JP2020023484A - β-lactamase inhibitor - Google Patents

Abstract

To provide a β-lactamase inhibitor which is used for therapy of a bacterial infection caused by β-lactamase production bacteria, since, a β-lactamase inhibitor having a diazabicyclooctane skeleton which is available, exhibits effects to class type A and class type C out of the β-lactamase production bacteria, on the other hand, only partially exhibits effect to class type D, so that, sufficient effect to matrix expansion type β-lactamase production bacteria is not achieved.SOLUTION: There is provided the compound expressed by following formula (1)(chemical formula 1), a salt thereof which is permitted in a medical aspect, or a solvate thereof.SELECTED DRAWING: None

Description

  The present invention relates to novel diazabicyclooctene derivatives, pharmaceutically acceptable salts, and solvates thereof. The present invention also relates to the use of these β-lactamase inhibitors in treating bacterial infections. Furthermore, the present invention relates to pharmaceutical compositions and methods for treating bacterial infections using the compounds of the present invention.

  Penicillins and cephalosporins are most widely and frequently used in medical practice having a β-lactam ring in their skeleton, and are called β-lactam antibiotics. However, in recent years, various infection-causing bacteria have acquired resistance to β-lactam antibiotics, and their therapeutic effects have been reduced. The most prominent mechanism of resistance is the production of class A, C and D types of β-lactamases with a serine residue in the active center. These enzymes degrade β-lactam antibiotics, leading to inactivation of antibacterial activity. Class A β-lactamases have substrate specificity mainly for penicillins, and class C β-lactamases have substrate specificity mainly for cephalosporins. Commercially available β-lactamase inhibitors, clavulanic acid, sulbactam, and tazobactam are effective mainly for class A β-lactamase-producing bacteria and are combined with penicillin antibiotics. Avibactam is effective against class A-type and C-type β-lactamase-producing bacteria, but has only a limited effect on class D-type β-lactamase-producing bacteria.

  Under the circumstances where more than 1500 types of β-lactamases have been reported, the spread of the above-mentioned commercially available inhibitors, such as the diffusion of class C β-lactamases and extended substrate-specific β-lactamases belonging to classes A and D (ESBL), has been reported. There is a demand for the development of a new inhibitor for the invalid cases. In recent years, infectious diseases caused by the above-mentioned resistant bacteria have been scattered not only in severe infectious diseases but also in community-acquired infectious diseases, and first-line drugs (eg, penicillins or cephalosporins, etc.) There is a strong demand for the development of new inhibitors that can be used in combination with the above. However, although there are reports of potential inhibitors and reports for the treatment of severe infectious diseases, there are not many candidate compounds to be developed.

  In recent years, WO2002 / 010172 (Patent Document 1) or WO2003 / 063864 (Patent Document 2) has disclosed that a certain diazabicyclooctane derivative has an antibacterial agent having a non-β-lactam skeleton. Or as a β-lactamase inhibitor as a promising compound for treating infectious diseases. As a production method, in addition to the above-mentioned documents, a method disclosed in WO 2013/150296 (Patent Document 3) is disclosed.

International Publication No. WO2002 / 010172 International Publication No. WO 2003/063864 International Publication No. 2013/150296

  Avibactam and Relebactam, currently available β-lactamase inhibitors having a diazabicyclooctane skeleton, are effective against class A and class C among β-lactamase producing bacteria. On the other hand, the effect on class D type is limited, and the effect on extended substrate β-lactamase producing bacteria (ESBL) is not sufficient. An object of the present invention is to provide a novel β-lactamase inhibitor for use in treating bacterial infections caused by all these β-lactamase-producing bacteria.

  The present inventors conducted a search for a novel β-lactamase inhibitor effective against β-lactamase-producing bacteria at issue, particularly class A, class C and class D β-lactamases, and obtained the formula (1) ), A novel diazabicyclooctene derivative was found. In addition, it has been found that the compound of the present invention, when used in combination with a β-lactam antibiotic, strongly restores the antibacterial activity of the antibiotic-resistant bacteria, and thus completed the present invention.

［式（１）中、Ｒ^１は、−ＮＨＣＯＲ^２又は−ＯＲ^３であり、
Ｒ^２はＣ_１−６アルキル、Ｃ_３−６シクロアルキル、Ｃ_１−６アルコキシ、Ｃ_３−６シクロアルコキシ、アミノ、フェニル、ヘテロシクリル、又はヘテロアリールであり、
前記Ｒ^２は、ハロゲン原子、ヒドロキシ、フェニル、ハロゲン原子で置換されていてもよいＣ_１−６アルキル、ハロゲン原子で置換されていてもよいＣ_３−６シクロアルキル、ハロゲン原子で置換されていてもよいＣ_１−６アルコキシ、ハロゲン原子で置換されていてもよいＣ_３−６シクロアルコキシ、アミノ、Ｃ_１−６アルキルアミノ、ジＣ_１−６アルキルアミノ、ヘテロシクリル及びヘテロアリールからなる群から選択される１から４個の基で置換されていてもよく、
Ｒ^３は、Ｃ_１−６アルキル、Ｃ_３−６シクロアルキル、フェニル、ヘテロシクリル、又はヘテロアリ−ルであり、
前記Ｒ^３は、ハロゲン原子、ヒドロキシ、フェニル、ハロゲン原子で置換されていてもよいＣ_１−６アルキル、ハロゲン原子で置換されていてもよいＣ_３−６シクロアルキル、ハロゲン原子で置換されていてもよいＣ_１−６アルコキシ、ハロゲン原子で置換されていてもよいＣ_３−６シクロアルコキシ、カルボキシ、アミノカルボニル、ヘテロシクリルアミノカルボニル、スルファモイル、アミノ、Ｃ_１−６アルキルアミノ、ジＣ_１−６アルキルアミノ、Ｃ_３−６シクロアルキルアミノ、ジＣ_１−６アルキルアミノカルボニル、Ｃ_１−６アルキルスルホニル、次式：−ＮＨＣＯＲ^４で表される基、ヘテロシクリル及びヘテロアリールからなる群から選択される１から４個の基で置換されていてもよく、
Ｒ^４は、Ｃ_１−６アルキル、Ｃ_３−６シクロアルキル、フェニル、アミノ、ヘテロシクリル又はヘテロアリールであり、
前記Ｒ^４は、ハロゲン原子、ヒドロキシ、アミノ、フェニル、Ｃ_１−６アルキルアミノ、ジＣ_１−６アルキルアミノ及びＣ_１−６アルキルからなる群から選択される１から４個の基で置換されていてもよく、
Ｍは、水素原子、ナトリウム原子又はカリウム原子である。］
［２］前記式（１）中、Ｒ^２が、Ｃ_１−６アルキル基であり、
前記Ｒ^２は、アミノ基で置換されていてもよく、
Ｒ^３が、ヘテロシクリル基である［１］に記載の化合物、その医学的に許容されうる塩、又はその溶媒和物。
［３］前記式（１）で表される化合物が、
（２Ｓ，５Ｒ）−Ｎ−（２−アミノエトキシ）−３−メチル−７−オキソ−６−（スルホオキシ）−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−２−カルボキサミド、
（２Ｓ，５Ｒ）−３−メチル−７−オキソ−Ｎ‘−［（３Ｒ）−ピペリジン−３−カルボニル］−６−（スルホオキシ）−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−２−カルボヒドラジド、
ナトリウム[({（２Ｓ，５Ｒ）−２−[(２−メトキシエトキシ）カルバモイル］−３−メチル−７−オキソ−６−（スルホオキシ）−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−６−イル｝オキシ）スルホニル］オキシダニド、
（２Ｓ，５Ｒ）−Ｎ−｛［（２Ｓ）−アゼチジン−２−イル］メトキシ｝−３−メチル−７−オキソ−６−（スルホオキシ）−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−２−カルボキサミド、
（２Ｓ，５Ｒ）−Ｎ−（３−アミノプロポキシ）−３−メチル−７−オキソ−６−（スルホオキシ）−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−２−カルボキサミド、
（２Ｓ，５Ｒ）−３−メチル−７−オキソ−Ｎ−｛［（２Ｓ）−ピロリジン−２−イル］メトキシ｝−６−（スルホオキシ）−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−２−カルボキサミド、
（２Ｓ，５Ｒ）−３−メチル−７−オキソ−Ｎ−｛［（３Ｒ）−ピペリジン−３−イル］メトキシ｝−６−（スルホオキシ）−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−２−カルボキサミド、
（２Ｓ，５Ｒ）−Ｎ−［（２Ｓ）−２−アミノプロポキシ］−３−メチル−７−オキソ−６−（スルホオキシ）−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−２−カルボキサミド、
（２Ｓ，５Ｒ）−３−メチル−７−オキソ−Ｎ−｛［（２Ｒ）−ピロリジン−２−イル］メトキシ｝−６−（スルホオキシ）−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−２−カルボキサミド、
（２Ｓ，５Ｒ）−Ｎ−［２−（エチルアミノ）エトキシ］−３−メチル−７−オキソ−６−（スルホオキシ）−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−２−カルボキサミド、
（２Ｓ，５Ｒ）−３−メチル−Ｎ−［２−（メチルアミノ）エトキシ］−７−オキソ−６−（スルホオキシ）−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−２−カルボキサミド、
（２Ｓ，５Ｒ）−３−メチル−７−オキソ−Ｎ−｛［（３Ｓ）−ピロリジン−３−イル］オキシ｝−６−（スルホオキシ）−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−２−カルボキサミド、
（２Ｓ，５Ｒ）−Ｎ−｛［アゼチジン−３−イル］メトキシ｝−３−メチル−７−オキソ−６−（スルホオキシ）−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−２−カルボキサミド、
（２Ｓ，５Ｒ）−Ｎ‘−［（２Ｓ）−２−アミノプロパノイル］−３−メチル−７−オキソ−６−（スルホオキシ）−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−２−カルボヒドラジド、
（２Ｓ，５Ｒ）−３−メチル−７−オキソ−Ｎ‘−［（２Ｓ）−ピロリジン−２−カルボニル］−６−（スルホオキシ）−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−２−カルボヒドラジド、
ナトリウム ({［（２Ｓ，５Ｒ）−２− (エトキシカルバモイル）−３−メチル−７−オキソ−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−６−イル］オキシ｝スルホニル）オキシダニド、
ナトリウム ({［（２Ｓ，５Ｒ）−２−{［ ２−(ジメチルアミノ) −２−オキソエトキシ］カルバモイル｝−３−メチル−７−オキソ−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−６−イル］オキシ｝スルホニル）オキシダニド、
ナトリウム ({［（２Ｓ，５Ｒ）−２− (メトキシカルバモイル）−３−メチル−７−オキソ−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−６−イル］オキシ｝スルホニル）オキシダニド、
ナトリウム［({（２Ｓ，５Ｒ）−２−［ (シクロプロピルメトキシ) カルバモイル］−３−メチル−７−オキソ−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−６−イル｝オキシ）スルホニル］オキシダニド、
ナトリウム ({［（２Ｓ，５Ｒ）−３−メチル−７−オキソ−２− (フェノキシカルバモイル）−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−６−イル］オキシ｝スルホニル）オキシダニド、又は
ナトリウム ({［（２Ｓ，５Ｒ）−３−メチル−２−｛［(オキセタン−３−イル)メトキシ］カルバモイル｝−７−オキソ−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−６−イル］オキシ｝スルホニル）オキシダニドである［１］又は［２］に記載の化合物、その医学的に許容されうる塩、又はその溶媒和物。
［４］前記式（１）で表される化合物が、下記式：

