Ceftibuten Dosing Regimen

Abstract

Disclosed herein is a dosage regimen of ceftibuten in combination with a β-lactamase inhibitor. The dosage regimen includes a daily dose of ceftibuten greater than 400 mg (e.g., 400 mg twice a day, 600 mg once or twice a day, or 800 mg once or twice a day). Disclosed herein is a pharmaceutical composition including a dose of ceftibuten greater than 400 mg and a β-lactamase inhibitor. Also disclosed herein is a method of treating bacterial infection, comprising administering to a subject in need of treating bacterial infection a dose of ceftibuten greater than 400 mg in combination with a β-lactamase inhibitor.

Description

[Technical field]

[0001] (Incorporating by reference any priority applications) Any and all applications for which a foreign or domestic priority claim is indicated in an Application Data Sheet filed with this application are hereby incorporated by reference under 37 CFR.

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 170,936, filed April 5, 2021, which is incorporated by reference in its entirety.

[0003] STATEMENT REGARDING U.S. GOVERNMENT SPONSORED RESEARCH OR DEVELOPMENT This invention was made with United States Government support under Department of Health and Human Services Contract No. HHSO100201600026C. The United States Government has certain rights in this invention.

[0004] BACKGROUND OF THEINVENTION FIELD OF THEINVENTION This application relates to the field of medicine, and in particular to ceftibuten and its formulations and uses. [Background technology]

[0005] (Description of related fields) Ceftibuten is a third generation cephalosporin antibiotic. It is approved by the FDA for oral administration at a dose of 400 mg once a day. Ceftibuten is susceptible to the development of bacterial resistance. Therefore, there is a need for new therapies using ceftibuten that can be effective against resistance development. Summary of the Invention [Means for solving the problem]

[0006] (Summary of the invention) Disclosed herein is a pharmaceutical composition comprising ceftibuten in an amount greater than 400 mg and a β-lactamase inhibitor. Also disclosed herein is a method of treating a bacterial infection, comprising administering to a subject in need of treating a bacterial infection a combination of ceftibuten in an amount greater than 400 mg and a β-lactamase inhibitor. [Brief description of the drawings]

[0007] [Figure 1] FIG. 1 is a graph showing the AUC0-12 of cis-ceftibuten following administration of a 400 mg dose, a 600 mg dose, or an 800 mg dose.

[0008] [Diagram 2] FIG. 2 is a graph showing the AUC0-12 of trans-ceftibuten following administration of a 400 mg dose, a 600 mg dose, or an 800 mg dose. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Some embodiments disclosed herein relate to treating bacterial infections by administering ceftibuten in combination with a β-lactamase inhibitor. In some embodiments, the ceftibuten dose is greater than 400 mg. As described below, it has been surprisingly discovered that administering ceftibuten at a dose greater than 400 mg per dose provides dose-proportional exposure. Furthermore, it has been discovered that higher concentrations of ceftibuten can reduce the development of bacterial resistance in combination with a β-lactamase inhibitor. Taken together, these findings support administering ceftibuten at a dose greater than 400 mg per dose in combination with a β-lactamase inhibitor.

[0010] In various embodiments, the single dose of ceftibuten is greater than 450 mg, 500 mg, 550 mg, 600 mg, 750 mg, 800 mg, or 850 mg. In some embodiments, the single dose of ceftibuten is in the range between any two doses selected from 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 750 mg, 800 mg, and 850 mg. In various embodiments, the single dose of ceftibuten is administered once, twice, or three times a day. In some embodiments, 400 mg of ceftibuten is administered twice a day. In some embodiments, ceftibuten and a beta-lactamase inhibitor are administered in the same formulation. In other embodiments, ceftibuten and a beta-lactamase inhibitor are administered in separate formulations.

[0011] (definition) As used herein, "C" refers to a set of integers where "a" and "b" are integers. a ~C b " or "C a~b " refers to the number of carbon atoms in the specified group; that is, the group may contain from "a" to "b" (inclusive) carbon atoms. Thus, for example, a "C1-C4 alkyl" group or a "C 1~4 An "alkyl" group refers to all alkyl groups having one to four carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-.

[0012] The term "halogen" or "halo" as used herein means any one of the radio-stable atoms in column 7 of the periodic table of the elements, e.g., fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.

[0013] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., contains no double or triple bonds). The alkyl group can have 1 to 20 carbon atoms (wherever an alkyl group appears herein, a numerical range such as "1 to 20" refers to each integer in the given range, e.g., "1 to 20 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, but this definition also includes the occurrence of the term "alkyl" without any numerical range given). The alkyl group can also be a medium-sized alkyl having 1 to 9 carbon atoms. The alkyl group can also be a lower alkyl having 1 to 4 carbon atoms. The alkyl group can also be a "C 1~4 For illustrative purposes only, "C alkyl" or similar names may be used. 1~4 "Alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Representative alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.

[0014] As used herein, "alkoxy" refers to a group of the formula -OR, where R is alkyl as defined above (e.g., "C 1~9 "Alkoxy") refers to alkoxy groups including, but not limited to, methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0015] As used herein, "alkylthio" refers to a group of the formula -SR (e.g., "C 1~9"alkylthio", etc.), including, but not limited to, methyl mercapto, ethyl mercapto, n-propyl mercapto, 1-methylethyl mercapto (isopropyl mercapto), n-butyl mercapto, isobutyl mercapto, sec-butyl mercapto, tert-butyl mercapto, and the like.

[0016] As used herein, "alkenyl" refers to a straight or branched hydrocarbon chain containing one or more double bonds. An alkenyl group can have 2 to 20 carbon atoms, although this definition also includes the existence of the term "alkenyl" without any numerical range being given. An alkenyl group can also be a medium size alkenyl having 2 to 9 carbon atoms. An alkenyl group can also be a lower alkenyl having 2 to 4 carbon atoms. An alkenyl group is defined as "a cyclic alkyl group having 2 to 4 carbon atoms, i.e., 1 to 10 carbon atoms, 1 to 2 ... 2~4 Alkenyl" or similar names. For illustrative purposes only, "C 2~4 "Alkenyl" indicates that there are 2 to 4 carbon atoms in the alkenyl chain, i.e., the alkenyl chain is selected from the group consisting of ethenyl, propen-1-yl, propen-2-yl, propen-3-yl, buten-1-yl, buten-2-yl, buten-3-yl, buten-4-yl, 1-methyl-propen-1-yl, 2-methyl-propen-1-yl, 1-ethyl-ethen-1-yl, 2-methyl-propen-3-yl, buta-1,3-dienyl, buta-1,2-dienyl, and buta-1,2-dien-4-yl. Representative alkenyl groups include, but are in no way limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

[0017] As used herein, "alkynyl" refers to a straight or branched hydrocarbon chain containing one or more triple bonds. An alkynyl group can have 2 to 20 carbon atoms, although this definition also includes the occurrence of the term "alkynyl" without any numerical range being given. An alkynyl group can also be a medium size alkynyl having 2 to 9 carbon atoms. An alkynyl group can also be a lower alkynyl having 2 to 4 carbon atoms. An alkynyl group can be a "C 2~4 For purposes of example only, "C 2~4 "Alkynyl" indicates that there are 2 to 4 carbon atoms in the alkynyl chain, i.e., the alkynyl chain is selected from the group consisting of ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-3-yl, butyn-4-yl, and 2-butynyl. Representative alkynyl groups include, but are in no way limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0018] As used herein, "heteroalkyl" refers to a straight or branched hydrocarbon chain that contains one or more heteroatoms (i.e., elements other than carbon, including, but not limited to, nitrogen, oxygen, and sulfur) in the backbone of the chain. Heteroalkyl groups can have from 1 to 20 carbon atoms, although this definition also includes the existence of the term "heteroalkyl" without any numerical range being given. Heteroalkyl groups can also be medium size heteroalkyls having from 1 to 9 carbon atoms. Heteroalkyl groups can also be lower heteroalkyls having from 1 to 4 carbon atoms. Heteroalkyl groups are defined as "heteroalkyl groups having from 1 to 20 carbon atoms, but are not limited to, heteroalkyl groups having from 1 to 20 carbon atoms, and are not limited to, heteroalkyl groups having from 1 to 20 carbon atoms. Heteroalkyl groups can also be low molecular weight heteroalkyls having from 1 to 4 carbon atoms. 1~4 A heteroalkyl group may be referred to as "heteroalkyl" or similar names. A heteroalkyl group may contain one or more heteroatoms. For purposes of example only, "C 1~4 "Heteroalkyl" indicates that the heteroalkyl chain has from 1 to 4 carbon atoms and further includes one or more heteroatoms in the backbone of the chain.

