Orally administered combinations of amoxicillin and avibactam derivatives for treating mycobacterial infections

Abstract

To provide pharmaceutical compositions and treatment methods for treating mycobacterial infections.SOLUTION: A pharmaceutical composition is provided comprising amoxicillin or a pharmaceutically acceptable salt thereof, and an avibactam derivative having the following structure, which 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 or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to the oral administration of a combination of an amoxicillin derivative and an avibactam derivative.The pharmaceutical composition of the present invention can be used to treat mycobacterial infections. [Background technology]

[0002] Resistance to the widely used β-lactam anti-infective drugs is caused by the target bacteria. β-lactamase enzymes are involved in the expression of β-lactam antibiotics. It is possible to hydrolyze the β-lactam ring of the substance, thus converting β-lactam antibiotics into β-lactams. This makes them ineffective against β-lactamase-producing bacteria. Inhibition of β-lactamase prevents the degradation of β-lactam antibiotics, thereby reducing the This will increase the effectiveness of the beta-lactam antibiotics used and reduce the emergence of resistance.

[0003] Avibactam is a beta-lactam approved for intravenous use in combination with ceftazidime (a cephalosporin antibiotic) to treat intra-abdominal infections, urinary tract infections, and pneumonia. Avibactam derivatives have been developed that, when administered orally, produce therapeutically effective plasma concentrations of avibactam. Avibactam derivatives, when co-administered with amoxicillin, inhibit the activity of bacteria caused by bacteria that produce β-lactamase enzymes. This offers the possibility of treating rheumatoid arthritis.

[0004] Mycobacteria are naturally susceptible to infection due to the presence of β-lactamases and the permeability barrier of their cell walls. It is resistant to most β-lactams. Story-Roller, et al., Front Microbiol. 2018 9:2273. A limited number of intravenous beta-lactams are used for the treatment of nontuberculous mycobacterial (NTM) infections. Floto, et al., Thorax. 2016 71:88-90. For example, cefoxitin and imipenem are used to treat infections caused by M. abscessus. These antibiotics are effective against mycobacterial β-lactamase-mediated infections. Treatment with β-lactam antibiotics is long-term. It requires multiple intravenous (IV) injections per day (recommended initial treatment phase of up to 12 weeks). The maintenance phase of treatment may extend for a year or more. al., ID. Can be used to treat NTM disease There are no oral β-lactam antibiotics that can be administered orally. This is because the efficacy of all orally administered β-lactam antibiotics is insufficient. For example, compared to amoxicillin (oral / intravenous antibiotic), The minimum inhibitory concentrations (MICs) of NTM are often significantly higher than the concentrations that reach the site of infection after oral administration, which prevents the clearance of the infection. If an effective oral treatment is available, it would be useful not only during the initial treatment phase of NTM infection but also during the maintenance phase (approximately 12 months). (In this case, only oral or inhaled antibiotics are more readily available. (It would be.) [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Story-Roller, et al., Front Microbiol. 2018 9:2273 [Non-patent document 2] Floto, et al., Thorax. 2016 71:88-90 Summary of the Invention

[0006] According to the present invention, the pharmaceutical composition comprises amoxicillin or a pharmaceutically acceptable salt thereof; and avibactam derivatives of formula (1):

[0007] [ka]

[0008] or a pharmaceutically acceptable salt thereof Including: wherein Each R 1 is C 1-6 alkyl, or each R 1 and the geminal carbon atom to which they are bonded are 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 arenediyl, and substituted C 5-6 Selected from heteroarenediyl; 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; where 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 substitution C 5-10 heteroarylalkyl; R 5 is hydrogen, C 1-6 Alkyl, C 5-8Cycloalkyl, C 6-12 Cycloalkylalkyl, C 2-6 Heteroalkyl, C 5-8 Heterocyclo Alkyl, C 6-12 Heterocycloalkylalkyl, substituted C 1-6 Alkyl, substituted C 5-8 Cycloa Rukill, Substitute C 6-12 Cycloalkylalkyl, substituted C 2-6 Heteroalkyl, substituted C 5-8 Hetero Cycloalkyl and substituted C 6-12 heterocycloalkyl; and R 6 is hydrogen, C 1-6 Alkyl, C 5-8 Cycloalkyl, C 6-12 Cycloalkylalkyl, C 2-6 Haitai Roalkyl, 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 Heterocycloalkyl Chosen by Rukiru.

[0009] According to the present invention, an oral dosage form comprises a pharmaceutical composition according to the present invention. According to the invention, the kit comprises a pharmaceutical composition according to the invention. According to the present invention, the kit comprises a first pharmaceutical composition comprising amoxicillin or a pharmaceutically acceptable salt thereof; and a compound of formula (1):

[0010] [ka]

[0011] a second pharmaceutical composition comprising the avibactam derivative of formula (I) or a pharmaceutically acceptable salt thereof; wherein Each R 1 is C 1-6 alkyl, or each R 1 and the geminal carbon atom to which they are bonded are 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 arenediyl, and substituted C 5-6 Selected from heteroarenediyl; 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; where 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 substitution 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, exchange C 1-6 Alkyl, substituted C 5-8 Cycloalkyl, substituted C6-12 Cycloalkylalkyl, substituted C 2-6 Heteroalkyl, substituted C 5-8 Heterocycloalkyl, and substituted C 6-12 heterocycloalkyl; and 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, exchange 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.

[0012] In accordance with the present invention, a method for treating a bacterial infection in a patient in need thereof comprises administering a therapeutically effective amount of amoxicillin or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of an avibactam derivative of formula (1):

[0013] [ka]

[0014] or a pharmaceutically acceptable salt thereof, wherein: Each R 1 is C 1-6 alkyl, or each R 1 and the geminal carbon atom to which they are bonded are 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 arenediyl, and substituted C 5-6 Selected from heteroarenediyl; 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; where R 4 is hydrogen, C 1-8 Alkyl, C 1-8 Heteroalkyl, C5-8 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 substitution 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, exchange 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 heterocycloalkyl; and 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 6-12heterocycloalkylalkyl, exchange 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.

[0015] According to the present invention, a method for treating a bacterial infection in a patient in need thereof comprises orally administering to the patient a therapeutically effective amount of a pharmaceutical composition according to the present invention. DETAILED DESCRIPTION OF THE INVENTION

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

[0017] "Alkyl" means a group consisting of 1 to 1 carbon atoms of a parent alkane, parent alkene, or parent alkyne. represents a branched or straight-chain monovalent saturated hydrocarbon radical derived by removing one or more hydrogen atoms. An alkyl group is, for example, C 1-10 Alkyl, C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, or C 1-3 It may be alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or isobutyl.

[0018] "Alkoxy" refers to the group -OR where R is alkyl as defined above. Examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups include C 1-6 Alkoxy, C 1-5 Alkoxy, C1-4 Alkoxy, C 1-3 It may be alkoxy, ethoxy, or methoxy.

[0019] "Aryl" by itself or as part of another substituent means a carbon atom of a parent aromatic ring system. represents a monovalent saturated hydrocarbon group derived by removing one hydrogen atom from an atom. Aryl includes 5- and 6-membered carbocyclic aromatic rings (e.g., benzene); bicyclic ring systems where at least one ring is carbocyclic and aromatic (e.g., naphthalene, indane, and tetralin); and tricyclic ring systems where at least one ring is carbocyclic and aromatic (e.g., fluorene). Aryl includes at least one carbocyclic aromatic ring, cycloalkyl ring, or heterocyclic ring. Includes polycyclic ring systems having at least one carbocyclic aromatic ring fused to a cycloalkyl ring. Examples: 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. Only one of the two rings is carbocyclic. In the case of such fused bicyclic ring systems, the radical carbon atom is an aromatic ring. The aryl groups may be located in a carbocyclic aromatic ring or in a heterocycloalkyl ring. Examples of aryl groups include aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indacene, s-in ... Examples of the aryl group include groups derived from indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. 6-10 Aryl, C 6-9 Aryl, C 6-8aryl, or phenyl. However, aryl is not limited to heteroaryl. does not contain or overlap in any way with heteroaryl.

[0020] "Arylalkyl" means a group in which one of the hydrogen atoms bonded to a carbon is replaced by an aryl group. Examples of arylalkyl groups include benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, and 2-naphthylethan-1-yl. , 2-naphthylethen-1-yl, naphthobenzyl, and 2-naphthophenylethan-1-yl. Where individual alkyl moieties are intended, the nomenclature arylalkanyl, arylalkenyl, or arylalkynyl is used. Arylalkyl groups include those listed in C 7-16 Arylalkyl (e.g., an arylalkyl group in which the alkanyl, alkenyl, or alkynyl moiety is C 1-6 and the aryl moiety is C 6-10 The arylalkyl group may be C 7-16 Arylalkyl (the alkanyl, alkenyl, or alkynyl moiety of the arylalkyl group is C 1-6 and the aryl moiety is C 6-10 The arylalkyl group can be any group in which the alkyl moiety is C 1-3 C is alkyl, where the aryl moiety may be phenyl; 7-9 The arylalkyl 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), its pharmaceutically acceptable salts, Formula (1) represents a salt thereof, a hydrate thereof, a solvate thereof, or a combination of any of the foregoing. The avibactam derivatives include sub-genuses and specific compounds within the scope of formula (1). Avibactam derivatives, when administered orally, result in avibactam in the patient's plasma.

[0022] "Avibactam equivalents" refers to the amount of avibactam provided by the present invention. This represents the amount of avibactam in the avibactam derivative. The avibactam derivatives provided by the present invention are absorbed in the gastrointestinal tract and release avibactam in the systemic circulation. The avibactam derivatives contain promoieties that enhance 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 promoieties. For example, the avibactam derivative ethyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)-2,2-dimethylpropanoate has a molecular weight of 393.41 Da. Therefore, this avibactam derivative contains 0.674 avibactam equivalents. When administered orally, assuming 100% bioavailability and 100% in vivo conversion efficiency, 1 mg of the avibactam derivative will reach the patient's systemic circulation. 0.674 mg of avibactam in a single dose. The amount of avibactam equivalent administered will depend, at least in part, on several factors that affect the oral bioavailability of a particular avibactam derivative (e.g., the amount of avibactam in the gastrointestinal tract). The efficacy of avibactam depends on the stability of the avibactam derivative, the extent of absorption in the systemic circulation, and the efficiency of conversion of the avibactam derivative to avibactam in the systemic circulation. The oral bioavailability is expressed as %. The derivative can exhibit oral bioavailability in a patient (e.g., a human) of, for example, greater than 20%F, greater than 30%F, greater than 40%F, greater than 50%F, or greater than 60%F. For example, an oral bioavailability of 25% or greater can be achieved. A 1 mg dose of the irritable avibactam derivative ethyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)-2,2-dimethylpropanoate can result in 0.25 mg of avibactam in the patient's systemic circulation.

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

[0024] "Oral bioavailability" (F%) refers to the percentage of an orally administered drug that reaches the systemic circulation compared to an equivalent dose delivered intravenously. The "compounds" and moieties provided by the present invention include all individual compounds contained within the above chemical formula. Compounds may be identified by chemical structure and / or chemical name. Compounds were analyzed using ChemBioDraw Professional Version 17.1.0.105(19) (CambridgeSoft, The compounds are named using the (Cambridge, MA) naming / structure program. In the event of a conflict between the chemical structure and the chemical name, the chemical structure will dictate the name of the compound. The compounds described herein may contain one or more stereocenters and / or double bonds and therefore may form double bond isomers (all of which may be substituted). isomers, i.e., geometric isomers, enantiomers, diastereomers, or atropisomers. Therefore, any chemical structure within the scope of specification that is shown wholly or partially in a certain relative configuration may be obtained in stereoisomerically pure form ( The described compounds, including, for example, geometrically pure, enantiomerically pure, or diastereomerically pure forms, enantiomeric mixtures, and stereoisomeric mixtures, are also included. Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomeric forms using separation and chiral synthesis methods well known to those skilled in the art.

[0025] The compounds and moieties provided by the present invention include optical isomers of the compounds and moieties, their racemates, and other mixtures thereof. In such embodiments, single enantiomers or diastereomers can be obtained by asymmetric synthesis or by resolution of a racemate. Resolution of a racemate can be accomplished by conventional methods, such as, for example, crystallization in the presence of a resolving agent or chromatography using, for example, a chiral high-pressure liquid chromatography column having a chiral stationary phase. Additionally, the compounds include Z- and E-forms (or cis- and trans-forms) of compounds with double bonds, either as single geometric isomers or as mixtures thereof.

[0026] Compounds and moieties may also exist in several tautomeric forms, including the enol form, the keto form, and mixtures thereof. Thus, the chemical structures depicted herein encompass all possible tautomeric forms of the described compounds. Compounds may exist in solvated forms, including hydrated forms, as well as unsolvated forms. Certain compounds may exist in polycrystalline, co-crystalline, or amorphous forms. Compounds include pharmaceutically acceptable salts thereof, or the free acid form of any of the compounds, as well as pharmaceutically acceptable solvates of any crystalline form of the compounds.

[0027] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group. A cycloalkyl group is a C 3-6 Cycloalkyl, C 3-5 Cycloalkyl, C 5-6 It may be cycloalkyl, cyclopropyl, cyclopentyl, or cyclohexyl. Cycloalkyl may be selected from, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0028] "Cycloalkylalkyl" means a group in which one of the hydrogen atoms bonded to a carbon atom is a cycloalkyl group, as defined herein. represents an acyclic alkyl group substituted with a cycloalkyl group as defined herein. 4-30 Cycloalkylalkyl (e.g., when the alkyl moiety of the cycloalkylalkyl group is C 1-10 wherein the cycloalkyl of the cycloalkylalkyl moiety is Moiety is C 3-20 The cycloalkylalkyl group may be C 4-20 Cycloa Alkylalkyl (e.g., the alkanyl moiety of a cycloalkylalkyl group, alkenyl C 1-8 wherein the cycloalkyl moiety of the cycloalkylalkyl group is C 3-12 The cycloalkylalkyl group may be C 4-9cycloalkylalkyl, where the alkyl moiety of the cycloalkylalkyl group is C 1-3 alkyl, and the cycloalkyl moiety of the cycloalkylalkyl group is C 3-6 Cycloalkyl is a cycloalkyl group. 4-12 cycloalkyl Alkyl, C 4-10 Cycloalkylalkyl, C 4-8 Cycloalkylalkyl, or C 4-6 S The cycloalkylalkyl group may be cyclopropylmethyl (-CH2-cyclo-C3H5), cyclopentylmethyl (-CH2-cyclo-C5H9), or cyclohexylmethyl (-CH2-cyclo-C6H 11 The cycloalkylalkyl group may be cyclopropyl. pyrethenyl (-CH=CH-cyclo-C3H5) or cyclopentylethynyl (-C≡C-cyclo-C5H9) It may be.

[0029] "Cycloalkylheteroalkyl" by itself or as part of another substituent means that one or more of the carbon atoms (and certain associated hydrogen atoms) of the alkyl group may independently be the same or different. represents a heteroalkyl group replaced by a different heteroatom group, and a heteroalkyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced by a cycloalkyl group. In alkylheteroalkyl, the heteroatom group is -O-, -S-, -NH-, -N(-CH3)-, -SO-, and -SO2-, or the heteroatom group can be selected from -O- and -NH-, or the heteroatom group is -O- or -NH-.

[0030] "Cycloalkyloxy" refers to - where R is cycloalkyl as defined herein. The cycloalkyloxy group represents an OR group. Examples of the cycloalkyloxy group include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy. The cycloalkyloxy group is C 3-6 Cycloalkyloxy, C 3-5 Cycloalkyloxy, C 5-6 It may be cycloalkyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, or cyclohexyloxy.

[0031] "Disease" means any disease, disorder, condition, or represents any of the above symptoms. "Heteroalkoxy" means an alkoxy group in which one or more carbon atoms are replaced by a heteroatom. The heteroalkoxy group is, for example, C 1-6 Heteroalkoxy, C 1-5 Heteroalkoxy, C 1-4 Heteroalkoxy, or C 1-3 In the heteroalkoxy, the heteroatom group is selected from -O-, -S-, -NH-, -NR-, -SO-, and -SO2-. Alternatively, the heteroatom group can be selected from -O- and -NH-, or The atomic group is -O- or -NH-. Heteroalkoxy groups are C 1-6 Heteroalkoxy, C 1-5 F Teloalkoxy, C 1-4 Heteroalkoxy, or C 1-3 It may be heteroalkoxy.