である［１］又は［２］に記載の化合物、その医学的に許容されうる塩、又はその溶媒和物。
［５］［１］から［４］のうちのいずれかに記載の化合物、その医学的に許容されうる塩、及びその溶媒和物からなる群から選択される少なくとも１種を有効成分として含有し、場合によっては医学的に許容される担体を含んでなる医薬組成物。
［６］β−ラクタム系抗生物質と併用して投与するための、［５］に記載の医薬組成物。
［７］細菌感染症を治療するための、［５］又は［６］に記載の医薬組成物。
［８］［１］から［４］のうちのいずれかに記載の化合物、その薬理的に許容される塩、及びその溶媒和物からなる群から選択される少なくとも１種を有効成分として含有するβ−ラクタマーゼ阻害剤。
［９］［８］に記載のβ−ラクタマーゼ阻害剤と、β−ラクタム系抗生物質と、場合によっては医学的に許容される担体を含んでなる医薬組成物。
［１０］β−ラクタム系抗生物質が、アンピシリン、アモキシシリン、ピペラシリン、チカルシリン、フロモキセフ、セフォタキシム、セフトリアキソン、セフタジジム、セフェピム、セフタロリン、セフトロザン、セフィデロコール、イミペネム、メロペネム、ビアペネム、ドリペネム、エルタペネム又はアズトレオナムである［９］に記載の医薬組成物。
［１１］［８］に記載のβ−ラクタマーゼ阻害剤と、β−ラクタム系抗生物質とを併用して投与する細菌感染症の治療方法。
［１２］β−ラクタム系抗生物質が、アンピシリン、アモキシシリン、ピペラシリン、チカルシリン、フロモキセフ、セフォタキシム、セフトリアキソン、セフタジジム、セフェピム、セフタロリン、セフトロザン、セフィデロコール、イミペネム、メロペネム、ビアペネム、ドリペネム、エルタペネム又はアズトレオナムである［１１］に記載の細菌感染症の治療方法。 That is, the present invention includes the following aspects.
[1] A compound represented by the following formula (1), a medically acceptable salt thereof, or a solvate thereof.

[In the formula (1), R ¹ is —NHCOR ² or —OR ³ ;
R ² is C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, amino, phenyl, heterocyclyl, or heteroaryl;
R ² is a halogen atom, hydroxy, phenyl, C _1-6 alkyl optionally substituted with a halogen atom, C _3-6 cycloalkyl optionally substituted with a halogen atom, substituted with a halogen atom. also a _{C 1-6} alkoxy, optionally _{C 3-6} cycloalkoxy optionally substituted with halogen atoms selected _{amino, C 1-6} alkylamino, _{di-C 1-6} alkylamino, from the group consisting of heterocyclyl and heteroaryl May be substituted with 1 to 4 groups represented by
R ³ is C _1-6 alkyl, C _3-6 cycloalkyl, phenyl, heterocyclyl, or heteroaryl;
R ³ is a halogen atom, hydroxy, phenyl, C _1-6 alkyl optionally substituted with a halogen atom, C _3-6 cycloalkyl optionally substituted with a halogen atom, substituted with a halogen atom. C _1-6 alkoxy, C _3-6 cycloalkoxy optionally substituted with a halogen atom, carboxy, aminocarbonyl, heterocyclylaminocarbonyl, sulfamoyl, amino, C _1-6 alkylamino, diC _1-6 alkyl Amino, C _3-6 cycloalkylamino, di C _1-6 alkylaminocarbonyl, C _1-6 alkylsulfonyl, a group represented by the following formula: —NHCOR ⁴ , 1 selected from the group consisting of heterocyclyl and heteroaryl May be substituted with 4 groups,
R ⁴ is C _1-6 alkyl, C _3-6 cycloalkyl, phenyl, amino, heterocyclyl or heteroaryl;
R ⁴ is substituted with 1 to 4 groups selected from the group consisting of a halogen atom, hydroxy, amino, phenyl, C _1-6 alkylamino, diC _1-6 alkylamino and C _1-6 alkyl. May be
M is a hydrogen atom, a sodium atom or a potassium atom. ]
[2] In the formula (1), R ² is a C _1-6 alkyl group,
R ² may be substituted with an amino group,
The compound according to [1], wherein R ³ is a heterocyclyl group, a pharmaceutically acceptable salt thereof, or a solvate thereof.
[3] The compound represented by the formula (1) is
(2S, 5R) -N- (2-aminoethoxy) -3-methyl-7-oxo-6- (sulfoxy) -1,6-diazabicyclo [3.2.1] oct-3-en-2-carboxamide ,
(2S, 5R) -3-Methyl-7-oxo-N '-[(3R) -piperidine-3-carbonyl] -6- (sulfoxy) -1,6-diazabicyclo [3.2.1] oct-3 -En-2-carbohydrazide,
Sodium [({(2S, 5R) -2-[(2-methoxyethoxy) carbamoyl] -3-methyl-7-oxo-6- (sulfoxy) -1,6-diazabicyclo [3.2.1] oct- 3-en-6-yl {oxy) sulfonyl] oxydanide,
(2S, 5R) -N-{[(2S) -azetidin-2-yl] methoxy} -3-methyl-7-oxo-6- (sulfooxy) -1,6-diazabicyclo [3.2.1] oct -3-en-2-carboxamide,
(2S, 5R) -N- (3-aminopropoxy) -3-methyl-7-oxo-6- (sulfoxy) -1,6-diazabicyclo [3.2.1] oct-3-en-2-carboxamide ,
(2S, 5R) -3-methyl-7-oxo-N-{[(2S) -pyrrolidin-2-yl] methoxy} -6- (sulfooxy) -1,6-diazabicyclo [3.2.1] oct -3-en-2-carboxamide,
(2S, 5R) -3-methyl-7-oxo-N-{[(3R) -piperidin-3-yl] methoxy} -6- (sulfooxy) -1,6-diazabicyclo [3.2.1] oct -3-en-2-carboxamide,
(2S, 5R) -N-[(2S) -2-aminopropoxy] -3-methyl-7-oxo-6- (sulfoxy) -1,6-diazabicyclo [3.2.1] oct-3-ene -2-carboxamide,
(2S, 5R) -3-methyl-7-oxo-N-{[(2R) -pyrrolidin-2-yl] methoxy} -6- (sulfooxy) -1,6-diazabicyclo [3.2.1] oct -3-en-2-carboxamide,
(2S, 5R) -N- [2- (ethylamino) ethoxy] -3-methyl-7-oxo-6- (sulfoxy) -1,6-diazabicyclo [3.2.1] oct-3-ene- 2-carboxamide,
(2S, 5R) -3-methyl-N- [2- (methylamino) ethoxy] -7-oxo-6- (sulfooxy) -1,6-diazabicyclo [3.2.1] oct-3-ene- 2-carboxamide,
(2S, 5R) -3-methyl-7-oxo-N-{[(3S) -pyrrolidin-3-yl] oxy} -6- (sulfooxy) -1,6-diazabicyclo [3.2.1] oct -3-en-2-carboxamide,
(2S, 5R) -N-{[azetidin-3-yl] methoxy} -3-methyl-7-oxo-6- (sulfoxy) -1,6-diazabicyclo [3.2.1] oct-3-ene -2-carboxamide,
(2S, 5R) -N '-[(2S) -2-aminopropanoyl] -3-methyl-7-oxo-6- (sulfoxy) -1,6-diazabicyclo [3.2.1] oct-3 -En-2-carbohydrazide,
(2S, 5R) -3-methyl-7-oxo-N '-[(2S) -pyrrolidine-2-carbonyl] -6- (sulfooxy) -1,6-diazabicyclo [3.2.1] oct-3 -En-2-carbohydrazide,
Sodium ({[(2S, 5R) -2- (ethoxycarbamoyl) -3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yl] oxy} sulfonyl ) Oxidanid,
Sodium ({[(2S, 5R) -2-{[2- (dimethylamino) -2-oxoethoxy] carbamoyl} -3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct -3-en-6-yl] oxy} sulfonyl) oxydanide,
Sodium ({[(2S, 5R) -2- (methoxycarbamoyl) -3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yl] oxy} sulfonyl ) Oxidanid,
Sodium [({(2S, 5R) -2-[(cyclopropylmethoxy) carbamoyl] -3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yl [｝ Oxy) sulfonyl] oxydanide,
Sodium ({[(2S, 5R) -3-methyl-7-oxo-2- (phenoxycarbamoyl) -1,6-diazabicyclo [3.2.1] oct-3-en-6-yl] oxy} sulfonyl ) Oxanidide or sodium ({[(2S, 5R) -3-methyl-2-{[(oxetan-3-yl) methoxy] carbamoyl} -7-oxo-1,6-diazabicyclo [3.2.1] The compound according to [1] or [2], which is oct-3-en-6-yl] oxy {sulfonyl) oxydanide, a pharmaceutically acceptable salt thereof, or a solvate thereof.
[4] The compound represented by the formula (1) is represented by the following formula:

The compound according to [1] or [2], a pharmaceutically acceptable salt thereof, or a solvate thereof.
[5] The compound according to any one of [1] to [4], a pharmaceutically acceptable salt thereof, and at least one selected from the group consisting of a solvate thereof as an active ingredient. A pharmaceutical composition, optionally comprising a pharmaceutically acceptable carrier.
[6] The pharmaceutical composition according to [5], for administration in combination with a β-lactam antibiotic.
[7] The pharmaceutical composition according to [5] or [6], for treating a bacterial infection.
[8] The compound according to any one of [1] to [4], a pharmaceutically acceptable salt thereof, and at least one selected from the group consisting of solvates thereof, as an active ingredient. β-lactamase inhibitors.
[9] A pharmaceutical composition comprising the β-lactamase inhibitor according to [8], a β-lactam antibiotic, and optionally a medically acceptable carrier.
[10] The β-lactam antibiotic is ampicillin, amoxicillin, piperacillin, ticarcillin, flomoxef, cefotaxime, ceftriaxone, ceftazidime, cefepime, ceftaroline, ceftrozan, cefiderocole, imipenem, meropenem, biapenem leopanet, or biapenem leoprenem The pharmaceutical composition according to [9], which is
[11] A method for treating bacterial infection, which comprises administering the β-lactamase inhibitor according to [8] and a β-lactam antibiotic in combination.
[12] The β-lactam antibiotic is ampicillin, amoxicillin, piperacillin, ticarcillin, flomoxef, cefotaxime, ceftriaxone, ceftazidime, cefepime, ceftaroline, ceftrozan, cefiderocole, imipenem, meropenem, biapenem olepenem, dopepenem leopenem, biapenem leonem [11] The method for treating a bacterial infection according to [11].

