156. The compound of Aspect 155, wherein each R ¹ , together with the carbon atom to which it is bonded, forms a tetrahydro-2H-pyran-2-one ring.

Aspect 157. Connection according to aspect 155, wherein

R ⁵ , R ⁶ and R ⁷ are each hydrogen;

A represents a single bond;

each R ¹ is independently selected from C _1-3 alkyl;

R ² is selected from C _2–4 alkanediyl; And

R ³ is a substituted C _5-6 heterocycloalkyl in which one or more heteroatoms are independently selected from N and O, and one or more substituents are independently selected from C _1-3 alkyl and =O.

Aspect 158. The compound according to aspect 157, wherein R ⁴ has the structure of formula (6):

(6)

in which R ⁹ is selected from hydrogen, C _1–6 alkyl, C _4–6 cycloalkyl, C _1–6 heteroalkyl, C _4–6 heterocycloalkyl, substituted C _1–6 alkyl, substituted C _4–6 cycloalkyl, substituted C _{1– 6} heteroalkyl and substituted C _4–6 heterocycloalkyl.

Aspect 159. The compound of Aspect 158, wherein R ⁹ is selected from hydrogen and C _1-6 alkyl.

Aspect 160. The connection according to aspect 1, wherein the connection is selected from:

ethyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( 3);

benzyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( 4);

methyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( 10);

isopropyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( eleven);

hexyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( 12);

heptyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( 13);

tert-butyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2- dimethylpropanoate (14);

2-methoxyethyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2- dimethylpropanoate (15);

oxetan-3-yl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2, 2-dimethylpropanoate (16);

ethyl 1-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclohexanecarboxylate (17 );

ethyl 1-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclopropanecarboxylate (18 );

ethyl 1-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclobutanecarboxylate (19 );

hexyl 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate ( 36);

heptyl 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate ( 37);

(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl ((3-methyl-2-oxotetrahydrofuran-3-yl)methyl) sulfate (42);

S–(3–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–2,2– dimethylpropyl) ethanethiate (53);

propyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( 57);

butyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate ( 58);

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1] octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (59);

a pharmaceutically acceptable salt of any of the above; And

combinations of any of the above.

Aspect 161. Compound of Formula (4):

(4)

or a pharmaceutically acceptable salt thereof, wherein

each R ¹ is independently selected from C _1-3 alkyl, or each R ¹ together with the carbon atom to which they are bonded form a C _3-6 cycloalkyl ring;

R ² represents a single bond; And

R ³ is –C(O)–O–R ⁴ in which R ⁴ is selected from C _1-10 alkyl, C _1-10 heteroalkyl, C _5-10 arylalkyl, C _3-6 heterocycloalkyl and substituted C _4-10 heterocycloalkylalkyl.

Aspect 162. The compound of Aspect 161, wherein each R ¹ is independently selected from C _1-3 alkyl.

Aspect 163. The compound of Aspect 161, wherein each R ¹ together with the carbon atom to which it is bonded forms a C _3-6 cycloalkyl ring.

Aspect 164. A compound according to any of aspects 161-163, wherein R ⁴ is selected from C _1-7 alkyl, C _1-10 heteroalkyl in which one or more heteroatoms is oxygen, –CH ₂ –C _4-6 cycloalkyl, – (CH ₂ ) ₂ –C _4–6 cycloalkyl, C _3–6 heterocycloalkyl, in which one or more heteroatoms is oxygen, –CH ₂ –C _3–6 substituted heterocycloalkyl and –(CH ₂ ) ₂ –C _3–6 substituted heterocycloalkyl.

Aspect 165. The compound of Aspect 163, wherein in the substituted C _3-6 heterocycloalkyl, one or more heteroatoms is oxygen and one or more substituents are independently selected from C _1-3 alkyl and =O.

Aspect 166. The compound of aspect 161, wherein each R ¹ is methyl, or each R ¹ together with the carbon atom to which they are bonded form a cyclohexyl ring or a cyclopentyl ring.

Aspect 167. A compound according to any of aspects 161-166, wherein R ⁴ is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, n-hexyl, n-heptyl, –CH ₂ –CH ₂ –O–CH ₃ , benzyl, 3-oxetanyl and methyl-5-methyl-1,3-dioxol-2-one.

Aspect 168. Connection according to aspect 161, wherein

R ⁵ , R ⁶ and R ⁷ are each hydrogen;

A represents a single bond;

R ² represents a single bond; And

R ³ is –C(O)–O–R ⁴ in which R ⁴ is C _1–10 alkyl.

Aspect 169 The compound of formula (4) is selected from:

ethyl 2,2-dimethyl-3-(((((2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy )sulfonyl)oxy)propanoate (20);

2-methoxyethyl 2,2-dimethyl-3-(((((2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl )oxy)sulfonyl)oxy)propanoate (21);

4–((2S,5R)–6–(((3–(hexyloxy)–2,2–dimethyl–3–oxopropoxy)sulfonyl)oxy)–7–oxo–1,6–diazabicyclo[3.2.1]octane –2-carboxamido)piperidine-1-ium 2,2,2-trifluoroacetate (22);

4–((2S,5R)–6–(((3–(heptyloxy)–2,2–dimethyl–3–oxopropoxy)sulfonyl)oxy)–7–oxo–1,6–diazabicyclo[3.2.1]octane –2-carboxamido)piperidine-1-ium 2,2,2-trifluoroacetate (23);

4–((2S,5R)–6–((((1–(ethoxycarbonyl)cyclohexyl)methoxy)sulfonyl)oxy)–7–oxo–1,6–diazabicyclo[3.2.1]octane–2–carboxamido)piperidine –1-ium 2,2,2-trifluoroacetate (24);

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2,2-dimethyl-3-(((((2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl )-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)propanoate (25);

a pharmaceutically acceptable salt of any of the above; And

combinations of any of the above.

Aspect 170 The compound of formula (4) is selected from:

ethyl 2,2-dimethyl-3-(((((2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy )sulfonyl)oxy)propanoate (20);

4–((2S,5R)–6–(((3–(hexyloxy)–2,2–dimethyl–3–oxopropoxy)sulfonyl)oxy)–7–oxo–1,6–diazabicyclo[3.2.1]octane –2-carboxamido)piperidine-1-ium 2,2,2-trifluoroacetate (22);

4–((2S,5R)–6–(((3–(heptyloxy)–2,2–dimethyl–3–oxopropoxy)sulfonyl)oxy)–7–oxo–1,6–diazabicyclo[3.2.1]octane –2-carboxamido)piperidine-1-ium 2,2,2-trifluoroacetate (23);

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2,2-dimethyl-3-(((((2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl )-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)propanoate (25);

a pharmaceutically acceptable salt of any of the above; And

combinations of any of the above.

Aspect 171 The compound of formula (5) is selected from:

ethyl 3–(((((2S,5R)–2–((2–aminoethoxy)carbamoyl)–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy) –2,2-dimethylpropanoate (27);

2-methoxyethyl 3-(((((2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl) oxy)-2,2-dimethylpropanoate (28);

TFA salts (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 3-(((((2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1 ,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (29);

TFA salts hexyl 3–(((((2S,5R)–2–((2-aminoethoxy)carbamoyl)–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl) hydroxy)-2,2-dimethylpropanoate (30);

TFA salts heptyl 3–(((((2S,5R)–2–((2-aminoethoxy)carbamoyl)–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl) oxy)-2,2-dimethylpropanoate (31);

TFA salts ethyl-1-(((((2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy) sulfonyl)oxy)methyl)cyclohexanecarboxylate (32);

a pharmaceutically acceptable salt of any of the above; And

combinations of any of the above.

Aspect 172. A pharmaceutical composition comprising a compound according to any one of aspects 76 to 171 and a pharmaceutically acceptable base.

Aspect 173. The pharmaceutical composition according to aspect 172, further containing an antibiotic.

Aspect 174. The pharmaceutical composition of Aspect 173, wherein the antibiotic is a β-lactam antibiotic.

Aspect 175. The pharmaceutical composition according to any one of aspects 172 to 174, wherein the pharmaceutical composition is in an oral dosage form.

Aspect 176. The pharmaceutical composition according to any one of aspects 172-175, wherein the pharmaceutical composition is in an oral dosage form.

Aspect 177. A pharmaceutical composition according to any one of aspects 172-176, comprising an amount of a compound according to any one of aspects 76-171 effective for treating a bacterial infection in a patient.

Aspect 178. A method of treating a bacterial infection in a patient, comprising administering to the patient in need of such treatment a therapeutically effective amount of a compound according to any one of aspects 76-171.

Aspect 179. The method of aspect 178, wherein administration comprises oral administration.

Aspect 180. The method of any one of aspects 178-179, wherein administration comprises administering an oral dosage form.

Aspect 181. A method according to any one of aspects 178-180, further comprising administering an antibiotic to a patient.

Aspect 182. The method of any one of aspects 178-181, wherein the antibiotic is a β-lactam antibiotic.

Aspect 183. A method of treating a bacterial infection in a patient, comprising administering to the patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition according to any one of aspects 172-177.

Aspect 184. The method of aspect 183, wherein administration comprises oral administration.

Aspect 185. The method of any one of aspects 183-184, wherein administration comprises administering an oral dosage form.

Aspect 186. A method according to any one of aspects 183-185, further comprising administering an antibiotic to a patient.

Aspect 187. The method of Aspect 184, wherein the antibiotic is a β-lactam antibiotic.

Aspect 188. A method of inhibiting β-lactamase in a patient comprising administering to the patient an effective amount of a compound according to any one of aspects 76-171.

Aspect 189. The method of aspect 188, wherein administration comprises oral administration.

Aspect 190. According to any one of aspects 188-189, wherein administration includes administration of an oral dosage form.

Aspect 191 A method of inhibiting β-lactamase in a patient comprising administering to the patient an effective amount of a pharmaceutical composition according to any one of aspects 172-177.

Aspect 192. The method of aspect 191, wherein administration comprises oral administration.

Aspect 193. The method of any one of aspects 191-192, wherein administration comprises administering an oral dosage form.

Aspect 194: A method for producing a cyclic hydroxamic acid monoester sulfuric acid analogue, comprising reacting cyclic hydroxamic acid with a chlorosulfonic acid ester in the presence of a base to produce a sulfuric acid monoester analogue.

Aspect 195. The method of Aspect 194, wherein the cyclic hydroxamic acid has the structure of formula (82) and the chlorosulfonic acid ester has the structure of the formula (83):

(82) (83)

Where

R is selected from C _1-8 alkyl, C _1-8 heteroalkyl, C _5-8 cycloalkyl, C _5-8 heterocycloalkyl, C _5-10 cycloalkylalkyl, C _5-10 heterocycloalkylalkyl, C _6-8 aryl, C _5-8 heteroaryl , C _7–10 arylalkyl, C _5–10 heteroarylalkyl, substituted C _1–8 alkyl, substituted C _1–8 heteroalkyl, substituted C _5–8 cycloalkyl, substituted C _5–8 heterocycloalkyl, substituted C _5–10 cycloalkylalkyl, substituted C _5-10 heterocycloalkylalkyl, substituted _C6-8 aryl, substituted _C5-8 heteroaryl, substituted _C7-10 arylalkyl and substituted _C5-10 heteroarylalkyl;

n is an integer from 1 to 6;

each A is independently selected from –(CH ₂ )–, –(CHR)–, –(CR ₂ )–, –NH–, –NR–, O and S, where R is independently selected from hydrogen, C _1-8 alkyl, C _1–8 heteroalkyl, C _5–8 cycloalkyl, C _5–8 heterocycloalkyl, C _5–10 cycloalkylalkyl, C _5–10 heterocycloalkylalkyl, C _6–8 aryl, C _5–8 heteroaryl, C _7–10 arylalkyl, C _{5 –10} heteroarylalkyl, substituted C _1–8 alkyl, substituted C _1–8 heteroalkyl _{, substituted C 5–8 cycloalkyl, substituted C 5–8 heterocycloalkyl, substituted C 5–10 cycloalkylalkyl, substituted C 5–10 heterocycloalkylalkyl , substituted} C _{6– 8} aryl, substituted C _5–8 heteroaryl, substituted C _7–10 arylalkyl and substituted C _5–10 heteroarylalkyl; or one A is linked to another A through a –L– group, where L is selected from C _1-8 alkyl, C _1-8 heteroalkyl, substituted C _1-8 alkyl and substituted C _1-8 heteroalkyl.

Aspect 196. The method of Aspect 194, wherein the sulfuric acid monoester analog contains a compound of formula (80a) and the cyclic hydroxamic acid contains a compound of formula (80b):

(80a) (80b)

in which

R is selected from C _1-8 alkyl, C _1-8 heteroalkyl, C _5-8 cycloalkyl, C _5-8 heterocycloalkyl, C _5-10 cycloalkylalkyl, C _5-10 heterocycloalkylalkyl, C _6-8 aryl, C _5-8 heteroaryl , C _7–10 arylalkyl, C _5–10 heteroarylalkyl, substituted C _1–8 alkyl, substituted C _1–8 heteroalkyl, substituted C _5–8 cycloalkyl, substituted C _5–8 heterocycloalkyl, substituted C _5–10 cycloalkylalkyl, substituted C _5-10 heterocycloalkylalkyl, substituted _C6-8 aryl, substituted _C5-8 heteroaryl, substituted _C7-10 arylalkyl and substituted _C5-10 heteroarylalkyl;

R ⁵ is selected from hydrogen, C _1-6 alkyl, C _5-8 cycloalkyl, C _6-12 cycloalkylalkyl, C _2-6 heteroalkyl, C _5-8 heterocycloalkyl, C _6-12 heterocycloalkylalkyl, substituted C _1-6 alkyl, substituted _C5-8 cycloalkyl, substituted _C6-12 cycloalkylalkyl, substituted _C2-6 heteroalkyl, substituted _C5-8 heterocycloalkyl and substituted _C6-12 heterocycloalkylalkyl;

R ⁶ is selected from hydrogen, C _1-6 alkyl, C _5-8 cycloalkyl, C _6-12 cycloalkylalkyl, C _2-6 heteroalkyl, C _5-8 heterocycloalkyl, C _6-12 heterocycloalkylalkyl, substituted C _1-6 alkyl, substituted _C5-8 cycloalkyl, substituted _C6-12 cycloalkylalkyl, substituted _C2-6 heteroalkyl, substituted _C5-8 heterocycloalkyl and substituted _C6-12 heterocycloalkylalkyl; And

A represents a single bond (–) and R ⁷ represents hydrogen, or A represents a double bond (=) and R ⁷ represents C _1–3 alkyl.

Aspect 197. The method of any one of aspects 194-196, wherein the chlorosulfonic acid monoester is a neopentyl chlorosulfonic acid ester.

Aspect 198. The method according to any one of aspects 194-197, wherein the neopentyl chlorosulfonic acid ester has the structure of formula (81):

(81)

in which

each R ¹ is independently selected from C _1–6 alkyl, or each R ¹ and the geminal carbon atom to which they are bonded forms a C _3–6 cycloalkyl ring, a C _3–6 heterocycloalkyl ring, a substituted C _3–6 cycloalkyl ring, or a substituted C _3–6 heterocycloalkyl ring;

R ² is selected from single bond, C _1-6 alkanediyl, C _1-6 heteroalkanediyl, C _5-6 cycloalkanediyl, C _5-6 heterocycloalkanediyl, C ₆ arenediyl, C _5-6 heteroarendiyl, substituted C _1-6 alkanediyl, substituted C _1-6 heteroalkanediyl, substituted _C5-6 cycloalkanediyl, substituted _C5-6 heterocycloalkanediyl, substituted _C6 arenediyl and substituted _C5-6 heteroarendiyl; And

R ³ is selected from C _1–6 alkyl, –O–C(O)–R ⁴ , –S–C(O)–R ⁴ , –NH–C(O)–R ⁴ , –O–C(O) –O–R ⁴ , –S–C(O)–O–R ⁴ , –NH–C(O)–O–R ⁴ , –C(O)–O–R ⁴ , –C(O)–S –R ⁴ , –C(O)–NH–R ⁴ , –O–C(O)–O–R ⁴ , –O–C(O)–S–R ⁴ , –O–C(O)–NH –R ⁴ , –S–S–R ⁴ , –S–R ⁴ , –NH–R ⁴ , –CH(–NH ₂ )(–R ⁴ ), C _5–6 heterocycloalkyl, C _5–6 heteroaryl, substituted C _5–6 cycloalkyl, substituted C _5–6 heterocycloalkyl, substituted C _5–6 aryl, substituted C _5–6 heteroaryl and –CH=C(R ⁴ ) ₂ , in which

R ⁴ is selected from hydrogen, C _1–8 alkyl, C _1–8 heteroalkyl, C _5–8 cycloalkyl, C _5–8 heterocycloalkyl, C _5–10 cycloalkylalkyl, C _5–10 heterocycloalkylalkyl, C _6–8 aryl, C _{5 –8} heteroaryl, C _7–10 arylalkyl, C _5–10 heteroarylalkyl, substituted C _1–8 alkyl, substituted C _1–8 heteroalkyl, substituted C _5–8 cycloalkyl, substituted C _5–8 heterocycloalkyl, substituted C _5–10 cycloalkylalkyl , substituted C _5–10 heterocycloalkylalkyl, substituted C _6–8 aryl, substituted C _5–8 heteroaryl, substituted C _7–10 arylalkyl and substituted C _5–10 heteroarylalkyl.

Aspect 199. A method according to any one of aspects 194-198, wherein chlorosulfonic acid monoesters are prepared by reacting an alcohol with sulfuryl chloride.

Aspect 200. The method of aspect 199, wherein the alcohol is neopentyl alcohol.

Aspect 201. The method of Aspect 194, wherein the sulfuric acid monoester analogue has the structure of formula (1):

(1)

or a pharmaceutically acceptable salt thereof, wherein

each R ¹ is independently selected from C _1–6 alkyl, or each R ¹ and the geminal carbon atom to which they are bonded forms a C _3–6 cycloalkyl ring, a C _3–6 heterocycloalkyl ring, a substituted C _3–6 cycloalkyl ring, or a substituted C _3–6 heterocycloalkyl ring;

R ² is selected from single bond, C _1-6 alkanediyl, C _1-6 heteroalkanediyl, C _5-6 cycloalkanediyl, C _5-6 heterocycloalkanediyl, C ₆ arenediyl, C _5-6 heteroarendiyl, substituted C _1-6 alkanediyl, substituted C _1-6 heteroalkanediyl, substituted _C5-6 cycloalkanediyl, substituted _C5-6 heterocycloalkanediyl, substituted _C6 arenediyl and substituted _C5-6 heteroarendiyl;

R ³ is selected from C _1–6 alkyl, –O–C(O)–R ⁴ , –S–C(O)–R ⁴ , –NH–C(O)–R ⁴ , –O–C(O) –O–R ⁴ , –S–C(O)–O–R ⁴ , –NH–C(O)–O–R ⁴ , –C(O)–O–R ⁴ , –C(O)–S –R ⁴ , –C(O)–NH–R ⁴ , –O–C(O)–O–R ⁴ , –O–C(O)–S–R ⁴ , –O–C(O)–NH –R ⁴ , –S–S–R ⁴ , –S–R ⁴ , –NH–R ⁴ , –CH(–NH ₂ )(–R ⁴ ), C _5–6 heterocycloalkyl, C _5–6 heteroaryl, substituted C _5–6 cycloalkyl, substituted C _5–6 heterocycloalkyl, substituted C _5–6 aryl, substituted C _5–6 heteroaryl and –CH=C(R ⁴ ) ₂ , in which

R ⁴ is selected from hydrogen, C _1–8 alkyl, C _1–8 heteroalkyl, C _5–8 cycloalkyl, C _5–8 heterocycloalkyl, C _5–10 cycloalkylalkyl, C _5–10 heterocycloalkylalkyl, C _6–8 aryl, C _{5 –8} heteroaryl, C _7–10 arylalkyl, C _5–10 heteroarylalkyl, substituted C _1–8 alkyl, substituted C _1–8 heteroalkyl, substituted C _5–8 cycloalkyl, substituted C _5–8 heterocycloalkyl, substituted C _5–10 cycloalkylalkyl , substituted C _5-10 heterocycloalkylalkyl, substituted C _6-8 aryl, substituted C _5-8 heteroaryl, substituted C _7-10 arylalkyl and substituted C _5-10 heteroarylalkyl;

R ⁵ is selected from hydrogen, C _1-6 alkyl, C _5-8 cycloalkyl, C _6-12 cycloalkylalkyl, C _2-6 heteroalkyl, C _5-8 heterocycloalkyl, C _6-12 heterocycloalkylalkyl, substituted C _1-6 alkyl, substituted _C5-8 cycloalkyl, substituted _C6-12 cycloalkylalkyl, substituted _C2-6 heteroalkyl, substituted _C5-8 heterocycloalkyl and substituted _C6-12 heterocycloalkylalkyl;

R ⁶ is selected from hydrogen, C _1-6 alkyl, C _5-8 cycloalkyl, C _6-12 cycloalkylalkyl, C _2-6 heteroalkyl, C _5-8 heterocycloalkyl, C _6-12 heterocycloalkylalkyl, substituted C _1-6 alkyl, substituted _C5-8 cycloalkyl, substituted _C6-12 cycloalkylalkyl, substituted _C2-6 heteroalkyl, substituted _C5-8 heterocycloalkyl and substituted _C6-12 heterocycloalkylalkyl; And

A represents a single bond (–) and R ⁷ represents hydrogen, or A represents a double bond (=) and R ⁷ represents C _1–3 alkyl.

EXAMPLES

The following examples describe in detail the synthesis of compounds of formula (1), characterization of compounds of formula (1), and use of compounds of formula (1). Those skilled in the art will appreciate that many modifications of both materials and methods can be practiced without departing from the scope of the disclosure.

Example 1

Synthesis of (2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1)

Reference is made to the publication of International Application No. WO 2012/086241 and International Application No. PCT/2012/016553 together with the corresponding techniques from the patent literature. Shake mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (550 mg, 2.0 mmol), palladium on carbon (10% by weight; 340 mg, 0.3 mmol) and MeOH (18 ml) were hydrated at 1 atm. (balloon) did not show completion of the reaction before analysis by thin layer chromatography (TLC) (approximately 30 minutes; the reaction was monitored by TLC using MeOH/CH ₂ Cl ₂ 5:95 as eluent). The mixture was filtered through a pad of Celite® and the layer was washed thoroughly with MeOH (about 20 ml). The filtrate was concentrated in vacuo (water bath temperature not exceeding 25°C) to obtain the product as a clear and colorless oil. The oil was dried in vacuum for 1 hour, and the residue was immediately used in the next step without further purification. The output was taken by quantity. LC–MS: m/z=186.0 [M+H] ⁺ .

Example 2

Synthesis of 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl benzoate (2)

Step 1: Synthesis of 3-hydroxy-2,2-dimethylpropyl benzoate (2a).

Benzoyl chloride (4.0 ml, 34.5 mmol) was added dropwise to a shaking solution of 2,2-dimethylpropane-1,3-diol (10.8 g, 103.4 mmol), pyridine (5.8 ml, 71. 6 mmol) and N,N-4-dimethylaminopyridine (840 mg, 6.9 mmol) in dichloromethane (207 ml) at approximately 0°C. The mixture was shaken overnight with gradual heating to room temperature, quenched by adding 1 N. HCl (100 ml) at 0°C and extracted twice with dichloromethane. The combined organic extracts were washed with saturated aqueous NaHCO ₃ (100 ml), brine (100 ml), dried (Na ₂ SO ₄ ), filtered, and the solvent was concentrated in vacuo to give a crude residue. The residue was split into two batches and purified by silica gel column chromatography using EtOAc/hexanes (0:1-1:4) to give the product (5.95 g, 99%) as a colorless oil (note: oil dried in vacuum for 2 days). LC–MS: m/z=209.0 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): 8.05 (m, 2H), 7.58 (m, 1H), 7.45 (m, 2H), 4.19 (s, 2H), 3, 38 (d, J=6.3 Hz, 2H), 2.29 (t, J=6.3 Hz, 1H), 1.02 (s, 6H).

Step 2: Synthesis of 3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl benzoate (2b).

Reference is made to J. Am. Chem. Soc. 2006, 128, 1605–1610. A solution of distilled sulfuryl chloride (1.2 ml, 15.8 mmol) in Et ₂ O (15 ml) was cooled to –78°C under argon. A solution of 3-hydroxy-2,2-dimethylpropyl benzoate (2a) (3.0 g, 14.4 mmol) and pyridine (1.2 mL, 14.4 mmol) in Et ₂ O ( 3.0 ml) for 1 hour. The syringe was washed with Et ₂ O (3×1 ml), and each wash was added to the reaction mixture. The acetone/ _CO2 bath was removed and the mixture was allowed to warm to room temperature, then shaken at room temperature for 4 hours. TLC analysis (EtOAc/hexanes; 3:7) did not indicate completion of the reaction, so it was re-cooled to -78°C. and further SO ₂ Cl ₂ (0.1 ml) was added, then allowed to warm to room temperature and shaken for a further 2 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give the product (3.97 g, 89%) as oils ¹ H–NMR (300 MHz, CDCl ₃ ): 8.03 (m, 2H), 7.61–7.57 (m, 1H), 7.49–7.44 (m, 2H), 4.41 (s, 2H), 4.18 (s, 2H), 1.16 (s, 6H).

Step 3: Synthesis of 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2 –dimethylpropyl benzoate (2).

Reference is made to J. Am. Chem. Soc. 2006, 128, 1605–1610. (2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (370 mg, 2.0 mmol) was dissolved in THF (7.0 ml) and 1,3-dimethyltetrahydropyrimidine-2(1H)-one (3.0 ml), and the resulting solution was cooled to –78°C under argon. A solution of NaHMDS in THF (1M; 2.2 mL, 2.2 mmol) was added dropwise and the mixture was shaken at –78°C for 10 min. 3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl benzoate (2b) (674 mg, 2.2 mmol) was then quickly added to the reaction mixture. After 10 min at –78°C, the reaction mixture was allowed to warm to room temperature and shaken at room temperature until LC–MS and TLC analysis were completed. EtOAc (20 mL) and saturated aqueous NaHCO ₃ (20 mL) were added and the organic and aqueous layers were separated. The organic layer was washed with water (3×20 ml), brine (20 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo to obtain a crude residue. The residue was purified by silica gel column chromatography using EtOAc/hexanes (1:9-1:0) to give the product (400 mg, 43%) as a solid. After purification by column chromatography, the product appeared to degrade to some extent after drying the compound in vacuo over the weekend - one degradation product was suspected to be avibactam by LC–MS, m/z=529.0 [2M–H]– . A portion of the material was subsequently re-purified by silica gel column chromatography using the eluent system detailed above. The product was then stored at –20°C immediately after isolation. LC–MS: m/z=456.2 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 8.05 (d, J=6.9 Hz, 2H), 7.59–7.54 (m, 1H), 7.47–7.42 ( m, 2H), 6.49 (s, 1H), 5.91 (s, 1H), 4.69 (d, J=9.3 Hz, 1H), 4.44 (d, J=9.3 Hz, 1H), 4.16–4.14 (m, 3H), 4.00 (d, J=7.5 Hz, 1H), 3.24–3.20 (m, 1H), 2.96 (d, J=11.7 Hz, 1H), 2.43–2.36 (m, 1H), 2.16–2.09 (m, 1H), 1.97–1.80 (m, 2H ), 1.13 (s, 3H), 1.12 (s, 3H). ¹³ C–NMR (300 MHz, CDCl ₃ ): δ 171.1, 167.1, 166.4, 133.3, 130.0, 129.8, 128.6, 80.7, 69.1, 62 ,0, 60.2, 47.1, 35.7, 21.5, 20.8, 17.6.

Example 3

Synthesis of ethyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (3)

Step 1: Synthesis of ethyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (3a).

A solution of distilled sulfuryl chloride (0.55 ml, 7.5 mmol) in Et ₂ O (10 ml) was cooled to –78°C under argon. A solution of ethyl 3-hydroxy-2,2-dimethylpropanoate (2a) (1.0 g, 6.8 mmol) and pyridine (0.55 ml, 6.8 mmol) was then added dropwise over 1 h using a syringe. Et ₂ O (1.0 ml). The syringe was washed with Et ₂ O (3×1 ml), and each wash was added to the reaction mixture. The acetone/CO ₂ bath was removed and the mixture was allowed to warm to room temperature, then shaken at room temperature for 4 hours. TLC analysis (EtOAc/hexanes; 3:7) did not indicate that the reaction was complete. The mixture was re-cooled to -78°C and further SO ₂ Cl ₂ (0.11 ml) was added and the mixture was allowed to warm to room temperature and shaken for a further 2 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give the product (yield was taken by quantity). ¹ H–NMR (300 MHz, CDCl ₃ ): δ 4.50 (s, 2H), 4.19 (q, J=6.9 Hz, 2H), 1.31 (s, 6H), 1.28 (t, J=6.9 Hz, 3H).

Step 2: Synthesis of ethyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2, 2-dimethylpropanoate (3).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (370 mg, 2.0 mmol) was dissolved in THF (7.0 ml) and 1,3-dimethyltetrahydropyrimidine-2(1H)-one (3.0 ml), and the resulting solution was cooled to –78°C under argon. A solution of NaHMDS in THF (1M; 2.2 mL, 2.2 mmol) was added dropwise and the mixture was shaken at –78°C for 10 min. A solution of ethyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (3a) (538 mg, 2.2 mmol) in THF (1 ml) was then quickly added to the reaction mixture using a syringe. The syringe was washed with THF (3×0.5 ml), and each wash was added to the reaction mixture. After 10 min at –78°C, the reaction mixture was allowed to warm to room temperature and shaken at room temperature until LC–MS and TLC analysis were completed (ca. 2 h). EtOAc (20 mL) and saturated aqueous NaHCO ₃ (20 mL) were added and the organic and aqueous layers were separated. The organic layer was washed with saturated NaHCO ₃ (20 ml), water (3×20 ml), brine (20 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a crude residue. The residue was purified by silica gel column chromatography using EtOAc/hexanes (1:9-1:0) to give the product (318 mg, 39%) as a solid. LC–MS: m/z=394.1 [M+H] ⁺ . ¹ H–NMR (CDCl ₃ , 300 MHz): δ 6.50 (s, 1H), 5.78 (s, 1H), 4.71 (d, J=8.7 Hz, 1H), 4.59 (d, J=8.7 Hz, 1H), 4.22–4.12 (m, 3H), 4.05 (d, J=6.9 Hz, 1H), 3.34–3.30 ( m, 1H), 3.01 (d, J=12.3 Hz, 1H), 2.46–2.40 (m, 1H), 2.18–2.12 (m, 1H), 2.00 –1.79 (m, 2H), 1.28–1.24 (m, 9H). ¹³ C–NMR (300 MHz, CDCl ₃ ): δ 174.2, 171.2, 167.1, 80.5, 61.9, 61.4, 60.2, 47.2, 42.8, 22 ,2, 21.7, 20.8, 17.5, 14.2.

Example 4

Synthesis of benzyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (4)

Step 1: Synthesis of benzyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (4a).

A solution of distilled sulfuryl chloride (0.77 ml, 10.6 mmol) in Et ₂ O (10 ml) was cooled to –78°C under argon. Then, a solution of ethyl 3-hydroxy-2,2-dimethylpropanoate (2a) (Sigma-Aldrich; 2.0 g, 9.6 mmol) and pyridine (0.85 ml, 10. 6 mmol) in Et ₂ O (2.0 ml). The syringe was washed with Et ₂ O, and each wash was added to the reaction mixture. The acetone/CO ₂ bath was removed and the mixture was allowed to warm to room temperature, then shaken at room temperature for 30 minutes, TLC analysis (EtOAc/hexanes; 3:7) did not indicate completion of the reaction, so re-cooled to -78°C, and further SO ₂ Cl ₂ (0.07 ml) was added, then allowed to warm to room temperature and shaken for a further 1 hour. Et ₂ O (5 ml) was added and the mixture was shaken for several minutes, then filtered, and the filtrate was concentrated in vacuum to obtain the product (2.19 g, 75%). ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.41–7.32 (m, 4H), 5.18 (s, 2H), 4.52 (s, 2H), 1.34 (s, 6H).

Step 2: Synthesis of benzyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2, 2-dimethylpropanoate (4).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (370 mg, 2.0 mmol) was dissolved in THF (7.0 ml) , and 1,3-dimethyltetrahydropyrimidin-2(1H)-one (2.0 ml) was added and the resulting solution was cooled to –78°C under argon. A solution of NaHMDS in THF (1M; 2.2 mL, 2.2 mmol) was added dropwise and the mixture was shaken at –78°C for 10 min. A solution of ethyl benzyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (4a) (674 mg, 2.2 mmol) in THF (1 ml) was then quickly added to the reaction mixture using a syringe. The syringe was washed with THF (3×0.5 ml), and each wash was added to the reaction mixture. After 10 min at –78°C, the reaction mixture was allowed to warm to room temperature and shaken at room temperature until LC–MS and TLC analysis were completed. EtOAc (20 mL) and saturated aqueous NaHCO ₃ (20 mL) were added and the organic and aqueous layers were separated. The organic layer was washed with saturated NaHCO ₃ (20 ml), water (3×20 ml), brine (20 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a crude residue. The residue was purified by silica gel column chromatography using EtOAc/hexanes (1:9-1:0) to give the product (244 mg, 26%) as a solid. LC–MS: m/z=456.2 [M+H] ⁺ . ¹ H–NMR (CDCl ₃ , 300 MHz): δ 7.39–7.28 (m, 4H), 6.49 (s, 1H), 5.84 (s, 1H), 5.20–5, 11 (m, 2H), 4.74 (d, J=9.0 Hz, 1H), 4.61 (d, J=9.0 Hz, 1H), 4.15–4.14 (m, 1H ), 4.04 (d, J=6.9 Hz, 1H), 3.29–3.25 (m, 1H), 2.99 (d, J=11.7 Hz, 1H), 2.45 –2.38 (m, 1H), 2.17–2.10 (m, 1H), 1.99–1.78 (m, 2H), 1.30 (s, 3H), 1.29 (s , 3H). ¹³ C–NMR (CDCl ₃ , 75 MHz): δ 174.1, 171.1, 167.1, 135.7, 128.7, 128.4, 128.0, 80.3, 67.0, 62 ,0, 60.2, 47.2, 43.0, 22.2, 21.7, 20.8, 17.5.

Example 5

Synthesis of (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl phenyl sulfate (5)

Step 1: Synthesis of phenyl sulfochloride (5a).

Reference is made to J. Am. Chem. Soc. 2013, 135, 10638–10641. A solution of distilled sulfuryl chloride (2.6 ml, 35.1 mmol) in Et ₂ O (30 ml) was cooled to –78°C under argon. Then, simultaneously, but from different syringes, a solution of phenol (3.0 g, 31.9 mmol) in Et ₂ O (3.0 ml) and pyridine (2.6 ml, 31.9 mmol) was added dropwise over 1 hour ). Each syringe was washed with Et ₂ O, and each wash was added to the reaction mixture. Allow the mixture to warm slowly to room temperature and shake at room temperature overnight. The mixture was filtered and the filtrate was concentrated in vacuo to give a product (4.65 g) contaminated with other products and phenolic starting material. The phenyl sulfochloride product was not further purified and was used directly in the next step.

Step 2: Synthesis of (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl phenyl sulfate (5).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (370 mg, 2.0 mmol) was dissolved in THF (7.0 ml) and 1,3-dimethyltetrahydropyrimidine-2(1H)-one (2.0 ml), and the resulting solution was cooled to –78°C under argon. A solution of NaHMDS in THF (1M; 2.2 mL, 2.2 mmol) was added dropwise and the mixture was shaken at –78°C for 10 min. Neat phenyl sulfochloride (5a) (423 mg, 2.2 mmol) was then quickly added to the reaction mixture using a syringe. The syringe was washed with THF (3×0.5 ml), and each wash was added to the reaction mixture. After 10 min at –78°C, the reaction mixture was allowed to warm to room temperature and shaken at room temperature until LC–MS and TLC analysis were completed (about 1 h). EtOAc (20 mL) and saturated aqueous NaHCO ₃ (20 mL) were added and the organic and aqueous layers were separated. The organic layer was washed with saturated NaHCO ₃ (20 ml), water (3×20 ml), brine (20 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a crude residue. The residue was purified by silica gel column chromatography using EtOAc/hexanes (1:9-1:0) to give the product (126 mg, 18%) as a solid. LC–MS: m/z=342.2 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.54–7.51 (m, 2H), 7.47–7.42 (m, 2H), 7.39–7.33 (m, 1H ), 6.53 (s, 1H), 5.88 (s, 1H), 4.24 (fd, J=2.4 Hz, 1H), 4.09 (d, J=6.9 Hz, 1H ), 3.34 (d, J=11.7 Hz, 1H), 3.05 (d, J=12.3 Hz, 1H), 2.46–2.39 (m, 1H), 2.19 –2.11 (m, 1H), 2.02–1.81 (m, 2H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 171.2, 166.8, 150.9, 130.2, 128.1, 121.3, 62.1, 60.6, 47.0, 20 ,8, 17.6.

Example 6

Synthesis of 4-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl benzoate (6)

Step 1: Synthesis of 2,2-dimethylbutane-1,4-diol (6a).

To a suspension of lithium aluminum hydride (8.3 g, 219.0 mmol) in THF (80 ml) at 0°C (ice bath), a solution of 2,2-dimethylsuccinic acid (10.0 g, 68.4 mmol) was added dropwise. in THF (150 ml). The mixture was warmed to room temperature for 20 minutes and then refluxed for 1.5 hours. Once complete (the reaction was monitored by TLC using MeOH/CH ₂ Cl ₂ 5:95 as eluent), the reaction was quenched very carefully and by adding dropwise water (10 ml), 3 M NaOH (15 ml) and water (20 ml). The mixture was shaken at room temperature for 20 minutes and the solids were filtered through a pad of Celite®. The filter cake was thoroughly washed with THF. The filtrate was concentrated in vacuo to obtain a mixture of the title compound and unidentified by-products as a crude oil. The oil was purified by silica gel column chromatography using MeOH/CH ₂ Cl ₂ (0:1-1:9) as eluent to give the product (4.649 g, 57%) as an oil. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 4.11 (s, 2H), 3.66 (t, J=5.9 Hz, 2H), 3.30 (s, 2H), 1.52 (t, J=5.6 Hz, 2H), 0.89 (s, 6H).

Step 2: Synthesis of 4-hydroxy-3,3-dimethylbutyl benzoate (6b).

Benzoyl chloride (0.30 mL, 2.5 mmol), Et ₃ N (0.71 ml, 5.1 mmol) and a catalytic amount of N, N-4-dimethylaminopyridine at 0°C (ice bath). The mixture was gradually warmed to room temperature and shaken overnight. After complete consumption of the starting material (the reaction was monitored by TLC using EtOAc/hexanes 2:8 as eluent), the reaction was quenched by adding 1 N. HCl (20 ml) at 0°C (ice bath), and the mixture was extracted twice with dichloromethane. The combined organic layers were washed with saturated aqueous NaHCO ₃ , brine, dried (Na ₂ SO ₄ ), filtered, and the solvent was concentrated to provide a mixture of at least two products as a clear and colorless oil. The oil was purified by silica gel column chromatography using EtOAc/hexanes (0:1-4:6) as eluent to give the product (0.29 g, 51%) as an oil (which was dried at high vacuum for 2 d ). ¹ H–NMR (300 MHz, CDCl ₃ ): δ 8.04–8.01 (m, 2H), 7.58–7.53 (m, 1H), 7.46–7.41 (m, 2H ), 4.41 (t, J=7.4 Hz, 2H), 3.41 (s, 2H), 1.78 (t, J=7.4 Hz, 2H), 1.70 (s, 1H ), 0.99 (s, 6H).

Step 3: Synthesis of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl benzoate (6c).

A solution of freshly distilled sulfuryl chloride (0.11 ml, 1.5 mmol) in Et ₂ O (3 ml) was cooled to –78°C under argon. A solution of 4-hydroxy-3,3-dimethylbutyl benzoate (6b) (0.28 g, 1.3 mmol) and pyridine (0.10 ml, 1.3 mmol) was added dropwise to the cooled solution (over 1 h). in Et ₂ O (2 ml). The mixture was warmed to room temperature and shaken for 30 minutes. (the reaction was monitored by TLC using EtOAc/hexanes 2:8 as eluent). The mixture was re-cooled to –78°C and sulfuryl chloride (0.02 ml) was added. Allow the mixture to warm to room temperature and shake for 30 minutes. Et ₂ O (5 ml) was added and the mixture was shaken for several minutes. The mixture was filtered and the filtrate was concentrated in vacuo to give product (6c) (0.305 g, 75%). ¹ H–NMR (300 MHz, CDCl ₃ ): δ 8.03 (d, J=8.1 Hz, 2H), 7.60–7.54 (m, 1H), 7.47–7.42 ( m, 2H), 4.44–4.38 (m, 2H), 4.29 (s, 2H), 1.89–1.85 (m, 2H), 1.13 (s, 6H).

Step 4: Synthesis of 4–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–3,3 –dimethylbutyl benzoate (6).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (176 mg, 1.0 mmol) was dissolved in THF (4 ml) and 1 ,3-dimethyltetrahydropyrimidine-2(1H)-one (1 ml), and the resulting solution was cooled to –78°C under argon. NaHMDS (1.0 M in THF; 1.05 mL, 1.05 mmol) was added dropwise to the cooled solution and the mixture was shaken at –78°C for 10 min. 4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl benzoate (6c) (305 mg, 1.0 mmol) in THF (0.5 ml) was quickly added to the mixture. The syringe was washed with THF (3×0.5 ml), and also added to the mixture. After 10 min, the mixture was warmed to room temperature and shaken until the TLC assay was complete. EtOAc (10 mL) and saturated aqueous NaHCO ₃ (10 mL) were added to the mixture, and the organic and aqueous layers were separated. The organic layer was washed with saturated aqueous NaHCO ₃ (10 ml), water (6×10 ml), brine (10 ml), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purification by silica gel column chromatography using EtOAc/hexanes (1:9-1:0) as eluent gave product (6) (215 mg, 18%) as a solid. LC–MS: 470.2 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 8.04–8.01 (m, 2H), 7.58–7.53 (m, 1H), 7.46–7.41 (m, 2H ), 6.48 (s, 1H), 5.80 (s, 1H), 4.60 (d, J=9.3 Hz, 1H), 4.40 (t, J=6.9 Hz, 2H ), 4.29 (d, J=9.3 Hz, 1H), 4.17–4.16 (m, 1H), 4.02 (d, J=7.8 Hz, 1H), 3.34 –3.30 (m, 1H), 3.00 (d, J=12.3 Hz, 1H), 2.45–2.35 (m, 1H), 2.17–2.11 (m, 1H ), 1.98–1.78 (m, 4H), 1.10 (s, 6H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 171.1, 167.1, 166.6, 133.1, 130.2, 129.7, 128.5, 83.7, 61.9, 61 ,5, 60.2, 47.2, 36.9, 34.1, 24.1, 23.8, 20.8, 17.5.