[0032] "Heteroalkyl" by itself or as part of another substituent means a heteroalkyl group consisting of carbon atoms (and represents an alkyl group in which one or more of the hydrogen atoms bonded to the alkyl group are independently replaced with the same or different heteroatom groups. Examples of heteroatom groups include -O-, -S-, -NH-, -NR-, -OO-, -SS-, =NN=, -N=N-, -N=N-NR-, -PR-, -P(O)OR-, -P(O)R-, -POR-, -SO-, -SO2-, and -Sn(R)-, where each R is hydrogen, C 1-6 Alkyl, substituted C 1-6 Alkyl, C 6-12 Aryl, substituted C 6-12 Aryl, C 7-18 Aryl alkyl, substituted C 7-18 Arylalkynyl Lu, 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 Hetero Aryl, substituted C 6-12 Heteroaryl, C 7-18 Heteroarylalkyl, and substituted C 7-18 Each R in the heteroatom group can be independently selected from: Hydrogen and C 1-3 alkyl, e.g., C 1-6 Heteroalkyl is a C in which at least one of the carbon atoms (and certain associated hydrogen atoms) has been replaced with a heteroatom. 1-6 It means an alkyl group. For example, C 1-6 Heteroalkyl is a group consisting of five carbon atoms and one heterocyclic group. In heteroalkyl, the heteroatom groups can be selected from -O-, -S-, -NH-, -N(-CH3)-, -SO-, and -SO2-, or the heteroatom groups can be selected from -O- and -NH-, or the heteroatom groups can be selected from -O-, -S-, -NH-, -N(-CH3)-, -SO-, and -SO2-. The heteroatom group may be -O- or -NH-. The heteroalkyl group is 1-6 Heteroalkyl , C 1-5 Heteroalkyl, C 1-4 Heteroalkyl, or C 1-3 It may be heteroalkyl.

[0033] "Heteroaryl" by itself or as part of another substituent means a monovalent heteroaromatic ring derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system. Heteroaryl represents a group. Heteroaryl is a group having at least one ring, which may be aromatic or non-aromatic. Polycyclic ring systems include those having at least one heteroaromatic ring fused to another ring. Aryl includes bicyclic rings in which one ring is heteroaromatic and the other ring is a heterocycloalkyl ring. Fused bicyclic heterocyclic rings in which only one of the rings contains one or more heteroatoms are also included. In the case of a heteroaryl ring system, the radical carbon may be located in the aromatic ring or in the heterocycloalkyl ring. When the total number of N, S, and O atoms in the heteroaryl group is greater than 1, the heteroatoms may or may not be adjacent to one another. The total number of heteroatoms in the heteroaryl group is 2 or less. wherein the heteroatom group can be selected from -O-, -S-, -NH-, -N(-CH3)-, -S(O)-, and -SO2-; or the heteroatom group can be selected from -O- and -NH-; or The atomic group may be -O- or -NH-. Heteroaryl groups include, for example, C 5-10 Heteroaryl, C 5-9 Heteroaryl, C 5-8 Heteroaryl, C 5-7 Heteroaryl, C 5-6 It can be selected from heteroaryl, C5 heteroaryl, or C6 heteroaryl.

[0034] Examples of suitable heteroaryl groups are acridine, arsindole, carbazole, α- Included are groups derived from carboline, chroman, 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 a C5 heteroaryl and can be selected from furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, or isoxazolyl. Heteroaryl can be a C6 heteroaryl and can be selected from pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl.

[0035] "Heteroarylalkyl" means that one of the carbon atoms (and certain attached hydrogen atoms) is It represents an arylalkyl group substituted with a heteroatom. Heteroarylalkyl groups include, for example, C 6-16 Heteroarylalkyl, C 6-14 Heteroarylalkyl, C 6-12 Hetero ant C 6-10 Heteroarylalkyl, C 6-8 Heteroarylalkyl, C7 heteroaryl In the heteroarylalkyl, the heteroatom group can be selected from, for example, -O-, -S-, -NH-, -N(-CH3)-, -SO-, and -SO2-, or the heteroatom group can be selected from -O- and -NH-, or Alternatively, the heteroatom group may be -O- or -NH-.

[0036] "Heterocycloalkyl" by itself or as part of another substituent means a heterocyclic group having a carbon atom ( and certain associated hydrogen atoms) are independently replaced with the same or different heteroatoms; or a parent aromatic ring system in which one or more of the carbon atoms (and certain associated hydrogen atoms) are independently replaced with the same or different heteroatoms such that the ring system violates Hückel's rule. Examples of heterocycloalkyl groups 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 can be C5 heterocycloalkyls and can be selected from pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, dioxolanyl, and dithiolanyl. Heterocycloalkyls can be C6 heterocycloalkyls and can be selected from piperidinyl, tetrahydropyranyl, oxazinyl, dithianyl, and dioxanyl. Heterocycloalkyl groups can be C 3-6 Heterocycloalkyl, C 3-5 Heterocycloalkyl, C 5-6 It may be a heterocycloalkyl, a C5 heterocycloalkyl, or a C6 heterocycloalkyl. In the heterocycloalkyl, the heteroatom groups can be selected from -O-, -S-, -NH-, -N(-CH3)-, -SO-, and -SO2-, or the heteroatom groups can be selected from -O- and -NH-, or The heteroatom group may be -O- or -NH-.

[0037] "Heterocycloalkylalkyl" means a heterocyclic group consisting of a carbon atom (and certain Heterocycloalkylalkyl is, for example, C 4-12 F Tetracycloalkylalkyl, C 4-10 Heterocycloalkylalkyl, C 4-8 Heterocyclo Alkyl alkyl, C 4-6 Heterocycloalkylalkyl, C 6-7 Heterocycloalkyl In heterocycloalkylalkyl, the heteroatom can be selected from -O-, -S-, -NH-, -N(-CH3)-, -SO-, and -SO2-, or the heteroatom can be selected from -O- and -NH-, or the heteroatom can be -O- or -NH-.

[0038] "Parent aromatic ring system" means a ring having a cyclic conjugated π-electron system containing 4n+2 electrons (Hückel's rule). represents an unsaturated cyclic or polycyclic ring system in which one or more of the rings is aromatic and one or more of the rings is saturated or unsaturated (e.g., fluorene, indane, indene, or phenalene, etc.) are included within the definition of "parent aromatic ring system." 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, o Examples include ctacene, octaphene, octalene, ovalene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene.

[0039] "Hydrate" means a compound in which water is incorporated into the crystal lattice in stoichiometric proportions (hence the adduct The hydrates are formed by, for example, using a solvent containing water vapor. storage in an atmosphere containing water; dosage forms containing water; or normal pharmaceutical processing steps (e.g., water or aqueous mixtures) These include crystallization from a solvent, freeze-drying, wet granulation, aqueous film coating, or spray drying. Hydrates can also be produced under certain circumstances by exposing crystalline solvates to water vapor or by suspending anhydrous materials in water. Hydrates can also crystallize in more than one form, resulting in hydrate polymorphism. The compound may be, for example, a monohydrate, a dihydrate, or a trihydrate.

[0040] "Metabolic intermediate" refers to a compound that is formed in vivo by metabolism of a parent compound and that undergoes further reactions in vivo to release an active drug. Compounds of formula (1) are the protected sulfonate nucleophile precursors of the non-β-lactam β-lactamase inhibitor avibactam. It is a prodrug that is metabolized in vivo to yield avibactam ([2S,5R]-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate). The metabolic intermediate undergoes a nucleophilic cyclization reaction to release avibactam and one or more reaction products. It is desirable that the compound or its metabolites are non-toxic.

[0041] "Neopentyl" means that the methylene carbon is bonded to a carbon atom, and there are three carbon atoms. represents a group in the form of a group bonded to a non-hydrogen substituent of the formula: 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 can be carbon, and the third non-hydrogen substituent can be oxygen and nitrogen. The neopentyl group has the chemical structure:

[0042] [ka]

[0043] (In the formula, each R 1 and R can be defined in the same way as in formula (1). "Parent aromatic ring system" refers to an unsaturated cyclic or polycyclic ring system having a conjugated pi-electron system. It includes fused ring systems (e.g., fused rings) in which one or more of the rings is aromatic and one or more of the rings is saturated or unsaturated. fluorene, indane, indene, or phenalene) are within the definition of "parent aromatic ring system." Examples of parent aromatic ring systems are aceanthrylene, acenaphthylene, acephenanthylene, Phenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene acene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenane Examples of such alkylenes include pyrene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene.

[0044] A "parent heteroaromatic ring system" is a heteroaromatic ring system in which one or more of the carbon atoms (and any associated hydrogen atoms) The number of π electrons (4n+2) corresponding to the continuous π electron system and Hückel's rule is "Aromatic ring systems" refers to aromatic ring systems that are independently replaced by the same or different heteroatoms, so long as the rings retain their aromaticity. Examples of heteroatoms replacing carbon atoms include N, P, O, S, and Si. Fused ring systems (e.g., fused ring systems) in which one or more of the rings is aromatic and one or more of the rings is saturated or unsaturated are also included. Heteroaromatic ring systems such as arsindoles, benzodioxanes, benzofurans, chromans, indoles, indolines, and xanthenes are included within the definition of "parent heteroaromatic ring system." Examples of aromatic ring systems include arsindoles, carbazoles, β-carbolines, chromans, Examples of such an alkyl group include 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.

[0045] "Patient" refers to a mammal (e.g., a human). "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the federal or state government, or listed in the United States Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more specifically, in humans.

[0046] "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 one or more protonatable functional groups (e.g., primary amine, secondary amine, or tertiary amine) in the parent compound and an inorganic acid. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Salts may be prepared from 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, glucoheptanoic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid Salts can be formed using organic acids such as hydroxybenzoates, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. Salts are formed by replacing one or more acidic protons present in the parent compound with a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion, an aluminum ion, or a combination thereof). or when coordinated with organic bases such as ethanolamine, diethanolamine, triethanolamine, and N-methylglucamine. The pharmaceutically acceptable salt may be a hydrochloride salt. The pharmaceutically acceptable salt may be a sodium salt. In compounds with two or more ionizable groups, the pharmaceutically acceptable salt may be a sodium salt. The salt may contain one or more counterions, such as a bi-salt (eg, dihydrochloride).

[0047] "Pharmaceutically acceptable salts" includes hydrates, other solvates, and salts in crystalline or amorphous form. Where a particular pharmaceutically acceptable salt is disclosed, the particular salt, such as the hydrochloride salt, is one example of a salt, and other salts may be prepared using techniques known to those skilled in the art. Additionally, it should be understood that one of ordinary skill in the art can convert pharmaceutically acceptable salts into the corresponding compounds, free bases, and / or free acids using techniques commonly known in the art. Pharmaceutically acceptable salts may include pharmaceutically acceptable esters.

[0048] "Pharmaceutically acceptable vehicle" refers to a pharmaceutically acceptable diluent, pharmaceutically acceptable adjuvant, pharmaceutically acceptable excipient, pharmaceutically acceptable carrier, or any combination of the foregoing, that may be administered to a patient, together with a compound of the invention, which does not impair the pharmacological activity of the compound of the invention and which is non-toxic when administered in a dosage sufficient to provide a therapeutically effective amount of the compound.

[0049] "Pharmaceutical composition" refers to amoxicillin 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 that is administered to a patient together with amoxicillin or a pharmaceutically acceptable salt thereof, and / or an avibactam derivative of formula (1) or a pharmaceutically acceptable salt thereof. The present invention relates to a composition comprising:

[0050] "Preventing" or "prevention" refers to reducing the risk of acquiring a disease or disorder (i.e., preventing a person from becoming susceptible to the disease but still developing it). In patients who have not previously shown symptoms of the disease, at least one of the clinical symptoms of the disease is manifested. "Preventing" or "prevention" refers to taking a compound of the present invention in a prophylactic manner. The administration of a therapeutic agent to prevent a disease or disorder is known as prophylaxis.

[0051] "Prodrug" refers to a derivative of a drug molecule that requires a transformation within the body to release the active drug. Prodrugs are often, but not necessarily, pharmacologically inactive until converted to the parent drug. Avibactam derivatives of formula (1) are It is a prodrug of Tam.

[0052] "Promoiety" means a compound that is attached via a bond that is cleavable under specific conditions of use. The promoiety represents a group attached to a drug (typically to a functional group on the drug) via enzymatic or non-enzymatic methods. For example, under specific conditions of use, after administration to a patient, the bond between the drug and the promoiety can be cleaved to release the parent drug. Cleavage of the promoiety can proceed spontaneously, for example, via a hydrolysis reaction, or can be catalyzed or induced by another agent (e.g., an enzyme), by light, by acid, or by exposure to a physical or environmental parameter (e.g., a change in temperature or pH). The drug can be endogenous to the condition of use (e.g., present in the systemic circulation of the patient to whom the prodrug is administered). The promoiety can be supplied exogenously (enzymes, acidic conditions in the stomach, etc.). For example, in the case of the avibactam derivative of formula (1), the promoiety has the chemical structure

[0053] [ka]

[0054] (In the formula, R 1 , R 2 , and R 3 is as defined with respect to formula (1). "R 2 The "single bond" in the expression "is selected from single bonds" means that R 2 is a single bond (-) For example, R 2 Structure -C(R1 )2-R 2 -R 3 Moi with In eti, -R 2 - corresponds to a single bond "-", and the moiety has the structure -C(R 1 )2-R 3 It has.

[0055] A "solvate" is a mixture of a compound with one or more solvent molecules in either a stoichiometric or non-stoichiometric amount. These solvent molecules are those commonly used in the pharmaceutical industry and are known to be harmless to patients (e.g., water and ethanol). Molecular complexes between a compound or a moiety of a compound and a solvent are formed by non-covalent bonds. The term "hydrate" refers to a solvate in which one or more of the solvent molecules is water. Methods for producing solvates include, for example, storage in an atmosphere containing a solvent, a dosage form containing a solvent, or conventional pharmaceutical processing steps (e.g., crystallization (i.e., removal of a solvent or mixed solution)). Solvates can also be formed by other crystalline solvates or crystals. Crystalline hydrates can be produced under certain circumstances by exposure to or suspension in a solvent. Solvates may crystallize in more than one form, resulting in solvate polymorphs. There is a saying.

[0056] "Substituted" refers to a group in which one or more hydrogen atoms are independently replaced with the same or different substituents. Each substituent may be deuterium, halogen, -OH, -CN, -CF3, -OCF3, =O, -NO2, C 1-6 Alkoxy, C 1-6 Alkyl, -COOR, -NR2, and -CONR2 (where each R is hydrogen and C 1-6 Each of the alkyl groups may be independently selected from the group consisting of aryl, aryl(s), ... Substituents include deuterium, halogen, -NH2, -OH, C 1-3 Alkoxy, and C 1-3 Alkyl, Tri Each substituent can be independently selected from, for example, deuterium, —OH, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, and trifluoromethoxy. Each substituent can be independently selected from, for example, deuterium, —OH, C 1-3 Alkyl, =O, C 1-3 Alkyl, C 1-3 alkoxy, and phenyl. Each substituent can be, for example, deuterium, -OH, -NH2, C 1-3 Alkyl, and C 1-3 Arco You can choose from Kishi.

[0057] "Treating" a disease or "treatment" of a disease means preventing or ameliorating at least one clinical symptom of the disease or disorder, reducing the risk of suffering from at least one of the clinical symptoms of a disease or a clinical symptom of a disease "Treating" or "treatment" also refers to slowing the progression of at least one of the symptoms of a disease, or reducing the risk of developing a disease or at least one of the clinical symptoms of a disease. "Treating" or "treatment" also refers to alleviating one or more symptoms resulting from a disease; reducing the severity of a disease; stabilizing a disease. To improve the condition of a patient (e.g., to prevent or slow the progression of a disease, to prevent or slow the spread of a disease, to prevent or slow the recurrence of a disease, to slow or slow the progression of a disease, to improve the condition of a patient, to bring about remission of a disease (whether partial or total), reducing the dose of one or more other medications needed to treat the disease; slowing the progression of the disease; improving quality of life; and / or prolonging survival.

[0058] "Treating" or "treatment" also refers to the physical suppression of a disease (e.g., and / or at least one physical parameter or symptom that is perceived by the patient. "To treat" refers to the suppression of symptoms, which may or may not be discernible. "Treatment" also refers to the treatment of a disease or at least one disorder in a patient who is predisposed to the disease or disorder, even if the patient does not yet show symptoms of the disease. This means delaying the onset of the above symptoms.