  The novel diazabicyclooctene derivative represented by the formula (1) provided by the present invention exhibits a strong inhibitory activity against various β-lactamases, and in particular, class A-type, class C-type, and class D-type β-lactamase Has strong inhibitory activity against Specifically, they show strong inhibitory activity against class C β-lactamases, extended-substrate β-lactamases (ESBL), KPC-2 and OXA-48β-lactamases, and produce β-lactamases that produce these β-lactamases. -Antibacterial activity of β-lactam antibiotics can be strongly restored to bacteria that are resistant to lactam antibiotics by using them together with existing β-lactam antibiotics. As described above, the compound of the present invention has excellent β-lactamase inhibitory activity and is useful for treating bacterial infections.

  In one embodiment, the present invention provides a compound represented by the following formula (1), a pharmaceutically acceptable salt thereof, or a solvate thereof, and further comprising β- A lactamase inhibitor is provided.

In the above formula (1), R ¹ is —NHCOR ² or —OR ³ ;
R ² is C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, amino, phenyl, heterocyclyl, or heteroaryl;
R ² is a halogen atom, hydroxy, phenyl, C _1-6 alkyl optionally substituted with a halogen atom, C _3-6 cycloalkyl optionally substituted with a halogen atom, substituted with a halogen atom. also a _{C 1-6} alkoxy, optionally _{C 3-6} cycloalkoxy optionally substituted with halogen atoms selected _{amino, C 1-6} alkylamino, _{di-C 1-6} alkylamino, from the group consisting of heterocyclyl and heteroaryl May be substituted with 1 to 4 groups represented by
R ³ is C _1-6 alkyl, C _3-6 cycloalkyl, phenyl, heterocyclyl, or heteroaryl;
R ³ is a halogen atom, hydroxy, phenyl, C _1-6 alkyl optionally substituted with a halogen atom, C _3-6 cycloalkyl optionally substituted with a halogen atom, substituted with a halogen atom. C _1-6 alkoxy, C _3-6 cycloalkoxy optionally substituted with a halogen atom, carboxy, aminocarbonyl, heterocyclylaminocarbonyl, sulfamoyl, amino, C _1-6 alkylamino, diC _1-6 alkyl Amino, C _3-6 cycloalkylamino, di C _1-6 alkylaminocarbonyl, C _1-6 alkylsulfonyl, a group represented by the following formula: —NHCOR ⁴ , 1 selected from the group consisting of heterocyclyl and heteroaryl May be substituted with 4 groups,
R ⁴ is C _1-6 alkyl, C _3-6 cycloalkyl, phenyl, amino, heterocyclyl or heteroaryl;
R ⁴ is substituted with 1 to 4 groups selected from the group consisting of a halogen atom, hydroxy, amino, phenyl, C _1-6 alkylamino, diC _1-6 alkylamino and C _1-6 alkyl. May be
M is a hydrogen atom, a sodium atom or a potassium atom.

  Hereinafter, the compound represented by the formula (1) of the present invention, the β-lactamase inhibitor, and the use of the compound of the present invention for the treatment of bacterial infection will be described in detail. It is not limited to the range.

In this specification,
The “salt” is a pharmaceutically acceptable salt, and examples thereof include an acid addition salt and the like from an inorganic acid or an organic acid.

  Examples of the “solvate” include a hydrate, a methanol solvate, an ethanol solvate, an isopropanol solvate, an acetone solvate, a methyl ethyl ketone solvate and the like, and preferably a hydrate.

“C _1-6 alkyl” means an alkyl group having 1 to 6 carbon atoms, which may be linear or branched. Specific examples of C _1-6 alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, s-butyl, isobutyl, pentyl, 1,1-dimethylpropyl, 1,2- Examples include alkyl groups such as dimethylpropyl, neopentyl, 1-methylbutyl, 2-methylbutyl, isopentyl, and hexyl, and preferred are methyl, ethyl, propyl, isopropyl, n-butyl and tert-butyl.

“C _3-6 cycloalkyl” means a cycloalkyl group having 3 to 6 carbon atoms or a methyl group to which a cyclic alkyl group having 3 to 5 carbon atoms is bonded. Specific examples of “C _3-6 cycloalkyl” include cycloalkyl and cycloalkylmethyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl and cyclopentylmethyl, and are preferred. Is cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl.

“C _1-6 alkoxy” means a group in which one of the above C _1-6 alkyl is bonded to an oxygen atom. Specific examples of C _1-6 alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, s-butoxy, isobutoxy, n-pentoxy, 1,1-dimethylpropoxy, , 2-dimethylpropoxy, neopentoxy, 1-methylbutoxy, 2-methylbutoxy, isopentoxy, hexyloxy, benzyloxy, etc., preferably methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy. is there.

“C _3-6 cycloalkoxy” means a group in which one of the above C _3-6 cycloalkyl is bonded to an oxygen atom. Specific examples of C _3-6 cycloalkoxy include cycloalkoxy groups such as cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, and preferably cyclopropoxy, Cyclobutyl methoxy.

  "Heterocyclyl" means a 3-7 membered monocyclic non-aromatic heterocycle having 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. Specific examples of heterocyclyl include aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, imidazolidine, oxazolidine, thiazolidine, pyrazolidine, piperidine, tetrahydro-2H-pyran, tetrahydro-2H-thiopyran , Hexahydropyridazine, piperazine, morpholine, thiomorpholine, 1,2-oxazolidine, 1,2-oxadinane, 1,4-dioxane, 1,2-thiazinane, azepane, oxepane, tiepan, 1,4-diazepane, 1, 4-oxazepane, 1,4-thiazepane, 1,2,5-triazepane, 1,4,5-oxadiazepane, 1,2,5-oxadiazepane, 1,4,5-thiadiazepane, 1,5,2-di Sazepan, 1,5,2-oxathiazepan, 3,4-dihydro-2H-pyrrole, 4,5-dihydro-1H-pyrazole, 4,5-dihydro-1H-imidazole, 4,5-dihydro-1,2- Oxazole, 4,5-dihydro-1,3-oxazole, 4,5-dihydro-1,3-thiazole, 2,3,4,5-tetrahydropyridine, 1,2,3,6-tetrahydropyrazine, 5, Groups derived from 6-dihydro-4H-1,2-oxazine and 3,6-dihydro-2-H-1,4-oxazine; and preferably azetidine, pyrrolidine, tetrahydrofuran, piperidine, tetrahydro-2H. -Pyran, imidazolidine, oxazolidine, 1,2-oxazolidine, hexahydropyridazine, piperazine, morpholine, 1, - oxazinan, azepane, 1,4-diazepane, a group 1,2-oxazepane, derived from oxetane.

  “Heteroaryl” means a 5- to 6-membered monocyclic aromatic heterocycle having 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. Specific examples of heteroaryl include pyrrole, furan, thiophene, pyrazole, imidazole, 1,2-oxazole, 1,3-oxazole, 1,2-thiazole, 1,3-thiazole, 1,2,3- Triazole, 1,2,4-triazole, 1,2,3-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole, tetrazole, pyridine, Examples include groups derived from pyridazine, pyrimidine, pyrazine, 1,2,4-triazine, 1,3,5-triazine, and the like, and preferably groups derived from pyrrole, furan, imidazole, oxazole, and pyridine.

  "Halogen atom" is a fluorine, chlorine, bromine or iodine atom.

  “Optionally substituted” and “optionally substituted” mean that each group may be further substituted with one or more substituents.

“C _1-6 alkylamino” means a group in which one hydrogen atom of an amino group is substituted with the above-mentioned C _1-6 alkyl. Specific examples of C _1-6 alkylamino include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, tert-butylamino, s-butylamino, isobutylamino, pentylamino, And alkylamino groups such as 1,1-dimethylpropylamino, 1,2-dimethylpropylamino, neopentylamino, 1-methylbutylamino, 2-methylbutylamino, isopentylamino, and n-hexylamino.

“Di C _1-6 alkylamino” means a group in which two hydrogen atoms of an amino group are substituted with the above C _1-6 alkyl. Specific examples of diC _1-6 alkylamino include dialkylamino groups such as dimethylamino, ethylmethylamino, diethylamino, di-n-propylamino and diisopropylamino.

  “Heterocyclylaminocarbonyl” means a group in which one hydrogen atom of an amino group of an aminocarbonyl group is substituted with the above-mentioned heterocyclyl. Specific examples of heterocyclylaminocarbonyl include (piperidin-4-yl) aminocarbonyl, (piperidin-3-yl) aminocarbonyl, (pyrrolidin-3-yl) aminocarbonyl, and (azetidin-3-yl) aminocarbonyl And the like.

“C _3-6 cycloalkylamino” means a group in which one hydrogen atom of an amino group is substituted with the above C _3-6 cycloalkyl. Specific examples of C _3-6 cycloalkylamino include cycloalkylamino groups such as cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cyclopropylmethylamino, cyclobutylmethylamino, and cyclopentylmethylamino; Examples include an alkylmethylamino group, preferably cyclopropylamino, cyclobutylamino, cyclopropylmethylamino, cyclobutylmethylamino and the like.

“Di C _1-6 alkylaminocarbonyl” means a group in which the di C _1-6 alkylamino group is amide-bonded to a carbonyl group. Specific examples of diC _1-6 alkylaminocarbonyl include dialkylaminocarbonyl groups such as dimethylaminocarbonyl, diethylaminocarbonyl, di-n-propylaminocarbonyl, diisopropylaminocarbonyl, and di-n-butylaminocarbonyl. And preferably dimethylaminocarbonyl and diethylaminocarbonyl.

“C _1-6 alkylsulfonyl” means a group formed by bonding the above C _1-6 alkyl to a sulfonyl group. Specific examples of C _1-6 alkylsulfonyl include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, tert-butylsulfonyl, s-butylsulfonyl, isobutylsulfonyl, n-pentylsulfonyl An alkylsulfonyl group such as 1,1,1-dimethylpropylsulfonyl, 1,2-dimethylpropylsulfonyl, neopentylsulfonyl, 1-methylbutylsulfonyl, 2-methylbutylsulfonyl, isopentylsulfonyl, and n-hexylsulfonyl; Preferred are methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, and n-butylsulfonyl.

