Orally administered combination of a beta-lactam antibiotic and an avibactam derivative for treating bacterial infections - Patents.com

Abstract

A pharmaceutical composition containing a β-lactam antibiotic and an avibactam derivative and a method for treating bacterial infections using the pharmaceutical composition are disclosed. The pharmaceutical composition can be formulated for oral administration, and after oral administration, provides therapeutically effective amounts of the β-lactam antibiotic and avibactam in the patient's systemic circulation. The oral pharmaceutical composition and method can be used to treat infections caused by bacteria that produce β-lactamase enzymes.

Description

[Technical field]

[0001] This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 62 / 893,612, filed August 29, 2019, and U.S. Provisional Application No. 62 / 953,852, filed December 26, 2019, each of which is incorporated by reference in its entirety.

[0002] The present disclosure relates to an orally administered combination of a β-lactam antibiotic and an avibactam derivative. The pharmaceutical composition can be used to treat bacterial infections. [Background technology]

[0003] Antibiotic overuse, misapplication, and agricultural use have led to the emergence of resistant bacteria that are resistant to treatment with traditional anti-infectives, such as those based on the β-lactam or fluoroquinolone structures. Alarmingly, many of these resistant bacteria are the cause of common infections, including, for example, pneumonia and sepsis.

[0004] The development of resistance to commonly used β-lactam anti-infective drugs is related to the expression of β-lactamase by target bacteria. β-lactamase enzymes can hydrolyze the β-lactam ring of β-lactam antibiotics, rendering the antibiotics ineffective against β-lactamase-producing bacteria. Inhibition of β-lactamase with appropriate substrates can prevent the degradation of β-lactam antibiotics, thereby increasing the effectiveness of the administered β-lactam antibiotics and mitigating the development of resistance.

[0005] Avibactam is a β-lactamase inhibitor approved for IV use in combination with ceftazidime. Avibactam derivatives are in development that can provide therapeutically effective systemic concentrations of avibactam when administered orally. When co-administered with β-lactam antibiotics such as ceftibuten, avibactam derivatives offer the opportunity to orally treat bacterial infections caused by bacteria that produce β-lactamase enzymes. Summary of the Invention [Problem to be solved by the invention]

[0006] [Means for solving the problem]

[0007] According to the present invention, the pharmaceutical composition comprises: a β-lactam antibiotic or a pharma- ceutically acceptable salt thereof; and Avibactam derivatives of formula (1):

[0008] [ka] or a pharma- ceutically acceptable salt thereof [In the formula, Each R 1 are independent, C 1~6 alkyl, or each R 1 and the geminal carbon atom to which they are bonded is C 3~6 Cycloalkyl ring, C 3~6 Heterocycloalkyl ring, substituted C 3~6 Cycloalkyl ring, or substituted C 3~6 forming a heterocycloalkyl ring, R 2 is a single bond, C 1~6 Alkanediyl, C 1~6 Heteroalkanediyl, C 5~6 Cycloalkanediyl, C 5~6 Heterocycloalkanediyl, C6 arenediyl, C 5~6 Heteroarenediyl, substituted C 1~6 Alkanediyl, substituted C 1~6 Heteroalkanediyl, substituted C 5~6 Cycloalkanediyl, substituted C 5~6 Heterocycloalkanediyl, substituted C6 arenesiyl, and substituted C 5~6 selected from heteroarylene diyls, R 3 is C 1~6 Alkyl, -OC(O)-R4 , -SC(O)-R 4 , -NH-C(O)-R 4 , -OC(O)-OR 4 , -SC(O)-OR 4 , -NH-C(O)-OR 4 , -C(O)-OR 4 , -C(O)-SR 4 , -C(O)-NH-R 4 , -OC(O)-OR 4 , -OC(O)-SR 4 , -OC(O)-NH-R 4 , -SSR 4 , -SR 4 , -NH-R 4 , -CH(-NH2)(-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 is selected, R 4 is 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 Aryl alkyl, 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 5~8Heteroaryl, substituted C 7~10 Aryl alkyl and substituted C 5~10 heteroarylalkyl; R 5 is 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 C 5~8 Cycloalkyl, substituted C 6~12 Cycloalkylalkyl, substituted C 2~6 Heteroalkyl, substituted C 5~8 Heterocycloalkyl and substituted C 6~12 heterocycloalkylalkyl; R 6 is 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 C 5~8 Cycloalkyl, substituted C 6~12 Cycloalkylalkyl, substituted C 2~6 Heteroalkyl, substituted C 5~8 Heterocycloalkyl and substituted C 6~12 heterocycloalkylalkyl] Includes.

[0009] According to the present invention, an oral dosage form comprises a pharmaceutical composition according to the present invention.

[0010] According to the present invention, the kit comprises a pharmaceutical composition according to the present invention.

[0011] In accordance with the present invention, a method for treating a bacterial infection in a patient in need of such treatment comprises administering to the patient a therapeutically effective amount of: a β-lactam antibiotic or a pharma- ceutically acceptable salt thereof; and Avibactam derivatives of formula (1):

[0012] [ka] or a pharma- ceutically acceptable salt thereof [In the formula, Each R 1 are independent, C 1~6 alkyl, or each R 1 and the geminal carbon atom to which they are bonded is C 3~6 Cycloalkyl ring, C 3~6 Heterocycloalkyl ring, substituted C 3~6 Cycloalkyl ring, or substituted C 3~6 forming a heterocycloalkyl ring, R 2 is a single bond, C 1~6 Alkanediyl, C 1~6 Heteroalkanediyl, C 5~6 Cycloalkanediyl, C 5~6 Heterocycloalkanediyl, C6 arenediyl, C 5~6 Heteroarenediyl, substituted C 1~6 Alkanediyl, substituted C 1~6 Heteroalkanediyl, substituted C 5~6 Cycloalkanediyl, substituted C 5~6 Heterocycloalkanediyl, substituted C6 arenesiyl, and substituted C 5~6 selected from heteroarylene diyls, R 3 is C 1~6 Alkyl, -OC(O)-R 4 , -SC(O)-R 4 , -NH-C(O)-R 4 , -OC(O)-OR 4 , -SC(O)-OR 4 , -NH-C(O)-OR 4 , -C(O)-OR 4 , -C(O)-SR 4 , -C(O)-NH-R 4, -OC(O)-OR 4 , -OC(O)-SR 4 , -OC(O)-NH-R 4 , -SSR 4 , -SR 4 , -NH-R 4 , -CH(-NH2)(-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 is selected, R 4 is 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 Aryl alkyl, 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 Aryl alkyl and substituted C 5~10 heteroarylalkyl; R 5 is hydrogen, C 1~6 Alkyl, C 5~8 Cycloalkyl, C 6~12 Cycloalkylalkyl, C 2~6 Heteroalkyl, C 5~8Heterocycloalkyl, C 6~12 Heterocycloalkylalkyl, substituted C 1~6 Alkyl, substituted C 5~8 Cycloalkyl, substituted C 6~12 Cycloalkylalkyl, substituted C 2~6 Heteroalkyl, substituted C 5~8 Heterocycloalkyl and substituted C 6~12 heterocycloalkylalkyl; R 6 is 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 C 5~8 Cycloalkyl, substituted C 6~12 Cycloalkylalkyl, substituted C 2~6 Heteroalkyl, substituted C 5~8 Heterocycloalkyl and substituted C 6~12 heterocycloalkylalkyl] orally administering

[0013] According to the present invention, a method of treating a bacterial infection in a patient in need of such treatment comprises orally administering to the patient a therapeutically effective amount of a pharmaceutical composition according to the present invention.

[0014] The drawings described herein are for illustrative purposes only and are not intended to limit the scope of the present disclosure. [Brief description of the drawings]

[0015] [Figure 1] Results of a ceftibuten dose-finding study, expressed as mean log10 CFU / mL over time, for a total population of Escherichia coli (E. coli) ATCC 25922 exposed to ceftibuten doses ranging from 12.5 mg / L to 267 mg / L q8h are presented. [Diagram 2] The change in log10 CFU / mL from baseline at 24 hours is shown for ceftibuten %T>MIC for the entire E. coli ATCC 25922 population exposed to ceftibuten doses ranging from 12.5 mg / L to 267 mg / L q8h. [Diagram 3] Figures 3A-3I show the results of mean ceftibuten / avibactam dosing frequency studies for K. pneumoniae BAA-1705 (Figures 3A, 3D, and 3H), K. pneumoniae 908 (Figures 3B, 3E, and 3H), and K. pneumoniae 79 (Figures 3C, 3F, and 3I) with ceftibuten at total daily doses of 400 mg / L (Figures 3A-3C), 800 mg / L (Figures 3D-3F), and 1,200 mg / L (Figures 3G-3I) administered in combination with avibactam at a total dose of 1,500 mg / L q8h, q12h, or q24h. [Figure 4] Results of a ceftibuten / avibactam dose-finding study, expressed as mean log10 CFU / mL over time, for the entire K. pneumoniae 19701 population using a ceftibuten 200 mg / L q8h dose combined with an avibactam regimen of 31.3 mg / L to 750 mg / L q8h are presented. [Diagram 5] Results of a ceftibuten / avibactam dose-finding study for E. cloacae 4184 using a dose of ceftibuten 200 mg / L q8h alone or in combination with avibactam regimens of 31.3 mg / L to 750 mg / L q8h are presented. [Figure 6] Mean E. coli 4643 total bacterial loads following exposure to ceftibuten 400 mg / L q8h alone or in combination with avibactam concentrations ranging from 31.3 mg / L to 750 mg / L q8h are shown. [Figure 7]Figures 7A-7H show the mean E. coli 4643 total bacterial load following exposure to ceftibuten 400 mg / L q8h alone or in combination with avibactam concentrations ranging from 31.3 mg / L to 750 mg / L q8h. [Figure 8] Mean K. pneumoniae 19701 total bacterial loads following exposure to ceftibuten 400 mg q8h alone or in combination with avibactam concentrations ranging from 31.3 mg / L to 750 mg / L q8h are shown. [Figure 9] Figures 9A-9I show the mean K. pneumoniae 19701 total bacterial load following exposure to ceftibuten 400 mg q8h alone or in combination with avibactam concentrations ranging from 31.3 mg / L to 750 mg / L q8h. [Figure 10] Mean E. cloacae 4184 total bacterial loads following exposure to ceftibuten 400 mg q8h alone or in combination with avibactam concentrations ranging from 31.3 mg / L to 750 mg / L q8h are shown. [Figure 11] Figures 11A-11I show the mean E. cloacae 4184 total bacterial load following exposure to ceftibuten 400 mg q8h alone or in combination with avibactam concentrations ranging from 31.3 mg / L to 750 mg / L q8h. [Figure 12] The absolute bioavailability of avibactam is shown for equivalent doses of orally administered avibactam derivative (3). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment of a moiety or substituent. For example, -CONH2 is attached through a carbon atom.

[0017] "Alkyl" refers to a saturated or unsaturated branched or straight-chain monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene, or alkyne. Examples of alkyl groups include methyl; ethyl, such as ethanyl, ethenyl, and ethynyl; propyl, 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-yn-1-yl, and prop-2-yn-1-yl; butan-1-yl, butan-2-yl, and 2-methyl-propan-1-yl. butyl, 2-methyl-propan-2-yl, but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc. The term "alkyl" is specifically intended 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 a combination of carbon-carbon single, double, and triple bonds. Where a specific level of saturation is intended, the terms alkanyl, alkenyl, and alkynyl are used. Alkyl groups include those having a C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, C 1~3 It may be alkyl, ethyl or methyl.

[0018] "Alkoxy" refers to the radical -OR, where R is alkyl as defined herein. Examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. An alkoxy group is one selected from the group consisting of C 1~6 Alkoxy, C 1~5 Alkoxy, C 1~4 Alkoxy, C 1~3 It may be alkoxy, ethoxy, or methoxy.

[0019] "Aryl" alone or as part of another substituent refers to a monovalent aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Aryl includes 5- and 6-membered carbocyclic aromatic rings, e.g., benzene; bicyclic ring systems in which at least one ring is carbocyclic and aromatic, e.g., naphthalene, indane, and tetralin; and tricyclic ring systems in which at least one ring is carbocyclic and aromatic, e.g., fluorene. Aryl includes multi-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 includes a phenyl ring fused to a 5- to 7-membered heterocycloalkyl ring containing one or more heteroatoms selected from N, O, and S. In such fused bicyclic ring systems in which only one of the rings is a carbocyclic aromatic ring, the radical carbon atom may be in the carbocyclic aromatic ring or in the heterocycloalkyl ring. Examples of aryl groups include groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like. 6~10 Aryl, C 6~9 Aryl, C 6~8 It may be aryl, or phenyl, however aryl does not in any way encompass or overlap with heteroaryl, which is separately defined herein.

[0020] "Arylalkyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom is replaced by an aryl group. Examples of arylalkyl groups include benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethene-1-yl, naphthobenzyl, and 2-naphthophenylethan-1-yl. Where specific alkyl moieties are intended, the nomenclature arylalkanyl, arylalkenyl, or arylalkynyl is used. Arylalkyl groups are those having the C 7~16 It may be an arylalkyl, for example, the alkanyl, alkenyl or alkynyl portion of the arylalkyl group may be C 1~6 and the aryl moiety is C 6~10 The arylalkyl group is C 7~16 For example, the alkanyl, alkenyl or alkynyl portion of the arylalkyl group may be C 1~6 and the aryl moiety is C 6~10 The arylalkyl group is C 7~9 arylalkyl, the alkyl moiety being C 1~3 The aryl alkyl group may be C 7~16 Aryl alkyl, C 7~14 Aryl alkyl, C 7~12 Aryl alkyl, C 7~10 Aryl alkyl, C 7~8 It may be arylalkyl, or benzyl.

[0021] "Avibactam derivative" refers to an avibactam derivative of formula (1), a pharma- ceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, or a combination of any of the foregoing. Avibactam derivatives of formula (1) include subgeneric and specific compounds within the scope of formula (1). When orally administered, the avibactam derivatives provide avibactam in the systemic circulation of a patient.

[0022] "Avibactam equivalent" refers to the amount of avibactam in the avibactam derivatives provided by the present disclosure. The avibactam derivatives provided by the present disclosure are absorbed in the gastrointestinal tract and release avibactam in the systemic circulation. The avibactam derivatives include a promoiety that enhances the absorption of avibactam from the gastrointestinal tract. Avibactam has a molecular weight of 265.25 Da, and the corresponding avibactam derivatives have a higher molecular weight due to the promoiety. For example, the avibactam derivative ethyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate has a molecular weight of 393.41 Da. Thus, this avibactam derivative contains 0.674 avibactam equivalents. In other words, the avibactam derivative ethyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate has an avibactam equivalent of 0.674. When administered orally, assuming 100% bioavailability and 100% in vivo conversion efficiency, 1 mg of avibactam derivative should provide 0.674 mg of avibactam in the patient's systemic circulation. The avibactam equivalent provided by a particular avibactam derivative depends, at least in part, on factors that affect the oral bioavailability of a particular avibactam derivative, such as, for example, the stability of the avibactam derivative in the gastrointestinal tract, the extent of absorption into the systemic circulation, and the conversion efficiency of the avibactam derivative to avibactam in the systemic circulation. The oral bioavailability percentage depends on these multiple factors. The avibactam derivatives provided by the present disclosure may exhibit oral bioavailability in a patient, such as a human, of, for example, greater than 20F%, greater than 30F%, greater than 40F%, greater than 50F%, or greater than 60F%.For example, a 1 mg dose of the avibactam derivative ethyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate, which has an oral bioavailability of 25F%, may provide 0.25 mg of avibactam in the patient's systemic circulation.

[0023] "Bioavailability" refers to the fraction and amount of drug that reaches a patient's systemic circulation following administration of the drug or a prodrug thereof to a patient, and can be determined, for example, by evaluating the plasma concentration-versus-time profile for the drug. Parameters useful in characterizing a plasma or blood concentration-versus-time curve include the area under the curve (AUC), the time to maximum concentration (T max ), half-maximum concentration time (T 1 / 2 ), and maximum drug concentration (C max ) and C max is the maximum concentration of drug in a patient's plasma after administration of a dose of drug or drug form to a patient, and T max is the maximum concentration of a drug in a patient's plasma after administration of a dose of the drug or drug form to the patient (C max ) until

[0024] "Oral bioavailability" (F%) refers to the fraction of an orally administered drug that reaches the systemic circulation compared to a comparable dose delivered intravenously.

[0025] The "compounds" and moieties provided by this disclosure include any specific compounds within these formulas. Compounds can be identified by either their chemical structure and / or chemical name. Compounds are named using ChemBioDraw Ultra Version 14.0.0.117 (CambridgeSoft, Cambridge, MA) naming / structure program. In case of conflict between chemical structure and chemical name, the chemical structure is determinative of the identity of the compound. Compounds described herein may contain one or more asymmetric centers and / or double bonds, and therefore may exist as stereoisomers, such as double bond isomers (i.e., geometric isomers), enantiomers, diastereoisomers, or atropisomers. As such, any chemical structure within the scope of this specification that is depicted in whole or in part in a relative configuration encompasses all of the possible enantiomers and stereoisomers of the depicted compound, including stereomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) as well as enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation or chiral synthesis techniques well known to those skilled in the art.

[0026] The compounds and moieties provided by the present disclosure include the optical isomers of the compounds and moieties, their racemates, and other mixtures. In such embodiments, single enantiomers or diastereoisomers can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be achieved by conventional methods, such as, for example, crystallization in the presence of a resolving agent, or chromatography, for example, using a chiral high pressure liquid chromatography (HPLC) column equipped with a chiral stationary phase. In addition, the compounds include the (Z) and (E) forms (or cis and trans forms) of compounds with double bonds, either as single geometric isomers or mixtures thereof.

[0027] Compounds and moieties may also exist in several tautomeric forms, including enol, keto, and mixtures thereof. Thus, the chemical structures depicted herein encompass all possible tautomeric forms of the depicted compounds. Compounds may exist in unsolvated forms as well as solvated forms, including hydrated forms. Certain compounds may exist in multiple crystalline, co-crystalline, or amorphous forms. Compounds include their pharmaceutically acceptable salts, or pharmaceutically acceptable solvates of the free acid forms of any of the above, as well as crystalline forms of any of the above.

[0028] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl radical. A cycloalkyl group is a C 3~6 Cycloalkyl, C 3~5 Cycloalkyl, C 5~6 Cycloalkyl may be cyclopropyl, cyclopentyl, or cyclohexyl. Cycloalkyl may be selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0029] "Cycloalkylalkyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom is replaced with a cycloalkyl group, as defined herein. Where specific alkyl moieties are intended, the nomenclature cycloalkylalkyl, cycloalkylalkenyl, or cycloalkylalkynyl is used. A cycloalkylalkyl group is a C 4~30 For example, the alkanyl, alkenyl, or alkynyl portion of the cycloalkylalkyl group may be C 1~10 and the cycloalkyl portion of the cycloalkyl alkyl moiety is C 3~20 The cycloalkyl group is C 4~20 For example, the alkanyl, alkenyl, or alkynyl portion of the cycloalkylalkyl group may be C 1~8 The cycloalkyl portion of the cycloalkylalkyl group is C 3~12 Cycloalkylalkyl is C 4~9The alkyl portion of the cycloalkylalkyl group may be C 1~3 The cycloalkyl group is a C alkyl group. 3~6 Cycloalkylalkyl groups are C 4~12 Cycloalkylalkyl, C 4~10 Cycloalkylalkyl, C 4~8 Cycloalkylalkyl, and C 4~6 The cycloalkylalkyl group can be cyclopropylmethyl (-CH2-cyclo-C3H5), cyclopentylmethyl (-CH2-cyclo-C5H9), or cyclohexylmethyl (-CH2-cyclo-C6H 11 The cycloalkylalkyl group can be cyclopropylethenyl (-CH=CH-cyclo-C3H5), or cyclopentylethynyl (-C≡C-cyclo-C5H9).

[0030] "Cycloalkylheteroalkyl," alone or as part of another substituent, refers to a heteroalkyl group in which one or more of the carbon atoms (and some associated hydrogen atoms) of the alkyl group are independently replaced with the same or different heteroatom group or groups, and one of the hydrogen atoms bonded to the carbon atom is replaced with a cycloalkyl group. When specific alkyl moieties are intended, the nomenclature cycloalkylheteroalkanyl, cycloalkylheteroalkenyl, and cycloalkylheteroalkynyl is used. In cycloalkylheteroalkyl, the heteroatom group may be selected from -O-, -S-, -NH-, -N(-CH3)-, -SO-, and -SO2-, or the heteroatom group may be selected from -O- and -NH-, or the heteroatom group is -O- or -NH-.

[0031] "Cycloalkyloxy" refers to the radical -OR, where R is cycloalkyl as defined herein. Examples of cycloalkyloxy groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy. A cycloalkyloxy group is one selected from the group consisting of C 3~6 Cycloalkyloxy, C 3~5 Cycloalkyloxy, C 5~6 It may be cycloalkyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, or cyclohexyloxy.

[0032] "Disease" refers to any disease, disorder, condition, or symptom of those mentioned above.

[0033] "Fluoroalkyl" refers to an alkyl group, as defined herein, in which one or more of the hydrogen atoms have been replaced with fluoro. A fluoroalkyl group is a C 1~6 Fluoroalkyl, C 1~5 Fluoroalkyl, C 1~4 Fluoroalkyl, or C 1~3 It may be fluoroalkyl. The fluoroalkyl group may be pentafluoroethyl (-CF2CF3) or trifluoromethyl (-CF3).

[0034] "Fluoroalkoxy" refers to an alkoxy group, as defined herein, in which one or more of the hydrogen atoms have been replaced with fluoro. A fluoroalkoxy group is a C 1~6 Fluoroalkoxy, C 1~5 Fluoroalkoxy, C 1~4 Fluoroalkoxy, C 1~3 , fluoroalkoxy, -OCF2CF3, or -OCF3.

[0035] "Halogen" refers to a fluoro, chloro, bromo, or iodo group.

[0036] "Heteroalkoxy" refers to an alkoxy group in which one or more of the carbon atoms is replaced with a heteroatom. Heteroalkoxy groups include, for example, C 1~6 Heteroalkoxy, C 1~5 Heteroalkoxy, C 1~4 Heteroalkoxy, or C 1~3 In the heteroalkoxy, the heteroatom group may be selected from -O-, -S-, -NH-, -NR-, -SO2-, and -SO2-, or the heteroatom group may be selected from -O- and -NH-, or the heteroatom group is -O- and -NH-. The heteroalkoxy group is selected from C 1~6 Heteroalkoxy, C 1~5 Heteroalkoxy, C 1~4 Heteroalkoxy, or C 1~3 It may be a heteroalkoxy.

[0037] "Heteroalkyl," alone or as part of another substituent, refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatomic groups. Examples of heteroatomic groups include -O-, -S-, -NH-, -NR-, -OO-, -SS-, =NN=, -N=N-, -N=N-NR-, -PR-, -P(O)OR-, -P(O)R-, -POR-, -SO-, -SO2-, -Sn(R)2-, and the like, where each R is independently hydrogen, C, C-C, C-D, C-D, C-H ... 1~6 Alkyl, substituted C 1~6 Alkyl, C 6~12 Aryl, Substituted C 6~12 Aryl, C 7~18 Aryl alkyl 、 substitution C 7~18 Aryl alkyl, 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 6~12Heteroaryl, C 7~18 Heteroarylalkyl, and substituted C 7~18 Each R in the heteroatom group may be independently selected from hydrogen and C 1~3 For example, C 1~6 Reference to heteroalkyl refers to a C alkyl group in which at least one of the carbon atoms (and any associated hydrogen atoms) is replaced with a heteroatom. 1~6 It means an alkyl group. For example, C 1~6 Heteroalkyl includes groups having 5 carbon atoms and 1 heteroatom, groups having 4 carbon atoms and 2 heteroatoms, etc. In heteroalkyl, the heteroatom group may be selected from -O-, -S-, -NH-, -N(-CH3)-, -SO-, and -SO2-, the heteroatom group may be selected from -O- and -NH-, or the heteroatom group may be -O- or -NH-. Heteroalkyl groups include C 1~6 Heteroalkyl, C 1~5 Heteroalkyl, or C 1~4 Heteroalkyl, or C 1~3 It may be a heteroalkyl.