[0059] A "therapeutically effective amount" is an amount administered to a patient to treat a disease or at least one clinical symptom of a disease. "Therapeutically effective amount" refers to an amount of a compound sufficient to affect treatment of a disease or its symptoms when administered to a subject. A "therapeutically effective amount" can vary depending, for example, on the type of 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 being treated; and the judgment of the prescribing physician. The appropriate amount in any given case can be ascertained by one of ordinary skill in the art or can be determined by routine experimentation.

[0060] A "therapeutically effective dose" refers to a dose that provides effective treatment for a patient's disease or disorder. Therapeutically effective doses may vary depending on the compound, the type of patient, and 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.

[0061] "Therapeutically effective amount" means the amount of a compound that, when administered to a patient for treating a disease, is sufficient to treat the disease. The "therapeutically effective amount" will vary depending, for example, on the type of compound; the type of disease and its severity; and the age, weight, absorption, distribution, metabolism, and excretion of the patient to be treated. With respect to bacterial infections, a therapeutically effective amount is sufficient to reduce the total number of bacteria present in the patient's body and / or slow the rate of bacterial growth. A therapeutically effective amount may comprise an amount sufficient to prevent or slow the progression of a bacterial infection. A therapeutically effective amount may be an amount sufficient to prevent or slow the recurrence of a bacterial infection. A therapeutically effective amount may reduce the number of bacterial cells; may prevent or delay the onset and / or recurrence of a bacterial infection; and / or may alleviate to some extent one or more of the symptoms associated with a bacterial infection. do.

[0062] "Concurrent administration" means that the first and second administrations in a combination therapy are administered less than 30 minutes apart (e.g., for example, less than 15 minutes, less than 10 minutes, less than 5 minutes, or less than 1 minute For example, two therapeutically active compounds can be administered simultaneously in a single dosage form or in two separate dosage forms.

[0063] "Sequential administration" refers to a first administration and a second administration that are separated by, for example, more than 30 minutes, more than 60 minutes, or more than 120 minutes. For example, two therapeutically active compounds can be administered sequentially in two separate dosage forms.

[0064] "Vehicle" refers to a diluent, excipient, or carrier with which a compound is administered to a patient. In some embodiments, the vehicle is pharmaceutically acceptable. "MIC" refers to the minimum inhibitory concentration of an antimicrobial agent that inhibits the growth (e.g., visible growth) of a microorganism after a specified period of incubation (e.g., after overnight incubation). 90 and MIC 50 is the resistance of bacterial isolates to specific antimicrobial agents or combinations of antimicrobial agents. MIC is a metric used to assess the in vitro susceptibility of a cohort of strains using a test method. 90 Value and MIC 50 The values ​​represent the minimum antibiotic concentration at which the growth of 90% and 50% of the isolates was inhibited, respectively. MIC 90 The MIC can be defined as the lowest concentration of antibiotic at which the growth of 90% of microbial isolates is inhibited after overnight incubation. 50 can be defined as the minimum concentration of antibiotic at which the growth of 50% of microbial isolates is inhibited after overnight (e.g., 12 hours) incubation.

[0065] "Pharmacokinetics" (PK) refers to the time course of drug concentration in plasma resulting from a particular dosing regimen. "Pharmacodynamics" (PD) describes the relationship between plasma drug concentrations and resulting pharmacological effects. represent.

[0066] The "PK / PD index" for antimicrobial agents is a pharmacodynamic parameter expressed as bacteriostatic activity. is a metric (e.g., 1-log kill or 2-log kill) and is measured against the MIC of a given bacterial isolate. These are linked to pharmacokinetics to construct a well-defined exposure-response relationship (PK / PD). The most common PK / PD metrics related to efficacy are the area under the concentration-time curve (AUC) to MIC ratio (AUC:MIC), peak concentration (C max ) to MIC ratio (C max MIC), when drug concentrations exceed the MIC over the dosing interval. The proportion of time that the drug concentration exceeds the concentration threshold (T > MIC), and the proportion of time that the drug concentration exceeds the concentration threshold (T > C t ) is free To represent the bound, unbound, or microbiologically active drug, the PK / PD index is fAUC:MIC, fC max :MIC, and fT>Ct.

[0067] Certain embodiments of the compounds, compositions, and methods are now described in detail. 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, improvements, and equivalents.

[0068] The pharmaceutical compositions provided by the present invention comprise amoxicillin and avibactam derivatives that, upon oral administration, provide therapeutically effective amounts of amoxicillin and avibactam in the plasma of a patient for treating bacterial infections, such as mycobacterial infections.

[0069] Methods provided by the present invention include a method of treating a mycobacterial infection in a patient comprising orally administering to a patient in need of treatment therapeutically effective amounts of amoxicillin or a pharmaceutically acceptable salt thereof and an avibactam derivative or a pharmaceutically acceptable salt thereof.

[0070] The susceptibility of mycobacteria such as M. abscessus and M. ulcerans to amoxicillin is It is significantly lower in the absence of β-lactamase inhibitors. Dubee et al., J Antimicrob Chemother.2015 70:1051-8;Arenaz-Callao et al., PLoS Negl Trop Dis.2019. 13:e0007126. However, avibactam enhances the efficacy of amoxicillin and, using in vitro methods, This reduces the MIC to 8 μg / ml to 16 μg / ml or lower. These susceptibility methods are not optimized, and if improved methods are found, even lower MIC values ​​may be obtained. If [free drug time] > MIC, amoxicillin and other β-lactam antibiotics Generally, the percentage of time above the MIC is increased depending on the bacterial species and The required concentration is approximately 30% to 6%, depending on the type of beta-lactam antibiotic. de Velde et al. have shown that a dosing regimen of amoxicillin at a concentration of 500 mg to 1000 mg can achieve sustained blood levels higher than the MIC of 8 μg / ml between dosing intervals. de Velde, J Antimicrob Chemother. 2016. 71:2909-17. Studies have shown that amoxicillin is effective against other non-mycobacterial pathogens. The breakpoint for susceptibility to amoxicillin against the body is 8 μg / ml, and the intermediate strain In the case of 16μg / ml. and Laboratory Standard Institute(CLSI),2019. Performance Standards for Antimicrobial Susceptibility Testing-Twenty-Ninth Informational Supplement.CLSI Document M100S;PA,USA.

[0071] These findings suggest that a treatment based on oral amoxicillin and oral avibactam prodrugs is feasible. This treatment should deliver sustained levels of amoxicillin over a period of time to eliminate infection with strains with MICs of 8 μg / ml to 16 μg / ml or lower (in vitro methods for determining MICs have not yet been developed, so values ​​may be even lower). This dosing regimen may require frequent oral administration for up to 6 hours. MICs in this range are sufficient for mycobacterial infection. These values ​​are similar to those used for cefoxitin and imipenem in the treatment of HIV infection, and if If the MIC of amoxicillin is equivalent, avibactam can be delivered orally in the form of a prodrug. These findings suggest that, in combination with the use of oral amoxicillin, it should be possible to design an effective oral amoxicillin treatment regimen for treating mycobacterial infections. For mycobacterial infections and amoxicillin, the values ​​of % free concentration associated with efficacy are unknown. Although no data have been published, it can be predicted that for MICs in the range of 8 μg / ml to 16 μg / ml or lower, dosing regimens of 500 mg, 875 mg, or 1000 mg amoxicillin q6h, q8h, or q12h will be effective and capable of eliminating infection. The MICs of amoxicillin for mycobacteria can be quite high (Dubee et al. al., J Antimicrob Chemother. 2015 70:1051-8), oral delivery of avibactam should effectively enhance the efficacy of orally administered amoxicillin, which is well suited for long-term treatment based on the drug's safety.

[0072] Amoxicillin is a class of beta-lactam antibiotics. Amoxicillin, (1S,4S,7S)-7-((R)-2-amino-2-(4-hydroxyphenyl)acetamido)-3,3-dimethyl-2-thia-6-azabicyclo[3.2.0]heptane-4-carboxylic acid, has the following structure:

[0073] [ka]

[0074] It has. β-lactams bind to penicillin-binding proteins, inhibiting a process called transpeptidation. They act by binding to the substrate, which results in the activation of autolytic enzymes in the bacterial cell wall. This process causes the cell wall to lyse, thus destroying the bacterial cell. This type of action is called bactericidal.

[0075] Amoxicillin is effective against gram-positive and gram-negative bacteria, including most Streptococcus species, including Listeria monocytogenes, Enterococcus, Haemophilus, some Escherichia coli, Actinomyces, Clostridial species, Salmonella, Shigella, and Corynebacteria. It is used to treat infections caused by bacteria.

[0076] Amoxicillin is approved by the FDA for the treatment of urogenital tract infections, ear infections, nasal infections, throat infections, lower respiratory tract infections, Helicobacter pylori infection, pharyngitis, tonsillitis, skin infections, and skin and structure infections. Amoxicillin is approved by the Infectious Diseases Society of America (IDSA) As a first-line treatment for more acute bacterial sinusitis and as a treatment for community-acquired pneumonia It is recommended as one of the

[0077] Amoxicillin is often used in combination with β-lactamase inhibitors such as clavulanic acid and sulbactam. These β-lactamase inhibitors can be administered in combination with the It functions by irreversibly binding to the catalytic site of the β-lactam enzyme, which binds to the parent β-lactam ring. These drugs, in combination with amoxicillin (a β-lactamase inhibitor), When combined, they can extend the spectrum of amoxicillin's activity against organisms that produce the penicillinase enzyme.

[0078] The avibactam derivatives provided by the present invention are sulfonate ester prodrugs of the non-β-lactam β-lactamase inhibitor avibactam ([2S,5R]-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate; (1R,2R,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate), and avibactam has the following structure:

[0079] [ka]

[0080] It has. Avibactam derivatives that result in bioavailability of avibactam in the systemic circulation of a patient after oral administration are disclosed in US Pat. No. 10,085,999.

[0081] In avibactam prodrugs, the nucleophilic moiety is located closest to the hydrogen sulfate group. In vivo, the nucleophilic moiety reacts to release avibactam. Avibactam is an inhibitor of class A β-lactamases, class C β-lactamases, and certain class D β-lactamases, and may be useful in the treatment of bacterial infections when used in combination with amoxicillin.

[0082] Avibactam derivatives have the formula (1):

[0083] [ka]

[0084] or a pharmaceutically acceptable salt thereof, wherein Each R 1 is C 1-6 alkyl, or each R 1 and the geminal carbon atom to which they are bonded are 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 arenediyl, and substituted C 5-6 Selected from heteroarenediyl; 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 5-6Heterocycloalkyl, 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; where 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 substitution 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, exchange C 1-6 Alkyl, substituted C 5-8 Cycloalkyl, substituted C 6-12 Cycloalkylalkyl, substituted C 2-6Heteroalkyl, substituted C 5-8 Heterocycloalkyl, and substituted C 6-12 heterocycloalkyl; and 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, exchange 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.

[0085] The compound of formula (1) has the formula (1a):

[0086] [ka]

[0087] It may have the stereochemistry: In the compound of formula (1), each R 1 is independently C 1-6 It may be alkyl. In the compound of formula (1), each R 1 are independently methyl, ethyl, or n-propyl; good.

[0088] In the compound of formula (1), each R 1 may be the same and may be methyl, ethyl, or n-propyl. It may be. In the compound of formula (1), each R 1 is methyl.

[0089] In the compound of formula (1), each R 1 and the geminal carbon atoms to which they are bonded Become, C 3-6 Cycloalkyl ring or substituted C 3-6 A cycloalkyl ring may be formed. In the compound of formula (1), each R 1 and the geminal carbon atoms to which they are bonded Become, C 3-6 For example, each R 1 and the geminal carbon atom to which they are attached may together form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl ring.

[0090] In the compound of formula (1), each R 1 and the geminal carbon atoms to which they are bonded Become, C 3-6 Heterocycloalkyl ring or substituted C 3-6 It may form a heterocycloalkyl ring.

[0091] In the compound of formula (1), R 2 is a single bond, C 1-2 Alkanediyl and substituted C 1-2 Arca You can choose from a variety of options. In the compound of formula (1), R 2 may be a single bond.

[0092] In the compound of formula (1), R 2 is a single bond, and R 3 C 1-6 It may be alkyl. In the compound of formula (1), R 2 is C 1-2 Alkanediyl and Substituted C 1-2 Alkandiyl? You can choose from:

[0093] In the compound of formula (1), R 2is methanediyl, ethanediyl, substituted methanediyl, or or substituted ethanediyl. In the compound of formula (1), R 2 is a substitution C 1-2 alkanediyl, where 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 Selected from alkyl do.

[0094] In the compound of formula (1), R 2 is a substitution C 1-2 alkanediyl, where the substituents are For example, R 2 is a substitution C 1-2 alkanediyl, where the substituents are -OH, -CF3, -OCF3, =O, -NO2, -OC(O)-R 4 , -SC(O)-R 4 , -NH-C(O)-R 4 , -OC(O)-R 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 ) can be selected, where each R 4 is as defined for equation (1), or each R 4 teeth Hydrogen and C 1-8 is selected from alkyl.

[0095] In the compound of formula (1), R 2 is a substitution C 1-2 alkanediyl, where the substituents are , -OH, -OC(O)-R 4 , -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 , and -CH(-NH2)(-R 4 ) and each R 4 is as defined for equation (1), or each R 4 is hydrogen and C 1-8 is selected from alkyl.

[0096] In the compound of formula (1), R 2 But substitution C 1-6 Alkanediyl, substituted C 1-6 Heteroalkanedi ile, or replacement C 5-6 When it is an arenediyl, the stereochemistry of the carbon atom to which the substituent is attached may be in the (S) configuration.

[0097] In the compound of formula (1), R 2 But substitution C 1-6 Alkanediyl, substituted C 1-6 Heteroalkanedi ile, or replacement C 5-6 When it is an arenediyl, the stereochemistry of the carbon atom to which the substituent is attached may be in the (R) configuration.

[0098] In the compound of formula (1), R 2 is C 5-6 Cycloalkanediyl, C 5-6Heterocycloalkane Njiil, C 5-6 Arendjiil, and C 5-6 Heterocycloalkanediyl is selected from. In the compound of formula (1), R 2 may be cyclopenta-1,3-diene-diyl, substituted cyclopenta-1,3-diene-diyl, benzene-diyl, or substituted benzene-diyl. Ba, R 2 may be 1,2-benzene-diyl or substituted 1,2-benzene-diyl.

[0099] In the compound of formula (1), R 3 is -OC(O)-R 4 , -SC(O)-R 4 , -NH-C(O)-R 4 , -OC(O)-R 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 ) You can do this here 4 is as defined for equation (1), or each R 4 is hydrogen and C 1-8 is selected from alkyl.

[0100] 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 , -SSR4 , -NH-R 4 , and -CH(-NH2)(-R 4 ) where R 4 is in terms of equation (1) as defined, or each R 4 is hydrogen and C 1-8 is selected from alkyl.

[0101] In the compound of formula (1), R 3 Ha-OC(O)-R 4 where R 4 is as defined for equation (1), or R 4 is hydrogen and C 1-8 is selected from alkyl. In the compound of formula (1), R 4 is hydrogen, C 1-3 Alkyl, C 5-6 Cycloalkyl, C 5-6 Haitai Cycloalkyl, 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 can be selected from aryl.

[0102] In the compound of formula (1), R 4 is selected from methyl, ethyl, phenyl, and benzyl It is possible. In the compound of formula (1), R 4 is hydrogen and C 1-8 It can be selected from alkyl.

[0103] In the compound of formula (1), R 4 is C 1-8 Alkyl, C 1-8 Heteroalkyl, C 7-9 Arirua Lukil, C 5-7 Heterocycloalkyl, substituted C 1-8 Alkyl, substituted C 1-8 Heteroalkyl, substituted C7-9 Aryl alkyl, and substituted C 5-7 It can be selected from heterocycloalkyl.

[0104] In the compound of formula (1), R 4 is C 1-8 Alkyl, C 1-8 Heteroalkyl, C 7-9 Arirua Lukil, and C 5-7 It can be selected from heterocycloalkyl. In the compound of formula (1), R 4 is methyl, ethyl, n-propyl, isopropyl, n-butyl butyl, sec-butyl, isobutyl, tert-butyl, 2-methoxyethyl, methylbenzene, oxalyl It can be selected from cetane-3-oxy-yl, cyclopentyl, cyclohexyl, and 2-pyrrolidinyl.

[0105] In the compound of formula (1), R 3 -C(O)-OR 4 R 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 substituted C 7-9 It can be selected from arylalkyl.