  Specific examples of the acid forming the “acid addition salt” include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, hemisulfuric acid, thiocyanic acid, acetic acid, butyric acid, propionate, cyclopentanepropionic acid, Pivalic acid, heptanoic acid, hexanoic acid, 3-phenylpropionic acid, undecanoic acid, lactic acid, oxalic acid, malonic acid, succinic acid, citric acid, tartaric acid, malic acid, maleic acid, fumaric acid, adipic acid, alginic acid, aspartic acid , Benzoic acid, digluconic acid, nicotinic acid, pamoic acid, pectic acid, glucoheptanic acid, glycerophosphoric acid, benzenesulfonic acid, tosylic acid, methanesulfonic acid, ethanesulfonic acid, camphorsulfonic acid, dodecyl sulfate, 2-hydroxyethane sulfone Acid, and 2-naphthalenesulfonic acid, and the like, preferably, hydrochloric acid, sulfuric acid, acetic acid, lactic acid,檎酸, citric acid, methanesulfonic acid, tosyl acid.

In the formula ^(1), R 2, ^{R 3} or ^{R 4} is _{"C 1-6} alkyl", as the _{"C 1-6} alkyl", "hydroxy" group is substituted as the group which may be substituted Is 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxy-1-methylethyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 1,1-dimethyl-2-hydroxy Ethyl, 2-hydroxy-1-methylpropyl, 3-hydroxy-2-methylpropyl are preferred.

In the formula ^(1), R 2, ^{R 3} or ^{R 4} is _{"C 1-6} alkyl", as the _{"C 1-6} alkyl", "amino" group is substituted as the group which may be substituted Is aminomethyl, 2-aminoethyl, 2-aminopropyl, 3-aminopropyl, 2-amino-1-methylethyl, 2-aminobutyl, 3-aminobutyl, 4-aminobutyl, 2-amino-1, 1-dimethylethyl, 2-amino-1-methylpropyl, 3-amino-2-methylpropyl are preferred.

In the formula (1), when R ² , R ³ or R ⁴ is “C _1-6 alkyl”, “C ₁ -alkylamino” may be substituted as “C _1-6 alkylamino” group. _-6 alkyl "includes 2-methylaminoethyl, 2-ethylaminoethyl, 2-propylaminoethyl, 2-isopropylaminoethyl, 3-methylaminopropyl, 3-ethylaminopropyl, 3-propylaminopropyl, -Isopropylaminopropyl is preferred.

In the formula ^(1), R 2, if ^{R 3} or ^{R 4} is _{"C 1-6} alkyl", _{"di-C 1-6} alkylamino" group is substituted as the group which may be substituted "C _1-6 alkyl "includes 2-dimethylaminoethyl, 2-ethylmethylaminoethyl, 2-diethylaminoethyl, 2-dipropylaminoethyl, 2-diisopropylaminoethyl, 3-dimethylaminopropyl, 3-diethylaminopropyl, 3-Dipropylaminopropyl and 3-diisopropylaminopropyl are preferred.

In the formula (1), when R ² or R ³ is a "C _1-6 alkyl", of the "heterocyclyl" group is substituted "C _1-6 alkyl" as a group which may be substituted, methyl Specific examples of substitution with a group or an ethyl group include azetidin-2-ylmethyl, azetidin-3-ylmethyl, pyrrolidin-2-ylmethyl, 2- (pyrrolidin-2-yl) ethyl, pyrrolidin-3-ylmethyl, tetrahydrofuran -3-ylmethyl, tetrahydrothiophen-3-ylmethyl, pyrazolidin-4-ylmethyl, 1,2-oxazolidin-3-ylmethyl, piperidin-2-ylmethyl, piperidin-3-ylmethyl, piperidin-4-ylmethyl, tetrahydro-2H- Pyran-4-ylmethyl, tetrahydro-2H-thiopyran-4-ylmethyl , Hexahydropyridazin-4-ylmethyl, piperazin-2-ylmethyl, 2- (piperazin-2-yl) ethyl, 1,2-oxazinan-3-ylmethyl, morpholin-2-ylmethyl, morpholin-3-ylmethyl, thiol Morpholin-2-ylmethyl, thiomorpholin-3-ylmethyl, azepan-2-ylmethyl, azepan-4-ylmethyl, oxepan-2-ylmethyl, oxepan-4-ylmethyl, 1,4-diazepan-2-ylmethyl, 1,4 -Diazepan-6-ylmethyl, 2- (azetidin-1-yl) ethyl, 2- (pyrrolidin-1-yl) ethyl, 2- (pyrazolidin-1-yl) ethyl, 2- (piperidin-1-yl) ethyl , 2- (hexahydropyridazin-1-yl) ethyl, 2- (piperazin-1-yl) Ethyl, 2- (morpholin-4-yl) ethyl, 2- (thiomorpholin-4-yl) ethyl, 2- (1,2-oxazolidin-2-yl) ethyl, 2- (1,2-oxadinane-2 -Yl) ethyl, 2- (azepan-1-yl) ethyl, 2- (1,4-diazepan-1-yl) ethyl, oxetan-3-ylmethyl and the like.

In the formula (1), when R ² or R ³ is “C _1-6 alkyl”, among “C _1-6 alkyl” substituted by a “heteroaryl” group as an optionally substituted group, Specific examples of substitution with a methyl group or an ethyl group include pyrrol-2-ylmethyl, furan-2-ylmethyl, pyrazol-3-ylmethyl, pyrazol-4-ylmethyl, 2- (pyrazol-4-yl) ethyl, Imidazol-2-ylmethyl, imidazol-4-ylmethyl, 1,2-oxazol-3-ylmethyl, 2- (1,2-oxazol-4-yl) ethyl, 1,3-oxazol-2-ylmethyl, 1,3 -Oxazol-4-ylmethyl, 1,3-thiazol-2-ylmethyl, 1,3-thiazol-4-ylmethyl, 1,2,3-triazol-4-i Methyl, 1,2,3-oxadiazol-4-ylmethyl, 1,2,4-triazol-3-ylmethyl, 1,3,4-oxadiazol-2-ylmethyl, tetrazol-5-ylmethyl, pyridine- 2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, 2- (pyridin-4-yl) ethyl, pyridazin-3-ylmethyl, pyridazin-4-ylmethyl, pyrimidin-2-ylmethyl, pyrimidin-4-ylmethyl , Pyrazin-2-ylmethyl, 1,2,4-triazin-3-ylmethyl, 1,2,4-triazin-5-ylmethyl, 1,3,5-triazin-2-ylmethyl, 2- (pyrrole-1- Yl) ethyl, 2- (pyrazol-1-yl) ethyl, 2- (imidazol-1-yl) ethyl, 2- (1,2,2 - triazol-1-yl) ethyl, 2- (1,2,4-triazol-4-yl) ethyl, 2- (tetrazol-1-yl) ethyl.

In the formula (1), when R ³ is a "C _1-6 alkyl", of the "C _1-6 alkylsulfonyl" group is substituted as the group which may be substituted "C _1-6 alkyl" Specific examples of substitution with a methyl group or an ethyl group include 2- (methylsulfonyl) ethyl, 2- (ethylsulfonyl) ethyl, and ethylsulfonylmethyl.

In the formula (1), when R ³ is “C _1-6 alkyl”, among the “C _1-6 alkyl” substituted by the “aminocarbonyl” group as the optionally substituted group, a methyl group or Specific examples of substitution with an ethyl group include aminocarbonylmethyl, 2-aminocarbonylethyl, 3-aminocarbonylpropyl, and the like.

In the formula (1), when R ³ is a "C _1-6 alkyl" refers to all "heterocyclylalkyl aminocarbonyl" group is substituted "C _1-6 alkyl" as a group which may be substituted, a methyl group Alternatively, specific examples of substitution with an ethyl group include N- (piperidin-4-yl) aminocarbonylmethyl, N- (pyrrolidin-3-yl) aminocarbonylmethyl, and the like.

In the formula (1), when ^{R 3} is a _{"C 1-6} alkyl", _{"di-C 1-6} alkylaminocarbonyl" groups is substituted as the group which may be substituted _{"C 1-6} alkyl" Among them, specific examples of substitution with a methyl group or an ethyl group include dimethylaminocarbonylmethyl, 2-dimethylaminocarbonylethyl, 3-dimethylaminocarbonylpropyl, and the like.

In the formula (1), when ^{R 2} or ^{R 3} is a _{"C 1-6} alkyl", _{"C 1-6} alkoxy" group is substituted as the group which may be substituted _{"C 1-6} alkyl" Among them, specific examples of substitution with a methyl group or an ethyl group include 2-methoxyethyl, 2-ethoxyethyl, methoxymethyl, ethoxymethyl and the like.

In the formula (1), when R ³ is a "C _1-6 alkyl", of the "sulfamoyl" group substituted "C _1-6 alkyl" as a group which may be substituted, methyl group or ethyl Specific examples of the substituent include 2-sulfamoylethyl, sulfamoylmethyl, and the like.

In the formula (1), when R ³ is “C _1-6 alkyl”, “C _1-6 substituted with a group represented by the following formula:“ —NHCOR ⁴ ”as an optionally substituted group. Specific examples of “alkyl” substituted with a methyl group or an ethyl group include acetamidomethyl, cyclopropanecarboxamidomethyl, benzamidomethyl, 3,4-dihydrobenzamidomethyl, 2-chloro-3,4-dihydrobenzamidomethyl , 2-benzamidoethyl, 2- (2-chloro-3,4-dihydrobenzamido) ethyl, N-2- (carbamido) ethyl, 2-acetamidoethyl, 2- (3,4-dihydrobenzamido) ethyl and the like. Can be