[0038] "Heteroaryl" refers to a monovalent heteroaromatic radical derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system, alone or as part of another substituent. Heteroaryl encompasses multiple ring systems with 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. In such fused bicyclic heteroaryl ring systems in which only one of the rings contains one or more heteroatoms, the radical carbon may be in the aromatic ring or in the heterocycloalkyl ring. When the total number of N, S, and O atoms in a heteroaryl group is more than 1, the heteroatoms may or may not be adjacent to each other. The total number of heteroatoms in a heteroaryl group is 2 or less. In the heteroaryl, the heteroatom group may be selected from -O-, -S-, -NH-, -N(-CH3)-, -S(O)-, and -SO2-, or the heteroatom group may be selected from -O- and -NH-, or the heteroatom group may be -O- or -NH-. Heteroaryl groups include, for example, 5~10 Heteroaryl, C 5~9 Heteroaryl, C 5~8 Heteroaryl, C 5~7 Heteroaryl, C 5~6 It may be selected from heteroaryl, C5 heteroaryl, or C6 heteroaryl.

[0039] Examples of suitable heteroaryl groups include groups derived from acridine, arsindole, carbazole, α-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, 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, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, thiazolidine, or oxazolidine. Heteroaryl groups can be derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole, or pyrazine.For example, heteroaryl can be C5 heteroaryl and can be selected from furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, or isoxazolyl.Heteroaryl can be C6 heteroaryl and can be selected from pyridinyl, pyrazinyl, pyrimidinyl, and pyridazinyl.

[0040] "Heteroarylalkyl" refers to an arylalkyl group in which one of the carbon atoms (and some associated hydrogen atoms) is replaced with a heteroatom. Heteroarylalkyl groups include, for example, C 6~16 Heteroarylalkyl, C 6~14 Heteroarylalkyl, C 6~12 Heteroarylalkyl, C 6~10 Heteroarylalkyl, C 6~8Heteroarylalkyl may be C7 heteroarylalkyl, or C6 heteroarylalkyl. In heteroarylalkyl, the heteroatom group may be, for example, selected from -O-, -S-, -NH-, -N(-CH3)-, -SO-, and -SO2-, or the heteroatom group may be selected from -O- and -NH-, or the heteroatom group may be -O- or -NH-.

[0041] "Heterocycloalkyl", alone 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 with the same or different heteroatoms; or a parent aromatic ring system in which one or more carbon atoms (and some associated hydrogen atoms) are independently replaced with the same or different heteroatoms, such that the ring system violates the Hückel rule. Examples of heteroatoms replacing carbon atoms include N, P, O, S, and Si. Examples of heterocycloalkyl groups include groups derived from epoxides, azirines, thiiranes, imidazolidines, morpholines, piperazines, piperidines, pyrazolidines, pyrrolidines, and quinuclidines. Heterocycloalkyls may be C5 heterocycloalkyls and may be selected from pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, doxolanyl, and dithiolanyl. The heterocycloalkyl may be a C6 heterocycloalkyl and may be selected from piperidinyl, tetrahydropyranyl, piperidinyl, oxazinyl, dithianyl, and dioxanyl. The heterocycloalkyl group may be selected from C 3~6 Heterocycloalkyl, C 3~5 Heterocycloalkyl, C 5~6Heterocycloalkyl may be a C5 heterocycloalkyl or a C6 heterocycloalkyl. In the heterocycloalkyl, the heteroatom group may be selected from -O-, -S-, -NH-, -N(-CH3)-, -SO-, and -SO2-, or the heteroatom group may be selected from -O- and -NH-, or the heteroatom group may be -O- or -NH-.

[0042] "Heterocycloalkylalkyl" refers to a cycloalkylalkyl group in which one or more carbon atoms (and any associated hydrogen atoms) of the cycloalkyl ring are independently replaced with the same or different heteroatoms. Heterocycloalkylalkyl includes, for example, C 4~12 Heterocycloalkylalkyl, C 4~10 Heterocycloalkylalkyl, C 4~8 Heterocycloalkylalkyl, C 4~6 Heterocycloalkylalkyl, C 6~7 Heterocycloalkylalkyl, or C6 heterocycloalkylalkyl or C7 heterocycloalkylalkyl. In the heterocycloalkylalkyl, the heteroatom group may be selected from -O-, -S-, -NH-, -N(-CH3)-, -SO-, and -SO2-, or the heteroatom group may be selected from -O- and -NH-, or the heteroatom group may be -O- or -NH-.

[0043] "Parent Aromatic Ring System" refers to an unsaturated cyclic or polycyclic ring system having a cyclic conjugated π (pi) electron system containing 4n+2 electrons (Hückel's rule). Included within the definition of "parent aromatic ring system" are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, fluorene, indane, indene, or phenalene. Examples of parent aromatic ring systems include aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene.

[0044] "Hydrate" refers to a compound in which water is incorporated in stoichiometric proportions into the crystal lattice, forming an adduct. Methods for making hydrates include, for example, storage in an atmosphere containing water vapor, dosage forms containing water, or routine pharmaceutical processing steps such as crystallization from water or mixed aqueous solvents, freeze-drying, wet granulation, aqueous film coating, or spray drying. Hydrates can also be formed under certain circumstances from crystalline solvates, exposed to water vapor, or suspended in water of anhydrous material. Hydrates can also be crystallized in more than one form, resulting in hydrate polymorphism. Compounds can be, for example, monohydrates, dihydrates, or trihydrates.

[0045] "Metabolic intermediate" refers to a compound formed in vivo by metabolism of a parent compound and undergoing further reactions in vivo to release an active drug. The compound of formula (1) is a protected sulfonate nucleophile prodrug of the non-β-lactam β-lactamase inhibitor avibactam that is metabolized in vivo to provide avibactam ([2S,5R]-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate). The metabolic intermediate undergoes nucleophilic cyclization to release avibactam and one or more reaction products. It is desirable that the reaction product or its metabolites are not toxic.

[0046] "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 may 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. A neopentyl group has the structure:

[0047] [ka] [In the formula, each R 1 and R may be defined as for formula (1).

[0048] "Parent Aromatic Ring System" refers to an unsaturated cyclic or polycyclic ring system having a conjugated pi-electron system. Included within the definition of "parent aromatic ring system" are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, fluorene, indane, indene, and phenalene. Examples of parent aromatic ring systems include aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene.

[0049] "Parent Heteroaromatic Ring System" refers to an aromatic ring system in which one or more carbon atoms (and some associated hydrogen atoms) are independently replaced with the same or different heteroatom groups, so as to maintain the contiguous π-electron system characteristic of aromatic systems and the number of π-electrons corresponding to Hückel's rule (4n+2). Examples of heteroatoms replacing carbon atoms include N, P, O, S, and Si. Included within the definition of "parent heteroaromatic ring system" are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, arsindoles, benzodioxa, benzofurans, chromans, chromenes, indoles, indolines, and xanthenes. Examples of parent heteroaromatic ring systems include arsindole, carbazole, β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, 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, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, thiazolidine, and oxazolidine.

[0050] "Patient" refers to a mammal, e.g., a human. "Pharmaceutically acceptable" refers to approved or approvable by a regulatory agency of the U.S. Federal or state government, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopoeias, for use in animals, especially humans.

[0051] "Pharmaceutically acceptable salt" refers to a salt of a compound that possesses 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, and phosphoric acid. Salts 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, 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, and muconic acid. Salts can be formed when one or more acidic protons present in the parent compound are replaced by metal ions such as alkali metal ions, alkaline earth metal ions, or aluminum ions, or combinations thereof; or coordinate with organic bases such as ethanolamine, diethanolamine, triethanolamine, and N-methylglucamine. Pharmaceutically acceptable salts can be hydrochloride salts. Pharmaceutically acceptable salts can be sodium salts. For compounds with two or more ionizable groups, pharma-ceutically acceptable salts can include one or more counterions, such as disalts, e.g., hydrochloride salts.

[0052] The term "pharmaceutically acceptable salts" includes hydrates and other solvates, as well as salts in crystalline or non-crystalline form. When a specific pharmaceutically acceptable salt is disclosed, it is understood that the specific salt, such as the hydrochloride salt, is an example of a salt, and other salts can be formed using techniques known to those skilled in the art. In addition, those skilled in the art will be able to convert the pharmaceutically acceptable salts to the corresponding compounds, free bases and / or free acids, using techniques generally known in the art. Pharmaceutically acceptable salts can include pharmaceutically acceptable esters.

[0053] "Pharmaceutically acceptable vehicle" refers to a pharma- ceutically acceptable diluent, a pharma- ceutically acceptable adjuvant, a pharma- ceutically acceptable excipient, a pharma- ceutically acceptable carrier, or a combination of any of the foregoing, that may be administered to a patient with a compound provided by the present disclosure, which does not destroy its pharmacological activity and which is non-toxic when administered in a dosage sufficient to provide a therapeutically effective amount of said compound.

[0054] "Pharmaceutical composition" refers to ceftibuten or a pharmaceutically acceptable salt thereof, and / or an avibactam derivative of formula (1) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable vehicle with which the ceftibuten or a pharmaceutically acceptable salt thereof and / or the avibactam derivative of formula (1) or a pharmaceutically acceptable salt thereof is administered to a patient.

[0055] "Preventing" or "prevention" refers to reducing the risk of acquiring a disease or disorder (i.e., not developing at least one clinical symptom of the disease in a patient who may be exposed to or susceptible to the disease, but who has not yet experienced or displayed symptoms of the disease). "Preventing" or "prevention" refers to reducing the symptoms of the disease by prophylactically taking the compound. Preventing the onset of a disorder, or applying a treatment to prevent it, is known as prophylaxis.

[0056] "Prodrug" refers to a derivative of a drug molecule that requires transformation in the body to release the active drug. Prodrugs are often, but not necessarily, pharmacologically inactive until converted to the parent drug. The avibactam derivative of formula (1) is a prodrug of avibactam.

[0057] A "promoiety" refers to a group that is attached to a drug, typically to a functional group of the drug, via a bond that is cleavable under defined conditions of use. The bond between the drug and the promoiety may be cleaved by enzymatic or non-enzymatic means. Under conditions of use, for example after administration to a patient, the bond between the drug and the promoiety may be cleaved to release the parent drug. Cleavage of the promoiety may proceed spontaneously, such as via a hydrolysis reaction, or may be catalyzed or induced by another agent, such as an enzyme, light, acid, or a change or exposure to a physical or environmental parameter, such as a change in temperature or pH. The agent may be endogenous to the conditions of use, such as an enzyme present in the systemic circulation of a patient to whom the prodrug is administered, or the agent may be exogenously supplied. For example, in the avibactam derivative of formula (1), the promoiety has the structure:

[0058] [ka] [In the formula, R 1 , R 2 , and R 3 may have the following definition:

[0059] "R 2 A "single bond" such as in the expression "is selected from a single bond" is R 2 refers to the part where R is a single bond (-). For example, R 2 Structure -C(R 1 )2-R 2 -R 3 In the part with -R 2 - corresponds to a single bond, "-", and the portion corresponds to the structure -C(R 1 )2-R 3 has.

[0060] "Solvate" refers to a molecular complex of a compound with one or more solvent molecules in stoichiometric or non-stoichiometric amounts. Such solvent molecules are those commonly used in the pharmaceutical field that are known to be harmless to patients, such as water, ethanol, etc. Molecular complexes of a compound or a portion of a compound with a solvent can be stabilized by non-covalent intramolecular forces, such as electrostatic forces, van der Waals forces, or hydrogen bonds. The term "hydrate" refers to a solvate in which one or more solvent molecules are water. Methods for making solvates include, but are not limited to, storage in an atmosphere containing the solvent, a dosage form that contains the solvent, or a routine pharmaceutical processing step, such as, for example, vapor diffusion crystallization (i.e., from a solvent or a mixture of solvents). Solvates can also form from other crystalline solvates or hydrates, on exposure to a solvent, or on suspension of a substance in a solvent, under certain circumstances. Solvates can crystallize in more than one form, resulting in solvate polymorphism.

[0061] "Substituted" refers to a group in which one or more hydrogen atoms are independently replaced with the same or different substituents. Each substituent is independently deuterium, halogen, -OH, -CN, -CF3, -OCF3, =O, -NO2, C 1~6 Alkoxy, C 1~6 each R may be independently selected from hydrogen and C 1~6 Each substituent is independently selected from deuterium, halogen, -NH2, -OH, C 1~3 Alkoxy, and C 1~3 Each substituent may be independently selected from deuterium, -OH, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, and trifluoromethoxy. Each substituent may be independently selected from deuterium, C 1~3 Alkyl, =O, C 1~3 Alkyl, C 1~3 Each substituent may be selected from deuterium, -OH, -NH2, C 1~3 Alkyl, and C1~3 It may be selected from alkoxy.

[0062] "Curing" a disease refers to eliminating the disease or disorder or eliminating the symptoms of the disease or disorder.

[0063] "Treating" or "treatment" of a disease refers to halting or ameliorating at least one of the clinical symptoms of a disease or disorder, reducing the risk of acquiring at least one of the clinical symptoms of a disease or disorder, reducing the occurrence of at least one of the clinical symptoms of a disease or disorder, or reducing the risk of acquiring at least one of the clinical symptoms of a disease or disorder. "Treating" or "treatment" also refers to stabilizing a disease, such as relieving one or more symptoms caused by a disease, reducing the extent of a disease, preventing or slowing the progression of a disease, preventing or slowing the recurrence of a disease, slowing or slowing the progression of a disease, improving the pathology, providing partial or total remission of a disease, reducing the dose of one or more other drugs required to treat the disease, slowing the progression of a disease, improving the quality of life, and / or prolonging survival. "Treating" or "treatment" of a disease or disorder refers to producing a clinical beneficial effect without curing the underlying disease or disorder.

[0064] "Treating" or "treatment" also refers to inhibiting a disease either physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of a physical parameter), or both, and inhibiting at least one physical parameter or symptom manifestation that may or may not be discernible to the patient. "Treating" 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 exposed to or susceptible to a disease or disorder, but who has not yet experienced or displayed symptoms of the disease.

[0065] "Therapeutically effective amount" refers to the amount of a compound that, when administered to a patient for treating a disease or at least one of the clinical symptoms of the disease, is sufficient to affect such treatment of the disease or its symptoms. "Therapeutically effective amount" may vary, for example, depending on 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 of the patient receiving treatment, and the judgment of the prescribing physician. The appropriate amount in any given case can be ascertained by one skilled in the art or can be determined by routine experimentation.

[0066] "Therapeutically effective dose" refers to a dose that results in an effective treatment of a disease or disorder in a patient. Therapeutically effective doses can vary from compound to compound and from patient to patient, and can depend on factors such as the condition of the patient and the route of delivery. Therapeutically effective doses can be determined according to routine pharmacological procedures known to those skilled in the art.

[0067] "Therapeutically effective amount" means an amount of a compound that, when administered to a patient to treat a disease, is sufficient to affect such treatment for the disease. "Therapeutically effective amount" may vary, for example, depending on the compound, the disease and its severity, and the age, weight, adsorption, distribution, metabolism and excretion of the patient to be treated. With respect to bacterial infection, a therapeutically effective amount may include an amount sufficient to reduce the total number of bacteria present in a patient and / or slow down the rate of bacterial growth. A therapeutically effective amount may be an amount sufficient to prevent bacterial infection or delay its recurrence. A therapeutically effective amount may reduce the number of bacterial cells; inhibit, slow, slow down, preferably stop to some extent the growth of bacterial cells; prevent or delay the occurrence and / or recurrence of bacterial infection; and / or relieve to some extent one or more of the symptoms associated with bacterial infection.

[0068] By "concurrent administration" it is meant that the first administration and the second administration in the combination treatment are administered within a time separation of less than 30 minutes, for example, less than 15 minutes, less than 10 minutes, less than 5 minutes, or less than 1 minute.

[0069] By "sequential administration" it is meant that a first administration and a second administration are administered within a time separation of, for example, more than 30 minutes, more than 60 minutes, or more than 120 minutes.

[0070] "Vehicle" refers to a diluent, excipient, or carrier with which a compound is administered to a patient. In some embodiments, the vehicle is pharma- ceutically acceptable.

[0071] "MIC" refers to the minimum inhibitory concentration of an antimicrobial agent that prevents visible growth of a microorganism after a particular incubation time, e.g., overnight incubation. MIC 90 and MIC 50 MIC is a metric used to assess the in vitro susceptibility of a cohort of bacterial isolates to a specific antimicrobial agent or combination of antimicrobial agents using a test method. 90 and MIC 50 The MIC values ​​refer to the minimum concentration of antibiotic at which 90% and 50% of the isolates are inhibited, respectively. 90 The MIC can be defined as the lowest concentration of antibiotic that inhibits visible growth of 90% of microbial isolates after overnight incubation. 50 may be defined as the minimum concentration of antibiotic that inhibits visible growth of 50% of microbial isolates after overnight incubation.

[0072] "Pharmacokinetics" (PK) refers to the time course of drug concentration in plasma resulting from a particular dosing regimen.

[0073] "Pharmacodynamics" (PD) refers to the relationship between drug concentrations in plasma and the resulting pharmacological effects.

[0074] The "PK / PD index" for an antimicrobial drug is a pharmacodynamic parameter expressed as bacteriostatic, 1 log kill or 2 log kill, which, in conjunction with pharmacokinetics, constitutes an exposure-response relationship (PK / PD) modulated by the MIC for a given bacterial isolate. The most common PK / PD measures associated with efficacy are the ratio of area under the concentration-time curve (AUC) to MIC (AUC:MIC), peak concentration (C max ) and the MIC (C max The PK / PD indices can be corrected for plasma protein binding to reflect free or unbound or microbiologically active drug, and are fAUC:MIC, fCt, and fCt. max :MIC, fT>MIC, and fT>C t Efficacy for the β-lactam class of antibiotics is controlled by the fT>MIC exposure, and a magnitude of 40%fT>MIC to 60%fT>MIC has been demonstrated to be associated with bacteriostatic activity by ceftibuten against various strains of Enterobacteriaceae.

[0075] Reference will now be made in detail to certain embodiments of the compounds, compositions and methods. The disclosed embodiments are not intended to limit the scope of the claims. On the contrary, the claims are intended to cover all alternatives, modifications and equivalents.

[0076] Pharmaceutical compositions provided by the present disclosure include ceftibuten and avibactam derivatives that, when orally administered, provide a therapeutically effective amount of ceftibuten and avibactam in the systemic circulation of a patient to treat bacterial infections, such as bacterial infections caused by bacteria that produce β-lactamase enzymes.

[0077] Methods provided by the present disclosure include a method of treating a bacterial infection in a patient comprising orally administering to a patient in need of such treatment a therapeutically effective amount of ceftibuten, or a pharma- ceutically acceptable salt thereof, and an avibactam derivative, or a pharma-ceutically acceptable salt thereof.

[0078] The pharmaceutical compositions provided by the present disclosure may include a β-lactam antibiotic or a combination of β-lactam antibiotics, and the methods of treatment may include administering the β-lactam antibiotic or combination of β-lactam antibiotics to a patient orally or by another suitable route.

[0079] The β-lactam antibiotic may be an oral β-lactam antibiotic that may have an oral bioavailability of greater than 10F%, greater than 20F%, greater than 30F%, greater than 40F%, greater than 50F%, greater than 60F%, greater than 70F%, greater than 80F%, or greater than 90F%.

[0080] The β-lactam antibiotic may include a β-lactam antibiotic derivative that provides an oral bioavailability of greater than 10F%, greater than 20F%, greater than 30F%, greater than 40F%, greater than 50F%, greater than 60F%, greater than 70F%, greater than 80F%, or greater than 90F% of the parent β-lactam antibiotic following oral administration.

[0081] Examples of suitable β-lactam antibiotics include amoxicillin, ampicillin, bacampicillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, mecillinam, nafcillin, oxacillin, penicillins, including penicillin G, penicillin V, piperacillin, pivampicillin, pivmecillinam, and ticarcillin; cephacetrile, cefadroxil, cephalexin, cephaloglycin, cephalonium, cephaloridine, cephalothin, cephalosporin ... Fapirine, Cefatrizine, Cefazaflur, Cefazedone, Cefazolin, Cephradine, Cefroxadine, Ceftezole, Cefaclor, Cefamandole, Cefmetazole, Cefonicide, Cefotetan, Cefoxitin, Cefprozil, Cefuroxime, Cefuzonam, Cefcapene, Cefdaloxime, Cefdinir, Cefditoren, Cefetamet, Cefixime, Cefmenoxime, Cefodizime, Cefotaxime, Cefpimizole, Cefpodoxime, Cef Teram, ceftibuten, ceftiofur, ceftiolene, ceftizoxime, ceftriaxone, cefoperazone, ceftazidime, cefclidine, cefepime, cefluprenam, cefoselis, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftaroline, cefaclomezine, cephaloram, cefaparol, cefcanel, cephedrolol, cephempidon, cefetrizole, cefibitril, cefmatilen, cefmepidium, cefovecin, cefoxazole, Cephalosporins, including cefpodoxime, cefrotil, cefsumide, cefracetime, ceftaxisme, ceftizoxime, ceftazidime, ceftolozane, ceftaroline, cefipime, ceftriaxone, cefoperazone, cephalain, loracarbef, and cefuroxime; monobactams, including aztreonam; and carbapenems, including imipenem, doripenem, ertapenem, faropenem, meropenem, sulopenem, and tebipenem.

[0082] The beta-lactam antibiotic may include ceftibuten, including cis-ceftibuten and / or trans-ceftibuten.

[0083] Ceftibuten, (6R,7R)-7-((Z)-2-(2-amino-4-thiazolyl)-4-carboxycrotonamido)-8-oxo-5-thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid, is a third generation cephalosporin antibiotic. Ceftibuten is used to treat bacterial infections such as upper or lower respiratory tract infections, urinary tract infections, intraperitoneal infections, and skin infections. Ceftibuten includes cis and trans isomers, the latter of which exhibits approximately 1 / 8 the antibiotic activity of the cis isomer. Ceftibuten may be provided as a pharmaceutically acceptable salt, hydrate, solvate, or any combination of the above. Pharmaceutically acceptable salts of ceftibuten include, for example, the dihydrate salt.

[0084] Oral ceftibuten, as a single pharmacologic active ingredient, is currently approved in the United States to treat bacterial infections such as acute bacterial exacerbations of chronic bronchitis, acute bacterial otitis media, and pharyngitis, and tonsillitis. For example, ceftibuten alone is approved for clinical use at doses of 200 mg and 400 mg per day (once daily (QD)).