[0106] In the compound of formula (1), R 3 -C(O)-OR 4 R 4 is C 1-8 Alkyl, C 1-8 Heteroalkyl, C 7-9 Aryl alkyl, C 5-7Heterocycloalkyl, substituted C 1-8 Alkyl, substituted C 1-8 Heteroalkyl, substituted C 7-9 Aryl alkyl, and substituted C 5-7 It can be selected from heterocycloalkyl.

[0107] In the compound of formula (1), R 3 -C(O)-OR 4 R 4 is C 1-8 Alkyl, C 1-8 Heteroalkyl, C 7-9 Aryl alkyl, and C 5-7 It can be selected from heterocycloalkyl.

[0108] In the compound of formula (1), R 3 are -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 nyl, -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)-S-CH3, -C(O)-S-CH2-CH3, -C(O)-S-phenyl, -C(O)-S-CH2-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, -OC(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). You can choose from:

[0109] In the compound of formula (1), R 3 comprises at least one nucleophilic group, C 5-6 Cycloalkyl, C 5-6 Heterocycloalkyl, C 5-6 Aryl, C5-6 Heteroaryl, substituted C 5-6 Cycloalkyl, substituted C 5-6 Heterocycloalkyl, substituted C 5-6 Aryl and substituted C 5-6 Heteroaryl can be selected from, for example, R 3 has a structure of formula (2a) or formula (2b):

[0110] [ka]

[0111] may have In the compound of formula (1), R 4 is C 1-3 Alkyl, C 5-6 Cycloalklyl, C 5-6 Heterothymic Roalkyl, C 5-6 Aryl, substituted C 1-3 Alkyl, substituted C 5-6 Cycloalkane, substituted C 5-6 Heterocycloalkyl, and substituted C 5-6 It can be selected from aryl.

[0112] In the compound of formula (1), each R 1 and the carbon atoms to which they are attached form a C containing two adjacent S atoms. 4-6 heterocycloalkyl ring, or at least one selected from O and S Substituted C groups containing one heteroatom and a carbonyl (=O) substituent bonded to a carbon atom adjacent to at least one heteroatom. 4-6 Forms a heterocycloalkyl ring.

[0113] In the compound of formula (1), R 2 may be a direct bond; R 3 is C 1-3 may be alkyl; And each R 1 and the carbon atoms to which they are attached form a C containing two adjacent S atoms. 4-6Heterocycloalkyl ring or at least one heteroatom selected from O and S and a substituted C containing an =O substituent attached to the carbon atom adjacent to the heteroatom. 4-6 Forms a heterocycloalkyl ring.

[0114] In the compound of formula (1), the moiety -CH2-C(R 1 )2-R 3 -R 4 has the following structure:

[0115] [ka]

[0116] [ka]

[0117] where R 3 is C 1-6 Alkyl (e.g., C 1-4 Alkyl (e.g. , methyl or ethyl). In the compound of formula (1), R 2 may be a single bond; R 3 is C 1-3 It may be alkyl; And each R 1 and the carbon atoms to which they are attached form C 4-6 Heterocycloalkyl ring or substituted C 4-6 It may form a heterocycloalkyl ring.

[0118] In the compound of formula (1), R 2 may be a single bond; R 3 is C 1-3 It may be alkyl; And each R 1 and the carbon atoms to which they are attached form a C with two adjacent S atoms. 4-6a heterocycloalkyl ring or at least one heteroatom selected from O and S, and Substituted C containing a carbonyl (=O) substituent attached to the carbon atom adjacent to the heteroatom 4-6 Haitai It may form a cycloalkyl ring.

[0119] In the compound of formula (1), R 2 may be a single bond; R 3 is C 1-3 It may be alkyl; And each R 1 and the carbon atoms to which they are attached together form a 1,2-dithiolane, 1,2-dithane ring, thietan-2-one ring, dihydrothiophen-2(3H)-one ring, tetrahydro-2H-thiopyran-2-one ring, oxetan-2-one ring, dihydrofuran-2(3H)-one ring, or tetrahydro-2H-thiopyran-2-one ring. A hydro-2H-pyran-2-one ring may be formed.

[0120] In the compound of formula (1), Each R 1 may be methyl; R 2 is a single bond, methanediyl, ethanediyl, -CH(-OH)-, -CH(-OC(O)-CH2CH3)-, and and 1,2-benzenediyl; and 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 ) where R 4 can be selected from hydrogen, methyl, ethyl, cyclopentyl, cyclohexyl, phenyl, benzyl, and 2-pyrrolidinyl.

[0121] In the compound of formula (1), Each R 1 and the geminal carbon to which they are bonded are C 3-6 may form a cycloalkyl; R 2 is a direct bond, methanediyl, ethanediyl, -CH(-OH)-, -CH(-OC(O)-CH2CH3)-, and and 1,2-benzenediyl; and 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 ) where R 4 can be selected from hydrogen, methyl, ethyl, cyclopentyl, cyclohexyl, phenyl, benzyl, and 2-pyrrolidinyl.

[0122] In the compound of formula (1), R 2 may be a direct bond; R 3 is C 1-3 is alkyl; and Each R 1 and the carbon atoms to which they are attached together form a 1,2-dithiolane, 1,2-dithane ring, thietan-2-one ring, dihydrothiophen-2(3H)-one ring, tetrahydro-2H-thiopyran-2-one ring, oxetan-2-one ring, dihydrofuran-2(3H)-one ring, or tetrahydro A rh-2H-pyran-2-one ring may be formed.

[0123] In the compound of formula (1), each R 1 may be methyl; R 2 is a single bond, methanediyl, ethanediyl, -CH(-OH)-, -CH(-OC(O)-CH2CH3)-, and and 1,2-benzenediyl; and 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 ) where R 4 is C 1-8 Alkyl, C 1-8 Heteroalkyl, C 7-9 Aryl alkyl, and C 5-7 It can be selected from heterocycloalkyl.

[0124] In the compound of formula (1), Each R 1 may be methyl; R 2 is a single bond, methanediyl, ethanediyl, -CH(-OH)-, -CH(-OC(O)-CH2CH3)-, and and 1,2-benzenediyl; and R 3 -C(O)-OR 4 where R 4 is C 1-8 Alkyl, C 1-8 Heteroalkyl, C 7-9 Aryl alkyl, and C 5-7 It can be selected from heterocycloalkyl.

[0125] In the compound of formula (1), Each R 1 may be methyl; R 2 is a single bond, methanediyl, ethanediyl, -CH(-OH)-, -CH(-OC(O)-CH2CH3)-, and and 1,2-benzenediyl; and 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 ) where R 4 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2-methoxyethyl, methylbenzene It can be selected from zene, oxetan-3-oxy-yl, cyclopentyl, cyclohexyl, and 2-pyrrolidinyl.

[0126] In the compound of formula (1), Each R 1 may be methyl; R 2 is a single bond, methanediyl, ethanediyl, -CH(-OH)-, -CH(-OC(O)-CH2CH3)-, and and 1,2-benzenediyl; and R 3 is -C(O)-OR 4 where R 4 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2-methoxyethyl, methylbenzene It can be selected from zene, oxetan-3-oxy-yl, cyclopentyl, cyclohexyl, and 2-pyrrolidinyl.

[0127] In the compound of formula (1), Each R 1 may be methyl; R 2 can be a single bond; and R 3 -C(O)-OR 4 where R 4 is C 1-10 Alkyl, C 1-10 Heteroalkyl, C 7-10 Alkyl arenes, and C5-10 Heterocycloalkyl can be selected from:

[0128] In the compound of formula (1), Each R 1 may be methyl; R 2 can be a single bond; and R 3 -C(O)-OR 4 where R 4 is C 1-10 Alkyl, C 1-10 Heteroalkyl, C 7-10 Alkyl arenes, and C 5-10 heterocycloalkylalkyl; R 5 , R 6 , and R 7 may each be hydrogen.

[0129] In the compound of formula (1), the compound is 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl) (2)-(2,2-dimethylpropyl)sulfonyl)oxy)-2,2-dimethylpropylbenzoate (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) (I)oxy)sulfonyl)oxy)-3,3-dimethylbutylbenzoate (6); 4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl) (I)oxy)sulfonyl)oxy)-3,3-dimethylbutylpropionate (7); Benzyl (4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octyl) Tan-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]octadecanoate benzo-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]o 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]octadecanoate (6-phenyl)oxy)sulfonyl)oxy)methyl)cyclohexanecarboxylate (17); Ethyl 1-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octadecanoate (6-methyl-6-yl)oxy)sulfonyl)oxy)methyl)cyclopropanecarboxylate (18); Ethyl 1-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octadecanoate Benzene-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) (I)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) (40) 2,2,4,4-tetramethylpentylbenzoate (40); 5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl) (I)oxy)sulfonyl)oxy)-2,2,4,4-tetramethylpentyl 2,6-dimethylbenzoate To(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) (43)-(2,2-dimethylpropyl)sulfonyloxy)-2,2-dimethylpropyl pivalate; 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl) (44) 3-chloro-2,6-dimethoxybenzoate; 4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl) (45) 2,2,3,3-tetramethylbutyl 2,6-dimethylbenzoate; 4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl) (46) tetramethylbutylbenzoate (46); 4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl) (47) tetramethylbutyl)sulfonyloxy)-2,2,3,3-tetramethylbutylpropionate; (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)phenyl pivalate (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) (n-1)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) (n-hydroxy)sulfonyl)oxy)-2,2-dimethylpropyl adamantane-1-carboxylate (55); Diethyl 2-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octyl) Tan-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) (I)oxy)sulfonyl)oxy)-3,3-dimethylbutyl pivalate (60); Ethyl 2-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octadecanoate benzo-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) (I)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) (n-hydroxy)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) (I)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) (4,4-dimethylpentyl)benzoate (65); 5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl) ((((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) (4,4-dimethylpentyl 2,6-dimethylbenzoate (67); 5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl) (4,4-dimethylpentyl 2-methylbenzoate (68); 4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl) (l)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)methyl)-2-methylpropane-1,3-diyl diacetate (71) (I)oxy)sulfonyl)oxy)-2,2,4,4-tetramethylpentyl 2,6-dimethoxybenzoate rt(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 pharmaceutically acceptable salt of any of the above compounds; and Any combination of the above compounds You can choose from.

[0130] 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]o 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]octadecanoate (6-phenyl)oxy)sulfonyl)oxy)methyl)cyclohexanecarboxylate (17); Ethyl 1-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octadecanoate (6-methyl-6-yl)oxy)sulfonyl)oxy)methyl)cyclopropanecarboxylate (18); Ethyl 1-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octadecanoate Benzene-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 pharmaceutically acceptable salt of any of the above compounds; and Any combination of the above compounds You can choose from.

[0131] 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]o 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]octadecanoate (6-phenyl)oxy)sulfonyl)oxy)methyl)cyclohexanecarboxylate (17); Ethyl 1-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octadecanoate (6-methyl-6-yl)oxy)sulfonyl)oxy)methyl)cyclopropanecarboxylate (18); Ethyl 1-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octadecanoate Benzene-6-yl)oxy)sulfonyl)oxy)methyl)cyclobutanecarboxylate (19); a pharmaceutically acceptable salt of any of the above compounds; and Any combination of the above compounds You can choose from.

[0132] In the compound of formula (1), the compound is 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 pharmaceutically acceptable salt of any of the above compounds; and Any combination of the above compounds You can choose from.

[0133] In the compound of formula (1), Each R 1 is C 1-3 alkyl, or each R 1 and the geminal carbon atoms to which they are bonded, form 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 -C(O)-OR 4 and 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 can be selected from heterocycloalkyl.

[0134] In the compound of formula (1), Each R 1 is C 1-3 alkyl, or each R 1 and the carbon atoms to which they are attached form C 3-6 forming a cycloalkyl ring; R 2 can be selected from a single bond, methane-diyl, and ethane-diyl; and R 3 is -C(O)-OR 4 and -SC(O)-R 4 You can choose from R 4 is C1-10 Alkyl, C 1-10 Heteroalkyl, C 5-10 Aryl alkyl, C 3-6 Heterocycloalkyl, and substituted C 4-10 Heterocycloalkyl can be selected from:

[0135] In the compound of formula (1), Each R 1 is C 1-3 alkyl, or each R 1 and the carbon atoms to which they are attached form C 3-6 forming a cycloalkyl ring; R 2 can be a single bond; and R 3 -C(O)-OR 4 where R 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 can be selected from:

[0136] In the compound of formula (1), Each R 1 is C 1-3 alkyl, or each R 1 and the carbon atoms to which they are attached form C 3-6 forming a cycloalkyl ring; R 2 may be —(CH)—; and R 3 -C(O)-OR 4 where R 4 is C 1-10 Alkyl, C 1-10 Heteroalkyl, C 5-10 Aryl alkyl, C 3-6 Heterocycloalkyl, and substituted C 4-10Heterocycloalkyl can be selected from:

[0137] In the compound of formula (1), Each R 1 is C 1-3 alkyl, or each R 1 and the carbon atoms to which they are attached form C 3-6 forming a cycloalkyl ring; R 2 can be -CH2-; and R 3 HA-SC(O)-R 4 where R 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 can be selected from:

[0138] In the compound of formula (1), Each R 1 and the carbon atoms to which they are attached form C 3-6 Cycloalkyl ring or C 3-6 forming a heterocycloalkyl ring; R 2 can be a single bond; and R 3 is C 1-3 It may be alkyl.

[0139] In the compound of formula (1), Each R 1 is C 1-3 alkyl; R 2 may be selected from a single bond and methanediyl; and R 3 is -OC(O)-R 4 and -C(O)-OR 4 You can choose from R 4 is C 1-10Alkyl and substituted Phenyl can be selected.

[0140] In the compound of formula (1), Each R 1 is C 1-3 alkyl; R 2 can be a single bond; and R 3 is -CH=C(R 4 )2, where each R 4 -C(O)-OR 8 Alternatively, each R 4 and together with the carbon atoms to which they are attached form a substituted heterocyclohexyl ring, and R 8 is C 1-4 It may be alkyl.

[0141] In the compound of formula (1), Each R 1 is C 1-3 alkyl; R 2 may be selected from a single bond and methanediyl; and R 3 may be a substituted phenyl, where one or more of the substituents is -CH-OC(O)-R 4 and -OC(O)-R 4 can be chosen independently from R 4 is C 1-10 It can be selected from alkyl and phenyl.

[0142] In the compound of formula (1), Each R 1 is C 1-3 alkyl; R 2 is -C(R 8 )2- and -CH2-C(R 8 )2-, where each R 8 is C 1-3 alkyl; and R3 is -C(O)-OR 4 and -OC(O)-R 4 You can choose from R 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.

[0143] In the compound of formula (1), each R 1 and the carbon atoms to which they are attached form exchange C 5-6 forming a heterocyclic ring; R 2 can be a single bond; and R 3 is C 1-3 It may be alkyl.

[0144] The compound of formula (1) may be a compound of subgenus (1A) or a pharmaceutically acceptable salt thereof: , where Each R 1 is C 1-3 alkyl, or each R 1 and the carbon atoms to which they are attached form C 3-6 forming a cycloalkyl ring; R 2 can be selected from a single bond, methane-diyl, and ethane-diyl; and R 3 is -C(O)-OR 4 and -SC(O)-R 4 You can choose from R 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 can be selected from:

[0145] In compounds of subgenus (1A), each R is C 1-3 alkyl. In the compounds of subgenus (1A), each R 1 and the carbon atoms to which they are attached form C 3-6 Forms a cycloalkyl ring.

[0146] In the compounds of subgenus (1A), R 2 may be a single bond. In the compounds of subgenus (1A), R 2 may be methane-diyl. In the compounds of subgenus (1A), R 2 may be ethane-diyl.

[0147] In the compounds of subgenus (1A), R 3 -C(O)-OR 4 It may be. In the compounds of subgenus (1A), R 3 HA-SC(O)-R 4 It may be. In the compounds of subgenus (1A), R 4 is C 1-10 It may be alkyl.

[0148] In the compounds of subgenus (1A), R 4 is C 1-10 It may be heteroalkyl. In the compounds of subgenus (1A), R 4 is C 5-10 It may be arylalkyl. In the compounds of subgenus (1A), R 4 is C 3-6 It may be a heterocycloalkyl.