More specific examples of compounds provided by the present invention preferably include:
(2S, 5R) -N- (2-aminoethoxy) -3-methyl-7-oxo-6- (sulfoxy) -1,6-diazabicyclo [3.2.1] oct-3-en-2-carboxamide ,
(2S, 5R) -3-Methyl-7-oxo-N '-[(3R) -piperidine-3-carbonyl] -6- (sulfoxy) -1,6-diazabicyclo [3.2.1] oct-3 -En-2-carbohydrazide,
Sodium [({(2S, 5R) -2-[(2-methoxyethoxy) carbamoyl] -3-methyl-7-oxo-6- (sulfoxy) -1,6-diazabicyclo [3.2.1] oct- 3-en-6-yl {oxy) sulfonyl] oxydanide,
(2S, 5R) -N-{[(2S) -azetidin-2-yl] methoxy} -3-methyl-7-oxo-6- (sulfooxy) -1,6-diazabicyclo [3.2.1] oct -3-en-2-carboxamide,
(2S, 5R) -N- (3-aminopropoxy) -3-methyl-7-oxo-6- (sulfoxy) -1,6-diazabicyclo [3.2.1] oct-3-en-2-carboxamide ,
(2S, 5R) -3-methyl-7-oxo-N-{[(2S) -pyrrolidin-2-yl] methoxy} -6- (sulfooxy) -1,6-diazabicyclo [3.2.1] oct -3-en-2-carboxamide,
(2S, 5R) -3-methyl-7-oxo-N-{[(3R) -piperidin-3-yl] methoxy} -6- (sulfooxy) -1,6-diazabicyclo [3.2.1] oct -3-en-2-carboxamide,
(2S, 5R) -N-[(2S) -2-aminopropoxy] -3-methyl-7-oxo-6- (sulfoxy) -1,6-diazabicyclo [3.2.1] oct-3-ene -2-carboxamide,
(2S, 5R) -3-methyl-7-oxo-N-{[(2R) -pyrrolidin-2-yl] methoxy} -6- (sulfooxy) -1,6-diazabicyclo [3.2.1] oct -3-en-2-carboxamide,
(2S, 5R) -N- [2- (ethylamino) ethoxy] -3-methyl-7-oxo-6- (sulfoxy) -1,6-diazabicyclo [3.2.1] oct-3-ene- 2-carboxamide,
(2S, 5R) -3-methyl-N- [2- (methylamino) ethoxy] -7-oxo-6- (sulfooxy) -1,6-diazabicyclo [3.2.1] oct-3-ene- 2-carboxamide,
(2S, 5R) -3-methyl-7-oxo-N-{[(3S) -pyrrolidin-3-yl] oxy} -6- (sulfooxy) -1,6-diazabicyclo [3.2.1] oct -3-en-2-carboxamide,
(2S, 5R) -N-{[azetidin-3-yl] methoxy} -3-methyl-7-oxo-6- (sulfoxy) -1,6-diazabicyclo [3.2.1] oct-3-ene -2-carboxamide,
(2S, 5R) -N '-[(2S) -2-aminopropanoyl] -3-methyl-7-oxo-6- (sulfoxy) -1,6-diazabicyclo [3.2.1] oct-3 -En-2-carbohydrazide,
(2S, 5R) -3-methyl-7-oxo-N '-[(2S) -pyrrolidine-2-carbonyl] -6- (sulfooxy) -1,6-diazabicyclo [3.2.1] oct-3 -En-2-carbohydrazide,
Sodium ({[(2S, 5R) -2- (ethoxycarbamoyl) -3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yl] oxy} sulfonyl ) Oxidanid,
Sodium ({[(2S, 5R) -2-{[2- (dimethylamino) -2-oxoethoxy] carbamoyl} -3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct -3-en-6-yl] oxy} sulfonyl) oxydanide,
Sodium ({[(2S, 5R) -2- (methoxycarbamoyl) -3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yl] oxy} sulfonyl ) Oxidanid,
Sodium [({(2S, 5R) -2-[(cyclopropylmethoxy) carbamoyl] -3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yl [｝ Oxy) sulfonyl] oxydanide,
Sodium ({[(2S, 5R) -3-methyl-7-oxo-2- (phenoxycarbamoyl) -1,6-diazabicyclo [3.2.1] oct-3-en-6-yl] oxy} sulfonyl ) Oxidanid,
Sodium ({[(2S, 5R) -3-methyl-2-{[(oxetan-3-yl) methoxy] carbamoyl} -7-oxo-1,6-diazabicyclo [3.2.1] oct-3- [En-6-yl] oxy} sulfonyl) oxydanide,
And the like.

Further, specific examples of the compound of the present invention preferably include the following compounds.

  The medicament provided by the present invention contains as an active ingredient a substance selected from the group consisting of a compound represented by the formula (1), a pharmaceutically acceptable salt thereof, or a solvate thereof. And administered orally or parenterally, preferably parenterally. The compound of the present invention and the β-lactam antibiotic may be used in combination with each drug prepared separately for errands, by simultaneous or separate administration, or generally by mixing both drugs in advance, generally one or more. A pharmaceutical composition can be produced and administered using the pharmaceutical additives (carriers) described above.

  Specific examples of the pharmaceutical composition for oral administration include tablets, capsules, granules, powders, pills, aqueous and non-aqueous oral solutions, suspensions and the like.

  Parenteral administration routes include intranasal, ophthalmic, ocular, transdermal, intratracheal, intrarectal, urinary, subcutaneous, intramuscular, intravenous, and the like.

  Specific examples of the pharmaceutical composition for parenteral administration include, for intravenous administration, an intravenous injection solution using a solvent acceptable for the powdered form of the pharmaceutical composition. Acceptable solvents include, for example, sterile water for injection, physiological saline solution, glucose solution, Ringer's solution, bacteriostatic water for injection containing methylparaben and propylparaben, or bacteriostatic water for injection containing benzyl alcohol.

  A pharmaceutical composition in the form of a powder for intravenous administration is prepared by subjecting the compound of the present invention, which is an active ingredient, and a β-lactam antibiotic to a sterilized process, dispensing the mixture into a sealed vial, and then freeze-drying the pharmaceutical composition. Manufactured by dispensing the composition into a sealed vial. As a specific method of the sterilization step, preferably, a method of removing endotoxin, individually or mixed solution, crystallization after filtration of insoluble foreign matter, filling in a sealed vial and irradiating with gamma rays; removing the individual or mixed solution with endotoxin, Aseptic filtration, high-pressure steam sterilization, pulse light irradiation, final sterilization and freeze-drying; individual solution removal of endotoxin, aseptic filtration under aseptic atmosphere, filling in sealed vials in sequence, freezing and freeze-drying; individual A method of removing endotoxin, aseptic filtration, and crystallizing under sterile atmosphere of a compound solution; a sterile powdered drug crystallized under a sterile atmosphere, and a sterile powdered drug freeze-dried in a sealed vial. Overlaid under sterile atmosphere; either lyophilized drug in sterile powder form and crystals in sterile atmosphere And a method of mixing, sterile powder form drugs under sterile atmosphere. More preferably, endotoxin removal of individual solutions, sterile filtration under a sterile atmosphere, successively filling and sealing in sealed vials, freeze-drying and then freeze-drying, or individually endotoxin removal of a solution of the compound, sterile filtration, under a sterile atmosphere This is a method of crystallization.

  The above pharmaceutical composition can be stored at room temperature or lower until it is made into a solution for intravenous injection at a medical site, and is used after dissolving it. The concentration of the compound of the invention in the reconstituted intravenous solution is, for example, in the range of 1 mg / mL to 50 mg / mL.

  The dose and the number of administrations of the medicament of the present invention are not particularly limited, but may be appropriately determined according to various conditions such as the purpose of treatment or prevention, the type of disease, the age of the patient, body weight, and symptoms. Can be determined. The effective blood concentration of the compound of the present invention used in combination with the β-lactam antibiotic is preferably adjusted so as to maintain 1 μg / mL or more during administration of the β-lactam antibiotic. The dose of the compound of the present invention is preferably 2 to 75 mg / kg for intravenous administration and 4 to 300 mg / kg for oral administration several times a day in accordance with the number of administrations of the β-lactam antibiotic. Is preferably administered 2 to 6 times.

  Here, the β-lactam antibiotics that can be used in combination with the compound of the present invention include penicillins, cephems, carbapenems and the like.

  Specific examples of penicillins include benzylpenicillin, pheneticillin, cloxacillin, dicloxacillin, ampicillin, cyclacillin, amoxicillin, tarampicillin, bacampicillin, lenampicillin, aspoxicillin, piperacillin, sulbenicillin, pivumecilicillin, sultamicinillin, sultamicilinillin, sultamicinillin , Episilin, ticarcillin, pyrbenicillin, azulocillin, mezlocillin, and other known penicillins.

  Specific examples of cephems include cefaclor, cefazolin, cefatridine, cefadroxil, cephapirin, cephamandole naphate, cepharazine, cephalexin, cephalothin, cefepime, cefxitin, cefxime, cefdzimu, cefditolen, cefuzinil, cefsulzine, cefsulzine, cefsulzine, cefsulzine, cefsulozin Ceftoxime, Ceftazidime, Ceftaroline, Ceftiam, Ceftizoxime, Ceftibutene, Ceftesol, Ceftetam, Ceftriaxone, Cefnicid, Cefpyramide, Cefpirome, Cefbuperazone, Cefprodil, Cefperazone, Cefpodoxime, Cefomex, Cefumex, Cefumex, Cefomex, Cefoxazine (6R, 7R) -3- [5- Mino-4- [3- (2-aminoethyl) ureido] -1-methyl-1H-pyrazol-2-ium-2-ylmethyl] -7- [2- (5-amino-1,2,4-thiadiazole -3-yl) -2-[(Z) -1-carboxy-1-methylethoxyimino] acetamide] -3-cephem-4-carboxylic acid hydrogensulfate), cefiderochol and other known cephems Is mentioned.

  Examples of the carbapenems include imipenem, panipenem, meropenem, biapenem, doripenem, ertapenem, tebipenem and the like, and if necessary, a DHP-1 inhibitor such as cilastatin sodium can be used in combination.

  Examples of β-lactam antibiotics other than carbapenems, penicillins, and cephems include β-lactam antibiotics such as aztreonam, carmonam, ratamoxef, flomoxef, loracarbef, faropenem, and litipenem.

  Particularly suitable penicillins for co-administration with the compounds of the present invention include ampicillin, amoxicillin, carbenicillin, piperacillin, azlocillin, mezlocillin and ticarcillin. Such penicillins can be used in the form of a pharmaceutically acceptable salt, for example, the sodium salt. Alternatively, ampicillin or amoxicillin may be used in the form of microparticles of the invention in the form of microparticles of the zwitterionic form (ampicillin trihydrate or amoxicillin trihydrate) for injection or infusion suspensions. It can be used in combination with a compound. Cephems particularly suitable for co-administration with the compounds of the present invention include cefotaxime, ceftriaxone, ceftazidime and cefepime, which may be used in the form of pharmaceutically acceptable salts such as the sodium salt. it can. Carbapenems particularly suitable for co-administration with the compounds of the present invention are imipenem, meropenem, biapenem, doripenem and ertapenem.

  A particularly preferred β-lactam antibiotic other than carbapenems, penicillins and cephems for co-administration with the compounds of the present invention is aztreonam.

  By using the compound of the present invention in combination with a β-lactam antibiotic, in addition to bacterial infections included in the antibacterial spectrum of the antibiotic, class A, class C and class D β-lactamase-producing bacteria, It can be used to treat infections caused by ESBL, KPC-2 carbapenemase producing bacteria.

  Β-lactamase-producing bacteria of class A, class C and class D and ESBL and KPC2 carbapenemase-producing bacteria include Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacare, Citrobacter Citrobacter freundii, Serratia marcescens, Morganella morgani, M. aeruginosa (Pseudomonas aeruginosa), and Acinetobacter baumannii (Acinetiab.

  Hereinafter, a general method for producing the compound of the present invention will be described. The compound of the present invention is produced, for example, according to the following Scheme 1, but is not limited thereto. The compound subjected to the search and evaluation of the present invention is produced from the compound represented by the formula (2) as a starting material according to the method of the following scheme 1 including the method described in WO 2013/150296.

<Scheme 1>

  The compound represented by the formula (2) can be synthesized, for example, by a method based on the method described in WO 2013/150296.

The compound represented by the formula (1) (in the formula (1), R ¹ has the same meaning as described above) can be produced using the compound represented by the formula (2) as a starting material.