Example 7

Synthesis of 4-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl propionate (7)

Step 1: Synthesis of 4-hydroxy-3,3-dimethylbutyl propionate (7a).

A solution of propionyl chloride (0.74 ml, 8.5 mmol) in anhydrous dichloromethane (5 ml) was added to a shaking solution of 2,2-dimethylbutane-1,4-diol (6a) (1.00 g, 8.5 mmol), Et ₃ N (2.4 ml, 16.9 mmol) and 4-N, N-dimethylaminopyridine (52 mg) in anhydrous dichloromethane (20 ml) at –78°C under argon. The mixture was shaken for 10 minutes and then allowed to warm to room temperature, shaken at room temperature for 1 hour, then re-cooled to –78°C and allowed to warm slowly to room temperature, allowing the mixture to remain in the cold bath and allowing the dry substance to sublimate. ice (after adding all reagents, it is recommended to ensure heating to room temperature from –78°C). After complete consumption of the starting material (TLC 50% EtOAc/hexanes), the reaction was quenched by adding 0.5 N HCl (10 ml) at 0°C. The organic and aqueous layers were separated, and the aqueous layer was extracted with dichloromethane (2×20 ml). The combined organic layers were washed with saturated aq. NaHCO ₃ (20 mL), brine (20 mL), then dried (Na ₂ SO ₄ ), filtered, and the solvent was concentrated in vacuo to give a crude oil. The oil was purified by silica gel column chromatography using EtOAc/hexanes (0:1-4:1) as eluent to give product (7a) (463 mg, 22%) as an oil contaminated with significant residual EtOAc solvent. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 4.14 (t, J=7.4 Hz, 2H), 3.32 (s, 2H), 2.30 (q, J=7.6 Hz , 2H), 1.88 (s, 1H), 1.61 (t, J=7.7 Hz, 2H), 1.13 (t, J=7.5 Hz, 3H), 0.91 (fd , J=1.2 Hz, 6H).

Step 2: Synthesis of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl propionate (7b).

A solution of freshly distilled sulfuryl chloride (0.15 ml, 2.0 mmol) in Et ₂ O (3.5 ml) was cooled to –78°C under argon. A solution of 4-hydroxy-3,3-dimethylbutyl propionate (7a) (purity 73%, rest EtOAc; 441 mg, 1.8 mmol) and pyridine (0.15 ml, 1.8 mmol) in Et ₂ O (2, 5 ml) was added dropwise to the cooled solution over 1 hour. Allow the mixture to warm to room temperature, and shake for 30 minutes (monitored with TLC, 30% EtOAc/hexanes), re-cool to -78°C, and add sulfuryl chloride (0.03 ml) and pyridine (0.03 ml ), warmed to room temperature and shook for 30 minutes. The mixture was again re-cooled to -78°C and another portion of sulfuryl chloride (0.15 ml) was added. Allow the mixture to warm to room temperature and shake for 30 minutes. Et ₂ O (5 ml) was added and the mixture was shaken for several minutes. The mixture was filtered and the filtrate was concentrated in vacuo to give product (7b) (401 mg, 79%). ¹ H–NMR: (300 MHz, CDCl ₃ ): 4.22 (s, 2H), 4.14 (t, J=6.8 Hz, 2H), 2.30 (q, J=7.6 Hz , 2H), 1.70 (t, J=6.8 Hz, 2H), 1.11 (t, J=7.7 Hz, 3H), 1.05 (s, 6H).

Step 3: Synthesis of 4–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–3,3 –dimethylbutyl propionate (7).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (185 mg, 1.0 mmol) was dissolved in THF (4 ml) and 1 ,3-dimethyltetrahydropyrimidine-2(1H)-one (1 ml) in an argon atmosphere. The resulting solution was cooled to –78°C. NaHMDS (1.0 M in THF; 1.1 mL, 1.1 mmol) was added dropwise to the cooled solution and the mixture was shaken for 10 min. 4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl propionate (7b) (272 mg, 1.0 mmol) in THF (1 mL) was quickly added to the reaction mixture. The syringe was washed with THF (3×0.5 ml), and also added to the mixture. More THF (3 mL) was added to the mixture, providing the reaction with efficient stirring. After 10 minutes, the mixture was allowed to warm to room temperature. Upon completion (1 h; TLC, 70% EtOAc/hexanes), EtOAc (10 mL) and saturated aq. NaHCO ₃ (10 mL) were added to the mixture. The aqueous and organic layers were separated and the organic layer was washed with saturated aqueous NaHCO ₃ (10 ml), water (6 x 10 ml), brine (10 ml), then dried (Na ₂ SO ₄ ), filtered, and the solvent was concentrated in vacuo with obtaining a crude residue. The residue was purified by silica gel column chromatography using EtOAc/hexanes (1:0-1:0) as eluent to give product (7) (93 mg, 22%) as a solid. LC–MS: 422.1 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 6.51 (s, 1H), 5.76 (s, 1H), 4.54 (d, J=8.7 Hz, 1H), 4.25 (d, J=8.7 Hz, 1H), 4.17–4.12 (m, 3H), 4.04 (d, J=6.9 Hz, 1H), 3.36–3.32 ( m, 1H), 3.02 (d, J=12.3 Hz, 1H), 2.47–2.40 (m, 1H), 2.32 (q, J=7.6 Hz, 2H), 2.18–2.15 (m, 1H), 2.00–1.79 (m, 2H), 1.75–1.61 (m, 2H), 1.13 (t, J=7.7 Hz, 3H), 1.03 (s, 6H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 174.5, 171.0, 167.1, 83.6, 62.0, 60.8, 60.2, 47.2, 36.8, 34 ,0, 27.7, 24.1, 23.7, 20.8, 17.6, 9.2.

Example 8

Synthesis of benzyl (4-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3- dimethylbutyl) adipate (8)

Step 1: Synthesis of benzyl (perfluorophenyl) adipate (8a).

N, N'– dicyclohexylcarbodiimide (0.97 g, 4.7 mmol). Allow the mixture to warm to room temperature and then shake overnight. The resulting solid was removed by vacuum filtration through a pad of Celite®. The filter cake was washed with EtOAc. The filtrate was loaded onto silica gel by dry injection and purified by silica gel column chromatography using EtOAc/hexanes (0:1-4:6) as eluent to give product (8a) (1.59 g, 93%) as a solid substances. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.37–7.35 (m, 5 H), 5.13 (s, 2H), 2.68 (t, J=6.8 Hz, 2H ), 2.44 (t, J=6.5 Hz, 2H), 1.82–1.78 (m, 4H).

Step 2: Synthesis of benzyl (4-hydroxy-3,3-dimethylbutyl) adipate (8b).

To a shaken solution of 2,2-dimethylbutane-1,4-diol (6a) (0.22 g, 1.8 mmol) in anhydrous dichloromethane (4 ml) at approximately 0°C (ice bath) under argon, benzyl ( perfluorophenyl) adipate (8a) (0.36 g, 0.9 mmol), Et ₃ N (0.25 ml, 1.8 mmol) and a catalytic amount of 4-N, N-dimethylaminopyridine (small unweighed amount). The mixture was gradually warmed to room temperature and then at room temperature overnight. The mixture was loaded onto silica gel by dry injection and purified by silica gel column chromatography using EtOAc/hexanes (0:1–3:7) as eluent to obtain a regioisomeric contaminated product. This mixture was re-purified by silica gel column chromatography using EtOAc/hexanes (0:1-3:7) to give pure product (8b) (113 mg 38%). ¹ H–NMR (300 MHz, CDCl ₃ ): 7.36–7.34 (m, 5H), 5.11 (s, 2H), 4.14 (t, J=7.2 Hz, 2H), 3.34 (d, J=5.7 Hz, 2H), 2.38–2.31 (m, 4H), 1.68–1.59 (m, 6H), 0.92 (s, 6H) . The reaction can be repeated to obtain more material.

Step 3: Synthesis of benzyl (4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl) adipate (8c).

A solution of freshly distilled sulfuryl chloride (0.12 ml, 1.6 mmol) in Et ₂ O (5 ml) was cooled to –78°C under argon. A solution of benzyl (4-hydroxy-3,3-dimethylbutyl) adipate (8b) (446 mg, 1.3 mmol) and pyridine (0.11 ml, 1.3 mmol) in Et ₂ O (3.5 ml). Allow the mixture to warm to room temperature and shake for 30 minutes (monitored with TLC, 30% EA/hex). The reaction was not complete, so the mixture was cooled again to –78°C, then sulfuryl chloride (0.05 ml) and pyridine (0.05 ml) were added. Allow the mixture to warm to room temperature and shake for 30 minutes. Et ₂ O (5 ml) was added and the mixture was shaken for several minutes. The mixture was filtered and the filtrate was concentrated in vacuo to give product (8c) (446 mg, 77%). ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.39–7.29 (m, 5H), 5.11 (s, 2H), 4.22 (s, 2H), 4.15 (t, J=6.8 Hz, 2H), 2.40–2.29 (m, 4H), 1.73–1.59 (m, 6H), 1.06 (s, 6H).

Step 4: Synthesis of benzyl (4–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–3 ,3-dimethylbutyl) adipate (8).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (185 mg, 1.0 mmol) was dissolved in THF (9 ml) and 1 ,3-dimethyltetrahydropyrimidine-2(1H)-one (1 ml), and the resulting solution was cooled to –78°C under argon. NaHMDS (1.0 M solution in THF; 1.1 mL, 1.1 mmol) was added dropwise to the cooled solution and shaken for 10 min. Benzyl (4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl) adipate (8c) (435 mg, 1.0 mmol) in THF (1 ml) was quickly added to the mixture. The syringe was washed with THF (3×0.5 ml), and also added to the mixture. After 10 minutes, the mixture was allowed to warm to room temperature. Upon completion (30 min; TLC, 70% EtOAc/hexanes), EtOAc (10 mL) and saturated aqueous NaHCO ₃ (10 mL) were added. The aqueous and organic layers were separated and the organic layer was washed with saturated aqueous NaHCO ₃ (10 ml), water (3 x 10 ml), brine (10 ml), then dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the crude remainder. The residue was purified by silica gel column chromatography using EtOAc/hexanes (1:9-1:0) as eluent to give a solid. The solid was triturated with Et ₂ O (2 x 2 ml) to give product (8) (43 mg, 7%) as a solid [along with less pure material (99 mg, 93% pure) which was used for next stage without additional purification]. Data for the 43 mg pure product are detailed below. LC–MS: 584.2 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.39–7.30 (m, 5H), 6.52 (s, 1H), 5.65 (s, 1H), 5.11 (s, 2H), 4.54 (d, J=9.6 Hz, 1H), 4.24 (d, J=8.7 Hz, 1H), 4.16–4.08 (m, 3H), 4, 04 (d, J=7.2 Hz, 1H), 3.35–3.31 (m, 1H), 3.01 (d, J=12.3 Hz, 1H), 2.47–2.30 (m, 5H), 2.18–2.12 (m, 1H), 1.99–1.77 (m, 2H), 1.74–1.65 (m, 6H), 1.03 (s , 6H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 173.34, 173.31, 171.0, 167.1, 136.1, 128.7, 128.4, 128.3, 83.5, 66 ,4, 62.0, 60.9, 60.2, 47.2, 36.8, 34.0, 24.5, 24.4, 24.2, 23.8, 20.8, 17.6 .

Example 9

Synthesis of 6–(4–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–3,3 –dimethylbutoxy)–6-oxohexanoic acid (9)

Into a Parr flask loaded with benzyl (4–(((((2S,5R)–2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)– 3,3-dimethylbutyl) adipate (8) (purity 93%; 50 mg, 0.1 mmol) in MeOH (14 ml), palladium on carbon (10% by weight; 13 mg) was added. The mixture was hydrated at 1 atmosphere of H ₂ (balloon), at room temperature for 30 minutes (monitored by TLC, 100% EtOAc; PMA staining; LC–MS: product room temperature=4.66 min and m/z=494, 2 [M+H] ⁺ , room temperature of the starting material = 5.48 min and m/z = 584.3 [M+H] ⁺ ). The mixture was filtered through a pad of Celite® and the filter cake was washed with MeOH (about 20 ml). The filtrate was concentrated in vacuo then purified by silica gel column chromatography using MeOH/CH ₂ Cl ₂ (0:1-4:96) as eluent to give product (9) (12 mg) as a solid (purity approx. 73% according to LC/MS). LC–MS: 494.2 [M+H] ⁺ .

Example 10

Synthesis of methyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (10)

Step 1: Reaction to produce methyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (10a).

A solution of freshly distilled sulfuryl chloride (3.3 ml, 45.4 mmol) in Et ₂ O (45 ml) was cooled to –78°C under argon. A solution of methyl 2,2-dimethyl-3-hydroxypropionate (3.0 g, 22.7 mmol) and pyridine (2.2 ml, 27.2 mmol) in Et ₂ O ( 20 ml). The flask was washed with Et ₂ O (3×5 ml), and the wash was added to the reaction mixture. The mixture was shaken at –78°C until complete (monitored with TLC, 30% EA/hex, 30 min). The precipitate was filtered and the filtrate was concentrated in vacuo to give methyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (10a) (5.6 g, 70% yield). The mixture was stored at –78°C and immediately used for the next step without further purification. ¹ H–NMR (300 MHz, CDCl ₃ ) δ 4.50 (s, 2H), 3.74 (s, 3H), 1.31 (s, 6H).

Step 2: Reaction to produce methyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2 ,2-dimethylpropanoate (10).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (673 mg, 3.6 mmol) was dissolved in THF (35 ml) and 1 ,3-dimethyltetrahydropyrimidine-2(1H)-one (5 ml), and the resulting solution was cooled to –78°C under argon. A 1.0 M solution of NaHMDS in THF (4.0 mL, 4.0 mmol) was added dropwise to the cooled solution. After addition was complete, the mixture was shaken for 10 minutes. Neat methyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (10a) (1.27 g, 3.6 mmol, 1.0 equiv., 66% purity) was quickly added to the reaction mixture. The syringe was rinsed with THF (3 x 2.5 ml), and the rinse was added to the mixture. After 10 minutes, the reaction mixture was heated to 23°C. Once complete, EtOAc (50 mL) and saturated aqueous NaHCO ₃ (50 mL) were added to the reaction mixture by TLC (30 min; 70% EtOAc/hexanes). The layers were separated and the organic layer was washed with saturated aqueous NaHCO ₃ (50 ml), water (3×50 ml), brine (50 ml), then dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a crude residue. The residue was purified by silica gel column chromatography using EtOAc/hexanes (1:9-1:0) to give product (10) (98 mg, 7% yield). LC–MS: 380.2 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 6.47 (s, 1H), 5.61 (s, 1H), 4.72 (d, J=9.3 Hz, 1H), 4.58 (d, J=9.3 Hz, 1H), 4.18 (m, 1H), 4.05 (d, J=6.9 Hz, 1H), 3.72 (s, 3H), 3.35 –3.31 (m, 1H), 3.02 (d, J=12.3 Hz, 1H), 2.47–2.41 (m, 1H), 2.19–2.13 (m, 1H ), 2.01–1.79 (m, 2H), 1.29 (s, 3H), 1.28 (s, 3H), ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 174.7, 171.1, 167.1, 80.4, 62.0, 60.2, 52.6, 47.2, 43.0, 22.2, 21.8, 20.9, 17.6

Example 11

Synthesis of isopropyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (eleven)

Step 1: Reaction to produce isopropyl 3-hydroxy-2,2-dimethylpropanoate (11a).

Reference is made to German Publication Application No. DE3045373. A mixture of 3-hydroxy-2,2-dimethylpropionic acid (4.7 g, 40 mmol), isopropanol (70 ml) and concentrated sulfuric acid (or fuming sulfuric acid; 1 ml) was refluxed and shaken overnight. Once cooled, the mixture was concentrated in vacuo and the residue was partitioned into EtOAc (100 ml) and saturated aqueous NaHCO ₃ (100 ml). The aqueous mixture was washed with H ₂ O (50 ml), saturated NaHCO ₃ (50 ml) and brine (50 ml), then dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the product as an oil. Product (11a) was used directly in the next step without further purification. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 5.08–4.95 (m, 1H), 3.53 (fd, J=1.8 Hz, 2H), 2.49 (s, 1H) , 1.25 (fd, J=2.4 Hz, 3H), 1.22 (fd, J=2.4 Hz, 3H), 1.17 (s, 3H), 1.16 (s, 3H) .

Step 2: Reaction to produce isopropyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (11b).

A solution of sulfuryl chloride (2.7 ml, 37.5 mmol) in Et ₂ O (45 ml) was cooled to –78°C under Ar. A solution of isopropyl 3-hydroxy-2,2-dimethylpropanoate (11a) (3.0 g, 18.7 mmol) and pyridine (1.82 ml, 22.5 mmol) in Et was added dropwise to the sulfuryl chloride solution over 30 min. ₂ O (20 ml). The flask was washed with Et ₂ O (3×5 ml), and the wash was added to the reaction mixture. The mixture was shaken at −78°C until complete with TLC (30 min; 30% EA/hex). The precipitate was filtered and the filtrate was concentrated in vacuo to give isopropyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (11b) (4.1 g, 85% yield). The mixture was stored at –78°C and immediately used for the next step without further purification. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 5.10–4.98 (m, 1H), 4.49 (s, 2H), 1.29 (s, 6H), 1.26 (s, 3H), 1.24 (s, 3H).

Step 3: Reaction to produce isopropyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2 ,2-dimethylpropanoate (11).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (673 mg, 3.6 mmol) was dissolved in THF (35 ml) and 1 ,3-dimethyltetrahydropyrimidine-2(1H)-one (5 ml), and the resulting solution was cooled to –78°C under Ar. A 1.0 M solution of NaHMDS in THF (4.0 mL, 4.0 mmol) was added dropwise to the cooled solution and shaken for 20 min. Neat isopropyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (11b) (0.94 g, 3.6 mmol) was quickly added to the reaction mixture. The syringe was rinsed with THF (3 x 3 ml), and the rinse was also added to the mixture. After 20 minutes, the mixture was allowed to warm to room temperature. Once the reaction was complete, EtOAc (50 mL) and saturated aqueous NaHCO ₃ (50 mL) were added to the reaction mixture by TLC (30 min; 70% EtOAc/hexanes). The aqueous and organic layers were separated and the organic layer was washed with saturated aqueous NaHCO ₃ (50 ml), water (3×50 ml), brine (50 ml), then dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a crude residue. The residue was purified by column chromatography (ISCO 40 g column) on silica gel using EtOAc/hexanes (1:9-1:0) as eluent to give product (11) (63 mg, 4%) as a solid. LC–MS: 408.2 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 6.50 (s, 1H), 5.74 (s, 1H), 5.02 (quint, J=6.3 Hz, 1H), 4.70 (d, J=8.7 Hz, 1H), 4.60 (d, J=9.3 Hz, 1H), 4.17 (m, 1H), 4.05 (d, J=7.2 Hz , 1H), 3.34–3.30 (m, 1H), 3.02 (d, J=11.7 Hz, 1H), 2.47–2.40 (m, 1H), 2.19– 2.12 (m, 1H), 2.04–1.66 (m, 2H), 1.26–1.23 (m, 12H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 173.7, 171.1, 167.0, 80.6, 68.8, 62.0, 60.2, 47.2, 42.9, 22 ,2, 21.7, 21.6, 20.9, 17.5.

Example 12

Synthesis of hexyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (12)

Step 1: Reaction to produce hexyl 3-hydroxy-2,2-dimethylpropanoate (12a).

Reference is made to German Publication Application No. DE3045373. A mixture of 3-hydroxy-2,2-dimethylpropionic acid (4.7 g, 40 mmol), 1-hexanol (70 ml) and concentrated sulfuric acid (or fuming sulfuric acid; 1 ml) was heated to 80°C and shaken for nights. Once cooled, the mixture was concentrated in vacuo (high vacuum pump required) and the residue partitioned into EtOAc (100 ml) and saturated aq. NaHCO ₃ (100 ml). The aqueous mixture was washed with H ₂ O (50 ml), saturated NaHCO ₃ (50 ml) and brine (50 ml), then dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give product (12a) as an oil. The product was used directly in the next step without further purification. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 4.04–3.98 (m, 2H), 3.47–3.45 (m, 2H), 2.26 (s, 1H), 1, 58–1.32 (m, 2H), 1.32–1.23 (m, 6H), 1.12 (s, 3H), 1.11 (s, 3H).

Step 2: Reaction to produce hexyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (12b).

A solution of sulfuryl chloride (2.1 ml, 29.7 mmol) in Et ₂ O (40 ml) was cooled to –78°C under argon. A solution of hexyl 3-hydroxy-2,2-dimethylpropanoate (12a) (3.0 g, 14.8 mmol) and pyridine (1.4 ml, 17.8 mmol) in Et was added dropwise to the sulfuryl chloride solution over 30 min. ₂ O (15 ml). The flask was washed with Et ₂ O (3×5 ml), and the wash was added to the reaction mixture. The mixture was shaken at −78°C until complete with TLC (30 min; 30% EA/hex). The precipitate was filtered and the filtrate was concentrated in vacuo to give product (12b) (3.7 g, 83% yield). The mixture was stored at –78°C and immediately used for the next step without further purification. ¹ H–NMR (300 MHz, CDCl ₃ ): 4.50 (s, 2H), 4.13 (t, J=6.8 Hz, 2H), 1.69–1.60 (m, 2H), 1.40–1.27 (m, 12H), 0.91–0.87 (m, 3H).

Step 3: Reaction to produce hexyl 3–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–2 ,2-dimethylpropanoate (12).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (673 mg, 3.6 mmol) was dissolved in THF (35 ml) and 1 ,3-dimethyltetrahydropyrimidine-2(1H)-one (5 ml), and the resulting solution was cooled to –78°C under Ar. A 1.0 M solution of NaHMDS in THF (4.0 mL, 4.0 mmol) was added dropwise to the cooled solution and shaken for 20 min. Neat hexyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (12b) (1.1 g, 3.6 mmol) was quickly added to the reaction mixture. The syringe was rinsed with THF (3 x 3 ml), and the rinse was also added to the mixture. After 10 min, the reaction mixture was heated to 23°C and shaken until the reaction was complete, as determined by TLC and LC–MS. EtOAc (50 ml) and saturated aqueous NaHCO ₃ (50 ml) were added to the mixture. The layers were separated and the organic layer was washed with saturated aqueous NaHCO ₃ (50 ml), water (3×50 ml), brine (50 ml), then dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to obtain a crude residue. The residue was purified by silica gel column chromatography using EtOAc/hexanes (1:9-1:0) as eluent followed by high performance liquid chromatography to give product (12) (44 mg, 3%) as a solid. LC–MS: 450.1 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 6.49 (s, 1H), 5.71 (s, 1H), 4.71 (d, J=8.7 Hz, 1H), 4.60 (d, J=9.3 Hz, 1H), 4.17–4.04 (m, 4H), 3.34–3.30 (m, 1H), 3.04–3.00 (d, J =12.6 Hz, 1H), 2.47–2.40 (m, 1H), 2.18–2.13 (m, 1H), 2.01–1.79 (m, 2H), 1, 66–1.59 (m, 2H), 1.37–1.27 (m, 12H), 0.91–0.86 (m, 3H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 174.3, 171.1, 167.0, 80.5, 65.6, 62.0, 60.2, 47.2, 43.0, 31 ,5, 28.6, 25.6, 22.6, 22.3, 21.8, 20.9, 17.6, 14.1.

Example 13

Synthesis of heptyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (13)

Step 1: Reaction to produce heptyl 3-hydroxy-2,2-dimethylpropanoate (13a).

Reference is made to German Publication Application No. DE3045373. A mixture of 3-hydroxy-2,2-dimethylpropionic acid (4.7 g, 40 mmol), 1-heptanol (70 ml) and concentrated sulfuric acid (or fuming sulfuric acid; 1 ml) was heated to 80°C and shaken for nights. After allowing the mixture to cool, the mixture was concentrated in vacuo (high vacuum pump required) and the residue was partitioned into EtOAc (100 ml) and saturated aq. NaHCO ₃ (100 ml). The aqueous solution was washed with H ₂ O (50 ml), saturated NaHCO ₃ (50 ml) and brine (50 ml), then dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give product (13a) as an oil. The product was used directly in the next step without further purification. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 4.31 (t, J=6.5 Hz, 2H), 3.77 (s, 2H), 1.87–1.81 (m, 2H) , 1.53–1.50 (m, 8H), 1.41 (s, 6H), 1.12–1.08 (m, 3H).

Step 2: Reaction to produce heptyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (13b).

A solution of sulfuryl chloride (2.0 ml, 27.7 mmol) in Et ₂ O (40 ml) was cooled to –78°C under argon. A solution of heptyl 3-hydroxy-2,2-dimethylpropanoate (13a) (3.0 g, 13.9 mmol) and pyridine (1.4 ml, 16.6 mmol) in Et was added dropwise to the sulfuryl chloride solution over 30 min. ₂ O (15 ml). The flask was washed with Et ₂ O (3×5 ml), and the wash was added to the reaction mixture. The mixture was shaken at −78°C until complete, which was monitored by TLC (30 min; 30% EA/hex). The precipitate was filtered and the filtrate was concentrated in vacuo to give heptyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (13b) (3.3 g, 75%). The mixture was stored at –78°C and immediately used for the next step without further purification. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 4.46 (s, 2H), 4.11–4.00 (m, 2H), 1.64–1.55 (m, 2H), 1, 26–1.24 (m, 8H), 0.85–0.81 (m, 3H).

Step 3: Reaction to produce heptyl 3–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–2 ,2-dimethylpropanoate (13).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (673 mg) was dissolved in THF (35 ml) and 1,3-dimethyltetrahydropyrimidine- 2(1H)–one (5 ml), and the resulting solution was cooled to –78°C in an Ar atmosphere. A 1.0 M solution of NaHMDS in THF (4.0 mL, 4.0 mmol) was added dropwise to the cooled solution and shaken for 20 min. Neat heptyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (13b) (1.3 g, 4.0 mmol) was quickly added to the reaction mixture. The syringe was rinsed with THF (3 x 3 ml), and the rinse was also added to the mixture. After 10 min, the reaction mixture was heated to 23°C and shaken until complete, as determined by TLC and LC–MS. EtOAc (50 ml) and saturated aqueous NaHCO ₃ (50 ml) were added to the mixture. The aqueous and organic layers were separated and the organic layer was washed with saturated aqueous NaHCO ₃ (50 ml), water (3 x 50 ml), brine (50 ml), then dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the crude remainder. The residue was purified by silica gel column chromatography using EtOAc/hexanes (1:9-1:0) as eluent followed by high performance liquid chromatography to give product (13) (65 mg, 4%) as a solid. . LC–MS: 464.3 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 6.48 (s, 1H), 5.71 (s, 1H), 4.71 (d, J=9.6 Hz, 1H), 4.60 (d, J=9.3 Hz, 1H), 4.18–4.04 (m, 4H), 3.34–3.29 (m, 1H), 3.02 (d, J=11.7 Hz, 1H), 2.47–2.40 (m, 1H), 2.19–2.11 (m, 1H), 2.01–1.79 (m, 2H), 1.66–1, 59 (m, 2H), 1.37–1.26 (m, 14H), 0.90–0.86 (m, 3H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 174.3, 171.1, 167.0, 80.5, 65.6, 62.0, 60.2, 47.2, 43.0, 31 ,8, 29.0, 28.6, 25.9, 22.7, 22.2, 21.8, 20.9, 17.6, 14.2.

Example 14

Synthesis of tert-butyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2 –dimethylpropanoate (14)

Step 1 and Step 2: Reaction to produce tert-butyl 3-hydroxy-2,2-dimethylpropanoate (14a).

the compound was synthesized in accordance with PCT International Application Publication No. WO 2007116922. Sodium hydride (60% in mineral oil; 2. 0 g). The mixture was shaken at 0°C for 10 min. MeI (3.2 ml) was added to the mixture and shaking was continued for 3 hours (at which time the mixture was at room temperature). Brine and EtOAc were added to the mixture and the organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give product (about 4.5 g) which was used directly in the next step.

Solid lithium tri-tert-butoxyaluminum hydride (7.1 g, 28 mmol) was added portionwise to a solution of tert-butyl methyl 2,2-dimethyl-malonate (2.2 g) in THF (100 ml) under Ar atmosphere over 15 min. . The mixture was then refluxed and shaken overnight. After cooling to room temperature, a saturated solution of NH ₄ Cl and EtOAc was added and the aqueous and organic layers were separated. The organic layer was washed with H ₂ O and brine, then dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a crude residue. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-3:7) to give product (14a) (900 mg) as an oil. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 3.50 (d, J=5.1 Hz, 2H), 2.53 (t, J=6.5 Hz, 1H), 1.45 (s , 9H), 1.14 (s, 6H)

Step 3: Reaction to produce tert-butyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (14b).

A solution of sulfuryl chloride (0.31 ml, 4.2 mmol) in Et ₂ O (6 ml) was cooled to –78°C under Ar. A solution of tert-butyl 3-hydroxy-2,2-dimethylpropanoate (14a) (0.49 g, 2.8 mmol) and pyridine (0.25 ml, 3.1 mmol) was added dropwise to the sulfuryl chloride solution over 10 min. in Et ₂ O (6 ml). After TLC indicated that the reaction was incomplete (10% EtOAc/hexanes), the mixture was shaken at –78°C for 90 minutes and allowed to warm to 23°C. The mixture was re-cooled to -78°C, and an additional 1 equivalent of sulfuryl chloride was added, shaken for 10 minutes, and the mixture was allowed to warm to 23°C (note: after addition and during the heating period, the mixture was shaken for a total of 1 hour ). The precipitate was filtered and the filtrate was concentrated in vacuo to give tert-butyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (14b) (961 mg, yield as calculated) as a clear oil. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 4.46 (fd, J=1.5 Hz, 2H), 1.47 (fd, J=1.2 Hz, 9H), 1.27 (s , 6H).

Step 4: Reaction to produce tert-butyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy) –2,2-dimethylpropanoate (14).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (463 mg, 2.5 mmol) was dissolved in THF (25 ml) and 1 ,3-dimethyltetrahydropyrimidine-2(1H)-one (1.5 ml), and the resulting solution was cooled to –78°C under Ar. A 1.0 M solution of NaHMDS in THF (2.8 mL, 2.8 mmol) was added dropwise to the cooled solution and the mixture was shaken for 10 min. Undiluted tert-butyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (14b) (0.75 g, 2.8 mmol) was quickly added to the reaction mixture. The syringe was flushed with THF (3 x 3 ml), and these washes were also quickly added to the mixture. After 20 minutes, the reaction mixture was heated to 23°C. After shaking for 70 min, the reaction was complete as determined by TLC (70% EA/hexanes). The mixture was cooled to 0°C, diluted with EtOAc (50 ml) and quenched with saturated aqueous NaHCO ₃ (50 ml). The aqueous and organic layers were separated and the organic layer was washed with saturated aqueous NaHCO ₃ (50 ml), water (3×50 ml) and brine (50 ml), then dried (Na ₂ SO ₄ ) and concentrated in vacuo to obtain a crude residue. The residue was purified by silica gel column chromatography using EtOAc/hexanes (1:9-1:0) to give product (14) (368 mg, 35% yield) as a solid. LC–MS: 422.1 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 6.50 (s, 1H), 5.85 (s, 1H), 4.66 (d, J=9 Hz, 1H), 4.56 (d , J=8.7 Hz, 1H), 4.17 (s, 1H), 4.04 (d, J=6.9 Hz, 1H), 3.33–3.29 (m, 1H), 3 .02 (d, J=12 Hz, 1H), 2.46–2.39 (m, 1H), 2.17–2.12 (m, 1H), 2.00–1.79 (m, 2H ), 1.45 (s, 9H), 1.23 (s, 3H), 1.21 (s, 3H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 173.3, 171.1, 167.0, 81.6, 80.9, 62.0, 60.2, 47.2, 43.4, 28 ,0, 22.2, 21.6, 20.8, 17.6.

Example 15

Synthesis of 2-methoxyethyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2 –dimethylpropanoate (15)

Step 1: Reaction to produce 2-methoxyethyl 3-hydroxy-2,2-dimethylpropanoate (15a).

3-Hydroxy-2,2-dimethylpropanoic acid (1.2 g, 10.3 mmol) and Cs2CO3 (3.4 g, 10.4 mmol) were suspended in DMF (25 ml) at 23°C, then 2- bromoethyl methyl ether (1.0 ml, 10.4 mmol). The resulting mixture was shaken at 70°C overnight. After cooling, the mixture was filtered through a pad of Celite®. The filtrate was diluted with EtOAc (150 ml) and the mixture was washed with water (3×100 ml) and brine, then dried (Na ₂ SO ₄ ), filtered and concentrated to give a crude residue. The residue was purified by silica gel column chromatography using EtOAc/hexanes (1:4-4:1) as eluent to give product (15a) (crude mass 1.3 g) as an oil. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 4.28 (t, J=4.8 Hz, 2H), 3.62–3.55 (m, 4H), 3.38 (s, 3H) , 2.65 (t, J=6.0 Hz, 1H), 1.21 (s, 6H).

Step 2: Reaction to produce 2-methoxyethyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (15b).

A solution of freshly distilled sulfuryl chloride (0.2 ml, 2.8 mmol) in Et ₂ O (7.0 ml) was cooled to –78°C under Ar. A solution of 2-methoxyethyl 3-hydroxy-2,2-dimethylpropanoate (15a) (0.48 g, 2.7 mmol) and pyridine (0.24 ml, 3.0 mmol) was added dropwise to the sulfuryl chloride solution over 11 min. in Et ₂ O (1 ml). The flask was washed with Et ₂ O (3×1 ml), which was also added to the reaction mixture. The mixture was shaken at –78°C until complete (monitored with TLC, 30% EtOAc/hex, 30 min). The precipitate was filtered and the filtrate was concentrated in vacuo to give product (15b) (0.5 g, 67%) as an oil, which was used directly in the next step without further purification [Note: 1HNMR showed the desired product with a pyridine residue and together with the starting material material].

Step 3: Reaction to produce 2-methoxyethyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy) –2,2-dimethylpropanoate (15).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (162 mg, 0.9 mmol) was dissolved in THF (2.5 ml) and 1,3-dimethyltetrahydropyrimidine-2(1H)-one (0.3 ml), and the resulting solution was cooled to –78°C under Ar. A 1.0 M solution of NaHMDS in THF (1.0 mL, 1.0 mmol) was added dropwise to the cooled solution and the mixture was shaken for 10 min. 2-methoxyethyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (15b) (0.3 g, 1.1 mmol) in THF (2 ml) was quickly added to the reaction mixture. After 10 minutes at –78°C, the mixture was heated to 23°C and shaken for 30 minutes. The mixture was diluted with EtOAc (40 ml) and water. The aqueous and organic layers were separated, and the organic layer was washed with water (3×20 ml), and brine (50 ml), then dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to obtain a crude residue. The crude residue was purified by silica gel column chromatography (4 g column) using EtOAc/hexanes (3:7-1:0) as eluent to obtain a solid containing impurities. The product was dissolved in Et ₂ O (20 ml) by sonication and precipitated with hexanes. The resulting solid was filtered and dried in vacuo to give product (15) (72 mg, 19.4%) as a solid. LCMS: m/z=424.3 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 6.48 (br. s, 1H), 5.56 (br. s, 1H), 4.62 (dd, J=28.8, 8.7 Hz, 2H), 4.33–4.22 (m, 2H), 4.17 (br. s, 1H), 4.05 (d, J=6.9 Hz, 1H), 3.60 (t , J=4.6 Hz, 2H), 3.38 (s, 3H), 3.33 (d, J=11.1 Hz, 1H), 3.02 (d, J=12.0 Hz, 1H ), 2.46–2.41 (m, 1H), 2.18–2.13 (m, 1H), 1.98–1.84 (m, 2H), 1.31 (s, 3H), 1.29(s, 3H). ¹³ C–NMR (75 MHz, CDCl ₃ ), δ 174.1, 170.8, 166.9, 80.2, 70.2, 64.1, 61.8, 60.0, 59.0, 47 ,1, 42.9, 22.1, 21.6, 20.7, 17.4.

Example 16

Synthesis of oxetan-3-yl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2 ,2-dimethylpropanoate (16)

Step 1: Reaction to produce oxetan-3-yl 3-hydroxy-2,2-dimethylpropanoate (16a).

3-Hydroxy-2,2-dimethylpropanoic acid (4.7 g, 40 mmol) and Cs2CO3 (13.0 g, 40 mmol) were suspended in DMF (100 ml) at 23°C, then 3-iodoxetane (7, 4 g, 40 mmol). The resulting mixture was shaken at 70°C overnight. After cooling, the mixture was diluted with EtOAc (150 ml), and the mixture was washed with water (3×100 ml) and brine, then dried (Na ₂ SO ₄ ), filtered and concentrated to obtain a crude residue. The residue was purified by silica gel column chromatography using EtOAc/hexanes as eluent to give product (16a) (3.6 g, 51%) as an oil.

Step 2: Reaction to produce oxetan-3-yl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (16b).

A solution of freshly distilled sulfuryl chloride (0.2 ml, 2.7 mmol) in Et ₂ O (3 ml) was cooled to –78°C under Ar. A solution of oxetan-3-yl 3-hydroxy-2,2-dimethylpropanoate (16a) (0.46 g, 2.6 mmol) and pyridine (0.2 ml, 2.7 mmol) was added dropwise to the sulfuryl chloride solution over 11 min. mmol) in Et ₂ O (2 ml). The flask was washed with Et ₂ O (3×1 ml), which was also added to the reaction mixture. The mixture was shaken at –78°C until complete (monitored with TLC, 30% EtOAc/hex, 30 min). The precipitate was filtered and the filtrate was concentrated in vacuo to give product (16b) (0.5 g, 69%) as an oil, which was used directly in the next step without further purification. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 5.50–5.46 (m, 1H), 4.94–4.89 (m, 2H), 4.65–4.60 (m, 2H ), 4.52 (s, 2H), 1.72 (br. s, 1H), 1.36 (s, 6H).

Step 3: Reaction to produce oxetan-3-yl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl) oxy)-2,2-dimethylpropanoate (16).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (200 mg, 1.1 mmol) was dissolved in THF (3 ml) and 1 ,3-dimethyltetrahydropyrimidine-2(1H)-one (2 ml), DMPU was added and the resulting solution was cooled to –78°C under Ar. A 1.0 M solution of NaHMDS in THF (1.2 mL, 1.2 mmol) was added dropwise to the cooled solution and the mixture was shaken for 10 min. A solution of oxetan-3-yl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (16b) (0.37 g, 1.4 mmol) in THF (2 ml) was quickly added to the reaction mixture. After shaking at –78°C for 10 minutes, allow the mixture to warm to 23°C and shake for a total of 1 hour. The mixture was diluted with EtOAc (40 ml) and H ₂ O. The aqueous and organic layers were separated and the organic layer was washed with H ₂ O (3×20 ml), brine (50 ml), then dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to obtain a crude residue. The crude residue was purified by silica gel column chromatography (4 g column) using EtOAc/hexanes (3:7-1:0) as eluent to give an oil. The oil was triturated with Et ₂ O by sonication and the filter cake was washed with Et ₂ O to give product (16) (170 mg, 37%) as a solid. LCMS: m/z=422.3 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 6.48 (br. s, 1H), 5.54 (br. s, 1H), 5.48–5.44 (m, 1H), 4, 89 (t, J=7.4 Hz, 2H), 4.79 (d, J=8.7 Hz, 1H), 4.66– 4.58 (m, 3H), 4.18 (br. s , 1H), 4.05 (d, J=6.9 Hz, 1H), 3.33 (d, J=12.3 Hz, 1H), 2.44–2.42 (m, 1H), 2 .20–2.16 (m, 1H), 2.00–1.80 (m, 2H), 1.32 (s, 3H), 1.31 (s, 3H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 173.4, 170.8, 167.0, 80.0, 68.6, 76.6, 61.9, 60.2, 47.1, 42 ,7, 21.9, 21.6, 20.7, 17.4.

Example 17

Synthesis of ethyl 1-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclohexanecarboxylate ( 17)

Step 1: Reaction to produce ethyl 1-(((chlorosulfonyl)oxy)methyl)cyclohexanecarboxylate (17a).

A solution of freshly distilled sulfuryl chloride (77 µl, 1.1 mmol) in Et ₂ O (3 ml) was cooled to –78°C under Ar. A solution of ethyl 1-(hydroxymethyl)cyclohexanecarboxylate (0.2 g, 1.0 mmol) and pyridine (85 μl, 1.1 mmol) in Et ₂ O (2 ml) was added dropwise to the sulfuryl chloride solution over 11 min. The flask was washed with Et ₂ O (3×1 ml), and the wash was added to the reaction mixture. The mixture was shaken at –78°C until complete (about 30 min; monitored with TLC, 30% EtOAc/hex). The precipitate was filtered and the filtrate was concentrated in vacuo to give the title compound as an oil, which was used directly in the next step without purification. A second batch using 476 mg of starting alcohol yielded 600 mg of product (17a) (approximately 85% purity by ^1H -NMR).