[0085] The β-lactam antibiotic may include an orally bioavailable aztreonam derivative having the structure of formula (3):

[0086] [ka] or a pharma- ceutically acceptable salt thereof [In the formula, Each R 1 are independent, C 1~6 alkyl, or each R 1 and each R 1 The geminal carbon atom to which is bonded is C 3~6 Cycloalkyl ring, C 3~6 Heterocycloalkyl ring, substituted C 3~6 Cycloalkyl ring, or substituted C 3~6 forming a heterocycloalkyl ring, R2 is a single bond, C 1~6 Alkanediyl, C 1~6 Heteroalkanediyl, C 5~6 Cycloalkanediyl, C 5~6 Heterocycloalkanediyl, C6 arenediyl, C 5~6 Heteroarenediyl, substituted C 1~6 Alkanediyl, substituted C 1~6 Heteroalkanediyl, substituted C 5~6 Cycloalkanediyl, substituted C 5~6 Heterocycloalkanediyl, substituted C6 arenesiyl, and substituted C 5~6 selected from heteroarylene diyls, R 3 is C 1~6 Alkyl, -OC(O)-R 4 , -SC(O)-R 4 , -NH-C(O)-R 4 , -OC(O)-OR 4 , -SC(O)-OR 4 , -NH-C(O)-OR 4 , -C(O)-OR 4 , -C(O)-SR 4 , -C(O)-NH-R 4 , -OC(O)-OR 4 , -OC(O)-SR 4 , -OC(O)-NH-R 4 , -SSR 4 , -SR 4 , -NH-R 4 , -CH(-NH2)(-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 and substituted C 5~6 heteroaryl; R 4 is hydrogen, C 1~8 Alkyl, C 1~8 Heteroalkyl, C 5~8 Cycloalkyl, C 5~8 Heterocycloalkyl, C5~10 Cycloalkylalkyl, C 5~10 Heterocycloalkylalkyl, C 6~8 Aryl, C 5~8 Heteroaryl, C 7~10 Aryl alkyl, 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 Aryl alkyl and substituted C 5~10 heteroarylalkyl; R 5 is 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 C 5~8 Cycloalkyl, substituted C 6~12 Cycloalkylalkyl, substituted C 2~6 Heteroalkyl, substituted C 5~8 Heterocycloalkyl and substituted C 6~12 heterocycloalkylalkyl; R 6 is 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 C 5~8 Cycloalkyl, substituted C 6~12 Cycloalkylalkyl, substituted C2~6 Heteroalkyl, substituted C 5~8 Heterocycloalkyl and substituted C 6~12 heterocycloalkylalkyl; R 7 is 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 C 5~8 Cycloalkyl, substituted C 6~12 Cycloalkylalkyl, substituted C 2~6 Heteroalkyl, substituted C 5~8 Heterocycloalkyl and substituted C 6~12 heterocycloalkylalkyl] may have:

[0087] Orally bioavailable aztreonam derivatives are disclosed in US Pat. No. 10,280,161, which is incorporated by reference in its entirety.

[0088] Avibactam derivatives that provide bioavailability of avibactam in the systemic circulation of a patient after oral administration are disclosed in US Pat. No. 10,085,999, which is incorporated by reference in its entirety.

[0089] The avibactam derivatives provided by the present disclosure are sulfonate ester prodrugs of the non-β-lactam β-lactamase inhibitor avibactam. In the avibactam prodrugs, the nucleophilic moiety is located proximal to the hydrogen sulfate group. In vivo, the nucleophilic moiety reacts to release avibactam. Avibactam is an inhibitor of class A, class C, and certain class D β-lactamases and is useful in the treatment of bacterial infections when used in combination with β-lactam antibiotics such as ceftibuten.

[0090] Avibactam derivatives have the structure of formula (1):

[0091] [ka] or a pharma- ceutically acceptable salt thereof [In the formula, Each R 1 are independent, C 1~6 alkyl, or each R 1 and the geminal carbon atom to which they are bonded is C 3~6 Cycloalkyl ring, C 3~6 Heterocycloalkyl ring, substituted C 3~6 Cycloalkyl ring, or substituted C 3~6 forming a heterocycloalkyl ring, R 2 is a single bond, C 1~6 Alkanediyl, C 1~6 Heteroalkanediyl, C 5~6 Cycloalkanediyl, C 5~6 Heterocycloalkanediyl, C6 arenediyl, C 5~6 Heteroarenediyl, substituted C 1~6 Alkanediyl, substituted C 1~6 Heteroalkanediyl, substituted C 5~6 Cycloalkanediyl, substituted C 5~6 Heterocycloalkanediyl, substituted C6 arenesiyl, and substituted C 5~6 selected from heteroarylene diyls, R 3 is C 1~6 Alkyl, -OC(O)-R 4 , -SC(O)-R 4 , -NH-C(O)-R 4 , -OC(O)-OR 4 , -SC(O)-OR 4 , -NH-C(O)-OR 4 , -C(O)-OR 4 , -C(O)-SR 4 , -C(O)-NH-R 4 , -OC(O)-OR 4 , -OC(O)-SR 4, -OC(O)-NH-R 4 , -SSR 4 , -SR 4 , -NH-R 4 , -CH(-NH2)(-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 is selected, R 4 is 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 Aryl alkyl, 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 Aryl alkyl and substituted C 5~10 heteroarylalkyl; R 5 is 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 C1~6 Alkyl, substituted C 5~8 Cycloalkyl, substituted C 6~12 Cycloalkylalkyl, substituted C 2~6 Heteroalkyl, substituted C 5~8 Heterocycloalkyl and substituted C 6~12 heterocycloalkylalkyl; R 6 is 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 C 5~8 Cycloalkyl, substituted C 6~12 Cycloalkylalkyl, substituted C 2~6 Heteroalkyl, substituted C 5~8 Heterocycloalkyl and substituted C 6~12 heterocycloalkylalkyl] may have:

[0092] In the compound of formula (1), each R 1 are independent, C 1~6 It may be alkyl.

[0093] In the compound of formula (1), each R 1 may independently be methyl, ethyl, or n-propyl.

[0094] In the compound of formula (1), each R 1 may be the same and is methyl, ethyl, or n-propyl.

[0095] In the compound of formula (1), each R 1 is methyl.

[0096] In the compound of formula (1), each R 1 together with the geminal carbon atom to which they are attached, C 3~6Cycloalkyl ring or substituted C 3~6 It may form a cycloalkyl ring.

[0097] In the compound of formula (1), each R 1 together with the geminal carbon atom to which they are attached, C 3~6 For example, each R 1 may, together with the geminal carbon atom to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl ring.

[0098] In the compound of formula (1), each R 1 together with the geminal carbon atom to which they are attached, C 3~6 Heterocycloalkyl ring or substituted C 3~6 It may form a heterocycloalkyl ring.

[0099] In the compound of formula (1), R 2 is a single bond, C 1~2 Alkanediyl and substituted C 1~2 The alkyl group may be selected from alkanediyls.

[0100] In the compound of formula (1), R 2 may be a single bond.

[0101] In the compound of formula (1), R 2 may be a single bond, R 3 is C 1~6 It may be alkyl.

[0102] In the compound of formula (1), R 2 is C 1~2 Alkanediyl and Substituted C 1~2 The alkyl group may be selected from alkanediyls.

[0103] In the compound of formula (1), R 2 may be methanediyl, ethanediyl, substituted methanediyl, or substituted ethanediyl.

[0104] In the compound of formula (1), R 2 is a substitution C 1~2 It may be an alkanediyl, and the substituents are -OH, -CN, -CF3, -OCF3, =O, -NO2, C 1~6 Alkoxy, C 1~6 alkyl, -COOR, -NR2, and -CONR2, where each R is independently selected from hydrogen and C 1~6 is selected from alkyl.

[0105] In the compound of formula (1), R 2 is a substitution C 1~2 The substituent may be a nucleophilic group. For example, R 2 is a substitution C 1~2 It may be an alkanediyl, and the substituents are -OH, -CF3, -O-CF3, -NO2, -OC(O)-R 4 , -SC(O)-R 4 , -NH-C(O)-R 4 , -OC(O)-OR 4 , -SC(O)-OR 4 , -NH-C(O)-OR 4 , -C(O)-OR 4 , -C(O)-SR 4 , -C(O)-NH-R 4 , -OC(O)-OR 4 , -OC(O)-SR 4 , -OC(O)-NH-R 4 , -SSR 4 , -SR 4 , -NH-R 4 , -CH(-NH2)(-R 4 ), each R 4 is defined as for formula (1), or each R 4 is hydrogen and C 1~8 is selected from alkyl.

[0106] In the compound of formula (1), R 2 is a substitution C 1~2 It may be an alkanediyl, the substituents being -OH, -OC(O)-R4 , -SC(O)-R 4 , -NH-C(O)-R 4 , -C(O)-OR 4 , -C(O)-SR 4 , -C(O)-NH-R 4 , -SSR 4 , -SR 4 , -NH-R 4 , -CH(-NH2)(-R 4 ), permutation C 5~6 Aryl, -NHR 4 , -CH(-NH2)(-R 4 ) and R 4 is defined as for formula (1), or each R 4 is hydrogen and C 1~8 is selected from alkyl.

[0107] In the compound of formula (1), R 2 Substitute C 1~6 Alkanediyl, substituted C 1~6 Heteroalkanediyl or substituted C 5~6 When it is an arenadiyl, the stereochemistry of the carbon atom to which the substituent is attached may be in the (S) configuration.

[0108] In the compound of formula (1), R 2 Substitute C 1~6 Alkanediyl, substituted C 1~6 Heteroalkanediyl or substituted C 5~6 When it is an arenadiyl, the stereochemistry of the carbon atom to which the substituent is attached may be in the (R) configuration.

[0109] In the compound of formula (1), R 2 is C 5~6 Cycloalkanediyl, C 5~6 Heterocycloalkanediyl, C 5~6 Arrangele, and C 5~6 Heterocycloalkanediyl may be selected from.

[0110] In the compound of formula (1), R 2may be cyclopenta-1,3-diene-diyl, substituted cyclopenta-1,3-diene-diyl, benzene-diyl or substituted benzene-diyl. For example, R 2 may be 1,2-benzene-diyl or substituted 1,2-benzene-diyl.

[0111] In the compound of formula (1), R 3 is -OC(O)-R 4 , -SC(O)-R 4 , -NH-C(O)-R 4 , -OC(O)-OR 4 , -SC(O)-OR 4 , -NH-C(O)-OR 4 , -C(O)-OR 4 , -C(O)-SR 4 , -C(O)-NH-R 4 , -OC(O)-OR 4 , -OC(O)-SR 4 , -OC(O)-NH-R 4 , -SSR 4 , -SR 4 , -NH-R 4 , and -CH(-NH2)(-R 4 ), R 4 is defined as for formula (1), or each R 4 is hydrogen and C 1~8 It may be selected from alkyl.

[0112] In the compound of formula (1), R 3 is -OC(O)-R 4 , -C(O)-OR 4 , -SC(O)-R 4 , -C(O)-SR 4 , -SSR 4 , -NH-R 4 , and -CH(-NH2)(-R 4 ), R 4 is defined as for formula (1), or each R 4 is hydrogen and C 1~8It may be selected from alkyl.

[0113] In the compound of formula (1), R 3 is -C(O)-OR 4 R may be 4 is defined as for formula (1), or each R 4 is hydrogen and C 1~8 It may be selected from alkyl.

[0114] In the compound of formula (1), R 4 is 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, substituted C 5~6 Heterocycloalkyl and substituted C 5~6 It may be selected from aryl.

[0115] In the compound of formula (1), R 4 may be selected from methyl, ethyl, phenyl, and benzyl.

[0116] In the compound of formula (1), R 4 is hydrogen and C 1~8 It may be selected from alkyl.

[0117] In the compound of formula (1), R 4 is C 1~8 Alkyl, C 1~8 Heteroalkyl, C 7~9 Aryl alkyl, C 5~7 Heterocycloalkyl, Substituted C 1~8 Alkyl, substituted C 1~8 Heteroalkyl, substituted C 7~9 Aryl alkyl and substituted C 5~7 It may be selected from heterocycloalkyl.

[0118] In the compound of formula (1), R 4 is C1~8 Alkyl, C 1~8 Heteroalkyl, C 7~9 Arylalkyl, and C 5~7 It may be selected from heterocycloalkyl.

[0119] In the compound of formula (1), R 4 may 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.

[0120] In the compound of formula (1), R 3 is -C(O)-OR 4 R may be 4 is C 1~8 Alkyl, C 1~8 Heteroalkyl, C 5~7 Cycloalkyl, C 5~7 Heterocycloalkyl, C6 aryl, C 7~9 Aryl alkyl, substituted C 1~8 Alkyl, substituted C 1~8 Heteroalkyl, substituted C 5~6 Cycloalkyl, substituted C 5~6 Heterocycloalkyl, substituted C6 aryl, and C 7~9 It may be selected from arylalkyl.

[0121] In the compound of formula (1), R 3 is -C(O)-OR 4 R may be 4 is C 1~8 Alkyl, C 1~8 Heteroalkyl, C 7~9 Aryl alkyl, C 5~7 Heterocycloalkyl, Substituted C 1~8 Alkyl, substituted C 1~8 Heteroalkyl, substituted C 7~9 Aryl alkyl and substituted C 5~7 It may be selected from heterocycloalkyl.

[0122] In the compound of formula (1), R 3 is -C(O)-OR 4 R may be 4 is C 1~8 Alkyl, C 1~8 Heteroalkyl, C 7~9 Arylalkyl, and C 5~7 It may be selected from heterocycloalkyl.

[0123] In the compound of formula (1), R 3are -OC(O)-CH3, -OC(O)-CH2-CH3, -OC(O)-phenyl, -OC(O)-CH2-phenyl, -SC(O)-CH3, -SC(O)-CH2-CH3, -SC(O)-phenyl, -SC(O)-CH2-phenyl, -NH-C(O)-CH3, -NH-C(O)-CH2-CH3, -NH-C(O)-phenyl, -NH-C(O)-CH2-phenyl, -OC(O)-O-CH3, -OC(O)-O-CH2-CH3, -OC(O)-O-phenyl, -OC(O)-O-CH2-phenyl, -SC(O )-O-CH3, -SC(O)-O-CH2-CH3, -SC(O)-O-phenyl, -SC(O)-O-CH2-phenyl, -NH-C(O)-O-CH3, -NH-C(O)-O-CH2-CH3, -NH-C(O)-O-phenyl, -NH-C(O)-O-CH2-phenyl, -C(O)-O-CH3,-C(O)-O-CH2-CH3, -C(O)-O-phenyl, -C(O)-O-CH2-phenyl, -C(O)-O-CH3,-C(O)-O-CH2-CH3, -C(O)-O-phenyl, -C(O)-O-CH2-phenyl, -C(O)-S-CH3,-C(O)-S-CH2-CH3, -C(O)-S-phenyl, -C(O)-S-CH2-fu phenyl, -C(O)-NH-CH3, -C(O)-NH-CH2-CH3, -C(O)-NH-phenyl, -C(O)-NH-CH2-phenyl, -OC(O)-O-CH3, -OC(O)-O-CH2-CH3, -OC(O)-O-phenyl, -OC(O)-O-CH2-phenyl, -OC(O)-S-CH3, -OC(O)-S-CH2-CH3, -OC(O)-S-phenyl, -OC(O)-S-CH2-phenyl, -OC(O)-NH-CH3, -OC(O)-NH-CH2-CH3, -OC(O)-NH-phenyl, -O C(O)-NH-CH2-phenyl, -S-SH, -SS-CH3, -SS-CH2-CH3, -SS-phenyl, -SS-CH2-phenyl, -SH, -S-CH3, -S-CH2-CH3, -S-phenyl, -S-CH2-phenyl, -NH2, -NH-CH3, -NH-CH2-CH3, -NH-phenyl, -NH-CH2-phenyl, -CH(-NH2)(-CH3), -CH(-NH2)(-CH2-CH3), -CH(-NH2)(-phenyl), and -CH(-NH2)(-CH2-phenyl).

[0124] In the compound of formula (1), R 3 is 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 may be selected from the group consisting of aryl, heteroaryl, and containing at least one nucleophilic group. For example, R 3 has a structure of formula (2a) or formula (2b):

[0125] [ka] may have

[0126] In the compound of formula (1), R 4 is 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 It may be selected from aryl.

[0127] In the compound of formula (1), each R 1 is a C that contains two adjacent S atoms together with the carbon atom to which they are attached. 4~6 Heterocycloalkyl rings or substituted C rings containing at least one heteroatom selected from O and S and a carbonyl (=O) substituent bonded to the carbon atom adjacent to the at least one heteroatom. 4~6 It forms a heterocycloalkyl ring.

[0128] In the compound of formula (1), R 2 may be a bond, R 3 is C1~3 alkyl, and each R 1 is a C that contains two adjacent S atoms together with the carbon atom to which they are attached. 4~6 Heterocycloalkyl ring or substituted C containing at least one heteroatom selected from O and S and an =O substituent bonded to the carbon atom adjacent to the heteroatom. 4~6 It forms a heterocycloalkyl ring.

[0129] In the compound of formula (1), the promoiety -CH-C(R 1 )2-R 3 -R 4 may have any of the following structures, where R 3 is C 1~6 Alkyl, e.g., C 1~4 Alkyl may be, for example, methyl or ethyl:

[0130] [ka]

[0131] [ka]

[0132] In the compound of formula (1), R 2 may be a single bond, R 3 is C 1~3 alkyl, and each R 1 together with the carbon atom to which they are attached, C 4~6 Heterocycloalkyl ring or substituted C 4~6 It may form a heterocycloalkyl ring.

[0133] In the compound of formula (1), R 2 may be a single bond, R 3 is C 1~3 alkyl, and each R 1 is a C that contains two adjacent S atoms together with the carbon atom to which they are attached. 4~6Heterocycloalkyl rings or substituted C containing at least one heteroatom selected from O and S and a carbonyl (=O) substituent bonded to the carbon atom adjacent to the heteroatom. 4~6 It may form a heterocycloalkyl ring.

[0134] In the compound of formula (1), R 2 may be a single bond, R 3 is C 1~3 alkyl, and each R 1 may, together with the carbon atoms to which they are attached, form a 1,2-dithiolane, 1,2-dithane ring, a thietan-2-one ring, a dihydrothiophen-2(3H)-one ring, a tetrahydro-2H-thipyran-2-one ring, an oxetan-2-one ring, a dihydrofuran-2(3H)-one ring, or a tetrahydro-2H-pyran-2-one ring.

[0135] In the compound of formula (1), Each R 1 may be methyl; R 2 may be selected from a single bond, methanediyl, ethanediyl, -CH(-OH)-, -CH(-OC(O)-CHCH)-, and 1,2-benzene-diyl; R 3 is -OC(O)-R 4 , -C(O)-OR 4 , -SC(O)-R 4 , -C(O)-SR 4 , -SSR 4 , -NHR 4 , and -CH(-NH2)(-R 4 ), R 4 may be selected from hydrogen, methyl, ethyl, cyclopentyl, cyclohexyl, phenyl, benzyl, and 2-pyrrolidinyl.

[0136] In the compound of formula (1), Each R 1 and the geminal carbon to which they are bonded is C 3~6may form a cycloalkyl ring, R 2 may be selected from a bond, methanediyl, ethanediyl, -CH(-OH)-, -CH(-OC(O)-CHCH)-, and 1,2-benzene-diyl; R 3 is -OC(O)-R 4 , -C(O)-OR 4 , -SC(O)-R 4 , -C(O)-SR 4 , -SSR 4 , -NHR 4 , and -CH(-NH2)(-R 4 ), R 4 may be selected from hydrogen, methyl, ethyl, cyclopentyl, cyclohexyl, phenyl, benzyl, and 2-pyrrolidinyl.

[0137] In the compound of formula (1), R 2 may be a bond, R 3 is C 1~3 may be alkyl, Each R 1 may, together with the carbon atoms to which they are attached, form a 1,2-dithiolante, 1,2-ditane ring, a thietan-2-one ring, a dihydrothiophen-2(3H)-one ring, a tetrahydro-2H-thipyran-2-one ring, an oxetan-2-one ring, a dihydrofuran-2(3H)-one ring, or a tetrahydro-2H-pyran-2-one ring.

[0138] In the compound of formula (1), each R 1 may be methyl; R 2 may be selected from a single bond, methanediyl, ethanediyl, -CH(-OH)-, -CH(-OC(O)-CHCH)-, and 1,2-benzene-diyl; R 3 is -OC(O)-R 4 , -C(O)-OR 4 , -SC(O)-R4 , -C(O)-SR 4 , -SSR 4 , -NHR 4 , and -CH(-NH2)(-R 4 ), R 4 is C 1~8 Alkyl, C 1~8 Heteroalkyl, C 7~9 Arylalkyl, and C 5~7 It may be selected from heterocycloalkyl.

[0139] In the compound of formula (1), Each R 1 may be methyl; R 2 may be selected from a single bond, methanediyl, ethanediyl, -CH(-OH)-, -CH(-OC(O)-CHCH)-, and 1,2-benzene-diyl; R 3 is -C(O)-OR 4 and R 4 is C 1~8 Alkyl, C 1~8 Heteroalkyl, C 7~9 Arylalkyl, and C 5~7 It may be selected from heterocycloalkyl.

[0140] In the compound of formula (1), Each R 1 may be methyl; R 2 may be selected from a single bond, methanediyl, ethanediyl, -CH(-OH)-, -CH(-OC(O)-CHCH)-, and 1,2-benzene-diyl; R 3 is -OC(O)-R 4 , -C(O)-OR 4 , -SC(O)-R 4 , -C(O)-SR 4 , -SSR 4 , -NHR 4 , and -CH(-NH2)(-R4 ), R 4 may 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.

[0141] In the compound of formula (1), Each R 1 may be methyl; R 2 may be selected from a single bond, methanediyl, ethanediyl, -CH(-OH)-, -CH(-OC(O)-CHCH)-, and 1,2-benzene-diyl; R 3 is -C(O)-OR 4 and R 4 may 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.

[0142] In the compound of formula (1), Each R 1 may be methyl; R 2 may be a single bond, R 3 is -C(O)-OR 4 and R 4 is C 1~10 Alkyl, C 1~10 Heteroalkyl, C 7~10 Alkyl arenes, and C 5~10 It may be selected from heteroalkyl and cycloalkyl.

[0143] In the compound of formula (1), Each R 1 may be methyl; R2 may be a single bond, R 3 is -C(O)-OR 4 R may be 4 is C 1~10 Alkyl, C 1~10 Heteroalkyl, C 7~10 Alkyl arenes, and C 5~10 heteroalkylcycloalkyl; R 5 , R 6 , and R 7 Each may be hydrogen.

[0144] The compound of formula (1) 3-(((((1R,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-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (3); Benzyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (4); 4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutylbenzoate (6); 4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutylpropionate (7); benzyl(4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl)adipate (8); 6-(4-(((((1R,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-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (10); Isopropyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (11); Hexyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (12); Heptyl 3-(((((1R,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-(((((1R,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-(((((1R,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-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (16); Ethyl 1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclohexanecarboxylate (17); Ethyl 1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclopropanecarboxylate (18); Ethyl 1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclobutanecarboxylate (19); (1R,2S,5R)-2-Carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl 1H-imidazole-1-sulfonate (34); Ethyl 5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate (35); Hexyl 5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate (36); Heptyl 5-(((((1R,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-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate (38); 5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,4,4-tetramethylpentylpropionate (39); 5-(((((1R,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-(((((1R,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); (1R,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-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl pivalate (43); 3-(((((1R,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-(((((1R,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-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,3,3-tetramethylbutylbenzoate (46); 4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,3,3-tetramethylbutylpropionate (47); (1R,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-(((((1R,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-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl)phenylpivalate (50); S-(4-(((((1R,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-(((((1R,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-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl)ethanethioate (53); 3-(((((1R,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-(((((1R,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-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonate (56); Propyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (57); Butyl 3-(((((1R,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-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (59); 4-(((((1R,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-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylbutanoate (61); 4-(((((1R,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-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyladamantane-1-carboxylate (63); 4-(((((1R,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-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentyl benzoate (65); 5-(((((1R,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-(((((1R,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-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentyl 2-methylbenzoate (68); 4-(((((1R,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-((((((1R,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-((((((1R,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-(((((1R,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-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylbutanoate (73); (1R,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 pharma- ceutically acceptable salt of any of the above; and Any combination of the above may be selected from.

[0145] The compound of formula (1) Ethyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (3); Benzyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (4); Methyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (10); Isopropyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (11); Hexyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (12); Heptyl 3-(((((1R,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-(((((1R,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-(((((1R,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-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (16); Ethyl 1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclohexanecarboxylate (17); Ethyl 1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclopropanecarboxylate (18); Ethyl 1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclobutanecarboxylate (19); Hexyl 5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate (36); Heptyl 5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate (37); (1R,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-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl)ethanethioate (53); Propyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (57); Butyl 3-(((((1R,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-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (59); A pharma- ceutically acceptable salt of any of the above; and Any combination of the above may be selected from.