[0019] As used herein, "alkylene" refers to a branched or straight chain, fully saturated diradical chemical group (i.e., alkanediyl) containing only carbon and hydrogen, attached to the remainder of the molecule by two points of attachment. Alkylene groups can have from 1 to 20 carbon atoms, although this definition also includes the occurrence of the term alkylene without any numerical range being given. Alkylene groups can also be medium size alkylenes having from 1 to 9 carbon atoms. Alkylene groups can also be lower alkylenes having from 1 to 4 carbon atoms. An alkylene group is defined as "a cyclic alkylene having from 1 to 4 carbon atoms, and is an alkyl group .... 1~4 For illustrative purposes only, "C 1~4 "Alkylene" indicates that there are 1 to 4 carbon atoms in the alkylene chain, i.e., the alkylene chain is selected from the group consisting of methylene, ethylene, ethane-1,1-diyl, propylene, propane-1,1-diyl, propane-2,2-diyl, 1-methyl-ethylene, butylene, butane-1,1-diyl, butane-2,2-diyl, 2-methyl-propane-1,1-diyl, 1-methyl-propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, 1,2-dimethyl-ethylene, and 1-ethyl-ethylene.

[0020] As used herein, "alkenylene" refers to a straight or branched chain diradical chemical group containing only carbon and hydrogen and at least one carbon-carbon double bond attached to the rest of the molecule by two points of attachment. An alkenylene group can have 2 to 20 carbon atoms, but this definition also includes the existence of the term alkenylene without any numerical range being given. An alkenylene group can also be a medium size alkenylene having 2 to 9 carbon atoms. An alkenylene group can also be a lower alkenylene having 2 to 4 carbon atoms. An alkenylene group can be any of the groups defined as "C 2~4 Alkenylene" or similar names. For illustrative purposes only, "C 2~4"Alkenylene" means that the alkenylene chain has 2 to 4 carbon atoms, i.e., the alkenylene chain is selected from the group consisting of ethenylene, ethene-1,1-diyl, propenylene, propene-1,1-diyl, prop-2-ene-1,1-diyl, 1-methyl-ethenylene, but-1-enylene, but-2-enylene, buta-1,3-dienylene, butene-1,1-diyl, buta-1,3-diene-1,1-diyl, buta-2-ene-1, 1-diyl, but-3-ene-1,1-diyl, 1-methyl-prop-2-ene-1,1-diyl, 2-methyl-prop-2-ene-1,1-diyl, 1-ethyl-ethenylene, 1,2-dimethyl-ethenylene, 1-methyl-propenylene, 2-methyl-propenylene, 3-methyl-propenylene, 2-methyl-propene-1,1-diyl, and 2,2-dimethyl-ethen-1,1-diyl.

[0021] The term "aromatic" refers to a ring or ring system having a conjugated pi-electron system, and includes both carbocyclic aromatic (e.g., phenyl) and heterocyclic aromatic (e.g., pyridine) groups. The term includes monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of atoms) groups, provided that the entire ring system is aromatic.

[0022] As used herein, "aryl" refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent carbon atoms) that contains only carbon in its ring backbone. When aryl is a ring system, every ring in the system is aromatic. An aryl group can have 6 to 18 carbon atoms, although this definition also includes the occurrence of the term "aryl" without any numerical range being given. In some embodiments, an aryl group has 6 to 10 carbon atoms. An aryl group is defined as "a ring having a carbon atom, a fused ring, or a fused ... 6~10 Aryl, C6 or C 10 Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.

[0023] As used herein, "aryloxy" and "arylthio" refer to RO- and RS- (e.g., "C 6~10 aryloxy" or "C 6~10 "arylthio", etc.), including, but not limited to, phenyloxy.

[0024] "Aralkyl" or "arylalkyl" refers to an aryl group (e.g., "C 7~14 arylalkyl, "arylalkyl" and the like), including, but not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and naphthylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., C 1~4 alkylene group).

[0025] As used herein, "heteroaryl" refers to an aromatic ring or ring system (i.e., two or more fused rings sharing two adjacent atoms) that contains one or more heteroatoms (i.e., elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur) in its ring backbone. When heteroaryl is a ring system, every ring in the system is aromatic. Heteroaryl groups can have 5-18 ring members (i.e., the number of atoms that make up its ring backbone, including carbon atoms and heteroatoms), although this definition also includes the occurrence of the term "heteroaryl" without any numerical range being given. In some embodiments, heteroaryl groups have 5-10 ring members or 5-7 ring members. Heteroaryl groups may be referred to as "5-7 membered heteroaryl", "5-10 membered heteroaryl", or similar names. Examples of heteroaryl rings include, but are not limited to, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinlinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and benzothienyl.

[0026] A "heteroaralkyl" or "heteroarylalkyl" is a heteroaryl group bound, as a substituent, by an alkylene group. Examples include, but are not limited to, 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazollylalkyl, and imidazolylalkyl. In some cases, the alkylene group may be a lower alkylene group (i.e., C 1~4 alkylene group).

[0027] As used herein, "carbocyclyl" refers to a non-aromatic cyclic ring or ring system that contains only carbon atoms in its ring system backbone. When a carbocyclyl is a ring system, two or more rings can be linked together in a fused, bridged or spiro-linked fashion. A carbocyclyl can have some degree of saturation, provided that at least one ring of the ring system is not aromatic. Thus, carbocyclyl includes cycloalkyl, cycloalkenyl, and cycloalkynyl. A carbocyclyl group can have 3 to 20 carbon atoms, but this definition also includes the existence of the term "carbocyclyl" without any numerical range being given. A carbocyclyl group can also be a medium sized carbocyclyl having 3 to 10 carbon atoms. A carbocyclyl group can also be a carbocyclyl having 3 to 6 carbon atoms. A carbocyclyl group can be a "C 3~6 Examples of carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicycle[2.2.2]octanyl, adamantyl, and spiro[4.4]nonanyl.

[0028] "(Carbocyclyl)alkyl" refers to a carbocyclyl group (e.g., "C 4~10 (Carbocyclyl)alkyl" and the like), including, but not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like. In some cases, the alkylene group is a lower alkylene group.

[0029] As used herein, "cycloalkyl" means a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0030] As used herein, "cycloalkenyl" means a carbocyclyl ring or carbocyclyl ring system having at least one double bond, where no ring in the ring system is aromatic. An example is cyclohexenyl.

[0031] As used herein, "heterocyclyl" refers to a non-aromatic cyclic ring or ring system that contains at least one heteroatom in its ring backbone. Heterocyclyls can be joined together in a fused, bridged, or spiro-linked fashion. Heterocyclyls can have some degree of saturation, provided that at least one ring in the ring system is not aromatic. The heteroatom(s) can be present in either the non-aromatic or aromatic ring of the ring system. Heterocyclyl groups can have 3-20 ring members (i.e., the number of atoms that make up the ring backbone, including carbon atoms and heteroatoms), although this definition also includes the existence of the term "heterocyclyl" without any numerical range being given. Heterocyclyl groups can also be medium size heterocyclyls having 3-10 ring members. Heterocyclyl groups can also be heterocyclyls having 3-6 ring members. Heterocyclyl groups can also be referred to as "3-6 membered heterocyclyl" or similar names. In preferred 6-membered monocyclic heterocyclyls, the heteroatom(s) are selected from 1 to 3 of O, N or S, and in preferred 5-membered monocyclic heterocyclyls, the heteroatom(s) are selected from 1 or 2 heteroatoms selected from O, N, or S.Examples of heterocyclyl rings include azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, xylanyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathiyl, 1,4-oxathiinyl, 1,4-oxathiyl, 2H-1,2-oxazinyl, trioxanyl, hexaphenyl, 1,2- ... These include, but are not limited to, hydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.