Step 2: Reaction to produce ethyl-1-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy) methyl)cyclohexanecarboxylate (17).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (0.33 g, 1.8 mmol) was dissolved in THF (7 ml) and 1,3-dimethyltetrahydropyrimidine-2(1H)-one (3.5 ml), and the resulting solution was cooled to –78°C under Ar. A 1.0 M solution of NaHMDS in THF (1.8 mL, 1.8 mmol) was added dropwise over 20 min and the mixture was shaken for 10 min. Ethyl 1-(((chlorosulfonyl)oxy)methyl)cyclohexanecarboxylate (17a) (0.51 g, 1.8 mmol) in THF (2 mL) was quickly added to the reaction mixture. After 10 minutes of shaking at –78°C, the mixture was heated to 23°C and shaken for a total of 1 hour. The reaction mixture was diluted with EtOAc (40 ml) and H ₂ O at –60°C. The aqueous and organic layers were separated and the organic layer was washed with H ₂ O (3×20 ml) and brine (50 ml), then dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a crude residue (330 mg). The oil was purified by silica gel column chromatography (4 g column) using EtOAc/hexanes (3:7-1:0) as eluent, followed by purification using preparative HPLC (10-90% MeCN/ _H2O for 20 min using UV detection at 254/220 nM) to obtain product (17) (223 mg, 34%) as a solid. LCMS: m/z=434.3 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 6.50 (br.s, 1H), 5.80 (br.s, 1H), 4.66 (dd, J=48.6, 12.8 Hz, 2H), 4.21–4.15 (m, 3H), 4.04 (d, J=6.9 Hz, 1H), 3.31 (d, J=3.0 Hz, 1H), 3.01 (d, J=11.7 Hz, 1H), 2.44–2.39 (m, 1H), 2.16–1.78 (m, 5H), 1.57–1.39 ( m, 8H), 1.27 (t, J=7.1 Hz, 3H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 173.2, 171.0, 167.0, 80.2, 61.8, 61.1, 60.1, 47.1, 30.4, 30 ,0, 25.4, 22.2, 22.0, 20.7, 17.4, 14.1.

Example 18

Synthesis of ethyl-1-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclopentane- 1-carboxylate (18)

Step 1: Reaction to produce ethyl 1-(((chlorosulfonyl)oxy)methyl)cyclopentane-1-carboxylate (18a).

A solution of freshly distilled sulfuryl chloride (200 µl, 2.7 mmol) in Et ₂ O (3 ml) was cooled to –78°C under Ar. A solution of ethyl 1-(hydroxymethyl)cyclopentanecarboxylate (0.48 g, 2.7 mmol) and pyridine (222 μl, 2.7 mmol) in Et ₂ O (2 ml) was added dropwise to the sulfuryl chloride solution over 7 min. The flask was washed with Et ₂ O (2×1 ml) and both washes were added to the reaction mixture. The mixture was shaken at –78°C for 1.5 hours. The precipitate was filtered and the filter cake was washed with Et ₂ O (4 ml). The filtrate was concentrated in vacuo to give the title compound (18a) as an oil, which was used directly in the next step without further purification.

Step 2: Reaction to produce ethyl-1-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy) methyl)cyclopentane-1-carboxylate (18).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (200 mg, 1.1 mmol) was dissolved in THF (5 ml) and 1 ,3-dimethyltetrahydropyrimidine-2(1H)-one (2 ml), and the resulting solution was cooled to –78°C under Ar. A 1.0 M solution of NaHMDS in THF (1.3 mL, 1.3 mmol) was added dropwise over 10 min. Note: Since sulfonyl chloride contains approximately 20% starting alcohol, an additional 0.2 eq of NaHMDS was added. Note: The reaction mixture was immersed in and out of the cooling bath to form a shaking solution, otherwise it was a gel. Ethyl 1-(((chlorosulfonyl)oxy)methyl)cyclopentanecarboxylate (18a) (0.47 g, 1.7 mmol) in THF (2×1 ml) was quickly added to the reaction mixture. After 10 minutes, the mixture was heated to 23°C and shaken for a total of 2 hours. The reaction mixture was diluted with EtOAc (40 ml) and brine at –60°C. The aqueous and organic layers were separated and the organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a crude residue. The residue was purified by silica gel column chromatography using EtOAc/hexanes (3:7–1:0) as eluent, followed by preparative reverse phase HPLC to give the title compound (18) (62 mg, 14%) as a solid substances. LCMS: m/z=420.3 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 6.55 (br. s, 1H), 6.15 (br. s, 1H), 4.69 (dd, J=20.9, 9.3 Hz, 2H), 4.20–4.10 (m, 3H), 4.02 (d, J=6.6 Hz, 1H), 3.29 (d, J=12.3 Hz, 1H), 3.01 (d, J=11.7, 1H), 2.40–2.36 (m, 1H), 2.14–1.66 (m, 11 h), 1.24 (t, J= 7.4 Hz, 3H). ¹³ C–NMR (75 Hz, CDCl ₃ ): δ 174.4, 171.2, 167.0, 78.9, 61.8, 61.2, 60.1, 53.0, 47.0, 33 ,9, 32.9, 25.6, 25.5, 20.7, 17.5, 14.1.

Example 19

Synthesis of ethyl 1-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclobutanecarboxylate ( 19)

Step 1: Reaction to produce ethyl 1-(((chlorosulfonyl)oxy)methyl)cyclobutane carboxylate (19a).

A solution of freshly distilled sulfuryl chloride (451 µl, 6.2 mmol) in Et ₂ O (5 ml) was cooled to –78°C under Ar. A solution of ethyl 1-(hydroxymethyl)cyclobutanecarboxylate (1.0 g, 6.1 mmol) and pyridine (500 μl, 6.2 mmol) in Et ₂ O (10 ml) was added dropwise to the sulfuryl chloride solution over 11 min. The flask was washed with Et ₂ O (3×1 ml), which was also added to the reaction mixture. The mixture was shaken at -78°C, then warmed to ambient temperature for 4 hours. The precipitate was filtered and the filtrate was concentrated in vacuo to give the title compound (1.2 g, 76%) as an oil, which was used directly in the next step. without additional cleaning. Note: 1HNMR showed the desired product (19a) along with the starting material.

Step 2: Reaction to produce ethyl-1-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy) methyl)cyclobutanecarboxylate (19).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (0.33 g, 1.8 mmol) was dissolved in THF (8 ml) and 1,3-dimethyltetrahydropyrimidine-2(1H)-one (2 ml), and the resulting solution was cooled to –78°C under argon. A 1.0 M solution of NaHMDS in THF (2 mL, 2.1 mmol) was added dropwise over 10 min. Note: Since sulfonyl chloride contains approximately 30% starting alcohol, an additional 0.3 eq of NaHMDS was added. Ethyl 1-(((chlorosulfonyl)oxy)methyl)cyclobutanecarboxylate (19a) (1.0 g, 3.9 mmol) in THF (2 x 1 mL) was quickly added to the reaction mixture. After 10 minutes, the mixture was heated to 23°C and shaken for 1 hour. The mixture was diluted with EtOAc (40 ml) and H ₂ O at –60°C. The aqueous and organic layers were separated and the organic layer was washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a crude residue. The oil was purified by preparative HPLC to give a solid (303 mg). The solid was dissolved in DCM and filtered through a syringe filter to obtain product (19) (273 mg, 35%) as a solid. LCMS: m/z=406.1 [M+H] ⁺ , ¹ H–NMR (300 MHz, CDCl ₃ ): δ 6.57 (br. s, 1H), 6.28 (br. s, 1H) , 4.85 (dd, J=63.9, 9.3 Hz, 2H), 4.30–4.13 (m, 3H), 4.01 (d, J=7.2 Hz, 1H), 3.27 (d, J=10.8 Hz, 1H), 3.01 (d, J=11.7 Hz, 1H), 2.50–2.35 (m, 3H), 2.13–1 .76 (m, 8H), 1.24 (t, J=7.3 Hz, 3H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ173.1, 171.3, 167.2, 77.9, 61.8, 61.2, 60.7, 60.1, 47.0, 46, 3, 27.1, 26.1, 20.7, 17.5, 15.6, 14.0.

Example 20

Synthesis of ethyl 2,2-dimethyl-3-(((((2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl) oxy)sulfonyl)oxy)propanoate (20)

Step 1: Synthesis of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (20a).

A solution of distilled sulfuryl chloride (0.61 ml, 7.5 mmol) in Et ₂ O (10 ml) was cooled under nitrogen to –78°C. A solution of ethyl 3-hydroxy-2,2-dimethylpropanoate (2a) (1.0 g, 6.8 mmol) and pyridine (0.55 ml, 6.8 mmol) was then added dropwise over 1 h using a syringe. Et ₂ O (2.0 ml). The reaction mixture was shaken for 1 hour at –78°C and allowed to warm to room temperature and shaken for a further 2 hours. After filtering the mixture, the filtrate was concentrated in vacuo to give product (20a) as a colorless liquid (1.46 g, yield 87%). ¹ H–NMR (300 MHz, CDCl ₃ ): δ 4.50 (s, 2H), 4.19 (q, J=6.9 Hz, 2H), 1.31 (s, 6H), 1.28 (t, J=6.9 Hz, 3H).

Step 2: Synthesis of tert-butyl 4-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate (20b) .

To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (20a) (10 g, 36.2 mmol), tert-butyl 4-Aminopiperidine-1-carboxylate (7.26 g, 36.2 mmol) in DCM (200 ml) was added with HATU (13.76 g, 36.2 mmol) and DIPEA (6.31 ml, 36.2 mmol) . The reaction mixture was shaken at room temperature overnight. The mixture was washed with saturated NH ₄ Cl solution, water and brine. The organic layer was dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to obtain a crude residue. The residue was purified by silica gel column chromatography using EtOAc/hexane (1:1) as eluent to give product (20b) (10.3 g, 62% yield) as a white solid. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.36–7.44 (m, 5H), 6.55 (d, 1H, J=8.1 Hz), 5.05 (d, 1H, J=11.7 Hz), 4.90 (d, 1H, J=11.1 Hz), 4.02 (br, s, 1H), 3.87–3.99 (m, 2H), 3, 29 (s, 1H), 3.01 (d, 1H), 2.85 (t, 2H), 2.64 (d, 1H), 2.37 (dd, 1H), 1.84–2.05 (m, 4H), 1.55–1.67 (m, 2H), 1.45 (s, 9H), 1.23–1.36 (m, 2H). MS (ESI) C24H ₃ 4N4O5=459.1 (M+1) ⁺ .

Step 3: Synthesis of tert-butyl 4-((2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate (20c).

Into a solution of tert-butyl 4-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate (20b) (0 .6 g, 1.31 mmol) in MeOH (6 ml) was added 10% palladium on carbon (0.2 g). The reaction mixture was shaken for 1 hour at a hydrogen pressure of 1 atm. After filtering the mixture through a pad of Celite®, the filtrate was concentrated in vacuo to give crude product (20c) (0.48 g, 100% yield) which was used directly for the next step. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 6.62 (d, 1H, J=7.8 Hz), 3.86–4.01 (m, 4H), 3.75 (s, 1H) , 3.17 (d, 1H), 2.91 (t, 2H), 2.81 (d, 1H), 2.42 (m, 1H), 2.13 (m, 1H), 1.88 ( m, 4H), 1.74 (m, 1H), 1.45 s, 9H), 1.31 (m, 2H).

Step 4: Synthesis of tert-butyl 4-((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[ 3.2.1]octane-2-carboxamido)piperidine-1-carboxylate (20d).

Tert-butyl 4-((2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate (20c) (1.31 mmol) dissolved in THF (7.0 ml) and 1,3-dimethyltetrahydropyrimidin-2(1H)-one (3 ml), and the resulting solution was cooled to –78°C under nitrogen atmosphere. A solution of NaHMDS in THF (1M, 1.31 mL, 1.31 mmol) was added dropwise and the mixture was shaken at –78°C for 10 min. A solution of ethyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (3a) (352 mg, 1.44 mmol) in THF (1 ml) was then added to the reaction mixture using a syringe. After 10 min at –78°C, the reaction mixture was allowed to warm to room temperature and shaken overnight. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO ₃ , water and brine. The organic layer was dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to obtain a crude residue. The residue was purified by silica gel column chromatography using EtOAc/hexane (1:1) as eluent to give product (20d) (330 mg, 44% yield) as a white foam. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 6.44 (d, 1H, J=8.1 Hz), 4.59–4.73 (dd, 2H, J=8.7 Hz), 3 .89–4.23 (m, 7H), 3.28 (d, 1H), 2.83–2.92 (m, 3H), 2.42–2.49 (m, 1H), 2.14 –2.17 (m, 1H), 1.80–1.97 (m, 4H), 1.46 (s, 9H), 1.58–1.23 (m, 11H). MS (ESI) C24H ₄ 0N4O10S=577 (M+1) ⁺ .

Step 5: Synthesis of ethyl 2,2-dimethyl-3-(((((2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octane-6 –yl)oxy)sulfonyl)oxy)propanoate (TFA salt) (20).

Into the mixture tert-butyl 4-((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2. 1]octane-2-carboxamido)piperidine-1-carboxylate (20d) (240 mg, 0.42 mmol) in DCM (1.4 ml) was added with trifluoroacetic acid (1.4 ml) at –10°C. The reaction mixture was shaken at –10°C for 30 minutes. LC/MS analysis showed that the starting material was completely consumed. The mixture was concentrated in vacuo to obtain a crude residue. The residue was purified by preparative HPLC on a C18 column eluting with MeCN/ _H2O containing 0.1% TFA (5-100%) to give the title compound (20) (103 mg, 42% yield) as an off-white powder colors. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 9.42 (br s, 1H), 9.06 (br s, 1H), 6.71 (d, 1H, J=7.8 Hz), 4 .57–4.73 (dd, 2H, J=9.0 Hz), 3.99–4.19 (m, 5H), 3.48 (d, 2H), 3.26 (d, 1H), 3.00 (m, 2H), 2.88 (d, 1H), 1.82–2.39 (m, 7H), 1.23–1.30 (m, 9H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 174.5, 168.9, 167.3, 80.8, 62.0, 61.6, 60.4, 46.8, 44.9, 43 ,6, 43.3, 28.7, 22.3, 21.9, 20.9, 18.0, 14.4. 19F NMR (282 MHz, CDCl ₃ ): δ –75.8. MS (ESI) C19H ₃ 2N4O8S=477 (M+1) ⁺ .

Analytical HPLC was performed on an Agilent 1200 system using a C18 Phenomenex column (150 × 4.6 mm i.d.). The mobile phase was MeCN and water with a linear gradient (0.1% TFA, from 5% MeCN to 100% MeCN in 15 min). The flow rate was maintained at 1 ml/min, and the eluent was monitored using a UV detector at 220 and 254 nM. HPLC retention time: 7.31 min.

Example 21

Synthesis of 2-methoxyethyl 2,2-dimethyl-3-(((((2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octane-6- yl)oxy)sulfonyl)oxy)propanoate (21).

Step 1: Synthesis of 2-methoxyethyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (21a).

A solution of distilled sulfuryl chloride (0.51 ml, 6.2 mmol) in Et ₂ O (10 ml) was cooled under nitrogen to –78°C. Then a solution of 2-methoxyethyl 3-hydroxy-2,2-dimethylpropanoate (15a) (1.0 g, 5.68 mmol) and pyridine (0.46 ml, 5.68 mmol) was added dropwise using a syringe over 1 h. ) in Et ₂ O (2.0 ml). The reaction mixture was shaken at –78°C for 1 hour and then allowed to warm to room temperature and shaken for 2 hours. After filtering the mixture, the filtrate was concentrated in vacuo to give product (21a) as a colorless liquid (1.5 g, yield 96%). ¹ H–NMR (300 MHz, CDCl ₃ ): δ 4.40 (s, 2H), 4.29 (t, 3H), 3.59 (t, 3H), 3.37 (s, 3H), 1 .32 (s, 6H).

Step 2: Synthesis of tert-butyl 4-((2S,5R)-6-(((3-(2-methoxyethoxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1, 6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate (21b).

tert-butyl 4-((2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate (20c) (3.26 mmol) dissolved in THF (14 ml) and 1,3-dimethyltetrahydropyrimidin-2(1H)-one (6 ml), and the resulting solution was cooled to –78°C under nitrogen. A solution of NaHMDS in THF (1M, 3.59 mL, 3.59 mmol) was added dropwise and the mixture was shaken at –78°C for 10 min. A solution of 2-methoxyethyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (21a) (878 mg, 3.59 mmol) in THF (2 ml) was then added to the reaction mixture using a syringe. After 10 min at –78°C, the reaction mixture was allowed to warm to room temperature and shaken overnight. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO ₃ , water and brine. The organic layer was dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to obtain a crude residue. The residue was purified by silica gel column chromatography using EtOAc/hexane (1:1) as eluent to give product (21b) (0.96 g, 48% yield) as a white foam. MS (ESI) C25H ₄ 2N4O11S=607.0 (M+1) ⁺ .

Step 3: Synthesis of 2-methoxyethyl 2,2-dimethyl-3-(((((2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octane –6-yl)oxy)sulfonyl)oxy)propanoate (TFA salt) (21).

Into the mixture tert-butyl 4-((2S,5R)-6-(((3-(2-methoxyethoxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6- diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate (21b) (0.86 g, 1.42 mmol) in DCM (4.3 ml) was added trifluoroacetic acid (4.3 ml) at – 10°C. The reaction mixture was shaken at –10°C for 30 minutes. LC/MS analysis showed that the starting material was completely consumed. The mixture was concentrated in vacuo to obtain a crude residue. The residue was purified by preparative HPLC on a C18 column eluting with MeCN/H ₂ O containing 0.1% TFA (5-75%) to give the title compound (21) (513 mg, 58% yield) as a yellow powder. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 9.09 (br s, 1H), 8.75 (br s, 1H), 6.83 (d, 1H, J=7.8 Hz), 4 .59–4.71 (dd, 2H, J=9.3 Hz), 3.99–4.36 (m, 5H), 3.60 (m, 2H), 3.50 (d, 2H), 3.39 (s, 3H), 3.30 (d, 1H), 3.02 (m, 2H), 2.89 (d, 1H), 1.87–2.40 (m, 7H), 1 .25–1.30 (m, 9H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 174.4, 168.9, 167.4, 80.6, 70.6, 64.5, 62.0, 60.4, 59.3, 46 ,8, 44.9, 43.6, 43.2, 28.7, 22.4, 21.8, 20.9, 18.0. 19F NMR (282 MHz, CDCl ₃ ): δ –75.8. MS (ESI) C20H ₃ 4N4O9S=507 (M+1) ⁺ . HPLC retention time (MeCN/H ₂ O in 0.1% TFA): 6.75 min.

Example 22

Synthesis of 4–((2S,5R)–6–(((3–(hexyloxy)–2,2–dimethyl–3–oxopropoxy)sulfonyl)oxy)–7–oxo–1,6–diazabicyclo[3.2.1] octane-2-carboxamido)piperidine-1-ium 2,2,2-trifluoroacetate (22).

Step 1: Synthesis of hexyl 3-hydroxy-2,2-dimethylpropanoate (22a).

A mixture of 3-hydroxy-2,2-dimethylpropionic acid (4.7 g, 40 mmol), -1-hexanol (70 ml) and concentrated sulfuric acid (or fuming sulfuric acid, 1 ml) was heated to 80°C and shaken in during the night. Once cooled, the mixture was concentrated in vacuo (high vacuum pump required) and then the residue was partitioned into EtOAc (100 ml) and saturated aq. NaHCO ₃ (100 ml). The aqueous phase was washed with H ₂ O (50 ml), saturated NaHCO ₃ (50 ml) and brine (50 ml) and then dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the product as an oil. The product was difficult to purify using silica gel chromatography; and consequently the product was distilled under high pressure at 47°C to obtain 4.92 g of pure ester product (22a) (yield 61%). ¹ H–NMR (300 MHz, CDCl ₃ ) δ 4.10 (td, J=6.7, 1.3 Hz, 2H), 3.55 (d, J=5.1 Hz, 2H), 2, 42 (s, 1H), 1.64 (s, 1H), 1.72–1.56 (m, 1H), 1.35 (s, 1H), 1.31 (s, 6H), 1.27 –1.11 (m, 6H), 0.95–0.84 (m, 3H). MS (ESI) C11H ₂ 2O3=203 (M+1) ⁺ .

Step 2: Synthesis of hexyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (22b).

A solution of freshly distilled sulfuryl chloride (0.60 ml, 7.4 mmol) in Et ₂ O (10 ml) was cooled to –78°C under N ₂ atmosphere. A solution of hexyl 3-hydroxy-2,2-dimethylpropanoate (22a) (1.0 g, 4.94 mmol) and pyridine (0.48 ml, 5.93 mmol) in Et was added dropwise to the sulfuryl chloride solution over 20 min. ₂ O (5 ml). The flask was washed with Et ₂ O (3×1 ml), and the wash was added to the reaction mixture. The mixture was shaken at −78°C until complete with TLC (30 min; 30% EA/hexane). The precipitate was filtered and the filtrate was concentrated in vacuo to give the crude product (22b) as a solid foam and used in the next step without further purification. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 4.50 (s, 2H), 4.13 (t, J=6.8 Hz, 2H), 1.69–1.60 (m, 2H) , 1.40–1.27 (m, 12H), 0.91–0.87 (m, 3H).

Step 3: Synthesis of tert-butyl 4-((2S,5R)-6-(((3-(hexyloxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6- diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate (22d).

Hydroxamic acid (2.39 mmol) was dissolved in THF (12 ml) and 1,3-dimethyltetrahydropyrimidine-2(1H)-one (3.4 ml), and the resulting solution was cooled to -78°C under N ₂ . A solution of NaHMDS in THF (2.4 mL, 1.0 M, 2.4 mmol) was added dropwise and the mixture was shaken for 20 min. Neat hexyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (22b) (0.973 g, 2.64 mmol) was quickly added to the reaction mixture. The syringe was rinsed with THF (3x4 ml) and the rinse was also added to the mixture. After 10 min, the reaction mixture was warmed to room temperature and shaken until complete, as determined by TLC and LC–MS. EtOAc (30 ml) and saturated aqueous NaHCO ₃ (30 ml) were added to the mixture. The layers were separated and the organic layer was washed with saturated aqueous NaHCO ₃ (30 ml), water (3×20 ml) and brine (30 ml), and then dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to obtain a crude residue. The residue was purified by silica gel column chromatography using EtOAc/hexane (1:9-1:0) as eluent followed by high performance liquid chromatography to give product (22d) (740 mg, 49% yield over 3 steps) as solid foam. ¹ H–NMR (300 MHz, CDCl ₃ ) δ 6.43 (d, J=8.2 Hz, 1H), 4.76–4.64 (m, 1H), 4.60 (d, J=9 .0 Hz, 1H), 4.19–4.03 (m, 5H), 3.98 (d, J=7.5 Hz, 2H), 3.28 (d, J=12.0 Hz, 1H ), 2.90 (d, J=12.0 Hz, 2H), 2.45 (dd, J=14.8, 6.2 Hz, 1H), 2.14 (s, 1H), 1.97 –1.84 (m, 3H), 1.62 (q, J=7.0 Hz, 11H), 1.46 (s, 9H), 1.34–1.19 (m, 14H), 0. 88 (d, J=7.0 Hz, 3H). MS (ESI) C28H ₄ 8N4O10S=633 (M+1) ⁺ .

Step 4: Synthesis of 4-((2S,5R)-6-(((3-(hexyloxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2 .1]octane-2-carboxamido)piperidine-1-ium 2,2,2-trifluoroacetate (22).

Tert-butyl 4-((2S,5R)-6-(((3-(hexyloxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2. 1]Octane-2-carboxamido)piperidine-1-carboxylate (22d) (300 mg, 0.474 mmol) was dissolved in DCM (2 ml) and cooled to –10 oC. TFA (2 ml) was added dropwise to the solution. The reaction was monitored by LCMS or TLC until completion (about 10 min). The solvent was removed in vacuo and the residue was purified using preparative HPLC with MeCN/H ₂ O containing 0.1% TFA (20-100%) as eluent to give the title compound (22) after lyophilization (212.4 mg, yield 84%) in the form of foam. ¹ H–NMR (300 MHz, CDCl ₃ ) δ 9.08 (s, 1H), 8.74 (s, 1H), 6.88 (d, J=7.9 Hz, 1H), 4.70– 4.51 (m, 2H), 4.23–3.92 (m, 6H), 3.47 (d, J=12.6 Hz, 2H), 3.31–3.19 (m, 1H) , 2.95 (dd, J=19.6, 11.0 Hz, 3H), 2.34 (dd, J=15.0, 6.2 Hz, 1H), 2.10 (s, 2H), 1.91 (ddd, J=15.8, 12.6, 8.0 Hz, 1H), 1.61 (ddd, J=12.5, 8.1, 6.3 Hz, 3H), 1, 40–1.16 (m, 14H), 0.91–0.80 (m, 3H). ¹³ C–NMR (75 MHz, CDCl ₃ ) δ 174.2, 168.6, 167.1, 80.4, 65.5, 61.7, 60.1, 46.6, 44.7, 43, 3, 42.9, 42.9, 31.4, 31.4, 28.5, 25.6, 25.5, 22.2, 22.2, 21.6, 20.7, 17.8, 14.0. 19F NMR (282 MHz, CDCl ₃ ) δ –75.6. MS (ESI) C ₂₃ H ₄₀ N ₄ O ₈ S=533 (M+1) ⁺ . HPLC retention time (MeCN/H ₂ O in 0.1% TFA): 8.18 min.

Example 23

Synthesis of 4–((2S,5R)–6–(((3–(heptyloxy)–2,2–dimethyl–3–oxopropoxy)sulfonyl)oxy)–7–oxo–1,6–diazabicyclo[3.2.1] octane-2-carboxamido)piperidine-1-ium 2,2,2-trifluoroacetate (23)

Step 1: Synthesis of heptyl 3-hydroxy-2,2-dimethylpropanoate (23a).

A mixture of 3-hydroxy-2,2-dimethylpropionic acid (4.7 g, 40 mmol), 1-heptanol (70 ml) and concentrated sulfuric acid (1 ml) was heated to 80°C and shaken overnight. Once cooled, the mixture was concentrated in vacuo (high vacuum pump required) and the residue partitioned into EtOAc (100 ml) and saturated aqueous NaHCO ₃ (100 ml). The aqueous phase was washed with H ₂ O (50 ml), saturated NaHCO ₃ (50 ml) and brine (50 ml) and then dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the product as an oil. The product was distilled under high pressure at 65°C to give the title compound (23a) as an oil (6.7 g, 77% yield). ¹ H–NMR (300 MHz, CDCl ₃ ) δ 4.09 (td, J=6.7, 0.9 Hz, 2H), 3.55 (d, J=6.1 Hz, 2H), 2, 43 (t, J=6.7 Hz, 1H), 1.60 (d, J=22.8 Hz, 4H), 1.3–1.58 (m, 6H), 1.27–1.14 (m, 6H), 0.92–0.83 (m, 3H).

Step 2: Synthesis of heptyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (23b)

A solution of sulfuryl chloride (0.6 ml, 7.4 mmol) in Et ₂ O (15 ml) was cooled to –78°C under N ₂ atmosphere. A solution of heptyl 3-hydroxy-2,2-dimethylpropanoate (23a) (1.0 g, 4.94 mmol) and pyridine (479 μL, 5.93 mmol) in Et ₂ O was added dropwise to the sulfuryl chloride solution over 30 min. (1 ml). The flask was washed with Et ₂ O (3×1 ml), and the wash was added to the reaction mixture. The mixture was shaken at −78°C until complete, which was monitored by TLC (30 min; 30% EA/hexane). The precipitate was filtered and the filtrate was concentrated in vacuo to give heptyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (23b) (1.37 g, 92% yield). The mixture was stored at –78°C and used in the next step without further purification. ¹ H–NMR (300 MHz, CDCl ₃ ) δ 4.50 (s, 2H), 4.20–4.02 (m, 2H), 1.68 (m, 2H), 1.31 (d, J =3.1 Hz, 13H), 1.23 (s, 1H), 0.95–0.83 (m, 3H).

Step 3: Synthesis of tert-butyl 4-((2S,5R)-6-(((3-(heptyloxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6- diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate (23c).

Hydroxamic acid (1) (2.399 mmol, by hydrogenation without further purification) was dissolved in THF (12 ml) and 1,3-dimethyltetrahydropyrimidin-2(1H)-one (3 ml), and the resulting solution was cooled to –78 °C in a nitrogen atmosphere. A 1.0 M solution of NaHMDS in THF (2.4 mL, 2.4 mmol) was added dropwise to the cooled solution and shaken for 20 min. Heptyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (23b) (0.79 g, 2.63 mmol) in THF (5 mL) was quickly added to the reaction mixture. The syringe was rinsed with THF (3 x 2 ml), and the rinse was also added to the mixture. After 10 min, the reaction mixture was warmed to room temperature and shaken until complete, as determined by TLC and LC–MS. EtOAc (50 ml) and saturated aqueous NaHCO ₃ (50 ml) were added to the mixture. The aqueous and organic layers were separated and the organic layer was washed with saturated aqueous NaHCO ₃ (10 ml), water (3 x 10 ml), brine (20 ml) and then dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give unrefined residue. The residue was purified by silica gel column chromatography using EtOAc/hexane (5% to 95%) as eluent to give 740.0 mg (49% yield) of product (23c).

Step 4: Synthesis of 4-((2S,5R)-6-(((3-(heptyloxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2 .1]octane-2-carboxamido)piperidine-1-ium 2,2,2-trifluoroacetate (23).

Cooled to –10°C tert-butyl 4-((2S,5R)-6-(((3-(heptyloxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1, 6-Diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate (23c) (472.1 mg, 0.73 mmol), dissolved in DCM (5 ml), to which TFA (5) was added dropwise ml). Once complete, the solvent was evaporated in vacuo and the residue was purified by preparative HPLC using MeCN/ _H2O containing 0.1% TFA (20-100%) to give the title compound (23) (390 mg, 81% yield). in the form of solid foam. ¹ H–NMR (300 MHz, CDCl ₃ ) δ 8.93 (d, J=10.4 Hz, 1H), 8.62 (s, 1H), 6.90 (d, J=7.8 Hz, 1H), 4.70–4.51 (m, 2H), 4.18–3.92 (m, 6H), 3.48 (d, J=12.2 Hz, 2H), 3.26 (d , J=11.5 Hz, 1H), 2.98 (dt, J=24.4, 11.7 Hz, 3H), 2.34 (dd, J=15.1, 6.3 Hz, 1H) , 2.10 (s, 2H), 1.60 (h, J=6.6 Hz, 3H), 1.24 (q, J=11.1, 9.8 Hz, 18H), 0.90– 0.79 (m, 4H). ¹³ C–NMR (75 MHz, CDCl ₃ ) δ 174.2, 168.6, 167.1, 80.3, 73.9, 65.4, 61.6, 60.1, 46.5, 44, 6, 43.4, 42.8, 42.8, 31.6, 28.8, 28.4, 28.3, 25.8, 25.7, 22.5, 22.1, 22.1, 21.5, 20.6, 17.8, 14.0. 19F NMR (282 MHz, CDCl ₃ ) δ –75.7. MS (ESI) C24H ₄ 2N4O8S=547 (M+1) ⁺ . HPLC retention time (MeCN/H ₂ O in 0.1% TFA): 9.59 min.

Example 24

Synthesis of 4–((2S,5R)–6–((((1–(ethoxycarbonyl)cyclohexyl)methoxy)sulfonyl)oxy)–7–oxo–1,6–diazabicyclo[3.2.1]octane–2–carboxamido) piperidine-1-ium 2,2,2-trifluoroacetate (24)

Step 1: Synthesis of ethyl 1-(hydroxymethyl)cyclohexanecarboxylate (24a).

Diethyl cyclohexane-1,1-dicarboxylate (2.12 g, 9.29 mmol) was dissolved in THF (50 ml), to which LiAl(OtBu)3 (5.9 g, 23.2 mmol) was added portionwise. The reaction mixture was shaken at reflux overnight. The reaction mixture was cooled in an ice bath and carefully treated with 10% aqueous KHSO ₄ solution (30 ml) with shaking for 10 minutes. The resulting precipitate was filtered through a layer of Celite®. The filtrate was extracted with EtOAc (3×40 ml) and the organic phase was combined and washed with brine (50 ml), dried over NaSO ₄ , filtered and concentrated in vacuo. The residue was purified using CombiFlash (SiO ₂ ) in 0-5% MeOH/DCM to give the desired product (24) as an oil (1.23 g, 71% yield). ¹ H–NMR (300 MHz, CDCl ₃ ) δ 4.19 (qd, J=7.1, 0.8 Hz, 2H), 3.62 (d, J=6.4 Hz, 2H), 3, 46 (s, 1H), 2.00 (dt, J=11.5, 6.4 Hz, 4H), 1.57–1.22 (m, 9H).

Step 2: Synthesis of ethyl 1-(((chlorosulfonyl)oxy)methyl)cyclohexanecarboxylate (24b).

A solution of freshly distilled sulfuryl chloride (294 µl, 3.63 mmol) in Et ₂ O (10 ml) was cooled to –78°C under nitrogen. A solution of ethyl 1-(hydroxymethyl)cyclohexanecarboxylate (24a) (0.615 g, 3.3 mmol) and pyridine (294 μL, 3.63 mmol) in Et ₂ O (6 ml) was added dropwise to the sulfuryl chloride solution over 15 min. . The flask was washed with Et ₂ O (3×1 ml), and the wash was added to the reaction mixture. The mixture was shaken at –78°C until complete (about 30 min; monitored with TLC, 30% EtOAc/hexane). The precipitate was filtered and the filtrate was concentrated in vacuo to give the title compound (24b) as an oil, 0.94 g in quantitative yield, which was used directly in the next step without purification. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 4.52 (s, 2H), 4.21 (q, J=7.1 Hz, 2H), 2.04 (s, 2H), 1.53 –1.39 (m, 8H), 1.39–1.21 (m, 3H).

Step 3: Synthesis of tert-butyl 4-((2S,5R)-6-((((1-(ethoxycarbonyl)cyclohexyl)methoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1] octane-2-carboxamido)piperidine-1-carboxylate (24c).

Hydroxamic acid (2.73 mmol) was dissolved in THF (14 ml) and 1,3-dimethyltetrahydropyrimidine-2(1H)-one (7 ml), and the resulting solution was cooled to –78°C under nitrogen. A 1.0 M solution of NaHMDS in THF (2.73 mL, 2.73 mmol) was added dropwise over 20 min and the mixture was shaken for 10 min. Ethyl 1-(((chlorosulfonyl)oxy)methyl)cyclohexanecarboxylate (24b) (0.94 g, 3.3 mmol) in THF (2 mL) was quickly added to the reaction mixture. After 10 minutes of shaking at –78°C, the mixture was allowed to warm to room temperature and shaken for 1 hour. The reaction mixture was diluted with EtOAc (60 ml) and H ₂ O at –60°C. The aqueous and organic layers were separated and the organic layer was washed with H ₂ O (3×30 ml) and brine (50 ml), then dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a crude residue (330 mg). The oil was purified by silica gel column chromatography using EtOAc/hexane (3:7-1:0) as eluent to give product (24c) (0.98 g, 59% yield) as a solid. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 6.43 (d, J=8.2 Hz, 1H), 4.75 (d, J=9.2 Hz, 1H), 4.59 (d , J=9.1 Hz, 1H), 4.28–4.05 (m, 5H), 4.04–3.90 (m, 3H), 2.87 (t, J=12.4 Hz, 3H), 2.45 (dd, J=15.0, 5.7 Hz, 1H), 2.08–1.84 (m, 4H), 1.56 (d, J=10.6 Hz, 3H ), 1.46 (s, 9H), 1.46–1.34 (m, 5H), 1.37–1.20 (m, 8H). MS (ESI) C27H ₄ 4N4O10S: 617 (M+H) ⁺ .

Step 4: 4–((2S,5R)–6–((((1–(ethoxycarbonyl)cyclohexyl)methoxy)sulfonyl)oxy)–7–oxo–1,6–diazabicyclo[3.2.1]octane–2– carboxamido)piperidine-1-ium 2,2,2-trifluoroacetate (24).

Cooled to –10°C (salt ice bath) tert-butyl 4–((2S,5R)–6–((((1–(ethoxycarbonyl)cyclohexyl)methoxy)sulfonyl)oxy)–7–oxo–1,6 –diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate (24c) (403.3 mg, 0.65 mmol), dissolved in DCM (4 ml), to which TFA (4 ml) was added dropwise ). The reaction was monitored using LCMS. After 30 minutes it ended. The solvent was removed in vacuo and the residue was purified by preparative HPLC in MeCN/H ₂ O containing 0.1% TFA (20-100%) to give the title compound (24) (263.7 mg, 78% yield) in in the form of solid foam. ¹ H–NMR (300 MHz, CDCl ₃ ) δ 9.02 (d, J=10.6 Hz, 1H), 8.66 (s, 1H), 6.87 (d, J=7.8 Hz, 1H), 4.70 (d, J=9.1 Hz, 1H), 4.54 (d, J=9.0 Hz, 1H), 4.16 (dtd, J=12.9, 6.7 , 6.3, 3.1 Hz, 4H), 4.00 (q, J=8.7, 7.2 Hz, 3H), 3.47 (d, J=12.3 Hz, 2H), 3 .26 (d, J=11.5 Hz, 1H), 2.95 (dd, J=25.8, 11.9 Hz, 3H), 2.35 (dd, J=15.3, 6.3 Hz, 1H), 2.11 (t, J=10.3 Hz, 4H), 1.99 (s, 2H), 2.08–1.87 (m, 2H), 1.89–1.72 (m, 4H), 1.54 (d, J=8.0 Hz, 5H), 1.25 (dd, J=14.4, 3.8 Hz, 2H). ¹³ C–NMR (75 MHz, CDCl ₃ ) δ 173.2, 168.5, 167.0, 80.2, 61.7, 61.1, 60.0, 47.0, 46.6, 44, 6, 43.3, 30.4, 29.9, 28.3, 25.3, 22.4, 22.2, 22.0, 20.6, 17.7, 14.1. 19F NMR (282 MHz, CDCl ₃ ) δ –75.7. MS (ESI) C22H ₃ 6N4O8S=517 (M+1) ⁺ . HPLC retention time (MeCN/H ₂ O in 0.1% TFA): 8.15 min.

Example 25

Synthesis of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2,2-dimethyl-3-(((((2S,5R)-7-oxo-2-(piperidine-4- ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)propanoate (25)

Step 1: Synthesis of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 3-hydroxy-2,2-dimethylpropanoate (25a).

Dropwise into a shaken solution of 3-hydroxy-2,2-dimethylpropanoic acid (4.0 g, 33.9 mmol) and potassium carbonate (4.68 g, 33.9 mmol) in DMF (45 ml) at 0°C 4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one (5.03 g, 33.9 mmol) in DMF (5 ml) was added over 1 h. The reaction mixture was shaken at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to obtain a crude residue. The residue was purified by silica gel column chromatography using EtOAc/hexane (1:4–2:3) as eluent to give product (25a) as a yellow liquid (1.6 g, 21% yield). ¹ H–NMR (300 MHz, CDCl ₃ ): δ 4.86 (s, 2H), 3.58 (s, 2H), 2.18 (s, 3H), 1.20 (s, 6H).

Step 2: Synthesis of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (25b).

A solution of distilled sulfuryl chloride (0.61 ml, 7.53 mmol) in Et ₂ O (15 ml) was cooled under nitrogen to –78°C. A solution of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 3-hydroxy-2,2-dimethylpropanoate (25a) (1.48 g, 6.43 mmol) in Et ₂ O ( 1 ml). Thereafter, a solution of pyridine (0.55 ml, 6.86 mmol) in Et ₂ O (1 ml) was added over a period of 1 hour. The reaction mixture was shaken at –78°C for 1 hour. After filtering the mixture, the filtrate was concentrated in vacuo to give product (25b) as a yellow oil (1.6 g, 76% yield). ¹ H–NMR (300 MHz, CDCl ₃ ): δ 4.90 (s, 2H), 4.49 (s, 2H), 2.19 (s, 3H), 1.33 (s, 6H).

Step 3: Synthesis of tert-butyl 4-((2S,5R)-6-(((2,2-dimethyl-3-((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy )-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate (25c).

tert-butyl 4-((2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate (20c) (2.18 mmol) dissolved in THF (14 ml) and 1,3-dimethyltetrahydropyrimidin-2(1H)-one (6 ml), and the resulting solution was cooled under nitrogen to –78°C. A solution of NaHMDS in THF (1M, 2.62 mL, 2.62 mmol) was added dropwise and the mixture was shaken at –78°C for 10 min. Then a solution of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (25b) (106b) ( 0.86 g, 2.62 mmol) in THF (1 ml). After shaking for 1 h at –78°C, the reaction mixture was diluted with EtOAc and washed with saturated NaHCO ₃ , water and brine. The organic layer was dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to obtain a crude residue. The residue was purified by silica gel column chromatography using EtOAc/hexane (1:3–1:1) as eluent to give product (25c) as a yellow paste (0.44 g, 31% yield). ¹ H–NMR (300 MHz, CDCl ₃ ): δ 6.73 (d, 1H, J=8.1 Hz), 4.78–4.98 (m, 3H), 4.47 (d, 1H, J=8.7 Hz), 3.93–4.15 (m, 5H), 3.27 (d, 1H), 2.83–2.92 (m, 3H), 2.41–2.45 (m, 1H), 2.18 (s, 3H), 2.15 (m, 1H), 1.78–1.92 (m, 4H), 1.45 (s, 9H), 1.23– 1.58 (m, 8H). MS (ESI) C27H ₄ 0N4O13S=661 (M+1) ⁺ .

Step 5: Synthesis of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2,2-dimethyl-3-(((((2S,5R)-7-oxo-2-(piperidine –4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)propanoate (TFA salt) (25).

In solution tert-butyl 4-((2S,5R)-6-(((2,2-dimethyl-3-((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)- 3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate (25c) (100 mg, 0.15 mmol) in DCM (3 ml) trifluoroacetic acid (0.4 ml) was added at –10°C. The reaction mixture was shaken at –10°C for 1 hour. LC/MS analysis showed that the starting material was consumed. The mixture was concentrated in vacuo to obtain a crude residue. The residue was purified by preparative HPLC on a C18 column eluting with MeCN/ _H2O containing 0.1% TFA (5-80%) to give the title compound (25) as an off-white powder (55.2 mg, yield 55%). ¹ H–NMR (300 MHz, CDCl ₃ ): δ 9.43 (br s, 1H), 9.05 (br s, 1H), 7.14 (d, 1H, J=6.9 Hz), 4 .99 (d, 1H, J=13.5 Hz), 4.95 (d, 1H, J=8.1 Hz), 4.78 (d, 1H, J=14.1 Hz), 4.41 (d, 1H, J=9.3 Hz), 4.14 (s, 1H), 4.06 (m, 1H), 3.98 (d, 1H, J=6.3 Hz), 3.47 (d, 2H), 3.29 (d, 1H), 3.04 (m, 2H), 2.86 (d, 1H), 1.82–2.40 (m, 11H), 1.29– 1.33 (ds, 6H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 173.9, 169.1, 167.3, 152.9, 141.0, 133.7, 80.3, 62.0, 60.4, 54 ,8, 46.8, 44.7, 43.4, 43.3, 28.5, 22.3, 22.0, 20.8, 18.0, 9.6. 19F NMR (282 MHz, CDCl ₃ ): δ –75.9. MS (ESI) C22H ₃ 2N4O11S=561 (M+1) ⁺ .