[0146] In the compound of formula (1), the compound is Ethyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (3); Benzyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (4); Methyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (10); Isopropyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (11); Hexyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (12); Heptyl 3-(((((1R,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-(((((1R,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-(((((1R,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-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (16); Ethyl 1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclohexanecarboxylate (17); Ethyl 1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclopropanecarboxylate (18); Ethyl 1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclobutanecarboxylate (19); A pharma- ceutically acceptable salt of any of the above; and Any combination of the above may be selected from.

[0147] The compound of formula (1) Hexyl 5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate (36); Heptyl 5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate (37); (1R,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-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl)ethanethioate (53); Propyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (57); Butyl 3-(((((1R,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-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (59); A pharma- ceutically acceptable salt of any of the above; and Any combination of the above may be selected from.

[0148] In the compound of formula (1), Each R 1 are independent, C 1~3 alkyl, or each R 1 together with the geminal carbon atom to which they are attached, C 3~6 Cycloalkyl ring, substituted C 3~6 Cycloalkyl ring, C 3~6 Heterocycloalkyl ring, or substituted C 3~6 forming a heterocycloalkyl ring, R 2 may be a single bond, R 3 is -C(O)-OR 4 and R 4 is C 1~8 Alkyl, C 1~8 Heteroalkyl, C7~9 Aryl alkyl, C 5~7 Heterocycloalkyl, Substituted C 1~8 Alkyl, substituted C 1~8 Heteroalkyl, substituted C 7~9 Aryl alkyl and substituted C 5~7 It may be selected from heterocycloalkyl.

[0149] In the compound of formula (1), Each R 1 are independent, C 1~3 alkyl, or each R 1 together with the carbon atom to which they are attached, C 3~6 It forms a cycloalkyl ring, R 2 may be selected from a single bond, methane-diyl, and ethane-diyl; R 3 is -C(O)-OR 4 and -SC(O)-R 4 R may be selected from 4 is C 1~10 Alkyl, C 1~10 Heteroalkyl, C 5~10 Aryl alkyl, C 3~6 Heterocycloalkyl and substituted C 4~10 Heterocycloalkyl may be selected from alkyl.

[0150] In the compound of formula (1), Each R 1 are independent, C 1~3 alkyl, or each R 1 together with the carbon atom to which they are attached, C 3~6 It forms a cycloalkyl ring, R 2 may be a single bond, R 3 is -C(O)-OR 4 R may be 4 is C 1~10 Alkyl, C 1~10 Heteroalkyl, C 5~10 Aryl alkyl, C3~6 Heterocycloalkyl and substituted C 4~10 Heterocycloalkyl may be selected from alkyl.

[0151] In the compound of formula (1), Each R 1 are independent, C 1~3 alkyl, or each R 1 together with the carbon atom to which they are attached, C 3~6 It forms a cycloalkyl ring, R 2 may be -(CH2)2-, R 3 is -C(O)-OR 4 R may be 4 is C 1~10 Alkyl, C 1~10 Heteroalkyl, C 5~10 Aryl alkyl, C 3~6 Heterocycloalkyl and substituted C 4~10 Heterocycloalkyl may be selected from alkyl.

[0152] In the compound of formula (1), Each R 1 is C 1~3 alkyl, or each R 1 together with the carbon atom to which they are attached, C 3~6 It forms a cycloalkyl ring, R 2 may be -CH2-, R 3 is -SC(O)-R 4 R may be 4 is C 1~10 Alkyl, C 1~10 Heteroalkyl, C 5~10 Aryl alkyl, C 3~6 Heterocycloalkyl, Substituted C 4~10 Heterocycloalkyl may be selected from alkyl.

[0153] In the compound of formula (1), Each R 1together with the carbon atom to which they are attached, C 3~6 Cycloalkyl ring, C 3~6 Heterocycloalkyl ring, C 3~6 Cycloalkyl ring, or C 3~6 forming a heterocycloalkyl ring, R 2 may be a single bond, R 3 is C 1~3 It may be alkyl.

[0154] In the compound of formula (1), Each R 1 are independent, C 1~3 alkyl, R 2 may be selected from a single bond and methanediyl; R 3 is -OC(O)-R 4 and -C(O)-OR 4 R may be selected from 4 is C 1~10 It may be selected from alkyl and substituted phenyl.

[0155] In the compound of formula (1), Each R 1 are independent, C 1~3 alkyl, R 2 may be a single bond, R 3 is -CH=C(R 4 ) 2, each R 4 is -C(O)-OR 8 or each R 4 together with the carbon atom to which they are attached form a substituted heterocyclohexyl ring; Each R 8 is C 1~4 It may be alkyl.

[0156] In the compound of formula (1), Each R 1 are independent, C 1~3alkyl, R 2 may be selected from a single bond and methanediyl; R 3 may be a substituted phenyl, where one or more of the substituents are independently -CH-OC(O)-R 4 and -OC(O)-R 4 R may be selected from 4 is C 1~10 It may be selected from alkyl and phenyl.

[0157] In the compound of formula (1), Each R 1 are independent, C 1~3 alkyl, R 2 is -C(R 8 )2- and -CH2-C(R 8 )2-, each R 8 are independent, C 1~3 alkyl, R 3 is -C(O)-OR 4 and -OC(O)-R 4 R may be selected from 4 is 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.

[0158] In the compound of formula (1), Each R 1 together with the carbon atom to which they are attached, the substitution C 5~6 It forms a heterocyclic ring, R 2 may be a single bond, R 3 is C 1~3 It may be alkyl.

[0159] The compound of formula (1) is represented by the formula Each R 1 Independently, C 1~3 alkyl, or each R 1 together with the carbon atom to which they are attached, C 3~6 It forms a cycloalkyl ring, R 2 may be selected from a single bond, methane-diyl, and ethane-diyl; R 3 -C(O)-OR 4 and -SC(O)-R 4 R may be selected from 4 But, C 1~10 Alkyl, C 1~10 Heteroalkyl, C 5~10 Aryl alkyl, C 3~6 Heterocycloalkyl and substituted C 4~10 Heterocycloalkylalkyl may be selected from the compounds of subgenus (1A), or a pharma- ceutically acceptable salt thereof.

[0160] In the compounds of subgenus (1A), each R 1 are independent, C 1~3 It may be selected from alkyl.

[0161] In the compounds of subgenus (1A), each R 1 together with the carbon atom to which they are attached, C 3~6 It forms a cycloalkyl ring.

[0162] In the compounds of subgenus (1A), R 2 may be a single bond.

[0163] In the compounds of subgenus (1A), R 2 may be methane-diyl.

[0164] In the compounds of subgenus (1A), R 2 may be ethane-diyl.

[0165] In the compounds of subgenus (1A), R 3 is -C(O)-OR4 It may be.

[0166] In the compounds of subgenus (1A), R 3 is -SC(O)-R 4 It may be.

[0167] In the compounds of subgenus (1A), R 4 is C 1~10 It may be alkyl.

[0168] In the compounds of subgenus (1A), R 4 is C 1~10 It may be a heteroalkyl.

[0169] In the compounds of subgenus (1A), R 4 is C 5~10 It may be arylalkyl.

[0170] In the compounds of subgenus (1A), R 4 is C 3~6 It may be a heterocycloalkyl.

[0171] In the compounds of subgenus (1A), R 4 is a substitution C 4~10 It may be a heterocycloalkylalkyl.

[0172] The compound of formula (1) is represented by the formula Each R 1 Independently, C 1~3 alkyl, or each R 1 together with the carbon atom to which they are attached, C 3~6 It forms a cycloalkyl ring, R 2 may be a single bond, R 3 -C(O)-OR 4 R may be 4 But, C 1~10 Alkyl, C 1~10 Heteroalkyl, C 5~10 Aryl alkyl, C 3~6Heterocycloalkyl and substituted C 4~10 Heterocycloalkylalkyl may be selected from the compounds of subgenus (1B), or a pharma- ceutically acceptable salt thereof.

[0173] In the compounds of subgenus (1B), each R 1 are independent, C 1~3 It may be selected from alkyl.

[0174] In the compounds of subgenus (1B), each R 1 together with the carbon atom to which they are attached, C 3~6 It forms a cycloalkyl ring.

[0175] In the compounds of subgenus (1B), R 4 is C 1~7 Alkyl, C 1~10 Heteroalkyl (wherein one or more heteroatoms may be oxygen), -CH2-C 4~6 Cycloalkyl, -(CH2)2-C 4~6 Cycloalkyl, C 3~6 heterocycloalkyl (wherein one or more heteroatoms may be oxygen), -CH2-C 3~6 Substituted heterocycloalkyl, and -(CH2)2-C 3~6 substituted heterocycloalkyl.

[0176] In the compounds of subgenus (1B), the substitution C 3~6 In heterocycloalkyl, one or more heteroatoms may be oxygen and one or more substituents may independently be C 1~3 It may be selected from alkyl and =O.

[0177] In the compounds of subgenus (1B), each R 1 may be methyl, or each R 1 together with the carbon atom to which they are attached form a cyclohexyl or cyclopentyl ring.

[0178] In the compounds of subgenus (1B), R 4may be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, n-hexyl, n-heptyl, -CH2-CH2-O-CH3, benzyl, 3-oxetanyl, and methyl-5-methyl-1,3-dioxol-2-one.

[0179] In the compounds of subgenus (1B), Each R 1 may be methyl, or each R 1 together with the carbon atoms to which they are attached form a cyclohexyl or a cyclopentyl ring, R 2 may be a single bond, R 3 is -C(O)-OR 4 R may be 4 may be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, n-hexyl, n-heptyl, -CH2-CH2-O-CH3, -CH2-phenyl (benzyl), 3-oxetanyl, and methyl-5-methyl-1,3-dioxol-2-one.

[0180] The compound of formula (1) is represented by the formula Each R 1 Independently, C 1~3 alkyl, or each R 1 together with the carbon atom to which they are attached, C 3~6 It forms a cycloalkyl ring, R 2 may be -(CH2)2-; R 3 -C(O)-OR 4 R may be 4 But, C 1~10 Alkyl, C 1~10 Heteroalkyl, C 5~10 Aryl alkyl, C 3~6 Heterocycloalkyl and substituted C 4~10 Heterocycloalkylalkyl may be selected from the compounds of subgenus (1C), or a pharma- ceutically acceptable salt thereof.

[0181] In the compounds of subgenus (1C), each R 1 are independent, C 1~3 It may be selected from alkyl.

[0182] In the compounds of subgenus (1C), each R 1 together with the carbon atom to which they are attached, C 3~6 It forms a cycloalkyl ring.

[0183] In the compounds of subgenus (1C), R 4 is C 1~7 Alkyl, C 1~10 Heteroalkyl (one or more heteroatoms may be oxygen), -CH2-C 4~6 Cycloalkyl, -(CH2)2-C 4~6 Cycloalkyl, C 3~6 heterocycloalkyl (wherein one or more heteroatoms may be oxygen), -CH2-C 3~6 Substituted heterocycloalkyl, and -(CH2)2-C 3~6 substituted heterocycloalkyl.

[0184] In the compounds of subgenus (1C), the substitution C 3~6 In heterocycloalkyl, one or more heteroatoms may be oxygen and one or more substituents may independently be C 1~3 It may be selected from alkyl and =O.

[0185] In the compounds of subgenus (1C), R 4 is C 1~10 It may be alkyl.

[0186] In the compounds of subgenus (1C), Each R 1 may be methyl; R 2 may be -(CH2)2-, R 3 is -C(O)-OR 4 R may be 4may be selected from n-hexyl and n-heptyl.

[0187] The compound of formula (1) is represented by the formula Each R 1 But, C 1~3 alkyl, or each R 1 together with the carbon atom to which they are attached, C 3~6 It forms a cycloalkyl ring, R 2 may be -CH2-, R 3 But -SC(O)-R 4 R may be 4 But, C 1~10 Alkyl, C 1~10 Heteroalkyl, C 5~10 Aryl alkyl, C 3~6 Heterocycloalkyl and substituted C 4~10 Heterocycloalkylalkyl may be selected from the compounds of subgenus (1D), or a pharma- ceutically acceptable salt thereof.

[0188] In the compounds of subgenus (1D), each R 1 are independent, C 1~3 It may be selected from alkyl.

[0189] In the compounds of subgenus (1D), each R 1 together with the carbon atom to which they are attached, C 3~6 It forms a cycloalkyl ring.

[0190] In the compounds of subgenus (1D), R 4 is C 1~7 Alkyl, C 1~10 Heteroalkyl (one or more heteroatoms may be oxygen), -CH2-C 4~6 Cycloalkyl, -(CH2)2-C 4~6 Cycloalkyl, C 3~6 heterocycloalkyl (wherein one or more heteroatoms may be oxygen), -CH2-C 3~6 Substituted heterocycloalkyl, and -(CH2)2-C3~6 substituted heterocycloalkyl.

[0191] In the compounds of subgenus (1D), the substitution C 3~6 In heterocycloalkyl, one or more heteroatoms may be oxygen and one or more substituents may independently be C 1~3 It may be selected from alkyl and =O.

[0192] In the compounds of subgenus (1D), R 4 is C 1~10 It may be alkyl.

[0193] In the compounds of subgenus (1D), Each R 1 may be methyl; R 2 may be -CH2-, R 3 is -SC(O)-R 4 R may be 4 may be methyl.

[0194] The compound of formula (1) is represented by the formula Each R 1 together with the carbon atom to which they are attached, C 3~6 Cycloalkyl ring, C 3~6 Heterocycloalkyl ring, C 3~6 Cycloalkyl ring, or C 3~6 forming a heterocycloalkyl ring, R 2 may be a single bond, R 3 But, C 1~3 It may be a compound of subgenus (1E), which may be alkyl, or a pharma- ceutically acceptable salt thereof.

[0195] In the compounds of subgenus (1E), each R 1 together with the carbon atom to which they are attached, C 3~6 Heterocycloalkyl ring or C 3~6 It forms a heterocycloalkyl ring.

[0196] In the compounds of subgenus (1E), one or more of the heteroatoms may be oxygen and one or more of the substituents may be ═O.

[0197] In the compounds of subgenus (1E), Each R 1 together with the carbon atom to which they are attached form a dihydrofuran-2(3H)-one ring, R 2 may be a single bond, R 3 may be methyl.

[0198] The compound of formula (1) is represented by the formula Each R 1 Independently, C 1~3 alkyl, R 2 may be selected from a single bond and methanediyl; R 3 But -OC(O)-R 4 and -C(O)-OR 4 R may be selected from 4 But, C 1~10 The compound may be of the subgenus (1F), which may be selected from alkyl and substituted phenyl, or a pharma- ceutically acceptable salt thereof.

[0199] In the compounds of subgenus (1F), R 2 may be a single bond.

[0200] In the compounds of subgenus (1F), R 2 may be methanediyl.

[0201] In the compounds of subgenus (1F), R 3 is -OC(O)-R 4 It may be.

[0202] In the compounds of subgenus (1F), R 2 may be methanediyl, R 3 is -OC(O)-R4 It may be.

[0203] In the compounds of subgenus (1F), R 3 is -C(O)-OR 4 It may be.

[0204] In the compounds of subgenus (1F), R 2 may be a single bond, R 3 is -C(O)-OR 4 It may be.

[0205] In the compounds of subgenus (1E), R 2 may be a single bond, R 3 is -C(O)-OR 4 R may be 4 is C 1~3 It may be alkyl.

[0206] In the compounds of subgenus (1F), R 4 is C 1~10 It may be alkyl.

[0207] In the compounds of subgenus (1F), R 4 is C 1~4 It may be alkyl.

[0208] In the compounds of subgenus (1F), R 4 may be a substituted phenyl.

[0209] In the compounds of subgenus (1F), R 2 may be methanediyl, R 3 is -OC(O)-R 4 R may be 4 may be a substituted phenyl.

[0210] In the compounds of subgenus (1F), one or more of the substituents are independently selected from the group consisting of halogen, C 1~3 Alkyl, and C 1~3 It may be selected from alkoxy.

[0211] Within compounds of subgenus (1F), the substituted phenyl may be 2,6-substituted phenyl.

[0212] In the compounds of subgenus (1F), the substituents are each C 1~3 Alkyl and C 1~3 It may be selected from alkoxy.

[0213] Within compounds of subgenus (1F), the substituted phenyl may be 2,5,6-substituted phenyl.

[0214] In the compounds of subgenus (1F), the substituents at the 2 and 6 positions are each independently selected from the group consisting of C 1~3 Alkyl and C 1~3 The substituent at the 5-position may be selected from alkoxy and the substituent at the 5-position may be halogen.

[0215] The compound of formula (1) is represented by the formula Each R 1 Independently, C 1~3 alkyl, R 2 may be a single bond, R 3 But -CH=C(R 4 ) 2, each R 4 -C(O)-OR 8 or each R 4 together with the carbon atom to which they are attached form a substituted heterocyclohexyl ring; Each R 8 But, C 1~4 It may be a compound of subgenus (1G), which may be alkyl, or a pharma- ceutically acceptable salt thereof.

[0216] In the compounds of subgenus (1G), each R 4 is -C(O)-OR 8 It may be.

[0217] In the compounds of subgenus (1G), each R 4 is -C(O)-OR 8 or each R 4together with the carbon atom to which they are attached form a substituted heterocyclohexyl ring.

[0218] In compounds of subgenus (1G), in the substituted heterocyclohexyl ring, one or more of the heteroatoms may be oxygen.

[0219] In compounds of subgenus (1G), in the substituted heterocyclohexyl ring, one or more of the substituents are independently selected from the group consisting of C 1~3 It may be selected from alkyl and =O.

[0220] In compounds of subgenus (1G), the substituted heterocycloalkyl ring can be 2,2-dimethyl-5-yl-1,3-dioxane-4,6-dione.

[0221] The compound of formula (1) is represented by the formula Each R 1 Independently, C 1~3 alkyl, R 2 may be selected from a single bond and methanediyl; R 3 may be a substituted phenyl, where one or more of the substituents are independently -CH-OC(O)-R 4 and -OC(O)-R 4 R may be selected from 4 But, C 1~10 The compound may be of the subgenus (1H), which may be selected from alkyl and phenyl, or a pharma- ceutically acceptable salt thereof.

[0222] In the compounds of subgenus (1H), R 2 may be a single bond.

[0223] In the compounds of subgenus (1H), R 2 may be a 2-substituted phenyl.

[0224] In the compounds of subgenus (1H), one or more of the substituents is -CH2-OC(O)-R 4 It may be.

[0225] In the compounds of subgenus (1H), one or more of the substituents is -OC(O)-R 4 It may be.

[0226] In the compounds of subgenus (1H), R 4 is C 1~10 It may be alkyl.

[0227] In the compounds of subgenus (1H), R 4 may be selected from methyl, ethyl, iso-propyl, pivaloyl, and phenyl.

[0228] The compound of formula (1) is represented by the formula Each R 1 Independently, C 1~3 alkyl, R 2 But -C(R 8 )2- and -CH2-C(R 8 )2-, each R 8 Independently, C 1~3 alkyl, R 3 -C(O)-OR 4 and -OC(O)-R 4 R may be selected from 4 But, 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, or a pharma- ceutically acceptable salt thereof.

[0229] In the compounds of subgenus (1I), each R 1 may be methyl.

[0230] In the compounds of subgenus (1I), R 2 is -C(R 8 )2- may be.

[0231] In the compounds of subgenus (1I), R 2 is -CH2-C(R 8 )2- may be.

[0232] In the compounds of subgenus (1I), each R 1 may be methyl.

[0233] In the compounds of subgenus (1I), each R 1 may be methyl, and each R 8 may be methyl.

[0234] In the compounds of subgenus (1I), R 3 is -C(O)-OR 4 It may be.

[0235] In the compounds of subgenus (1I), R 3 is -OC(O)-R 4 It may be.

[0236] The compound of formula (1) is represented by the formula Each R 1 together with the carbon atom to which they are attached, 5~6 It forms a heterocyclic ring, R 2 may be a single bond, R 3 But, C 1~3 It may be a compound of subgenus (1J), which may be alkyl, or a pharma- ceutically acceptable salt thereof.

[0237] In the compounds of subgenus (1J), the substitution C 5~6 In the heterocyclic ring, one or more of the heteroatoms may be oxygen, and one or more of the substituents may independently be C 1~3 It may be selected from alkyl and =O.

[0238] In the compounds of subgenus (1J), each R 1 together with the carbon atoms to which they are attached form a tetrahydro-2H-pyran-2-one ring.

[0239] In the compounds of subgenus (1J), Each R 1 are independent, C 1~3 alkyl, R 2 is C 2~4 alkanediyl, R 3 is a substitution C 5~6 heterocycloalkyl, where 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 It may be selected from alkyl and =O.

[0240] In the compounds of subgenus (1J), R 3 has the structure of formula (3):

[0241] [ka] [In the formula, R 9 is 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] may have

[0242] In the compounds of subgenus (1J), R 9 is hydrogen and C 1~6 Alkyl, e.g., C 1~4 Alkyl may be selected from, for example, methyl or ethyl.

[0243] The avibactam derivatives provided by the present disclosure are compounds of formula (1a):

[0244] [ka] or a pharma- ceutically acceptable salt thereof [In the formula, each R 1 are independent, C 1~6 alkyl; R 3 is C 1~6 It may be alkyl.

[0245] In the avibactam derivative of formula (1a), each R 1 are independent, C 1~3 may be alkyl, R 3 is C 1~3 It may be alkyl.

[0246] In the avibactam derivative of formula (1a), each R 1 may be methyl, R 3 is C 1~3 It may be alkyl.

[0247] Avibactam derivatives are Methyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate; Ethyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate; Propyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate; Methyl 2-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylbutanoate; Ethyl 2-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylbutanoate; Propyl 2-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylbutanoate; Methyl 2-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-propylpentanoate; Ethyl 2-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-propylpentanoate; Propyl 2-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-propylpentanoate; A pharma- ceutically acceptable salt of any of the above; and Any combination of the above may be selected from.

[0248] Avibactam derivatives have the structure:

[0249] [ka] Ethyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (3) or a pharma- ceutically acceptable salt thereof.

[0250] Avibactam derivatives have the structure:

[0251] [ka] 2-Methoxyethyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (15) or a pharma- ceutically acceptable salt thereof.

[0252] Avibactam derivatives have the structure:

[0253] [ka] Oxetan-3-yl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (16) or a pharma- ceutically acceptable salt thereof.

[0254] Avibactam derivatives have the structure:

[0255] [ka] Ethyl 1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclohexanecarboxylate (17) or a pharma- ceutically acceptable salt thereof.

[0256] Avibactam derivatives have the structure:

[0257] [ka] Ethyl 1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclopentane-1-carboxylate (18) or a pharma- ceutically acceptable salt thereof.

[0258] Avibactam derivatives have the structure:

[0259] [ka] Ethyl 1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclobutanecarboxylate (19) or a pharma- ceutically acceptable salt thereof.

[0260] Avibactam derivatives have the structure:

[0261] [ka] (1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl((3-methyl-2-oxotetrahydrofuran-3-yl)methyl)sulfate (42) or a pharma- ceutically acceptable salt thereof.

[0262] Avibactam derivatives have the structure:

[0263] [ka] S-(3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl)ethanethioate (53) or a pharma- ceutically acceptable salt thereof.

[0264] Avibactam derivatives have the structure:

[0265] [ka] (5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (59) or a pharma- ceutically acceptable salt thereof.

[0266] The compound of formula (1) may be a solvate, a pharma- ceutically acceptable salt, or a combination thereof.

[0267] The pharma- ceutically acceptable salt of the compound of formula (1) may be the hydrochloride salt.

[0268] The pharma- ceutically acceptable salt of the compound of formula (1) may be the dihydrochloride salt.

[0269] The compound of formula (1) may be a pharma- ceutically acceptable salt of a compound of formula (1), a hydrate thereof, or a solvate of any of the above.