[0149] In the compounds of subgenus (1A), R 4 is a substitution C 4-10 It may be heterocycloalkyl. stomach. The compound of formula (1) may be a compound of subgenus (1B) or a pharmaceutically acceptable salt thereof , where Each R 1 is C 1-3 alkyl, or each R 1 and the carbon atoms to which they are attached form C 3-6 forming a cycloalkyl ring; R 2 can be a single bond; and R 3 -C(O)-OR 4 where R 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 can be selected from:

[0150] In the compounds of subgenus (1B), each R 1 is C 1-3 alkyl. In the compounds of subgenus (1B), each R 1 and the carbon atoms to which they are attached form C 3-6 Forms a cycloalkyl ring.

[0151] In the compounds of subgenus (1B), R 4 is C 1-7 Alkyl, C 1-10 Heteroalkyl (one or more heteroalkyl groups) The heteroatom may be oxygen), -CH2-C 4-6 Cycloalkyl, -(CH2)2-C 4-6 Cycloalkyl, C 3-6 heterocycloalkyl (one or more heteroatoms may be oxygen), —CH—C 3-6 Substituted heterocycloalkyl, and -(CH2)2-C 3-6 substituted heterocycloalkyl.

[0152] In the compounds of subgenus (1B), the substitution C 3-6 One or more heterocyclic groups in heterocycloalkyl The atom may be oxygen and one or more of the substituents may be C 1-3 Independently selected from alkyl and =O can be done.

[0153] In the compounds of subgenus (1B), each R 1 may be methyl, or each R 1 and the carbon atoms to which they are attached together form a cyclohexyl or cyclopentyl ring.

[0154] In the compounds of subgenus (1B), R 4 can be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, n-hexyl, n-heptyl, —CH—CH—O—CH, benzyl, 3-oxetanyl, and methyl-5-methyl-1,3-dioxol-2-one.

[0155] In the compounds of subgenus (1B), Each R 1 may be methyl, or each R 1 and the carbon atoms to which they are attached together form a cyclohexyl or cyclopentyl ring; R 2 can be a single bond; and R 3 -C(O)-OR 4 where R 4 is methyl, ethyl, n-propyl, isopropyl, n-butyl, n-hexyl, n-heptyl, -CH2-CH2-O-CH3, -CH2-phenyl (benzyl), 3- It can be selected from oxetanyl, and methyl-5-methyl-1,3-dioxol-2-one.

[0156] The compound of formula (1) may be a compound of subgenus (1C) or a pharmaceutically acceptable salt thereof: , where Each R1 is C 1-3 alkyl, or each R 1 and the carbon atoms to which they are attached form C 3-6 forming a cycloalkyl ring; R 2 may be —(CH)—; and R 3 -C(O)-R 4 where R 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 It can be selected from alkyl.

[0157] In the compounds of subgenus (1C), each R 1 is C 1-3 alkyl. In the compounds of subgenus (1C), each R 1 and the carbon atoms to which they are attached form C 3-6 Forms a cycloalkyl ring.

[0158] In compounds of subgenus (1C), R 4 is C 1-7 Alkyl, C 1-10 Heteroalkyl (one or more heteroalkyl groups) The heteroatom may be oxygen), -CH2-C 4-6 Cycloalkyl, -(CH2)2-C 4-6 Cycloalkyl, C 3-6 heterocycloalkyl (one or more heteroatoms may be oxygen), —CH—C 3-6 Substituted heterocycloalkyl, and -(CH2)2-C 3-6 substituted heterocycloalkyl.

[0159] In the compounds of subgenus (1C), the substitution C 3-6One or more heterocyclic groups in heterocycloalkyl The atom may be oxygen and one or more of the substituents may be C 1-3 Independently selected from alkyl and =O can be done.

[0160] In compounds of subgenus (1C), R 4 is C 1-10 It may be alkyl. In the compounds of subgenus (1C), Each R 1 may be methyl; R 2 can be —(CH)—; and R 3 -C(O)-OR 4 where R 4 is n-hexyl The alkyl group can be selected from n-butyl and n-heptyl.

[0161] The compound of formula (1) may be a compound of subgenus (1D) or a pharmaceutically acceptable salt thereof , where Each R 1 is C 1-3 alkyl, or each R 1 and the carbon atoms to which they are attached form C 3-6 forming a cycloalkyl ring; R 2 can be -CH2-; and R 3 HA-SC(O)-R 4 where R 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 can be selected from:

[0162] In the compounds of subgenus (1D), each R 1 is C 1-3 alkyl. In the compounds of subgenus (1D), each R 1 and the carbon atoms to which they are attached form C 3-6 Forms a cycloalkyl ring.

[0163] In compounds of subgenus (1D), R 4 is C 1-7 Alkyl, C 1-10 Heteroalkyl (one or more heteroalkyl groups) The heteroatom may be oxygen), -CH2-C 4-6 Cycloalkyl, -(CH2)2-C 4-6 Cycloalkyl, C 3-6 heterocycloalkyl (one or more heteroatoms may be oxygen), —CH—C 3-6 Substituted heterocycloalkyl, and -(CH2)2-C 3-6 substituted heterocycloalkyl.

[0164] In the compounds of subgenus (1D), the substitution C 3-6 One or more heterocyclic groups in heterocycloalkyl The atom may be oxygen and one or more of the substituents may be C 1-3 Independently selected from alkyl and =O can be done.

[0165] In compounds of subgenus (1D), R 4 is C 1-10 It may be alkyl. In the compounds of subgenus (1D), each R 1 may be methyl; R 2 can be —(CH)—; and R 3 HA-SC(O)-R 4 where R 4 may be methyl.

[0166] The compound of formula (1) may be a compound of subgenus (1E) or a pharmaceutically acceptable salt thereof: , Each R 1 and the carbon atoms to which they are attached form C3-6 Cycloalkyl ring, C 3-6 Heterocycloalkyl ring, C 3-6 Cycloalkyl ring, or C 3-6 forming a heterocycloalkyl ring; R 2 can be a single bond; and R 3 is C 1-3 It may be alkyl.

[0167] In the compounds of subgenus (1E), each R 1 and the carbon atoms to which they are attached form C 3-6 Cycloalkyl ring or C 3-6 Forms a heterocycloalkyl ring. In compounds of subgenus (1E), one or more heteroatoms may be oxygen and one or more substituents may be =0.

[0168] In the compounds of subgenus (1E), Each R 1 and the carbon atoms to which they are attached together form a dihydrofuran-2(3H)-one ring Forming; R 2 can be a single bond; and R 3 may be methyl.

[0169] The compound of formula (1) may be a compound of subgenus (1F) or a pharmaceutically acceptable salt thereof: , Each R 1 is C 1-3 alkyl; R 2 may be selected from a single bond and methanediyl; and R 3 is -OC(O)-R 4 and -C(O)-OR 4 You can choose from R 4 is C 1-10 Alkyl and substituted Phenyl can be selected.

[0170] In the compounds of subgenus (1F), R 2 may be a single bond. In the compounds of subgenus (1F), R 2 may be methanediyl. In the compounds of subgenus (1F), R 3 may be —OC(O)—R4.

[0171] In the compounds of subgenus (1F), R 2 may be methanediyl; R 3 is -OC(O)-R4 good. In the compounds of subgenus (1F), R 3 -C(O)-OR 4 It may be.

[0172] In the compounds of subgenus (1F), R 2 may be a single bond; R 3 -C(O)-OR 4 It may be. In the compounds of subgenus (1F), R 2 may be a single bond; R 3 -C(O)-OR 4 and R 4 is C 1-3 It may be alkyl.

[0173] In the compounds of subgenus (1F), R 4 is C 1-10 It may be alkyl. In the compounds of subgenus (1F), R 4 is C 1-4 It may be alkyl. In the compounds of subgenus (1F), R 4 may be a substituted phenyl.

[0174] In the compounds of subgenus (1F), R 2 may be methanediyl; R 3 Ha-OC(O)-R 4 And well; and R 4 may be a substituted phenyl. In compounds of subgenus (1F), one or more of the substituents may be halogen, C 1-3 Alkyl, and C 1- 3 alkoxy can be independently selected.

[0175] In compounds of subgenus (1F), the substituted phenyl may be 2,6-substituted phenyl. In compounds of subgenus (1F), each of the substituents is C 1-3 Alkyl and C 1-3 It can be selected from alkoxy.

[0176] In compounds of subgenus (1F), the substituted phenyl may be 2,5,6-substituted phenyl. In compounds of subgenus (1F), each of the substituents at the 2 and 6 positions is C 1-3 Alkyl and C 1-3 the substituent at the 5-position may be a halogen.

[0177] The compound of formula (1) may be a compound of subgenus (1G) or a pharmaceutically acceptable salt thereof: , where Each R 1 is C 1-3 alkyl; R 2 may be a single bond; R 3 is -CH=C(R 4 )2, where each R 4 -C(O)-OR 8 Alternatively, each R 4 together with the carbon atoms to which they are attached form a substituted heterocyclohexyl ring; and Each R 8 is C 1-4 It may be alkyl.

[0178] In each compound of subgenus (1G), each R4 -C(O)-OR 8 It may be. In each compound of subgenus (1G), each R 4 -C(O)-OR 8 Alternatively, each R 4 and the carbon atom to which they are attached together form a substituted heterocyclohexyl ring.

[0179] In the compounds of subgenus (1G), one or more heterocyclic groups in the substituted heterocyclohexyl ring may be The atom may be oxygen. In the compounds of subgenus (1G), one or more substituents on the substituted heterocyclohexyl ring is C 1-3 It can be independently selected from alkyl and =O.

[0180] In the compounds of subgenus (1G), the substituted heterocyclohexyl ring can be 2,2-dimethyl-5-yl-1,3-dioxane-4,6-dione. The compound of formula (1) may be a compound of subgenus (1H) or a pharmaceutically acceptable salt thereof: , where Each R 1 is C 1-3 alkyl; R 2 may be selected from a single bond and methanediyl; and R 3 may be a substituted phenyl, where one or more of the substituents is -CH-OC(O)-R 4 and -OC(O)-R 4 can be chosen independently from R 4 is C 1-10 It can be selected from alkyl and phenyl.

[0181] In compounds of subgenus (1H), R 2 may be a single bond. In compounds of subgenus (1H), R 2 may be a 2-substituted phenyl. In compounds of subgenus (1H), one or more of the substituents is -CH2-OC(O)-R 4 It may be.

[0182] In compounds of subgenus (1H), one or more of the substituents may be -OC(O)-R4. In compounds of subgenus (1H), R 4 is C 1-10 It may be alkyl. In compounds of subgenus (1H), R 4 can be selected from methyl, ethyl, isopropyl, pivaloyl, and phenyl.

[0183] The compound of formula (1) may be a compound of subgenus (1I) or a pharmaceutically acceptable salt thereof: , where Each R 1 is C 1-3 alkyl; R 2 is -C(R 8 )2- and -CH2-C(R 8 )2-You can choose from each R 8 is C 1-3 alkyl; and R 3 is -C(O)-OR 4 and -OC(O)-R 4 You can choose from R 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.

[0184] In the compounds of subgenus (1I), each R 1 may be methyl. In the compounds of subgenus (1I), R 2 -C(R 8 )2- may be. In the compounds of subgenus (1I), R2 is -CH2-C(R 8 )2- may be.

[0185] In the compounds of subgenus (1I), each R 1 may be methyl. In the compounds of subgenus (1I), each R 1 may be methyl; each R 8 may be methyl. In the compounds of subgenus (1I), R 3 -C(O)-OR 4 It may be.

[0186] In the compounds of subgenus (1I), R 3 Ha-OC(O)-R 4 It may be. The compound of formula (1) may be a compound of subgenus (1J) or a pharmaceutically acceptable salt thereof , where Each R 1 and the carbon atoms to which they are attached form the substitution C 5-6 forming a heterocyclic ring; R 2 can be a single bond; and R 3 is C 1-3 It may be alkyl.

[0187] In the compounds of subgenus (1J), the substitution C 5-6 One or more heteroatoms in the heterocycle may be oxygen. and one or more of the substituents may be C 1-3 It can be independently selected from alkyl and =O.

[0188] In the compounds of subgenus (1J), each R 1 and the carbon atoms to which they are attached together form a tetrahydro-2H-pyran-2-one ring. In the compounds of subgenus (1J), Each R 1 is C 1-3 alkyl; R2 is C 2-4 alkanediyl; and R 3 is a substitution C 5-6 heterocycloalkyl, where one or more heteroatoms are selected from N and O one or more of the substituents may be independently selected from C 1-3 It can be independently selected from alkyl and =O.

[0189] In compounds of subgenus (1J), R 3 is expressed as equation (3).

[0190] [ka]

[0191] where 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 It can be selected from heterocycloalkyl.

[0192] In compounds of subgenus (1J), R 9 is hydrogen and C 1-6 Alkyl (e.g., C 1-4 Alkyl (e.g. For example, methyl and ethyl). The avibactam derivatives provided by the present invention are represented by the formula (1b):

[0193] [ka]

[0194] or a pharmaceutically acceptable salt thereof, wherein each R1 is C 1-6 alkyl; R 3 is C 1-6 It may be alkyl. In the avibactam derivative of formula (1b), each R 1 is independently C 1-3 may be alkyl, and R 3 is C 1-3 It may be alkyl.

[0195] In the avibactam derivative of formula (1b), each R 1 may be methyl, R 3 is C 1-3 It may be alkyl (eg, methyl, ethyl, n-propyl, or isopropyl). 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]octadecanoate benzo-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylbutanoate; Ethyl 2-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octadecanoate benzo-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylbutanoate; Propyl 2-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octyl) Tan-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylbutanoate; Methyl 2-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octadecanoate benzo-6-yl)oxy)sulfonyl)oxy)methyl)-2-propylbutanoate; Ethyl 2-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octadecanoate benzo-6-yl)oxy)sulfonyl)oxy)methyl)-2-propylpentanoate; Propyl 2-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octyl) Tan-6-yl)oxy)sulfonyl)oxy)methyl)-2-propylpentanoate; a pharmaceutically acceptable salt of any of the above compounds; and Any combination of the above compounds You can choose from.

[0196] Avibactam derivatives include avibactam derivative (10), methyl 3-(((((1R,2S,5R)-2-carbamate 7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy dimethylpropanoate (10), which has the following structure:

[0197] [ka]

[0198] The avibactam derivative may be 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 (3), having the following structure:

[0199] [ka]

[0200] The compounds of formula (1), (1a), or (1b) may be used in the form of a solvate, a pharmaceutically acceptable salt, or a mixture thereof. It may be a combination of these. In the compounds of formula (1), (1a), or (1b), the pharmaceutically acceptable salt is the hydrochloride salt. good.

[0201] In the compounds of formula (1), (1a), or (1b), the pharmaceutically acceptable salt is the dihydrochloride salt. That's fine. The compound of formula (1), (1a), or (1b) may be a pharmaceutically acceptable salt of the compound of formula (1), a hydrate thereof, or a solvate of any of the foregoing.

[0202] The avibactam derivatives described herein can be synthesized using the methods described in US Patent No. 10,085,999.The pharmaceutical compositions provided by the present invention can be administered orally.

[0203] Avibactam derivatives, when administered orally, have the same oral bioavailability as the parent β-lactamase inhibitors. For example, the avibactam derivatives of formula (1) provide a higher oral bioavailability compared to the oral bioavailability of at least 10%, at least 20%, at least 30%, or at least At least 40%, at least 50%, at least 60%, at least 70%, or at least 80% of the Avibactam oral bioavailability (%F) may be shown. The oral bioavailability of avibactam in humans is approximately 7%.

[0204] 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) have oral bioavailability of greater than 10%. Additionally, compounds 36, 37, 42, 53, 57, 58, and 59 also demonstrated oral avibactam bioavailability of greater than 10% in Sprague-Dawley rats. In a similar study, avibactam demonstrated an oral bioavailability (%F) of 1.2% 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. Avibactam derivative (3) exhibits an avibactam bioavailability of over 50% in human patients. ctam oral bioavailability.

[0205] The pharmaceutical composition provided by the present invention comprises amoxicillin or a pharmaceutically acceptable salt thereof, and an avibactam derivative of formula (1) or a pharmaceutically acceptable salt thereof. good.

[0206] The pharmaceutical composition provided by the present invention may comprise a therapeutically effective amount of amoxicillin or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of an avibactam derivative of formula (1) (i.e., an avibactam derivative provided by the present invention) or a pharmaceutically acceptable salt thereof. .

[0207] The pharmaceutical composition may comprise a pharmaceutically acceptable carrier or excipient, or a combination of pharmaceutically acceptable carriers or excipients. The pharmaceutical composition may include an oral formulation. The oral formulation may be, for example, in the form of a liquid dosage form or a solid dosage form. The solid dosage form for oral administration may be in the form of a solution, suspension, capsule, tablet, powder, pill, or granule. The oral solid dosage form may include, for example, a filler, an extender, a binder, a humectant, a disintegrant, an absorption enhancer, a wetting agent, an absorbent, a lubricant, a buffer, or a combination of any of the above. Examples of liquid oral dosage forms include softgel capsules containing liquids, oral suspensions, syrups, and elixirs.