Analytical HPLC was performed on an Agilent 1200 system using a C18 Phenomenex column (150 × 4.6 mm i.d.). The mobile phase was MeCN and water with a linear gradient (0.1% TFA, from 5% MeCN to 100% MeCN in 15 min). The flow rate was maintained at 1 ml/min, and the eluent was monitored using a UV detector at 220 nM and 254 nM. HPLC retention time: 7.25 min.

Example 26

Synthesis of (2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate (26)

Step 1: Synthesis of tetrabutylammonium (2S,5R)–2–((1–(tert-butoxycarbonyl)piperidin–4–yl)carbamoyl)–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl sulfate (26a).

In a solution of tert-butyl 4-((2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate (20c) (1.92 g, 5.21 mmol) to DCM (30 mL) was added triethylamine (3 mL) and sulfur trioxide pyridine complex (3.34 g, 21.0 mmol). The reaction mixture was shaken at 35°C overnight. The mixture was concentrated in vacuo to obtain a crude residue. The residue was shaken with 0.5 N aqueous potassium dihydrogen phosphate (30 ml) for 1 hour. The resulting solution was extracted three times with DCM. The combined organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give triethylamine salt (2S,5R)-2-((1-(tert-butoxycarbonyl)piperidin-4-yl)carbamoyl)-7-oxo-1 ,6-diazabicyclo[3.2.1]octan-6-yl sulfate (26a) (2.3 g, 80% yield).

To a solution of the above product (26a) (2.2 g, 4.0 mmol) in DCM (30 ml) was added 0.5 N aqueous potassium hydrogen phosphate (12.4 ml) at 0°C. After shaking at 0°C for 10 min, tetrabutyl ammonium hydrogen sulfate (1.49 g, 4.4 mmol) was added. The resulting solution was shaken at room temperature for 30 minutes. After the organic layer was separated, the aqueous layer was extracted three times with DCM. The combined organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to leave a residue. The residue was purified by silica gel column chromatography using 10% MeOH in DCM as eluant to give product (26a) (1.35 g, 49% yield) as a white solid. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 6.55 (d, 1H, J=8.1 Hz), 4.33 (br s, 1H), 4.03 (m, 2H), 3, 91–3.95 (m, 1H), 3.86 (d, 1H), 3.48 (m, 1H), 3.25–3.31 (m, 10H), 2.85 (m, 2H) , 2.73 (d, 1H), 2.39 (dd, 1H), 2.13 (m, 1H), 1.81–1.92 (m, 4H), 1.60–1.71 (m , 11H), 1.29–1.50 (m, 14H), 1.00 (t, 12H). MS (ESI) C17H ₂ 8N4O8S=446.9 (M–1) ⁺ .

Step 2: Synthesis of (2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate (26).

Into a solution of tetrabutylammonium (2S,5R)–2–((1–(tert-butoxycarbonyl)piperidin–4–yl)carbamoyl)–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl sulfate ( 26a) (1.35 g, 1.96 mmol) in DCM (15 ml) at –10°C was added TFA (15 ml). After consumption of the starting material by LC/MS, the mixture was concentrated in vacuo to obtain a crude residue. The residue was shaken with diethyl ether to give a precipitate. The solid was filtered and washed twice with acetone to give the title compound (26) as an off-white solid (0.56 g, 82% yield). ¹ H–NMR (300 MHz, DMSO–d6): δ 8.30 (br s, 2H), 8.21 (d, 1H, J=7.5 Hz), 3.97 (s, 1H), 3 .86 (m, 1H), 3.71 (d, 1H), 3.25 (m, 2H), 2.97 (m, 4H), 2.06 (m, 1H), 1.83 (m, 3H), 1.64 (m, 4H). ¹³ C–NMR (75 MHz, DMSO–d6): 169.5, 166.7, 59.6, 58.0, 46.7, 43.9, 42.5, 28.0, 20.6, 18 ,6. MS (ESI) C12H ₂ 0N4O6S=346.9 (M+1) ⁺ . HPLC retention time (MeCN/H ₂ O in 0.1% TFA): 1.60 min.

Example 27

Synthesis of ethyl 3–(((((2S,5R)–2–((2-aminoethoxy)carbamoyl)–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy )–2,2-dimethylpropanoate (27).

Step 1: Synthesis of N-(2-tert-Boc-aminoethoxy)phthalimide (27a).

Triethylamine (7 .46 ml, 53.5 mmol). The reaction mixture was shaken at 70°C for 20 hours and then concentrated. The mixture was diluted with ethyl acetate and washed extensively with 1 N HCl, saturated NaHCO ₃ and water. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give crude product (27a) as an off-white solid (3.8 g, 56% yield). ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.76–7.87–4.90 (m, 4H), 5.65 (m, 1H), 4.25 (t, 3H), 3, 44 (t, 3H), 1.46 (s, 9H).

Step 2: Synthesis of tert-butyl (2-(aminooxy)ethyl)carbamate (27b).

Hydrazine monohydrate (0.63 mL, 13.0 mmol) was added to a solution of N-(2-tert-Boc-aminoethoxy)phthalimide (27a) (3.8 g, 12.4 mmol) in EtOH (38 mL) at room temperature. ). The reaction mixture was shaken at room temperature for 2 hours. The mixture was filtered and washed with ethyl acetate. The filtrate was concentrated to form a white solid. The white solid was removed by filtration and washed with ethyl acetate. This process was repeated three more times. The combined filtrate was then concentrated to give product (27b) as a yellow paste (2.16 g, 99% yield). ¹ H–NMR (300 MHz, CDCl ₃ ): δ 5.46 (br s, 2H), 4.91 (br s, 1H), 3.70 (m, 2H), 3.35 (m, 2H) , 1.44 (s, 9H).

Step 3: Synthesis of tert-butyl (2-(((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)oxy)ethyl)carbamate ( 27c).

To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (20a) (3.19 g, 11.6 mmol), tert -butyl (2-(aminooxy)ethyl)carbamate (27b) (2.06 g, 11.7 mmol) in DCM (20 ml) was added HATU (4.39 g, 11.6 mmol) and DIPEA (2.02 ml, 11.6 mmol). The reaction mixture was shaken at room temperature overnight. The mixture was washed with saturated NH ₄ Cl solution, water and brine. The organic layer was dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to obtain a crude residue. The residue was purified by silica gel column chromatography using EtOAc/hexane (1:1–3:1) as eluent to give product (27c) as a white paste (4.0 g, 79% yield). ¹ H–NMR (300 MHz, CDCl ₃ ): δ 9.46 (br, s, 1H), 7.26–7.43 (m, 5H), 5.46 (t, 1H), 4.80– 5.10 (dd, 2H, J=11.1 Hz), 2.75–3.97 (m, 8H), 1.61–2.33 (m. 4H), 1.43 (t, 9H) . MS (ESI) C21H ₃ 0N4O6=435 (M+1) ⁺ .

Step 4: Synthesis of tert-butyl (2-(((2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)oxy)ethyl)carbamate (27d) .

In a solution of tert-butyl (2-(((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)oxy)ethyl)carbamate (27c) (1.0 g, 2.30 mmol) in MeOH (10 ml) was added 10% palladium on carbon (0.3 g). The reaction mixture was shaken for 1 hour at a hydrogen pressure of 1 atm. After filtering the mixture through a pad of Celite®, the filtrate was concentrated in vacuo to give crude product (27d) (0.79 g, 100% yield), which was used directly in the next step.

Step 5: Synthesis of ethyl 3–(((((2S,5R)–2–((2–((tert-butoxycarbonyl)amino)ethoxy)carbamoyl)–7-oxo-1,6-diazabicyclo[3.2.1] octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (27e).

Tert-butyl (2-(((2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)oxy)ethyl)carbamate (27d) (0.79 g, 2.30 mmol) was dissolved in THF (14 ml) and 1,3-dimethyltetrahydropyrimidin-2(1H)-one (6 ml), and the resulting solution was cooled to –78°C under nitrogen. A solution of NaHMDS in THF (1M, 3.45 mL, 3.45 mmol) was added dropwise and the mixture was shaken at –78°C for 10 min. A solution of ethyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (3a) (675 mg, 2.76 mmol) in THF (2 mL) was then added to the reaction mixture using a syringe. After 10 min at –78°C, the reaction mixture was allowed to warm to room temperature and shaken overnight. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO ₃ , water and brine. The organic layer was dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to obtain a crude residue. The residue was purified by silica gel column chromatography using EtOAc/hexane (1:1–3:1) as eluent to give product (27e) as an off-white foam (0.68 g, 54% yield). ¹ H–NMR (300 MHz, CDCl ₃ ): δ 9.60 (br, s, 1H), 5.27 (br, t, 1H), 4.58–4.73 (dd, 2H, J=9 .3 Hz), 3.02–4.22 (m, 10H), 1.62–2.40 (m. 4H), 1.44 (t, 9H), 1.26–1.28 (m, 9H). MS (ESI) C21H ₃ 6N4O11S=553 (M+1) ⁺ .

Step 6: Synthesis of ethyl 3-(((((2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy) sulfonyl)oxy)-2,2-dimethylpropanoate (27).

Into the mixture ethyl 3–(((((2S,5R)–2–((2–((tert-butoxycarbonyl)amino)ethoxy)carbamoyl)–7–oxo–1,6–diazabicyclo[3.2.1]octane– 6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (27e) (340 mg, 0.62 mmol) in DCM (4 ml) was added with trifluoroacetic acid (4 ml) at –10°C. The reaction mixture was shaken at –10°C for 30 minutes. LC/MS analysis showed complete consumption of the starting material. The mixture was concentrated in vacuo to obtain a crude residue. The residue was purified by preparative HPLC on a C18 column eluting with MeCN/ _H2O containing 0.1% TFA (5-80%) to give the title compound (27) as an off-white foam (243 mg, 72% yield ). ¹ H–NMR (300 MHz, CDCl ₃ ): δ 8.10 (br s, 3H), 4.52–4.67 (dd, 2H, J=9.3 Hz), 3.12–4.21 (m, 10H), 1.93–2.23 (m, 4H), 1.19–1.29 (m, 9H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 174.7, 169.5, 167.6, 80.8, 73.0, 61.7, 60.7, 60.2, 46.5, 43 ,1, 38.5, 22.3, 21.9, 20.6, 18.5, 14.3. 19F NMR (282 MHz, CDCl ₃ ): δ –75.6. MS (ESI) C ₁₆ H ₂₈ N ₄ O ₉ S=453 (M+1) ⁺ .

Analytical HPLC was performed using an Agilent 1200 system with a C18 Phenomenex® column (150 x 4.6 mm i.d.). The mobile phase was MeCN and water with a linear gradient (0.1% TFA, from 5% MeCN to 100% MeCN in 15 min). The flow rate was maintained at 1 ml/min, and the eluent was monitored using a UV detector at 220 nM and at 254 nM. HPLC retention time: 7.10 min.

Example 28

Synthesis of 2-methoxyethyl 3-(((((2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl )oxy)-2,2-dimethylpropanoate (28)

Step 1: Synthesis of 2-methoxyethyl 3-(((((2S,5R)-2-((2-((tert-butoxycarbonyl)amino)ethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2. 1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (28a).

Tert-butyl (2-(((2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)oxy)ethyl)carbamate (27d) (0.79 g, 2.30 mmol) was dissolved in THF (14 ml) and 1,3-dimethyltetrahydropyrimidin-2(1H)-one (6 ml), and the resulting solution was cooled to –78°C under nitrogen. A solution of NaHMDS in THF (1M, 2.76 mL, 2.76 mmol) was added dropwise and the mixture was shaken at –78°C for 10 min. A solution of 2-methoxyethyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (15b) (758 mg, 2.76 mmol) in THF (2 ml) was then added to the reaction mixture using a syringe. After 10 min at –78°C, the reaction mixture was allowed to warm to room temperature and shaken overnight. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO ₃ , water and brine. The organic layer was dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to obtain a crude residue. The residue was purified by silica gel column chromatography using EtOAc/hexane (1:1–3:1) as eluent to give product (28a) as a white foam (0.65 g, 49% yield). ¹ H–NMR (300 MHz, CDCl ₃ ): δ 9.60 (br, s, 1H), 5.30 (br, t, 1H), 4.60–4.72 (dd, 2H, J=8 .7 Hz), 3.02–4.22 (m, 15H), 1.62–2.40 (m. 4H), 1.45 (t, 9H), 1.21–1.30 (m, 6H). MS (ESI) C22H ₃ 8N4O12S=583 (M+1) ⁺ .

Step 2: Synthesis of 2-methoxyethyl 3-(((((2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl) oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (28).

Into the mixture 2-methoxyethyl 3-(((((2S,5R)-2-((2-((tert-butoxycarbonyl)amino)ethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1] octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (28a) (0.33 g, 0.57 mmol) in DCM (4 ml) was added trifluoroacetic acid (4 ml) at –10°C . The reaction mixture was shaken at –10°C for 30 minutes. LC/MS analysis showed that the starting material was completely consumed. The mixture was concentrated in vacuo to obtain a crude residue. The residue was purified by preparative HPLC on a C18 column eluting with MeCN/ _H2O containing 0.1% TFA (5-80%) to give the title compound (28) as an off-white foam (128 mg, yield 39%). ¹ H–NMR (300 MHz, CDCl ₃ ): δ 8.10 (br s, 3H), 4.53–4.68 (dd, 2H, J=8.7 Hz), 3.11–4.21 (m, 15H), 1.96–2.23 (m, 4H), 1.28 (s, 6H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 174.6, 169.5, 167.6, 80.6, 72.9, 70.6, 64.5, 60.6, 60.1, 59 ,2, 46.5, 43.2, 38.4, 22.2, 21.9, 20.5, 18.5. 19F NMR (282 MHz, CDCl ₃ ): δ 75.6. MS (ESI) C17H ₃ 0N4O10S=483 (M+1) ⁺ . HPLC retention time (MeCN/H ₂ O in 0.1% TFA): 6.59 min.

Example 29

Synthesis of TFA salt (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 3-(((((2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo- 1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (29)

Step 1: Synthesis of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 3-(((((2S,5R)–2–((2–((tert-butoxycarbonyl)amino) ethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (29a).

Tert-butyl (2-(((2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)oxy)ethyl)carbamate (27d) (0.80 g, 2.32 mmol) was dissolved in THF (23 ml) and 1,3-dimethyltetrahydropyrimidin-2(1H)-one (3.3 ml), and the resulting solution was cooled to –78°C under nitrogen. A solution of NaHMDS in THF (1M, 2.32 mL, 2.32 mmol) was added dropwise and the mixture was shaken at –78°C for 10 min. Then a solution of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (25b) (916 mg, 2.8 mmol) in THF (2 ml). After 10 min at –78°C, the reaction mixture was allowed to warm to room temperature and shaken overnight. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to obtain a crude residue. The residue was purified by silica gel column chromatography using EtOAc/hexane (0-99%) to give product (29a) as an off-white foam (399.8 mg, 27% yield). ¹ H–NMR (300 MHz, chloroform–d) δ 9.75 (s, 1H), 5.37 (s, 1H), 5.30 (d, J=0.7 Hz, 2H), 5.00 –4.76 (m, 2H), 4.46 (d, J=9.3 Hz, 1H), 4.16–4.00 (m, 2H), 3.94 (s, 4H), 3, 42 (s, 2H), 3.38–3.26 (m, 4H), 3.03 (d, J=12.2 Hz, 2H), 2.19 (s, 6H), 2.16 (d , J=5.5 Hz, 2H), 2.02 (d, J=14.0 Hz, 3H), 1.92 (s, 2H), 1.56 (m, 1H), 1.48–1 .41 (m, 9H), 1.41–1.20 (m, 6H). MS (ESI) C24H ₃ 6N4O14S: 637 (M+1) ⁺ .

Step 2: Synthesis of TFA salt (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 3-(((((2S,5R)-2-((2-aminoethoxy)carbamoyl)-7 –oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (29)

Into the mixture (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 3-(((((2S,5R)–2–((2–((tert-butoxycarbonyl)amino)ethoxy) carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (29a) (0.33 g, 0.52 mmol) in DCM (3 ml) was added trifluoroacetic acid (0.3 ml) at –10°C. The reaction mixture was shaken at –10°C for 4 hours. LC/MS analysis showed that the starting material was completely consumed. The mixture was concentrated in vacuo to obtain a crude residue. The residue was purified by preparative HPLC on a C18 column eluting with MeCN/ _H2O containing 0.1% TFA (0-80%) to give the title compound (29) as an off-white foam (9.1 mg , yield 3.2%). ¹ H–NMR (300 MHz, MeCN–d3): δ 7.61 (s, 1H), 4.97–4.83 (m, 3H), 4.74–4.60 (m, 1H), 4 .55 (d, J=9.3 Hz, 1H), 4.24–4.00 (m, 2H), 3.94–3.83 (m, 1H), 3.73–3.62 (m , 2H), 3.29 (d, J=12.3 Hz, 2H), 3.19 (s, 3H), 2.15 (dq, J=1.3, 0.6 Hz, 3H), 1 .93 (s, 1H), 1.39–1.07 (m, 8H). 19F NMR (282 MHz, MeCN–d3): δ –76.1, –76.3. MS (ESI) C19H ₂ 8N4O12S: 537 (M+1) ⁺

Example 30

Synthesis of TFA salt hexyl 3-(((((2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl )oxy)-2,2-dimethylpropanoate (30)

Step 1: Synthesis of hexyl 3–(((((2S,5R)–2–((2–((tert-butoxycarbonyl)amino)ethoxy)carbamoyl)–7-oxo-1,6-diazabicyclo[3.2.1] octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (30a).

Tert-butyl (2-(((2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)oxy)ethyl)carbamate (27d) (0.51 g, 1.48 mmol) was dissolved in THF (18 ml) and 1,3-dimethyltetrahydropyrimidin-2(1H)-one (2.8 ml), and the resulting solution was cooled to –78°C under nitrogen. A solution of NaHMDS in THF (1M, 1.9 mL, 1.9 mmol) was added dropwise and the mixture was shaken at –78°C for 10 min. A solution of hexyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (730 mg, 2.42 mmol) in THF (2 ml) was then added to the reaction mixture using a syringe. After 10 min at –78°C, the reaction mixture was allowed to warm to room temperature and shaken overnight. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to obtain a crude residue. The residue was purified by silica gel column chromatography using EtOAc/hexane (0-99%) to give product (30a) as an off-white foam (194.3 mg, 22% yield). ¹ H–NMR (300 MHz, CDCl ₃ ): δ 9.54 (s, 1H), 5.26 (s, 1H), 4.60 (d, J=9.0 Hz, 2H), 4.21 –4.02 (m, 7H), 3.46 (d, J=16.3 Hz, 1H), 3.31 (s, 2H), 3.03 (d, J=12.0 Hz, 1H) , 2.39 (dd, J=14.9, 6.3 Hz, 1H), 2.19 (s, 1H), 2.08–1.89 (m, 2H), 1.65–1.55 (m, 2H), 1.45 (s, 10H), 1.35–1.19 (m, 10H), 0.94–0.79 (m, 3H). MS (ESI) C25H ₄ 4N4O11S: 607 (M–1) ⁺ .

Step 2: Synthesis of TFA salt hexyl 3-(((((2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl) oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (30).

Into the solution hexyl 3–(((((2S,5R)–2–((2–((tert-butoxycarbonyl)amino)ethoxy)carbamoyl)–7–oxo–1,6–diazabicyclo[3.2.1]octane– 6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (30a) (144.3 mg, 0.237 mmol) in DCM (3 ml) was added with trifluoroacetic acid (0.15 ml) at 0°C. The reaction mixture was shaken at 0°C for 1 hour. LC/MS analysis showed that the starting material was completely consumed. The mixture was concentrated in vacuo to obtain a crude residue. The residue was purified by preparative HPLC on a C18 column eluting with MeCN/ _H2O containing 0.1% TFA (0-80%) to give the title compound (30) as a brown oil (68.1 mg, yield 56%). ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.80–7.73 (m, 2H), 6.94 (s, 1H), 4.57 (dt, J=28.2, 14.1 Hz, 2H), 4.22 (s, 1H), 4.08 (ddt, J=17.3, 13.2, 8.0 Hz, 6H), 3.96 (s, 2H), 3.28 (d, J=10.2 Hz, 2H), 2.10 (s, 1H), 1.93 (s, 1H), 1.62 (m, 2H), 1.28 (ddd, J=12, 8, 6.5, 3.7 Hz, 12H), 1.19 (s, 2H), 0.94–0.82 (m, 3H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 176.6, 174.3, 169.2, 167.3, 161.6, 118.2, 114.3, 80.4, 73.7, 72 ,6, 65.5, 65.3, 60.3, 59.9, 46.3, 42.9, 42.8, 38.4, 31.4, 28.4, 28.3, 25.5 , 25.5, 22.5, 22.1, 22.0, 21.6, 20.3, 18.2, 14.0. 19F NMR (282 MHz, CDCl ₃ ): δ –75.8. MS (ESI) C20H ₃ 6N4O9S: 509 (M+1) ⁺ . HPLC retention time (MeCN/H ₂ O in 0.1% TFA): 8.96 min.

Example 31

Synthesis of TFA salt heptyl 3-(((((2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl )oxy)-2,2-dimethylpropanoate (31).

Step 1: Synthesis of heptyl 3–(((((2S,5R)–2–((2–((tert-butoxycarbonyl)amino)ethoxy)carbamoyl)–7-oxo-1,6-diazabicyclo[3.2.1] octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (31a).

A method similar to step 1 of Example 30 was used to obtain 274.0 mg of title compound (31a) (44% yield) as an off-white solid. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 9.75 (s, 1H), 5.37 (t, J=6.2 Hz, 1H), 4.72–4.52 (m, 2H) , 4.09 (dddd, J=18.6, 10.4, 3.8, 2.1 Hz, 3H), 3.91 (t, J=4.8 Hz, 2H), 3.51–3 .19 (m, 3H), 3.05 (d, J=12.1 Hz, 1H), 2.43–2.29 (m, 1H), 2.21–2.07 (m, 1H), 2.06–1.77 (m, 3H), 1.62 (t, J=6.9 Hz, 2H),1.40 (s, 9H), 1.40–1.17 (m, 16H) , 0.92–0.81 (m, 3H). MS (ESI) C26H ₄ 6N4O11S: 523 (M+1–Bock) ⁺ .

Step 2: Synthesis of TFA salt heptyl 3-(((((2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl) oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (31).

A method similar to step 2 of Example 30 was used to obtain the title compound (31) (214.5 mg, 93%) as a brown oil. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 10.61 (s, 1H), 8.02 (s, 3H), 4.63 (d, J=8.7 Hz, 1H), 4.53 (d, J=8.9 Hz, 1H), 4.17 (d, J=13.3 Hz, 3H), 4.12–3.97 (m, 4H), 3.95 (s, 1H) , 3.26 (s, 3H), 3.18–3.08 (m, 1H), 2.22 (s, 1H), 2.10 (s, 1H), 1.61 (q, J=7 .0 Hz, 2H), 1.25 (m, 12H), 1.18 (s, 2H), 0.87 (m, 3H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 176.5, 174.3, 169.1, 167.3, 80.3, 73.7, 72.6, 65.5, 65.3, 60 ,3, 59.9, 46.3, 42.9, 42.8, 38.3, 31.7, 31.7, 28.9, 28.9, 28.4, 25.8, 25.8 , 22.6, 22.1, 22.0, 22.0, 21.6, 20.3, 18.3, 14.0. 19F NMR (282 MHz, CDCl ₃ ): δ –75.71. MS (ESI) C21H ₃ 8N4O9S: 523 (M+1) ⁺ . HPLC retention time (MeCN/H ₂ O in 0.1% TFA): 9.37 min.

Example 32

Synthesis of TFA salt ethyl-1-(((((2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy )sulfonyl)oxy)methyl)cyclohexanecarboxylate (32)

Step 1: Synthesis of ethyl-1-(((((2S,5R)-2-((2-((tert-butoxycarbonyl)amino)ethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2. 1]octan–6–yl)oxy)sulfonyl)oxy)methyl)cyclohexanecarboxylate (32a).

A method similar to that of step 1 of Example 30 was used for the connection between tert-butyl (2-(((2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido )oxy)ethyl)carbamate and ethyl 1-(((chlorosulfonyl)oxy)methyl)cyclohexanecarboxylate (27d) to give 122.2 mg of the title compound (32a) (14% yield over 3 steps) as an off-white solid substances. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 9.92 (d, J=5.6 Hz, 1H), 5.46 (d, J=5.7 Hz, 1H), 4.68 (d , J=9.2 Hz, 1H), 4.52 (d, J=9.2 Hz, 1H), 4.24–3.98 (m, 5H), 3.88 (t, J=4, 8 Hz, 2H), 3.37 (d, J=6.7 Hz, 1H), 3.25 (dt, J=10.1, 5.1 Hz, 2H), 3.04 (d, J= 12.1 Hz, 1H), 2.30 (t, J=6.8 Hz, 1H), 2.16–1.80 (m, 6H), 1.52 (d, J=9.3 Hz, 3H), 1.4 (s, 9H), 1.34 (m, 2H), 1.22 (td, J=7.2, 5.0 Hz, 3H). MS (ESI) C24H ₄ 0N4O11S: 593 (M+1) ⁺ .

Step 2: Synthesis of TFA salt ethyl–1–(((((2S,5R)–2–((2-aminoethoxy)carbamoyl)–7–oxo–1,6–diazabicyclo[3.2.1]octane–6– yl)oxy)sulfonyl)oxy)methyl)cyclohexanecarboxylate (32).

A method similar to step 2 of Example 30 was used to obtain 91.4 mg of the title compound (32) (90% yield) as an off-white solid. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 10.74 (s, 1H), 7.98 (s, 3H), 4.65 (d, J=9.2 Hz, 1H), 4.50 (d, J=9.1 Hz, 1H), 4.26–4.04 (m, 3H), 4.13 (s, 3H), 3.95 (s, 1H), 3.26 (d, J=9.9 Hz, 3H), 3.14 (d, J=11.6 Hz, 1H), 2.02 (s, 4H), 1.92 (s, 3H), 1.50–1, 22 (m, 8H), 1.22 (d, J=7.5 Hz, 2H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 175.6, 173.5, 169.2, 167.3, 118.5, 114.6, 80.3, 73.6, 72.6, 61 ,3, 61.1, 60.3, 60.0, 47.2, 47.1, 46.2, 38.2, 30.6, 30.2, 30.1, 25.5, 25.3 , 22.4, 22.1, 22.0, 20.3, 18.3, 14.1. 19F NMR (282 MHz, CDCl ₃ ): δ –75.7. MS (ESI) C19H ₃ 2N4O9S: 493 (M+1) ⁺ . HPLC retention time (MeCN/H ₂ O in 0.1% TFA): 8.05 min.

Example 33

Synthesis of (2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate (33)

Step 1: Synthesis of tetrabutylammonium (2S,5R)–2–((2–((tert-butoxycarbonyl)amino)ethoxy)carbamoyl)–7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl sulfate (33a).

Into a solution of tert-butyl (2-(((2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)oxy)ethyl)carbamate (27d) (0 .79 g, 2.30 mmol) in pyridine (35 ml) was added sulfur trioxide-pyridine complex (1.46 g, 9.2 mmol). The reaction mixture was shaken at room temperature for 64 hours. More sulfur trioxide pyridine complex (1.46 g, 9.2 mmol) was added and the reaction mixture was shaken at 35°C for 16 hours. The mixture was concentrated in vacuo to give the crude remainder. To a solution of the above product in DCM (30 ml) was added 0.5 N aqueous potassium hydrogen phosphate (7.4 ml) at 0°C. After shaking at 0°C for 10 min, tetrabutyl ammonium hydrogen sulfate (0.86 g, 2.53 mmol) was added. The resulting solution was shaken at room temperature for 30 minutes. After the organic layer was separated, the aqueous layer was extracted three times with DCM. The combined extracted organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to leave a residue. The residue was purified by silica gel column chromatography using 10% MeOH in DCM as eluent to give product (33a) as an off-white solid (0.51 g, 33% yield). MS (ESI) C14H ₂ 4N4O9S=423 (M–1) ⁺ .

Step 2: Synthesis of (2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate (33).

Into a solution of tetrabutylammonium (2S,5R)–2–((2–((tert-butoxycarbonyl)amino)ethoxy)carbamoyl)–7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl sulfate (33a ) (0.51 g, 0.77 mmol) in DCM (10 ml) at –10°C was added TFA (10 ml). LC/MS analysis showed that the reaction was complete after 1 hour. The mixture was concentrated in vacuo to give a crude residue. The residue was shaken with diethyl ether to obtain a yellow precipitate. The solid was filtered and washed with acetone. The residue was dissolved in water and acetonitrile (1:1) and lyophilized to give a yellow solid. The residue was washed again with acetone. The residue was dissolved in water and acetonitrile (1:1) and lyophilized to give the title compound (33) as a yellow solid (68 mg, 27% yield). ¹ H–NMR (300 MHz, DMSO–d6): δ 7.84 (br s, 3H), 3.82–4.00 (m, 3H), 2.92–3.33 (m, 5H), 2.00 (m, 1H), 1.87 (m, 1H), 1.68 (m, 2H). ¹³ C–NMR (75 MHz, DMSO–d6): 169.1, 166.5, 72.8, 58.6, 58.3, 47.7, 38.2, 21.3, 19.0. MS (ESI) C9H16N4O7S=323 (M–1) ⁺ . HPLC retention time (MeCN/H ₂ O in 0.1% TFA): 1.52 min.

Example 34

Synthesis of (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl 1H-imidazol-1-sulfonate (34)

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (741 mg, 4.0 mmol) was dissolved in tetrahydrofuran (36 ml) and 1 ,3-dimethyltetrahydropyrimidine-2(1H)-one (2 ml), and the resulting solution was cooled to –78°C. A solution of NaHMDS, 1.0 M in THF (4.4 mL, 4.4 mmol) was added dropwise to the cooled solution and shaken for 10 min. 1-((1H-imidazol-1-yl)sulfonyl)-3-methyl-1H-imidazole-3-ium trifluoromethanesulfonate (prepared according to Org. Lett. 2013, 15, 18–21 & J. Org) was quickly added to the reaction mixture Chem. 2003, 68, 115–119) (2.90 g, 8.0 mmol). After 10 min, the reaction mixture was warmed to 0°C (the reaction was monitored by TLC using 70% EtOAc/hexanes). The mixture was shaken for 1 hour at room temperature, then diluted with EtOAc (50 ml) and quenched with saturated aqueous NaHCO ₃ (50 ml). The organic and aqueous layers were separated and the organic layer was washed with saturated aqueous NaHCO ₃ (50 ml), H ₂ O (3 x 50 ml) and brine (50 ml) and then dried (Na ₂ SO ₄ ) and concentrated in vacuo to give unrefined residue. The residue was purified by silica gel column chromatography using EtOAc/hexanes (1:9-1:0) to give product (34) (0.393 g, 31%) as a solid. LC–MS: m/z=316.0 [M+H] ⁺ . ¹ H–NMR (300 MHz, 1,4–dioxane–d8): δ 8.15 (s, 1H), 7.58 (ft, J=1.5 Hz, 1H), 7.15 (s, 1H ), 6.92 (s, 1H), 6.48 (s, 1H), 3.95 (d, J=6.3 Hz, 1H), 3.70 (s, 1H), 3.08 (s , 2H), 2.23–2.17 (m, 1H), 2.04–1.97 (m, 1H), 1.88–1.74 (m, 2H). ¹³ C–NMR (75 MHz, 1,4–dioxane–d8): δ 171.4, 167.6, 139.2, 132.0, 119.9, 62.9, 61.8, 46.9, 21.5, 18.7.

Example 35

Synthesis of ethyl 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate (35)

Step 1: Synthesis of ethyl 5-hydroxy-4,4-dimethylpentanoate (35a).

A solution of isopropyl chloroformate, 1.0 M in toluene (27.0 ml, 27.0 mmol) at 0°C. The mixture was shaken at 0°C for 10 minutes and then allowed to warm to room temperature and shaken for 2 hours. The solution was cooled to 0°C and sodium borohydride (1.21 g, 35.9 mmol) was added. The mixture was shaken for 20 minutes, then methanol (6.5 ml) was added to the solution. After 10 minutes of shaking, ethyl acetate (25 ml) modified with a few drops of triethylamine and a saturated aqueous solution of NH ₄ Cl (25 ml) were added. The layers were separated and the aqueous layer was extracted with EtOAc (2×40 ml). The combined organic layers were washed with brine, dried (MgSO ₄ ), filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes modified with 0.1% TEA (5:95–4:6) to give product (35a) (2.01 g, 64% crude) as a colorless oil. To suppress lactonization, one drop of triethylamine was added to the product.

Step 2: Synthesis of ethyl 5-((chlorosulfonyl)oxy)-4,4-dimethylpentanoate (35b).

A solution of sulfuryl chloride (0.64 ml, 8.7 mmol) in Et ₂ O (10 ml) was cooled to –78°C under nitrogen. A solution of ethyl 5-hydroxy-4,4-dimethylpentanoate (35a) (0.76 g, 4.4 mmol) and pyridine (0.39 ml, 4.8 mmol) in Et was added dropwise to the sulfuryl chloride solution over 10 min. ₂ O (10 ml). The syringe was washed with Et ₂ O (3×1 ml), and also added to the mixture. The mixture was shaken at –78°C for 1.5 hours, more pyridine (0.9 equiv.) was added and the mixture was filtered through a pad of Celite®. The filtrate was concentrated in vacuo to give product (35b) (0.897 g) as a colorless oil. It was used in the next step without further purification.

Step 3: Synthesis of ethyl 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4, 4-dimethylpentanoate (35).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (278 mg, 1.5 mmol) was dissolved in THF (14 ml) and HMPA (0.6 ml), and the resulting solution was cooled to –78°C under a nitrogen atmosphere. A solution of ethyl 5-((chlorosulfonyl)oxy)-4,4-dimethylpentanoate (35b) (0.45 g, 1.6 mmol) in THF (3 ml) was cooled to –78°C and quickly added to the mixture. The flask containing the sulfating reagent was washed with THF (1 ml), while the flask temperature was maintained at -78°C, and this was quickly added to the reaction mixture. After shaking for 15 min, the mixture was warmed to room temperature and shaken for 45 min. The mixture was diluted with EtOAc (30 ml) and the reaction was quenched with saturated aqueous NaHCO ₃ (30 ml). The organic and aqueous layers were separated, and the organic layer was washed with water (3×30 ml) and brine (30 ml), dried (MgSO ₄ ), and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (3:7-4:1) to give product (35) (157 mg, 25%) as a solid. LC–MS: m/z=422.2 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 5.52 (s, 1H), 5.83 (s, 1H), 4.49 (d, J=9.3 Hz, 1H), 4.21 –4.08 (m, 4H), 4.03 (d, J=6.9 Hz, 1H), 3.34–3.30 (m, 1H), 3.02 (d, J=12.3 Hz, 1H), 2.43–2.38 (m, 1H), 2.32–2.26 (m, 2H), 2.17–2.11 (m, 1H), 1.99–1, 82 (m, 2H), 1.72–1.66 (m, 3H), 1.25 (t, J=7.1 Hz, 3H), 0.98 (s, 6H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ173.5, 171.1, 167.1, 83.4, 62.0, 60.6, 60.3, 47.2, 34.2, 33, 3, 29.3, 23.6, 23.3, 20.8, 17.6, 14.3.

Example 36

Synthesis of hexyl 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate (36)

Step 1: Synthesis of sodium 5-(hexyloxy)-2,2-dimethyl-5-oxopentanoate (36a).

To a solution of 2,2-dimethylglutaric anhydride (5.0 g, 35.2 mmol) in 1-hexanol (50 ml) was added a solution of sodium hexan-1-olate (5.4 g, 43.5 mmol) in 1-hexanol . After 20 hours of shaking, the solvent was evaporated and the resulting solid was suspended in diethyl ether (80 ml). The mixture was filtered and the solid was washed with diethyl ether (2×40 ml). The solid was dried under high pressure to give product (36a) (3.84 g, 41%) as a solid. ¹ H–NMR (300 MHz, D2O): δ 4.14 (t, J=6.5 Hz, 2H), 2.38–2.33 (m, 2H), 1.82–1.77 (m , 2H), 1.75–1.63 (m, 2H), 1.43–1.28 (m, 6H), 1.12 (s, 6H), 0.92–0.88 (m, 3H ). The spectrum showed that the product was contaminated with a small amount of an unidentified substance.

Step 2: Synthesis of hexyl 5-hydroxy-4,4-dimethylpentanoate (36b).

Isopropyl chloroformate, 1 .0 M in toluene (21.6 ml, 21.6 mmol) at 0°C, and the mixture was shaken for 10 min. After shaking for 3.3 hours at room temperature, the solution was cooled to 0°C and sodium borohydride (0.98 g, 28.8 mmol) was added. The mixture was shaken for 20 min and MeOH (5.2 ml) was added to the solution (the reaction was monitored by TLC using 2:8 ethyl acetate/hexanes as eluent). After 15 minutes, a few drops of triethylamine were added. After another 15 minutes, ethyl acetate (25 ml) was shaken, and a solution of saturated aqueous NH ₄ Cl (25 ml) was added. The organic and aqueous layers were separated, and the aqueous layer was extracted with EtOAc (2×40 ml). The combined organic layers were washed with brine, dried (MgSO ₄ ) and filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes modified with 0.1% Et ₃ N (5:95-3:7) to give product (36b) (2.16 g, 65%) as a colorless oil . To suppress lactonization, one drop of Et ₃ N was added.

Step 3: Synthesis of hexyl 5-((chlorosulfonyl)oxy)-4,4-dimethylpentanoate (36c).

A solution of sulfuryl chloride (0.38 ml, 5.2 mmol) in Et ₂ O (8.5 ml) was cooled to –78°C under nitrogen. A solution of hexyl 5-hydroxy-4,4-dimethylpentanoate (36b) (0.60 g, 2.6 mmol) and pyridine (0.42 ml, 5.2 mmol) in Et was added dropwise to the sulfuryl chloride solution over 10 min. ₂ O (8.5 ml). The syringe was washed with Et ₂ O (3×1 ml), and the wash was also added to the mixture. The mixture was shaken for 4.5 hours (the reaction was monitored by TLC using 2:8 EtOAc/hexanes as eluent). The solids were filtered and the solvent was concentrated in vacuo to give product (36c) as a colorless oil in quantitative yield. 3 ml of THF was added to it, and the solution was stored at –78°C. It was used in the next step without further purification.

Step 4: Synthesis of hexyl 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4, 4-dimethylpentanoate (36).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (370 mg, 2.0 mmol) was dissolved in tetrahydrofuran (19 ml) and HMPA (0.8 ml), and the resulting solution was cooled to -78°C in atmosphere. A solution of NaHMDS, 1.0 M in THF (2.2 mL, 2.2 mmol) was added dropwise to the cooled solution and shaken for 10 min. A solution of hexyl 5-((chlorosulfonyl)oxy)-4,4-dimethylpentanoate (36c) (0.72 g, 2.2 mmol) in THF (3 ml) was cooled to –78°C and quickly added to the reaction mixture. The flask containing the sulfating reagent was washed with THF (3 x 1 ml), while the temperature of the flask was maintained at –78°C, and the rinse was quickly added to the reaction mixture. After shaking for 10 min, the mixture was warmed to room temperature and shaken overnight. The reaction was then quenched with saturated NaHCO ₃ (40 ml) and extracted with EtOAc (40 ml). The organic layer was concentrated and the oily residue was partitioned into H ₂ O (40 ml) and EtOAc (40 ml). The organic layer was washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (1:9-8:2) to give product (36) (421 mg, 44%) as a solid. LC–MS: m/z=478.0 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 6.48 (s, 1H), 5.59 (s, 1H), 4.51 (d, J=8.7 Hz, 1H), 4.22 –4.18 (m, 2H), 4.08–4.04 (m, 3H), 3.36–3.32 (m, 1H), 3.02 (d, J=12.6 Hz, 1H ), 2.47–2.41 (m, 1H), 2.33–2.28 (m, 2H), 2.18–2.13 (m, 1H), 2.01–1.79 (m , 2H), 1.72–1.59 (m, 4H), 1.35–1.31 (m, 6H), 0.99 (s, 6H), 0.91–0.87 (m, 3H ). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 173.6, 170.9, 167.1, 83.5, 64.9, 62.0, 60.2, 47.3, 34.3, 33 ,3, 31.6, 29.3, 28.7, 25.7, 23.6, 23.3, 22.7, 20.9, 17.6, 14.1.

Example 37

Synthesis of heptyl 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate (37)

Step 1: Synthesis of sodium 5-(heptyloxy)-2,2-dimethyl-5-oxopentanoate (37a).

To a solution of 2,2-dimethylglutaric anhydride (5.0 g, 35.2 mmol) in 1-heptanol (40 ml) was added a solution of sodium heptan-1-olate (6.01 g, 43.5 mmol) in 1-heptanol (30 ml). After shaking overnight, the solvent was evaporated and the resulting solid was suspended in Et ₂ O (80 ml). The mixture was filtered and the solid was washed with Et ₂ O (2×40 ml). The solid was dried under high pressure to obtain product (37a) (7.89 g, 80%) as a solid. ¹ H–NMR (300 MHz, D2O): δ 4.14 (t, J=6.5 Hz, 2H), 2.36–2.32 (m, 2H), 1.82–1.77 (m , 2H), 1.74–1.63 (m, 2H), 1.40–1.31 (m, 8H), 1.11 (s, 6H), 0.92–0.87 (m, 3H ). The spectrum showed that the product was contaminated with a small amount of an unidentified substance.

Step 2: Synthesis of heptyl 5-hydroxy-4,4-dimethylpentanoate (37b).