[0270] The avibactam derivatives described herein can be synthesized using the methods described in US Pat. No. 10,085,999.

[0271] The pharmaceutical compositions provided by the present disclosure may be administered orally.

[0272] When orally administered, the avibactam derivatives provide enhanced oral bioavailability of the β-lactamase inhibitor compared to the oral bioavailability of the parent β-lactamase inhibitor, avibactam. For example, the avibactam derivatives of formula (1) may exhibit an avibactam oral bioavailability (F%) of at least 10%F, at least 20%F, at least 30%F, at least 40%F, at least 50%F, at least 60%F, at least 70%F, or at least 80%F. The oral bioavailability of avibactam in humans is about 6%F.

[0273] As disclosed in U.S. Pat. No. 10,085,999, avibactam derivatives (3), (4), (10), (11), (12), (13), (14), (15), (16), (17), (18), and (19) exhibit oral bioavailability (%F) of greater than 10%F. Additionally, compounds (36), (37), (42), (53), (57), (58), and (59) exhibit oral bioavailability (%F) of avibactam in Sprague-Dawley rats of greater than 10%F. In a similar study, avibactam exhibited an oral bioavailability (%F) of 1.2%F in Sprague-Dawley rats. Avibactam derivatives (3), (13), and (15) demonstrated oral avibactam bioavailability of greater than 50%F in male beagle dogs and cynomolgus monkeys.

[0274] The avibactam derivative may include crystalline ethyl 3-((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate anhydrate (crystalline avibactam anhydrate). Crystalline ethyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate anhydrate and methods for preparing the crystalline avibactam anhydrate are disclosed in U.S. Patent Application No. 16 / 813,930, filed March 10, 2020, which is incorporated by reference in its entirety.

[0275] Crystalline avibactam anhydrate may be characterized by an X-ray powder diffraction (XRPD) pattern (2θ) having characteristic scattering angles (2θ) of at least 3.16°±0.2°, 6.37°±0.2°, 5.38°±0.2°, and 17.35°±0.2° using Kα2 / Kα1 (0.5) wavelengths.

[0276] Crystalline avibactam anhydrate may be characterized by an XRPD pattern having characteristic scattering angles (2θ) at least at 3.16°±0.1°, 6.37°±0.1°, 5.38°±0.1°, and 17.35°±0.1° using Kα2 / Kα1 (0.5) wavelengths.

[0277] Crystalline avibactam anhydrate may be characterized by an XRPD pattern having characteristic scattering angles (2θ) at least at 3.16°±0.2°, 6.37±0.2°, 5.38°±0.2°, 15.77°±0.2°, and 17.35°±0.2° using Kα2 / Kα1 (0.5) wavelengths.

[0278] Crystalline avibactam anhydrate may be characterized by an XRPD pattern having characteristic scattering angles (2θ) at least at 3.16°±0.1°, 6.37±0.1°, 5.38°±0.1°, 15.77°±0.1°, and 17.35°±0.1° using Kα2 / Kα1 (0.5) wavelengths.

[0279] Crystalline avibactam anhydrate may be characterized by an XRPD pattern having characteristic scattering angles (2θ) at least at 3.16°±0.2°, 6.37°±0.2°, 5.38°±0.2°, 12.75°±0.2°, 15.77°±0.2°, 17.35°±0.2°, 25.68°±0.2°, and 27.13°±0.2° using Kα2 / Kα1 (0.5) wavelengths.

[0280] Crystalline avibactam anhydrate may be characterized by an XRPD pattern having characteristic scattering angles (2θ) at least at 3.16±0.1°, 6.37±0.1°, 5.38±0.1°, 12.75°±0.1°, 15.77°±0.1°, 17.35°±0.1°, 25.68°±0.1°, and 27.13°±0.1° using Kα2 / Kα1 (0.5) wavelengths.

[0281] Those skilled in the art will recognize that some variation in observed °2θ diffraction angles can be expected based, for example, on the particular diffractometer, analyst, and sample preparation techniques used. Greater variations in relative peak intensities can be expected. Comparisons of diffraction patterns may be based primarily on °2θ diffraction angles, with less importance being attributed to relative peak intensities.

[0282] Crystalline avibactam anhydrate may be characterized by a melting point, e.g., 123.0°C to 127.0°C, 123.0°C to 126.0°C, 123.0°C to 125°C, 123.5°C to 124.5°C, 123.8°C to 124.2°C, or 123.9°C to 124.1°C, e.g., 123.99°C, as determined using differential scanning calorimetry (DSC).

[0283] The crystalline avibactam anhydrate may have a weight loss, as determined by thermogravimetric analysis (TGA), of 7.2% to 9.2%, e.g., 7.6% to 8.8%, 8% to 8.4%, or 8.1% to 8.3% in the temperature range of 125° C. to 50° C. There is no measurable weight loss in the range of 30° C. to 125° C.

[0284] Crystalline avibactam anhydrate may exhibit reversible moisture absorption in the humidity range from 0% RH to 95% RH with a maximum increase in mass of about 3% by weight at 25° C. / 95% RH.

[0285] Crystalline avibactam anhydrate as a powder can be stable during storage at 25° C. / 60% RH for a period of time, e.g., 4 weeks, 8 weeks, or 12 weeks. By storage stable, it is meant that the properties of crystalline avibactam anhydrate in powder form, such as XRPD spectrum, melting point, weight loss, and moisture absorption, are substantially the same before and after storage at 25° C. / 60% RH for the indicated period of time. By substantially the same, it is meant that the values ​​differ by, e.g., less than 5%, less than 2%, or less than 1%.

[0286] The crystalline anhydrate (1) was jet milled to obtain a uniform particle size of less than 10 μm for use in pharmaceutical formulations. The XRPD patterns of the crystalline anhydrate (1) before and after jet milling are compared in FIG. 3 and show that the crystal forms before and after jet milling are the same. The TGA and DSC scans of the jet milled material are shown in FIG. 4 and are similar to those for the unmilled material shown in FIG. 2.

[0287] The pharmaceutical compositions provided by the present disclosure may include the crystalline anhydrate (1) and a pharma- ceutically acceptable excipient.

[0288] An aqueous formulation of crystalline anhydrate (1) was prepared by suspending 100 mg of crystalline anhydrate (1) in 100 mL of an aqueous solution containing 0.25 wt% Tween® 80, 10 wt% PEG400, 0.5 wt% methylcellulose (400 cps), and pH 3.0 citrate buffer (wherein the wt% is based on the total weight of the aqueous formulation). The suspension was sonicated and allowed to stand for 24 hours at 25° C., after which the crystalline anhydrate (1) was filtered off. The XRPDs of the material obtained from the jet-milled crystalline anhydrate (1) and the filtered suspension are compared in FIG. 6.

[0289] Pharmaceutical compositions provided by the present disclosure may comprise a therapeutically effective amount of a β-lactam antibiotic, or a pharma- ceutically acceptable salt thereof, and a therapeutically effective amount of an avibactam derivative, or a pharma- ceutically acceptable salt thereof.

[0290] The pharmaceutical composition may include a pharma- ceutically acceptable carrier or excipient, or a combination of a pharma- ceutically acceptable carrier or excipient.

[0291] The pharmaceutical composition may comprise an oral formulation. The oral formulation may be in the form of, for example, liquid or solid dosage form. The solid dosage form for oral administration may be in the form of capsules, tablets, powders, pills, or granules. The oral solid dosage form may comprise, for example, a filler, a bulking agent, a binder, a humectant, a disintegrant, an absorption enhancer, a wetting agent, an absorbent, a lubricant, a buffer, or any combination of the above. Examples of liquid oral dosage forms include soft gel capsules containing liquid, oral suspensions, syrups, and elixirs.

[0292] The oral dosage form may comprise a therapeutically effective amount of a β-lactam antibiotic or a pharma- ceutically acceptable salt thereof and an avibactam derivative or a pharma- ceutically acceptable salt thereof. The oral dosage form may comprise a therapeutically effective amount of a portion of a β-lactam antibiotic or a pharma- ceutically acceptable salt thereof, and / or a therapeutically effective amount of a portion of an avibactam derivative or a pharma- ceutically acceptable salt thereof. Oral dosage forms containing a therapeutically effective amount of a β-lactam antibiotic and / or a portion of an avibactam derivative may be intended to be administered simultaneously as multiple dosage forms that together provide a therapeutically effective amount, or may be intended to be administered over a period of time, such as 2-5 times a day, to provide a therapeutically effective amount of the β-lactam antibiotic and the avibactam derivative.

[0293] The β-lactam antibiotic and the avibactam derivative can be provided in separate dosage forms or can be combined in a single dosage form.

[0294] The β-lactam antibiotic and the avibactam derivative can be co-formulated such that the compounds are uniformly dispersed throughout the oral dosage form.

[0295] The β-lactam antibiotic and the avibactam derivative can be segregated into different portions of an oral dosage form, for example, one or both compounds can be contained within microparticles dispersed in a carrier, or the compounds can be independently dispersed within separate portions of the oral dosage form, for example forming a core-shell structure.

[0296] An oral dosage form containing both a β-lactam antibiotic, such as ceftibuten, and an avibactam derivative may, for example, contain a weight ratio of the β-lactam antibiotic, such as ceftibuten, to an avibactam equivalent within the range of 1:1 to 1:4, 1:1 to 1:3, 1:1 to 1:2, or 1:1 to 1:1.5.

[0297] Oral dosage forms may contain, for example, 100 mg to 1,400 mg of a β-lactam antibiotic such as ceftibuten, 100 mg to 1,200 mg, 100 mg to 1,000 mg, 100 mg to 800 mg, or 100 mg to 600 mg of a β-lactam antibiotic such as ceftibuten.

[0298] The current FDA oral dosages of ceftibuten are 200 mg and 400 mg. Oral dosage forms may contain, for example, 100 mg to 300 mg of ceftibuten, 150 mg to 250 mg of ceftibuten, or 175 mg to 225 mg of ceftibuten. Oral dosage forms may contain, for example, 300 mg to 500 mg of ceftibuten, 350 mg to 450 mg of ceftibuten, or 375 mg to 425 mg of ceftibuten.

[0299] Oral dosage forms may contain, for example, the equivalent of 25 mg to 2,000 mg of avibactam, 100 mg to 1,600 mg of avibactam, 200 mg to 1,400 mg, 250 mg to 1,200 mg, 300 mg to 900 mg, 350 mg to 850 mg, 400 mg to 800 mg, 450 mg to 750 mg, 500 mg to 700 mg of ceftibuten. Oral dosage forms may contain, for example, the equivalent of 500 mg to 700 mg of ceftibuten, 700 mg to 900 mg of ceftibuten, or 900 mg to 1,300 mg of ceftibuten.

[0300] The oral dosage form may contain, for example, 25mg to 2,000mg of the avibactam derivative of formula (1), 100mg to 1,600mg, 200mg to 1,400mg, 250mg to 1,200mg, 300mg to 900mg, 350mg to 850mg, 400mg to 800mg, 450mg to 750mg, 500mg to 700mg of the avibactam derivative of formula (1). The oral dosage form may contain, for example, 200mg to 1,400mg of the avibactam derivative of formula (1), 250mg to 1,200mg, 300mg to 1,000mg, or 400mg to 900mg of the avibactam derivative of formula (1).

[0301] Oral dosage forms may contain, for example, the equivalent of 100 mg to 10,000 mg of a β-lactam antibiotic, such as ceftibuten, and 25 mg to 2,000 mg of avibactam; 200 mg to 600 mg of a β-lactam antibiotic, such as ceftibuten, and 300 mg to 900 mg of avibactam; 250 mg to 550 mg of a β-lactam antibiotic, such as ceftibuten, and 350 mg to 850 mg of avibactam; 300 mg to 500 mg of a β-lactam antibiotic, such as ceftibuten, and 400 mg to 800 mg of avibactam; or 350 mg to 450 mg of a β-lactam antibiotic, such as ceftibuten, and 450 mg to 750 mg of avibactam.

[0302] Oral dosage forms may contain, for example, 100 mg to 10,000 mg of a β-lactam antibiotic, such as ceftibuten, and 25 mg to 2,000 mg of an avibactam derivative of formula (1); 200 mg to 600 mg of a β-lactam antibiotic, such as ceftibuten, and 300 mg to 900 mg of an avibactam derivative of formula (1); 250 mg to 550 mg of a β-lactam antibiotic, such as ceftibuten, and 350 mg to 850 mg of an avibactam derivative of formula (1); 300 mg to 500 mg of a β-lactam antibiotic, such as ceftibuten, and 400 mg to 800 mg of an avibactam derivative of formula (1); or 350 mg to 450 mg of a β-lactam antibiotic, such as ceftibuten, and 450 mg to 750 mg of an avibactam derivative of formula (1).

[0303] An oral dosage form may, for example, contain 100 mg to 300 mg of ceftibuten and 200 mg to 1,400 mg of the avibactam derivative of formula (1) or 300 mg to 900 mg of the avibactam derivative of formula (1).

[0304] An oral dosage form may, for example, contain 300 mg to 500 mg of ceftibuten and 200 mg to 1,400 mg of the avibactam derivative of formula (1) or 300 mg to 900 mg of the avibactam derivative of formula (1).

[0305] The oral dosage form may be a sustained release oral dosage form.

[0306] The oral dosage form may be a controlled release oral dosage form.

[0307] The dose and administration regimen of the β-lactam antibiotic and avibactam derivative may be any suitable dose and administration regimen that achieves the desired therapeutic effect, such as the treatment of a bacterial infection.

[0308] Combinations of β-lactam antibiotics such as ceftibuten and avibactam derivatives may be used, for example, in a total daily dose of 50 mg to 2,000 mg of β-lactam antibiotics such as ceftibuten, a total daily dose of 400 mg to 1,800 mg of ceftibuten, and a total daily dose of 800 mg to 2,400 mg of avibactam equivalent; for example, 500 mg to 1,700 mg of β-lactam antibiotics such as ceftibuten and 900 mg to 2,300 mg of avibactam equivalent; 600 mg to 1,600 mg of β-lactam antibiotics such as ceftibuten and 1,000 mg to 2,200 mg of avibactam equivalent; It can be administered to obtain 700mg to 1,500mg of a beta-lactam antibiotic such as ceftibuten and 1,100mg to 2,100mg of an avibactam equivalent; 800mg to 1,400mg of a beta-lactam antibiotic such as ceftibuten and 1,200mg to 2,000mg of an avibactam equivalent; 900mg to 1,300mg of a beta-lactam antibiotic such as ceftibuten and 1,300mg to 1,800mg of an avibactam equivalent; or 1,000mg to 1,200mg of a beta-lactam antibiotic such as ceftibuten and 1,400mg to 1,700mg of an avibactam equivalent.

[0309] For example, the total daily dose of a beta-lactam antibiotic, such as ceftibuten, may be, for example, 200 mg to 2,000 mg, 400 mg to 1,800 mg, 500 mg to 1,700 mg, 600 mg to 1,600 mg, 700 mg to 1,500 mg, 800 mg to 1,400 mg, 900 mg to 1,300 mg, or 1,000 mg to 1,200 mg.

[0310] For example, the total daily dose of avibactam equivalents administered as avibactam derivatives provided by the present disclosure may be, for example, 50 mg to 2,400 mg, 100 mg to 2,300 mg, 200 mg to 2,200 mg, 300 mg to 2,100 mg, 400 mg to 2,000 mg, 500 mg to 1,900 mg, 600 mg to 1,800 mg, 700 mg to 1,700 mg, 800 mg to 1,600 mg, 900 mg to 1,500 mg, or 1,000 mg to 1,400 mg.

[0311] For example, a total daily dose of an avibactam derivative provided by the present disclosure may be, for example, 50 mg to 2,400 mg, 100 mg to 2,300 mg, 200 mg to 2,200 mg, 300 mg to 2,100 mg, 400 mg to 2,000 mg, 500 mg to 1,900 mg, 600 mg to 1,800 mg, 700 mg to 1,700 mg, 800 mg to 1,600 mg, 900 mg to 1,500 mg, or 1,000 mg to 1,400 mg.

[0312] For example, a combination of a β-lactam antibiotic such as ceftibuten and an avibactam derivative of formula (1) can be administered, for example, 1 to 6 times per day, 2 to 4 times per day, or 2 to 3 times per day. For example, the β-lactam antibiotic such as ceftibuten and the avibactam derivative can be administered independently 1, 2, 3, 4, 5, or 6 times per day. For example, the β-lactam antibiotic such as ceftibuten and the avibactam derivative can each be administered 1, 2, 3, 4, 5, or 6 times per day.

[0313] For example, β-lactam antibiotics such as ceftibuten and avibactam derivatives can be administered every 8 hours, three times per day (TID), such as q8h.

[0314] When administered more than once a day, the β-lactam antibiotic such as ceftibuten and the avibactam derivative can be administered in equal doses, meaning that each dose administered during the day contains the same amount of each drug.For example, each TID dose of 1,200 mg of a β-lactam antibiotic such as ceftibuten can contain 400 mg of a β-lactam antibiotic such as ceftibuten.Similarly, a TID dose of 1,200 mg of a daily dose of avibactam equivalents can contain 400 mg of avibactam equivalents; a TID dose of 1,200 mg of a daily dose of avibactam derivative of formula (1) can contain 400 mg of avibactam derivative of formula (1).

[0315] For example, the total daily dose of a β-lactam antibiotic such as ceftibuten may be in the range of 200 mg to 600 mg, and the total daily dose of an avibactam derivative of formula (1) may be in the range of 50 mg to 1,600 mg of avibactam equivalent or 50 mg to 1,600 mg of an avibactam derivative of formula (1).

[0316] The total daily dose of the β-lactam antibiotic, such as ceftibuten, and the avibactam derivative can be provided as a single daily dose or as divided daily doses administered, for example, once, twice, three times, or four times per day. Each divided daily dose may have the same amount of the β-lactam antibiotic, such as ceftibuten, and / or the avibactam derivative, or may have different amounts of the β-lactam antibiotic, such as ceftibuten, and / or the avibactam derivative.

[0317] The appropriate dose of the β-lactam antibiotic may be the dose approved by FDA. The β-lactam antibiotic is approved by FDA to treat certain bacterial infections. The pharmaceutical composition, dose and administration regimen for the specific β-lactam antibiotic may be equivalent to the amount and regimen approved by FDA. Based on the MIC of the β-lactam antibiotic for bacteria, based on the fAUC:MIC ratio determined for avibactam, the dose and regimen of the avibactam derivative of formula (1) for treating bacterial infections caused by bacteria can be determined in combination with the FDA-approved dose and regimen for the specific β-lactam antibiotic.

[0318] If provided as separate dosage forms, the β-lactam antibiotic, such as ceftibuten, and the avibactam derivative can be administered simultaneously or sequentially.

[0319] For example, for simultaneous administration, the separate dosage forms can be administered at the same time or within less than 60 minutes of each other, eg, less than 30 minutes, less than 20 minutes, less than 10 minutes, or less than 5 minutes of each other.

[0320] In sequential administration, the separate oral dosage forms can be administered, for example, within 1 to 6 hours after administration of the first oral dosage form, e.g., within 1 to 5 hours, 1 to 4 hours, or 1 to 3 hours.

[0321] The β-lactam antibiotic and the avibactam derivative can be administered, for example, in a weight ratio of β-lactam antibiotic to avibactam equivalent within the range of 1:1 to 1:5, 1:1 to 1:4, 1:1 to 1:3, 1:1 to 1:2, or 1:1 to 1:1.5.

[0322] The β-lactam antibiotic and the avibactam derivative can each be independently administered at least twice per day, such as twice per day, three times per day, or four times per day.

[0323] The β-lactam antibiotic and the avibactam derivative may be administered simultaneously. For simultaneous administration, the β-lactam antibiotic and the avibactam derivative of formula (1) may be administered in the same dosage form or in separate dosage forms.

[0324] The β-lactam antibiotic and the avibactam derivative can be administered non-concurrently.The β-lactam antibiotic and the avibactam derivative can be administered at the same daily dosing frequency or at different daily dosing frequencies.For example, the β-lactam antibiotic can be administered twice a day, and the avibactam derivative can be administered three times a day.

[0325] The combination of the β-lactam antibiotic and the avibactam derivative may be administered to a patient for a period of time sufficient to obtain the desired therapeutic effect.

[0326] The combination of the β-lactam antibiotic and the avibactam derivative can be administered for a period of time sufficient to treat the bacterial infection. The treatment can last for days or weeks. For example, the pharmaceutical composition can be administered once, twice, or less than five times. For example, the pharmaceutical composition provided by the present disclosure can be administered for 3-30 days, 7-21 days, or 7-14 days. The treatment can continue for a prescribed number of days or until a specified end point. For example, the pharmaceutical composition provided by the present disclosure can be administered for 1-15 weeks, 2-12 weeks, or 3-9 weeks. The treatment can continue for a prescribed number of days or until a specified end point. The treatment can continue until the symptoms of the bacterial infection are alleviated and / or there are no detectable signs of the bacterial infection.

[0327] A method of treating a bacterial infection may include administering a β-lactam antibiotic such as ceftibuten and an avibactam derivative of formula (1). The β-lactam antibiotic such as ceftibuten can be administered to obtain, for example, greater than 40% fT>MIC, greater than 45% fT>MIC, or greater than 50% fT>MIC in the patient's systemic circulation. For example, the β-lactam antibiotic ceftibuten can be administered at a total daily dose of 1,200 mg divided into 400 mg doses administered q8h.

[0328] After oral administration of a therapeutically effective amount of an avibactam derivative of formula (1), the fAUC / MIC in the patient's plasma may be, for example, greater than 20, greater than 30, greater than 40, or greater than 50 for the bacteria causing the infection. The fAUC / MIC ratio may be, for example, 10-40, 20-40, or 25-35, greater than 50 for the bacteria causing the infection. This ratio refers to the fAUC of avibactam relative to the MIC of a β-lactam antibiotic, such as ceftibuten, for the particular bacteria in the presence of avibactam.

[0329] Following oral administration, a therapeutically effective amount of avibactam may, for example, produce a 40% fT>C t Over 50%fT>C t or 60%fT>C t The avibactam concentration may be greater than 100 mg / kg.

[0330] After oral administration of 300 mg of avibactam derivative (3) to healthy patients, the mean C max may be about 2,500 ng / mL, and the AUC inf may be about 7,600 ng×h / mL, and T 1 / 2 may be about 1.5 hours.

[0331] After oral administration of 600 mg of avibactam derivative (3) to healthy patients, the mean C max may be about 2,500 ng / mL, and the AUC inf may be about 7,600 ng×h / mL, and T 1 / 2 may be about 1.5 hours.

[0332] The MIC of ceftibuten when used in combination with avibactam can be, for example, 8 mg / mL or less, 4 mg / L or less, 2 mg / L or less, 1 mg / L or less, or 0.5 mg / L or less.

[0333] The MIC of ceftibuten for ESBL-producing Enterobacteriaceae can be, for example, greater than 10 mg / L, greater than 20 mg / L, greater than 40 mg / L, or greater than 60 mg / L.

[0334] The MIC of ceftibuten for an ESBL-producing Enterobacteriaceae can be, for example, 200 or more times higher, 100 or more times higher, 50 or more times higher, 20 or more times higher, 10 or more times higher, or 5 or more times higher than the MIC of the combination of ceftibuten and avibactam for the same strain.

[0335] The minimum bactericidal concentration (MBC) of ceftibuten when used in combination with an avibactam derivative can be, for example, less than 8 times, less than 4 times, or less than 2 times the MIC of ceftibuten when used in combination with an avibactam derivative. The MBC of ceftibuten when used in combination with an avibactam derivative can be equal to or greater than the MIC of ceftibuten when used in combination with an avibactam derivative.