[0208] The oral dosage form may comprise a therapeutically effective amount of amoxicillin or a pharmaceutically acceptable salt thereof, and an avibactam derivative of formula (1) or a pharmaceutically acceptable salt thereof. may contain a proportion of a therapeutically effective amount of amoxicillin or a pharmaceutically acceptable salt thereof, and / or a proportion of a therapeutically effective amount of an avibactam derivative of formula (1) or a pharmaceutically acceptable salt thereof. Oral dosage forms containing the compounds can be intended to be administered simultaneously as multiple dosage forms that together provide a therapeutically effective amount, or to be administered over a period of time (e.g., 1 to 6 times daily) to provide a therapeutically effective amount of amoxicillin and avibactam in the patient's plasma.

[0209] The amoxicillin and avibactam derivative may be supplied in separate dosage forms or may be combined into a single dosage form. The amoxicillin and avibactam derivative may be co-formulated to provide uniform distribution of the compounds throughout the oral dosage form.

[0210] The amoxicillin and avibactam derivatives can be sequestered in 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 dispersed separately within separate portions of the oral dosage form, for example, forming a core-shell structure.

[0211] Oral dosage forms containing amoxicillin and avibactam derivatives are The weight ratio of [tam equivalent amount] may be within a certain range (e.g., 1:1 to 1:4, 1:1 to 1:3, 1:1 to 1:2, 1:1 to 1:1.5, 1:1 to 1:0.9, 1:1 to 1:0.5).

[0212] Oral dosage forms include, for example, 100 mg to 1,400 mg of amoxicillin, 100 mg to 1,200 mg of amoxicillin, 100 mg to 1,000 mg of amoxicillin, 100 mg to 800 mg of amoxicillin, or 100 mg It may contain ~600mg of amoxicillin.

[0213] The current FDA oral dosage for amoxicillin is 600 mg to 1,000 mg TID and 1,000 mg BID, with 1,000 mg q6h also being used. Oral dosage forms such as tablets and capsules are available in doses of 100 mg, for example. ~1,000mg amoxicillin, 125mg to 875mg amoxicillin, or 250mg to 775mg amoxicillin Tablets and capsules may contain, for example, 125 mg amoxicillin, 250 mg amoxicillin, 500 mg amoxicillin, 775 mg amoxicillin, 875 mg amoxicillin, and Amoxicillin suspensions may contain 1,000 mg of amoxicillin or 1,000 mg of amoxicillin. For example, 5 ml may contain 125 mg, 200 mg, 250 mg, or 400 mg of amoxicillin.

[0214] Oral dosage forms include, for example, 25 mg to 2,000 mg of avibactam equivalent, 100 mg to 1,600 mg of avibactam equivalent, Avibactam equivalent, 200mg to 1,400mg Avibactam equivalent, 250mg to 1,2000mg Avibactam Oral dosage forms may contain, for example, 500 mg to 700 mg of amoxicillin, 700 mg to 900 mg of amoxicillin, or 900 mg to 1,300 mg of amoxicillin.

[0215] Oral dosage forms include, for example, 25 mg to 2,000 mg of the avibactam derivative of formula (1), 100 mg to 1,600 mg of the avibactam derivative of formula (1), 200 mg to 1,400 mg of the avibactam derivative of formula (1), 250 mg to 1,200 mg of the avibactam derivative of formula (1), 300 mg to 900 mg of the avibactam derivative of formula (1), 350 mg 400 mg to 800 mg of an avibactam derivative of formula (1), 450 mg to 750 mg of an avibactam derivative of formula (1), or 500 mg to 700 mg of an avibactam derivative of formula (1). The oral dosage form may contain, for example, 200 mg to 1,400 mg of the avibactam derivative of formula (1). , 250 mg to 1,200 mg of the avibactam derivative of formula (1), 300 mg to 1,000 mg of the avibactam derivative of formula (1), or 400 mg to 900 mg of the avibactam derivative of formula (1).

[0216] Oral dosage forms include, for example, 100 mg to 1,000 mg of amoxicillin and 25 mg to 2,000 mg of avibacter. amoxicillin equivalent, 200mg to 800mg and avibactam equivalent, 300mg to 900mg ~750mg amoxicillin and 350mg-850mg avibactam equivalent, 300mg-700mg amoxicillin It may contain amoxicillin and an equivalent amount of 400 mg to 800 mg of avibactam, or 350 mg to 650 mg of amoxicillin and an equivalent amount of 450 mg to 750 mg of avibactam.

[0217] Oral dosage forms include, for example, 100 mg to 1,000 mg of amoxicillin and 25 mg to 2,000 mg of an avibactam derivative of formula (1), 200 mg to 800 mg of amoxicillin and 300 mg to 900 mg of an avibactam derivative of formula (1), The composition may contain 250 mg to 750 mg of amoxicillin and 350 mg to 850 mg of an avibactam derivative of formula (1), 300 mg to 700 mg of amoxicillin and 400 mg to 800 mg of an avibactam derivative of formula (1), or 400 mg to 600 mg of amoxicillin and 450 mg to 750 mg of an avibactam derivative of formula (1).

[0218] Oral dosage forms may contain, for example, 100 mg to 1,000 mg of amoxicillin and 200 mg to 1,400 mg of an amoxicillin of formula (1). It may contain 300 mg to 900 mg of a vibactam derivative or an avibactam derivative of formula (1). Oral dosage forms may contain, for example, 200 mg to 800 mg of amoxicillin and 200 mg to 1,400 mg of the abirater of formula (1). The composition may contain 300 mg to 900 mg of a bactam derivative or an avibactam derivative of formula (1).

[0219] The oral dosage form may be a sustained release oral dosage form. The oral dosage form may be a controlled release oral dosage form. The dose and administration regimen of amoxicillin and avibactam derivatives may be any suitable dose and administration regimen that achieves a therapeutic effect.

[0220] A combination of amoxicillin and an avibactam derivative is administered, for example, to provide a total daily dose of 50 mg to 4,000 mg of amoxicillin and a total daily dose of 800 mg to 2,400 mg of the equivalent amount of avibactam. Doses can be supplied (e.g., 500 mg to 3,500 mg amoxicillin and 900 mg to 2,300 mg avibactam equivalent; 750 mg to 3,000 mg amoxicillin and 1,000 mg to 2,200 mg avibactam equivalent; 1,000 mg to 2,500 mg amoxicillin and 1,100 mg to 2,100 mg avibactam equivalent). amoxicillin and avibactam equivalents (1,200 mg to 2,400 mg); amoxicillin and avibactam equivalents (1,200 mg to 2,000 mg); amoxicillin and avibactam equivalents (1,600 mg to 2,200 mg); amoxicillin and avibactam equivalents (1,300 mg to 1,800 mg); or amoxicillin and avibactam equivalents (1,800 mg to 2,000 mg).

[0221] The total daily dose of amoxicillin is, for example, 200 mg to 4,000 mg, 600 mg to 3,600 mg, 1,000 mg It may be 1,400 mg to 2,800 mg, 1,600 mg to 2,600 mg, 1,800 mg to 2,400 mg, or 2,000 mg to 2,200 mg.

[0222] The total daily dose of the avibactam equivalent administered as the avibactam derivative provided by the present invention 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.

[0223] The total daily dose of the avibactam derivative provided by the present invention 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.

[0224] The combination of amoxicillin and the 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. Moxicillin and avibactam derivatives can be administered independently once, twice, three times, four times, five times, or For example, amoxicillin and avibactam derivatives can be administered in 6 doses. Each can be administered once, twice, three times, four times, five times, or six times per day.

[0225] For example, amoxicillin and avibactam derivatives can be administered three times per day (TID) (eg, every 8 hours) (q8h). When given more than once daily, amoxicillin and avibactam derivatives are equally distributed. The drugs may be administered in divided doses, meaning that each dose administered throughout the day contains the same amount of each drug. For example, each TID dose of a 1,200 mg daily dose of amoxicillin may contain 400 mg of amoxicillin. Therefore, the TID dose of 1,200 mg avibactam equivalent daily dose contains 400 mg avibactam equivalent. a 1,200 mg daily TID dose of the avibactam derivative of formula (1) may contain 400 mg of the avibactam derivative of formula (1).

[0226] For example, the total daily dose of amoxicillin may be in the range of 1,500 mg to 4,000 mg, and the total daily dose of the 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 the avibactam derivative of formula (1).

[0227] Pediatric dosages of amoxicillin can be 20 mg / kg to 40 mg / kg TID, or up to 90 mg TID. The total daily dose of amoxicillin and avibactam derivative can be administered as a single daily dose or as divided daily doses administered, for example, once, twice, three times, or four times per day, with each divided daily dose having the same or different amounts of amoxicillin and / or avibactam derivative.

[0228] Suitable doses of amoxicillin may be those approved by the FDA. Amoxicillin is approved by the FDA to treat certain bacterial infections. Pharmaceutical compositions, doses, and administration schedules for phosphorus are based on FDA-approved amounts and schedules. Based on the MIC of amoxicillin against specific bacterial species, and fAUC:MIC ratio or Time > C determined for the t Based on the ratio, The dosage and schedule of the avibactam derivatives of formula (1) for treating bacterial infections such as amoxil, benzodiazepine, benzocaine ... Determine the combination with the FDA-approved dose and schedule for concurrent fluticasone / avibactam therapy. It is possible.

[0229] When supplied as separate dosage forms, the amoxicillin and avibactam derivative may be administered simultaneously or sequentially. For example, when administered simultaneously, the separate dosage forms can be administered simultaneously or within less than 60 minutes of each other (e.g., less than 30 minutes, less than 20 minutes, less than 10 minutes, or less than 5 minutes of each other). It is also possible to do so.

[0230] In the case of sequential administration, the separate oral dosage forms may be administered, for example, 1 to 6 hours after the first oral dosage form is administered. It can be administered within 1 to 5 hours, within 1 to 4 hours, or within 1 to 3 hours.

[0231] The amoxicillin and the avibactam derivative can be administered in a weight ratio of amoxicillin to avibactam derivative of, for example, 1:1 to 1:5, 1:1 to 1:4, 1:1 to 1:3, 1:1 to 1:2, 1:1 to 1:1.5, 1:1 to 1:0.9, or 1:1 to 1:0.5.

[0232] Each of the amoxicillin and avibactam derivative can be administered independently at least twice per day (eg, twice per day, three times per day, or four times per day).

[0233] Amoxicillin and an avibactam derivative may be administered simultaneously. In the case of simultaneous administration, amoxicillin and an avibactam derivative of formula (1) may be administered in the same dosage form. Alternatively, they may be administered in separate dosage forms.

[0234] The amoxicillin and avibactam derivative can be administered non-concurrently. The amoxicillin and avibactam derivative can be administered at the same daily dosing frequency or at different daily dosing frequencies. For example, amoxicillin can be administered at 2 doses per day. The avibactam derivative can be administered three times per day.

[0235] The combination of amoxicillin and an avibactam derivative may be administered to a patient for a period of time sufficient to provide the desired therapeutic effect. The combination of amoxicillin and an avibactam derivative can be administered for a sufficient period of time to treat the bacterial infection. Treatment can continue for several days or several months. The pharmaceutical composition can be administered, for example, once, twice, or less than five times. The pharmaceutical composition provided by the present invention can be administered for, for example, 3 to 30 days, 7 to 21 days, or 7 to 14 days. The treatment can be continued for a predetermined number of days or until a predetermined endpoint is reached. The pharmaceutical composition provided by the present invention can be administered for, for example, 1 week to 15 weeks, 2 weeks to 12 weeks, or 3 weeks to 9 weeks. The treatment can be continued for a predetermined number of days or until a predetermined endpoint is reached. The treatment can be continued until the symptoms of the bacterial infection are alleviated and / or the bacterial infection is cured. The procedure may continue until there are no detectable signs of

[0236] The bacterial infection treatment methods provided by the present invention include multiple phase treatment regimens. For example, to treat a bacterial infection, an initial therapeutic In the treatment phase, a combination of amoxicillin and an avibactam derivative was administered in the first dose and / or regimen can be administered to patients in a first treatment phase and in a second treatment phase. In this case, the combination of amoxicillin and an avibactam derivative can be administered to the patient at a second dose and / or a second schedule, where the first and second doses and / or schedules may be different. For example, the target plasma concentration of amoxicillin and / or avibactam during the first phase may be higher than during the second phase; The amount of benzodiazepine and / or avibactam derivative may be higher in the second phase than in the first phase; and / or The frequency of administration during the first phase may be higher than during the second phase. The second phase may be called a maintenance phase. The first phase may last, for example, less than 4 weeks, less than 6 weeks, less than 8 weeks, or less than 12 weeks. The second phase, or maintenance phase, may, for example, , may have a duration of less than 12 months, less than 8 months, or less than 6 months. The treatment for bacterial infections involves administering amoxicillin and an avibactam derivative of formula (1). Amoxicillin may be administered, for example, to provide an fT>MIC of greater than 40%, greater than 45%, or greater than 50% in the patient's systemic circulation. can be administered, for example, in 400 mg divided doses (q8h) for a total daily dose of 1200 mg.

[0237] After oral administration of a therapeutically effective amount of the avibactam derivative of formula (1), the fAUC / MIC in the patient's plasma is, for example, greater than 20, greater than 30, greater than 40, or greater than 50 against bacteria causing an infection. The fAUC / MIC ratio may be, for example, 10-40, 20-40, 25-35, or greater than 50 against bacteria causing infection. This ratio represents the [fAUC of avibactam / MIC of amoxicillin] against a particular bacterial species in the presence of avibactam.

[0238] After oral administration, a therapeutically effective avibactam concentration is, for example, 40% fT>C t Over 50% fT>C t > or 60%fT>C t It can be super. After oral administration of 300 mg of avibactam derivative (3) to healthy patients, the mean C max is approximately 2,500 ng / ml, and AUC inf is approximately 7,600 ngxh / ml, and T 1 / 2 It took about 1.5 hours.

[0239] After oral administration of 300 mg of avibactam derivative (3) to eight healthy patients, the mean C max teeth Approximately 2,740 ng / ml, and T max is approximately 1.75 hours, and AUC inf is approximately 8,505ngxh / ml, and T 1 / 2 was approximately 1.51 hours.

[0240] After oral administration of 600 mg of avibactam derivative (3) to healthy patients, the mean C max is approximately 2,500 ng / ml, and AUC inf is approximately 7,600 ngxh / ml, and T 1 / 2 It took about 1.5 hours. After oral administration of 900 mg of avibactam derivative (3) to eight healthy patients, the mean C max teeth Approximately 8,360 ng / ml, and T max is approximately 2.75 hours, and AUC inf is approximately 36,072ngxh / ml, and T 1 / 2 was approximately 2.65 hours.

[0241] After oral administration of 1,350 mg of avibactam derivative (3) to eight healthy patients, the mean C max is approximately 10,300 ng / ml, and T max is approximately 2.25 hours, and AUC inf is approximately 45,933ngxh / ml, and T 1 / 2 was approximately 2.33 hours.

[0242] The MIC when amoxicillin and avibactam are used in combination may be, for example, 8 mg / ml or less, 4 mg / L or less, 2 mg / liter or less, 1 mg / liter or less, or 0.5 mg / liter or less.

[0243] The MIC of amoxicillin against β-lactamase-producing mycobacteria may be, for example, 10 mg / liter or more, 20 mg / liter or more, 40 mg / liter or more, or 60 mg / liter or more.

[0244] The MIC of amoxicillin against β-lactamase-producing mycobacteria can be, for example, 200 times or more, 100 times or more, 50 times or more, 20 times or more, 10 times or more, or 50 times or more than the MIC of the combination of amoxicillin and avibactam against the same bacterial strain.

[0245] The minimum bacterial concentration (MBC) when amoxicillin is used in combination with an avibactam derivative may be, for example, 8-fold less, 4-fold less, or 2-fold less than the MIC when amoxicillin is used in combination with an avibactam derivative. The MBC when used in combination with amoxicillin is The MIC of amoxicillin may be equal to or greater than the MIC of amoxicillin when used in combination.