Isopropyl chloroformate, 1 .0 M in toluene (42.2 ml, 42.2 mmol) at 0°C, and the mixture was shaken for 10 min. After shaking for 4 hours at room temperature, the suspension was cooled to 0°C and sodium borohydride (1.9 g, 56.3 mmol) was added. The mixture was shaken for 20 min and then MeOH (10 ml) was added to the solution (the reaction was monitored by TLC using 2:8 ethyl acetate/hexanes). After shaking EtOAc (50 ml) for 30 minutes, a few drops of Et ₃ N and saturated aqueous NH ₄ Cl (50 ml) were added. The aqueous and organic layers were separated and the aqueous layer was extracted with EtOAc (2×80 ml). The combined organic layers were washed with brine (80 ml) and the filtrate was concentrated in vacuo. The residual solution was washed with H ₂ O (3×100 ml), brine (100 ml), dried (Na ₂ SO ₄ ) and concentrated. During all extractions, a few drops of Et ₃ N were added to the organic layer to suppress lactonization. The residue was purified by silica gel column chromatography using EtOAc/hexanes modified with 0.1% Et ₃ N (0:1–3:7) as eluent. ), giving product (37b) (3.35 g, 49% crude) as a colorless oil.

Step 3: Synthesis of heptyl 5-((chlorosulfonyl)oxy)-4,4-dimethylpentanoate (37c).

A solution of sulfuryl chloride (0.60 ml, 8.2 mmol) in Et ₂ O (13 ml) was cooled to –78°C under nitrogen. A solution of heptyl 5-hydroxy-4,4-dimethylpentanoate (37b) (1.0 g, 4.1 mmol) and pyridine (0.66 ml, 8.2 mmol) in Et was added dropwise to the sulfuryl chloride solution over 10 min. ₂ O (13 ml). The syringe was washed with diethyl ether (3×1 ml), and also added to the mixture. The mixture was shaken for 4.5 hours (the reaction was monitored by TLC using ethyl acetate/hexanes 2:8 as eluent). The solids were filtered and the filtrate was concentrated in vacuo to give product (37c) (1.13 g) as a colorless oil. 3 ml of THF was added to it, and the solution was stored at –78°C. It was used in the next step without further purification.

Step 4: Synthesis of heptyl 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4, 4-dimethylpentanoate (37).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (0.56 g, 3.0 mmol) was dissolved in THF (28 ml) and HMPA (1.2 ml), and the resulting solution was cooled to –78°C under a nitrogen atmosphere. A solution of NaHMDS, 1.0 M in THF (3.3 mL, 3.3 mmol) was added dropwise to the cooled solution and shaken for 10 min. A solution of heptyl 5-((chlorosulfonyl)oxy)-4,4-dimethylpentanoate (37c) (1.13 g, 3.3 mmol) was dissolved in THF (3 ml, maintained at -78°C) and quickly added to reaction mixture. The flask containing the sulfating reagent was washed with THF (3×1 ml), while the flask temperature was maintained at –78°C, and was also quickly added to the reaction mixture. After shaking for 10 min, the mixture was warmed to room temperature and shaken overnight. The mixture was quenched with saturated aqueous sodium bicarbonate (60 ml) and extracted with EtOAc (60 ml). The organic layer was concentrated and the oily residue was diluted with EtOAc (60 ml) and washed with water (2×60 ml). The organic layer was washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (1:9-8:2) to give product (37) (473 mg, 32%) as a solid. LC–MS: m/z=492.0 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 6.48 (s, 1H), 5.62 (s, 1H), 4.51 (d, J=9.3 Hz, 1H), 4.22 –4.18 (m, 2H), 4.08–4.04 (m, 3H), 3.36–3.31 (m, 1H), 3.02 (d, J=12.6 Hz, 1H ), 2.47–2.41 (m, 1H), 2.33–2.28 (m, 2H), 2.18–2.13 (m, 1H), 2.01–1.80 (m , 2H), 1.72–1.60 (m, 4H), 1.31–1.28 (m, 8H), 0.99 (s, 6H), 0.91–0.86 (m, 3H ). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 173.6, 170.9, 167.1, 83.4, 64.9, 62.0, 60.2, 47.2, 34.2, 33 ,3, 31.8, 29.2, 29.0, 28.7, 26.0, 23.6, 23.3, 22.7, 20.8, 17.6, 14.2.

Example 38

Synthesis of 2-methoxyethyl 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4 –dimethylpentanoate (38)

Step 1: Synthesis of sodium 5-(2-methoxyethoxy)-2,2-dimethyl-5-oxopentanoate (38a).

To a solution of 2,2-dimethylglutaric anhydride (5.0 g, 35.2 mmol) in 2-methoxyethanol (30 ml) was added a solution of sodium 2-methoxyethanolate (4.27 g, 43.5 mmol) in 2-methoxyethanol (30 ml). After 20 hours of shaking, the solvent was evaporated and the resulting solid was suspended in Et ₂ O (80 ml). The mixture was filtered and the solid was washed with Et ₂ O (2×40 ml). The solid was dried under high pressure to give product (38a) (6.44 g, 76%) as a solid. ¹ H–NMR (300 MHz, D2O): δ 4.30–4.27 (m, 2H), 3.75–3.72 (m, 2H), 3.42 (s, 3H), 2.41 –2.36 (m, 2H), 1.83–1.78 (m, 2H), 1.12 (s, 6H). The spectrum showed that the product was contaminated with a small amount of an unidentified substance.

Step 2: Synthesis of 2-methoxyethyl 5-hydroxy-4,4-dimethylpentanoate (38b).

Isopropyl chloroformate was added to a suspension of sodium 5-(2-methoxyethoxy)-2,2-dimethyl-5-oxopentanoate (38a) (6.44 g, 26.8 mmol) in a mixture of THF (58 ml) and DMF (19 ml). , 1.0 M in toluene (40.2 ml, 40.2 mmol) at 0°C and shaken for 10 min. After shaking for 4 h at room temperature, the mixture was stored at −78°C overnight. The suspension was cooled to 0°C and sodium borohydride (1.81 g, 53.6 mmol) was added. The mixture was shaken for 20 min and then MeOH (9.6 ml) was added to the solution (the reaction was monitored by TLC using EtOAc/hexanes 3:7 as eluent). After 30 minutes of shaking, EtOAc (50 ml) was added with a few drops of Et ₃ N followed by saturated aqueous NH ₄ Cl (50 ml). The layers were separated and the aqueous layer was extracted with EtOAc (2×80 ml). The combined organic layers were washed with brine, dried (MgSO ₄ ), filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography to give product (38b) (2.54 g, 46% crude).

Step 3: Synthesis of 2-methoxyethyl 5-((chlorosulfonyl)oxy)-4,4-dimethylpentanoate (38c).

A solution of sulfuryl chloride (0.36 ml, 4.9 mmol) in Et ₂ O (8 ml) was cooled to –78°C under nitrogen. A solution of 2-methoxyethyl 5-hydroxy-4,4-dimethylpentanoate (38b) (0.50 g, 2.4 mmol) and pyridine (0.40 ml, 4.9 mmol) was added dropwise to the sulfuryl chloride solution over 10 min. in Et ₂ O (8 ml). The syringe was washed with Et ₂ O (3×1 ml), and the wash was also added to the mixture. The mixture was shaken for 4.5 hours (the reaction was monitored by TLC using 2:8 EtOAc/hexanes as eluent). The solids were filtered and the filtrate was concentrated in vacuo to give product (38c) (0.60 g, 2.0 mmol) as a colorless oil. 3 ml of THF was added to it, and the solution was stored at –78°C. It was used in the next step without further purification.

Step 4: Synthesis of 2-methoxyethyl 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)– 4,4-dimethylpentanoate (38).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (370 mg, 2.0 mmol) was dissolved in THF (19 ml) and HMPA (0.8 ml), and the resulting solution was cooled to –78°C under a nitrogen atmosphere. A 1.0 M solution of NaHMDS in THF (2.2 mL, 2.2 mmol) was added dropwise to the cooled solution and shaken for 10 min. 2-methoxyethyl 5-((chlorosulfonyl)oxy)-4,4-dimethylpentanoate (38c) (0.60 g, 2.0 mmol) dissolved in THF (3 ml) was quickly added to the reaction mixture, its temperature was maintained at –78° C). The flask containing the sulfating reagent was washed with THF (3 x 1 ml), while the temperature of the flask was maintained at –78°C, and the rinse was quickly added to the reaction mixture. After shaking for 10 min, the mixture was warmed to room temperature and shaken overnight. The reaction was quenched with saturated aqueous sodium bicarbonate (40 ml) and extracted with EtOAc (40 ml). The organic layer was concentrated and the oily residue was partitioned into H ₂ O (40 ml) and EtOAc (40 ml). The organic layer was washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (1:9-8:2) to give product (38) (164 mg, 18%) as a solid. LC–MS: 452.0 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 6.53 (s, 1H), 5.62 (s, 1H), 4.51 (d, J=9.3 Hz, 1H), 4.24 –4.18 (m, 4H), 4.05–4.03 (m, 1H), 3.61–3.58 (m, 2H), 3.39–3.32 (m, 4H), 3 .01 (d, J=11.7 Hz, 1H), 2.47–2.33 (m, 3H), 2.18–2.13 (m, 1H), 2.00–1.82 (m , 2H), 1.73–1.68 (m, 2H), 0.99 (s, 6H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 173.6, 171.0, 167.1, 83.4, 70.6, 63.7, 62.0, 60.2, 59.1, 47 ,2, 34.2, 33.2, 29.1, 23.6, 23.3, 20.8, 17.6.

Example 39

Synthesis of 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,4, 4-tetramethylpentyl propionate (39)

Step 1: Synthesis of 5,5-dimethyltetrahydro-2H-pyran-2-one (39a).

To a solution of ethyl 5-hydroxy-4,4-dimethylpentanoate (35a) (26.5 g, 152.1 mmol) in dichloromethane (683 ml) was added trifluoroacetic acid (1.75 ml, 22.8 mmol). The mixture was shaken at room temperature for 3 days. The reaction was quenched with saturated aqueous sodium bicarbonate (150 ml), shaken rapidly for 30 minutes, and the layers were separated. The organic layer was washed with brine (150 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel flash column chromatography using EtOAc/hexanes (0:1-45:55) to give product (39a) (8.79 g, 45%) as a colorless oil. The product was used in the next step without further purification and was contaminated with small amounts of unidentified by-products. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 3.97 (s, 2H), 2.56 (t, J=7.4 Hz, 2H), 1.69 (t, J=7.4 Hz , 2H), 1.05 (s, 6H).

Step 2: Synthesis of 3,3,5,5-tetramethyltetrahydro-2H-pyran-2-one (39b).

5,5-Dimethyltetrahydro-2H-pyran-2-one (39a) (8.79 g, 68.6 mmol) was dissolved in anhydrous DMF (150 ml) and the resulting solution was cooled to 0°C under an inert atmosphere of argon . Sodium hydride, 60% in mineral oil (8.23 g, 205.7 mmol) was added in one part and the mixture was shaken for 20 minutes. This was followed by dropwise addition of MeI (17.1 mL, 274.3 mmol). The resulting solution was shaken at 0°C for 20 min and then at room temperature for 3 d. The mixture was diluted with EtOAc (350 ml) and then quenched at 0°C by carefully adding dropwise saturated aqueous NH ₄ solution Cl (100 ml). The aqueous and organic layers were separated and the aqueous layer was extracted with EtOAc (350 ml). The combined organic layers were washed with H ₂ O (6×300 ml), brine (300 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (1:9) as eluent to give product (39b) (3.42 g, 32%). The product was used in the next step without further purification and was contaminated with small amounts of various unidentified by-products. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 4.01 (s, 2H), 1.62 (s, 2H), 1.30 (s, 6H), 1.02 (s, 6H).

Step 3: Synthesis of 2,2,4,4-tetramethylpentane-1,5-diol (39c).

A round-bottomed neck flask containing a shaken suspension of 95% LiAlH ₄ (0.87 g, 21.6 mmol) in Et ₂ O (126 ml) was cooled to 0° C. under argon. To this suspension was added a solution of 3,3,5,5-tetramethyltetrahydro-2H-pyran-2-one (39b) (2.94 g, 18.8 mmol) in Et ₂ O (50 ml) under an inert atmosphere of argon. It was warmed to room temperature and shaken overnight. The mixture was carefully quenched with H ₂ O (80 ml), then 3 M NaOH (120 ml) and shaken for 30 minutes. The mixture was filtered through a pad of Celite® and the layer was washed thoroughly with Et ₂ O. The aqueous and organic layers were separated and the aqueous layer was extracted with Et ₂ O (3×100 ml). The combined organic layers were concentrated in vacuo and the residue was purified by silica gel column chromatography using EtOAc/hexanes (2:8-6:4) to give product (39c) (2.59 g, 86%) as solid matter. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 3.41 (s, 4H), 2.55 (s, 2H), 1.34 (s, 2H), 0.95 (s, 12H)

Step 4: Synthesis of 5-hydroxy-2,2,4,4-tetramethylpentylpropionate (39d).

Into a shaken solution of 2,2,4,4-tetramethylpentane-1,5-diol (39c) (0.48 g, 3.0 mmol) and pyridine (0.24 mL, 3.0 mmol) in DCM (20 mL ) propionyl chloride (0.26 mL, 3.0 mmol) was added dropwise over 30 minutes at approximately 0°C (ice bath). The reaction mixture was shaken overnight at room temperature. The mixture was diluted with H ₂ O (20 ml) and the layers were separated. The aqueous layer was extracted with DCM (2×20 ml) and the combined organic layers were washed with brine (20 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc/hexanes (5:95–6:4) to give product (39d) (411 mg, 63%). ¹ H–NMR (300 MHz, CDCl ₃ ): δ 3.85 (s, 2H), 3.32 (s, 2H), 2.37 (q, J=7.7 Hz, 2H), 1.50 (s, 1H), 1.36 (s, 2H), 1.16 (t, J=7.5 Hz, 3H), 1.03 (s, 6H), 0.99 (s 6H).

Step 5: Synthesis of 5-((chlorosulfonyl)oxy)-2,2,4,4-tetramethylpentyl propionate (39e).

A solution of sulfuryl chloride (0.136 ml, 1.9 mmol) in Et ₂ O (6.4 ml) was cooled to –78°C under argon. A solution of 5-hydroxy-2,2,4,4-tetramethylpentyl propionate (39d) (404 mg, 1.9 mmol) and pyridine (0.15 ml, 1.9 mmol) was added dropwise to the sulfuryl chloride solution over 10 min. in Et ₂ O (6.4 ml). The mixture was warmed to room temperature and shaken for 70 minutes. The solids were filtered to obtain a solution of product (39e) in Et ₂ O as the filtrate. The yield was quantified and the mixture was used in the next step without further purification.

Step 6: Synthesis of 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2 ,4,4-tetramethylpentyl propionate (39).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (346 mg, 1.9 mmol) was dissolved in THF (21.8 ml) and 1,3-dimethyltetrahydropyrimidine-2(1H)-one (1.0 ml), and the resulting solution was cooled to –78°C under argon. A solution of NaHMDS, 1.0 M in THF (1.9 mL, 1.9 mmol) was added dropwise to the cooled solution and shaken for 90 min. A solution of 5-((chlorosulfonyl)oxy)-2,2,4,4-tetramethylpentyl propionate (39e) (0.59 g, 1.9 mmol) in Et ₂ O (about 20 ml) was added to the reaction mixture (cannula) . After shaking for 10 minutes, the mixture was warmed to room temperature and shaken for 4 hours. The reaction was then quenched with saturated aqueous sodium bicarbonate (40 ml) and extracted with EtOAc (40 ml). The organic layer was washed with H ₂ O (3×40 ml), brine (40 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel flash column chromatography using EtOAc/hexanes (1:9–8:2) to give product (39) (254 mg, 29%) as a solid. LC–MS: m/z=464.1 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 6.53 (s, 1H), 5.64 (s, 1H), 4.53 (d, J=9 Hz, 1H), 4.23 (d , J=9 Hz, 1H), 4.18 (m, 1H) 4.06–4.04 (m, 1H), 3.80 (s, 2H), 3.36–3.32 (m, 1H ), 3.01 (d, J=12.3 Hz, 1H), 2.47–2.33 (m, 3H), 2.19–2.13 (m, 1H), 2.01–1, 79 (m, 2H), 1.43 (s, 2H), 1.16 (t, J=7.7 Hz, 3H), 1.09 (s, 6H), 1.03 (s, 6H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 174.6, 171.1, 167.1, 84.9, 73.3, 61.9, 60.2, 47.2, 46.2, 36 ,0, 35.3, 27.8, 26.6, 26.3, 25.9, 25.3, 20.8, 17.5, 9.3.

Example 40

Synthesis of 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,4, 4-tetramethylpentyl benzoate (40)

Step 1: Synthesis of 5-hydroxy-2,2,4,4-tetramethylpentyl benzoate (40a).

Into a shaken solution of 2,2,4,4-tetramethylpentane-1,5-diol (39c) (0.48 g, 3.0 mmol) and pyridine (0.24 mL, 3.0 mmol) in DCM (20 mL ) benzoyl chloride (0.37 mL, 3.0 mmol) was added dropwise over 30 minutes at approximately 0°C (ice bath) under argon. The reaction mixture was shaken overnight at room temperature. The mixture was diluted with H ₂ O (20 ml) and the layers were separated. The aqueous layer was extracted with DCM (2×20 ml) and the combined organic layers were washed with brine (20 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (5:95-1:1) to give product (40a) (548 mg, 69%) as an oil. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 8.06 (d, J=8.4 Hz, 2H), 7.59–7.55 (m, 1H), 7.48–7.43 ( m, 2H), 4.09 (s, 2H), 3.35 (s, 2H), 1.48 (s, 2H), 1.13 (s, 6H), 1.02 (s, 6H).

Step 2: Synthesis of 5-((chlorosulfonyl)oxy)-2,2,4,4-tetramethylpentyl benzoate (40b).

A solution of sulfuryl chloride (0.15 ml, 2.0 mmol) in Et ₂ O (8.5 ml) was cooled to –78°C under argon. A solution of 5-hydroxy-2,2,4,4-tetramethylpentyl benzoate (40a) (541 mg, 2.0 mmol) and pyridine (0.17 ml, 2.0 mmol) was added dropwise to the sulfuryl chloride solution over 10 min. in Et ₂ O (8.5 ml). The mixture was shaken at 0°C for 20 min, then at room temperature for 90 min. The mixture was filtered and the filtrate was used to prepare a solution of product (40b) in Et ₂ O (about 20 ml). The yield was quantified and the product was used in the next step without further purification.

Step 3: Synthesis of 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2 ,4,4-tetramethylpentyl benzoate (40).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (370 mg, 2.0 mmol) was dissolved in THF (23 ml) and 1 ,3-dimethyltetrahydropyrimidine-2(1H)-one (1.5 ml), and the resulting solution was cooled to –78°C under argon. A solution of NaHMDS, 1.0 M in THF (2.0 mL, 2.0 mmol) was added dropwise to the cooled solution and shaken for 90 min. A solution of 5-((chlorosulfonyl)oxy)-2,2,4,4-tetramethylpentyl benzoate (40b) (0.73 g, 2.0 mmol, 1.0 equiv.) dissolved in Et ₂ O (about 20 ml). After shaking for 10 minutes, the mixture was warmed to room temperature and shaken for 4 hours. The mixture was quenched with saturated aqueous sodium bicarbonate (40 ml) and extracted with EtOAc (40 ml). The organic layer was washed with H ₂ O (3×40 ml), brine (40 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (1:9-8:2) to give product (40) (282 mg, 27%) as a solid. LC–MS: m/z=512.15 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 8.06 (d, J=7.8 Hz, 2H), 7.59–7.55 (m, 1H), 7.49–7.43 ( m, 2H), 6.49 (s, 1H), 5.70 (s, 1H), 4.57 (d, J=9 Hz, 1H), 4.26 (d, J=8.7 Hz, 1H), 4.17 (s, 1H), 4.10–4.01 (m, 3H), 3.29–3.25 (m, 1H), 2.98 (d, J=11.7 Hz , 1H), 2.45–2.35 (m, 1H), 2.17–2.11 (m, 1H), 1.99–1.77 (m, 2H), 1.56 (s, 2H ), 1.14–1.13 (m, 12H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 171.0, 167.0, 166.6, 133.1, 130.4, 129.7, 128.6, 85.0, 73.9, 61 ,9, 60.2, 47.2, 46.2, 36.1, 35.7, 26.7, 26.4, 25.9, 25.4, 20.8, 17.5.

Example 41

Synthesis of 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,4, 4-tetramethylpentyl 2,6-dimethylbenzoate (41)

Step 1: Synthesis of 5-hydroxy-2,2,4,4-tetramethylpentyl 2,6-dimethylbenzoate (41a).

Into a shaken solution of 2,2,4,4-tetramethylpentane-1,5-diol (39c) (0.48 g, 3.0 mmol) and pyridine (0.24 mL, 3.0 mmol) in DCM (20 mL ) 2,6-dimethylbenzoyl chloride (0.45 mL, 3.0 mmol) was added dropwise over 30 minutes at 0°C (ice bath) under argon. The reaction mixture was shaken overnight at room temperature. The mixture was diluted with H ₂ O (20 ml) and the layers were separated. The aqueous layer was extracted with DCM (2×20 ml) and the combined organic layers were washed with brine (20 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (5:95–1:1) to give product (41a) (462 mg, 53%) as an oil. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.22–7.17 (m, 1H), 7.04 (d, J=7.5 Hz, 2H), 4.10 (s, 2H) , 3.32 (s, 2H), 2.33 (s, 6H), 1.41 (s, 2H), 1.10 (s, 6H), 1.00 (s, 6H).

Step 2: Synthesis of 5-((chlorosulfonyl)oxy)-2,2,4,4-tetramethylpentyl 2,6-dimethylbenzoate (41b).

A solution of sulfuryl chloride (0.11 ml, 1.5 mmol) in Et ₂ O (7 ml) was cooled to –78°C under argon. A solution of 5-hydroxy-2,2,4,4-tetramethylpentyl 2,6-dimethylbenzoate (41a) (453 mg, 1.5 mmol) and pyridine (0.13 ml, 1 .5 mmol) in Et ₂ O (7 ml). The mixture was shaken in an ice bath for 20 min, then at room temperature for 90 min. The mixture was filtered and the filtrate was saved to give a solution of product (41b) in Et ₂ O (about 20 ml). The output was taken by quantity. This mixture was used in the next step without further purification (a small amount was concentrated in vacuo and NMR of the residue was performed). ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.21 (t, J=7.7 Hz, 1H), 7.05 (d, J=7.2 Hz, 2H), 4.20 (s , 2H), 4.07 (s, 2H), 2.32 (s, 6H), 1.50 (s, 2H), 1.14 (s, 6H), 1.12 (s, 6H).

Step 3: Synthesis of 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2 ,4,4-tetramethylpentyl 2,6-dimethylbenzoate (41).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (286 mg, 1.5 mmol) was dissolved in THF (18 ml) and 1 ,3-dimethyltetrahydropyrimidine-2(1H)-one (2.3 ml), and the resulting solution was cooled to –78°C under argon. A solution of NaHMDS, 1.0 M in THF (1.5 mL, 1.5 mmol) was added dropwise to the cooled solution and shaken for 90 min. A solution of 5-((chlorosulfonyl)oxy)-2,2,4,4-tetramethylpentyl 2,6-dimethylbenzoate (41b) (0.61 g, 1.5 mmol) in Et ₂ O ( about 20 ml). After shaking for 10 minutes, the mixture was warmed to room temperature and shaken for 4 hours. The mixture was quenched with saturated aqueous sodium bicarbonate (40 ml) and extracted with EtOAc (40 ml). The organic layer was washed with H ₂ O (3×40 ml), brine (40 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (1:9-8:2) to give product (41) (490 mg, 58%) as a solid. LC–MS: m/z=540.07 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.20 (t, J=7.7 Hz, 1H), 7.04 (d, J=7.5 Hz, 2H), 6.50 (s , 1H), 5.63 (s, 1H), 4.54 (d, J=8.7 Hz, 1H), 4.23 (d, J=8.7 Hz, 1H), 4.17 (s , 1H), 4.06–4.03 (m, 3H), 3.34–3.29 (m, 1H), 3.00 (d, J=11.7 Hz, 1H), 2.47– 2.40 (m, 1H), 2.32 (s, 6H), 2.18–2.14 (m, 1H), 2.00–1.78 (m, 2H), 1.49 (s, 2H), 1.11 (s, 12H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 170.9, 170.4, 167.0, 135.0, 134.2, 129.4, 127.7, 84.9, 74.5, 62 ,0, 60.2, 47.2, 46.2, 36.1, 35.4, 26.5, 26.4, 26.0, 25.3, 20.8, 20.0, 17.5 .

Example 42

Synthesis of (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl ((3-methyl-2-oxotetrahydrofuran-3-yl)methyl) sulfate (42)

Step 1: Synthesis of (3-methyl-2-oxotetrahydrofuran-3-yl)methyl sulfochloride (42a).

Pyridine (0.28 ml, 3.5 mmol) was added to a shaken mixture of 3-(hydroxymethyl)-3-methyldihydrofuran-2(3H)-one (prepared according to Synlett 2010, 2625-2627) (0.30 g, 2. 3 mmol) and Et ₂ O (8 ml) in an argon atmosphere. The solution was cooled to –78°C and sulfuryl chloride (0.28 ml, 3.5 mmol) in Et ₂ O (3 ml) was added slowly at –78°C. The mixture was shaken at –78°C for 1 hour and then warmed to room temperature and shaken for 1 hour. The reaction mixture was filtered to remove the pyridine salt and the filtrate was concentrated in vacuo to give product (42a) as an oil, which was used directly at the next stage without additional purification (yield was taken by quantity).

Step 2: Synthesis of (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl ((3-methyl-2-oxotetrahydrofuran-3-yl)methyl) sulfate (42).

Into a shaken mixture of (2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (0.24 g, 1.3 mmol) in THF (20 ml) in an argon atmosphere, a few drops of 1,3-dimethyltetrahydropyrimidin-2(1H)-one were added. The mixture was cooled to –78°C and shaken for 10 min, then a solution of NaHMDS, 1.0 M in THF (1.4 mL, 1.4 mmol) was added dropwise. The mixture was shaken at –78°C for 8 min, then (3-methyl-2-oxotetrahydrofuran-3-yl)methyl sulfochloride (42a) (0.30 g, 1.3 mmol) in THF (30 ml) was added at –78°C. The mixture was shaken at –78°C for 10 min, then allowed to warm to room temperature and shaken overnight. The mixture was diluted with EtOAc and saturated sodium bicarbonate solution. The aqueous and organic layers were separated, and the organic layer was washed with water, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-1:0) as eluent to give a solid (150 mg). NMR showed trace impurities which were removed by trituration with EtOAc to give product (42) (35 mg) as a solid. LC/MS: m/z=378.0 [M+H] ⁺ . ¹ H–NMR (300 MHz, d6–DMSO): δ 7.53 (s, 1H), 7.38 (s, 1H), 4.68–4.64 (m, 1H), 4.54 (d , J=9.3 Hz, 1H), 4.32–4.27 (m, 2H), 4.09 (s, 1H), 3.89 (d, J=6.0Hz, 1H), 3, 21–3.13(m, 2H), 2.38–2.28 (m, 1H), 2.13–2.00 (m, 2H), 1.91–1.66 (m, 3H), 1.21(s,3H). ¹³ C–NMR (75 MHz, d6–DMSO): δ 178.3, 171.0, 168.7, 77.9, 65.6, 61.7, 61.2, 46.3, 43.2, 31.2, 20.8, 19.1, 18.9.

(2S,5R)–2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl ((3-methyl-2-oxotetrahydrofuran-3-yl)methyl) sulfate (42) was separated into isomers (S) and (R), (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl (((S)-3-methyl-2 –oxotetrahydrofuran-3-yl)methyl) sulfate (42(S) and (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl (((R) –3-methyl-2-oxotetrahydrofuran-3-yl)methyl) sulfate (42(R):

Example 43

Synthesis of 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl pivalate (43)

Step 1: Synthesis of 3-hydroxy-2,2-dimethylpropyl pivalate (43a).

Trimethylacetyl chloride (2.0 mL, 16.2 mmol) was added to a shaken solution of 2,2-dimethylpropane-1,3-diol (5.07 g, 48.7 mmol) in DCM (50 mL) at 0°C under argon. ), pyridine (2.63 ml, 32.5 mmol) and N,N–4-dimethylaminopyridine (0.4 g, 3.2 mmol). Allow the mixture to warm to room temperature and shake at room temperature overnight. The mixture was cooled to 0°C, and the reaction was quenched by adding 1 N. HCl (50 ml), then extracted with DCM (twice). The combined organic layers were washed with saturated sodium bicarbonate and brine, then dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1–1:5) to give product (43a) as an oil. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 3.92 (s, 2H), 3.27 (s, 2H), 1.22 (s, 9H), 0.92 (s, 6H).

Step 2: Synthesis of 3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl pivalate (43b).

Pyridine (0.75 ml, 9.3 mmol) was added to a shaken mixture of 3-hydroxy-2,2-dimethylpropyl pivalate (43a) (1.17 g, 6.2 mmol) and Et ₂ O (20 ml) under atmosphere argon. The solution was cooled to –78°C and sulfuryl chloride (0.75 ml, 9.3 mmol) in Et ₂ O (8 ml) was added slowly at –78°C. The mixture was shaken at –78°C for 1 hour and then warmed to room temperature and shaken for 1 hour. The reaction mixture was filtered to remove the pyridine salt and the filtrate was concentrated in vacuo to give product (43b) as an oil, which was used directly at the next stage without additional purification (yield was taken by quantity).

Step 3: Reaction to produce 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2, 2-dimethylpropyl pivalate (43).

Into a shaken mixture of (2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (1.1 g, 5.9 mmol) in THF (20 ml) in an argon atmosphere, a few drops of 1,3-dimethyltetrahydropyrimidin-2(1H)-one were added. The mixture was cooled to –78°C and shaken for 10 min, then a solution of NaHMDS, 1.0 M in THF (6.5 mL, 6.5 mmol) was added dropwise. The mixture was shaken at –78°C for 8 min, then 3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl pivalate (43b) (1.7 g, 5.9 mmol) in THF (30 ml) was added at –78°C. The mixture was shaken at –78°C for 10 min, then allowed to warm to room temperature and shaken overnight. The mixture was diluted with EtOAc and saturated sodium bicarbonate solution. The aqueous and organic layers were separated, and the organic layer was washed with water, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-1:0) to give product (43) (654 mg) as a solid. LC/MS: m/z=436.0 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 6.48 (s, 1H), 5.58 (s, 1H), 4.60 (d, J=8.7 Hz, 1H), 4.36 (d, J=9.0 Hz, 1H), 4.17 (s, 1H), 4.04 (d, J=6.3 Hz, 1H), 3.95–3.84 (q, 2H) , 3.35–3.31 (m, 1H), 3.02 (d, J=12.3 Hz, 1H), 2.50–2.41 (m, 1H), 2.20–2.05 (m, 1H), 1.99–1.78 (m, 2H), 1.22 (s, 9H), 1.04 (s, 6H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 178.2, 171.1, 167.1, 80.6, 68.4, 62.0, 60.2, 47.2, 39.1, 35 ,6, 27.3, 21.3, 21.3, 20.8, 17.6.

Example 44

Synthesis of 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl 3 –chloro-2,6-dimethoxybenzoate (44)

Step 1: Synthesis of 3-hydroxy-2,2-dimethylpropyl 2,6-dimethoxybenzoate (44a).

2,6-Dimethoxybenzoyl chloride (80% purity; 3 .13 g, 12.5 mmol), pyridine (2.02 ml, 24.9 mmol) and N, N-4-dimethylaminopyridine (0.3 g, 2.5 mmol). Allow the mixture to warm to room temperature and shake at room temperature overnight. The mixture was cooled to 0°C and the reaction was quenched by adding 1N. HCl (50 ml), then extracted with DCM (twice). The combined organic layers were washed with saturated sodium bicarbonate and brine, then dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1–1:5) to give product (44a) as an oil. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.19 (t, J=5.0 Hz, 1H), 6.48 (d, J=8.1 Hz, 2H), 4.09 (s , 2H), 3.71 (s, 6H), 3.33 (s, 2H), 0.89 (s, 6H).

Step 2: Synthesis of 3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl 3-chloro-2,6-dimethoxybenzoate (44b).

Pyridine (0.16 ml, 2.0 mmol) was added to a shaken mixture of 3-hydroxy-2,2-dimethylpropyl 2,6-dimethoxybenzoate (44a) (0.35 g, 1.3 mmol) and Et ₂ O (10 ml) in an argon atmosphere. The solution was cooled to –78°C and sulfuryl chloride (0.16 ml, 2.0 mmol) in Et ₂ O (8 ml) was added slowly at –78°C. The mixture was shaken at –78°C for 1 hour and then warmed to room temperature and shaken for 1 hour. The reaction mixture was filtered to remove the pyridine salt and the filtrate was concentrated in vacuo to give product (44b) as an oil, which was used directly at the next stage without additional purification (yield was taken by quantity). ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.36 (d, J=8.7 Hz, 1H), 6.66 (d, J=8.7 Hz, 1H), 4.35 (s , 2H), 4.21 (s, 2H), 3.89 (s, 3H), 3.81 (s, 3H), 1.13 (s, 6H).

Step 3: Synthesis of 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2 –dimethylpropyl 3-chloro-2,6-dimethoxybenzoate (44).

Into a shaken mixture of (2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (237 mg, 1.3 mmol) in THF (15 ml) A few drops of 1,3-dimethyltetrahydropyrimidin-2(1H)-one were added in an argon atmosphere. The mixture was cooled to –78°C and shaken for 10 min, then a solution of NaHMDS, 1.0 M in THF (1.4 mL, 1.4 mmol) was added dropwise. The mixture was shaken at –78°C for 8 min, then 3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl 3-chloro-2,6-dimethoxybenzoate (44b) (0.47 g, 1.2 mmol) was added ) in THF (8 ml) at –78°C. The mixture was shaken at –78°C for 10 min, then allowed to warm to room temperature and shaken overnight. The mixture was diluted with EtOAc and saturated sodium bicarbonate solution. The aqueous and organic layers were separated, and the organic layer was washed with water, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1–1:0) as eluent to give product (44) as a solid. LC/MS: m/z=550.0 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.36–7.32 (dd, J=1.2 Hz, 1.2 Hz, 1H), 6.65 (d, J=8.1 Hz , 1H), 6.51 (s, 1H), 5.82 (s, 1H), 4.55 (d, J=8.7 Hz, 1H), 4.38 (d, J=9.0 Hz , 1H), 4.25–4.07 (m, 3H), 4.01 (d, J=6.6 Hz, 1H), 3.88 (s, 3H), 3.81 (s, 3H) , 3.27 (d, J=11.7 Hz, 1H), 2.98 (d, J=11.7 Hz, 1H), 2.41–2.37 (m, 1H), 2.14– 2.10 (m, 1H), 1.94–1.74 (m, 2H), 1.08 (s, 6H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 171.1, 167.1, 165.2, 156.1, 153.7, 131.7, 119.8, 119.5, 107.9, 80 ,4, 69.3, 62.2, 62.0, 60.2, 56.3, 47.1, 35.7, 21.3, 21.2, 20.8, 17.5.

Example 45

Synthesis of 4–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–2,2,3, 3-tetramethylbutyl 2,6-dimethylbenzoate (45)

Step 1: Synthesis of 2,2,3,3-tetramethylbutane-1,4-diol (45a).

To a shaken suspension of LiAlH ₄ (95%; 0.32 g, 8.1 mmol) in Et ₂ O (28 ml) was added a solution of 3,3,4,4-tetramethyldihydrofuran-2(3H)-one (prepared according to US patents No. 3658849) (1.0 g, 7.0 mmol) in Et ₂ O (28 ml) at 0°C in an argon atmosphere. The mixture was warmed to room temperature and shaken overnight. Sodium sulfate decahydrate was added slowly until the flask stopped bubbling. The solid was filtered through a pad of Celite® and the layer was washed with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-7:3) to give product (45a) (0.7 g) as a solid. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 3.41 (s, 4H), 0.88 (s, 12H).

Step 2: Synthesis of 4-hydroxy-2,2,3,3-tetramethylbutyl 2,6-dimethylbenzoate (45b).

2,6– dimethylbenzoyl chloride (0.2 ml, 1.6 mmol), pyridine (0.26 ml, 3.2 mmol) and N,N-4-dimethylaminopyridine (0.04 g, 0.3 mmol). Allow the mixture to warm to room temperature and shake at room temperature overnight. The mixture was cooled to 0°C and the reaction was quenched by adding 1N. HCl (15 ml), then extracted with DCM (twice). The combined organic layers were washed with saturated sodium bicarbonate and brine, then dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-3:2) to give product (45b) as an oil (266 mg). ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.18 (t, J=8.4 Hz, 1H), 7.02 (d, J=6.9 Hz, 2H), 4.25 (s , 2H), 3.51 (s, 2H), 2.31 (s, 6H), 0.98 (s, 6H), 0.93 (s, 6H).

Step 3: Synthesis of 4-((chlorosulfonyl)oxy)-2,2,3,3-tetramethylbutyl 2,6-dimethylbenzoate (45c).

_Pyridine (0 .11 ml, 1.3 mmol). The solution was cooled to –78°C and sulfuryl chloride (0.11 ml, 1.3 mmol) in Et ₂ O (3 ml) was added slowly at –78°C. The mixture was shaken at –78°C for 1 hour and then warmed to room temperature and shaken for 1 hour. The reaction mixture was filtered to remove the pyridine salt and the filtrate was concentrated in vacuo to give product (45c) as an oil, which was used directly at the next stage without additional purification (yield was taken by quantity).

Step 3: Synthesis of 4-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2 ,3,3-tetramethylbutyl 2,6-dimethylbenzoate (45).

Into a shaken mixture of (2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (255 mg, 1.4 mmol) in THF (10 ml) A few drops of 1,3-dimethyltetrahydropyrimidin-2(1H)-one were added in an argon atmosphere. The mixture was cooled to –78°C and shaken for 10 min, then a solution of NaHMDS, 1.0 M in THF (1.5 mL, 1.5 mmol) was added dropwise. The mixture was shaken at –78°C for 8 min, then 4-((chlorosulfonyl)oxy)-2,2,3,3-tetramethylbutyl 2,6-dimethylbenzoate (45c) (0.52 g, 1.4 mmol) was added ) in THF (5 ml) at –78°C. The mixture was shaken at –78°C for 10 minutes and then allowed to warm to room temperature and shaken for 1 hour. The mixture was diluted with EtOAc and saturated sodium bicarbonate solution. The aqueous and organic layers were separated, and the organic layer was washed with water, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1–1:0) as eluent to give product (45) as a solid. LC/MS: m/z=526.16 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.19 (t, J=7.7 Hz, 1H), 7.03 (d, J=6.9 Hz, 2H), 6.47 (s , 1H), 5.58 (s, 1H), 4.76 (d, J=9.3 Hz, 1H), 4.40 (d, J=9.6 Hz, 1H), 4.20–4 .16 (m, 3H), 4.04 (d, J=6.3 Hz, 1H), 3.33 (d, J=12.3 Hz, 1H), 2.99 (d, J=12, 3 Hz, 1H), 2.45–2.40 (m, 1H), 2.32 (s, 6H), 2.17–2.13 (m, 1H), 2.04–1.83 (m .2H), 1.05–1.03 (m, 12H). ¹³ C–NMR (75MHz, CDCl ₃ ): δ 170.9, 170.4, 167.1, 134.9, 134.2, 129.4, 127.6, 82.1, 70.8, 62, 0, 60.2, 47.3, 39.1, 38.5, 21.0, 20.9, 20.8, 20.5, 20.3, 20.0, 17.5.

Example 46

Synthesis of 4–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–2,2,3, 3-tetramethylbutyl benzoate (46)

Step 1: Synthesis of 4-hydroxy-2,2,3,3-tetramethylbutyl benzoate (46a).

Benzoyl chloride (0. 25 ml, 2.0 mmol), pyridine (0.33 ml, 4.0 mmol) and N, N-4-dimethylaminopyridine (0.05 g, 0.4 mmol). Allow the mixture to warm to room temperature and shake at room temperature overnight. The mixture was cooled to 0°C and the reaction was quenched by adding 1N. HCl (15 ml), then extracted with DCM (twice). The combined organic layers were washed with saturated sodium bicarbonate and brine, then dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1–3:2) to give product (46a) as an oil. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 8.05 (d, J=7.2 Hz, 2H), 7.58 (t, J=7.4 Hz, 1H), 7.46 (t , J=7.4 Hz, 2H), 4.27 (s, 2H), 3.59 (s, 2H), 1.05 (s, 6H), 0.99 (s, 6H).

Step 2: Synthesis of 4-((chlorosulfonyl)oxy)-2,2,3,3-tetramethylbutyl benzoate (46b).

_Pyridine (0.29 ml, 3.6 mmol). The solution was cooled to –78°C and sulfuryl chloride (0.29 ml, 3.6 mmol) in Et ₂ O (3 ml) was added slowly at –78°C. The mixture was shaken at –78°C for 1 hour and then warmed to room temperature and shaken for 1 hour. The reaction mixture was filtered to remove the pyridine salt and the filtrate was concentrated in vacuo to give product (46b) as an oil, which was used directly at the next stage without additional purification (yield was taken by quantity).

Step 3: Synthesis of 4-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2 ,3,3-tetramethylbutyl benzoate (46).

Into a shaken mixture of (2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (0.52 g, 2.8 mmol) in THF (10 ml) in an argon atmosphere, a few drops of 1,3-dimethyltetrahydropyrimidin-2(1H)-one were added. The mixture was cooled to –78°C and shaken for 10 min, then a solution of NaHMDS, 1.0 M in THF (3.1 mL, 3.1 mmol) was added dropwise. The mixture was shaken at –78°C for 8 min and then 4-((chlorosulfonyl)oxy)-2,2,3,3-tetramethylbutyl benzoate (46b) (0.98 g, 2.8 mmol) in THF was added (5 ml) at –78°C. The mixture was shaken at –78°C for 10 minutes and then allowed to warm to room temperature and shaken for 1 hour. The mixture was diluted with EtOAc and saturated sodium bicarbonate solution. The aqueous and organic layers were separated, and the organic layer was washed with water, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1–1:0) to give product (46) as a solid. LC/MS: m/z=498.10 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 8.05 (d, J=7.2 Hz, 2H), 7.57 (t, J=7.4 Hz, 1H), 7.45 (t , J=7.4 Hz, 2H), 6.47 (s, 1H), 5.61 (s, 1H), 4.87 (d, J=9.0 Hz, 1H), 4.52 (d , J=9.3 Hz, 1H), 4.22–4.17 (m, 3H), 4.01 (d, J=6.3 Hz, 1H), 3.35–3.31 (m, 1H), 2.99 (d, J=14.7 Hz, 1H), 2.43–2.39 (m, 1H), 2.17–2.12 (m, 1H), 1.92–1 .81 (m, 2H), 1.10–1.06 (m, 12H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 170.9, 167.1, 166.6, 133.1, 130.3, 129.7, 128.6, 82.4, 70.5, 62 ,0, 60.2, 47.3, 39.2, 38.8, 21.1, 21.0, 20.8, 20.5, 20.3, 17.5.