  The compound represented by the formula (3) is produced by reacting a compound represented by the formula (2), which is a starting material, with an oxidizing agent.

  The oxidizing agent used in the reaction includes, for example, oxygen, manganese dioxide, sodium periodate, hydrogen peroxide, ozone, m-chloroperbenzoic acid (mCPBA), 2-iodoxybenzoic acid ester (IBX ester), tetramethylpiperidine 1 -Oxyl (TEMPO), t-butyl hydroperoxide, cumene hydroperoxide, Dess-Martin periodinane (DMP), oxone, chromic acid, periodic acid and the like, and preferably chromic acid and periodic acid.

  The solvent used in the reaction includes, for example, water, acetone, dichloromethane, chloroform, acetonitrile, ethyl acetate, toluene, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, and the like. Preferably it is acetonitrile.

  The amount of the oxidizing agent used is in the range of 1 to 10 equivalents based on the compound represented by the formula (2). When the oxidizing agent is chromic acid, the amount used is in the range of 4 to 6 equivalents based on the compound represented by the formula (2).

  The reaction temperature is selected, for example, in the range of -30 to 60C, and preferably in the range of -10 to 10C. The reaction time ranges, for example, from 10 minutes to 24 hours, and preferably ranges from 30 minutes to 4 hours.

The compound represented by the formula (4) (R ^1a has the same meaning as the above R ¹ and may be protected by a protecting group if necessary) is obtained by condensation of the compound represented by the formula (3) with an amine It can be produced by a reaction.

  The compound represented by the formula (4) can be produced by a method using a dehydration condensing agent, an active esterifying agent or an active amidating agent in a suitable solvent, using a compound represented by the formula (3) as a starting material. These may be used in combination as needed.

  The reaction using a dehydrating condensing agent is often carried out by adding an active esterifying agent or an active amidating agent as a catalyst and generating an active ester or an active amide in the reaction system. Will be described.

  The solvent used in the reaction using the dehydration condensing agent includes, for example, water, methanol, ethanol, isopropanol, ethyl acetate, toluene, tetrahydrofuran, dioxane, acetonitrile, dichloromethane, chloroform, dimethylformamide, dimethylacetamide, and the like, preferably ethyl acetate. , Tetrahydrofuran, dichloromethane, acetonitrile, dimethylformamide, dimethylacetamide, and these may be used alone or in combination.

  When an active esterifying agent or an active amidating agent is used, the reaction may be carried out in the presence of a base, if necessary. Examples of the base used in the reaction include diisopropylethylamine, triethylamine, tributylamine, N-methylmorpholine, 4-dimethylaminopyridine, and the like, and preferably diisopropylethylamine and triethylamine.

  As the dehydration condensing agent, a carbodiimide-based reagent such as N, N'-diisopropylcarbodiimide, N, N'-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride may be used alone. Optionally, in combination with an active amidating agent or an active esterifying agent such as imidazole, 1-hydroxybenzotriazole monohydrate, N-hydroxysuccinimide, 2-hydroxypyridine-N-oxide as a catalyst. May be used.

  Other dehydrating condensing agents include carbonyldiimidazole, benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 2-chloro-1-methylpyridinium iodide, 4- (4,6-dimethoxychloride) -1,3,5-triazin-2-yl) -4-methylmorpholinium, 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium- Examples include active esterification or active amidation of 3-oxide hexafluorophosphate and the like, and preferably 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b]. Pyridinium-3-oxide hexafluorophosphate.

  The base used in the reaction is used, if necessary, in a range of 1 to 3 equivalents, preferably 1 to 1.5 equivalents, based on the compound represented by the formula (3). The amount of the dehydrating condensing agent, the active esterifying agent and the active amidating agent is in the range of 1 to 2 equivalents, preferably 1 to 1.5 equivalents, based on the compound represented by the formula (3). .

  The reaction temperature is in the range of -40C to 40C, preferably in the range of -20C to 40C. Reaction times range from 30 minutes to 24 hours, preferably from 2 hours to 16 hours.

The compound represented by the formula (5) (R ^1a has the same ^{meaning as} described above) is produced by reacting the compound represented by the formula (4) using a suitable catalyst in the presence or absence of an acid. can do.

  Examples of the catalyst used in the reaction include tetrakis (triphenylphosphine) palladium (0), palladium (II) acetate, bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0), allyl Palladium chloride (II), bis (triphenylphosphine) palladium dichloride (II), bis (tri-O-tolylphosphine) palladium dichloride (II), bis (acetonitrile) palladium dichloride (II), and the like are preferable, and tetrakis is preferable. (Triphenylphosphine) palladium (0).

  Examples of the acid used in the reaction include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfuric acid, hemisulfuric acid, thiocyanic acid, acetic acid, butyric acid, propionic acid, dimedone and the like, and acetic acid is preferred.

  Examples of the solvent used for the reaction include water, acetone, dichloromethane, chloroform, acetonitrile, ethyl acetate, toluene, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide and the like. , Preferably dichloromethane.

  The amount of the catalyst used in the reaction is in the range of 0.1 to 2 equivalents, preferably 0.2 to 1 equivalent based on the compound represented by the formula (4). The amount of the acid used in the reaction is in the range of 0 to 20.0 equivalents, preferably 2 to 10 equivalents, based on the compound represented by the formula (4).

  The reaction temperature is selected, for example, in the range of -30 to 60C, and preferably in the range of 10C to 30C. The reaction time ranges, for example, from 10 minutes to 24 hours, and preferably ranges from 30 minutes to 4 hours.

  The compound represented by the formula (1) can be produced by sulfoxylation of the compound represented by the formula (5) and, if necessary, deprotection of a protecting group.

  Examples of the sulfoxylating agent used in the reaction include chlorosulfonic acid, sulfur trioxide-pyridine complex, sulfur trioxide-dimethylformamide complex, sulfur trioxide-trimethylamine complex, sulfur trioxide-triethylamine complex, and the like. A sulfur trioxide-pyridine complex and a sulfur trioxide-dimethylformamide complex.

  Examples of the base used in the reaction include triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 2-picoline, 3-picoline, 2,6-lutidine, 2,4,6-collidine, 4-dimethylamino Pyridine, N-methylimidazole and the like can be mentioned, and preferred are pyridine, 2-picoline and 2,6-lutidine.

  Examples of the solvent used in the reaction include water, methanol, ethanol, isopropanol, dichloromethane, chloroform, 1,2-dichloroethane, pyridine, acetonitrile, dimethylformamide and the like, and these solvents may be used alone or as a mixture. Of these, dichloromethane, pyridine and acetonitrile are preferred, and these may be used alone or in combination.

  Solvents used in the deprotection reaction include, for example, water, methanol, ethanol, isopropanol, dichloromethane, chloroform, 1,2-dichloroethane, pyridine, acetonitrile, dimethylformamide and the like, preferably dichloromethane, pyridine, acetonitrile, and May be used alone or as a mixture.

  The amount of the sulfoxylating agent to be used in the present reaction is in the range of 1 to 10 equivalents, preferably 2 to 6 equivalents, based on the compound represented by the formula (5). The amount of the base to be used in this reaction is in the range of 1 equivalent to the amount of solvent, preferably 3 equivalents to the amount of solvent, based on the compound represented by the formula (5).

  The reaction temperature is in the range of 0 to 50C, preferably 10 to 30C. The reaction time ranges from 12 to 48 hours, preferably from 12 to 24 hours.

Compounds of formula (5) (R ^1a is wherein R ¹ as defined definitions, may be protected by a protecting group as needed.) Protecting group R ^1a (e.g. tert- butoxycarbonyl group ), If present, is further subjected to a deprotection step.

When the protecting group in R ^1a is tert-butoxycarbonyl, the deprotection step includes, for example, deprotection with an acid.

  Examples of the solvent used in this reaction include water, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, dioxane, dichloromethane, chloroform, 1,2-dichloroethane, 2,2,2-trifluoroethanol, and the like. It is dichloromethane, ethyl acetate or 2,2,2-trifluoroethanol.

  Examples of the acid used in this reaction include hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, chloromethanesulfonic acid, tetrafluoroboric acid and the like, preferably hydrochloric acid, sulfuric acid, Trifluoroacetic acid, methanesulfonic acid, and tetrafluoroboric acid are preferable, and hydrochloric acid, sulfuric acid, and trifluoroacetic acid are more preferable.

  The acid used in this reaction is used in the range of 1 equivalent to the amount of solvent, preferably 3 times to the amount of solvent, based on the compound represented by the formula (5). Here, the three-fold amount means, for example, when 1 g of the compound represented by the formula (5) is used, 3 mL of an acid is used.

  The reaction temperature is in the range of -25 to 50C, preferably -10 to 30C. The reaction time ranges from 30 minutes to 5 hours, preferably from 30 minutes to 1 hour.

  After the completion of the deprotection reaction, the reaction solution is concentrated, or a poor solvent is added to the reaction solution to precipitate a crude product, and then an aqueous solution having an optimum pH in the range of pH 5 to 6 is precipitated again, or octadecyl silica (ODS) Purified by a synthetic resin such as Diaion HP-20 or Sepabeads SP207, or an ion exchange resin such as DOWEX 50W-X8 (Na type), and then reprecipitated or freeze-dried to obtain the final form represented by the formula (1). Can be obtained.

  The hydroxy group, amino group, and carboxy group in the compounds represented by the formulas (1) to (5) in Scheme 1 may be protected by a selectively removable protecting group known in the art. By deprotecting at the stage, an intermediate for producing the compound represented by the formula (1) can be supplied. Examples of the protecting group include silyl protecting groups such as trimethylsilyl group, triethylsilyl group and tert-butyldimethylsilyl group; acyl protecting groups such as acetyl group, propionyl group and benzoyl group; benzyl group; 4-methoxybenzyl group; Ether protecting groups such as chlorobenzyl group, acetal protecting groups such as tetrahydropyranyl group, tetrahydrofuranyl group, 1-ethoxyethyl group, and carbonate protecting groups such as benzyloxycarbonyl group and tert-butyloxycarbonyl group. However, other protective groups described in Green's Protective Groups in Organic Synthesis (5th edition, 2014, edited by PGM Wuts) can also be used. The substituents of the compounds represented by formulas (1) to (5) in the present production method can be mutually converted by a known method.