[0246] A method for treating a bacterial infection in a patient includes obtaining a biological sample from the patient suffering from the bacterial infection; confirming the presence of bacteria in the sample; determining the MIC required to treat the confirmed bacteria; and administering a pharmaceutical composition comprising amoxicillin and an avibactam derivative provided by the present invention in a therapeutically effective amount based on the determined MIC. administering to the patient. The bacterial infection may be caused by bacteria that produce a β-lactamase enzyme.

[0247] The pharmaceutical compositions and methods provided herein can be used to treat bacterial infections (e.g., For example, Actinomycetales bacterial infections can be treated. These bacteria (Actinomycetales) are Gram-positive bacteria with complex cell wall structures that can be covered by the oral amoxicillin / avibactam combination prodrug. The order Actinomycetales has three major families of pathogenic bacteria: Mycobacteriaceae, Actinomycetaceae, and Nocardiaceae.

[0248] The Mycobacterium genus includes M. tuberculosis, M. bovis, M. africanum, M. leprae, and nontuberculous mycobacteria. Nontuberculous mycobacteria include M. arupense, M. avium, M. asiaticum, M. bohemicum, M. branderi, M.chemaera, M.selatum, M.conspicuum, M.doricum, M.florentinum, M.genavense, M.haemophilum, M.heckeshornense, M.heidelbergense, M.intermedium, M.interjectum, M.intracelluare, M.kansasii, M.kubicae, M.lacus, M.lentiflavum, M.malmoense, M.marinum, M.nebraskense, M.parmense, M.parascrofulaceum, M.palustre, M.saskatchewanse, M.scrofulaceum, M.selatum, M.sherrissii, M.shottsii, M.shimodei, M.simiae, M.szulgai, M.tusciae, M.triplex, M.ulcerans, M.xenopi, M.abscessus, M.chelonae, M.fortuitum, M.mucogenicum, M.peregrinum, M.porcinum, M.senegalense, M.alvei, M.boenickei, M.bollettii, M.brumae, M.canariasense, M.confluentis, M.cosmeticum, M.elephantis, M.goodii, M.hassiacum, M.holsaticum, M.immunogenum, M.mageritence, M.novocastrense, The genus Actinomycetes includes A. israelii, A. meyeri, A. naeslundii, A. odontolyticus, and A. viscosus. The genus Nocardia includes N. asteroides, N. abscessus, N. brasiliensis, N. cyriacigeorgica, There are several pathogenic species, including N. farcinica, N. nova, N. otitidiscaviarum, and N. veterana.

[0249] A combination of orally administered amoxicillin and an avibactam derivative can be used to treat bacterial infections caused by bacteria of the genus Mycobacteriaceae. A combination of orally administered amoxicillin and an avibactam derivative can be used to treat bacterial infections caused by M. ulcerans.

[0250] A combination of orally administered amoxicillin and an avibactam derivative can be used to treat infections caused by the M. abscessus complex, which can cause pulmonary disease, especially in vulnerable hosts with underlying structural lung disease.

[0251] A combination of orally administered amoxicillin and an avibactam derivative has been used to treat nontuberculous mycobacteria (e.g., M. avium, M. intracellulare, M. kansasii, M.xenopi, M.marinum, M.malmoense, M.simiae, M.abcessus, M.ulcerans, M.chelonae, The present invention can treat nontuberculous mycobacterial infections caused by M. fortuitum, M. fortuitum, or any combination of the foregoing bacteria.

[0252] A combination of orally administered amoxicillin and an avibactam derivative can be used to treat MAC infections caused by M. avium and M. intracellulare. The orally administered combination of amoxicillin and an avibactam derivative can be used to treat pulmonary infections, soft tissue infections, central nervous system infections, bacteremia, eye infections, or a combination of any of the foregoing infections. Kits provided by the present invention may include amoxicillin or a pharmaceutically acceptable salt thereof, an avibactam derivative or a pharmaceutically acceptable salt thereof, and instructions for administering a therapeutically effective amount of the compound to treat a bacterial infection in a patient.

[0253] The amoxicillin and avibactam derivatives may be formulated for oral administration, for example, in the form of a suspension or solid dosage form. Instructions for use may be provided, for example, as a written insert or in electronic form.

[0254] The kit may contain amoxicillin and an avibactam derivative in a single dosage form and / or in separate dosage forms. The multiple dosage forms may contain the compound in separate doses (as separate doses in multiple single dosage forms). Amoxicillin and amoxicillin can be administered over a period of time (e.g., one day). The total daily dose of the bactam derivative can be divided into separate doses intended to be administered, for example, once, twice, three times, or four times per day. For example, a 1,200 mg daily dose of amoxicillin can be provided as three doses of 400 mg amoxicillin administered three times per day, and a 1,200 mg daily dose of an avibactam derivative can be provided as three doses of 400 mg avibactam derivative administered three times per day. Other doses and other β-lactams Antibiotics may be supplied in the kit.

[0255] The kit may contain doses suitable for multi-day administration (e.g., 1, 2, 3, or 4 weeks). The daily doses of amoxicillin and the avibactam derivative may be supplied in separate packages.

[0256] The pharmaceutical composition provided by the present invention may comprise amoxicillin or a pharmaceutically acceptable salt thereof, and an avibactam derivative or a pharmaceutically acceptable salt thereof. The pharmaceutical composition comprises a therapeutically effective amount of amoxicillin and an avibactam derivative of formula (1) for treating bacterial infections. Amoxicillin and an avibactam derivative of formula (1) can be provided. A therapeutically effective amount of may be an amount appropriate as part of a therapeutically effective treatment regimen in which a combination of amoxicillin and an avibactam derivative is administered over a period of time.

[0257] The pharmaceutical composition can be used in combination with at least one therapeutic agent. The composition can be administered to a patient together with another compound for treating a bacterial infection in the patient, the at least one other therapeutic agent being another β-lactam antibiotic and / or an amphotericin. Amoxicillin, an avibactam derivative, and at least one other therapeutic agent may act additively or synergistically. The at least one additional therapeutic agent can be included in the same pharmaceutical composition or vehicle containing the amoxicillin and / or avibactam derivative, or can be included in a separate pharmaceutical composition or vehicle. Thus, the methods provided by the present invention further include administering amoxicillin and an avibactam derivative, in addition to administering amoxicillin and an avibactam derivative, a therapeutic agent effective in treating a different disease, disorder, or condition other than a bacterial infection. The method provided by the present invention includes administering the above therapeutic agents to a patient in need thereof, wherein the combined administration does not inhibit the therapeutic effects of amoxicillin and an avibactam derivative and / or does not cause any adverse effects. Amoxicillin and avibactam derivatives and one other drug, provided that no combination effect occurs. This includes administering other therapeutic agents as described above.

[0258] Pharmaceutical compositions containing amoxicillin and an avibactam derivative can be administered simultaneously with the administration of other therapeutic agents, which may be part of the same pharmaceutical composition or may be in different pharmaceutical compositions containing amoxicillin and / or an avibactam derivative. The amoxicillin and avibactam derivatives may be administered either before or after the administration of the other therapeutic agent. In certain combination therapies, the combination therapy may be used to minimize undesirable effects associated with certain drugs and / or to prevent or minimize adverse effects associated with certain drugs. To enhance the efficacy of the combination, the administration of amoxicillin and an avibactam derivative may be alternated with the administration of a composition containing another therapeutic agent. When amoxicillin and an avibactam derivative are administered simultaneously with another therapeutic agent that may cause adverse drug effects, including, for example, toxicity, the other therapeutic agent can be administered at a dose below the threshold at which an adverse drug reaction occurs.

[0259] The pharmaceutical composition comprising amoxicillin and an avibactam derivative can be administered with one or more substances to enhance, regulate, and / or control the release, bioavailability, therapeutic efficacy, therapeutic potential, stability, etc. of the amoxicillin and avibactam derivative. For example, to enhance the therapeutic efficacy of amoxicillin and an avibactam derivative, the pharmaceutical composition comprising amoxicillin and an avibactam derivative can be administered with one or more substances to enhance, regulate, and / or control the release, bioavailability, therapeutic efficacy, therapeutic potential, stability, etc. of the amoxicillin and avibactam derivative. to increase the absorption or diffusion of amoxicillin and / or avibactam derivatives from the gastrointestinal tract into the systemic circulation, or to reduce the degradation of amoxicillin and / or avibactam derivatives in the blood or plasma of a patient. Amoxicillin and avibactam can be co-administered with one or more other drugs for the treatment of rheumatoid arthritis. The pharmaceutical composition containing the body can be co-administered with an active agent that has a pharmacological effect that enhances the therapeutic efficacy of amoxicillin and avibactam derivatives.

[0260] Amoxicillin and avibactam derivatives can be administered with other therapeutic compounds if the amoxicillin and avibactam derivatives enhance the efficacy of the other therapeutic compound. For example, the other therapeutic compound can be an antibiotic such as amoxicillin, and the avibactam derivative (which provides a systemic β-lactamase inhibitor) inhibits β-lactamase-mediated β-lactamase activity. It is possible to increase the efficacy of β-lactam antibiotics by preventing hydrolysis of the lactam ring. do.

[0261] The pharmaceutical compositions provided by the present invention contain, in addition to amoxicillin, a β-lactam antibiotic. The agent may be administered in combination with an antibiotic such as Suitable antibiotics include, for example, aminoglycosides such as amikacin, gentamicin, neomycin, plazomicin, streptomycin, and tobramycin; ceftriaxone; Beta-lactams (cephalosporins, first generation), such as adroxil, cefazolin, and cephalexin; cefaclor, cefotetan, cefoxitin, cefprozil, and β-lactams (cephalosporins, second generation) such as cefuroxime; cefotaxime, cef β-lactams (cephalosporins, third generation) such as cephalosporins, ceftazidime, ceftibuten, cefixime, and ceftriaxone; β-lactams (cephalosporins, third generation) such as cefepime beta-lactams (cephalosporins, 6th generation) such as ceftaroline; amoxicillin, ampicillin, dicloxacillin, nafcillin, oxacillin, penicillin G, penicillin G benzathine, penicillin G procaine, piperacillin, and ticarctil β-lactams (penicillins) such as penicillin; β-lactam monobactams such as aztreonam Ertapenem, imipenem, meropenem, sulopenem, faropenem, tebipenem, β-lactam carbapenems such as flucloxacin, doripenem, and the like; fluoroquinolones such as ciprofloxacin, gemifloxacin, levofloxacin, moxifloxacin, norfloxacin, and ofloxacin; azithromycin, clarithromycin, erythromycin, Macrolides such as fidaxomicin, lactobionate, gluceptate, and telithromycin; sulfisoxazole, sulfamethizole, sulfamethoxazole sulfonamides such as cyclosporine, cyclosporine, and trimethoprim; doxycycline, minocycline, tetracycline, tetracyclines such as tracycline and tigecycline; and clindamycin Isin, chloramphenicol, colistin (polymyxin E), dalbavancin, dapt Other antibiotics such as cyclosporine, fosfomycin, linazolid, metronidazole, nitrofurantoin, oritavancin, quinupristin, dalfopristin, rifampin, rifapentine, tedizolid, telavancin, and vancomycin;

[0262] Other examples of suitable antibiotics include penicillins, such as the aminopenicillins, including amoxicillin and ampicillin, and the antipseudomonal penicillins, including carbenicillin, piperacillin, and ticarcillin; mecillinam and pivmecillinam; beta-lactamase inhibitors, including clavulanate, sulbactam, and tazobactam; penicillin g benzathine and penicillin Natural penicillins, including potassium phosphate and procaine penicillin, and oxacillin and penicillinase-resistant penicillins, including dicloxacillin and nafcillin; Cephalosporins such as cefadroxil, defazolin, cephalexin, and cefazolin; lomefloxacin, ofloxacin, and norfloxacin quinolones such as gatifloxacin, ciprofloxacin, moxifloxacin, levofloxacin, gemifloxacin, delafloxacin, cinoxacin, nalidixic acid, trovafloxacin, and sparfloxacin; macrolides such as ketolides including telithromycin; Macrolides such as erythromycin, azithromycin, clarithromycin, and fidaxomicin; sulfonamides such as sulfamethoxazole / trimethoprim and sulfisoxazole; glycopeptides; aminoglycosides such as paromomycin, tobramycin, gentamicin, amikacin, kanamycin, plazomycin, and neomycin; and doripenem, meropenem, ertapenem, tebipenem, sulopenem, fulvipen ... carbapenems such as alopenem and cilastatin / imipenem;

[0263] Examples of suitable β-lactam antibiotics include benzathine penicillin, benzylpenicillin, β-lactamase-active compounds such as penicillin, phenoxymethylpenicillin, and procaine penicillin Antibiotics: cloxacillin, dicloxacillin, flucloxacillin, methicillin, β-lactamase-resistant penams such as nafcillin and temocillin; broad-spectrum penams such as amoxicillin and ampicillin; broad-spectrum penams such as mecillinam; carboxypenicillins such as carbenicillin and ticarcillin; and azlocillin, mezlocillin, and Ureidopenicillins such as peperacillin:

[0264] Examples of suitable beta-lactam antibiotics include cefazolin, cephalexin, and cephalosporin. First-generation cefamicides such as cephalosporin C and cephalothin; cefaclor, cephalosporin ... Second-generation antihistamines such as cefamoandole, cefuroxime, cefotetan, and cefoxitin Cephalosporins: Cefixime, Cefotaxime, Cefpodoxime, Ceftazidime, and Cephalosporins Third-generation cephalosporins such as futriaxone; fourth-generation cephalosporins such as cefepime and cefpirome These include the cephalosporins; and the fifth-generation cefazolins such as ceftaroline.

[0265] Examples of suitable β-lactam antibiotics include carbapenems; and penems such as biapenem, doripenem, ertapenem, faropenem, imipenem, meropenem, panipenem, razupenem, tebipenem, sulopenem, and thienamycin.

[0266] Examples of suitable beta-lactam antibiotics include aztreonam, tigemonam, and nocardicin. and monobactams such as tabtoxin A and tabtoxin β-lactam. The pharmaceutical composition provided by the present invention contains, in addition to the avibactam derivative of formula (1), a β- It may be administered together with a lactamase inhibitor and / or a carbapenemase inhibitor. Examples of suitable β-lactamase inhibitors and / or carbapenemase inhibitors include clavulanate, acid, sulbactam, avibactam, tazobactam, relebactam, vaborbactam, ET X2514, 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).

[0267] The compounds and compositions provided by the present invention may be used in combination with one or more other active ingredients. The compounds can be administered in combination with or sequentially with other therapeutic agents, including those known to treat, prevent, or ameliorate infectious diseases.

[0268] Aspects of the invention The present invention is further defined by the following embodiments. Embodiment 1. Amoxicillin or a pharmaceutically acceptable salt thereof; and Formula (1):

[0269] [ka]

[0270] [In the formula, each R 1 is C 1-6 alkyl, or each R 1 and the geminal carbon atom to which they are bonded are 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 5-6Cycloalkanediyl, 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 arenediyl, and substituted C 5-6 Selected from heteroarenediyl; 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; where 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 5-10Heterocycloalkylalkyl, 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 substitution 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, exchange 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 heterocycloalkyl; and 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, exchange C 1-6 Alkyl, substituted C 5-8 Cycloalkyl, substituted C6-12 Cycloalkylalkyl, substituted C 2-6 Heteroalkyl, substituted C 5-8 Heterocycloalkyl, and substituted C 6-12 an avibactam derivative or a pharmaceutically acceptable salt thereof; A pharmaceutical composition comprising:

[0271] Aspect 2. The avibactam derivative has the structure of formula (1a):

[0272] [ka]

[0273] (In the formula, each R 1 is C 1-6 independently selected from alkyl; R 3 is C 1-6 alkyl), or 2. The pharmaceutical composition of embodiment 1, having the structure of a pharmaceutically acceptable salt thereof. Aspect 3. 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]octadecanoate benzo-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylbutanoate; Ethyl 2-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octadecanoate benzo-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylbutanoate; Propyl 2-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octyl) Tan-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylbutanoate; Methyl 2-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octadecanoate benzo-6-yl)oxy)sulfonyl)oxy)methyl)-2-propylpentanoate; Ethyl 2-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octadecanoate benzo-6-yl)oxy)sulfonyl)oxy)methyl)-2-propylpentanoate; Propyl 2-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octyl) Tan-6-yl)oxy)sulfonyl)oxy)methyl)-2-propylpentanoate; a pharmaceutically acceptable salt of any of the above compounds; and Any combination of the above compounds 2. The pharmaceutical composition according to aspect 1, selected from:

[0274] Aspect 4. An avibactam derivative having the structure:

[0275] [ka]

[0276] or a pharmaceutically acceptable salt thereof.