[0032] "(Heterocyclyl)alkyl" is a heterocyclyl group attached, as a substituent, by an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.

[0033] As used herein, "acyl" refers to -C(=O)R, where R is hydrogen, optionally substituted C(=O) 1~6 Alkyl, halogen, optionally substituted C 2~6 Alkenyl, optionally substituted C 2~6 Alkynyl, optionally substituted C 3~7 Carbocyclyl, optionally substituted C 6~10aryl, optionally substituted 5-10 membered heteroaryl, and optionally substituted 3-10 membered heterocyclyl. Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acryl.

[0034] An "O-carboxy" group refers to an "-OC(=O)R" group, where R is hydrogen, optionally substituted C, 1~6 Alkyl, halogen, optionally substituted C 2~6 Alkenyl, optionally substituted C 2~6 Alkynyl, optionally substituted C 3~7 Carbocyclyl, optionally substituted C 6~10 It is selected from aryl, optionally substituted 5-10 membered heteroaryl, and optionally substituted 3-10 membered heterocyclyl.

[0035] A "C-carboxy" group refers to a "-C(=O)OR" group, where R is hydrogen, halogen, optionally substituted C(=O) or aryl, as defined herein. 1~6 Alkyl, optionally substituted C 2~6 Alkenyl, optionally substituted C 2~6 Alkynyl, optionally substituted C 3~7 Carbocyclyl, optionally substituted C 6~10 aryl, optionally substituted 5-10 membered heteroaryl, and optionally substituted 3-10 membered heterocyclyl. Non-limiting examples include carboxyl (i.e., -C(=O)OH).

[0036] A "cyano" group refers to a "-CN" group.

[0037] A "cyanato" group refers to a "-OCN" group.

[0038] An "isocyanato" group refers to a "-NCO" group.

[0039] A "thiocyanato" group refers to a "-SCN" group.

[0040] An "isothiocyanato" group refers to a "-NCS" group.

[0041] A "sulfinyl" group refers to a "-S(=O)R" group, where R is hydrogen, optionally substituted C, 1~6 Alkyl, optionally substituted C 2~6 Alkenyl, optionally substituted C 2~6 Alkynyl, optionally substituted C 3~7 Carbocyclyl, optionally substituted C 6~10 It is selected from aryl, optionally substituted 5-10 membered heteroaryl, and optionally substituted 3-10 membered heterocyclyl.

[0042] A "sulfonyl" group refers to a "-SO2R" group, where R is hydrogen, optionally substituted C 1~6 Alkyl, optionally substituted C 2~6 Alkenyl, optionally substituted C 2~6 Alkynyl, optionally substituted C 3~7 Carbocyclyl, optionally substituted C 6~10 It is selected from aryl, optionally substituted 5-10 membered heteroaryl, and optionally substituted 3-10 membered heterocyclyl.

[0043] The "S-sulfonamide" group is "-SONR A R B " group, and in this formula R A and R B Each of the groups is selected from hydrogen, halogen, optionally substituted C 1~6 Alkyl, optionally substituted C 1~6 Alkoxy, optionally substituted C 2~6 Alkenyl, optionally substituted C 2~6 Alkynyl, optionally substituted C 3~7Carbocyclyl, optionally substituted C 6~10 are independently selected from aryl, optionally substituted 5-10 membered heteroaryl, and optionally substituted 3-10 membered heterocyclyl.

[0044] The "N-sulfonamide" group is "-N(R A )SO2R B " group, and in this formula R A and R B Each of the groups is selected from hydrogen, halogen, optionally substituted C 1~6 Alkyl, optionally substituted C 2~6 Alkenyl, optionally substituted C 2~6 Alkynyl, optionally substituted C 3~7 Carbocyclyl, optionally substituted C 6~10 are independently selected from aryl, optionally substituted 5-10 membered heteroaryl, and optionally substituted 3-10 membered heterocyclyl.

[0045] A "C-amide" group is "-C(=O)NR A R B " group, and in this formula R A and R B Each of the groups is selected from hydrogen, halogen, optionally substituted C 1~6 Alkyl, optionally substituted C 1~6 Alkoxy, optionally substituted C 2~6 Alkenyl, optionally substituted C 2~6 Alkynyl, optionally substituted C 3~7 Carbocyclyl, optionally substituted C 6~10 are independently selected from aryl, optionally substituted 5-10 membered heteroaryl, and optionally substituted 3-10 membered heterocyclyl.

[0046] The "N-amide" group is "-N(R A )C(=O)R B " group, and in this formula R A and RB Each of the groups is selected from hydrogen, halogen, optionally substituted C 1~6 Alkyl, optionally substituted C 1~6 Alkoxy, optionally substituted C 2~6 Alkenyl, optionally substituted C 2~6 Alkynyl, optionally substituted C 3~7 Carbocyclyl, optionally substituted C 6~10 are independently selected from aryl, optionally substituted 5-10 membered heteroaryl, and optionally substituted 3-10 membered heterocyclyl.

[0047] The "O-carbamyl" group is "-OC(=O)NR A R B " group, and in this formula R A and R B are each defined herein as hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 is independently selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0048] The "N-carbamyl" group is "-N(R A )OC(=O)R B " group, and in this formula R A and R B are each defined herein as hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 is independently selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0049] The "O-thiocarbamyl" group is "-OC(=S)NR A R B " group, and in this formula R A and RB are each defined herein as hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 is independently selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0050] The "N-thiocarbamyl" group is "-N(R A )OC(=S)R B " group, and in this formula R A and R B are each defined herein as hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 is independently selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0051] The "amino" group is "-NR A R B " group, and in this formula R A and R B Each of the groups is selected from hydrogen, halogen, optionally substituted C 1~6 Alkyl, optionally substituted C 2~6 Alkenyl, optionally substituted C 2~6 Alkynyl, optionally substituted C 3~7 Carbocyclyl, optionally substituted C 6~10 and optionally substituted 3- to 10-membered heterocyclyl. Non-limiting examples include free amino (i.e., -NH2).

[0052] An "aminoalkyl" group refers to an amino group linked through an alkylene group.

[0053] An "alkoxyalkyl" group is an alkoxy group linked by an alkylene group (e.g., "C 2~8 "alkoxyalkyl" and the like.

[0054] As used herein, a substituted group is derived from an unsubstituted parent group in which one or more hydrogen atoms have been replaced with another atom or group. Unless otherwise indicated, when a group is considered to be "substituted", it includes C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocyclyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7 carbocyclyl-C1-C6 alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy). 3-10 membered heterocyclyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 3-10 membered heterocyclyl-C1-C6 alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl (halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C6 haloalkyl, and C1-C6 haloalkoxy, optionally substituted), aryl(C1-C6)alkyl (halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy, optionally substituted), 5-10 membered heteroaryl (halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy, optionally substituted), 5-10 membered heteroaryl(C1-C6)alkyl (halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy, optionally substituted), halo, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6)alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(C1-C6)alkyl (e.g., -CF3), halo(C1-C6)alkoxy (e.g., -OCF3), C1-C6 alkylthio, arylthio, amino, amino(C1-C6)alkyl,It is meant that the group is substituted with one or more substituents independently selected from nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo (=O). Whenever a group is described as "optionally substituted," the group can be substituted with the above-mentioned substituents.

[0055] It should be understood that a particular radical naming convention can include either monoradicals or diradicals depending on the context. For example, if a substituent requires two points of attachment to the remainder of the molecule, it is understood that the substituent is a diradical. For example, a substituent identified as alkyl, which requires two points of attachment, includes diradicals such as -CH2-, -CH2CH2-, -CH2CH(CH3)CH2-. Other radical naming conventions specify that the radical is a diradical, such as "alkylene" or "alkenylene."

[0056] When two R groups are said to form a ring "together with the atom to which they are attached" (e.g., a carbocyclyl ring, a heterocyclyl ring, an aryl ring, or a heteroaryl ring), it is meant that the collective unit of the atoms and the two R groups is the recited ring. The ring is not otherwise limited by the definition of each R group when considered individually. For example, the substructure: [ka] exists and R 1 and R 2 is defined as being selected from the group consisting of hydrogen and alkyl, or R 1 and R 2 When together with the nitrogen to which they are attached form a heterocyclyl, R 1 and R 2may be selected from hydrogen or alkyl, or the moiety may have the structure: [ka] where ring A is a heteroaryl ring containing the indicated nitrogen.