Hereinafter, the present invention will be described more specifically with reference to Examples and Test Examples. However, the scope of the present invention is not limited to these Examples, and various applications, It is self-evident that changes and modifications are possible.
M: mol / L
mM: mmol / L
μM: μmol / L
nM: nmol / L
ESI: Electrospray ionization method MS: Mass spectrum n: Normal sec: Secondary tert: Tertiary TLC: Thin layer chromatography D ₂ O: Heavy water

（ａ）過ヨウ素酸（１６．８ｇ）を水２ｍＬとアセトニトリル２００ｍＬの混液に溶解し、次いで６価のクロム酸（３．９２ｇ）を加えた後、室温で撹拌して均一な溶液とした。（２Ｓ，５Ｒ）−２−（ヒドロキシメチル）−３−メチル−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−７−オン（国際公開第２０１３／１５０２９６号の方法に従って合成した化合物）（３４９ｍｇ）をアセトニトリル（１６ｍＬ）に溶解し、上記で調整したクロム酸溶液（２０ｍＬ）を氷冷下にて１０分間かけて滴下した。反応液を氷冷下で１時間撹拌後、２５％シュウ酸水溶液（１５ｍＬ）を加え、氷冷下でさらに３０分撹拌した後、クロロホルムで２回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥、濾過後、濾液を減圧濃縮して、（２Ｓ，５Ｒ）−３−メチル−７−オキソ−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−２−カルボン酸を粗生成物として得た。これを精製せずに次の反応に用いた。 Example 1 (2S, 5R) -N- (2-aminoethoxy) -3-methyl-7-oxo-6- (sulfoxy) -1,6-diazabicyclo [3.2.1] oct-3- En-2-carboxamide

(A) Periodic acid (16.8 g) was dissolved in a mixed solution of 2 mL of water and 200 mL of acetonitrile, and then hexavalent chromic acid (3.92 g) was added, followed by stirring at room temperature to obtain a uniform solution. (2S, 5R) -2- (hydroxymethyl) -3-methyl-6-[(prop-2-en-1-yl) oxy] -1,6-diazabicyclo [3.2.1] oct-3- En-7-one (compound synthesized according to the method of WO 2013/150296) (349 mg) was dissolved in acetonitrile (16 mL), and the chromic acid solution (20 mL) prepared above was cooled under ice-cooling for 10 minutes. It dripped over. After the reaction solution was stirred for 1 hour under ice cooling, a 25% oxalic acid aqueous solution (15 mL) was added, and the mixture was further stirred for 30 minutes under ice cooling, and extracted twice with chloroform. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give (2S, 5R) -3-methyl-7-oxo-6-[(prop-2-ene). -1-yl) oxy] -1,6-diazabicyclo [3.2.1] oct-3-en-2-carboxylic acid was obtained as a crude product. This was used for the next reaction without purification.

(B) The crude product obtained in the above (a) was dissolved in dichloromethane (20 mL), and diisopropylethylamine (1.1 mL), tert-butyl {2- (aminooxy) ethyl} carbamate (WO 2013/2013) Compound synthesized according to the method of No. 180197) (555 mg), 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium 3-oxidehexafluorophosphate (710 mg) Were sequentially added, and the mixture was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted three times with chloroform, and the organic layer was washed with saturated saline (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (ethyl acetate: methanol = 1: 0 to 20: 1), and tert-butyl {2-[({(2S, 5R) -3-methyl-7-oxo-6-[(prop-2-en-1-yl) oxy] -1,6-diazabicyclo [3.2.1] oct] 377 mg of -3-en-2-carbonyl {amino) oxy] ethyl} carbamate were obtained.
1H-NMR (400 MHz, CDCl3), δ: 1.45 (s, 9H), 1.80-1.89 (m, 3H), 3.23-3.29 (m, 2H), 3.33-3.47 (m, 2H), 3.78-3.83 ( m, 1H), 3.89-3.98 (m, 2H), 4.21-4.27 (m, 1H), 4.34-4.48 (m, 2H), 5.26-5.40 (m, 3H), 5.93-6.08 (m, 1H), 6.11-6.19 (m, 1H); MS (ESI) m / z 397 (M + H) ⁺ .

(C) The compound (101 mg) obtained in the above (b) is dissolved in dichloromethane (3 mL), acetic acid (0.03 mL) and tetrakistriphenylphosphine palladium (0) (240 mg) are added, and the mixture is stirred at room temperature for 1 hour. did. After confirming the disappearance of the raw materials by TLC, pyridine (3 mL) and sulfur trioxide-pyridine complex (245 mg) were added to the reaction solution, and the mixture was stirred at room temperature overnight. The reaction solution was filtered through celite, washed with dichloromethane (10 mL), and the residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography (ethyl acetate: acetone = 100: 1 to 10: 1 to 0: 1). Purified to give triphenyl (prop-2-en-1-yl) phosphanium ({[(2S, 5R) -2-({2-[(tert-butoxycarbonyl) amino] ethoxy} carbamoyl) -3-methyl 77 mg of -7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yl] oxy {sulfonyl) oxydanide was obtained.
MS (ESI) m / z 437 (M + H) ⁺

(D) The compound (77 mg) obtained in the above (c) was dissolved in methylene chloride (2 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. . The obtained residue was adjusted to pH 5 with aqueous sodium hydrogen carbonate, and purified by octadecyl silica gel column chromatography (water: methanol = 100: 0 to 1: 1) to obtain 15 mg of the title compound.
1H-NMR (400 MHz, D ₂ O), δ: 1.66 (s, 3H), 3.23-3.28 (m, 2H), 3.35-3.41 (m, 1H), 3.51-3.58 (m, 1H), 4.14- 4.18 (m, 2H), 4.22 (s, 1H), 4.29 (s, 1H), 6.23-6.29 (m, 1H); MS (ESI) m / z 336 (M + H) ⁺ .

（ａ）（２Ｓ，５Ｒ）−２−（ヒドロキシメチル）−３−メチル−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−７−オン（２８５ｍｇ）を用いて、実施例１（ａ）と同様の方法にて得られた（２Ｓ，５Ｒ）−３−メチル−７−オキソ−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−２−カルボン酸の粗生成物をジクロロメタン（１５ｍＬ）に溶解し、ジイソプロピルエチルアミン（０．８５ｍＬ）、ｔｅｒｔ−ブチル （３Ｒ）−３−（ヒドラジンカルボニル）ピペリジン−１−カルボキシレート（国際公開第２０１３／１８０１９７号の方法に従って合成した化合物）（９２７ｍｇ）、１−（ビス（ジメチルアミノ）メチレン）−１Ｈ−１，２，３−トリアゾロ［４，５−ｂ］ピリジニウム−３−オキシドヘキサフルオロホスフェート（７２０ｍｇ）を順次加え、室温にて終夜撹拌した。反応液に飽和重曹水を加え、クロロホルムで３回抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムにて乾燥、濾過後、濾液を減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝１：０〜２０：１〜８／１）にて精製して、ｔｅｒｔ−ブチル−（３Ｒ）−３−（２−｛（２Ｓ，５Ｒ）−３−メチル−７−オキソ−６−[（プロパ−２−エン−１−イル）オキシ]−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−２−カルボニル｝ヒドラジンカルボニル）ピペリジン−１−カルボキシラートを３１６ｍｇ得た。
¹H-NMR(400 MHz, CDCl₃), δ：1.45 (s, 9H), 1.61 (s, 2H), 1.64 - 1.77 (m, 1H), 1.88 (s, 3H), 2.39 - 2.52 (m, 1H), 3.25 - 3.44 (m, 3H), 3.32 - 3.38 (m, 2H), 3.78 - 3.83 (m, 1H), 4.33 - 4.37 (m, 1H), 4.37 - 4.48 (m, 2H), 5.27 - 5.39 (m, 1H), 5.33 - 5.40 (m, 1H), 5.95 - 6.06 (m, 1H), 6.08 - 6.16 (m, 1H), 8.60 - 8.77 (m, 1H);MS（ESI） m/z 464 (M+H)⁺. Example 2 (2S, 5R) -3-methyl-7-oxo-N ′-[(3R) -piperidine-3-carbonyl] -6- (sulfooxy) -1,6-diazabicyclo [3.2. 1] Oct-3-ene-2-carbohydrazide

(A) (2S, 5R) -2- (hydroxymethyl) -3-methyl-6-[(prop-2-en-1-yl) oxy] -1,6-diazabicyclo [3.2.1] oct (2S, 5R) -3-methyl-7-oxo-6-[(propa) obtained in the same manner as in Example 1 (a) using -3-en-7-one (285 mg). 2-en-1-yl) oxy] -1,6-diazabicyclo [3.2.1] oct-3-en-2-carboxylic acid crude product was dissolved in dichloromethane (15 mL), and diisopropylethylamine (0 .85 mL), tert-butyl (3R) -3- (hydrazinecarbonyl) piperidine-1-carboxylate (compound synthesized according to the method of WO 2013/180197) (927 mg), 1- (bis (dimethylamine) Mino) methylene) -1H-1,2,3-triazolo [4,5-b] pyridinium-3-oxidehexafluorophosphate (720 mg) was sequentially added, and the mixture was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted three times with chloroform, and the organic layer was washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 1: 0 to 20: 1 to 8/1). Tert-butyl- (3R) -3- (2-{(2S, 5R) -3-methyl-7-oxo-6-[(prop-2-en-1-yl) oxy] -1,6 316 mg of -diazabicyclo [3.2.1] oct-3-en-2-carbonyl {hydrazinecarbonyl) piperidine-1-carboxylate were obtained.
¹ H-NMR (400 MHz, CDCl ₃ ), δ: 1.45 (s, 9H), 1.61 (s, 2H), 1.64-1.77 (m, 1H), 1.88 (s, 3H), 2.39-2.52 (m, 1H), 3.25-3.44 (m, 3H), 3.32-3.38 (m, 2H), 3.78-3.83 (m, 1H), 4.33-4.37 (m, 1H), 4.37-4.48 (m, 2H), 5.27- 5.39 (m, 1H), 5.33-5.40 (m, 1H), 5.95-6.06 (m, 1H), 6.08-6.16 (m, 1H), 8.60-8.77 (m, 1H); MS (ESI) m / z 464 (M + H) ⁺ .

(B) The compound (167 mg) obtained in the above (a) was dissolved in dichloromethane (3.6 mL), and acetic acid (0.04 mL) and tetrakistriphenylphosphine palladium (0) (332 mg) were added. Stirred for hours. After confirming the disappearance of the raw materials by TLC, pyridine (3.6 mL) and sulfur trioxide-pyridine complex (345 mg) were added to the reaction solution, and the mixture was stirred at room temperature overnight. The reaction solution was filtered through celite, washed with dichloromethane, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: acetone = 100: 1 to 10: 1 to 0: 1). , Triphenyl (prop-2-en-1-yl) phosphanium ({[(2S, 5R) -2-} 2-[(3R) -1- (tert-butoxycarbonyl) piperidine-3-carbonyl] hydrazinecarbonyl 76 mg))-3-Methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yl) oxy) sulfonyl) oxide anion was obtained.
MS (ESI) m / z 504 (M + H) ⁺ .