Example 47

Synthesis of 4–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–2,2,3, 3-tetramethylbutyl propionate (47)

Step 1: Synthesis of 4-hydroxy-2,2,3,3-tetramethylbutyl propionate (47a).

Propionyl chloride (0. 25 ml, 3.1 mmol), pyridine (0.33 ml, 4.0 mmol) and N, N-4-dimethylaminopyridine (0.05 g, 0.4 mmol). Allow the mixture to warm to room temperature and shake at room temperature overnight. The mixture was cooled to 0°C and the reaction was quenched by adding 1N. HCl (15 ml) and then extracted with DCM (twice). The combined organic layers were washed with saturated sodium bicarbonate and brine, then dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-3:2) to give the diacylated material, followed by product (47a) (300 mg) as an oil. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 3.99 (s, 2H), 3.49 (s, 2H), 2.38–2.31 (q, 2H), 1.15 (t, J=7.8 Hz, 3H), 0.91 (d, J=4.8 Hz, 12H).

Step 2: Synthesis of 4-((chlorosulfonyl)oxy)-2,2,3,3-tetramethylbutyl propionate (47b).

Pyridine ( _0.16 ml, 1.9 mmol). The solution was cooled to –78°C and sulfuryl chloride (0.16 ml, 1.9 mmol) in Et ₂ O (3 ml) was added slowly at –78°C. The mixture was shaken at –78°C for 1 hour and then warmed to room temperature and shaken for 1 hour. The reaction mixture was filtered to remove the pyridine salt and the filtrate was concentrated in vacuo to give product (47b) as an oil, which was used directly at the next stage without additional purification (yield was taken by quantity).

Step 3: Synthesis of 4-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2 ,3,3-tetramethylbutyl propionate (47).

Into a shaken mixture of (2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 91) (271 mg, 1.5 mmol) in THF (10 ml) in A few drops of 1,3-dimethyltetrahydropyrimidin-2(1H)-one were added to an argon atmosphere. The mixture was cooled to –78°C and shaken for 10 min, then a solution of NaHMDS, 1.0 M in THF (1.6 mL, 1.6 mmol) was added dropwise. The mixture was shaken at –78°C for 8 min, then 4-((chlorosulfonyl)oxy)-2,2,3,3-tetramethylbutyl propionate (47b) (0.44 g, 1.5 mmol) in THF was added ( 5 ml) at –78°C. The mixture was shaken at –78°C for 10 minutes, then allowed to warm to room temperature and shaken for 1 hour. The mixture was diluted with EtOAc and saturated sodium bicarbonate solution. The aqueous and organic layers were separated, and the organic layer was washed with water, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-1:0) to give product (47) (300 mg) as a solid. LC/MS: m/z=450.09 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 6.49 (s, 1H), 5.62 (s, 1H), 4.77 (d, J=8.7 Hz, 1H), 4.45 (d, J=9.3 Hz, 1H), 4.19 (s, 1H), 4.05 (d, J=6.3 Hz, 1H), 3.95 (s, 2H), 3.35 (d, J=12.0 Hz, 1H), 3.01 (d, J=12.3 Hz, 1H), 2.46–2.34 (m, 3H), 2.19–2.15 ( m, 1H), 1.92–1.83 (m, 2H), 1.16 (t, J=7.7 Hz, 3H), 1.01 (d, J=9.3 Hz, 6H), 0.96(s,6H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 174.5, 171.0, 167.1, 82.5, 70.0, 62.0, 60.2, 47.3, 39.1, 38 ,4, 27.8, 21.0, 20.9, 20.8, 20.4, 20.2, 17.5, 9.3.

Example 48

Synthesis of (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl ((3-methyl-2-oxotetrahydro-2H-pyran-3-yl)methyl) sulfate (48)

Step 1: Synthesis of 3-((benzyloxy)methyl)-3-methyltetrahydro-2H-pyran-2-one (48a).

δ-valerolactone (5.23 g, 52.2 mmol) was dissolved in a mixture of THF (120 ml) and HMPA (9.2 ml) under argon. The reaction mixture was cooled to –78°C and shaken for 10 min. A solution of lithium diisopropylamide, 2.0 M in THF (28.7 mL, 57.5 mmol) was added dropwise over 5 min. The reaction mixture was shaken at –78°C for 30 minutes, and then undiluted MeI (3.3 mL, 52.8 mmol) was added to the reaction mixture over 5 min. The mixture was shaken at –78°C for 30 minutes, then removed from the cooling bath and warmed to 0°C and shaken for 30 minutes. (note: the mixture gradually turned yellow at this time). The mixture was re-cooled to –78°C and shaken for 10 min, and then additional lithium diisopropylamide, 2.0 M in THF (28.7 mL, 57.5 mmol) was added over 5 min. The reaction mixture was shaken at –78°C for 30 minutes, then undiluted benzyl chloromethyl ether (70%; 10.5 ml, 52.8 mmol) was added over 5 minutes. The mixture was allowed to warm to room temperature and shaken for 16 hours. The solvent was then removed in vacuo and the residue was partitioned into saturated ammonium chloride (200 ml) and EtOAc (200 ml). The aqueous layer was extracted with EtOAc (2×100 ml), and the combined organic layers were washed with brine (2×100 ml), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo (19 g). The residue was dry loaded onto silica gel and purified by silica gel column chromatography (120 g cartridge) using EtOAc/hexanes as eluent to give the contaminated product (6.9 g). The residue was repurified by silica gel column chromatography using DCM/hexanes (0:1-4:1) to give product (48a) (1.76 g) as a liquid. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.29–7.37 (m, 5H), 4.61 (dd, J=21.0, 12.3 Hz, 2H), 4.32– 4.38 (m, 2H), 3.26–3.81 (dd, J=15.8, 8.1 Hz, 2H), 2.21–2.30 (m, 1H), 1.87– 1.94 (m, 2H), 1.59–1.66 (m, 1H), 1.23 (s, 3H).

Step 2: Synthesis of 3-(hydroxymethyl)-3-methyltetrahydro-2H-pyran-2-one (48b).

3-((benzyloxy)methyl)-3-methyltetrahydro-2H-pyran-2-one (48a) (0.52 g, 2.2 mmol) was dissolved in 2-propanol (25 ml), and the solution was degassed and refluxed flushing with argon. (Note: MeOH was not used as a solvent because the lactone ring may open during hydrogenation). Palladium on carbon, 10% (0.26 g, 0.2 mmol) was added to the mixture and the system was sealed. The reaction mixture was degassed, backwashed with hydrogen (3 times) and shaken under hydrogen for 2 hours. The suspension was filtered through a pad of Celite® and the filter cake was washed with fresh 2-propanol (2 x 50 ml). The filtrate was concentrated in vacuo and product (48b) was used without further purification. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 4.27–4.45 (m, 2H), 3.67 (d, J=11.4 Hz, 1H), 3.52 (d, J= 11.1 Hz, 1H), 1.84–2.03 (m, 2H), 1.58–1.64 (m, 1H), 1.29 (s, 3H).

Step 3: Synthesis of (3-methyl-2-oxotetrahydro-2H-pyran-3-yl)methyl sulfochloride (48c).

A solution of 3-(hydroxymethyl)-3-methyltetrahydro-2H-pyran-2-one (48b) (0.32 g, 2.2 mmol) and pyridine (0.21 ml, 2.6 mmol) in Et ₂ O ( 10 ml) was cooled to –78°C in an argon atmosphere. Undiluted sulfuryl chloride (0.21 ml, 2.6 mmol) was added dropwise to the above solution using a syringe. The mixture was shaken at –78°C for 10 min, then the flask was warmed to room temperature and shaken for 1 h (monitored with TLC EtOAc/hexanes, 3:7). The precipitate was molded to obtain a thick suspension. The suspension was filtered through a 0.45 µM Teflon® filter and the filter cake was washed with fresh Et ₂ O (2×5 ml). An aliquot (0.5 ml) was taken and concentrated and NMR was performed on the mixture. The remaining solution containing product (48c) was used directly in the next step. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 4.87 (d, J=9.3 Hz, 1H), 4.25–4.50 (m, 2H), 4.32 (d, J= 8.7 Hz, 1H), 2.00–2.20 (m, 2H), 1.75–2.00 (m, 2H), 1.39 (s, 3H).

Step 4: Synthesis of (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl ((3-methyl-2-oxotetrahydro-2H-pyran-3-yl )methyl) sulfate (48).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (0.39 g, 2.1 mmol) was dissolved in THF (18 ml) and 1,3-dimethyltetrahydropyrimidine-2(1H)-one (0.65 ml), and the resulting solution was cooled to –78°C under argon. NaHMDS, 1.0 M in THF (2.3 mL, 2.3 mmol) was added dropwise to the cooled solution and shaken for 1 hour. A solution of (3-methyl-2-oxotetrahydro-2H-pyran) was quickly added to the reaction mixture –3-yl)methyl sulfochloride (48c) (0.51 g, 2.1 mmol) in Et ₂ O (from previous reaction). Allow the mixture to warm to room temperature and shake overnight. Brine (100 ml) and EtOAc (100 ml) were added to the reaction mixture, and the aqueous and organic layers were separated. The aqueous layer was extracted with EtOAc (2×100 ml), and the combined organic layers were washed with brine (3×100 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was dry loaded onto silica gel (8 g) and purified by silica gel column chromatography using EtOAc/hexanes (1:4-1:0) as eluent to give the desired product (48) (0.21 g) in the form of a solid. LC–MS: m/z=392 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 6.55 (br. d, J=9.3 Hz, 1H), 5.77 (br. s, 1H), 4.83–5.03 ( m, 1H), 4.56 (m, 0.5H), 4.33–4.45 (m, 2.5H), 4.17 (m, 1H), 4.06 (m, 1H), 3 .35 (d, J=9.3 Hz, 1H), 3.04 (m, 1H), 2.38–2.44 (m, 1H), 1.68–2.20 (m, 7H), 1.36 (d, J=7.2 Hz, 3H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 172.8, 172.5, 171.2, 171.0, 167.3, 167.1, 80.4, 79.9, 76.7, 70 ,8, 70.8, 62.0, 60.3, 60.2, 47.2, 47.1, 43.1, 43.0, 29.8, 29.6, 22.9, 22.9 , 20.9 20.8, 20.17. (Note: there are multiple signals that are separated due to chirality in the lactone product).

Example 49

Synthesis of 2–(3–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–2,2 –dimethylpropyl)phenylacetate (49)

Step 1: Synthesis of ethyl 3-(2-methoxyphenyl)-2,2-dimethylpropanoate (49a).

A shaken solution of lithium diisopropylamide, 2.0 M in THF (26.6 mL, 53.2 mmol) was diluted with THF (100 mL), cooled to –78°C under argon, and shaken for 5 min. Add undiluted ethyl isobutyrate (6.68 mL, 49.7 mmol) dropwise over 15 min and shake the mixture at –78°C for 1 h. Add dropwise a solution of 1-(bromomethyl)-2-methoxybenzene (prepared per J. Am. Chem. Soc. 2013, 135, 11951) (12.0 g, 59.7 mmol) in THF (100 ml) for 30 min. The mixture was allowed to warm to room temperature and shaken for 20 hours. The reaction was quenched with brine (100 ml) and extracted with Et ₂ O (4×100 ml). The combined organic layers were dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (120 g column) using EtOAc/hexanes (0:1-5:95) as eluent to give product (49a) as a liquid (8.06 g, 68%). ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.18 (dt, J=1.8, 8.1 Hz, 1H), 7.06 (dd, J=1.5, 8.1 Hz, 1H), 6.82–6.87 (m, 2H), 4.12 (q, J=6.9 Hz, 2H), 3.77 (s, 3H), 2.92 (s, 2H), 1.26 (t, J=6.9 Hz, 3H), 1.15 (s, 6H).

Step 2: Synthesis of 3,3-dimethylchroman-2-one (49b).

Ethyl 3-(2-methoxyphenyl)-2,2-dimethylpropanoate (49a) (8.1 g, 34.2 mmol) was dissolved in DCM (200 ml) and cooled to 0 °C under argon. A solution of BBr ₃ (3.6 ml, 37.7 mmol) in DCM (100 ml) was added dropwise to the cold solution. The mixture was warmed to room temperature and shaken overnight (a solid formed during the reaction). The colored suspension was cooled in an ice-water bath and water (150 ml) was added to the mixture. The organic and aqueous layers were separated, and the aqueous layer was extracted with DCM (3×75 ml). The combined organic layers were dried (MgSO ₄ ; note: the solution became darker), filtered and concentrated in vacuo to give product (49b) (4.85 g, 80%) as an oil. This material was used without further purification. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.01–7.25 (m, 3H), 2.85 (s, 2H), 1.29 (s, 6H).

Step 3: Synthesis of 2-(3-hydroxy-2,2-dimethylpropyl)phenol (49c).

LiAlH ₄ (1.94 g, 51.1 mmol) was suspended in Et ₂ O (52.5 ml) under argon, and the mixture was cooled to 0°C in an ice-water bath, and a solution of 3.3 was added dropwise to the suspension –dimethylchroman-2-one (49b) (4.85 g, 27.5 mmol) in Et ₂ O (50 ml) for 30 min. The mixture was warmed to room temperature and shaken for 20 hours. The mixture was cooled in an ice-water bath and water (2 ml), after which 15% aqueous sodium hydroxide (2 ml) and water (6 ml) were added by slow addition. The mixture was warmed to room temperature and shaken for 15 minutes. Anhydrous MgSO ₄ was added to the suspension and the mixture was shaken for 15 minutes. The mixture was filtered and the filter cake was washed with Et ₂ O (3×50 ml). The filtrate was concentrated in vacuo to give product (49c) (4.34 g, 88%) as a solid. This material was used without further purification. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.15 (dt, J=8.1, 1.5 Hz, 1H), 7.04 (dd, J=7.5, 1.8 Hz, 1H), 6.82–7.01 (m, 2H), 3.22 (s, 2H), 2.61 (s, 2H), 0.98 (s, 6H).

Step 4: Synthesis of 2-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)phenol (49d).

A solution of 2-(3-hydroxy-2,2-dimethylpropyl)phenol (49c) (4.0 g, 22.2 mmol) and imidazole (3.8 g, 56.0 mmol) was dissolved in DMF (50 ml), and tert-butyldimethylsilyl chloride (4.0 g, 26.6 mmol) was added to the solution and shaken for 2 hours. The solvent was removed under high vacuum, and the residue was purified using silica gel column chromatography (40 g cartridge) with hexanes (5 :95–2:3) as eluent to give product (49d) as an oil (7.34 g, >100%). The compound was approximately 90% pure and was used directly in the next step without further purification. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.11 (dt, J=7.5, 1.8 Hz, 1H), 7.10 (dd, J=7.5, 1.8 Hz, 1H), 6.90 (dd, J=8.1, 1.5 Hz, 1H), 6.79 (dt, J=6.9, 0.9 Hz, 1H), 3.17 (s, 2H ), 2.57 (s, 2H), 0.97 (s, 9H), 0.92 (s, 6H), 0.13 (s, 6H).

Step 5: Synthesis of 2-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)phenylacetate (49e).

A solution of 2-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)phenol (49d) (about 90% purity; 2.5 g, 7.6 mmol) and Et ₃ N (2.3 g , 22.9 mmol) in THF (90 ml) was cooled to 0°C in an ice bath under argon. Acetyl chloride (0.65 mL, 9.2 mmol) was added dropwise to the mixture and the ice bath was removed after addition was complete. Allow the reaction mixture to warm to room temperature and shake for 2 hours. The suspension is filtered and the solid is washed with fresh THF (2×20 ml). The filtrate was concentrated in vacuo and the residue was loaded onto silica gel by dry injection, then purified by silica gel column chromatography (40 g cartridge) using 0–8% EtOAc/hexanes (0:1–8:92) as eluent to obtain product (49e) (2.16 g, 84%) as an oil. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.11–7.27 (m, 3H), 7.04 (d, J=7.5 Hz, 1H), 3.25 (s, 2H) , 2.51 (s, 2H), 2.30 (s, 3H), 0.93 (s, 9H), 0.81 (s, 6H), 0.06 (s, 6H).

Step 6: Synthesis of 2-(3-hydroxy-2,2-dimethylpropyl)phenylacetate and 3-(2-hydroxyphenyl)-2,2-dimethylpropyl acetate (49f).

Pyridine hydrofluoride (70%, 1.3 mL, 10.4 mmol) was added to a shaken solution of 2-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)phenylacetate (49e) (0.70 g, 2.1 mmol) and pyridine (2.5 ml, 31.2 mmol) in THF (25 ml) at room temperature under argon, and the mixture was shaken for 24 hours. The solvent was removed in vacuo (bath temperature set to 25°C ), and the residue was dissolved in EtOAc (100 ml), washed with brine (3 x 75 ml), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to obtain a mixture of the desired alcohol and 3-(2-hydroxyphenyl)-2, 2-dimethylpropyl acetate 65:35. NMR analysis showed the presence of both esters of product (49f). This material was used directly in the next step without further purification. ¹ H–NMR (300 MHz, CDCl ₃ ) of the desired product: δ 6.8–7.26 (m, 4H), 3.79 (s, 2H), 3.27 (s, 2H), 2.62 ( s, 2H), 2.53 (s, 2H), 2.33 (s, 3H), 2.13 (s, 3H), 0.974 (s, 6H), 0.90 (s, 6H).

Step 7: Synthesis of 2-(3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl)phenylacetate (49g).

A solution of sulfuryl chloride (172 µl, 2.1 mmol) in Et ₂ O (6.8 ml) was cooled to –78°C under argon. A solution of 2-(3-hydroxy-2,2-dimethylpropyl)phenylacetate (49f) (0.43 g, 1.9 mmol) and pyridine (172 μl, 2.1 mmol) in Et was added dropwise to the sulfuryl chloride solution via a cannula. ₂ O (2.0 ml). The mixture was shaken at –78°C for 10 min, then the flask was warmed to room temperature and shaken for 1.5 h (monitored by TLC 30% EtOAc/hexanes). The suspension was filtered through a 0.45 μm PTFE syringe filter and the syringe filter was washed with fresh Et ₂ O (10 ml) to obtain the product (49g). The filtrate was immediately used in the next step without further purification. The yield was quantified.

Step 8: Synthesis of 2–(3–((((2S,5R)–2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)– 2,2-dimethylpropyl)phenylacetate (49).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (0.44 g, 2.4 mmol) was dissolved in THF (22 ml) and 1,3-dimethyltetrahydropyrimidine-2(1H)-one (0.8 ml), and the resulting solution was cooled to –78°C under argon. A solution of NaHMDS, 1.0 M in THF (2.1 mL, 2.1 mmol) was added dropwise to the cooled solution and shaken for 10 min. A solution of 2-(3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl)phenylacetate (49g) (0.62 g, 1.9 mmol) in Et ₂ O from the previous reaction was quickly added to the reaction mixture. After 10 min, the reaction mixture was warmed to room temperature and shaken overnight. Brine (100 ml) was added to the reaction mixture and the aqueous and organic layers were separated. The aqueous layer was extracted with EtOAc (2×200 ml), and the combined organic layers were washed with brine (3×75 ml), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was dissolved in DMF (6 ml) and filtered through a 0.45 µm filter and then purified by preparative HPLC with 20–90% MeCN/water (no modifier) as eluent to give product (49) (0.18 g , 20%) in the form of a solid. LC–MS: m/z=470 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.23–7.29 (m, 1H), 7.18–7.20 (m, 2H), 7.08 (d, J=7.5 Hz, 1H), 6.52 (br. s, 1H), 5.78 (br. s, 1H), 4.55 (d, J=7.5 Hz, 1H), 4.19–4.22 (m, 2H), 4.05 (br. d, J=7.2 Hz, 1H), 3.30 (br. d, J=11.7 Hz, 1H), 2.99 (d, J= 11.7 Hz, 1H), 2.51–2.62 (m, 2H), 2.39–2.44 (m, 1H), 2.34 (s, 3H), 2.10–2.19 (m, 1H), 1.84–2.00 (m, 2H), 0.98 (d, J=3.0 Hz, 6H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 171.1, 169.6, 167.1, 149.6, 132.8, 129.1, 128.0, 125.8, 122.7, 83 ,4, 62.0, 60.3, 47.2, 38.1, 36.3, 23.7, 21.3, 20.8, 17.6.

Example (50)

Synthesis of 2–(3–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–2,2 –dimethylpropyl)phenyl pivalate (50)

Step 1: Synthesis of 2-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)phenyl pivalate (50a).

2-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)phenol (0.9 g, 3.1 mmol) and N, N-4-dimethylaminopyridine (0.93 g, 7.6 mmol ) was dissolved in THF (50 ml) under argon. Trimethylacetyl chloride (0.45 mL, 3.7 mmol) was added dropwise to the mixture at room temperature with immediate formation of a white solid, and addition was continued until a suspension was formed. The reaction mixture was shaken at room temperature for 2 hours and then filtered, and the filter cake was washed with THF (10 ml). The filtrate was loaded onto silica gel by dry injection (15 g) and purified by silica gel column chromatography using EtOAc/hexanes (0:1-6:94) as eluent to give product (50a) contaminated with about 3% starting material by data from NMR analysis. This material was used without further purification. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.27 (dd, J=7.2, 2.1 Hz, 1H), 7.21 (dt, J=7.5, 1.8 Hz, 1H), 7.15 (dt, J=7.8, 1.8 Hz, 1H), 6.97 (dd, J=8.1, 1.8 Hz, 1H), 3.25 (s, 2H ), 2.49 (s, 2H), 1.38 (s, 9H), 0.92 (s, 9H), 0.82 (s, 6H), 0.05 (s 6H).

Step 2: Synthesis of 2-(3-hydroxy-2,2-dimethylpropyl)phenyl pivalate (50b).

Pyridine hydrofluoride (70%, 1.3 mL, 10.4 mmol) was added to a shaken solution of 2-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)phenyl pivalate (50a) (0.70 g, 1.8 mmol) and pyridine (2.5 ml, 31.2 mmol) in THF (25 ml) at room temperature under argon, and the mixture was shaken for 24 hours. The solvent was removed in vacuo (bath temperature set to 25°C ), and the residue was dissolved in EtOAc (100 ml) and washed with brine (3×75 ml), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the desired product (50b) as an oil. This material was used directly in the next step without further purification. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.12–7.26 (m, 3H), 6.98 (m, 1H), 3.31 (s, 2H), 2.51 (s, 2H), 1.39 (s, 9H), 0.89 (s, 9H).

Step 3: Synthesis of 2-(3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl)phenyl pivalate (50c).

A solution of sulfuryl chloride (173 µl, 2.1 mmol) in Et ₂ O (7.5 ml) was cooled to –78°C under argon. A solution of 2-(3-hydroxy-2,2-dimethylpropyl)phenyl pivalate (50b) (0.47 g, 1.8 mmol) and pyridine (173 μL, 2.1 mmol) in Et was added dropwise to the sulfuryl chloride solution via a cannula. ₂ O (2.2 ml). The mixture was shaken at –78°C for 10 min and then the flask was warmed to room temperature and shaken for 1.5 h (monitored by TLC 30% EtOAc/hexanes). The suspension was filtered through a 0.45 µm PTFE syringe filter and the syringe filter was washed with fresh Et ₂ O to give product (50c). The filtrate was immediately used in the next step without further purification. The yield was quantified.

Step 4: Synthesis of 2–(3–((((2S,5R)–2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)– 2,2-dimethylpropyl)phenyl pivalate (50).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (0.41 g, 2.2 mmol) was dissolved in THF (23 ml) and 1,3-dimethyltetrahydropyrimidine-2(1H)-one (0.8 ml), and the resulting solution was cooled to –78°C under argon. A solution of NaHMDS, 1.0 M in THF (2.2 mL, 2.2 mmol) was added dropwise to the cooled solution and the solution was shaken for 10 min. A solution of 2-(3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl)phenyl pivalate (50c) (0.65 g, 1.8 mmol) in Et ₂ O from the previous reaction was quickly added to the reaction mixture. After 10 min, the reaction mixture was warmed to room temperature and shaken overnight. Brine (100 ml) was added to the reaction mixture and the aqueous and organic layers were separated. The aqueous layer was extracted with EtOAc (2×200 ml), and the combined organic layers were washed with brine (3×75 ml), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was dissolved in DMF (6 mL) and filtered through a 0.45 µm filter and then purified by preparative HPLC to give product (50) (0.21 g, 23%) as a solid. LC–MS: m/z=512 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.12–7.28 (m, 3H), 6.99 (d, J=7.5 Hz, 1H), 6.50 (br. s, 1H), 5.78 (br. s, 1H), 4.57 (d, J=9.3 Hz, 1H), 4.26 (d, J=8.7 Hz, 1H), 4.17 ( br. s, 1H), 4.04 (d, J=6.3 Hz, 1H), 3.28 (br. d, J=11.7 Hz, 1H), 3.03 (d, J=11 .7 Hz, 1H), 2.52–2.62 (m, 2H), 2.39–2.50 (m, 1H), 2.10–2.20 (m, 1H), 1.78– 1.98 (m, 2H), 1.38 (s, 9H), 0.97 (d, J=4.2 Hz, 6H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 177.2, 171.1, 167.0, 150.1, 132.5, 129.2, 127.9, 125.6, 122.6, 83 ,7, 61.9, 60.2, 47.2, 39.3, 37.5, 36.2, 27.4, 23.5, 20.8, 17.6.

Example 51

Synthesis of S–(4–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–3,3 –dimethylbutyl)ethanethioate (51)

Step 1: Synthesis of S–(4–((chlorosulfonyl)oxy)–3,3-dimethylbutyl)ethanethioate (51a).

A solution of freshly distilled sulfuryl chloride (271 µl, 3.7 mmol) in Et ₂ O (5 ml) was cooled to –78°C under argon. A solution of S-(4-hydroxy-3,3-dimethylbutyl)ethanethioate (prepared according to Chem. Commun. 2011, 47, 2038) (500 mg, 2.8 mmol) and pyridine ( 267 µl, 3.3 mmol) in Et ₂ O (3 ml). The flask was washed with diethyl ether (2×5 ml), and the wash was also added to the reaction mixture. The mixture was shaken at –78°C for 1 hour and allowed to warm to room temperature and shaken at room temperature for an additional 20 minutes. The precipitate was filtered (quickly) and the filter cake was washed with Et ₂ O (12 ml). The filtrate was concentrated in vacuo at room temperature to give the title compound (51a) as an oil, which was immediately used for the next step without further purification.

Step 2: Synthesis of S–(4–((((2S,5R)–2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)– 3,3-dimethylbutyl)ethanethioate (51).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (430 mg, 2.3 mmol) was dissolved in pyridine (8 ml) and cooled up to 0°C in an argon atmosphere. A solution of S–(4–((chlorosulfonyl)oxy)-3,3-dimethylbutyl)ethanethioate (51a) (0.75 g, 2.7 mmol) in THF (4 ml) was added to the reaction mixture at 0°C. The resulting mixture was shaken for 1 hour and the solvents were removed under high vacuum at room temperature. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-9:1) to give product (50) as a solid. LCMS: m/z=424.2 [M+1] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 6.47 (br. s, 1H), 5.61 (br. s, 1H), 4.53 (d, J=8.7 Hz, 1H) , 4.24 (d, J=9.0 Hz, 1H), 4.17 (br. s, 1H), 4.05–4.03 (m, 1H), 3.39–3.30 (m , 1H), 3.01 (d, J=9.0 Hz, 1H), 2.85–2.80 (m, 2H), 2.48–2.40 (m, 1H), 2.32 ( s, 3H), 2.20–2.18 (m, 1H), 2.01–1.80 (m, 2H), 1.03 (s, 6H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 195.4, 170.9, 166.9, 83.1, 61.8, 60.0, 47.1, 38.4, 34.8, 30 ,5, 23.9, 23.4, 23.2, 20.6, 17.4.

Example 52

Synthesis of S–(5–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–4,4 –dimethylpentyl) ethanethiate (52)

Step 1: Synthesis of 5-bromo-2,2-dimethylpentan-1-ol (52a).

DCM (18 mL) was added to LiBH ₄ (0.66 g, 30.4 mmol), followed by dropwise addition of anhydrous MeOH (1.2 mL, 30.4 mmol) over 20 min under argon. After the evolution of _H2 gas ceased, a solution of ethyl 5-bromo-2,2-dimethylpentanoate (prepared according to PCT Application Publication No. 2011046771) (4.5 g, 19.0 mmol) in DCM (10 ml) was added dropwise over 20 min. . The reaction mixture was refluxed for 16 hours, cooled to room temperature and carefully hydrolyzed with saturated NH ₄ Cl solution (30 ml). The suspension was extracted with DCM (3×50 ml). The combined organic layers were washed with 1N. HCl (26 ml) and brine (40 ml), dried and concentrated in vacuo to give product (52a) (3.61 g, 97%) as an oil. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 3.39 (t, J=6.9 Hz, 2H), 3.24 (s, 2 H), 1.90–1.76 (m, 2 H), 1.48 (br. s, 1H), 1.41–1.36 (m, 2H), 0.88 (s, 6H).

Step 2: Synthesis of S-(5-hydroxy-4,4-dimethylpentyl)ethanethioate (52b).

A solution of 5-bromo-2,2-dimethylpentan-1-ol (52a) (2.0 g, 10.3 mmol) and potassium thioacetate (2.34 g, 20.5 mmol) in acetone (22 ml) was shaken in inert atmosphere at room temperature for 23 hours. After removal of solvents in vacuo at room temperature, the residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1–2:3) as eluent to give product (52b) (1.2 g, 61%) as an oil. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 3.31 (s, 2H), 2.85 (t, J=7.8 Hz, 2H), 2.32 (s, 3 H), 1, 62–1.48 (m, 2H), 1.32–1.21 (m, 2H), 0.86 (s, 6H).

Step 3: Synthesis of S–(5–((chlorosulfonyl)oxy)–4,4-dimethylpentyl)ethanethioate (52c).

A solution of freshly distilled sulfuryl chloride (379 µl, 5.2 mmol) in Et ₂ O (8 ml) was cooled to –78°C under argon. A solution of S-(5-hydroxy-4,4-dimethylpentyl)ethanethioate (52b) (700 mg, 3.6 mmol) and pyridine (374 μL, 4.6 mmol) in Et was added dropwise to the sulfuryl chloride solution over 5 min. ₂ O (4 ml). The mixture was shaken at –78°C for 1 hour and then allowed to warm to room temperature. The precipitate was filtered (quickly) and the filter cake was washed with Et ₂ O (10 ml). The filtrate was concentrated in vacuo at room temperature to give the title compound (52c) as an oil, which was immediately used for the next step without further purification.

Step 4: Synthesis of S–(((((2S,5R)–2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)– 4,4-dimethylpentyl)ethanethioate (52).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (600 mg, 3.2 mmol) was dissolved in pyridine (9 ml) and cooled up to 0°C in an argon atmosphere. A solution of S-(5-((chlorosulfonyl)oxy)-4,4-dimethylpentyl)ethanethioate (52c) (857 mg, 3.0 mmol) in THF (5 ml) was added to the reaction mixture at 0°C. The resulting mixture was shaken for 1 hour and the solvents were removed under high vacuum at room temperature. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-9:1) to give product (52) (70 mg, 5%) as a solid. LC–MS: m/z=438.2 [MH] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 6.48 (br. s, 1H), 5.56 (br. s, 1H), 4.49 (d, J=9.0 Hz, 1H) , 4.19 (d, J=9.6 Hz, 1H), 4.17 (br. s, 1H), 4.05–4.03 (m, 1H), 3.38–3.30 (m , 1H), 3.01 (d, J=9.0 Hz, 1H), 2.85 (t, J=6.9 Hz, 2H), 2.46–2.40 (m, 1H), 2 .32 (s, 3H), 2.21–2.18 (m, 1H), 1.98–1.82 (m, 2H), 1.40–1.33 (m, 2H), 0.97 (s, 3H), 0.96 (s, 3H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 175.7, 170.8, 166.9, 83.6, 61.8, 60.0, 47.1, 37.4, 34.3, 30 ,6, 29.4, 23.9, 23.6, 23.4, 20.6, 17.4.

Example 53

Synthesis of S–(3–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–2,2 –dimethylpropyl) ethanethiate (53)

Step 1: Synthesis of S-(3-hydroxy-2,2-dimethylpropyl)ethanethioate (53a).

Potassium thioacetate (4.1 g, 35.8 mmol) was dissolved in DMF (20 ml) under argon. 3-Hydroxy-2,2-dimethylpropyl 4-methylbenzenesulfonate (obtained from PCT Application Publication No. 2012165648) (4.2 g, 16.3 mmol) was added and the mixture was shaken at 80°C for 2.5 hours. After cooling brine (100 ml) was added and the mixture was extracted with Et ₂ O (3×100 ml). The combined organic layers were washed with brine (5×50 ml), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo (residual DMF was removed using high vacuum). The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-15:85) to give product (53a) (1.06 g, 40%) as an oil. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 3.23 (br. s, 2H), 2.89 (s, 2H), 2.62 (br. s, 1H), 2.37 (s, 3H), 0.94 (s, 6H).

Step 2: Synthesis of S–(3–((chlorosulfonyl)oxy)–2,2-dimethylpropyl)ethanethioate (53b).

A solution of freshly distilled sulfuryl chloride (283 µl, 3.9 mmol) in Et ₂ O (4 ml) was cooled to –78°C under argon. A solution of S-(3-hydroxy-2,2-dimethylpropyl)ethanethioate (53a) (520 mg, 3.1 mmol) and pyridine (327 μL, 4.0 mmol) in Et was added dropwise to the sulfuryl chloride solution over 5 min. ₂ O (6 ml). The mixture was shaken at –78°C for 1 hour, then allowed to warm to room temperature. The precipitate was filtered (quickly) and the filter cake was washed with Et ₂ O (10 ml). The filtrate was concentrated in vacuo at room temperature to give the title compound (53b) as an oil, which was immediately used for the next step without further purification.

Step 3: Synthesis of S–(3–((((2S,5R)–2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)– 2,2-dimethylpropyl)ethanethioate (53).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (600 mg, 3.2 mmol) was dissolved in pyridine (10 ml) and cooled up to 0°C in an argon atmosphere. A solution of S-(5-((chlorosulfonyl)oxy)-4,4-dimethylpentyl)ethanethioate (53b) (800 mg, 3.1 mmol) in THF (6 ml) was added to the reaction mixture at 0°C. The resulting mixture was shaken for 2 hours and the solvents were removed under high vacuum at room temperature. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-7:3) to give product (53) (90 mg, 7%) as a solid. LCMS: m/z=410.1 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 6.47 (br. s, 1H), 5.56 (br. s, 1H), 4.51 (d, J=9.3 Hz, 1H) , 4.25 (d, J=9.6 Hz, 1H), 4.17 (br. s, 1H), 4.06–4.03 (m, 1H), 3.36–3.24 (m , 1H), 3.06–2.88 (m, 2H), 2.51–2.41 (m, 1H), 2.36 (s, 3H), 2.21–2.08 (m, 1H ), 1.98–1.82 (m, 2H), 1.36–1.22 (m, 1H), 1.04 (s, 3H), 1.02 (s, 3H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 194.7, 170.8, 166.9, 81.9, 61.8, 60.1, 47.1, 36.7, 35.6, 30 ,6, 23.2, 22.9, 20.6, 17.4.

Example 54

Synthesis of 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl 2 ,6-dimethylbenzoate (54)

Step 1: Synthesis of 3-hydroxy-2,2-dimethylpropyl 2,6-dimethylbenzoate (54a).

2,6-Dimethylbenzoyl chloride ( 1.2 ml, 8.1 mmol), pyridine (1.1 ml, 13.7 mmol) and N, N-4-dimethylaminopyridine (99 mg, 0.8 mmol). The reaction mixture was allowed to gradually warm to room temperature and the mixture was shaken overnight. The reaction was quenched by adding 1 N. HCl and the mixture was extracted with DCM (twice). The combined organic extracts were washed with saturated aqueous NaHCO ₃ and brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (1:9-2:3) to give product (54a) (1.5 g, 78%) as an oil. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.21 (m, 1H), 7.04 (m, 2H), 4.18 (s, 2H), 3.41 (s, 2H), 2 .32 (s, 6H), 2.20 (br. s, 1H), 0.99 (s, 6H).

Step 2: Synthesis of 3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl 2,6-dimethylbenzoate (54b).

A solution of freshly distilled sulfuryl chloride (0.25 ml, 3.9 mmol) in Et ₂ O (6 ml) was cooled to –78°C under argon. A solution of 3-hydroxy-2,2-dimethylpropyl 2,6-dimethylbenzoate (54a) (500 mg, 2.1 mmol) and pyridine (0.26 ml, 3.3 mmol) was added dropwise to the sulfuryl chloride solution over 5 min. in Et ₂ O (6 ml). The mixture was shaken at –78°C for 1 hour and then allowed to warm to room temperature. The precipitate was filtered (quickly) and the filter cake was washed with Et ₂ O (12 ml). The filtrate was concentrated in vacuo at room temperature to give the title compound (54b) as an oil, which was immediately used in the next step without further purification.

Step 3: Synthesis of 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2 –dimethylpropyl 2,6-dimethylbenzoate (54).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (420 mg, 2.3 mmol) was dissolved in THF (12 ml) and 1 ,3-dimethyltetrahydropyrimidine-2(1H)-one (0.7 ml), and the resulting solution was cooled to –78°C under argon. A solution of NaHMDS, 1.0 M in THF (2.3 mL, 2.3 mmol) was added dropwise to the cooled solution and shaken for 10 min. A solution of 3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl 2,6-dimethylbenzoate (54b) (660 mg, 2.0 mmol) in THF (8 mL) was quickly added to the reaction mixture. After shaking at –78°C for 10 minutes, allow the mixture to warm to room temperature and shake for 2 hours. EtOAc (400 ml), saturated aq. NaHCO ₃ (40 ml) and water (40 ml) were added. The organic layer was separated and washed with saturated aqueous NaHCO ₃ (60 ml), H ₂ O (3×50 ml), brine (60 ml), and then dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-7:3) to give the product (180 mg, 19%) as a solid. LC–MS: m/z=484.01 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.19 (m, 1H), 7.04 (m, 2H), 6.47 (s, 1H), 5.55 (s, 1H), 4 .58 (d, J=9.3 Hz, 1H), 4.39 (d, J=9.0 Hz, 1H), 4.22 (d, J=11.1 Hz, 1H), 4.16 (m, 1H), 4.11 (d, J=11.1 Hz, 1H), 4.04–4.02 (m, 1H), 3.33–3.29 (m, 1H), 3, 01–2.98 (m, 1H), 2.45–2.40 (m, 1H), 2.32 (s, 6H), 2.20–2.08 (m, 1H), 1.93– 1.76 (m, 2H), 1.10 (s, 6H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 170.8, 169.9, 166.9, 134.9, 133.6, 129.4, 127.5, 80.2, 69.1, 61 ,8, 60.1, 47.1, 35.2, 21.4, 21.3, 20.7, 19.8, 17.4.

Example 55

Synthesis of 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl adamantane –1-carboxylate (55)

Step 1: Synthesis of 3-hydroxy-2,2-dimethylpropyl (3r,5r,7r)-adamantane-1-carboxylate (55a).

1-adamantanecarbonyl was added to a shaken solution of 2,2-dimethylpropane-1,3-diol (2.5 g, 24.3 mmol) in DCM (60 ml) at approximately 0°C (ice bath) under argon. chloride (1.36 g, 6.9 mmol), pyridine (1.1 ml, 13.7 mmol) and N,N-4-dimethylaminopyridine (99 mg, 0.8 mmol). The reaction mixture was allowed to gradually warm to room temperature and the mixture was shaken overnight. The reaction was quenched by adding 1 N. HCl and the mixture was extracted with DCM (twice). The combined organic extracts were washed with saturated aqueous NaHCO ₃ and brine, dried (MgSO ₄ ), filtered and concentrated in vacuo to give product (55a) (1.82 g, 100%) as an oil. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 3.91 (s, 2H), 3.25 (s, 2H), 2.01 (br. s, 3H), 1.89 (br. s, 6H), 1.71 (br. s, 7H), 0.91 (s, 6H).

Step 2: Synthesis of 3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl (3r,5r,7r)-adamantane-1-carboxylate (55b).

A solution of freshly distilled sulfuryl chloride (266 µl, 3.3 mmol) in Et ₂ O (4 ml) was cooled to –78°C under argon. A solution of 3-hydroxy-2,2-dimethylpropyl-adamantane-1-carboxylate (55a) (600 mg, 2.2 mmol) and pyridine (0.28 ml, 3.5 mmol) was added dropwise to the sulfuryl chloride solution over 5 min. ) in Et ₂ O (4 ml). The flask was washed with Et ₂ O (5 ml), and the wash was also added to the reaction mixture. The mixture was shaken at –78°C for 1 hour and then allowed to warm to room temperature. The precipitate was filtered (quickly) and the filter cake was washed with Et ₂ O (12 ml). The filtrate was concentrated in vacuo at room temperature to give the title compound (55b) as an oil, which was immediately used in the next step without further purification.

Step 3: Synthesis of 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2 –dimethylpropyl adamantane-1-carboxylate (55).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (442 mg, 2.4 mmol) was dissolved in THF (14 ml) and 1 ,3-dimethyltetrahydropyrimidine-2(1H)-one (0.8 ml), and the resulting solution was cooled to –78°C under argon. A solution of NaHMDS, 1.0 M in THF (2.6 mL, 2.6 mmol) was added dropwise to the cooled solution and shaken for 10 min. A solution of 3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl-adamantane-1-carboxylate (55b) (750 mg, 2.1 mmol) in THF (8 ml) was quickly added to the reaction mixture. After shaking at –78°C for 10 minutes, allow the mixture to warm to room temperature and shake for 2 hours. EtOAc (400 ml) and saturated aqueous NaHCO ₃ (40 ml) and H ₂ O (40 ml) were added. The organic layer was separated and washed with saturated aqueous NaHCO ₃ (60 ml), H ₂ O (3×50 ml), brine (60 ml), then dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-7:3) to give product (55) (180 mg, 17%) as a solid. LC–MS: m/z=514.12 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 6.48 (s, 1H), 5.55 (s, 1H), 4.58 (d, J=8.7 Hz, 1H), 4.36 (d, J=9.3 Hz, 1H), 4.17 (m, 1H), 4.05 (d, J=6.9 Hz, 1H), 3.93 (d, J=11.1 Hz , 1H), 3.84 (d, J=11.1 Hz, 1H), 3.34–3.32 (m, 1H), 3.03–2.99 (m, 1H), 2.49– 2.41 (m, 1H), 2.20–2.14 (m, 1H), 2.04 (br. s, 3H), 1.91–1.8 (m, 8H), 1.87 ( br. s, 6H), 1.03 (s, 7H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 178.0, 171.7, 167.7, 81.3, 68.7, 62.6, 60.8, 47.8, 41.6, 39 ,5, 37.2, 36.2, 28.6, 22.0, 21.9, 21.4, 18.1.