[0277] Aspect 5. The pharmaceutical composition of Aspect 1, wherein 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.

[0278] Embodiment 6 The pharmaceutical composition of any one of Embodiments 1 to 5, wherein the avibactam derivative comprises a hydrochloride salt. Aspect 7. The pharmaceutical composition of any one of Aspects 1 to 6, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0279] Aspect 8. The pharmaceutical composition of any one of Aspects 1 to 7, wherein the pharmaceutical composition comprises a synergistically effective amount of amoxicillin or a pharmaceutically acceptable salt thereof, and an avibactam derivative or a pharmaceutically acceptable salt thereof, for treating a bacterial infection in a patient.

[0280] Aspect 9. The pharmaceutical composition of any one of Aspects 1 to 8, wherein the pharmaceutical composition comprises a therapeutically effective amount of amoxicillin or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of an avibactam derivative or a pharmaceutically acceptable salt thereof, for treating a bacterial infection in a patient.

[0281] Aspect 10. The pharmaceutical composition of Aspect 9, wherein the bacterial infection is caused by a bacterium of the genus Mycobacterium. Aspect 11. The method of Aspect 10, wherein the mycobacterium is M. ulcerans and / or M. abscessus. The pharmaceutical composition described above.

[0282] Aspect 12. The bacterial infection is a pulmonary infection, a soft tissue infection, a central nervous system infection, bacteremia, or an ocular or any combination of said infections. .

[0283] Embodiment 13 The pharmaceutical composition of embodiment 9, wherein the bacterial infection comprises a nontuberculous mycobacterial infection. Aspect 14. The nontuberculous mycobacterial infection is M. avium, M.intracellulare, M.kansasii, M.xenopi, M.marinum, M.malmoense, M.simiae, Nontuberculous mycobacteria, including M. abcessus, M. ulcerans, M. chelonae, M. fortuitum, or any combination of the above bacteria. 14. The pharmaceutical composition according to aspect 13, wherein the compound is induced by sodium.

[0284] Aspect 15. The pharmaceutical composition according to any one of Aspects 1 to 14, wherein the pharmaceutical composition comprises 100 mg to 1,000 mg of amoxicillin. Embodiment 16: Any one of Embodiments 1 to 14, wherein the pharmaceutical composition comprises 200 mg to 900 mg of amoxicillin. The pharmaceutical composition described above.

[0285] Aspect 17. The pharmaceutical composition according to any one of Aspects 1 to 16, wherein the pharmaceutical composition comprises 200 mg to 2,000 mg of the avibactam derivative. Aspect 18. The pharmaceutical composition according to any one of Aspects 1 to 16, wherein the pharmaceutical composition comprises 300 mg to 1,000 mg of the avibactam derivative.

[0286] Aspect 19. The pharmaceutical composition according to any one of Aspects 1 to 18, wherein the pharmaceutical composition comprises an amount of avibactam equivalent of 200 mg to 2,000 mg. Aspect 20. The pharmaceutical composition according to any one of Aspects 1 to 18, wherein the pharmaceutical composition comprises an amount of avibactam equivalent of 300 mg to 1,000 mg.

[0287] Aspect 21. The pharmaceutical composition comprises 100 mg to 1,000 mg of amoxicillin or a pharmaceutically acceptable salt thereof. and 300 mg to 2,000 mg of an avibactam derivative or a pharmaceutically acceptable salt thereof. 15. The pharmaceutical composition according to any one of aspects 1 to 14, comprising:

[0288] Aspect 22: The pharmaceutical composition according to any one of Aspects 1 to 21, wherein the pharmaceutical composition comprises an oral formulation. . Aspect 23: The pharmaceutical composition of any one of Aspects 1 to 22, wherein the pharmaceutical composition comprises an oral dosage form. .

[0289] Aspect 24. An oral dosage form comprising the pharmaceutical composition of any one of Aspects 1 to 23. Aspect 25. A kit comprising the pharmaceutical composition according to any one of Aspects 1 to 23. Embodiment 26. A first pharmaceutical composition comprising amoxicillin or a pharmaceutically acceptable salt thereof; and Eq. (1)

[0290] [ka]

[0291] [In the formula, each R 1 is C 1-6 alkyl, or each R 1 and the geminal carbon atom to which they are bonded are 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 5-6Heterocycloalkanediyl, 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 arenediyl, and substituted C 5-6 Selected from heteroarenediyl; 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; where 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, C5-8 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 substitution 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, exchange 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 heterocycloalkyl; and 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, exchange C 1-6 Alkyl, substituted C 5-8 Cycloalkyl, substituted C 6-12 Cycloalkylalkyl, substituted C 2-6Heteroalkyl, substituted C 5-8 Heterocycloalkyl, and substituted C 6-12 or a pharmaceutically acceptable salt thereof. a second pharmaceutical composition comprising the compound;

[0292] Embodiment 27. The avibactam derivative is represented by the formula (1a):

[0293] [ka]

[0294] (In the formula, each R 1 is C 1-6 independently selected from alkyl; R 3 is C 1-6 alkyl) or 27. The kit of embodiment 26, having a structure of a pharmaceutically acceptable salt of Aspect 28. 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]octadecanoate benzo-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylbutanoate; Ethyl 2-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octadecanoate benzo-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylbutanoate; Propyl 2-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octyl) Tan-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylbutanoate; Methyl 2-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octadecanoate benzo-6-yl)oxy)sulfonyl)oxy)methyl)-2-propylpentanoate; Ethyl 2-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octadecanoate benzo-6-yl)oxy)sulfonyl)oxy)methyl)-2-propylpentanoate; Propyl 2-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octyl) Tan-6-yl)oxy)sulfonyl)oxy)methyl)-2-propylpentanoate; a pharmaceutically acceptable salt of any of the above compounds; and Any combination of the above compounds 27. The kit according to embodiment 26, selected from:

[0295] Embodiment 29. An avibactam derivative having the structure:

[0296] [ka]

[0297] or a pharmaceutically acceptable salt thereof.

[0298] Aspect 30. 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-dimethyl 27. The kit of embodiment 26, wherein the compound is propanoate.

[0299] Aspect 31. The kit according to any one of Aspects 26 to 30, wherein each of the first pharmaceutical composition and the second pharmaceutical composition is an oral formulation. Aspect 32. A patient in need of treatment for a bacterial infection is administered a therapeutically effective amount of amoxicillin or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a compound of formula (1):

[0300] [ka]

[0301] [In the formula, each R 1 is C 1-6 alkyl, or each R 1 and the geminal carbon atom to which they are bonded are 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 5-6Heteroarenediyl, substituted C 1-6 Alkanediyl, substituted C 1-6 Heteroalkanediyl, substituted C 5-6 Cycloalkanediyl, substituted C 5-6 Heterocycloalkanediyl, substituted C6 arenediyl, and substituted C 5-6 Selected from heteroarenediyl; 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; where 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 7-10Aryl 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 substitution 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, exchange 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 heterocycloalkyl; and 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, exchange C 1-6 Alkyl, substituted C 5-8 Cycloalkyl, substituted C 6-12 Cycloalkylalkyl, substituted C 2-6 Heteroalkyl, substituted C 5-8Heterocycloalkyl, and substituted C 6-12 an avibactam derivative or a pharmaceutically acceptable salt thereof; 1. A method for treating a bacterial infection in a patient in need thereof, comprising orally administering

[0302] Embodiment 33. An avibactam derivative is represented by formula (1a):

[0303] [ka]

[0304] (In the formula, each R 1 is C 1-6 independently selected from alkyl; R 3 is C 1-6 alkyl) or 33. The method of treatment of embodiment 32, wherein the compound has the structure of a pharmaceutically acceptable salt of Aspect 34. 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]octadecanoate benzo-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylbutanoate; Ethyl 2-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octadecanoate benzo-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylbutanoate; Propyl 2-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octyl) Tan-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylbutanoate; Methyl 2-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octadecanoate benzo-6-yl)oxy)sulfonyl)oxy)methyl)-2-propylpentanoate; Ethyl 2-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octadecanoate benzo-6-yl)oxy)sulfonyl)oxy)methyl)-2-propylpentanoate; Propyl 2-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octyl) Tan-6-yl)oxy)sulfonyl)oxy)methyl)-2-propylpentanoate; a pharmaceutically acceptable salt of any of the above compounds; and Any combination of the above compounds 33. The method of treatment according to aspect 32, selected from:

[0305] Embodiment 35. An avibactam derivative having the structure:

[0306] [ka]

[0307] 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) having the formula 33. The method of claim 32, wherein:

[0308] Aspect 36. 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-dimethylpropionate. 33. The method of claim 32, wherein the compound is lopanoate.

[0309] Aspect 37. The method of treatment of any one of Aspects 32 to 36, wherein the bacterial infection is caused by an Actinomycetales bacterium. Embodiment 38. The method of any one of Embodiments 32 to 36, wherein the bacterial infection is caused by a bacterium of the genus Mycobacteriaceae, a bacterium of the genus Actinomycetaceae, a bacterium of the genus Nocardiaceae, or a combination of said bacteria. The treatment method described in any one of the above.

[0310] Embodiment 39: The method of any one of embodiments 32 to 36, wherein the bacterial infection is caused by a bacterium of the genus Mycobacteriaceae. 10. The method of claim 1, wherein the patient is a patient of a class I or a group II. Embodiment 40. The method of treatment of any one of embodiments 32 to 36, wherein the bacterial infection is caused by M. ulcerans.

[0311] Embodiment 41: Any one of Embodiments 32 to 36, wherein the bacterial infection is caused by M. abscessus. The treatment method described in one of the above. Aspect 42. The bacterial infection is a pulmonary infection, a soft tissue infection, a central nervous system infection, bacteremia, or an ocular infection. or any combination of said infections. The treatment method described in

[0312] Embodiment 43. Any of Embodiments 32 to 36, wherein the bacterial infection comprises a nontuberculous mycobacterial infection. or the treatment method described in one of the preceding paragraphs. Aspect 44. The nontuberculous mycobacterial infection is M. avium, M.intracellulare, M.kansasii, M.xenopi, M.marinum, M.malmoense, M.simiae, Nontuberculous mycobacteria, including M. abcessus, M. ulcerans, M. chelonae, M. fortuitum, or any combination of the above bacteria. 44. The method of claim 43, wherein the treatment is caused by sodium.

[0313] 45. The method of claim 4, wherein the administering comprises administering amoxicillin or a pharmaceutically acceptable salt thereof and A method of treatment according to any one of aspects 32 to 44, comprising administering the avibactam derivative or a pharmaceutically acceptable salt thereof in separate doses one to four times per day.

[0314] Aspect 46. The method of any one of Aspects 32 to 45, wherein the method of treatment comprises orally administering to a patient a total daily dose of 600 mg to 1,500 mg of amoxicillin or a pharmaceutically acceptable salt thereof; and a total daily dose of 600 mg to 4,200 mg of an avibactam equivalent of an avibactam derivative.

[0315] Aspect 47. The treatment regimen comprises a total daily dose of 600 mg to 1,500 mg of amoxicillin or a pharmaceutically acceptable salt thereof; and 900 mg of an avibactam derivative or a pharmaceutically acceptable salt thereof. any one of aspects 32-45, comprising orally administering to the patient a total daily dose of 1,800 mg or more; The treatment described.

[0316] Aspect 48. The treatment achieves sustained plasma concentrations of amoxicillin above the MIC of 8 μg / ml or greater. 48. The method of any one of aspects 32 to 47, comprising administering an amount of amoxicillin or a pharmaceutically acceptable salt thereof

[0317] Embodiment 49. The method of any one of embodiments 32 to 47, wherein the method of treatment comprises administering amoxicillin or a pharmaceutically acceptable salt thereof in an amount that achieves a sustained plasma concentration of amoxicillin above the MIC of 16 μg / ml or more.

[0318] 50. Orally administering amoxicillin or a pharmaceutically acceptable salt thereof, and an avibactam derivative or a pharmaceutically acceptable salt thereof.

[0319] 51. Oral administration of amoxicillin or a pharmaceutically acceptable salt thereof and orally administering a second dosage form comprising an avibactam derivative or a pharmaceutically acceptable salt thereof.

[0320] 52. The method of treatment comprises administering amoxicillin or a pharmaceutically acceptable salt thereof and amoxicillin. 52. The method of treatment of any one of aspects 32 to 51, comprising co-administering to the patient a bactam derivative or a pharmaceutically acceptable salt thereof.

[0321] Embodiment 53. A method of treatment comprising orally administering to a patient a first amount of amoxicillin or a pharmaceutically acceptable salt thereof and a first amount of an avibactam derivative or a pharmaceutically acceptable salt thereof. a first treatment phase comprising administering an amount of amoxicillin or a pharmaceutical preparation thereof; and a second amount of amoxicillin or a pharmaceutical preparation thereof. a pharmaceutically acceptable salt thereof, and a second amount of an avibactam derivative or a pharmaceutically acceptable salt thereof. a second treatment phase comprising orally administering to the patient a salt of the compound of formula (I) or (II) above.

[0322] Aspect 54. The method of treatment of Aspect 53, wherein the first amount of amoxicillin or a pharmaceutically acceptable salt thereof is greater than the second amount of amoxicillin or a pharmaceutically acceptable salt thereof. Embodiment 55. Any of Embodiments 53-54, wherein the first amount of the avibactam derivative or a pharmaceutically acceptable salt thereof is greater than the second amount of the avibactam derivative or a pharmaceutically acceptable salt thereof. The treatment method described in any one of the above.

[0323] Embodiment 56. A method of treatment according to any one of embodiments 53 to 55, wherein the first treatment phase has a duration of less than 12 weeks. Embodiment 57. A method of treatment according to any one of embodiments 53 to 55, wherein the first treatment phase has a duration of less than 4 weeks.

[0324] Embodiment 58. The method of treatment of any one of embodiments 53 to 57, wherein the second treatment phase has a duration of less than 12 months. Embodiment 59. The method of treatment of any one of embodiments 53 to 57, wherein the second treatment phase has a duration of less than 6 months.

[0325] Aspect 60: A therapeutically effective amount of the pharmaceutical composition according to any one of claims 1 to 23 is orally administered to a patient. 10. A method for treating a bacterial infection in a patient in need thereof, comprising administering Example The following examples illustrate the pharmacokinetics of ceftibuten and avibactam derivatives for treating bacterial infections. It will be apparent to those skilled in the art that many modifications and variations can be made to the materials and methods of this invention without departing from the spirit and scope of the invention. [Example]

[0326] Oral administration of avibactam derivatives The pharmacokinetics of avibactam supplied as an orally administered avibactam derivative were investigated in healthy volunteers.

[0327] A randomized, double-blind, placebo-controlled, single ascending dose Phase 1 study was conducted in adult men and women. Three cohorts (each containing 10 patients) received 300 mg, 900 mg, or 1,350 mg of avibactam derivative (3) [ethyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabiphenyl]. Cyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoic acid A single oral dose of 10 mg / ml of suspension (n=8) or placebo (n=2) was administered. I received it.

[0328] Plasma and urine PK samples were collected pre-dose and at frequent intervals post-dose. After oral administration of avibactam derivative (3), avibactam was detected in the systemic compartment. Rapid clearance of Avibacter was observed in each cohort. The PK of the drug is shown in Table 1.

[0329] Table 1. PK parameters for avibactam after oral administration of avibactam derivatives (3)

[0330] [Table 1]

[0331] The oral dose of avibactam derivative (3) 300 mg (equivalent to 202 mg of avibactam) is 62.5 mg IV. The dose is close to that of avibactam and shows similar pharmacokinetics. The oral dose of avibactam (607 mg equivalent) is close to the 400 mg IV avibactam dose, and is comparable to similar drugs. Kinetics are shown.

[0332] demonstrated that it is possible to maintain high concentrations of amoxicillin in the systemic circulation, reaching approximately 40% T > MIC. Based on these results for amoxicillin and the PK results for orally administered avibactam derivatives, it is possible to predict the efficacy of M. abscessus et al. It should be possible to treat infections caused by Ichthobacteria using the combination of orally administered amoxicillin and orally administered avibactam derivatives provided by the present invention.

[0333] Finally, it should be noted that there may be alternative ways of implementing the embodiments disclosed herein. Accordingly, the embodiments of the present invention should be considered as illustrative and not restrictive, and the claims should not be limited to the details set forth herein, but modifications may be made within the scope and equivalents of the claims.

Claims

1. amoxicillin or a pharmaceutically acceptable salt thereof; and The following structure 【Transformation 3】 or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising:

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