[0057] Similarly, when two "adjacent" R groups are said to form a ring "together with the atom to which they are attached," it is meant that the collective unit of the atom, intervening bond, and the two R groups is the described ring. For example, the substructure: [ka] exists and R 1 and R 2 is defined as being selected from the group consisting of hydrogen and alkyl, or R 1 and R 2 When together with the atom to which they are attached form an aryl or carbocyclyl, R 1 and R 2 may be selected from hydrogen or alkyl, or the moiety may have the structure: [ka] where A is an aryl ring or carbocyclyl containing the double bond shown.

[0058] Whenever a substituent is shown as a diradical (i.e., having two points of attachment to the remainder of the molecule), it is to be understood that the substituent may be attached in any orientation unless otherwise indicated. Thus, for example, -AE- or [ka] Substituents depicted as include those where the A is oriented such that it is attached at the leftmost attachment point of the molecule, as well as instances where A is attached at the rightmost attachment point of the molecule.

[0059] When the compounds disclosed herein have at least one chiral center, they can exist as individual enantiomers and diastereomers, or as mixtures of such isomers, including racemates. Separation of these individual isomers or selective synthesis of these individual isomers can be achieved by applying various methods well known to those skilled in the art. Unless otherwise indicated, all such isomers and mixtures thereof are included within the scope of the compounds disclosed herein. Furthermore, the compounds disclosed herein can exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms are included within the scope of the compounds disclosed herein, including any polymorphic forms. Furthermore, some of the compounds disclosed herein can form solvates with water (i.e., hydrates) or common organic solvents. Unless otherwise indicated, such solvates are included within the scope of the compounds disclosed herein.

[0060] Those skilled in the art will recognize that some structures depicted herein may be resonance forms or tautomers of compounds that may be properly represented by other chemical structures, even those by dynamics, and that such structures may only represent a small portion of the sample of such compound(s). Although such resonance forms or tautomers are not depicted herein, such compounds are considered to be within the scope of the depicted structures.

[0061] Isotopes may be present in the described compounds. Each chemical element shown in the compound structure may include all isotopes of that element. For example, in a compound structure, a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position in the compound where a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen, including but not limited to hydrogen 1 (protium) and hydrogen 2 (deuterium). Thus, reference to a compound herein encompasses all possible isotopic forms, unless the context clearly indicates otherwise.

[0062] "Solvate" refers to a compound formed by the interaction of a solvent with a compound described herein (a metabolite, or a salt thereof). Suitable solvates are pharma- ceutically acceptable solvates, including hydrates.

[0063] The term "pharmaceutical acceptable salt" refers to a salt that retains the biological effectiveness and properties of a compound that is not biologically or otherwise undesirable for use in medicine. In many cases, the compounds herein can form acid salts and / or base salts due to the presence of amino and / or carboxy groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases that can be derived from salt include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc., with ammonium salt, potassium salt, sodium salt, calcium salt and magnesium salt being particularly preferred.Organic bases that can be derived from salt include, for example, primary amine, secondary amine, and tertiary amine, substituted amine (including naturally occurring substituted amine), cyclic amine, basic ion exchange resin, etc., specifically, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine.Many such salts are known in the art, as described in WO87 / 05297, published by Johnston et al. on September 11, 1987 (incorporated herein in its entirety by reference).

[0064] (β-lactamase inhibitors) In some embodiments, the β-lactamase inhibitor for use described herein has Formula (I)-(IX): [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof, wherein: Each R 1 is independently C 1~6 alkyl, or each R 1 together with the geminal carbon atom to which they are attached, optionally substituted C 3~6 forms a cycloalkyl ring or an optionally substituted 4- to 6-membered heterocycloalkyl ring; R 2 is a single bond, optionally substituted C 1~6 Alkyl, optionally substituted 2-6 membered heteroalkyl, optionally substituted C 5~6 cycloalkyl, optionally substituted 5-6 membered heterocycloalkyl, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl; R 3 is C 1~6 Alkyl, -OC(O)-R 4 , -SC(O)-R 4 , -NH-C(O)-R 4 , -OC(O)-OR 4 , -S(O)-OR 4 , -NH-C(O)-OR 4 , -(O)-OR 4 , -C(O)-SR 4 , -C(O)-NH-R 4 , -O-(O)-OR 4 , -OC(O)-SR 4 , -OC(O)-NH-R 4 , -SSR 4 , -SR 4 , -NH-R 4 , and -CH(-NH2)-R 4 ) are selected from; R 4 is hydrogen, optionally substituted C 1~8Alkyl, optionally substituted 2-8 membered heteroalkyl, optionally substituted C 5~8 Cycloalkyl, optionally substituted 5-8 membered heterocycloalkyl, optionally substituted C 5~10 Cycloalkylalkyl, optionally substituted 5-8 membered heterocycloalkyl-C 1~3 alkyl, optionally substituted phenyl, optionally substituted 5-8 membered heteroaryl, optionally substituted C 7~10 Arylalkyl and optionally substituted 5-8 membered heteroaryl-C 1~3 alkyl; R 5 is C 1~6 Alkyl, -NR 6 R 7 , -CH2C(O)NH2, and [ka] selected from the group consisting of; R 6 and R 7 , H, C 1~6 alkyl, and -CH2C(O)NH2.

[0065] Compounds of formulae (I)-(IX) may be prepared according to the procedures described in US Pat. No. 10,085,999, which is incorporated herein by reference in its entirety.

[0066] In other embodiments, the β-lactamase inhibitor for use described herein has the formula (X)-(XVII): [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 8 is C 1~9 Alkyl, -CR 10 R 11 O.C.(O)C 1~9 Alkyl, -CR 10 R 11 O.C.(O)C 3~7 Carbocyclyl, -CR 10 R 11 OC(O)(3-7 membered heterocyclyl), -CR 10 R 11 O.C.(O)C 2~8 Alkoxyalkyl, -CR 10 R 11 OC(O)OC 1~9 Alkyl, -CR 10 R 11 OC(O)OC 3~7 Carbocyclyl, -CR 10 R 11 OC(O)O(3-7 membered heterocyclyl), -CR 10 R 11 OC(O)OC 2~8 Alkoxyalkyl, -CR 10 R 11 O.C.(O)C 6~10 Aryl, -CR 10 R 11 OC(O)OC 6~10 Aryl, -CR 10 R 11 C(O)NR 13 R 14 , -CR 10 R 11 OC(O)O(CH2) 1~3 C(O)NR 13 R 14 , -CR 10 R 11 OC(O)O(CH2) 2~3 O.C.(O)C 1~4 Alkyl, -CR 10 R 11 OC(O)O(CH2) 1~3 C(O)OC 1~4 Alkyl, -CR 10 R 11 OC(O)(CH2)1~3 O.C.(O)C 1~4 Alkyl, and [ka] selected from the group consisting of; Each R 10 and R 11 H, optionally substituted C 1~4 Alkyl, optionally substituted C 3~7 Carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6~10 aryl, and optionally substituted 5-10 membered heteroaryl; Each R 13 and R 14 H, optionally substituted C 1~6 Alkyl, optionally substituted C 3~7 Carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6~10 aryl, and optionally substituted 5-10 membered heteroaryl; R 15 is replaced by C 1~6 It is an alkyl.

[0067] Compounds of formula (X)-(XVII) can be produced using the procedures described in PCT Publication Nos. WO2019 / 093450 or WO2018 / 005662, both of which are incorporated by reference herein in their entireties, or any other ester-forming procedures known in the art.

[0068] In some embodiments, the β-lactamase inhibitor for use described herein is [ka] or a pharmaceutically acceptable salt thereof. These compounds and their synthesis are described in U.S. Patent No. 10,085,999, U.S. Application Publication No. 2019 / 0202832, PCT Publication No. WO2019 / 093450, PCT Publication No. WO2018 / 005662, and PCT Application No. PCT / US2021 / 022799 (all of which are incorporated herein by reference in their entirety).