[0336] A method of treating a bacterial infection in a patient may include obtaining a biological sample from a patient having a bacterial infection, identifying the presence of bacteria in the sample, determining the MIC required to treat the identified bacteria, and administering to the patient a pharmaceutical composition comprising a β-lactam antibiotic, such as ceftibuten, and an avibactam derivative provided in the present disclosure in a therapeutically effective amount based on the determined MIC. The bacterial infection may be caused by bacteria that produce a β-lactamase enzyme.

[0337] The pharmaceutical compositions and methods provided by the present disclosure can be used to treat a bacterial infection in a patient, such as an Enterobacteriaceae infection.

[0338] The bacterial infection may be, for example, a urinary tract infection (UTI), such as complicated urinary tract infection (cUTI), acute pyelonephritis, uncomplicated UTI (uUTI), acute pyelonephritis, an upper respiratory tract infection, a lower respiratory tract infection, a primary or catheter-associated blood infection, neonatal sepsis, an intra-abdominal infection, otitis media, pneumonia, including community-acquired pneumonia (CAP), or a wound infection.

[0339] Pharmaceutical compositions provided by the present disclosure can be administered to patients who are known to have, suspected to have, or likely to have a bacterial infection caused by or associated with bacteria expressing a serine-based β-lactamase, such as an extended-spectrum β-lactamase (ESBL), KPC, OXA, or AmpC. The bacterial infection may be a bacterial infection associated with bacteria expressing ESBL, KPC, OXA, or AmpC, such as bacterial infections known to be caused by or associated with ESBL-, KPC-, OXA-, or AmpC-producing bacteria, on average in a population of patients with the infection.

[0340] The pharmaceutical compositions provided by the present disclosure can be used to treat bacterial infections caused by certain β-lactamase producing bacteria. The pharmaceutical compositions provided by the present disclosure can be used to treat bacterial infections caused by β-lactamase producing bacteria, where avibactam inhibits the β-lactamase produced by the bacteria. The pharmaceutical compositions provided by the present disclosure can be used to treat bacterial infections where a β-lactam antibiotic in combination with avibactam is effective in treating the bacterial infection.

[0341] The pharmaceutical compositions provided by the present disclosure can be used to treat bacterial infections caused by carbapenem-resistant Enterobacteriaceae (CRE) that produce K. pneumoniae carbapenemase (KPC), AmpC β-lactamase, oxacillinase (OXA) group of β-lactamases, or CMY carbapenemase.

[0342] The pharmaceutical compositions provided by the present disclosure can be used to treat bacterial infections where β-lactam antibiotic resistance is due to expression of serine-based β-lactamases by the bacteria causing the bacterial infection.The pharmaceutical compositions provided by the present disclosure can be used to treat bacterial infections caused by bacteria expressing serine-based β-lactamases.

[0343] The kit provided by the present disclosure may include a β-lactam antibiotic, such as ceftibuten, or a pharma- ceutically acceptable salt thereof, an avibactam derivative, or a pharma- ceutically acceptable salt thereof, and instructions for administering a therapeutically effective amount of the compounds to treat a bacterial infection in a patient. The β-lactam antibiotic, such as ceftibuten, and the avibactam derivative may be formulated for oral administration, for example, in the form of a suspension or solid dosage form. The instructions may be provided, for example, as a written package insert or in the form of an electronic media.

[0344] The kit may include a β-lactam antibiotic such as ceftibuten and an avibactam derivative in a single dosage form and / or in multiple single dosage forms as separate doses in separate dosage forms. Multiple dosage forms may be provided to be administered over a period of time, such as one day. The total daily dose of a β-lactam antibiotic such as ceftibuten and an avibactam may be divided into separate doses, intended to be administered, for example, one, two, three, or four times a day. For example, a daily dose of 1,200 mg of ceftibuten may be provided as three doses of 400 mg of ceftibuten administered three times a day, and a daily dose of 1,200 mg of an avibactam derivative may be provided as three doses of 400 mg of an avibactam derivative administered three times a day. Other doses and other β-lactam antibiotics may be provided in the kit.

[0345] The kit may contain dosages suitable for administration on multiple days, for example, for 1, 2, 3 or 4 weeks. The daily doses of ceftibuten and the avibactam derivative may also be provided as separate packages.

[0346] The pharmaceutical composition provided by the present disclosure may include a β-lactam antibiotic, such as ceftibuten, or a pharma- ceutically acceptable salt thereof, and an avibactam derivative, or a pharma- ceutically acceptable salt thereof. The pharmaceutical composition may provide a therapeutically effective amount of a β-lactam antibiotic, such as ceftibuten, and an avibactam derivative of formula (1) to treat a bacterial infection. The therapeutically effective amount of a β-lactam antibiotic, such as ceftibuten, and an avibactam derivative of formula (1) may be an amount appropriate as part of a therapeutically effective treatment regimen in which a combination of ceftibuten and an avibactam derivative is administered over a period of time.

[0347] The pharmaceutical compositions provided by the present disclosure may include avibactam derivatives of formula (1), which are prodrugs of the β-lactamase inhibitor avibactam. The pharmaceutical compositions provided by the present disclosure can be used to treat bacterial infections whose pathogenesis is associated with the production of β-lactamase. For example, certain bacterial infections are resistant to β-lactamase antibiotics because the β-lactamase produced by the bacteria hydrolyzes the β-lactam ring of the β-lactam antibiotics.

[0348] The pharmaceutical compositions provided by the present disclosure can be used to treat bacterial infections in patients. For example, the pharmaceutical compositions provided by the present disclosure can be used to treat bacterial infections associated with bacteria such as obligate aerobes, obligate anaerobes, facultative anaerobes, and microaerophiles.

[0349] Examples of obligate aerobes include gram-negative cocci such as Moraxella catarrhalis, Neisseria gonorrhoeae, and N. meningitidi; gram-positive bacilli such as Corynebacterium jeikeium; acid-fast bacteria such as Mycobacterium avium complex, M. kansasii, M. leprae, M. tuberculosis, and Nocardia; Acinetobacter calcoaceticus, Elizabethkingia meningoseptica, and other strains of the genus Mycobacterium avium. These include non-fermenting, non-Enterobacteriaceae such as Flavobacterium meningoseptica (formerly Flavobacterium meningosepticum), Pseudomonas aeruginosa, P. alcaligenes, other Pseudomonas species, and Stenotrophomonas maltophilia; fastidious Gram-negative coccobacilli such as Brucella, Bordetella, Francisella, and Legionella; and Treponemataceae (spiral-shaped bacteria) such as Leptospira.

[0350] Examples of obligate anaerobic bacteria include gram-negative bacilli such as Bacteroides fragilis, other Bacteroides species, and gram-negative cocci such as Fusobacterium and Prevotella species; 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, and other Clostridium species; and endospore-forming gram-positive bacilli such as Clostridium botulinum, C. perfringens, C. tetani, and other Clostridium species.

[0351] Examples of facultative anaerobic bacteria include gram-positive, catalase-positive cocci such as Staphylococcus aureus (coagulase positive), Staphylococcus epidermidis (coagulase negative), and other coagulase-negative staphylococci; Enterococcus faecalis, E. faecium, Streptococcus agalactiae, and others. agalactiae (group B streptococci), S. bovis, S. pneumoniae, S. pyogenes (group A streptococci), the viridans streptococci group (S. mutans, S. mitis, S. salivarius, S. sanguis), the S. anginosus group (S. anginosus, S. milleri, S. constellatus),Gram-positive catalase-negative cocci such as Bacillus anthracis, Erysipelothrix rhusiopathiae, and Gardnerella vaginalis (gram-variable); Enterobacteriaceae (Citrobacter sp, Enterobacter aerogenes, Escherichia coli, Klebsiella sp, Morganella morganii, Proteus sp, Plesiomonas shigelloides, Providencia rettgeri, and others); Gram-negative bacilli such as Salmonella rettgeri, Salmonella typhi, other Salmonella species, Serratia marcescens, and Shigella species, Yersinia enterocolitica, and Y. pestis; fermentative non-Enterobacteriaceae such as Aeromonas hydrophila, Chromobacterium violaceum, and Pasteurella multocida; Actinobacillus actinomycetemcomitans, Bartonella bacilliformis, and other fermentative bacteria. bacilliformis, B. henselae, B. quintanaThese include fastidious gram-negative coccobacilli and bacilli, such as Eikenella corrodens, Haemophilus influenzae, and other Haemophilus sp; mycoplasmas, such as Mycoplasma pneumoniae; and treponemataceae (spiral-shaped bacteria), such as Borrelia burgdorferi, and Treponema pallidum.

[0352] Examples of microaerophilic bacteria include curved bacilli such as Campylobacter jejuni, Helicobacter pylori, Vibrio cholerae, and V. vulnificus; obligate intracellular parasites; Chlamydiaceae bacteria such as Chlamydia trachomatis, Chlamydophila pneumoniae, and C. psittaci; Coxiellaceae bacteria such as Coxiella burnetii; and Rickettsia prowazekii. These include Rickettsiales bacteria such as R. prowazekii, R. rickettsii, R. typhi, R. tsutsugamushi, Ehrlichia chaffeensis, and Anaplasma phagocytophilum.

[0353] The pharmaceutical compositions provided by the present disclosure can be used to treat bacterial infections in which the bacteria produce β-lactamase. Examples of bacteria that produce β-lactamase include Mycobacterium tuberculosis, Methicillin-resistant Staphylococcus aureus, Staphylococcus, Enterobacteriaceae, Pseudomonas aeruginosa, Haemophilus influenzae, Klebsiella pneumoniae, Citrobacter, and Morganella.

[0354] The pharmaceutical compositions provided by the present disclosure can be used to treat bacterial infections in which a β-lactamase inhibitor is effective in treating the bacterial infection.

[0355] The bacterial infection may be a gram-positive infection.

[0356] The bacterial infection may be a gram-negative bacterial infection. Examples of gram-negative bacteria include Acinetobacter, Aeromonas, Bacteroides, Burkholderia, Citrobacter, Enterobacter, Escherichia, Fusobacterium, Haemophilus, Klebsiella, Moraxella, Morganella, Mycoplasma, Neisseria, Pantoea, and the like. The genus includes 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, and others.cloacae, Escherichia coli, Fusobacterium nucleatum, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Moraxella catarrhalis, Morganella morganii, Neisseria gonorrhoeae, Neisseria meningitidis, Pantoea agglomerans, Pasteurella multocida, Plesiomonas shigelloides shigelloides, Prevotella melaninogenica, Proteus mirabilis, Proteus rettgeri, Proteus vulgaris, Pseudomonas aeruginosa, Pseudomonas diminuta, Pseudomonas fluorescens, Pseudomonas stutzeri, Salmonella enterica, Salmonella enteritidis, Salmonella typhi, Serratia marcescens, Spirillum minus minus, Stenotrophomonas maltophilia, Streptobacillus moniliformis, Treponema pallidumpallidum, or Yersinia enterocolitica.

[0357] The emergence of antibiotic resistance continues to be a growing problem facing patients and clinicians. The U.S. Food and Drug Administration has identified the following pathogens as potentially significant threats to public health: Acinetobacter spp., Aspergillus spp., Burkholderia cepacia complex, Campylobacter spp., Candida spp., Clostridium difficile, Coccidioides spp., Cryptococcus spp., Enterobacteriaceae (e.g., Klebsiella pneumoniae), Enterococcus spp., Helicobacter pylori, Mycobacterium tuberculosis complex, Neisseria gonorrhoeae, N. meningitidis, nontuberculous mycobacteria spp., Pseudomonas spp., Staphylococcus aureus, aureus, Streptococcus agalactiae, S. pneumoniae, S. pyogenes, and Vibrio cholerae. The FDA has designated these organisms as "qualifying pathogens" for purposes of the Generating Antibiotic Incentives Now (GAIN) Act, which is intended to encourage the development of new antibacterial and antifungal drugs to treat serious or life-threatening infections. Other types of bacteria can be added or removed from the list of "qualifying pathogens," and the methods provided by this disclosure encompass any newly added bacteria. The pharmaceutical compositions, methods, and kits disclosed herein may also be useful for treating diseases and infections caused by many of these organisms.

[0358] The pharmaceutical compositions provided by the present disclosure may be used to treat or prevent various diseases caused by said bacteria, including, but not limited to, sexually transmitted diseases, pneumonia, complicated urinary tract infections, urinary tract infections, skin and soft tissue infections, complicated intraperitoneal infections, and intraperitoneal infections.

[0359] Avibactam derivatives can also be administered to patients to inhibit β-lactamase. The pharmaceutical compositions provided by the present disclosure can be administered to patients to inhibit any suitable type of β-lactamase. Examples of types of β-lactamase include extended-spectrum β-lactamases such as TEM β-lactamase (class A), SHV β-lactamase (class A), CTX-M β-lactamase (class A), OXA β-lactamase (class D), and other extended-spectrum β-lactamases such as PER, VEB, GES, and IBC β-lactamase; inhibitor-resistant β-lactamases; AmpC β-lactamase (class C); carbapenemases such as OXA (oxcillinase) group β-lactamase (class D), KPC (K. pneumoniae carbapenemase) (class A), and CMY (class C). Further examples of β-lactamase classes include cephalosporinases, penicillinases, cephalosporinases, extended-spectrum β-lactamases, extended-spectrum β-lactamases, inhibitor-resistant β-lactamases, carbenicillinases, cloxicillinases, oxacillinases, and carbapenemases. β-lactamase classes include class A, class C, and class D β-lactamases.

[0360] The pharmaceutical compositions provided by the present disclosure may further comprise one or more pharma- ceutically active compounds in addition to a β-lactam antibiotic, such as ceftibuten, and an avibactam derivative. Such compounds may be provided to treat bacterial infections treated with ceftibuten, or to treat diseases, disorders, or conditions other than bacterial infections treated with a β-lactam antibiotic, such as ceftibuten.

[0361] The pharmaceutical composition may be used in combination with at least one other therapeutic agent. The pharmaceutical composition may be administered to a patient together with another compound to treat bacterial infection in the patient. The at least one other therapeutic agent may be a different β-lactam antibiotic and / or avibactam derivative. The β-lactam antibiotic such as ceftibuten and the avibactam derivative and the 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 vehicle that includes ceftibuten and / or the avibactam derivative, or may be in a different pharmaceutical composition or vehicle. Thus, the method provided by the present disclosure further includes administering one or more therapeutic agents that are effective for treating bacterial infection or a disease, disorder or condition different from bacterial infection in addition to administering the β-lactam antibiotic such as ceftibuten and the avibactam derivative. The methods provided by the present disclosure include administering ceftibuten and an avibactam derivative and one or more other therapeutic agents, provided that the combined administration does not inhibit the therapeutic effectiveness of the β-lactam antibiotic, such as ceftibuten, and the avibactam derivative and / or does not produce adverse combination effects.

[0362] A pharmaceutical composition comprising a β-lactam antibiotic such as ceftibuten and / or an avibactam derivative can be administered simultaneously with the administration of another therapeutic agent, which may be part of the same pharmaceutical composition as the one comprising a β-lactam antibiotic such as ceftibuten and / or an avibactam derivative, or a different pharmaceutical composition. The β-lactam antibiotic such as ceftibuten and an avibactam derivative can be administered before or after the administration of the other therapeutic agent. In certain combination treatments, for example, to minimize adverse drug effects associated with a particular drug and / or to enhance the effectiveness of the drug combination, the combination treatment may include alternating administration of a β-lactam antibiotic such as ceftibuten and an avibactam derivative with a composition comprising another therapeutic agent. When a β-lactam antibiotic such as ceftibuten and an avibactam derivative are administered simultaneously with another therapeutic agent that may potentially result in adverse drug effects, including, for example, toxicity, the other therapeutic agent can be administered at a dose that falls below the threshold for inducing an adverse drug reaction.

[0363] A pharmaceutical composition comprising a β-lactam antibiotic such as ceftibuten and an avibactam derivative may be administered with one or more substances that enhance, regulate, and / or control the release, bioavailability, therapeutic efficacy, therapeutic potency, stability, etc. of the β-lactam antibiotic such as ceftibuten and an avibactam derivative. For example, to enhance the therapeutic efficacy of ceftibuten and an avibactam derivative, a pharmaceutical composition comprising a β-lactam antibiotic such as ceftibuten and an avibactam derivative may be co-administered with one or more active agents to increase the absorption or diffusion of the β-lactam antibiotic such as ceftibuten and / or the avibactam derivative from the gastrointestinal tract to the systemic circulation or to inhibit the degradation of the β-lactam antibiotic such as ceftibuten and / or the avibactam derivative in the patient's blood. A pharmaceutical composition comprising a β-lactam antibiotic, such as ceftibuten, and an avibactam derivative may be co-administered with an active agent that has a pharmacological effect that enhances the therapeutic effectiveness of the β-lactam antibiotic, such as ceftibuten, and the avibactam derivative.

[0364] The β-lactam antibiotics, such as ceftibuten, and avibactam derivatives may be administered together with another therapeutic compound, where the β-lactam antibiotics, such as ceftibuten, and avibactam derivatives enhance the effectiveness of the other therapeutic compound. For example, the other therapeutic compound may be an antibiotic, such as a β-lactam antibiotic, and an avibactam derivative that provides a systemic β-lactamase inhibitor and may enhance the effectiveness of the β-lactam antibiotic by inhibiting hydrolysis of the β-lactam ring by β-lactamase.

[0365] Pharmaceutical compositions provided by the present disclosure can be administered in combination with antibiotics such as β-lactam antibiotics in addition to β-lactam antibiotics such as ceftibuten.

[0366] Suitable antibiotics include, for example, aminoglycosides such as amikacin, gentamicin, neomycin, plazomicin, streptomycin, and tobramycin; β-lactams (cephalosporins, first generation) such as cefadroxil, cefazolin, and cephalexin; β-lactams (cephalosporins, second generation) such as cefaclor, cefotetan, cefoxitin, cefprozil, and cefuroxime; β-lactams (cephalosporins, second generation) such as cefotaxime, cefpodoxime, ceftazidime, ceftibuten, cefixime, and ceftriaxone. beta-lactams (cephalosporins, third generation) such as cefepime; beta-lactams (cephalosporins, sixth generation) such as ceftaroline; beta-lactams (cephalosporins, fifth generation) such as amoxicillin, ampicillin, dicloxacillin, nafcillin, and oxacillin, beta-lactams (penicillins) such as penicillin G, penicillin G benzathine, penicillin G procaine, piperacillin, and ticarcillin; beta-lactam monobactams such as aztreonam; ertapenem, imipenem, meropenem, sulopenem, faropenem, tebipenem, β-lactam carbapenems, such as cyclosporine, cyclosporine, and doripenem; fluoroquinolones, such as ciprofloxacin, gemifloxacin, levofloxacin, moxifloxacin, norfloxacin, and ofloxacin; macrolides, such as azithromycin, clarithromycin, erythromycin, fidaxomicin, lactobionate, gluceptate, and telithromycin; sulfones, such as sulfisoxazole, sulfamethizole, sulfamethoxazole, and trimethoprim. amides; tetracyclines such as doxycycline, minocycline, tetracycline, and tigecycline; and other antibiotics such as clindamycin, chloramphenicol, colistin (poloymyxin E), dalbavancin, daptomycin, fosfomycin, linezolid, metronidazole, nitrofurantoin, oritavancin, quinupristin, dalfopristin, rifampin, rifapentine, tedizolid, telavancin, and vancomycin. The antibiotic may be ceftazidime.

[0367] Other examples of suitable antibiotics include penicillins such as aminopenicillins, including amoxicillin and ampicillin, antipseudomonal penicillins, including carbenicillin, peperacillin, and ticarcillin; mecillinam and pivmecillinam; beta-lactamase inhibitors, including clavulanate, sulbactam, and tazobactam; natural penicillins, including penicillin G benzathine, penicillin V potassium, and procaine penicillin, and penicillinase-resistant penicillins, including oxacillin, dicloxacillin, and nafcillin; tetracyclines; cephalosporins, such as cefadroxil, defazolin, cephalexin, and cefazolin; lomefloxacin, ofloxacin, norfloxacin, gatifloxacin, ciprofloxacin, moxifloxacin, levofloxacin, and cephalosporins. quinolones such as sacine, gemifloxacin, delafloxacin, cinoxacin, nalidixic acid, trovafloxacin, and sparfloxacin; lincomycins such as lincomycin and clindamycin; macrolides such as ketolides 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, plazomycin, and neomycin; and carbapenems such as doripenem, meropenem, ertapenem, tebipenem, sulopenem, faropenem, and cilastatin / imipenem.Examples of suitable β-lactam antibiotics include β-lactamase-sensitive penams such as benzathine penicillin, benzylpenicillin, phenoxymethylpenicillin, 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-substrate penams such as mecillinam; carboxypenicillins such as carbenicillin and ticarcillin, and ureidopenicillins such as azlocillin, mezlocillin, and pereracillin.

[0368] 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, cefamandole, cefuroxime, cefotetan, and cefoxitin; third generation cephams such as cefixime, cefotaxime, cefpodoxime, ceftazidime, and ceftriaxone; fourth generation cephams such as cefepime and cefpirome; and fifth generation cephams such as ceftaroline.

[0369] Examples of suitable β-lactam antibiotics include carbapenems and penems such as biapenem, doripenem, ertapenem, faropenem, imipenem, meropenem, panipenem, razupenem, tebipenem, sulopenem, and thienamycin.

[0370] Examples of suitable β-lactam antibiotics include monobactams such as aztreonam, tigemonam, nocardicin A, and tabtoxin β-lactam.

[0371] The pharmaceutical compositions provided by the present disclosure can be administered with a β-lactamase inhibitor and / or a carbapenemase in addition to the avibactam derivative of formula (1). Examples of suitable β-lactamase inhibitors and / or carbapenemase inhibitors include clavulanic acid, sulbactam, avibactam, tazobactam, relebactam, vaborbactam, ETX2514, RG6068 (i.e., OP0565) (Livermore et al., J AntiMicrob Chemother 2015, 70:3032) and RPX7009 (Hecker et al., J Med Chem 2015 58:3682-3692).

[0372] Aspects of the invention The present invention is further defined by the following aspects.

[0373] Aspect 1. a β-lactam antibiotic or a pharma- ceutically acceptable salt thereof; Avibactam derivatives of formula (1):

[0374] [ka] or a pharma- ceutically acceptable salt thereof [In the formula, Each R 1 are independent, C 1~6 alkyl, or each R 1 and the geminal carbon atom to which they are bonded is C 3~6 Cycloalkyl ring, C 3~6 Heterocycloalkyl ring, substituted C 3~6 Cycloalkyl ring, or substituted C 3~6 forming a heterocycloalkyl ring, R 2 is a single bond, C 1~6 Alkanediyl, C 1~6 Heteroalkanediyl, C 5~6 Cycloalkanediyl, C 5~6 Heterocycloalkanediyl, C6 arenediyl, C 5~6 Heteroarenediyl, substituted C 1~6Alkanediyl, substituted C 1~6 Heteroalkanediyl, substituted C 5~6 Cycloalkanediyl, substituted C 5~6 Heterocycloalkanediyl, substituted C6 arenesiyl, and substituted C 5~6 selected from heteroarylene diyls, R 3 is C 1~6 Alkyl, -OC(O)-R 4 , -SC(O)-R 4 , -NH-C(O)-R 4 , -OC(O)-OR 4 , -SC(O)-OR 4 , -NH-C(O)-OR 4 , -C(O)-OR 4 , -C(O)-SR 4 , -C(O)-NH-R 4 , -OC(O)-OR 4 , -OC(O)-SR 4 , -OC(O)-NH-R 4 , -SSR 4 , -SR 4 , -NH-R 4 , -CH(-NH2)(-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 is selected, R 4 is 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 Aryl alkyl, C 5~10Heteroarylalkyl, 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 Aryl alkyl and substituted C 5~10 heteroarylalkyl; R 5 is 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 C 5~8 Cycloalkyl, substituted C 6~12 Cycloalkylalkyl, substituted C 2~6 Heteroalkyl, substituted C 5~8 Heterocycloalkyl and substituted C 6~12 heterocycloalkylalkyl; R 6 is 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 C 5~8 Cycloalkyl, substituted C 6~12 Cycloalkylalkyl, substituted C 2~6 Heteroalkyl, substituted C 5~8 Heterocycloalkyl and substituted C 6~12 heterocycloalkylalkyl] and a pharmaceutical composition comprising:

[0375] Aspect 2. The pharmaceutical composition of aspect 1, wherein the β-lactam antibiotic comprises an orally bioavailable β-lactam antibiotic or a pharma- ceutically acceptable salt thereof.