Example 56

Synthesis of diethyl 2–((((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)methyl)–2– methyl malonate (56)

Step 1: Synthesis of diethyl 2-(hydroxymethyl)-2-methylmalonate (56a).

Diethyl 2-methylmalonate (4.5 mL, 26.3 mmol) was added to a suspension of paraformaldehyde (1.3 g, 43.3 mmol) and K ₂ CO ₃ (11 g, 79 mmol) in EtOH (150 ml). The mixture was shaken at room temperature for 17 hours, then filtered through a pad of Celite® and the filter cake washed with EtOH (2 x 30 ml). The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-3:2) to give product (56a) (4.0 g, 74%) as an oil. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 4.22 (q, J=6.9 Hz, 4H), 3.83 (d, J=6.9 Hz, 2H), 2.90 (t , J=7.8 Hz, 1H), 1.42 (s, 3H), 1.26 (t, J=6.9 Hz, 6H).

Step 2: Synthesis of diethyl 2-(((chlorosulfonyl)oxy)methyl)-2-methylmalonate (56b).

A solution of freshly distilled sulfuryl chloride (248 µl, 3.0 mmol) in Et ₂ O (8 ml) was cooled to –78°C under argon. A solution of diethyl 2-(hydroxymethyl)-2-methylmalonate (56a) (500 mg, 2.4 mmol) and pyridine (0.26 ml, 3.2 mmol) in Et ₂ O was added dropwise to the sulfuryl chloride solution over 5 min. (4 ml). The flask was washed with Et ₂ O (5 ml), and the wash was also added to the reaction mixture. The mixture was shaken at –78°C for 1 hour and then allowed to warm to room temperature. The precipitate was filtered (quickly) and the filter cake was washed with Et ₂ O (12 ml). The filtrate was concentrated in vacuo at room temperature to give the title compound (56b) as an oil, which was immediately used in the next step without further purification.

Step 3: Synthesis of diethyl 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl) –2-methylmalonate (56).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (390 mg, 2.1 mmol) was dissolved in THF (10 ml) and 1 ,3-dimethyltetrahydropyrimidine-2(1H)-one (0.8 ml), and the resulting solution was cooled to –78°C under argon. A solution of NaHMDS, 1.0 M in THF (2.2 mL, 2.2 mmol) was added dropwise to the cooled solution and shaken for 10 min. A solution of diethyl 2-(((chlorosulfonyl)oxy)methyl)-2-methylmalonate (56b) (638 mg, 2.1 mmol) in THF (8 ml) was quickly added to the reaction mixture. After shaking at –78°C for 10 minutes, allow the mixture to warm to room temperature and shake for 2 hours. EtOAc (400 ml) and saturated aqueous NaHCO ₃ (40 ml) and H ₂ O (40 ml) were added. The organic layer was separated and washed with saturated aqueous NaHCO ₃ (60 ml), H ₂ O (3×50 ml), brine (60 ml), then dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-9:1) to give product (56) (166 mg, 17%) as a solid. LC–MS: m/z=452.03 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 6.49 (s, 1H), 5.58 (s, 1H), 5.02 (d, J=8.7 Hz, 1H), 4.93 (d, J=9.3 Hz, 1H), 4.24 (q, J=7.2 Hz, 4H), 4.17 (m, 1H), 4.05 (d, J=6.9 Hz , 1H), 3.35 (m, 1H), 3.01 (d, J=11.1 Hz, 1H), 2.49–2.41 (m, 1H), 2.20–2.14 ( m, 1H), 1.98–1.81 (m, 2H), 1.56 (s, 3H), 1.28 (t, J=7.2 Hz, 6H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 171.1, 168.6, 168.5, 167.1, 76.5, 62.3, 61.9, 60.2, 53.9, 47 ,1, 20.8, 17.8, 17.5, 14.0.

Example 57

Synthesis of propyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (57)

Step 1: Synthesis of propyl 3-hydroxy-2,2-dimethylpropanoate (57a).

A mixture of 3-hydroxy-2,2-dimethylpropanoic acid (1.15 g, 9.7 mmol), and 1-propanol (15 ml) and concentrated H ₂ SO ₄ (70 μl, 1.3 mmol) was loaded into 20 ml The microwave vessel was shaken at room temperature and then heated in a microwave reactor at 80°C for 2 hours, and shaken at room temperature overnight. When the desired product was identified by TLC (EtOAc/hexanes; 3:7), the mixture was concentrated in vacuo (40°C) and diluted with EtOAc (80 ml) and H ₂ O (30 ml). The organic layer was washed with H ₂ O (twice) and brine, then dried (Na ₂ SO ₄ ), filtered and concentrated to give product (57a) (1.18 g, 76%) as an oil. The material was used directly in the next step without purification. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 4.07 (t, J=6.6 Hz, 2H), 3.55 (s, 2H), 2.42 (br. s, 1H), 1 .70–1.61 (m, 2H), 1.19 (s, 6H), 0.95 (t, J=7.5 Hz, 3H).

Step 2: Synthesis of propyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (57b).

A solution of freshly distilled sulfuryl chloride (194 µl, 2.7 mmol) in Et ₂ O (1.0 ml) was cooled to –78°C under argon. A solution of propyl 3-hydroxy-2,2-dimethylpropanoate (57a) (0.42 g, 2.6 mmol) and pyridine (215 μl, 2.7 mmol) in Et ₂ O was added dropwise to the sulfuryl chloride solution over 5 min. The flask was washed with Et ₂ O (3 x 1 ml), and the wash was added to the reaction mixture. The mixture was shaken at –78°C for 5 minutes and then allowed to warm to room temperature and shaken for 1 hour. The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (57b) (0.56 g, 83%) in the form of an oil, which was immediately used in the next step without further purification. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 4.50 (s, 2H), 4.10 (t, J=6.6 Hz, 2H), 1.72–1.64 (m, 2H) , 1.32 (s, 6H), 0.95 (t, J=7.2 Hz, 3H).

Step 3: Synthesis of propyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2, 2-dimethylpropanoate (57).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (0.22 g, 1.2 mmol) was dissolved in THF (5.5 ml) and HMPA (1.0 ml), and the resulting stirred solution was cooled to –78°C under argon. A solution of NaHMDS, 1.0 M in THF (1.5 mL, 1.5 mmol) was added to the mixture, and then a solution of propyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (57b) was quickly added to the reaction mixture. (0.40 g, 1.5 mmol) in THF (2 x 1 ml). After 10 minutes of shaking at –78°C, the mixture was allowed to warm to room temperature and shaken for 1 hour. The mixture was quenched with H ₂ O and diluted with EtOAc (40 ml). The aqueous and organic layers were separated, and the organic layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (3:7-1:0) to give the desired product (57) (190 mg, 39%) as a solid. LCMS: m/z=408.1 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 6.47 (br. s, 1H), 5.57 (br. s, 1H), 4.66 (dd, J=9.0, 35.1 Hz, 2H), 4.17–4.04 (m, 4H), 3.32 (d, J=12.3 Hz, 1H), 3.02 (d, J=10.8 Hz, 1H), 2.46–2.41 (m, 1H), 2.14–2.13 (m, 1H), 1.99–1.83 (m, 2H), 1.71–1.66 (m, 2H ), 1.29 (s, 3H), 1.28 (s, 3H), 0.95 (t, J=7.6 Hz, 3H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ174.1, 170.9, 166.8, 80.3, 66.8, 61.8, 60.1, 47.1, 42.9, 22, 1, 21.9, 21.6, 20.7, 17.4, 10.3.

Example (58)

Synthesis of butyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (58)

Step 1: Synthesis of butyl 3-hydroxy-2,2-dimethylpropanoate (58a).

A mixture of 3-hydroxy-2,2-dimethylpropanoic acid (1.15 g, 9.7 mmol), and 1-butanol (15 ml) and concentrated H ₂ SO ₄ (70 μl, 1.3 mmol) was loaded into 20 ml Microwave vessel was shaken at room temperature, then heated in a microwave reactor at 80°C for 2 hours, then shaken at room temperature overnight. When the desired product was identified by TLC (EtOAc/hexanes; 3:7), the mixture was concentrated in vacuo (40°C; co-evaporated with toluene×3) and diluted with EtOAc (80 ml) and H ₂ O (30 ml). The organic layer was washed with H ₂ O (twice) and brine, then dried (Na ₂ SO ₄ ), filtered and concentrated to give product (58a) (1.24 g, 81%) as an oil. The material was used directly in the next step without purification. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 4.11 (t, J=6.5 Hz, 2H), 3.55 (s, 2H), 2.42 (br. s, 1H), 1 .65–1.58 (m, 2H), 1.43–1.35 (m, 2H), 1.19 (s, 6H), 0.94 (t, J=7.5 Hz, 3H).

Step 2: Synthesis of butyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (58b).

A solution of freshly distilled sulfuryl chloride (198 µl, 2.7 mmol) in Et ₂ O (1.0 ml) was cooled to –78°C under argon. A solution of propyl 3-hydroxy-2,2-dimethylpropanoate (58a) (0.47 g, 2.7 mmol) and pyridine (219 μl, 2.7 mmol) in Et ₂ O was added dropwise to the sulfuryl chloride solution over 5 min. The flask was washed with Et ₂ O (3×1 ml), which was added to the reaction mixture. The mixture was shaken at -78°C for 5 minutes and then allowed to warm to room temperature and shaken for 1 hour. The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (58b) (0.52 g, 72%) in the form of an oil, which was immediately used in the next step without further purification. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 4.50 (s, 2H), 4.14 (t, J=6.8 Hz, 2H), 1.66–1.59 (m, 2H) , 1.43–1.35 (m, 2H), 1.32 (s, 6H), 0.94 (t, J=7.4 Hz, 3H).

Step 3: Synthesis of butyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2, 2-dimethylpropanoate (58).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (0.22 g, 1.2 mmol) was dissolved in THF (5 ml) and HMPA (1 ml), and the resulting stirred solution was cooled to –78°C under argon. A solution of NaHMDS, 1.0 M in THF (1.5 mL, 1.5 mmol) was added and the mixture was shaken for 10 min. A solution of butyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (58b) (0.41 g, 1.5 mmol) in THF (5×1 ml) was quickly added to the reaction mixture. After 10 minutes of shaking at –78°C, the mixture was allowed to warm to room temperature and shaken for 1 hour. The mixture was quenched with H ₂ O and diluted with EtOAc (40 ml). The aqueous and organic layers were separated, and the organic layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was dissolved in DMF and purified by preparative HPLC to give the desired product (58) (70 mg, 14%) as a solid. LCMS: m/z=422.2 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 6.47 (br. s, 1H), 5.67 (br. s, 1H), 4.65 (dd, J=34.8, 9.0 Hz, 2H), 4.16–4.04 (m, 4H), 3.32 (d, J=11.7 Hz, 1H), 3.02 (d, J=12.3 Hz, 1H), 2.47–2.40 (m, 1H), 2.18–2.13 (m, 1H), 2.01–1.80 (m, 2H), 1.67–1.58 (m, 3H ), 1.45–1.32 (m, 2H), 1.28 (s, 3H), 1.27 (s, 3H), 0.94 (t, J=7.4 Hz, 3H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 174.1, 170.8, 166.8, 80.3, 65.1, 61.8, 60.1, 47.1, 42.8, 30 .5, 22.1, 21.6, 20.7, 19.0, 17.4, 13.6.

Example 59

Synthesis of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1 ]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (59)

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (0.22 g, 1.2 mmol) was dissolved in THF (10 ml) and HMPA (0.5 ml), and the resulting stirred solution was cooled to –78°C under argon. A solution of NaHMDS, 1.0 M in THF (1.3 mL, 1.3 mmol) was added to the mixture and the mixture was shaken for 10 minutes. A solution of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (0.42 g, 1.3 mmol) was quickly added to the reaction mixture ) in THF (5×1 ml). After 10 minutes of shaking at –78°C, the mixture was allowed to warm to room temperature and shaken for 1 hour. The mixture was cooled to 0°C, quenched with H ₂ O and diluted with EtOAc (40 ml). The aqueous and organic layers were separated, and the organic layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by preparative HPLC to give the desired product (59) (189 mg, 34%) as a solid. LCMS: m/z=478.1 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 6.68 (br. s, 1H), 5.74 (br. s, 1H), 4.95–4.79 (m, 3H), 4, 50 (d, J=9.3 Hz, 1H), 4.14 (br. s, 1H), 4.03 (d, J=7.2 Hz, 1H), 3.32 (d, J=12 .3 Hz, 1H), 3.02 (d, J=12.3 Hz, 1H), 2.45–2.39 (m, 1H), 2.17–2.09 (m, 4H), 1 .98–1.79 (m, 2H), 1.30 (s, 3H), 1.29 (s, 3H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 177.6, 171.0, 167.0, 152.2, 140.5, 133.2, 80.0, 61.8, 60.2, 54 ,4, 47.0, 43.0, 21.8, 21.7, 20.7, 17.5, 9.3.

Example 60

Synthesis of 4-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl pivalate ( 60)

Step 1: Synthesis of 4-hydroxy-3,3-dimethylbutyl pivalate (60a).

Trimethylacetyl chloride (0.89 mL) was added to a shaken solution of 2,2-dimethylbutane-1,4-diol (0.86 g, 7.3 mmol) in DCM (9 mL) at approximately 0°C (ice bath) under argon. , 7.3 mmol), Et ₃ N (1.17 ml, 14.5 mmol) and N, N-4-dimethylaminopyridine (catalytic amount). The reaction mixture was allowed to gradually warm to room temperature and the mixture was shaken overnight. The mixture was quenched by adding 1 N. HCl (50 ml). The organic and aqueous layers were separated, and the aqueous layer was extracted with DCM (twice). The combined organic layers were washed with saturated NaHCO ₃ and brine, then dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-3:7) to give the desired product (60a) (0.42 g, 28%). ¹ H–NMR (300 MHz, CDCl ₃ ): δ 4.13 (t, J=7.1 Hz, 2H), 3.35 (s, 2H), 1.61 (q, J=6.9 Hz , 2H), 1.19 (s, 9H), 0.93 (s, 6H).

Step 2: Synthesis of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl pivalate (60b).

A solution of freshly distilled sulfuryl chloride (153 µl, 2.1 mmol) in Et ₂ O (4.5 ml) was cooled to –78°C under argon. A solution of 4-hydroxy-3,3-dimethylbutyl pivalate (60a) (0.42 g, 2.1 mmol) and pyridine (203 μl, 2.5 mmol) in Et ₂ O ( 3 ml). Allow the mixture to warm to room temperature and shake for 30 minutes. The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (60b) as an oil, which was immediately used in the next step without further purification. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 4.23 (s, 2H), 4.13 (t, J=6.8 Hz, 2H), 1.71 (t, J=6.6 Hz , 2H), 1.19 (s, 9H), 1.08 (s, 6H).

Step 3: Synthesis of 4–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–3,3 –dimethylbutyl pivalate (60).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (0.41 g, 2.2 mmol) was dissolved in THF (18.5 ml) and HMPA (0.9 ml), and the resulting stirred solution was cooled to –78°C under argon. A solution of NaHMDS, 1.0 M in THF (2.2 mL, 2.2 mmol) was added to the mixture and the mixture was shaken for 10 minutes. A solution of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl pivalate (60b) (0.73 g, 2.4 mmol) in THF (20 ml) was quickly added to the reaction mixture. After 10 minutes of shaking at –78°C, the mixture was allowed to warm to room temperature and shaken for 16 hours. The mixture was quenched with H ₂ O and diluted with EtOAc. The aqueous and organic layers were separated, and the organic layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-1:0) to give product (60) (176 mg) as a solid. LCMS: m/z=450.15 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 6.49 (br. s, 1H), 5.59 (br. s, 1H), 4.55 (d, J=9.3 Hz, 1H) , 4.26–4.04 (m, 5H), 3.34 (d, J=11.7 Hz, 1H), 3.02 (d, J=12.3 Hz, 1H), 2.45– 2.41 (m, 1H), 2.19–2.15 (m, 1H), 2.01–1.85 (m, 2H), 1.69 (t, J=6.8 Hz, 2H) , 1.19 (s, 9H), 1.05 (s, 6H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ178.6, 171.0, 167.0, 83.8, 61.9, 60.8, 60.2, 47.2, 38.7, 36, 9, 34.0, 27.2, 24.0, 23.7, 20.8, 17.5.

Example 61

Synthesis of ethyl 2–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)methyl)–2– ethyl butanoate (61)

Step 1: Synthesis of ethyl 2-(((chlorosulfonyl)oxy)methyl)-2-ethylbutanoate (61a).

A solution of freshly distilled sulfuryl chloride (126 µl, 1.7 mmol) in Et ₂ O (3.2 ml) was cooled to –78°C under argon. A solution of ethyl 2-ethyl-2-(hydroxymethyl)butanoate (ex-enamine) (0.30 g, 1.7 mmol) and pyridine (153 μl, 1.9 mmol) in Et was added dropwise to the sulfuryl chloride solution over 60 min. ₂ O (2.1 ml). Allow the mixture to warm to room temperature and shake for 30 minutes. The mixture was re-cooled to –78°C, sulfuryl chloride (20 μL) was added, the reaction mixture was allowed to warm to room temperature, and the mixture was shaken for an additional 30 min. Et ₂ O (5 ml) was added and the mixture was shaken for 5 minutes, then filtered and the filtrate was concentrated in vacuo to give the title compound (61a), which was immediately used in the next step without further purification. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 4.62 (s, 2H), 4.21 (q, J=7.3 Hz, 2H), 1.78–1.58 (m, 4H) , 1.28 (t, J=7.1 Hz, 3H), 0.88 (t, J=7.7 Hz, 6H).

Step 2: Synthesis of ethyl 2-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl) –2-ethylbutanoate (61).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (0.25 g, 1.4 mmol) was dissolved in THF (11.2 ml) and HMPA (0.6 ml), and the resulting stirred solution was cooled to –78°C under argon. A solution of NaHMDS, 1.0 M in THF (1.4 mL, 1.4 mmol) was added to the mixture and the mixture was shaken for 10 minutes. A solution of ethyl 2-(((chlorosulfonyl)oxy)methyl)-2-ethylbutanoate (61a) (0.41 g, 1.5 mmol) in THF (20 ml) was quickly added to the reaction mixture. After 10 minutes of shaking at –78°C, the mixture was allowed to warm to room temperature and shaken for 16 hours. The mixture was quenched with H ₂ O and diluted with EtOAc. The aqueous and organic layers were separated, and the organic layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography to give product (61) (162 mg, 29%) as a solid. LCMS: m/z=422.03 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 6.50 (br. s, 1H), 5.66 (br. s, 1H), 4.87 (d, J=9.9 Hz, 1H) , 4.70 (d, J=9.9 Hz, 1H), 4.22–4.14 (m, 3H), 4.06 (d, J=7.2 Hz, 1H), 3.33 ( d, J=11.7 Hz, 1H), 3.02 (d, J=12.3 h, 1H), 2.47–2.41 (m, 1H), 2.22–2.12 (m , 1H), 2.01–1.60 (m, 6H), 1.27 (t, J=7.1 Hz, 3H), 0.92–0.83 (m, 6H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 173.3, 171.1, 167.1, 75.2, 62.0, 61.1, 60.2, 50.6, 47.2, 26 ,2, 25.8, 20.9, 17.5, 14.3, 8.4, 8.3.

Example 62

Synthesis of 4-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl 2 ,6-dimethylbenzoate (62)

Step 1: Synthesis of 4-hydroxy-3,3-dimethylbutyl 2,6-dimethylbenzoate (62a).

2,6-Dimethylbenzoyl chloride ( 1.0 g, 5.9 mmol), pyridine (0.96 ml, 11.9 mmol) and N, N-4-dimethylaminopyridine (catalytic amount). The reaction mixture was allowed to gradually warm to room temperature and the mixture was shaken overnight. The mixture was quenched by adding 1 N. HCl (50 ml). The organic and aqueous layers were separated, and the aqueous layer was extracted with DCM (twice). The combined organic layers were washed with saturated NaHCO ₃ and then dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-3:7) to give the desired product (62a) (0.42 g, 28%). ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.18 (t, J=7.6 Hz, 1H), 7.04–7.01 (m, 2H), 4.41 (t, J= 7.6 Hz, 2H), 3.37 (s, 2H), 2.31 (s, 6H), 1.76 (t, J=7.5 Hz, 2H), 0.97 (s, 6H) .

Step 2: Synthesis of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl 2,6-dimethylbenzoate (62b).

A solution of freshly distilled sulfuryl chloride (122 µl, 1.7 mmol) in Et ₂ O (1.0 ml) was cooled to –78°C under argon. A solution of 4-hydroxy-3,3-dimethylbutyl 2,6-dimethylbenzoate (62a) (0.42 g, 1.7 mmol) and pyridine (136 μl, 1.7 mmol) was added dropwise to the sulfuryl chloride solution over 15 min. in Et ₂ O (1.5 ml). The flask was washed with Et ₂ O (2×20 ml), and the wash was added to the reaction mixture. The mixture was shaken at –78°C for 10 minutes, then allowed to warm to room temperature and shaken for 1 hour. The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (62b) as an oil, which was immediately used in the next step without additional cleaning (not clean). ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.19 (t, J=7.7 Hz, 1H), 7.03 (d, J=7.5 Hz, 2H), 4.41 (t , J=7.4 Hz, 2H), 4.23 (s, 2H), 2.31 (s, 6H), 1.84 (t, J=6.9 Hz, 2H), 1.11 (s , 6H).

Step 3: Synthesis of 4–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–3,3 –dimethylbutyl 2,6-dimethylbenzoate (62).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (0.22 g, 1.2 mmol) was dissolved in THF (10 ml) and HMPA (0.5 ml), and the resulting stirred solution was cooled to –78°C under argon. A solution of NaHMDS, 1.0 M in THF (1.2 mL, 1.2 mmol) was added to the mixture and the mixture was shaken for 10 minutes. A solution of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl 2,6-dimethylbenzoate (62b) (0.42 g, 1.2 mmol) in Et ₂ O (20 ml) was quickly added to the reaction mixture. After 10 minutes of shaking at –78°C, the mixture was allowed to warm to room temperature and shaken for 1 hour. The mixture was cooled to 0°C, quenched with H ₂ O and diluted with EtOAc. The aqueous and organic layers were separated, and the organic layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-7:3) to give product (62) (192 mg, 32%) as a solid. LCMS: m/z=498.08 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.18 (t, J=7.5 Hz, 1H), 7.02 (d, J=7.5 Hz, 2H), 6.48 (br .s, 1H), 5.63 (br.s, 1H), 4.57 (d, J=9.0 Hz, 1H), 4.40 (t, J=7.5 Hz, 2H), 4 .25 (d, J=8.7 Hz, 1H), 4.17 (br. s, 1H), 4.04 (d, J=6.3 Hz, 1H), 3.32 (d, J= 12.3 Hz, 1H), 3.00 (d, J=12.3 Hz, 1H), 2.47–2.40 (m, 1H), 2.31 (s, 6H), 2.18– 2.14 (m, 1H), 1.97–1.80 (m, 4H), 1.08 (s, 6H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 170.9, 170.0, 167.1, 134.8, 133.8, 129.4, 127.6, 83.4, 61.9, 61 ,3, 60.1, 47.1, 36.7, 33.9, 23.9, 23.6, 20.7, 19.8, 17.4.

Example 63

Synthesis of 4-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl adamantane –1-carboxylate (63)

Step 1: Synthesis of 4-hydroxy-3,3-dimethylbutyl adamantane-1-carboxylate (63a).

1-adamantanecarbonyl was added to a shaken solution of 2,2-dimethylbutane-1,4-diol (0.72 g, 6.1 mmol) in DCM (20 ml) at approximately 0°C (ice bath) under argon. chloride (1.1 g, 10.1 mmol), pyridine (0.82 ml, 10.1 mmol) and N, N-4-dimethylaminopyridine (0.03 g, 0.3 mmol). The reaction mixture was allowed to gradually warm to room temperature and the mixture was shaken overnight. The mixture was quenched by adding 1 N. HCl. The organic and aqueous layers were separated, and the aqueous layer was extracted with DCM (twice). The combined organic layers were washed with saturated NaHCO ₃ and brine, then dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-1:1) to give the desired product (63a) (0.49 g, 35%). ¹ H–NMR (300 MHz, CDCl ₃ ): δ 4.14–4.09 (m, 2H), 3.34 (s, 2H), 2.00 (m, 3H), 1.90–1, 86 (m, 6H), 1.75–1.59 (m, 6H), 1.59 (t, J=7.1 Hz, 2H), 0.92 (s, 6H).

Step 2: Synthesis of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl adamantane-1-carboxylate (63b).

A solution of freshly distilled sulfuryl chloride (127 µl, 1.7 mmol) in Et ₂ O (1.2 ml) was cooled to –78°C under argon. A solution of 4-hydroxy-3,3-dimethylbutyl adamantane-1-carboxylate (63a) (0.48 g, 1.7 mmol) and pyridine (141 μl, 1.7 mmol) was added dropwise to the sulfuryl chloride solution over 15 min. in Et ₂ O (1.7 ml). The flask was washed with Et ₂ O (2×20 ml), and the wash was added to the reaction mixture. The mixture was shaken at –78°C for 10 minutes and then allowed to warm to room temperature and shaken for 1 hour. The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (63b) as an oil, which was immediately used in the next stage without additional purification (not pure). ¹ H–NMR (300 MHz, CDCl ₃ ): δ 4.25 (s, 2H), 4.13 (t, J=6.8 Hz, 2H), 2.01 (m, 3H), 1.90 –1.85 (m, 6H), 1.73–1.69 (m, 8H), 1.08 (s, 6H).

Step 3: Synthesis of 4–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–3,3 –dimethylbutyl adamantane-1-carboxylate (63).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (0.22 g, 1.2 mmol) was dissolved in THF (10 ml) and HMPA (0.5 ml), and the resulting stirred solution was cooled to –78°C under argon. A solution of NaHMDS, 1.0 M in THF (1.2 mL, 1.2 mmol) was added to the mixture and the mixture was shaken for 10 minutes. A solution of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl adamantane-1-carboxylate (63b) (0.66 g, 1.7 mmol) in Et ₂ O (20 ml) was quickly added to the reaction mixture. After 10 minutes of shaking at –78°C, the mixture was allowed to warm to room temperature and shaken for 1 hour. The mixture was cooled to 0°C, quenched with H ₂ O and diluted with EtOAc. The aqueous and organic layers were separated, and the organic layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-7:3) as eluent to give a solid, which was triturated with hexanes to give product (63) (230 mg, 36%) in form of a solid. LCMS: m/z=528.17 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.18 (t, J=7.5 Hz, 1H), 7.02 (d, J=7.5 Hz, 2H), 6.48 (br .s, 1H), 5.63 (br.s, 1H), 4.57 (d, J=9.0 Hz, 1H), 4.40 (t, J=7.5 Hz, 2H), 4 .25 (d, J=8.7 Hz, 1H), 4.17 (br. s, 1H), 4.04 (d, J=6.3 Hz, 1H), 3.32 (d, J= 12.3 Hz, 1H), 3.00 (d, J=12.3 Hz, 1H), 2.47–2.40 (m, 1H), 2.31 (s, 6H), 2.18– 2.14 (m, 1H), 1.97–1.80 (m, 4H), 1.08 (s, 6H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 177.8, 171.0, 167.1, 83.9, 62.0, 60.7, 60.2, 47.2, 40.7, 39 ,0, 39.0, 37.0, 36.6, 34.1, 28.0, 24.0, 23.8, 20.8, 17.5.

Example 64

Synthesis of 4-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl 2 ,6-dimethoxybenzoate (64)

Step 1: Synthesis of 4-hydroxy-3,3-dimethylbutyl 2,6-dimethoxybenzoate (64a).

2,6-Dimethoxybenzoyl chloride ( 80%; 3.93 g, 15.7 mmol), Et ₃ N (2.5 ml, 31.3 mmol) and N, N-4-dimethylaminopyridine (catalytic amount). The reaction mixture was allowed to gradually warm to room temperature and the mixture was shaken overnight. The mixture was concentrated in vacuo and suspended in EtOAc and then filtered and the filter cake washed with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-2:3) to give the desired product (64a) (about 80% purity; 0.92 g). ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.29–7.26 (m, 1H), 6.57–6.53 (m, 3H), 4.43–4.39 (m, 2H ), 3.83 (s, 6H), 3.36 (s, 2H), 1.74 (t, J=6.5 Hz, 2H), 0.95 (s, 6H).

Step 2: Synthesis of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl 2,6-dimethoxybenzoate (64b).

A solution of freshly distilled sulfuryl chloride (0.2 ml, 2.7 mmol) in Et ₂ O (1.9 ml) was cooled to –78°C under argon. A solution of 4-hydroxy-3,3-dimethylbutyl 2,6-dimethoxybenzoate (64a) (about 80% purity; 0.97 g, 2.7 mmol) and pyridine (222 μl, 2.7 mmol) in Et ₂ O (2.7 ml). The flask was washed with Et ₂ O (2×20 ml), and the wash was added to the reaction mixture. The mixture was shaken at –78°C for 10 minutes, then allowed to warm to room temperature and shaken for 1 hour. The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (64b) as an oil, which was immediately used in the next step without additional cleaning (not clean).

Step 3: Synthesis of 4–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–3,3 –dimethylbutyl 2,6-dimethoxybenzoate (64).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (0.21 g, 1.1 mmol) was dissolved in THF (9.4 ml) and HMPA (0.5 ml), and the resulting stirred solution was cooled to –78°C under argon. A solution of NaHMDS, 1.0 M in THF (1.1 mL, 1.1 mmol) was added to the mixture and the mixture was shaken for 10 minutes. A solution of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl 2,6-dimethoxybenzoate (64b) (0.65 g, 1.7 mmol) in Et ₂ O (20 ml) was quickly added to the reaction mixture. After 10 minutes of shaking at –78°C, the mixture was allowed to warm to room temperature and shaken for 1 hour. The mixture was cooled to 0°C, quenched with H ₂ O and diluted with EtOAc. The aqueous and organic layers were separated, and the organic layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-1:0) to give product (64) (100 mg, 17%) as a solid. LCMS: m/z=530.01 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.31–7.25 (m, 1H), 6.54 (d, J=9.0 Hz, 2H), 6.50 (br. s, 1H), 5.58 (br. s, 1H), 4.54 (d, J=8.7 Hz, 1H), 4.40 (t, J=6.8 Hz, 2H), 4.28 ( d, J=8.7 Hz, 1H), 4.16 (br. s, 1H), 4.03 (d, J=6.9 Hz, 1H), 3.81 (s, 6H), 3, 33 (d, J=11.7 Hz, 1H), 2.99 (d, J=7.2 Hz, 1H), 2.44–2.39 (m, 1H), 2.21–2.13 (m, 1H), 1.93–1.79 (m, 4H), 1.07 (s, 6H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ171.0, 167.1, 166.7, 157.3, 131.2, 113.1, 103.9, 84.0, 62.0, 61, 8, 60.2, 56.0, 47.2, 36.6, 34.1, 23.8, 23.6, 20.8, 17.5.

Example 65

Synthesis of 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentyl benzoate (65)

Step 1: Synthesis of 5-hydroxy-4,4-dimethylpentyl benzoate (65a).

Into a shaken solution of 2,2-dimethylpentane-1,5-diol (J. Org. Chem. 2010, 75, 1892–1897; PCT International Publication No. WO 2002092606) (1.55 g, 11.7 mmol) in DCM ( 20 ml) at approximately 0°C (ice bath) under argon, benzoyl chloride (1.5 ml, 12.9 mmol) was added. The reaction mixture was shaken at room temperature for 2.5 hours and concentrated in vacuo. EtOAc was added to the residue and the mixture was shaken. The filtrate was concentrated to the residue, purified by silica gel column chromatography using EtOAc/hexanes (0:1-1:4) as eluent to give product (65a) (1.38g, 50%) as an oil. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 8.04 (d, J=6.9 Hz, 2H), 7.56 (t, J=7.5 Hz, 1H), 7.44 (t , J=7.5 Hz, 2H), 4.31 (t, J=6.8 Hz, 2H), 3.36 (s, 2H), 1.81–1.71 (m, 2H), 1 .42–1.36 (m, 2H), 0.92 (s, 6H).

Step 2: Synthesis of 5-((chlorosulfonyl)oxy)-4,4-dimethylpentyl benzoate (65b).

A solution of freshly distilled sulfuryl chloride (0.2 ml, 2.7 mmol) in Et ₂ O (1.9 ml) was cooled to –78°C under argon. A solution of 4-hydroxy-3,3-dimethylpentyl benzoate (65a) (0.76 g, 3.2 mmol) and pyridine (218 μl, 2.7 mmol) in Et ₂ O was added dropwise to the sulfuryl chloride solution over 15 min. (2.7 ml). The flask was washed with Et ₂ O (2×20 ml), and the wash was added to the reaction mixture. The mixture was shaken at –78°C for 10 minutes, then allowed to warm to room temperature and shaken for 1 hour. The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (65b) as an oil, which was immediately used in the next step without additional cleaning (not clean). ¹ H–NMR (300 MHz, CDCl ₃ ): δ 8.04 (d, J=7.5 Hz, 2H), 7.57–7.55 (m, 1H), 7.48–7.33 ( m, 1H), 4.35–4.29 (m, 2H), 4.23 (s, 2H), 1.81–1.74 (m, 2H), 1.53–1.21 (m, 2H), 1.06 (s, 6H).

Step 3: Synthesis of 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4 –dimethylpentyl benzoate (65).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (0.21 g, 1.1 mmol) was dissolved in THF (9.4 ml) and HMPA (0.5 ml), and the resulting stirred solution was cooled to –78°C under argon. A solution of NaHMDS, 1.0 M in THF (1.1 mL, 1.1 mmol) was added to the mixture and the mixture was shaken for 10 min. A solution of 5-((chlorosulfonyl)oxy)-4,4-dimethylpentyl benzoate (65b) (0.42 g, 1.2 mmol) in Et ₂ O (20 ml) was quickly added to the reaction mixture. After 10 minutes of shaking at –78°C, the mixture was allowed to warm to room temperature and shaken for 1 hour. The mixture was cooled to 0°C, quenched with H ₂ O and diluted with EtOAc. The aqueous and organic layers were separated, and the organic layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-7:3) to give product (65) (160 mg, 29%) as a solid. LCMS: m/z=484.10 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 8.04 (d, J=7.5 Hz, 2H), 7.57–7.54 (m, 1H), 7.47–7.42 ( m, 2H), 6.43 (br. s, 1H), 5.51 (br. s, 1H), 4.56 (d, J=9.0 Hz, 1H), 4.32–4.17 (m, 4H), 4.02 (d, J=7.2 Hz, 1H), 3.28 (d, J=12.3 Hz, 1H), 2.97 (d, J=12.3 Hz , 1H), 2.44–2.40 (m, 1H), 2.20–2.14 (m, 1H), 1.94–1.72 (m, 4H), 1.51–1.45 (m, 2H), 1.02 (s, 6H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 171.0, 167.1, 166.8, 133.1, 130.4, 129.7, 128.5, 83.6, 65.3, 61 ,9, 60.2, 47.2, 34.8, 34.3, 23.9, 23.6, 23.3, 20.8, 17.5.

Example 66

Synthesis of 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentyl 2 ,6-dimethoxybenzoate (66)

Step 1: Synthesis of 5-hydroxy-4,4-dimethylpentyl 2,6-dimethoxybenzoate (66a).

One part of 2,6-dimethoxybenzoyl chloride (80 %; 1.4 g, 5.6 mmol). The reaction mixture was allowed to warm to room temperature over 3 hours. The reaction mixture was concentrated to dryness and EtOAc was added. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-3:7) to give product (66a) (0.65 g, 39%) as an oil. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.31–7.26 (m, 2H), 6.55 (d, J=8.1 Hz, 2H), 4.33 (t, J= 6.2 Hz, 2H), 3.82 (s, 6H), 3.33 (s, 2H), 1.77–1.67 (m, 2H), 1.41–1.35 (m, 2H ), 0.92 (s, 6H).

Step 2: Synthesis of 5-((chlorosulfonyl)oxy)-4,4-dimethylpentyl 2,6-dimethoxybenzoate (66b).

A solution of freshly distilled sulfuryl chloride (0.16 ml, 2.2 mmol) in Et ₂ O was cooled to –78°C under argon. A solution of 5-hydroxy-4,4-dimethylpentyl 2,6-dimethoxybenzoate (66a) (0.65 g, 2.2 mmol) and pyridine (177 μl, 2.2 mmol) was added dropwise to the sulfuryl chloride solution over 15 min. in Et ₂ O. The flask was washed with Et ₂ O (2×20 ml), and the wash was added to the reaction mixture. The mixture was shaken at –78°C for 10 minutes and then allowed to warm to room temperature and shaken for 1 hour. The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (66b) as an oil, which was immediately used in the next stage without additional purification (not pure). ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.32–7.26 (m, 1H), 6.56 (d, J=8.7 Hz, 2H), 4.34 (t, J= 6.2 Hz, 2H), 4.21 (s, 2H), 3.81 (s, 6H), 1.77–1.71 (m, 2H), 1.52–1.46 (m, 2H ), 1.03 (s, 6H).

Step 3: Synthesis of 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4 –dimethylpentyl 2,6-dimethoxybenzoate (66).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (0.21 g, 1.1 mmol) was dissolved in THF (9.4 ml) and HMPA (0.5 ml), and the resulting stirred solution was cooled to –78°C under argon. A solution of NaHMDS, 1.0 M in THF (1.1 mL, 1.1 mmol) was added to the mixture and the mixture was shaken for 10 min. A solution of 5-((chlorosulfonyl)oxy)-4,4-dimethylpentyl 2,6-dimethoxybenzoate (66b) (0.49 g, 1.2 mmol) in Et ₂ O (20 ml) was quickly added to the reaction mixture. After 10 minutes of shaking at –78°C, the mixture was allowed to warm to room temperature and shaken for 1 hour. The mixture was cooled to 0°C, quenched with H ₂ O and diluted with EtOAc. The aqueous and organic layers were separated, and the organic layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-1:0) to give product (66) (115 mg, 18%) as a solid. LCMS: m/z=544.17 [M+H] ⁺ . 589.11 [M+HCOOH] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.31–7.25 (m, 1H), 6.55 (d, J=8.7 Hz, 2H), 6.51 (br. s, 1H), 5.51 (br. s, 1H), 4.53 (d, J=9.0 Hz, 1H), 4.33 (t, J=6.2 Hz, 2H), 4.23– 4.16 (m, 2H), 4.03 (d, J=7.5 Hz, 1H), 3.82 (s, 6H), 3.31 (d, J=12.3 Hz, 1H), 2.98 (d, J=11.7 Hz, 1H), 2.42–2.39 (m, 1H), 2.20–2.18 (m, 1H), 2.00–1.68 ( m, 4H), 1.49–1.44 (m, 2H), 1.00 (s, 6H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 171.0, 167.0, 166.7, 157.4, 131.2, 110.1, 104.1, 83.9, 65.6, 62 ,0, 60.2, 56.1, 47.2, 34.7, 34.3, 23.8, 23.6, 23.4, 20.8, 17.6.

Example 67

Synthesis of 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentyl 2 ,6-dimethylbenzoate (67)

Step 1: Synthesis of 5-hydroxy-3,3-dimethylpentyl 2,6-dimethylbenzoate (67a).

One part of 2,6-dimethylbenzoyl chloride was added to a shaken solution of 2,2-dimethylpentane-1,5-diol (1.1 g, 8.3 mmol) in pyridine (8.3 ml) at 0°C under argon. The reaction mixture was allowed to warm to room temperature over 3 hours. The reaction mixture was concentrated to dryness and EtOAc was added. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-1:4) to give product (67a) (0.44 g, 25%) as an oil. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.18 (t, J=7.7 Hz, 1H), 7.03 (d, J=7.5 Hz, 2H), 4.32 (t , J=6.3 Hz, 2H), 3.34 (s, 2H), 2.32 (s, 6H), 1.78–1.68 (m, 2H), 1.40–1.34 ( m, 2H), 0.90 (s, 6H).

Step 2: Synthesis of 5-((chlorosulfonyl)oxy)-4,4-dimethylpentyl 2,6-dimethylbenzoate (67b).

A solution of freshly distilled sulfuryl chloride (122 µl, 1.7 mmol) in Et ₂ O was cooled to –78°C under argon. A solution of 5-hydroxy-4,4-dimethylpentyl 2,6-dimethylbenzoate (67a) (0.44 g, 1.7 mmol) and pyridine (135 μl, 1.7 mmol) was added dropwise to the sulfuryl chloride solution over 15 min. in Et ₂ O. The flask was washed with Et ₂ O (2×20 ml), and the wash was added to the reaction mixture. The mixture was shaken at –78°C for 10 minutes and then allowed to warm to room temperature and shaken for 1 hour. The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (67b), which was immediately used in the next step without further cleaning. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.19 (t, J=7.5 Hz, 1H), 7.03 (d, J=7.5 Hz, 2H), 4.33 (t , J=6.2 Hz, 2H), 4.20 (s, 2H), 2.32 (s, 6H), 1.81–1.71 (m, 2H), 1.51–1.45 ( m, 2H), 1.04 (s, 6H).