[0069] Administration and Pharmaceutical Compositions The administration of the compounds disclosed herein can be by any of the accepted modes of administration, including but not limited to oral, subcutaneous, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular.Oral and parenteral administration are conventional in treating the indications that are the subject of the preferred embodiments.

[0070] The disclosed compounds can be formulated into pharmaceutical compositions either individually or together.Standard pharmaceutical formulation techniques can be used, for example, those disclosed in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams and Wilkins (2005) (incorporated by reference in its entirety).Thus, some embodiments include pharmaceutical compositions comprising (a) one or more compounds disclosed herein, and (b) pharmaceutically acceptable carriers, diluents, excipients or combinations thereof.

[0071] In addition to the above-mentioned useful selected compounds, some embodiments include compositions that include pharma- ceutically acceptable carriers. The term "pharma-ceutically acceptable carriers" or "pharma-ceutically acceptable excipients" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharma-ceutically active substances is well known in the art. Except to the extent that any conventional media or agent is incompatible with the active ingredient, its use in therapeutic compositions is contemplated. In addition, various adjuvants, such as those commonly used in the art, may be included. Considerations regarding the inclusion of various ingredients in pharmaceutical compositions are described, for example, in Gilman et al. (eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Edition, Pergamon Press, which is incorporated herein by reference in its entirety.

[0072] Some examples of substances which can serve as pharma- ceutically acceptable carriers or components thereof are sugars (e.g., lactose, glucose, and sucrose); starches (e.g., corn starch and potato starch); cellulose and its derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose, and methylcellulose); powdered tragacanth; malt; gelatin; talc; solid lubricants (e.g., stearic acid and magnesium stearate); calcium sulfate; vegetable oils (e.g., peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and oil of the cocoa plant (theobroma); polyols (e.g., propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol); alginic acid; emulsifiers (e.g., TWEEN®); wetting agents (e.g., sodium lauryl sulfate); colorants; flavoring agents; tabletting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

[0073] The choice of a pharma- ceutically acceptable carrier for use in combination with the subject compounds is basically determined by the manner in which the compound is to be administered.

[0074] The compositions useful as described above can be in any of a variety of forms suitable for various routes of administration (e.g., for oral, nasal, rectal, topical (including transdermal), ophthalmic, intracerebral, intracranial, intrathecal, intraarterial, intravenous, intramuscular, or other parenteral routes). Those skilled in the art will appreciate that oral and nasal compositions, including compositions administered by inhalation, are prepared using available methodologies. Depending on the specific route of administration desired, various pharmacologic acceptable carriers well known in the art can be used. Pharmaceutically acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropes, surfactants, and encapsulating materials. Optional pharmacologic active substances can be included, which do not substantially interfere with the inhibitory activity of the compound. The amount of carrier used in combination with the compound is sufficient to provide a practical amount of the substance for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods described herein are described in the following references, all of which are incorporated herein by reference: Modern Pharmaceutics, 4th Edition, Chapters 9 and 10 (Banker and Rhodes, eds., 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms, 8th Edition (2004).

[0075] Various oral dosage forms may be used, including solid forms such as tablets, capsules, granules, and bulk powders. Tablets may be compressed, triturated, enteric-coated, sugar-coated, film-coated, or multiple-compressed, and may contain suitable binders, lubricants, diluents, disintegrants, colorants, flavorings, flow-inducing agents, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, and may contain suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, melting agents, colorants, and flavorings.

[0076] The pharma- ceutically acceptable carrier suitable for preparing unit dosage forms for oral administration is well known in the art. Tablets typically contain conventional pharma- ceutical compatible adjuvants such as inert diluents (e.g., calcium carbonate, sodium carbonate, mannitol, lactose and cellulose); binders (e.g., starch, gelatin and sucrose); disintegrants (e.g., starch, alginic acid and croscarmellose); lubricants (e.g., magnesium stearate, stearic acid and talc). Lubricants (e.g., silicon dioxide) can be used to improve the flow characteristics of powder mixtures. Colorants (e.g., FD&C dyes) can be added for appearance. Sweeteners and flavoring agents (e.g., aspartame, saccharin, menthol, peppermint and fruit flavors) are useful adjuvants for chewable tablets. Capsules typically contain one or more of the solid diluents disclosed above. The selection of carrier components will depend on secondary considerations such as taste, cost and shelf stability, which are not critical, and can be readily made by one of ordinary skill in the art.

[0077] Oral compositions also include liquid solutions, emulsions, suspensions, etc. Pharmaceutically acceptable carriers suitable for preparing such compositions are well known in the art. Representative components of carriers for syrups, elixirs, emulsions, and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol, and water. For suspensions, representative suspending agents include methylcellulose, sodium carboxymethylcellulose, AVICEL RC-591, tragacanth, and sodium alginate, representative wetting agents include lecithin and polysorbate 80, and representative preservatives include methylparaben and sodium benzoate. Oral liquid compositions can also include one or more components such as sweeteners, flavorings, and colorings disclosed above.

[0078] Such compositions can also be coated by conventional methods, typically with pH-dependent coatings or time-dependent coatings, so that the subject compounds are released in the vicinity of the desired local application in the digestive tract, or at various times to prolong the desired effect.Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethylcellulose, Eudragit coatings, waxes and shellacs.

[0079] The compositions described herein may optionally include other drug actives.

[0080] Other compositions useful for achieving systemic delivery of the subject compound include sublingual, buccal and nasal dosage forms.Such compositions typically include one or more soluble filler substances (e.g., sucrose, sorbitol and mannitol); and binders (e.g., gum arabic, microcrystalline cellulose, carboxymethylcellulose and hydroxypropylmethylcellulose).The above-disclosed glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents can also be included.

[0081] Liquid compositions formulated for topical ophthalmic use are formulated so that they can be administered locally to the eye. Its comfort should be maximized as much as possible, but sometimes formulation considerations (e.g., drug stability) may force less than optimal comfort. If comfort cannot be maximized, the liquid should be formulated so that it is acceptable to patients for topical ophthalmic use. Furthermore, ophthalmically acceptable liquids should either be packaged for single use or contain preservatives to prevent contamination over multiple uses.

[0082] For ophthalmic applications, solutions or medicaments are often prepared using saline solution as the primary vehicle. Ophthalmic solutions should preferably be maintained at a comfortable pH with an appropriate buffer system. The formulations may also contain conventional pharma- ceutically acceptable preservatives, stabilizers, and surfactants.

[0083] Preservatives that can be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate. Useful surfactants are, for example, Tween® 80. Similarly, various useful vehicles can be used in the ophthalmic preparations disclosed herein. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropylmethylcellulose, poloxamer, carboxymethylcellulose, hydroxyethylcellulose and purified water.

[0084] Tonicity adjusters may be added where necessary or convenient, including, but not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjuster.

[0085] Various buffers and means for adjusting pH can be used so long as the resulting preparation is ophthalmologically acceptable. For many compositions, the pH is between 4 and 9. Thus, buffers include acetate buffer, citrate buffer, phosphate buffer and borate buffer. Acid or base can be used to adjust the pH of these formulations when necessary.

[0086] Similarly, ophthalmically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.

[0087] Another vehicle component that may be included in the ophthalmic preparation is a chelating agent. A useful chelating agent is edetate disodium, although other chelating agents may also be used in place of or in combination therewith.

[0088] For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the compounds disclosed herein are used. Topical formulations may generally include pharmaceutical carriers, cosolvents, emulsifiers, permeation enhancers, preservative systems, and emollients.

[0089] For intravenous administration, the compounds and compositions described herein may be dissolved or dispersed in a pharma- ceutically acceptable diluent, such as (saline or dextrose solution). Suitable excipients may be included to achieve the desired pH, including, but not limited to, NaOH, sodium carbonate, sodium acetate, HCl, and citric acid. In various embodiments, the pH of the final composition is in the range of 2-8 or preferably in the range of 4-7. Antioxidant excipients may include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylate, thiourea, and EDTA. Other non-limiting examples of suitable excipients found in the final intravenous composition may include sodium or potassium phosphate, citric acid, tartaric acid, gelatin, and carbohydrates (e.g., dextrose, mannitol, and dextran). Additional acceptable excipients are described in Powell et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech, 1998, 52, 238-311, and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech, 2011, 65, 287-332, both of which are incorporated herein by reference in their entirety. Antimicrobial agents may also be included to achieve a bacteriostatic or fungistatic solution, including, but not limited to, phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.