[0376] Aspect 3. The pharmaceutical composition of any one of aspects 1 and 2, wherein the β-lactam antibiotic comprises ceftibuten or a pharma-ceutically acceptable salt thereof.

[0377] Aspect 4. The pharmaceutical composition of aspect 3, wherein the ceftibuten comprises ceftibuten dihydrate or a pharma- ceutically acceptable salt thereof.

[0378] Aspect 5. The pharmaceutical composition of aspect 1, wherein said beta-lactam antibiotic comprises an orally bioavailable derivative of aztreonam or a pharma- ceutically acceptable salt thereof, cefpodoxime or a pharma- ceutically acceptable salt thereof, cefixime or a pharma- ceutically acceptable salt thereof, pivmecillinam or a pharma- ceutically acceptable salt thereof, tebipenem or a pharma- ceutically acceptable salt thereof, sulopenem or a pharma- ceutically acceptable salt thereof, or a combination of any of the foregoing.

[0379] Aspect 6. The avibactam derivative has the structure of formula (1a):

[0380] [ka] or a pharma- ceutically acceptable salt thereof, 1 are independent, C 1~6 alkyl; R 3 is C 1~6 6. The pharmaceutical composition according to any one of embodiments 1 and 5, wherein:

[0381] Aspect 7. The avibactam derivative is Methyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate; Ethyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate; Propyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate; Methyl 2-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylbutanoate; Ethyl 2-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylbutanoate; Propyl 2-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylbutanoate; Methyl 2-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-propylpentanoate; Ethyl 2-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-propylpentanoate; Propyl 2-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-propylpentanoate; A pharma- ceutically acceptable salt of any of the above; and Any combination of the above 7. The pharmaceutical composition according to any one of aspects 1 and 6, selected from:

[0382] Aspect 8. The pharmaceutical composition of any one of aspects 1 and 5, wherein the avibactam derivative is ethyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (3), or a pharma-ceutically acceptable salt thereof.

[0383] Aspect 9. The pharmaceutical composition of any one of aspects 1 and 8, wherein the avibactam derivative comprises a hydrochloride salt.

[0384] Aspect 10. The pharmaceutical composition of aspect 1, wherein said avibactam derivative comprises crystalline ethyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate anhydrate.

[0385] Aspect 11. The pharmaceutical composition of aspect 10, wherein the crystalline avibactam anhydrate is characterized by an XRPD pattern having characteristic scattering angles (2θ) at Kα2 / Kα1 (0.5) wavelengths of at least 3.16°±0.2°, 6.37°±0.2°, 5.38°±0.2°, 15.77°±0.2°, and 17.35°±0.2°, and exhibits a melting point of 123.0°C to 127.0°C as determined by differential scanning calorimetry.

[0386] Embodiment 12. The pharmaceutical composition according to any one of embodiments 1 and 11, further comprising a pharma- ceutically acceptable excipient.

[0387] Embodiment 13. The pharmaceutical composition according to any one of embodiments 1 and 12, comprising a weight ratio of avibactam equivalents to β-lactam antibiotic equivalents from 1:1 to 4:1.

[0388] Aspect 14. A pharmaceutical composition according to any one of aspects 1 to 13, comprising a synergistically effective amount of a β-lactam antibiotic or a pharma- ceutical acceptable salt thereof and said avibactam derivative or a pharma-ceutical acceptable salt thereof for treating a bacterial infection that produces a β-lactamase enzyme in a patient.

[0389] Aspect 15. The pharmaceutical composition according to any one of aspects 1 to 14, wherein the bacterial infection is caused by an Enterobacteriaceae bacterium.

[0390] Aspect 16. The pharmaceutical composition of any one of aspects 1 to 15, wherein the bacterial infection is caused by a bacterium that produces an extended-spectrum β-lactamase enzyme.

[0391] Aspect 17. The pharmaceutical composition of any one of aspects 1 to 16, comprising between 200 mg and 1,400 mg of the β-lactam antibiotic.

[0392] Aspect 18. The pharmaceutical composition of any one of aspects 1 to 16, comprising between 200 mg and 900 mg of the β-lactam antibiotic.

[0393] Aspect 19. The pharmaceutical composition according to any one of aspects 1 to 18, comprising 200 mg to 1,400 mg of the avibactam derivative.

[0394] Aspect 20. The pharmaceutical composition according to any one of aspects 1 to 18, comprising 300 mg to 900 mg of the avibactam derivative.

[0395] Aspect 21. The pharmaceutical composition according to any one of aspects 1 to 20, comprising an avibactam equivalent amount of between 200 mg and 1,400 mg.

[0396] Aspect 22. The pharmaceutical composition according to any one of aspects 1 to 20, comprising an avibactam equivalent of between 300 mg and 900 mg.

[0397] Aspect 23. The pharmaceutical composition according to any one of aspects 1 to 20, comprising 100 mg to 500 mg of ceftibuten or a pharma- ceutically acceptable salt thereof; and 300 mg to 1,400 mg of the avibactam derivative or a pharma- ceutically acceptable salt thereof.

[0398] Embodiment 24. The pharmaceutical composition according to any one of embodiments 1 to 23, which, following oral administration to a patient, results in a plasma concentration of the β-lactam antibiotic of greater than 40% fT>MIC.

[0399] Aspect 25. After oral administration to a patient, 40% fT>C t 25. The pharmaceutical composition according to any one of aspects 1 to 24, wherein the pharmaceutical composition results in an avibactam plasma concentration of greater than

[0400] Embodiment 26. The pharmaceutical composition according to any one of embodiments 1 to 25, which, after oral administration to a patient, results in an avibactam plasma concentration characterized by a fAUC:MIC ratio of between 10 and 40.

[0401] Embodiment 27. The pharmaceutical composition according to any one of embodiments 1 to 26, comprising an oral formulation.

[0402] Embodiment 28. The pharmaceutical composition according to any one of embodiments 1 to 27, comprising an oral dosage form.

[0403] Embodiment 29. An oral dosage form comprising the pharmaceutical composition of any one of embodiments 1 to 28.

[0404] Embodiment 30. A kit comprising the pharmaceutical composition according to any one of embodiments 1 to 29.

[0405] Aspect 31. A patient is administered a therapeutically effective amount of a β-lactam antibiotic or a pharma- ceutically acceptable salt thereof; Avibactam derivatives of formula (1):

[0406] [ka] or a pharma- ceutically acceptable salt thereof [In the formula, Each R 1 are independent, C 1~6 alkyl, or each R 1 and the geminal carbon atom to which they are bonded is C 3~6 Cycloalkyl ring, C 3~6 Heterocycloalkyl ring, substituted C 3~6 Cycloalkyl ring, or substituted C 3~6 forming a heterocycloalkyl ring, R 2 is a single bond, C 1~6 Alkanediyl, C 1~6 Heteroalkanediyl, C 5~6 Cycloalkanediyl, C 5~6 Heterocycloalkanediyl, C6 arenediyl, C 5~6 Heteroarenediyl, substituted C 1~6 Alkanediyl, substituted C 1~6 Heteroalkanediyl, substituted C 5~6 Cycloalkanediyl, substituted C 5~6 Heterocycloalkanediyl, substituted C6 arenesiyl, and substituted C 5~6 selected from heteroarylene diyls, R 3 is C 1~6 Alkyl, -OC(O)-R 4 , -SC(O)-R 4 , -NH-C(O)-R 4 , -OC(O)-OR 4 , -SC(O)-OR 4 , -NH-C(O)-OR 4 , -C(O)-OR 4 , -C(O)-SR 4 , -C(O)-NH-R 4 , -OC(O)-OR 4 , -OC(O)-SR 4 , -OC(O)-NH-R 4 , -SSR 4 , -SR 4 , -NH-R 4 , -CH(-NH2)(-R 4 ), C 5~6 Heterocycloalkyl, C 5~6Heteroaryl, 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 is selected, R 4 is 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 Aryl alkyl, 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 Aryl alkyl and substituted C 5~10 heteroarylalkyl; R 5 is 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 C 5~8 Cycloalkyl, substituted C 6~12 Cycloalkylalkyl, substituted C 2~6 Heteroalkyl, substituted C 5~8 Heterocycloalkyl and substituted C 6~12heterocycloalkylalkyl; R 6 is 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 C 5~8 Cycloalkyl, substituted C 6~12 Cycloalkylalkyl, substituted C 2~6 Heteroalkyl, substituted C 5~8 Heterocycloalkyl and substituted C 6~12 heterocycloalkylalkyl] and (c) orally administering to said patient a compound comprising the compound of formula (I) and (II).

[0407] Aspect 32. The method of aspect 31, wherein the bacterial infection is caused by a bacterium that produces a β-lactamase enzyme.

[0408]

[0023] Aspect 33. The method of any one of aspects 31 to 32, wherein the bacterial infection is caused by an Enterobacteriaceae bacterium.

[0409] Aspect 34. The method of any one of aspects 31 to 33, wherein the bacterial infection is a bacterial infection in which intravenous administration of avibactam in combination with a β-lactam antibiotic is effective in treating the bacterial infection.

[0410] Aspect 35. The method of any one of aspects 31 to 34, wherein administering comprises independently administering the β-lactam antibiotic, or a pharmaceutically acceptable salt thereof, and the avibactam derivative, or a pharmaceutically acceptable salt thereof, 2 to 5 times per day.

[0411] Aspect 36. The method of any one of aspects 31 to 35, wherein administering comprises administering each of the β-lactam antibiotic, or a pharmaceutically acceptable salt thereof, and the avibactam derivative, or a pharmaceutically acceptable salt thereof, q8h.

[0412] Aspect 37. The method of any one of aspects 31 to 36, comprising orally administering to said patient a total daily dose of between 600 mg and 1,500 mg of said β-lactam antibiotic or a pharma-ceutically acceptable salt thereof; and a total daily dose of between 600 mg and 4,200 mg of the avibactam equivalent of said avibactam derivative.

[0413] Aspect 38. The method of any one of aspects 31 to 36, comprising orally administering to said patient a total daily dose of between 600 mg and 1,500 mg of said β-lactam antibiotic or a pharmaceutically acceptable salt thereof; and a total daily dose of between 900 mg and 1,800 mg of said avibactam derivative or a pharmaceutically acceptable salt thereof.

[0414] Aspect 39. The method of any one of aspects 31 to 36, comprising orally administering to said patient between 100 mg and 500 mg of ceftibuten or a pharma- ceutically acceptable salt thereof, three times per day (TID); and an amount of said avibactam derivative or a pharma- ceutically acceptable salt thereof, comprising between 600 mg and 1,400 mg of said avibactam derivative or a pharma- ceutically acceptable salt thereof, three times per day (TID).

[0415] Aspect 40. The method of any one of aspects 31 to 36, comprising orally administering to said patient 100 mg to 500 mg of ceftibuten or a pharma- ceutically acceptable salt thereof three times per day (TID); and 600 mg to 900 mg of said avibactam derivative or a pharma-ceutically acceptable salt thereof three times per day (TID).

[0416] Aspect 41. The method of any one of aspects 31 to 36, comprising orally administering a weight ratio of said β-lactam antibiotic to avibactam equivalent of from 1:1 to 1:4.

[0417] Aspect 42. The method of any one of aspects 31 to 41, comprising orally administering said avibactam derivative in an amount that results in a fAUC:MIC ratio of 10 to 40 for the bacterium causing said infection.

[0418] Embodiment 43. The method of any one of embodiments 31 to 42, wherein orally administering comprises orally administering an oral dosage form comprising ceftibuten and said avibactam derivative.

[0419] Aspect 44. The method of any one of aspects 31 to 43, comprising orally administering to said patient simultaneously said ceftibuten, or a pharma- ceutically acceptable salt thereof, and said avibactam derivative, or a pharma- ceutically acceptable salt thereof.

[0420]

[0036] Embodiment 45. The method of any one of embodiments 31 to 44, wherein orally administering comprises administering to said patient for at least 7 days.

[0421] Embodiment 46. A method of treating a bacterial infection in a patient in need of such treatment, comprising orally administering to said patient a therapeutically effective amount of the pharmaceutical composition of any one of embodiments 1 to 28. EXAMPLES

[0422] The following examples describe the pharmacokinetics of ceftibuten and avibactam derivatives for treating bacterial infections. It will be apparent to those skilled in the art that many variations, both to materials and methods, can be practiced without departing from the scope of the present disclosure.

[0423] Example 1 Development of a chemostat model for oral administration of ceftibuten and avibactam derivatives. Using intravenous (IV) data, a chemostat model for the PK of oral administration of ceftibuten and administration of avibactam (in the absence of PK data from oral administration of the prodrug) was obtained to determine a putative dosing regimen for treating bacterial infections. The model was based on a PK profile similar to that for IV-delivered avibactam based on Merdjan et al., poster presentation at Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, 2007). An in vitro chemostat PK / PD model was used, which is widely accepted for designing and evaluating novel antibiotic treatments to be tested in clinical studies. The FDA and EMA accept a 1 log reduction as a measure of efficacy for a 24-hour regimen in this model. However, for some indications, e.g., UTI (quiescent) or VAP (>1 log), other thresholds can be used depending on the severity of the infection. The chemostat model is often the first PK / PD study because it allows a large number of strains and treatment regimens to be tested in a short period of time. However, chemostat models cannot account for factors associated with the immune system or clearance mechanisms of bacterial debris in human or animal infections or enzymes such as β-lactamases that may increase survival of subsets of bacteria that persist after antibiotic exposure that would otherwise not be present.

[0424] MICs of the most relevant target bacteria and phenotypes 50 and MIC 90 A study was conducted to evaluate ceftibuten FDA-approved doses (200 mg and 400 mg), as well as multiple avibactam doses, against multiple Enterobacterial strains with MICs ranging from 0.125 µg / mL to 4 µg / mL (Table 1).

[0425] [Table 1]

[0426] The objective of the study was to identify the approved ceftibuten dose and IV equivalent avibactam dose that showed at least 1 log clearance against wild-type, ESBL-producing bacteria as the most common resistance phenotype, and other relevant bacterial phenotypes including KPC, OXA, and AmpC.

[0427] A ceftibuten-susceptible strain, E. coli ATCC25922 (MIC ceftibuten = 0.5 μg / mL), was used to determine the treatment frequency with ceftibuten alone. Results suggested that TID dosing is required with ceftibuten. This treatment regimen aligns well with the FDA-approved IV dosing regimen with avibactam, TID in combination with ceftazidime. AVYCAZ® Package Insert, Allergan, Madison, NJ, 2019.

[0428] The dose of ceftibuten to combine with avibactam in a TID regimen was then determined. The data showed that ceftibuten doses in the range of 200 mg to 267 mg, along with an avibactam dose of 500 mg, reached 1 log clearance for many strains. However, for strains with MICs ≥ 1 μg / mL, an avibactam dose of 750 mg was required. The results are shown in Table 2.

[0429] [Table 2]

[0430] Titration of the ceftibuten dose to 400 mg with a 500 mg avibactam dose resulted in improved outcomes.

[0431] A dose of ceftibuten 400 mg TID in combination with an avibactam dose of at least 375 mg IV equivalent reached 1 log target clearance in all strains tested. See Table 3. The reduction in bacterial load was more pronounced with higher avibactam doses. Therefore, a combination of ceftibuten 400 mg (FDA approved dose) TID with avibactam 375 mg to 500 mg TID (500 mg is the FDA approved dose) is predicted to be an effective combination ceftibuten / avibactam TID treatment.

[0432] [Table 3]

[0433] Inhibition of growth of resistant bacteria was monitored by plating samples at 5x MIC (ceftibuten / avibactam). No resistant subpopulations were observed with the ceftibuten 400 mg TID regimen with avibactam at doses of 350 mg TID or higher. Results supported the use of ceftibuten 400 mg TID and avibactam 375 mg to 500 mg TID regimens.

[0434] Bacterial and antimicrobial drugs A panel of 17 Enterobacteriaceae isolates was used in this study. The challenge isolate panel included five Enterobacter cloacae, four Escherichia coli, and eight Klebsiella pneumoniae known to express various Ambler class A, C, and D β-lactamase enzymes. E. coli ATCC 25922, E. coli ATCC 35218, and K. pneumoniae ATCC 700603 served as internal control strains.

[0435] In vitro susceptibility testing Minimum inhibitory concentration (MIC) values ​​were determined for ceftibuten and avibactam using Mueller-Hinton microbroth and agar dilution methods according to the Clinical and Laboratory Standards Institute (CLSI) guidelines, CLSIM07-A9. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, Ninth edition; CLSI supplement M07-A9. Wayne, PA. Clinical and Laboratory Standards Institute; 2012. All MIC values ​​were determined for ceftibuten and avibactam alone and in combination using a fixed concentration of 4 mg / L or 8 mg / L avibactam, as well as a 1:1 weight percent ratio of ceftibuten to avibactam. All MIC values ​​were determined in triplicate over two days, and the results are expressed as modal values.

[0436] One-compartment in vitro infection model A one-compartment in vitro infection model was utilized in these studies. VanScoy et al., Antimicrob Agents Chemother 2013;57:2809-2814; and VanScoy et al., Antimicrob Agents Chemother 2013;57:5924-5930. The in vitro infection model consisted of a central infection compartment attached to a magnetic stir plate placed inside a temperature-controlled incubator set at 35°C. Within the central compartment, a suspension of challenge bacteria was exposed to a concentration-time profile of ceftibuten designed to simulate free drug plasma concentrations in healthy volunteers after oral administration (PO). Lin et al., Antimicrob Agents Chemother.1995;39:359-361; and Nix et al., Pharmacotherapy.1997;17:121-125. Avibactam pharmacokinetic (PK) profiles were simulated using those determined for IV avibactam. Poster published at Merdjan et al., Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, 2007. A computer-controlled syringe pump was used to simulate the selected half-life, dosing frequency, and infusion duration. Samples for colony forming unit (CFU) determination and drug concentration assays were collected from the central infection compartment at pre-determined times throughout the study period.

[0437] For one-compartment in vitro infection model experiments, 1.0 x 10 6Bacterial suspensions of CFU / mL were prepared for each challenge isolate from overnight cultures grown on trypticase soy agar with 5% lysed sheep blood (BD Laboratories). A few isolated colonies were removed from the overnight cultures and grown to mid-logarithmic phase in Mueller-Hinton broth at 35°C and set at 125 revolutions per minute. Bacterial concentrations of the suspensions growing in the flasks were determined by optical density measurements and compared to previously established growth curves for each challenge isolate. Bacteria in the central compartment were then exposed to challenge concentrations of ceftibuten and avibactam simulating a human half-life of 2.8 hours. Lin et al., Antimicrob Agents Chemother. 1995, 39, 359-361; and Nix et al., Pharmacotherapy. 1997, 17, 121-125. All ceftibuten and avibactam dosing regimens were linearly scaled based on the free-drug plasma steady-state concentration profiles observed after a 400 mg PO dose, assuming plasma protein binding of 65.0% and 6.95% for ceftibuten and avibactam, respectively. Lin et al., Antimicrob Agents Chemother. 1995, 39, 359-361; and Nix et al., Pharmacotherapy. 1997, 17, 121-125; AVYCAZ® (ceftazidime and avibactam for injection), package insert, Allergan USA, Inc., Madison, NJ. 2019.

[0438] To determine the effect that ceftibuten and avibactam had on each bacterial population, a series of samples were collected at 0, 2, 4, 8, 12, and 24 hours. Each sample was centrifuged, decanted, and resuspended twice in sterile saline to prevent drug carryover. The washed samples were serially diluted in sterile saline and cultured on trypticase soy agar plates. All inoculated agar plates were then placed in a humidified incubator at 35°C for 24 hours. One milliliter samples were collected at various time points throughout the study period to ensure that the target ceftibuten and avibactam pharmacokinetic (PK) profiles were achieved in the one-compartment in vitro infection model. All samples used to determine ceftibuten and avibactam concentrations were frozen at -80°C immediately after collection until assayed for drug concentrations using liquid chromatography-tandem mass spectrometry (LC / MS / MS).

[0439] Ceftibuten dose-finding study A series of ceftibuten dose-finding studies were performed in duplicate with a single wild-type Escherichia coli (E. coli) isolate (ATCC 25922) to determine the percent time above the MIC (%T>MIC) values ​​associated with ceftibuten efficacy when administered every 8 hours (q8h). Using a 24-hour, one-compartment in vitro model, a dose of 1.0 × 10 6 Initial bacterial loads in CFU / mL were exposed to ceftibuten regimens ranging from 12.5 mg to 267 mg q8h. Samples were collected for PK and CFU determination.

[0440] Ceftibuten / avibactam dosing frequency study A 24-h one-compartment model was used to identify the optimal dosing frequency for ceftibuten in combination with avibactam. Three total daily ceftibuten doses (400 mg, 800 mg, and 1,200 mg) were divided into regimens administered every 8, 12, or 24 hours (q8h, q12h, and q24h, respectively). The ceftibuten regimens were administered in combination with a total daily dose of 1,500 mg avibactam divided into doses of 500 mg, 750 mg, and 1,500 mg administered q8h, q12h, and q24h, respectively. Three isolates, K. pneumoniae BAA-1705, 908, and 79, with avibactam-potentiated ceftibuten broth MIC values ​​of 0.125 mg / L, 0.5 mg / L, and 2 mg / L when evaluated in combination with avibactam 4 mg / L, were 6 Initial bacterial load in CFU / mL was assessed in duplicate. Samples were collected for PK and CFU.

[0441] Ceftibuten / avibactam dose-finding study A 24-hour one-compartment model was utilized to identify the optimal ceftibuten regimen to be used in combination with avibactam when administered q8h. Two ceftibuten doses, 200 mg and 400 mg q8h, were administered alone and in combination with avibactam regimens ranging from 31.3 mg to 750 mg q8h. Three isolates (K. pneumoniae 19701, E. coli 136-4643, and E. cloacae 4184) with avibactam-boosted ceftibuten broth MIC values ​​of 0.125 mg / L, 1 mg / L, and 4 mg / L when evaluated in combination with avibactam 4 mg / L were identified as having a MIC of 1.0 × 10 6 Initial bacterial loads in CFU / mL were assessed in duplicate.

[0442] To assess the presence of drug-resistant bacterial populations within a one-compartment model utilizing only the 400 mg ceftibuten regimen, aliquots from the 0 and 24-hour bacterial samples were plated onto Mueller-Hinton agar plates supplemented with 4 mg / L avibactam and a ceftibuten concentration that was five times the avibactam-boosted ceftibuten MIC value. Once growth was observed on the drug-supplemented agar plates, a subset of isolates (three per treatment regimen) were collected and ceftibuten MIC values ​​were determined in triplicate using an agar dilution protocol in combination with a fixed concentration of 4 mg / L avibactam.

[0443] Analysis method All samples were assayed using LC / MS / MS on a Sciex QTRAP® 5500 to determine the optimal concentrations of ceftibuten and avibactam.