Step 3: Synthesis of 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4 –dimethylpentyl 2,6-dimethylbenzoate (67).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (0.21 g, 1.1 mmol) was dissolved in THF (9.4 ml) and HMPA (0.5 ml), and the resulting stirred solution was cooled to –78°C under argon. A solution of NaHMDS, 1.0 M in THF (1.1 mL, 1.1 mmol) was added to the mixture and the mixture was shaken for 10 min. A solution of 5-((chlorosulfonyl)oxy)-4,4-dimethylpentyl 2,6-dimethylbenzoate (67b) (0.49 g, 1.4 mmol) in Et ₂ O (20 ml) was quickly added to the reaction mixture. After 10 minutes of shaking at –78°C, the mixture was allowed to warm to room temperature and shaken for 1 hour. The mixture was cooled to 0°C, quenched with H ₂ O and diluted with EtOAc. The aqueous and organic layers were separated, and the organic layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-7:3) to give product (67) (200 mg, 32%) as a solid. LCMS: m/z=512.18 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.19 (t, J=7.5 Hz, 1H), 7.03 (d, J=7.5 Hz, 2H), 6.45 (br .s, 1H), 5.52 (br.s, 1H), 4.54 (d, J=9.3 Hz, 1H), 4.31 (t, J=7.4 Hz, 2H), 4 .23–4.17 (m, 2H), 4.03 (d, J=7.2 Hz, 1H), 3.31 (d, J=11.7 Hz, 1H), 2.99 (d, J=12.3 Hz, 1H), 2.45–2.40 (m, 1H), 2.32 (s, 6H), 2.18–2.14 (m, 1H), 1.98–1 .70 (m, 4H), 1.48–1.42 (m, 2H), 1.00 (s, 6H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 170.9, 170.2, 167.1,135.0, 134.1, 129.4, 127.7, 83.6, 65.4, 62.0 , 60.2, 47.2, 34.9, 34.3, 23.7, 23.6, 23.3, 20.8, 19.9, 17.5.

Example 68

Synthesis of 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentyl 2 –methyl benzoate (68)

Step 1: Synthesis of 4-hydroxy-3,3-dimethylbutyl 2-methylbenzoate (68a).

Toluoyl chloride (0 .89 ml, 6.8 mmol). The reaction mixture was allowed to gradually warm to room temperature and the mixture was shaken for 4 hours. The mixture was concentrated in vacuo and suspended in EtOAc and then filtered and the filter cake washed with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-3:7) as eluent to give the desired product (68a) (0.7 g, 44%). ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.88 (d, J=8.4 Hz, 1H), 7.40 (t, J=7.1 Hz, 1H), 7.26–7 .24 (m, 2H), 4.38 (t, J=7.3 Hz, 2H), 3.41 (s, 3H), 2.60 (s, 3H), 1.78 (t, J= 7.5 Hz, 2H), 0.98 (s, 6H).

Step 2: Synthesis of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl 2-methylbenzoate (68b).

A solution of freshly distilled sulfuryl chloride (96 µl, 1.3 mmol) in Et ₂ O (0.8 ml) was cooled to –78°C under argon. A solution of 4-hydroxy-3,3-dimethylbutyl 2-methylbenzoate (68a) (0.31 g, 1.3 mmol) and pyridine (106 μL, 1.3 mmol) in Et was added dropwise to the sulfuryl chloride solution over 15 min. ₂ O (1.1 ml). The flask was washed with Et ₂ O (2×20 ml), which was added to the reaction mixture. The mixture was shaken at –78°C for 10 minutes, then allowed to warm to room temperature and shaken for 30 minutes. The mixture was filtered and product (68b) was immediately used in the next step without further purification. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.89 (d, J=8.1 Hz, 1H), 7.41–7.39 (m, 1H), 7.26–7.25 ( m, 2H), 4.41–4.35 (m, 2H), 4.28 (s, 2H), 2.61 (s, 3H), 1.87 (t, J=7.2 Hz, 2H ), 1.13 (s, 6H).

Step 3: Synthesis of 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4 –dimethylpentyl 2-methylbenzoate (68).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (0.22 g, 1.2 mmol) was dissolved in THF (10 ml) and HMPA (0.5 ml), and the resulting stirred solution was cooled to –78°C under argon. A solution of NaHMDS, 1.0 M in THF (1.2 mL, 1.2 mmol) was added to the mixture and the mixture was shaken for 10 minutes. A solution of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl 2-methylbenzoate (68b) (0.42 g, 1.3 mmol) in Et ₂ O (20 ml) was quickly added to the reaction mixture. After 10 minutes of shaking at –78°C, the mixture was allowed to warm to room temperature and shaken for 1 hour. The mixture was cooled to 0°C, quenched with H ₂ O and diluted with EtOAc. The aqueous and organic layers were separated, and the organic layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-7:3) to give product (68) (231 mg, 40%) as a solid. LCMS: m/z=484.06 [M+1] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.90 (d, J=7.5 Hz, 1H), 7.40 (t, J=7.5 Hz, 1H), 7.26–7 .24 (m, 2H), 6.44 (br. s, 1H), 5.53 (br. s, 1H), 4.60 (d, J=8.7 Hz, 1H), 4.35 ( t, J=7.1 Hz, 2H), 4.28 (d, J=9.0 Hz, 1H), 4.17 (br. s, 1H), 4.03 (d, J=7.2 Hz, 1H), 3.33 (d, J=12.3 Hz, 1H), 2.99 (d, J=11.7 Hz, 1H), 2.60 (s, 3H), 2.47– 2.40 (m, 1H), 2.18–2.14 (m, 1H), 1.95–1.82 (m, 4H), 1.10 (s, 6H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 171.0, 167.5, 167.1, 140.5, 132.2, 131.9, 130.7, 129.5, 125.9, 83 ,7, 62.0, 61.2, 60.2, 47.2, 36.9, 34.0, 24.1, 23.8, 21.9, 20.8, 17.5.

Example 69

Synthesis of 4–(((((2S,5R)–2–carbamoyl–7–oxo–1,6–diazabicyclo[3.2.1]octan–6–yl)oxy)sulfonyl)oxy)–2,2,3, 3-tetramethylbutyl 3-chloro-2,6-dimethoxybenzoate (69)

Step 1: Synthesis of 4-hydroxy-2,2,3,3-tetramethylbutyl 2,6-dimethoxybenzoate (69a).

2,6– dimethoxybenzoyl chloride (80%; 0.55 g, 2.2 mmol), pyridine (0.36 ml, 4.4 mmol) and N,N-4-dimethylaminopyridine (0.05 g, 0.4 mmol). Allow the mixture to warm to room temperature and shake at room temperature overnight. The mixture was cooled to 0°C and the reaction was quenched by adding 1N. HCl (15 ml) and then extracted with DCM (twice). The combined organic layers were washed with saturated sodium bicarbonate and brine, then dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1–3:2) to give product (69a) as an oil. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.29 (t, J=8.4 Hz, 1H), 6.56 (d, J=8.1 Hz, 2H), 4.24 (s , 2H), 3.81 (s, 6H), 3.49 (s, 2H), 0.98 (s, 6H), 0.92 (s, 6H).

Step 2: Synthesis of 4-((chlorosulfonyl)oxy)-2,2,3,3-tetramethylbutyl 3-chloro-2,6-dimethoxybenzoate (69b).

Pyridine ( _0.15 ml, 1.8 mmol). The solution was cooled to –78°C and sulfuryl chloride (0.15 ml, 1.8 mmol) in Et ₂ O (3 ml) was added slowly at –78°C. The mixture was shaken at –78°C for 1 hour and then warmed to room temperature and shaken for 1 hour. The reaction mixture was filtered to remove the pyridine salt and the filtrate was concentrated in vacuo to give the title compound (69b) as an oil, which used directly in the next step without additional purification (yield was taken based on quantity).

Step 3: Synthesis of 4-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2 ,3,3-tetramethylbutyl 3-chloro-2,6-dimethoxybenzoate (69).

Into a shaken mixture of (2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (235 mg, 1.3 mmol) in THF (10 ml) A few drops of 1,3-dimethyltetrahydropyrimidin-2(1H)-one were added in an argon atmosphere. The mixture was cooled to –78°C and shaken for 10 min, then a solution of NaHMDS, 1.0 M in THF (1.4 mL, 1.4 mmol) was added dropwise. The mixture was shaken at –78°C for 8 min, then 4-((chlorosulfonyl)oxy)-2,2,3,3-tetramethylbutyl 3-chloro-2,6-dimethoxybenzoate (69b) (0.52 g, 1.2 mmol) in THF (5 ml) at –78°C. The mixture was shaken at –78°C for 10 minutes, then allowed to warm to room temperature and shaken for 1 hour. The mixture was diluted with EtOAc and saturated sodium bicarbonate solution. The aqueous and organic layers were separated, and the organic layer was washed with water, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1–1:0) to give product (69) as a solid. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.33 (d, J=9.0 Hz, 1H), 6.65 (d, J=8.7 Hz, 1H), 6.51 (s , 1H), 5.74 (s, 1H), 4.75 (d, J=9.6 Hz, 1H), 4.44 (d, J=8.7 Hz, 1H), 4.22–4 .15 (m, 3H), 4.02 (d, J=6.3 Hz, 1H), 3.88 (s, 3H), 3.81 (s, 3H), 3.31 (d, J= 11.7 Hz, 1H), 2.99 (d, J=12.3 Hz, 1H), 2.43–2.39 (m, 1H), 2.16–2.12 (m, 1H), 1.91–1.80 (m, 2H), 1.05–1.01 (m, 12H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 171.1, 167.1, 165.6, 156.0, 153.6, 131.6, 120.1, 119.5, 107.8, 82 ,4, 71.2, 62.2, 61.9, 60.2, 56.2, 47.2, 39.0, 38.7, 20.8, 20.7, 20.3, 20.2 , 17.5.

Example 70

Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylpropane –1,3-diyl dibenzoate (70)

Step 1: Reaction to produce 2-(hydroxymethyl)-2-methylpropane-1,3-diyl dibenzoate (70a).

Benzoyl chloride (2.46 ml, 20.0 mmol) was added dropwise to a mixture of 2-(hydroxymethyl)-2-methylpropane-1,3-diol (1.2 g, 10.0 mmol), pyridine (2.02 ml , 25.0 mmol) and N,N-4-dimethylaminopyridine (0.06 g, 0.4 mmol) in DCM (30 ml) at room temperature. After shaking at room temperature overnight, the organic phase was washed with 1 M HCl, water and brine, dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-2:3) to give product (70a) (1.3 g, 40%) as an oil. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 8.06–8.02 (m, 4H), 7.62–7.56 (m, 2H), 7.49–7.42 (m, 4H ), 4.39 (s, 2H), 4.38 (s, 2H), 3.59 (s, 2H), 1.16 (s, 3H).

Step 2: Synthesis of 2-(((chlorosulfonyl)oxy)methyl)-2-methylpropane-1,3-diyl dibenzoate (70b).

A solution of freshly distilled sulfuryl chloride (0.3 ml, 3.7 mmol) in Et ₂ O (5 ml) was cooled to –78°C under argon. A solution of 2-(hydroxymethyl)-2-methylpropane-1,3-diyl dibenzoate (70a) (800 mg, 2.4 mmol) and pyridine (0.32 ml, 3.9 mmol) in Et ₂ O (5 ml). The flask was washed with Et ₂ O (3 ml), which was also added to the mixture. The mixture was shaken at –78°C for 1 hour and then allowed to warm to room temperature. The precipitate was filtered (quickly) and the filter cake was washed with Et ₂ O (12 ml). The filtrate was concentrated in vacuo at room temperature to give the title compound (70b) as an oil, which was immediately used in the next step without further purification.

Step 3: Synthesis of 2–(((((2S,5R)–2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)– 2-methylpropane-1,3-diyl dibenzoate (70).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (400 mg, 2.2 mmol) was dissolved in THF (10 ml) and HMPA (1.1 ml), and the resulting solution was cooled to –78°C under argon. A 1.0 M solution of NaHMDS in THF (2.3 mL) was added dropwise to the cooled solution and shaken for 10 min. 2-(((chlorosulfonyl)oxy)methyl)-2-methylpropane-1,3-diyl dibenzoate (70b) (922 mg, 2.2 mmol) was dissolved in THF (8 ml) and quickly added to the reaction mixture. After shaking at –78°C for 10 min, the reaction mixture was allowed to warm to room temperature. After shaking at room temperature for 2 hours, EtOAc (400 ml) and saturated aqueous NaHCO ₃ (40 ml) and H ₂ O (40 ml) were added. The aqueous and organic layers were separated and the organic layer was washed with saturated aqueous NaHCO ₃ (60 ml), water (3×50 ml), brine (60 ml), then dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-1:9) to give product (70) (186 mg, 15%) as an oil. LC–MS: m/z=576 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 8.06–8.03 (m, 4H), 7.60–7.55 (m, 2H), 7.44–7.26 (m, 4H ), 6.41 (s, 1H), 5.49 (s, 1H), 4.97 (d, J=9.3 Hz, 1H), 4.68 (d, J=9.3 Hz, 1H ), 4.43–4.39 (m, 4H), 4.13 (m, 1H), 4.01–3.99 (m, 1H), 3.13 (m, 1H), 2.95– 2.91 (m, 1H), 2.45–2.40 (m, 1H), 2.20–2.08 (m, 1H), 1.93–1.76 (m, 2H), 1, 12 (s, 3H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 170.8, 167.1, 166.1, 133.3, 129.8, 129.7, 128.5, 77.2, 66.1, 65 ,9, 61.8, 60.1, 46.9, 39.4, 20.6, 17.4, 16.9.

Example 71

Synthesis of 2-((((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylpropane –1,3-diyl diacetate (71)

Step 1: Synthesis of 2-(hydroxymethyl)-2-methylpropane-1,3-diyl diacetate (71a).

Into a mixture of 2-(hydroxymethyl)-2-methylpropane-1,3-diol (2.2 g, 18.0 mmol), pyridine (12 ml, 25.0 mmol) and N, N-4-dimethylaminopyridine (0. 05 g) at room temperature, acetic anhydride (3.46 ml, 36.6 mmol) was added dropwise. After shaking at room temperature overnight, the mixture was concentrated in vacuo. The mixture was suspended in EtOAc (100 ml) and H ₂ O (20 ml) was added slowly at 0°C. The aqueous and organic layers were separated, and the organic layer was washed with brine, dried (Na ₂ SO ₄ ), then concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-3:2) to give product (71a) (1.0 g, 26%). ¹ H–NMR (300 MHz, CDCl ₃ ): δ 4.02 (s, 4H), 3.41 (s, 2H), 2.08 (s, 6H), 0.96 (s, 3H).

Step 2: Synthesis of 2-(((chlorosulfonyl)oxy)methyl)-2-methylpropane-1,3-diyl diacetate (71b).

A solution of freshly distilled sulfuryl chloride (0.33 ml, 4.0 mmol) in Et ₂ O (4 ml) was cooled to –78°C under argon. A solution of 2-(hydroxymethyl)-2-methylpropane-1,3-diyl diacetate (71a) (550 mg, 2.7 mmol) and pyridine (0.35 ml, 4.3 mmol) in Et ₂ O (4 ml). The flask was washed with Et ₂ O (5 ml), which was also added to the mixture. The mixture was shaken at –78°C for 1 hour, then allowed to warm to room temperature. The precipitate was filtered (quickly) and the filter cake was washed with Et ₂ O (12 ml). The filtrate was concentrated in vacuo at room temperature to give the title compound (71b) as an oil, which was immediately used for the next step without further purification.

Step 3: Synthesis of 2–(((((2S,5R)–2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)– 2-methylpropane-1,3-diyl diacetate (71).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (430 mg, 2.3 mmol) was dissolved in THF (8 ml) and HMPA (0.8 ml), and the resulting solution was cooled to –78°C under argon. NaHMDS, 1.0 M in THF (2.4 mL, 2.4 mmol) was added dropwise to the cooled solution and shaken for 10 min. 2-(((chlorosulfonyl)oxy)methyl)-2-methylpropane-1,3-diyl diacetate (71b) (703 mg, 2.3 mmol) was dissolved in THF (8 ml), and quickly added to the reaction mixture. After shaking at –78°C for 10 min, the reaction mixture was allowed to warm to room temperature. After shaking at room temperature for 2 hours, EtOAc (400 ml) and saturated aqueous NaHCO ₃ (40 ml) and H ₂ O (40 ml) were added. The aqueous and organic layers were separated, and the organic layer was washed with saturated aqueous NaHCO ₃ (60 ml), H ₂ O (3×50 ml), brine (60 ml), and then dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-1:9) to give product (71) (198 mg, 19%) as an oil. LC–MS: m/z=452 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 6.50 (s, 1H), 5.68 (s, 1H), 4.72 (d, J=9.3 Hz, 1H), 4.46 (d, J=9.3 Hz, 1H), 4.16 (m, 1H), 4.12–4.08 (m, 4H), 3.36–3.32 (m, 1H), 3, 04–3.00 (m, 1H), 2.45–2.40 (m, 1H), 2.20–2.12 (m, 1H), 2.09 (s, 6H), 1.91– 1.76 (m, 2H), 1.11 (s, 3H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 171.1, 170.8, 170.7, 167.1, 76.9, 65.2, 61.9, 60.2, 47.1, 38 ,8, 20.8, 20.7, 17.5, 16.6.

Example 72

Synthesis of 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,4, 4-tetramethylpentyl 2,6-dimethoxybenzoate (72)

Step 1: Synthesis of 5-hydroxy-2,2,4,4-tetramethylpentyl 2,6-dimethoxybenzoate (72a).

Into a shaken solution of 2,2,4,4-tetramethylpentane-1,5-diol (39c) (0.64 g, 4.0 mmol) and pyridine (0.32 mL, 4.0 mmol) in DCM (27 mL ) 2,6-dimethoxybenzoyl chloride (80%; 1.0 g, 4.0 mmol) was added dropwise to DCM (10 mL) over 30 minutes at 0°C (ice bath) under argon. Allow the reaction mixture to warm to room temperature and shake overnight. The mixture was diluted with H ₂ O (30 ml) and the layers were separated. The aqueous layer was extracted with DCM (2×30 ml) and the combined organic layers were washed with brine (30 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-2:98) to give product (72a) (927 mg, 71%) as an oil. The compound was contaminated with a suspected diaceliated by-product. The material was used in the next step without further purification.

Step 2: Synthesis of 5-((chlorosulfonyl)oxy)-2,2,4,4-tetramethylpentyl 2,6-dimethoxybenzoate (72b).

A solution of sulfuryl chloride (0.21 ml, 2.8 mmol) in Et ₂ O (13 ml) was cooled to –78°C under argon. A solution of 5-hydroxy-2,2,4,4-tetramethylpentyl 2,6-dimethoxybenzoate (72a) (921 mg, 2.8 mmol) and pyridine (0.23 ml, 2 .8 mmol) in Et ₂ O (13 ml). The mixture was shaken at –78°C for 5 hours. The mixture was filtered and the filtrate was saved to give a solution of product (72b) in Et ₂ O (about 20 ml). The yield was quantified. This mixture was used in the next step without further purification.

Step 3: Synthesis of 5-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2 ,4,4-tetramethylpentyl 2,6-dimethoxybenzoate (72).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (525 mg, 2.8 mmol) was dissolved in THF (33 ml) and 1 ,3-dimethyltetrahydropyrimidine-2(1H)-one (4 ml), and the resulting solution was cooled to –78°C under argon. A solution of NaHMDS, 1.0 M in THF (2.8 mL, 2.8 mmol) was added dropwise to the cooled solution and shaken for 90 min. A solution of 5-((chlorosulfonyl)oxy)-2,2,4,4-tetramethylpentyl 2,6-dimethoxybenzoate (72b) (1.2 g, 2.8 mmol) in Et ₂ O ( about 20 ml). After shaking for 10 minutes, the mixture was warmed to room temperature and shaken for 2 hours. The mixture was quenched with saturated aqueous sodium bicarbonate (40 ml) and extracted with EtOAc (40 ml). The organic layer was washed with H ₂ O (3×40 ml), brine (40 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (2:3-9:1) to give product (72) (726 mg, 43%) as a solid. LC–MS: m/z=572.08 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.32–7.26 (m, 1H), 6.56 (d, J=8.1 Hz, 2H), 6.52 (s, 1H) , 5.64 (s, 1H), 4.53 (d, J=8.7 Hz, 1H), 4.24 (d, J=9.0 Hz, 1H), 4.17 (s, 1H) , 4.07–4.04 (m, 3H), 3.81 (s, 6H), 3.34–3.30 (m, 1H), 3.00 (d, J=12.3 Hz, 1H ), 2.47–2.40 (m, 1H), 2.14 (m, 1H), 2.05–1.84 (m, 2H), 1.48 (s, 2H), 1.11 ( s, 6H), 1.10 (s, 6H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 171.0, 167.0, 166.8, 157.5, 131.1, 113.3, 103.9, 85.2, 74.2, 61 ,9, 60.2, 56.0, 47.2, 46.1, 36.0, 35.7, 26.4, 26.3, 25.9, 25.2, 20.8, 17.5 .

Example 73

Synthesis of ethyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylbutanoate (73)

Step 1: Synthesis of R/S-ethyl 3-((chlorosulfonyl)oxy)-2,2-dimethylbutanoate (73a).

A solution of freshly distilled sulfuryl chloride (148 µl, 2.0 mmol) in Et ₂ O (0.2 ml) was cooled to –78°C under argon. A solution of ethyl 3-hydroxy-2,2-dimethylbutanoate (prepared according to J. Med. Chem. 1987, 30, 366–374 and Ad. Synth. Catal. 2009, 351, 3128–) was added dropwise to the sulfuryl chloride solution over 15 min. 3132) (324 mg, 2.0 mmol) and pyridine (164 μl, 2.0 mmol) in Et ₂ O (0.2 ml). The flask was washed with Et ₂ O (2×20 ml), which was added to the reaction mixture. The mixture was shaken at –78°C for 30 minutes. The mixture was filtered and product (73a) was used directly in the next step in the accepted quantitative yield. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 5.34–5.29 (m, 1H), 4.22–4.14 (m, 2H), 1.55–1.52 (m, 3H ), 1.35–1.08 (m, 9H).

Step 2: Synthesis of ethyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2, 2-dimethylbutanoate (73).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (0.22 g, 1.2 mmol) was dissolved in THF (10 ml) and HMPA (0.5 ml), and the resulting stirred solution was cooled to –78°C under argon. A solution of NaHMDS, 1.0 M in THF (1.2 mL, 1.2 mmol) was added to the mixture and the mixture was shaken for 10 minutes. A solution of ethyl 3-((chlorosulfonyl)oxy)-2,2-dimethylbutanoate (73a) (0.51 g, 2.0 mmol) in Et ₂ O (20 ml) was quickly added to the reaction mixture. After 10 minutes of shaking at –78°C, the mixture was allowed to warm to room temperature and shaken for 1 hour. The mixture was cooled to 0°C, quenched with H ₂ O and diluted with EtOAc. The aqueous and organic layers were separated, and the organic layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-7:3) to give product (73) (70 mg, 15%) as a solid. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 6.51 (br. s, 1H), 5.66 (br. s, 1H), 5.32 (q, J=6.3 Hz, 1H) , 4.21–4.14 (m, 3H), 4.07 (t, J=6.3 Hz, 1H), 3.35–3.31 (m, 1H), 3.04–2.98 (m, 1H), 2.44–2.39 (m, 1H), 2.17–2.09 (m, 1H), 1.95–1.83 (m, 2H), 1.58–1 .48 (m, 3H), 1.31–1.20 (m, 9H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 174.5, 174.4, 171.2, 171.1, 166.8, 166.6, 91.1, 90.6, 62.0, 62 ,0, 61.5, 61.5, 60.2, 47.2, 47.2, 47.1, 21.2, 20.9, 20.8, 20.8, 20.6, 20.3 , 17.5, 17.5, 15.9, 15.5, 14.2 (Note: ¹³ C–NMR showed some duplicate peaks due to a mixture of diastereomers).

Example 74

Synthesis of (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl ((3,5,5-trimethyl-2-oxotetrahydrofuran-3-yl)methyl) sulfate (74)

Step 1: Synthesis of 3,5,5-trimethyldihydrofuran-2(3H)-one (74a).

5,5-dimethyldihydrofuran-2(3H)-one (4.7 g, 41.2 mmol) was dissolved in THF (94 ml) and the mixture was cooled to –78°C under argon. To a solution of lithium diisopropylamide, 2.0 M, a solution in THF (22.6 ml, 45.2 mmol) was added dropwise over 10 min. The reaction mixture was shaken at –78°C for 2 h, and then undiluted MeI (2.6 mL, 41.6 mmol) was added to the reaction mixture over 5 min. The reaction mixture was shaken at –78°C for 45 minutes and then allowed to warm to room temperature and shaken for 16 hours. The reaction was quenched with saturated NH ₄ Cl (25 ml) and the mixture was concentrated to remove THF. The aqueous residue was diluted with H ₂ O to dissolve the solid and then extracted with ethyl acetate (3×40 ml). The combined organic layer was concentrated in vacuo and the residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-2:3) as eluent to give a liquid which solidified on standing. This solid was further purified by Kugelrohr distillation to give product (74a) (3.2 g) as an oil. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 2.78–2.87 (m, 1H), 2.33 (dd, J=9.3, 12.3 Hz, 1H), 1.71 ( t, J=12.3 Hz, 1H), 1.45 (s, 3H), 1.38 (s, 3H), 1.29 (d, J=6.9 Hz, 3H).

Step 2: Synthesis of 3-((benzyloxy)methyl)-3,5,5-trimethyldihydrofuran-2(3H)-one (74b).

3,5,5-Trimethyldihydrofuran-2(3H)-one (74a) (3.2 g, 25.0 mmol) was dissolved in THF (60 ml) and the mixture was cooled to –78°C under argon. A solution of lithium diisopropylamide, 2.0 M in THF (13.7 mL, 27.5 mmol) was added dropwise over 10 min. The mixture was shaken at –78°C for 30 minutes, then undiluted benzyl chloromethyl ether (90%; 4.2 ml, 27.5 mmol) was added over 5 minutes. Allow the mixture to warm to room temperature and shake for 16 hours. Saturated NH ₄ Cl (10 ml) and H ₂ O (10 ml) were added and the solvent was removed in vacuo. The residue was extracted with EtOAc (2×75 ml), and the combined organic layers were washed with brine (2×75 ml), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo (5.8 g). The residue was purified by silica gel column chromatography using EtOAc/hexanes (0:1-2:3) to give product (2.27 g) and impurity fractions (1.35 g). The impurity fractions were repurified by silica gel column chromatography using EtOAc/hexanes (0:1–1:4) as eluent to provide additional pure product (74b) (1.39 g). The product (3.66 g) was oil. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 7.28–7.34 (m, 5H), 4.62 (dd, J=11.7, 35.1 Hz, 2H), 3.61 ( d, J=11.7 Hz, 1H), 3.32 (d, J=11.7 Hz, 1H), 2.48 (d, J=12.9 Hz, 1H), 1.89 (d, J=12.9 Hz, 1H), 1.45 (d, J=6.9 Hz, 6H), 1.26 (s, 3H).

Step 3: Synthesis of 3-(hydroxymethyl)-3,5,5-trimethyldihydrofuran-2(3H)-one (74c).

3-((benzyloxy)methyl)-3,5,5-trimethyldihydrofuran-2(3H)-one (74b) (1.8 g, 7.2 mmol) was dissolved in 2-propanol (60 ml) and the solution was degassed argon. Solid 10.0% palladium on carbon (0.31 g, 0.3 mmol) was added to the flask. The flask was sealed, and vacuum degassing was carried out, followed by backwashing with hydrogen (3 times). The reaction mixture was shaken for 6 hours. The suspension was filtered through Celite®, and the filter cake was washed with 2-propanol (15 ml). The filtrate was concentrated in vacuo to give product (74c) as a crude oil. ¹ H–NMR (300 MHz, CDCl ₃ ): δδ 3.75 (dd, J=6.9, 11.1 Hz, 1H), 3.51 (dd, J=5.7, 11.1 Hz, 1H), 2.33 (d, J=12.9 Hz, 1H), 2.23 (t, J=6 Hz, 1H), 1.94 (d, J=12.9 Hz, 1H), 1 .48 (d, J=6.9 Hz, 6H), 1.32 (s, 3H).

Step 4: Synthesis of (3,5,5-trimethyl-2-oxotetrahydrofuran-3-yl)methyl sulfochloride (74d).

A solution of 3-(hydroxymethyl)-3,5,5-trimethyldihydrofuran-2(3H)-one (74c) (0.50 g, 3.2 mmol) and pyridine (0.28 ml, 3.5 mmol) in Et ₂ O (10 ml) was cooled to –78°C under argon. Undiluted sulfuryl chloride (0.28 ml, 3.5 mmol) was added dropwise to the above solution using a syringe. The mixture was shaken at –78°C for 10 min, then the flask was warmed to room temperature and shaken for 1 h (monitored by TLC 30% EA/hexanes). A precipitate formed to form a thick suspension. The suspension was filtered through a 0.45 µm Teflon® filter and the filter cake was washed with fresh Et ₂ O (2 x 5 ml). An aliquot (0.5 ml) was taken and concentrated and NMR was performed on the mixture. The remaining solution containing product (74d) was used directly in the next step. ¹ H–NMR (300 MHz, CDCl ₃ ): δ 4.60 (d, J=9.3 Hz, 1H), 4.36 (d, J=9.3 Hz, 1H), 2.37 (d , J=14.1 Hz, 1H), 2.09 (d, J=13.5 Hz, 1H), 1.51 (d, J=8.4 Hz, 6H), 1.44 (s, 3H ).

Step 5: Synthesis of (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl ((3,5,5-trimethyl-2-oxotetrahydrofuran-3-yl )methyl) sulfate (74).

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1) (0.64 g, 3.5 mmol) was dissolved in THF (30 ml) and 1,3-dimethyltetrahydropyrimidine-2(1H)-one (1.4 ml), and the resulting solution was cooled to –78°C under argon. NaHMDS, a 1.0 M solution in THF (3.5 mL, 3.5 mmol) was added dropwise to the cooled solution and the mixture was shaken for 1 hour. A solution of (3,5,5-trimethyl- 2-oxotetrahydrofuran-3-yl)methyl sulfochloride (74d) (0.81 g, 3.2 mmol) in Et ₂ O from the previous reaction. Allow the mixture to warm to room temperature and shake overnight. Brine (100 ml) and EtOAc (100 ml) were added and the aqueous and organic layers were separated. The aqueous layer was extracted with EtOAc (2×100 ml), and the combined organic layers were washed with brine (3×100 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc/hexanes (1:4-1:0) as eluent to give a solid (0.42 g). The solid was triturated with Et ₂ O (100 ml) for 16 hours, filtered and the cake washed with fresh Et ₂ O (3 x 20 ml) to give product (74) (0.28 g) as a solid . LC–MS: m/z=406 [M+H] ⁺ . ¹ H–NMR (300 MHz, CDCl ₃ ): δ, 6.55 (br. d, J=44.7 Hz, 1H), 5.82 (br. s, 1H), 4.86 (dd, J =9.3, 63.6 Hz, 1H), 4.55 (dd, J=9.3, 46.2 Hz, 1H), 4.03–4.16 (m, 2H), 3.30– 3.35 (m, 1H), 3.06 (dd, J=4.8, 12.3 Hz, 1H), 2.38–2.45 (m, 2H), 2.10–2.20 ( m, 1H), 1.8–2.04 (m, 3H), 1.48 (s, 3H), 1.477 (d, J=6.6 Hz, 3H), 1.40 (d, J=4 ,2 Hz, 3H). ¹³ C–NMR (75 MHz, CDCl ₃ ): δ 177.3, 177.0, 170.9, 170.8, 167.3, 167.0, 82.0, 81.9, 78.6, 77 ,8, 61.9, 60.2, 60.2, 47.1, 46.9, 45.8, 45.7, 43.6, 43.2, 30.1, 29.8, 29.7 , 22.5, 20.7, 20.7, 17.4 (Note: ¹³ C–NMR showed some duplicate peaks due to a mixture of diastereomers).

Example 75

Synthesis of ethyl 3-(((((2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy)sulfonyl) hydroxy)-2,2-dimethylpropanoate (75)

(2S,5R)-6-(Benzyloxy)-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide (1) (3.6 mg, 0. 01 mmol) was dissolved in a mixed solvent (EtOAc/H ₂ O/EtOH: 0.22/0.34/0.11 ml), to which Et ₃ N (0.25 μl, 0.002 mmol) and Pd/C ( dry, 10%; 1.3 mg, 20 mol%) in N ₂ at room temperature. To replace nitrogen, a hydrogen balloon was placed on the reaction flask. The reaction mixture was degassed in vacuo and charged with hydrogen (3 times). The mixture was shaken at room temperature for 5 h and monitored by LCMS. When the reaction was complete, the mixture was diluted with EtOAc (2 ml) and washed with brine. The organic phase was isolated and dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue (4.3 mg, 0.02 mmol) was dissolved in THF (0.4 ml) and cooled to –78°C. NaHMDS (1M in THF; 21.3 μL, 0.02 mmol) was added dropwise. The reaction mixture was shaken at –78°C for 20 min, and then ethyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (7.8 mg, 0.03 mmol) was added. The reaction mixture was shaken at –78°C for 20 min and then slowly warmed to room temperature and shaken overnight (the reaction was monitored using LCMS). After completion of the reaction, EtOAc (5 ml) was added and the organic layer was washed with saturated NaHCO ₃ followed by brine. The organic phase was isolated and dried (Na ₂ SO ₄ ) and the product (75) was concentrated in vacuo. LC/MS: m/z=406 [M+H] ⁺

Example 76

Oral Bioavailability in Rats

A pharmacokinetic (PK) study was performed on three male Sprague–Dawley (SD) rats following intravenous (IV) and oral (PO) administration of 2 mg/kg avibactam and 10 mg/kg test compounds, respectively, and avibactam was measured at plasma.

Avibactam was dissolved in phosphate buffered saline (PBS) (pH 7.5) at 0.4 mg/ml for intravenous (IV) injection. Compounds for oral administration half in 10% ethanol/40% polyethylene glycol (PEG) 400/50% water for injection (WFI) (pH 6.5) at 1 mg/ml. Dose volumes administered were 5 mL/kg for IV and 10 mL/kg for PO. All aspects of this work, including housing, experimental portions, and disposal of animals were conducted generally in accordance with the Guide for the Care and Use of Laboratory Animals: Eighth Edition (National Academies Press, Washington, D.C. 2011); and Suckow et al. Ed. Laboratory Rat. 2nd Edition. Academic Press. New York. 2005. Animals had access to standard laboratory chow and autoclaved tap water ad libitum.

Aliquots of blood (300 μL to 400 μL) were collected from rats with jugular vein catheterization into lithium heparin-coated tubes at various time points. The tubes were mixed gently and stored on ice and then centrifuged at 2500 rpm for 15 minutes at 4°C within 1 hour of collection. For animals in control groups, blood was collected by cardiac puncture, and plasma was collected and stored frozen at −70°C until further analysis. Beaudoin et al., Bioanalytical method validation for the simultaneous determination of ceftazidime and avibactam in rat plasma. Bioanalysis. 2016 8:111–22.

Plasma samples were processed using acetonitrile precipitation and analyzed by LC–MS/MS. A plasma calibration curve was prepared with aliquots of drug-free plasma spiked with test substance at the indicated concentration levels. Spiked plasma samples were processed together with unknown plasma samples using the same procedure. Treated plasma samples were stored at −70°C until LC–MS/MS analysis was obtained, in which peak areas were recorded over time, and test substance concentrations in unknown plasma samples were determined using an appropriate calibration curve. The reported linear range of the assay as well as the lower limit of quantitation (LLQ) were determined. Graphs were made of the dependence of the concentration of the compound in plasma on time. Compound pharmacokinetic parameters after intravenous and oral administration (AUC _last , AUC _INF , T1 _/2 , _Tmax , and _Cmax ) were obtained from noncompartmental analysis (NCA) of plasma data using WinNonlin. WinNonlin® Certara LP Pharsight, St. Louis, MO.

In these tests, avibactam showed an oral bioavailability (%F) of 1.2%, and compounds (3), (4), (10), (11), (12), (13), (14), (15), (16), (17), (18), and (19) showed oral bioavailability (%F) greater than 10%. In addition, compounds (36), (37), (42), (53), (57), (58) and (59) showed oral bioavailability (%F) greater than 10%.

In these tests, relabactam exhibited an oral bioavailability (%F) of 1.8%, and compounds (20), (22), (23), and (25) exhibited oral bioavailability (%F) greater than 5%.

Example 77

Minimum Inhibitory Concentration

Minimum inhibitor concentration (MIC) values for the study monobactams and β-lactamase inhibitors were determined using broth microdilution susceptibility testing performed in accordance with Clinical and Laboratory Standards Institute (CLSI) guidelines. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard–Tenth Edition. CLSI document M07–A10. CLSI, 950 West Valley Road, Suite 2500, Wayne, PA 19087–1898 USA, 2015; CLSI. Performance Standards for Antimicrobial Susceptibility Testing: Twenty– Sixth Informational Supplement. CLSI document M100–S26, CLSI, 950 West Valley Road, Suite 2500, Wayne, PA 19087 USA, 2016) regarding a panel of bacterial strains expressing characteristic β-lactamases that confer resistance to β-lactams. Zasowski et al., The β–Lactams Strike Back: Ceftazidime–Avibactam. Pharmacotherapy 2015 35:755–70; Levasseur et al., In vitro antibacterial activity of the ceftazidime–avibactam combination against enterobacteriaceae, including strains with well–characterized β–lactamases. Antimicrob Agents Chemother 2015 59:1931–4. The compounds were stored as dry powder and stored at −20°C until testing. These compounds and reference drugs were dissolved in the appropriate solvent on the day of analysis. All drugs were tested using a drug concentration range from 0.001 μg/ml to 64 μg/ml. β-lactamase inhibitors were tested at a constant concentration of 4 μg/ml. Isolates were spotted onto appropriate media and incubated overnight at 35°C. MIC values were determined using cation-standardized Mueller-Hinton broth (MHBII; BD, Sparks, MD) according to CLSI recommendations in 96-well format plates. MIC was recorded after 18 h of incubation at 35°C. The MIC was read and reported as the lowest drug concentration that inhibited visible growth of the organism.

Example 78

Oral Bioavailability in Dogs

The oral bioavailability of certain avibactam prodrugs disclosed herein was assessed in dogs.

The finished dosage forms were received on the day of administration. Intravenous formulations were prepared aseptically, sterile filtered and brought to room temperature before administration. The intravenous formulation contained avibactam at a final concentration of 2.0 mg/mL in PBS at pH 7.5.

The oral dosage formulations had a final concentration of either avibactam or avibactam prodrug of 2 mg/mL in a solution of 1 mL ethanol, 4 mL PEG400, and 5 mL water for injection with pH adjusted to 7 with 1 N. NaOH.

The prepared forms were administered to male Beagle dogs weighing from 8 kg to 410 kg. Animals were maintained in accordance with the Guide for the Care and Use of Laboratory Animals, National Research Council, National Academies Press, Washington, DC, 2011.

Dogs received either an IV bolus dose of 10 mg/kg or an oral dose of 20 mg/kg. Dose levels were chosen to bridge the gap between the primary historical control data and the NHP study (American Veterinary Medical Association. AVMA Guidelines for Euthanasia. 2013) to accurately predict prodrug activity in humans. Intravenous administration was carried out into the cephalic vein, followed by rinsing with 0.5 ml of sterile saline. Oral administration via the stomach using a French scale 18 catheter followed by rinsing with 15 ml of deionized water. Two dogs were used for each study group.

Plasma concentrations of avibactam were measured at intervals after administration. Within 2 minutes of collection, 100 μl of whole blood was transferred into K ₂ EDTA tubes containing 300 μl of acetonitrile. Each blood/acetonitrile mixture was vortexed for approximately 30 seconds and immediately frozen on dry ice and kept frozen (−55°C to −85°C) until analysis. Avibactam concentration was determined using LC/MS/MS.

The area under the concentration/time curves (AUC) was calculated using the linear trapezoidal method with linear interpolation. Percent oral bioavailability (%F) of avibactam was determined by comparing AUC after oral administration with AUC after IV administration on a standardized dose basis.

Compounds (3), (13) and (15) demonstrated an oral bioavailability of avibactam in male Beagle dogs of greater than 50%F.

Example 79

Oral Bioavailability in Monkeys

The oral bioavailability of certain avibactam prodrugs disclosed herein was assessed in male cynomolgus monkeys.

The finished dosage forms were received on the day of administration. Intravenous formulations were prepared aseptically, sterile filtered and brought to room temperature before administration. The intravenous formulation contained avibactam at a final concentration of 2.0 mg/mL in PBS at pH 7.5.

The oral dosage formulations had a final concentration of either avibactam or avibactam prodrug of 2 mg/mL in a solution of 1 mL ethanol, 4 mL PEG400, and 5 mL water for injection with pH adjusted to 7 with 1 N. NaOH.

The prepared forms were administered to male Cynomolgus monkeys weighing from 2 kg to 4 kg. Animals were maintained in accordance with the Guide for the Care and Use of Laboratory Animals, National Research Council, National Academies Press, Washington, DC, 2011.

Monkeys received either an IV bolus dose of 10 mg/kg or an oral dose of 20 mg/kg. dose levels were chosen to mimic therapeutically effective systemic concentrations in humans. Intravenous administration was carried out into the saphenous vein. Oral administration was accomplished by oral intubation through a flexible oral tube. Two monkeys were used for each study group.

Plasma concentrations of avibactam were measured at intervals after administration. Within 2 minutes of collection, 100 μl of whole blood was transferred into K ₂ EDTA tubes containing 300 μl of acetonitrile. Each blood/acetonitrile mixture was vortexed for approximately 30 seconds and immediately frozen on dry ice and kept frozen (−55°C to −85°C) until analysis. Avibactam concentration was determined using LC/MS/MS.

The area under the concentration/time curves (AUC) was calculated using the linear trapezoidal method with linear interpolation. Percent oral bioavailability (%F) of avibactam was determined by comparing AUC after oral administration with AUC after IV administration on a standardized dose basis.

Compounds (3), (13) and (15) demonstrated an oral bioavailability of avibactam in cynomolgus monkeys of greater than 50%F.

Finally, it should be noted that there are alternative ways of implementing the embodiments disclosed herein. Accordingly, the present embodiments are to be considered illustrative and not limiting, and the claims are not to be limited to the details set forth herein, but may be modified within their scope and equivalents.

Claims (3)

A method of treating a bacterial infection in a patient, comprising administering to a patient in need of such treatment a therapeutically effective amount of ethyl 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane- 6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (3) or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a β-lactam antibiotic, wherein the bacteria causing the bacterial infection produces a β-lactamase and wherein the β-lactam antibiotic is ceftibuten.