[0090] The composition for intravenous administration may be provided to the caregiver in one or more solid forms that are reconstituted with a suitable diluent (e.g., sterile water, saline in water, or dextrose) immediately prior to administration. In other embodiments, the composition is provided in a solution that is ready to be administered parenterally. In yet other embodiments, the composition is provided in a solution that is further diluted prior to administration. In embodiments that include administering a combination of a compound described herein and another agent, the combination may be provided to the caregiver as a mixture, or the caregiver may mix the two agents prior to administration, or the two agents may be administered separately.

[0091] Ceftibuten and a β-lactamase inhibitor may be co-administered. By "co-administered" it is meant that the two agents are administered to have a simultaneous biological effect, regardless of when or how they are actually administered. In some embodiments, the two agents may be found in the patient's bloodstream at the same time. In one embodiment, the agents are administered simultaneously. In one such embodiment, co-administration is achieved by combining the agents into a single dosage form. In another embodiment, the agents are administered sequentially. In one embodiment, the agents are administered through the same route (e.g., orally). In another embodiment, the agents are administered through different routes, for example, one agent is administered orally and another agent is administered intravenously (iv).

[0092] (Treatment Method) Some embodiments of the present invention include a method of treating bacterial infection with the compounds described herein and compositions comprising the compounds. Some methods include administering the compounds, compositions, pharmaceutical compositions described herein to a subject in need of treating bacterial infection. In some embodiments, the subject can be an animal, for example, a mammal (including human). In some embodiments, the bacterial infection comprises a bacterium described herein. As understood from the above, the method of treating bacterial infection includes a method for preventing bacterial infection in a subject at risk of bacterial infection.

[0093] As used herein, "subject" means a human or non-human mammal (e.g., dog, cat, mouse, rat, cow, sheep, pig, goat, non-human primate) or bird (e.g., chicken), as well as any other vertebrate or invertebrate.

[0094] The term "mammal" is used in its normal biological sense, and thus specifically includes, but is not limited to, primates (including simians (chimpanzees, apes, monkeys) and humans), cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rodents, rats, mice, guinea pigs, and the like.

[0095] As used herein, "treat", "treatment" or "treating" refers to administering a compound or pharmaceutical composition to a subject for preventive and / or therapeutic purposes. The term "prophylactic treatment" refers to treating a subject who has not yet shown symptoms of a disease or condition but is susceptible to or otherwise at risk for a particular disease or condition, thereby reducing the likelihood that the patient will develop the disease or condition. The term "therapeutic treatment" refers to administering treatment to a subject who is already suffering from a disease or condition.

[0096] The bacterial infections that can be treated by the compounds, compositions and methods described herein can include a wide range of bacteria.Examples of organisms include gram-positive bacteria, gram-negative bacteria, aerobic bacteria and anaerobic bacteria, such as Staphylococcus, Lactobacillus, Streptococcus, Sarcina, Escherichia, Enterobacter, Klebsiella, Pseudomonas, Acinetobacter, Mycobacterium, Proteus, Campylobacter, Citrobacter, Nisseria, Baccillus, Bacteroides, Peptococcus, Clostridium, Salmonella, Shigella, Serratia, Haemophilus, Brucella and other organisms.

[0097] Further examples of bacterial infections include Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonas hydrophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis、Bordetella parapertussis、Bordetella bronchiseptica、Haemophilus influenzae、Haemophilus parainfluenzae、Haemophilus haemolyticus、Haemophilus parahaemolyticus、Haemophilusducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella, Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, StaphylococcusExamples of bacteria that may be included include Staphylococcus haemolyticus, Staphylococcus hominis, or Staphylococcus saccharolyticus.

[0098] The following examples are included to further illustrate the present invention. These examples should not be interpreted as specifically limiting the present invention. Variations of these examples that fall within the scope of the claims are within the knowledge of one of ordinary skill in the art, and such variations are considered to be within the scope of the invention described and claimed herein. The reader will recognize that a person of ordinary skill in the art, armed with this disclosure and the skills in the field, can prepare and use the present invention without the need for exhaustive examples. The following examples further describe the present invention, and these examples are used merely for illustrative purposes and should not be interpreted as limiting. EXAMPLES

[0099] Example 1 A double-blind, randomized, placebo-controlled, sequential, single and multiple ascending dose study of ceftibuten in healthy adult subjects was conducted. There were four cohorts of 10 subjects each (8 active and 2 placebo) who received both single and multiple oral doses. The dosing scheme for cohorts 1 to 4 is shown in Table 1. [Table 1]

[0100] (safety) Ceftibuten was well tolerated in healthy volunteers in capsule formulations of 400 mg, 600 mg, and 800 mg once / twice daily. Safety conclusions from 40 enrolled subjects who received single and multiple doses of either ceftibuten or placebo over the study period are as follows: No serious, severe, life-threatening, treatment-emergent adverse events (TEAEs) or fatal TEAEs were reported throughout the study (single ascending dose [SAD] and multiple ascending dose [MAD] periods). All TEAEs were mild, regardless of causality, with the exception of two TEAEs that were moderate in severity: nausea (SAD 800 mg ceftibuten) and vulvovaginal candidiasis (MAD 800 mg ceftibuten). The case of nausea occurred in one subject during the SAD period after a single dose of ceftibuten, and the case of vulvovaginal candidiasis occurred in one subject during the MAD period after a single dose of ceftibuten. Both cases occurred in the subject receiving the highest single dose of ceftibuten (800 mg) and were considered by the investigator to be related to the study drug. There were two TEAEs (nausea and diarrhea) in one subject from the highest single dose group (800 mg ceftibuten) that led to discontinuation of study drug; the case of nausea also led to the subject discontinuing the study at the investigator's discretion. The nausea was considered to be moderate in severity, the diarrhea was considered to be mild in severity, and both cases were considered related to the study drug by the investigator. The nausea persisted from the first dose (SAD) through the morning dose (MAD) of Day 4 despite treatment with concomitant medications. The nausea resolved on Day 9 after the subject discontinued the study. During the SAD period of this study, the frequency of reported TEAEs did not increase with increasing ceftibuten dose (44 TEAEs reported in 18 of 32 subjects [56.3%] in all ceftibuten groups compared with 5 TEAEs reported in 4 of 8 subjects [50.0%] in the pooled placebo group). Fifteen (15) treatment-related TEAEs were reported in ten of 40 subjects (25.0%) during the SAD period of the study. The incidence of treatment-related TEAEs was similar for the 400 mg ceftibuten and 600 mg ceftibuten and pooled placebo groups (1 of 8 subjects [12.5%]), but was higher with the 800 mg ceftibuten dose (4 of 16 subjects [25.0%]). During the MAD period of this study, the frequency of reported TEAEs did not increase with increasing ceftibuten dose, but the number of subjects reporting TEAEs in all ceftibuten groups was approximately twice as high as the number of subjects reporting TEAEs in the pooled placebo groups (22 of 32 subjects [68.8%] and 3 of 8 subjects [37.5%], respectively). During the MAD period of the study, 32 treatment-related TEAEs were reported in 17 of 40 subjects (42.5%). The incidence of treatment-related TEAEs was similar in the 400 mg ceftibuten (1 of 8 subjects [12.5%]) and 600 mg ceftibuten (2 of 8 subjects [25.0%]) and pooled placebo groups (3 of 8 subjects [37.5%]). Treatment-related TEAEs were higher in the 800 mg ceftibuten group (11 of 16 subjects [68.8%]). Treatment-related TEAEs were reported at the highest incidence in SOC GI in the SAD, MAD and SAD / MAD combination studies. The highest incidence was reported at the highest single dose of ceftibuten (800 mg). The most common GI TEAEs in the 800 mg group during the MAD period were nausea in 4 of 16 subjects (25.0%), diarrhea in 4 of 16 subjects (25.0%), abdominal pain in 3 of 16 subjects (18.8%), upper abdominal pain in 3 of 16 subjects (18.8%) and abdominal discomfort in 2 of 16 subjects (12.5%). Most GI TEAEs were transient and mild in severity and did not require intervention. The exception was one treatment-related case of nausea, which was reported in subject 111-408 (800 mg ceftibuten) and was moderate in severity. Elevations in ALT occurred in several subjects across all ceftibuten arms during both the SAD and MAD periods of the study, and their incidence and severity did not increase with increasing ceftibuten dose. All cases were asymptomatic, resolved spontaneously after completion of study treatment, and were not associated with elevations in alkaline phosphatase or bilirubin. There were no trends of non-clinically significant (NCS) abnormalities in hematology, coagulation, or urinalysis parameters. There were four cases of abnormal findings in hematology, coagulation, or urinalysis that were considered clinically significant (CS): three cases of low neutrophil count and one case of low lymphocyte count, all of which were asymptomatic and did not meet the criteria for an adverse event (AE). No clinically significant (CS) abnormalities were reported in ECG parameters or physical examination. There were no trends in changes from baseline in vital sign parameters such as blood pressure (systolic and diastolic), pulse rate, temperature or respiratory rate.