[0444] Pharmacokinetic-pharmacodynamic analysis A one-compartment PK model was fitted to avibactam samples collected from a ceftibuten 400 mg / avibactam dose-finding study to evaluate the observed drug concentration-time profiles. Data from the avibactam dose-finding study in combination with ceftibuten 400 mg q8h were evaluated using the Hill model and nonlinear least-squares regression. All data were weighted using the inverse of the estimated measurement variance. Log 20-fold reductions from baseline at 24 hours were calculated using MICs determined at fixed avibactam concentrations of 4 mg / L and 8 mg / L or at a 1:1 ratio of ceftibuten:avibactam. 10 The relationship between the change in CFU / mL and the ratio of free-drug area under the avibactam concentration-time curve to the potentiated ceftibuten MIC (free-drug fAUC:MIC) was evaluated. Log changes from baseline at 24 hours were calculated using MICs determined at fixed avibactam concentrations of 4 mg / L and 8 mg / L or a 1:1 ratio of ceftibuten:avibactam. 10 An additional relationship between the change in CFU / mL and the percent of time that avibactam free drug concentrations exceeded the avibactam-boosted ceftibuten MIC was evaluated. 10The relationship between change in CFU / mL and percent time above avibactam concentration thresholds (Ct) ranging from 0.125 mg / L to 2 mg / L was also evaluated. The magnitude of each exposure associated with net bacterial stasis, as well as 1- and 2-log changes from baseline, were also evaluated. 10 CFU / mL reduction was determined based on the Hill model developed to describe the respective relationships for pooled data across all three Enterobacteriaceae isolates.

[0445] In vitro susceptibility testing Ceftibuten microbroth and agar MIC values ​​determined using various concentrations, alone or in combination with avibactam, are shown in Tables 4 and 5, respectively.

[0446] [Table 4]

[0447] [Table 5]

[0448] Ceftibuten microbroth MIC values ​​ranged from 8 mg / L to >64 mg / L for clinical isolates and were within the CLSI reference standard range for E. coli 25922. CLSI. Performance standards for antimicrobial susceptibility testing. 29th ed., CLSI supplement M100. Wayne, PA: Clinical and Laboratory Standards Institute; 2019. Avibactam showed only moderate activity with MIC values ​​ranging from 16 mg / L to >512 mg / L across the challenge isolate panel. When ceftibuten was boosted with avibactam 4 mg / L, MIC values ​​decreased to values ​​ranging from ≤0.03 mg / L to 8 mg / L, and when boosted with 8 mg / L, MIC values ​​decreased to values ​​ranging from ≤0.03 mg / L to 4 mg / L. When ceftibuten and avibactam were evaluated using a 1:1 weight percent ratio, the MIC distribution fell to values ​​ranging from 0.03 mg / L to 8 mg / L.

[0449] One-compartment in vitro infection model Ceftibuten dose-finding study Within the one-compartment model, a complete ceftibuten dose response was achieved. The lower ceftibuten regimen (12.5 mg q8h) represented treatment failure by matching growth in untreated controls by 24 h. The intermediate regimens (3.75 mg to 75 mg q8h) achieved net bacterial stasis, and the 100 mg and 267 mg q8h ceftibuten regimens achieved a reduction in bacterial load at 24 h. The results are shown in Figure 1.

[0450] As shown in FIG. 2, using a one-compartment model, the ceftibuten %T>MIC required to achieve net bacteriostasis against E. coli ATCC 25922 when administered every 8 hours was found to be approximately 45%.

[0451] Ceftibuten / avibactam dosing frequency study A higher degree of bactericidal activity was observed over 24 hours when ceftibuten / avibactam was administered more frequently. The q24h regimen resulted in treatment failure for all three isolates, with bacterial densities similar to untreated controls by the 24 hour time point, regardless of ceftibuten dose. Time course data for K. pneumoniae 79, K. pneumoniae 908, and K. pneumoniae BAA-1705 are shown in Figures 3A-3I.

[0452] The q12h and q8h regimens yielded similar time course profiles for K. pneumoniae BAA-1705 and 908. The similarity in activity is likely due to the relatively low avibactam-boosted ceftibuten MIC values ​​for these two strains. When evaluated against the isolate with the highest avibactam-boosted ceftibuten MIC, K. pneumoniae 79, the q8h regimen routinely yielded higher activity. The greatest differentiation between dosing frequencies was observed with ceftibuten 1,200 mg TDD.

[0453] Ceftibuten / avibactam dose-finding study - ceftibuten 200 mg q8h The results of a ceftibuten / avibactam dose-finding study utilizing a 200 mg q8h regimen in combination with avibactam doses ranging from 31.3 mg to 750 mg q8h for K. pneumoniae 19701 and E. cloacae 4184 are shown in Figures 4 and 5, respectively.

[0454] K. pneumoniae 19701 K. pneumoniae isolates grew well in the in vitro model, outgrowing untreated controls by 8 log by 4 hours. 10Bacterial loads of > CFU / mL were achieved and remained at that level for the remainder of the study. Ceftibuten monotherapy achieved no activity, with loads consistent with untreated controls throughout the study. Avibactam regimens of 125 mg q8h or less achieved an initial reduction in bacterial load, followed by immediate regrowth to values ​​above the initial bacterial load at 24 hours. Avibactam regimens of 250 mg to 500 mg q8h in combination with ceftibuten 200 mg achieved net bacterial stasis in the system. The avibactam dose of 750 mg was highly variable, decreasing by more than 1 log over 24 hours. 10 CFU / mL to 4 logs 10 A reduction in bacterial load to >CFU / mL was achieved.

[0455] E. cloacae 4184 E. cloacae 4184 grows well in an in vitro model, outgrowing untreated controls by 8 log by 4 hours. 10 Bacterial loads of >CFU / mL were achieved and maintained at that level for the remainder of the study. Ceftibuten monotherapy achieved no activity, with loads consistent with untreated controls throughout the study. Combined ceftibuten / avibactam regimens achieved a complete dose response with relatively low dose regimens of 31.3 mg to 125 mg q8h, consistent with growth in untreated controls throughout the study period. Intermediate avibactam dose regimens of 250 mg and 375 mg q8h achieved an initial reduction in bacterial load, followed by immediate regrowth. Avibactam regimens of 500 mg q8h and above achieved stasis and 1-log reductions in bacterial load over 24 hours. 10 It could result in a decrease in CFU / mL.

[0456] Ceftibuten / avibactam dose-finding study - ceftibuten 400 mg q8h Results of a ceftibuten / avibactam dose-finding study using a 400 mg q8h regimen combined with avibactam doses ranging from 31.3 mg to 750 mg q8h against E. coli 4643, K. pneumoniae 19701, and E. cloacae 4184 are shown in Figures 6–11 and Tables 6–8.

[0457] Escherichia coli (E.coli)4643 Data for E. coli 4643 (CTX-M-15) total bacterial load generated in a ceftibuten / avibactam dose-finding study are shown in Figures 6 and 7A-7H. Untreated controls grew well, reaching a 9 log 10 Ceftibuten monotherapy achieved a small initial reduction in bacterial load over the first 4 hours of exposure, followed by an initial regrowth to values ​​consistent with untreated controls by 12 hours. The ceftibuten / avibactam combination regimens evaluated achieved approximately a 1.5-5 log reduction in bacterial load at 24 hours. 10 This resulted in a decrease in CFU / mL.

[0458] Data representing the E. coli 4643 ceftibuten / avibactam resistant subpopulations generated in the dose-finding study are shown in Table 6. No resistant subpopulations were observed in the untreated control and all ceftibuten treatment regimens evaluated.

[0459] [Table 6]

[0460] K. pneumoniae 19701 Data for K. pneumoniae 19701 (KPC-2) total bacterial load generated in a ceftibuten / avibactam dose-finding study are shown in Figures 8 and 9A-9I. Untreated controls grew well, reaching a 9 log 10Bacterial loads approaching CFU / mL were achieved. Ceftibuten monotherapy did not reduce bacterial load over the study period, consistent with growth observed in untreated controls. Ceftibuten / avibactam combination regimens failed to prevent regrowth in the system, with avibactam regimens at or below 62.5 mg q8h producing a full exposure response. All avibactam regimens at or above 125 mg q8h prevented bacterial growth in the one-compartment model, reducing bacterial load by 2 log by 24 h. 10 A reduction of more than CFU / mL was achieved.

[0461] Data for K. pneumoniae 19701 ceftibuten / avibactam resistant subpopulations generated in the dose-finding study are shown in Table 7. Resistant subpopulations were observed in the untreated control, the ceftibuten monotherapy regimen, and combination regimens up to 62.5 mg q8h. Ceftibuten / avibactam resistant subpopulations observed within the ceftibuten monotherapy regimen did not achieve concentrations higher than those observed in the untreated control, indicating that these resistant subpopulations do not arise with treatment and represent inherent resistance within a given population. Resistant subpopulations found within the ceftibuten / avibactam combination regimens utilizing 31.3 mg and 62.5 mg q8h avibactam amplified to higher loads than those found in the untreated control. Ceftibuten / avibactam MIC values ​​for isolates collected from drug-supplemented agar plates ranged from 4 mg / L to 16 mg / L.

[0462] [Table 7]

[0463] E. cloacae 4184 Data for E. cloacae 4184 (derepressed AmpC) total bacterial load generated in a ceftibuten / avibactam dose-finding study are shown in Figures 10 and 11A-11I. Untreated controls grew well, reaching a 9 log 10Bacterial burdens approaching CFU / mL were achieved. Ceftibuten monotherapy did not reduce bacterial burdens over the study period, consistent with growth observed in untreated controls. Ceftibuten / avibactam combination regimens tested in the system failed to prevent regrowth in the system, with avibactam regimens at 250 mg q8h or less producing a total exposure response. All avibactam regimens at 375 mg q8h or greater were able to prevent bacterial growth in the one-compartment model, with a 1.5- to 2.5-log reduction by the 24-h time point. 10 Reductions in bacterial load in the CFU / mL range were achieved.

[0464] Data for E. cloacae 4184 ceftibuten / avibactam resistant subpopulations generated in dose-finding studies are shown in Table 8. The presence of resistant subpopulations was observed in untreated controls, ceftibuten monotherapy regimens, and combination regimens below 250 mg q8h. Ceftibuten / avibactam resistant subpopulations found within ceftibuten monotherapy and in combination with the avibactam 31.3 mg q8h regimen did not achieve concentrations higher than those observed in untreated controls, indicating that these resistant subpopulations do not arise with treatment and represent inherent resistance within a given population. Resistant subpopulations observed within ceftibuten / avibactam combination regimens ranging from avibactam 62.5 mg to 250 mg q8h amplified to loads greater than those found in untreated controls, with the 250 mg q8h combination regimen resulting in complete replacement of the total bacterial load by the 24-hour time point. Ceftibuten / avibactam MIC values ​​for isolates collected from drug-supplemented agar plates ranged from 16 mg / L to 64 mg / L.

[0465] [Table 8]

[0466] Pharmacokinetic-pharmacodynamic analysis Data from ceftibuten / avibactam dose-finding studies evaluating the 400 mg dose in combination with avibactam were pooled and modeled using a Hill-type model and nonlinear least-squares regression. Log-1 change from baseline at 24 hours using MIC values ​​determined with a fixed 4 mg / L or 8 mg / L avibactam or a 1:1 ratio of ceftibuten:avibactam 10 Relationship between CFU reduction and avibactam fAUC:MIC ratio.

[0467] r of 0.78 to 0.86 2 The free drug AUC:MIC ratio adequately described the activity of avibactam across this data set, as confirmed by the spread of data across the values ​​and fitted lines. Net bacterial stasis at 24 hours, 1 log of bacterial load 10 CFU / mL reduction, and 2 log 10 The magnitude of the fAUC:MIC ratio required to achieve an effective target, such as a CFU / mL reduction, is presented in the pooled data set in Table 9.

[0468] [Table 9]

[0469] Net bacterial stasis at 24 hours, 1 log of bacterial load 10 CFU / mL reduction, and 2 log 10 The magnitude of free drug %T>MIC required to achieve an effective target, such as CFU / mL reduction, is presented in the pooled data set in Table 10.

[0470] [Table 10]

[0471] Net bacterial stasis at 24 hours, 1 log of bacterial load 10 CFU / mL reduction, and 2 log 10The magnitude of free drug %T>MIC required to achieve an effective target, such as CFU / mL reduction, and a maximum r 2 Ct values ​​have been determined for those identified for use with ceftazidime (Coleman et al., Antimicrob Agents Chemother. 2014, 58, 3366-3372) and the results are shown in Table 11.

[0472] [Table 11]

[0473] PK / PD studies suggest that the time to clinical concentration of avibactam (fT>Ct) is a useful predictor of clinical efficacy. Although the limited number of test strains did not exclude that other PK drivers such as fT>Ct could also explain efficacy, in vitro PK / PD studies of ceftibuten and avibactam combinations indicate that the best correlation with efficacy was the AUC of free avibactam, >MIC of ceftibuten.

[0474] Example 2 Oral administration of avibactam derivatives to patients The pharmacokinetics of avibactam given as an orally administered avibactam derivative was determined in healthy human volunteers.

[0475] A cohort of eight healthy human volunteers was administered 300 mg, 900 mg, or 1,350 mg of the avibactam derivative (3) (ethyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate). Plasma concentrations of avibactam were measured. Free avibactam concentrations were compared between 5% and 8% protein bound (AUC 遊離 =AUC 0~inf × 0.918). max was 2,500 ng / mL, and the mean AUC 12was approximately 7,600 ng×h / mL for a 300 mg dose of avibactam derivative (3). A 300 mg dose of orally administered avibactam derivative (3) is close to a 62.5 mg dose of IV avibactam and shows similar pharmacokinetics. A 400 mg dose of orally administered avibactam derivative (3) is close to a 400 mg dose of IV avibactam and shows similar pharmacokinetics.

[0476] Based on this pK profile, avibactam AUC in the presence of 4 mg / L avibactam, MIC thresholds derived from the ceftibuten MIC were calculated for TID dosing and are presented in Table 12.

[0477] [Table 12]

[0478] Based on TID administration of 300 mg, 900 mg, or 1,350 mg doses of avibactam derivatives (3) to healthy human patients, and the AUC 0~24 is AUC 0~inf The estimated MIC thresholds based on the fAUC:MIC ratios from the chemostat model, assuming a 3-fold increase in the AUC threshold, are shown in Table 13.

[0479] [Table 13]

[0480] Estimated MICs from Study 1 and Study 2 50 (μg / mL) and MIC 90 The (μg / mL) values ​​are shown in Table 14.

[0481] [Table 14]

[0482] The results suggest that ceftibuten 400 mg in combination with 300 mg, 900 mg, or 1,350 mg of an avibactam derivative (3) administered TID would be effective in treating bacterial infections associated with ESBL, KPC, and OXA strains, as well as most AmpC strains.

[0483] Example 3 Oral administration of avibactam derivatives The pharmacokinetics of avibactam given as an orally administered avibactam derivative were determined in healthy human volunteers.

[0484] A randomized, double-blind, placebo-controlled, single ascending dose phase 1 study was conducted in healthy adult men and women. Three cohorts, each containing 10 patients, received a single oral dose of 300 mg, 900 mg, or 1,350 mg of the avibactam derivative (3) (ethyl 3-((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate) as a suspension at 10 mg / mL (n=8) or placebo (n-2) under prandial conditions.

[0485] Plasma and urine PK samples were collected pre-dose and at frequent intervals post-dose.

[0486] Following oral administration of the avibactam derivative (3), there was rapid clearance of avibactam in the whole body. The PK of avibactam in each cohort is shown in Table 15.

[0487] [Table 15]

[0488] The AUC data can be compared with data available for IV avibactam in comparable populations. Merdjan et al., Clin Drug Investig., March 27, 2015, DOI 10.1007 / s40261-015-0283-9. AUC for IV avibactam after a 2-hour infusion of a single dose (500 mg) in healthy subjects inf Data were obtained that provide a point estimate of F. An illustration of the absolute bioavailability F of equivalent doses of avibactam derivative (3) and the molecular weight of the prodrug moiety is shown in FIG. 12, which shows individual subject values ​​of F by cohort, where the dose shown is the amount of avibactam derivative (3) administered in mg. It should be noted that 900 mg of avibactam derivative (3) is equivalent to 607 mg of avibactam based on molecular weight. FIG. 12 also shows the full estimate of F in the study population (n=24), presented as a conventional box and whisker plot (median, interquartile range [25-75%] and Tukey whiskers). As shown in FIG. 12, avibactam derivative (3) is an effective prodrug for avibactam with an F of approximately 0.6-0.8.

[0489] Example 4 In vitro activity of antibiotic-avibactam combinations. The objective of the study was to determine the in vitro activity of aztreonam, cefixime, cefpodoxime, ceftibuten, sulopenem, and tebipenem in combination with fixed concentrations of avibactam, and ceftibuten in combination with clavulanic acid, against 314 Enterobacteriaceae. Isolates tested were selected based on prior molecular characterization to contain genes encoding extended-spectrum β-lactamases (ESBLs), chromosomal and plasmid AmpC, KPC, or OXA.

[0490] A total of 314 Enterobacteriaceae isolates were tested in this study, including a molecularly characterized subset of isolates containing genes encoding (n)ESBLs (28), KPC (23), OXA (22), chromosomally encoded AmpC (ChromAmpC) (20), and plasmid-encoded AmpC (PlasAmpC) (20). In addition, 201 wild-type Enterobacteriaceae bacteria that did not contain genes encoding metallo-β-lactamases were also tested. The study bacteria were clinical isolates that had already been collected between 2015 and 2017 and frozen at -70°C. The presence of genes encoding resistance mechanisms was preliminarily assessed using multiplex PCR followed by full-length gene amplification and sequencing.

[0491] Minimum inhibitory concentration (MIC) values ​​were determined by broth microdilution for aztreonam, cefixime, cefpodoxime, ceftibuten, sulopenem, and tebipenem alone and in combination with avibactam at a fixed concentration of 4 μg / mL, ceftibuten in combination with clavulanic acid at a fixed concentration of 4 μg / mL, and ceftazidime in combination with avibactam, levofloxacin, and meropenem at fixed concentrations of 4 μg / mL, according to CLSI guidelines, Clinical Laboratory Standards Institute (CLSI), 2018. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standards-Eleventh Edition., CLSI document M07-A11 (ISBN 1-56238-836-3). CLSI, Wayne, PA. All compounds were dissolved according to CLSI specifications. Clinical and Laboratory Standards Institute (CLSI), 2018. Performance Standards for Antimicrobial Susceptibility Testing-Twenty-Eighth Informational Supplement. CLSI Document M100S (ISBN 1-56238-923-8). CLSI, Wayne, PA. Stock solutions were further diluted in cation-adjusted Mueller-Hinton broth (CAMHB) for the serial dilutions used in the test panels.

[0492] The concentration range tested for antibiotics was 0.015 μg / mL to 32 μg / mL, except for levofloxacin, which was 0.008 μg / mL to 8 μg / mL, and meropenem, which was 0.004 μg / mL to 4 μg / mL. Colonies were picked directly from second-pass culture plates and prepared into suspensions equivalent to a 0.5 McFarland standard using saline. Inoculation of MIC plates was performed within 15 min after adjustment of inoculum suspension turbidity. Panels were incubated at 35°C for 16 to 20 h, after which MIC end points were determined.

[0493] Quality control (QC) testing was performed daily throughout the study using Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, and Klebsiella pneumoniae ATCC 700603 as specified by CLSI.

[0494] Total number of isolates, MICs, and CLSI 2018 breakpoints were used when available. 50 (μg / mL), MIC 90 (μg / mL), MIC ranges, and percent susceptible, intermediate, and resistant were determined for all antimicrobials tested.

[0495] The addition of a fixed concentration of 4 μg / mL of avibactam increased the MIC 90 The MICs for all isolates combined were reduced from >32 μg / mL to 0.5 μg / mL for aztreonam, >32 μg / mL to 1 μg / mL for cefixime, >32 μg / mL to 4 μg / mL for cefpodoxime, 32 μg / mL to 0.5 μg / mL for ceftibuten, 8 μg / mL to 0.25 μg / mL for sulopenem, and 2 μg / mL to 0.25 μg / mL for tebipenem. In comparison, the MICs for ceftazidime-avibactam were 90 The MIC value for ceftibuten in combination with clavulanate was 1 μg / mL. 90 did not show a decrease in MIC 90=>32μg / mL).

[0496] The addition of avibactam to aztreonam increased MICs for ESBL-, KPC-, and OXA-positive isolates by at least six-fold dilutions. 90 The addition of avibactam to cephalosporins (ceftibute, cefixime, and cefpodoxime) reduced MICs for ESBL-, KPC-, and OXA-positive isolates by at least five-fold dilutions. 90 The activity was comparable to that of the ceftazidime-avibactam combination.

[0497] The addition of avibactam to sulopenem and tebipenem increased MICs against KPC- and OXA-positive isolates. 90 values ​​from >32 μg / mL to 1 μg / mL but did not increase activity against wild-type, ESBL-positive, or AmpC-positive isolates.

[0498] The AmpC enzyme, encoded by both chromosomal and plasmid genes, has MICs ranging from 4 μg / mL to 16 μg / mL. 90 The activity of aztreonam-avibactam was at MICs of 1 μg / mL (ChromAmpC) and 2 μg / mL (PlasAmpC). 90 The addition of avibactam to sulopenem or tebipenem was slightly better than the MIC values ​​for ChromAmpC isolates. 90 values ​​8-16-fold but did not show any additional activity against PlasAmpC isolates.

[0499] In summary, the addition of avibactam increased MICs in the range of 0.25 μg / mL to 2 μg / mL for ESBL-positive isolates, 0.25 μg / mL to 4 μg / mL for KPC-positive isolates, and 0.25 μg / mL to 2 μg / mL for OXA-positive isolates. 90Values ​​increased the activity of cephalosporins, carbapenems, and aztreonam against this collection of Enterobacteriaceae. Aztreonam-avibactam and ceftibuten-avibactam were the most active combinations. The addition of avibactam increased the spectrum of activity of tebipenem and sulopenem to include KPC- and OXA-positive isolates.

[0500] Estimated MICs for various antibiotics and antibiotic / avibactam combinations against strains 90 (μg / mL) are shown in Table 16.

[0501] [Table 16]

[0502] CLSI breakpoints were used when available. Combinations of avibactam or clavulanate with approved cephalosporins have not been established, and CLSI breakpoints for approved cephalosporins were used. Sulopenem and tebipenem breakpoints have not been established, and published human serum PK and MIC values ​​were used to estimate breakpoints.

[0503] The results suggest that ceftibuten 400 mg in combination with 300 mg or 900 mg of an avibactam derivative (3) administered TID would be effective in treating bacterial infections associated with ESBL, KPC, and OXA strains, as well as many AmpC strains.

[0504] Finally, it should be noted that there are alternative ways of implementing the embodiments disclosed herein, and therefore the present embodiments should be considered as illustrative rather than restrictive, and the claims should not be limited to the details set forth herein, but rather may be modified within the scope and equivalents thereof.

Claims

1. A pharmaceutical composition comprising a β-lactam antibiotic or a pharma- ceutical acceptable salt thereof and an avibactam derivative or a pharma-ceutical acceptable salt thereof, the β-lactam antibiotic is ceftibuten; the avibactam derivative is ethyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate; 100 mg to 500 mg of ceftibuten or a pharma- ceutically acceptable salt thereof; 300 mg to 1,400 mg of the avibactam derivative or a pharma- ceutically acceptable salt thereof; 13. A pharmaceutical composition comprising:

2. 10. The pharmaceutical composition of claim 1 comprising a weight ratio of avibactam equivalents to β-lactam antibiotic equivalents of from 1:1 to 4:

1.

3. 3. The pharmaceutical composition of claim 1 or 2, which after oral administration to a patient results in a β-lactam antibiotic plasma concentration above 40% fT > MIC for the strain.

4. After oral administration to patients, 40% fT>C ｔ 3. The pharmaceutical composition of claim 1 or 2, which results in an avibactam plasma concentration of greater than 100 mg / kg.

5. 3. The pharmaceutical composition of claim 1 or 2, which after oral administration to a patient results in an avibactam plasma concentration characterized by an fAUC:MIC ratio of 10-40.

6. The pharmaceutical composition according to any one of claims 1 to 5, which is an oral formulation.

7. A pharmaceutical composition according to any one of claims 1 to 6 for use in the treatment of a bacterial infection.

8. 8. The pharmaceutical composition or oral formulation of claim 7, wherein the bacterial infection is caused by a bacterium that produces a β-lactamase enzyme.

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