[0101] Overall, ceftibuten was well tolerated in healthy volunteers in capsule formulations of 400 mg, 600 mg, and 800 mg once / twice daily.

[0102] (Pharmacokinetics) After single doses of 400 mg, 600 mg, and 800 mg ceftibuten, mean maximum cis-ceftibuten plasma concentrations reached 17.6 μg / mL, 24.1 μg / mL, and 28.1 μg / mL, respectively, and mean maximum trans-ceftibuten plasma concentrations reached 1.1 μg / mL, 1.5 μg / mL, and 2.2 μg / mL, respectively. The pharmacokinetic parameters of cis-ceftibuten and trans-ceftibuten on day 4 were similar to those of cis-ceftibuten and trans-ceftibuten on day 1.

[0103] After repeated doses of 400 mg, 600 mg, and 800 mg ceftibuten, mean maximum cis-ceftibuten plasma concentrations reached 21.7 μg / mL, 28.1 μg / mL, and 38.8 μg / mL, respectively, and mean maximum trans-ceftibuten plasma concentrations reached 1.4 μg / mL, 1.9 μg / mL, and 2.8 μg / mL, respectively.

[0104] Cis-ceftibuten plasma concentrations peaked 2.3 to 3.0 hours after dosing, whereas trans-ceftibuten plasma concentrations peaked 3.3 to 4.8 hours after dosing. The terminal half-life of cis-ceftibuten ranged from 2.3 to 3.1 hours, whereas that of trans-ceftibuten ranged from 3.0 to 3.6 hours. Total body clearance of cis-ceftibuten ranged from 3.9 L / h to 5.0 L / h.

[0105] After a single dose, urinary recovery as cis-ceftibuten and trans-ceftibuten accounted for 59.5% to 86.9% and 9.3% to 12.5% ​​of the administered dose, respectively. After repeated doses, urinary recovery as cis-ceftibuten and trans-ceftibuten accounted for 75.8% to 100% and 14.1% to 16.8% of the administered dose, respectively. Renal clearance of cis-ceftibuten was estimated to be between 2.9 L / h and 4.2 L / h. In general, renal clearance contributed the majority of the total body clearance of ceftibuten.

[0106] Dose proportionality was demonstrated graphically using dose-normalized Cmax, AUC 0~12 Value and AUC 0~∞ The AUC values ​​were examined using ANOVA tests. Exposure to cis-ceftibuten and trans-ceftibuten increased proportionally after administration of 400 mg, 600 mg, and 800 mg of ceftibuten. 0~12 Exposure is shown in Figure 1, and the AUC of trans-ceftibute 0~12 Exposure is shown in Figure 2. These figures show that the increase was dose proportional.

[0107] Example 2 Ninety-nine strains of Enterobacterales were treated with various concentrations of the following β-lactamase inhibitors: [ka] In a resistance development study using ceftibuten at 1 μg / ml or 2 μg / ml in combination with

[0108] Compound 1 is described in PCT Publication No. WO2018 / 005662, which is incorporated herein by reference in its entirety. Compound 1 concentrations included 1 μg / ml, 2 μg / ml, 4 μg / ml and 8 μg / ml. The purpose of this study was to identify the concentration of compound 1 that inhibits the emergence of mutants (MPC, mutant inhibiting concentration) at two different ceftibuten concentrations. Compound 1 data at 4 μg / ml is summarized in Table 2. [Table 2]

[0109] The data indicate that increasing the concentration of ceftibuten results in a higher proportion of strains in which resistance is prevented by ≦4 μg / ml of compound 1. Thus, increasing the ceftibuten dose to greater than 400 mg in combination with a β-lactamase inhibitor may result in a decrease in the development of resistance.

Claims

1. Ceftibuten in an amount greater than 400 mg; β-lactamase inhibitors and 23. A pharmaceutical composition comprising:

2. 2. The pharmaceutical composition of claim 1, wherein ceftibuten is present in an amount greater than 500 mg.

3. 2. The pharmaceutical composition of claim 1, wherein ceftibuten is present in an amount greater than 550 mg.

4. 2. The pharmaceutical composition of claim 1, wherein ceftibuten is present in an amount greater than 600 mg.

5. 2. The pharmaceutical composition of claim 1, wherein ceftibuten is present in an amount greater than 650 mg.

6. 2. The pharmaceutical composition of claim 1, wherein ceftibuten is present in an amount greater than 700 mg.

7. 2. The pharmaceutical composition of claim 1, wherein ceftibuten is present in an amount greater than 750 mg.

8. 2. The pharmaceutical composition of claim 1, wherein ceftibuten is present in an amount of about 600 mg.

9. 2. The pharmaceutical composition of claim 1, wherein ceftibuten is present in an amount of about 800 mg.

10. The β-lactamase inhibitor has formula (I)-(IX): 【Chemistry 16】 【Chemistry 17】 【Chemistry 18】 or a pharma- ceutically acceptable salt thereof, wherein Each R １ is independently C １～６ alkyl, or each R １ are optionally substituted C together with the geminal carbon atom to which they are attached. ３～６ forming a cycloalkyl ring or an optionally substituted 4- to 6-membered heterocycloalkyl ring; R ２ represents a single bond, optionally substituted C １～６ Alkyl, optionally substituted 2-6 membered heteroalkyl, optionally substituted C ５～６ selected from cycloalkyl, optionally substituted 5-6 membered heterocycloalkyl, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl; R ３ is selected from C １～６ alkyl, -O-C(O)-R ４ -S-C(O)-R ４ -NH-C(O)-R ４ -O-C(O)-O-R ４ -S(O)-O-R ４ -NH-C(O)-O-R ４ -(O)-O-R ４ -C(O)-S-R ４ -C(O)-NH-R ４ -O-(O)-O-R ４ -O-C(O)-S-R ４ -O-C(O)-NH-R ４ -S-S-R ４ -S-R ４ -NH-R ４ and -CH(-NH ２ )-R ４ and is selected from; R ４ is hydrogen, optionally substituted C １～８ Alkyl, optionally substituted 2-8 membered heteroalkyl, optionally substituted C ５～８ Cycloalkyl, optionally substituted 5- to 8-membered heterocycloalkyl, optionally substituted C ５～１０ Cycloalkylalkyl, optionally substituted 5- to 8-membered heterocycloalkyl-C １～３ alkyl, optionally substituted phenyl, optionally substituted 5- to 8-membered heteroaryl, optionally substituted C ７～１０ Arylalkyl and optionally substituted 5- to 8-membered heteroaryl-C １～３ alkyl; R ５ is C １～６ Alkyl, -NR ６ R ７ , -CH ２ C(O)NH ２ , and 【Chemistry 19】 selected from the group consisting of: R ６ and R ７ is H, C １～６ Alkyl, and -CH ２ C(O)NH ２ The pharmaceutical composition of any one of claims 1 to 9, wherein the compound is independently selected from the group consisting of:

11. The β-lactamase inhibitor has the formula (X)-(XVII): 【Chemistry 20】 【Chemistry 21】 or a pharma- ceutically acceptable salt thereof, wherein R ８ is C １～９ Alkyl, -CR １０ R １１ O.C.(O)C １～９ Alkyl, -CR １０ R １１ O.C.(O)C ３～７ Carbocyclyl, -CR １０ R １１ OC(O)(3- to 7-membered heterocyclyl), -CR １０ R １１ O.C.(O)C ２～８ Alkoxyalkyl, -CR １０ R １１ O.C. (O) O.C. １～９ Alkyl, -CR １０ R １１ O.C. (O) O.C. ３～７ Carbocyclyl, -CR １０ R １１ OC(O)O(3- to 7-membered heterocyclyl), -CR １０ R １１ O.C. (O) O.C. ２～８ Alkoxyalkyl, -CR １０ R １１ O.C.(O)C ６～１０ Aryl, -CR １０ R １１ O.C. (O) O.C. ６～１０ Aryl, -CR １０ R １１ C(O)NR １３ R １４ , -CR １０ R １１ O C (O) O (CH ２ ) １～３ C(O)NR １３ R １４ , -CR １０ R １１ O C (O) O (CH ２ ) ２～３ O.C.(O)C １～４ Alkyl, -CR １０ R １１ O C (O) O (CH ２ ) １～３ C(O)OC １～４ Alkyl, -CR １０ R １１ O C (O) (CH ２ ) １～３ O.C.(O)C １～４ Alkyl, and 【Chemical 22】 selected from the group consisting of: Each R １０ and R １１ is H, optionally substituted C １～４ Alkyl, optionally substituted C ３～７ Carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C ６～１０ independently selected from the group consisting of aryl, and optionally substituted 5-10 membered heteroaryl; Each R １３ and R １４ is H, optionally substituted C １～６ Alkyl, optionally substituted C ３～７ Carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C ６～１０ independently selected from the group consisting of aryl, and optionally substituted 5-10 membered heteroaryl; R １５ is optionally substituted C １～６ is alkyl, A pharmaceutical composition according to any one of claims 1 to 9.

12. The β-lactamase inhibitor is 【Chemistry 23】 10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the compound is selected from the group consisting of:

13. A combination for treating a bacterial infection comprising ceftibuten and a beta-lactamase inhibitor, characterized in that the combination is administered concomitantly to a subject in need of treatment for a bacterial infection, and characterized in that the ceftibuten is administered in an amount greater than 400 mg.

14. 14. A combination according to claim 13, characterized in that the ceftibuten is administered in an amount greater than 500 mg.

15. 14. A combination according to claim 13, characterized in that the ceftibuten is administered in an amount greater than 550 mg.

16. 14. The combination according to claim 13, characterized in that the ceftibuten is administered in an amount greater than 600 mg.

17. 14. A combination according to claim 13, characterized in that the ceftibuten is administered in an amount greater than 650 mg.

18. 14. A combination according to claim 13, characterized in that the ceftibuten is administered in an amount greater than 700 mg.

19. 14. A combination according to claim 13, characterized in that the ceftibuten is administered in an amount greater than 750 mg.

20. 14. The combination according to claim 13, characterized in that said ceftibuten is administered in an amount of about 600 mg.

21. 14. The combination according to claim 13, characterized in that said ceftibuten is administered in an amount of about 800 mg.

22. The β-lactamase inhibitor has formula (I)-(IX): 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 or a pharma- ceutically acceptable salt thereof, wherein Each R １ is independently C １～６ alkyl, or each R １ are optionally substituted C together with the geminal carbon atom to which they are attached. ３～６ forming a cycloalkyl ring or an optionally substituted 4- to 6-membered heterocycloalkyl ring; R ２ represents a single bond, optionally substituted C １～６ Alkyl, optionally substituted 2-6 membered heteroalkyl, optionally substituted C ５～６ selected from cycloalkyl, optionally substituted 5-6 membered heterocycloalkyl, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl; R ３ is selected from C １～６ alkyl, -O-C(O)-R ４ -S-C(O)-R ４ -NH-C(O)-R ４ -O-C(O)-O-R ４ -S(O)-O-R ４ -NH-C(O)-O-R ４ -(O)-O-R ４ -C(O)-S-R ４ -C(O)-NH-R ４ -O-(O)-O-R ４ -O-C(O)-S-R ４ -O-C(O)-NH-R ４ -S-S-R ４ -S-R ４ -NH-R ４ and -CH(-NH ２ )-R ４ selected from; R ４ is hydrogen, optionally substituted C １～８ Alkyl, optionally substituted 2-8 membered heteroalkyl, optionally substituted C ５～８ Cycloalkyl, optionally substituted 5- to 8-membered heterocycloalkyl, optionally substituted C ５～１０ Cycloalkylalkyl, optionally substituted 5- to 8-membered heterocycloalkyl-C １～３ alkyl, optionally substituted phenyl, optionally substituted 5- to 8-membered heteroaryl, optionally substituted C ７～１０ Arylalkyl and optionally substituted 5- to 8-membered heteroaryl-C １～３ alkyl; R ５ is C １～６ Alkyl, -NR ６ R ７ , -CH ２ C(O)NH ２ , and 【Chemical 27】 selected from the group consisting of: R ６ and R ７ is H, C １～６ Alkyl, and -CH ２ C(O)NH ２ Independently selected from the group consisting of: A combination according to any one of claims 13 to 21.

23. The β-lactamase inhibitor has the formula (X)-(XVII): 【Chemistry 28】 【Chemical Formula 29】 【Chemistry 30】 or a pharma- ceutically acceptable salt thereof, wherein R ８ is C １～９ Alkyl, -CR １０ R １１ O.C.(O)C １～９ Alkyl, -CR １０ R １１ O.C.(O)C ３～７ Carbocyclyl, -CR １０ R １１ OC(O)(3- to 7-membered heterocyclyl), -CR １０ R １１ O.C.(O)C ２～８ Alkoxyalkyl, -CR １０ R １１ O.C. (O) O.C. １～９ Alkyl, -CR １０ R １１ O.C. (O) O.C. ３～７ Carbocyclyl, -CR １０ R １１ OC(O)O(3- to 7-membered heterocyclyl), -CR １０ R １１ O.C. (O) O.C. ２～８ Alkoxyalkyl, -CR １０ R １１ O.C.(O)C ６～１０ Aryl, -CR １０ R １１ O.C. (O) O.C. ６～１０ Aryl, -CR １０ R １１ C(O)NR １３ R １４ , -CR １０ R １１ O C (O) O (CH ２ ) １～３ C(O)NR １３ R １４ , -CR １０ R １１ O C (O) O (CH ２ ) ２～３ O.C.(O)C １～４ Alkyl, -CR １０ R １１ O C (O) O (CH ２ ) １～３ C(O)OC １～４ Alkyl, -CR １０ R １１ O C (O) (CH ２ ) １～３ O.C.(O)C １～４ Alkyl, and 【Chemistry 31】 selected from the group consisting of: Each R １０ and R １１ is H, optionally substituted C １～４ Alkyl, optionally substituted C ３～７ Carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C ６～１０ independently selected from the group consisting of aryl, and optionally substituted 5-10 membered heteroaryl; Each R １３ and R １４ is H, optionally substituted C １～６ Alkyl, optionally substituted C ３～７ Carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C ６～１０ independently selected from the group consisting of aryl, and optionally substituted 5-10 membered heteroaryl; R １５ is optionally substituted C １～６ is alkyl, A combination according to any one of claims 13 to 21.

24. The β-lactamase inhibitor is 【Chemistry 32】 22. The combination according to any one of claims 13 to 21, which is selected from the group consisting of:

25. A combination according to any one of claims 13 to 24, characterized in that said amount of ceftibuten is administered once a day.

26. A combination according to any one of claims 13 to 24, characterized in that said amount of ceftibuten is administered twice a day.

27. ​​A composition for treating a bacterial infection comprising ceftibuten, wherein the composition is administered in combination with a beta-lactamase inhibitor to a subject in need of treatment for a bacterial infection, and wherein the ceftibuten is administered in an amount greater than 400 mg.

28. A composition for treating a bacterial infection comprising a beta-lactamase inhibitor, characterized in that the composition is administered in combination with ceftibuten to a subject in need of treatment for a bacterial infection, and the ceftibuten is administered in an amount greater than 400 mg.

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