(C) The compound (76 mg) obtained in the above (b) was dissolved in methylene chloride (2 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. . The obtained residue was adjusted to pH 5 with aqueous sodium hydrogen carbonate, and purified by octadecyl silica gel column chromatography (water: methanol = 100: 0 to 1: 1) to obtain 13 mg of the title compound.
¹ H-NMR (400 MHz, D ₂ O), δ: 1.70 (s, 3H), 1.72-1.81 (m, 2H), 1.87-1.97 (m, 1H), 1.99-2.12 (m, 1H), 2.78 -2.93 (m, 1H), 2.99-3.10 (m, 1H), 3.14-3.29 (m, 2H), 3.34-3.44 (m, 2H), 3.47-3.55 (m, 1H), 4.17-4.26 (m, 1H), 4.44 (s, 1H), 6.17-6.31 (m, 1H); MS (ESI) m / z 403 (M + H) ⁺ .

（ａ）（２Ｓ，５Ｒ）−２−（ヒドロキシメチル）−３−メチル−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−７−オン（２４８ｍｇ）を用いて実施例１（ａ）で得られた化合物とＯ−（２−メトキシエチル）ヒドロキシルアミンを用いて、実施例1（ｂ）と同様の方法で（２Ｓ，５Ｒ）−Ｎ−（２−メトキシエトキシ）−３−メチル−７−オキソ−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−２−カルボキサミドを１１５ｍｇ得た。
1H-NMR (400 MHz, CDCl3), δ：1.85 (s, 3H), 3.24 (s, 2H), 3.41 (s, 3H), 3.65 (t, J = 4.40 Hz, 2H), 3.80 (dt, J = 5.10, 1.73 Hz, 1H), 4.03 - 4.16 (m, 2H), 4.22 (s, 1H), 4.40 (m, 2H), 5.27 - 5.32 (m, 1H), 5.33 - 5.39 (m, 1H), 5.95 - 6.07 (m, 1H), 6.10 - 6.16 (m, 1H), 9.43 (s, 1H);MS（ESI） m/z 312 (M+H)⁺. Example 3 Sodium [({(2S, 5R) -2-[(2-methoxyethoxy) carbamoyl] -3-methyl-7-oxo-6- (sulfoxy) -1,6-diazabicyclo [3.2 .1] Oct-3-en-6-yl {oxy) sulfonyl] oxydanide

(A) (2S, 5R) -2- (hydroxymethyl) -3-methyl-6-[(prop-2-en-1-yl) oxy] -1,6-diazabicyclo [3.2.1] oct A method similar to that of Example 1 (b) using the compound obtained in Example 1 (a) using -3-en-7-one (248 mg) and O- (2-methoxyethyl) hydroxylamine. And (2S, 5R) -N- (2-methoxyethoxy) -3-methyl-7-oxo-6-[(prop-2-en-1-yl) oxy] -1,6-diazabicyclo [3.2 .1] 115 mg of oct-3-ene-2-carboxamide.
1H-NMR (400 MHz, CDCl3), δ: 1.85 (s, 3H), 3.24 (s, 2H), 3.41 (s, 3H), 3.65 (t, J = 4.40 Hz, 2H), 3.80 (dt, J = 5.10, 1.73 Hz, 1H), 4.03-4.16 (m, 2H), 4.22 (s, 1H), 4.40 (m, 2H), 5.27-5.32 (m, 1H), 5.33-5.39 (m, 1H), 5.95-6.07 (m, 1H), 6.10-6.16 (m, 1H), 9.43 (s, 1H); MS (ESI) m / z 312 (M + H) ⁺ .

(B) Using the compound (114 mg) obtained in the above (a), triphenyl (prop-2-en-1-yl) phosphanium [(｛[(2S , 5R) -2-[(2-Methoxyethoxy) carbamoyl] -3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yl {oxy) sulfonyl] 94.3 mg of oxydanide was obtained.
MS (ESI) m / z 352 (M + H) ⁺

(C) The compound (94.3 mg) obtained in the above (b) was dissolved in 50% acetone water, applied to DOWEX 50W × 8 (Na type, 30 ml), and the fraction eluted with water was concentrated under reduced pressure. The obtained residue was purified by octadecyl silica gel column chromatography (water: methanol = 100: 0 to 1: 1) to obtain 12 mg of the title compound.
1H-NMR (400 MHz, D ₂ O), δ: 1.65 (s, 3H), 3.34 (s, 3H), 3.37 (ddd, J = 11.30, 2.93, 1.10 Hz, 1H), 3.59 (d, J = 11.30 Hz, 1H), 3.64-3.69 (m, 2H), 4.02-4.07 (m, 2H), 4.21 (q, J = 2.57 Hz, 1H), 4.24 (s, 1H), 6.21-6.27 (m, 1H ); MS (ESI) m / z 352 (M + H) ⁺ .

（ａ）（２Ｓ，５Ｒ）−２−（ヒドロキシメチル）−３−メチル−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−７−オン（２９７ｍｇ）を用いて実施例１（ａ）で得られた化合物とｔｅｒｔ−ブチル（２Ｓ）−２−［（アミノオキシ）メチル］アゼチジン−１−カルボキシレートを用いて、実施例１（ｂ）と同様の方法でｔｅｒｔ−ブチル（２Ｓ）−２−｛［（｛（２Ｓ，５Ｒ）−３−メチル−７−オキソ−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−２−カルボニル｝アミノ）オキシ］メチル｝アゼチジン−１−カルボキシレートを１８５ｍｇ得た。
¹H-NMR(400 MHz, CDCl₃), δ：1.46 (s, 9H), 1.80 (s, 3H), 1.94 (br s, 1H), 2.23 - 2.38 (m, 1H), 3.21 - 3.32 (m, 1H), 3.42 (br s, 1H), 3.73 - 4.03 (m, 4H), 4.09 - 4.19 (m, 2H), 4.31 - 4.55 (m, 3H), 5.23 - 5.43 (m, 2H), 5.99 (ddt, J = 16.99, 10.48, 6.37, 6.37 Hz, 1 H), 6.12 (br d, J=3.30 Hz, 1H), 10.85 - 11.17 (m, 1H);MS（ESI） m/z 423 (M+H)⁺. Example 4 (2S, 5R) -N-{[(2S) -azetidin-2-yl] methoxy} -3-methyl-7-oxo-6- (sulfooxy) -1,6-diazabicyclo [3. 2.1] Oct-3-ene-2-carboxamide

(A) (2S, 5R) -2- (hydroxymethyl) -3-methyl-6-[(prop-2-en-1-yl) oxy] -1,6-diazabicyclo [3.2.1] oct Using the compound obtained in Example 1 (a) using -3-en-7-one (297 mg) and tert-butyl (2S) -2-[(aminooxy) methyl] azetidine-1-carboxylate Then, tert-butyl (2S) -2-{[({(2S, 5R) -3-methyl-7-oxo-6-[(prop-2-ene- 1-yl) oxy] -1,6-diazabicyclo [3.2.1] oct-3-ene-2-carbonyl {amino) oxy] methyl} azetidine-1-carboxylate was obtained in an amount of 185 mg.
¹ H-NMR (400 MHz, CDCl ₃ ), δ: 1.46 (s, 9H), 1.80 (s, 3H), 1.94 (br s, 1H), 2.23-2.38 (m, 1H), 3.21-3.32 (m , 1H), 3.42 (br s, 1H), 3.73-4.03 (m, 4H), 4.09-4.19 (m, 2H), 4.31-4.55 (m, 3H), 5.23-5.43 (m, 2H), 5.99 ( ddt, J = 16.99, 10.48, 6.37, 6.37 Hz, 1 H), 6.12 (br d, J = 3.30 Hz, 1H), 10.85-11.17 (m, 1H); MS (ESI) m / z 423 (M + H) ⁺ .

(B) Using the compound (185 mg) obtained in (a) above, triphenyl (prop-2-en-1-yl) phosphanium ({[(2S, 5R) -2-({[(2S) -1- (tert-butoxycarbonyl) azetidin-2-yl] methoxy} carbamoyl) -3-methyl-7-oxo-1,6-diazabicyclo [3.2.1 [Oct-3-en-6-yl] oxy} sulfonyl) oxide anion was obtained in an amount of 150 mg.
MS (ESI) m / z 463 (M + H) ⁺ .

(C) Using the compound (150 mg) obtained in (b) above, 5.3 mg of the title compound was obtained in the same manner as in Example 1 (d).
¹ H-NMR (400 MHz, D ₂ O), δ: 1.68 (s, 3H), 2.47-2.63 (m, 2H), 3.38 (d, J = 9.05 Hz, 1H), 3.74 (d, J = 12.47 Hz, 1H), 3.93-4.02 (m, 1H), 4.02-4.21 (m, 4H), 4.22-4.31 (m, 2H), 6.23 (br.s., 1H); MS (ESI) m / z 363 (M + H) ⁺ .

（ａ）（２Ｓ，５Ｒ）−２−（ヒドロキシメチル）−３−メチル−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−７−オン（２９８ｍｇ）を用いて実施例１（ａ）で得られた化合物とｔｅｒｔ−ブチル ［３−（アミノオキシ）プロピル］カルバメートを用いて、実施例１（ｂ）と同様の方法でｔｅｒｔ−ブチル ｛３−［（｛（２Ｓ，５Ｒ）−３−メチル−７−オキソ−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−２−カルボニル｝アミノ）オキシ］プロピル｝カーバメートを２２２ｍｇ得た。
¹H-NMR(400 MHz, CDCl₃), δ：1.44 (s, 9H), 1.74 - 1.90 (m, 5H), 3.18 - 3.40 (m, 4H), 3.81 (d, J = 5.14 Hz, 1H), 3.88 - 4.08 (m, 2H), 4.21 (s, 1H), 4.30 - 4.50 (m, 2H), 5.18 (br. s., 1H), 5.30 (dd, J = 10.33, 1.41 Hz, 1H), 5.32 - 5.39 (m, 1H), 6.00 (ddt, J = 17.01, 10.50, 6.36, 6.36 Hz, 1H), 6.14 (d, J = 4.16 Hz, 1H), 9.47 (br. s., 1H);MS（ESI） m/z 411 (M+H)⁺. Example 5 (2S, 5R) -N- (3-aminopropoxy) -3-methyl-7-oxo-6- (sulfoxy) -1,6-diazabicyclo [3.2.1] oct-3- En-2-carboxamide

(A) (2S, 5R) -2- (hydroxymethyl) -3-methyl-6-[(prop-2-en-1-yl) oxy] -1,6-diazabicyclo [3.2.1] oct Using the compound obtained in Example 1 (a) using -3-en-7-one (298 mg) and tert-butyl [3- (aminooxy) propyl] carbamate, In a similar manner, tert-butyl {3-[({(2S, 5R) -3-methyl-7-oxo-6-[(prop-2-en-1-yl) oxy] -1,6-diazabicyclo [ 3.2.1] Oct-3-en-2-carbonyl {amino) oxy] propyl} carbamate was obtained in an amount of 222 mg.
¹ H-NMR (400 MHz, CDCl ₃ ), δ: 1.44 (s, 9H), 1.74-1.90 (m, 5H), 3.18-3.40 (m, 4H), 3.81 (d, J = 5.14 Hz, 1H) , 3.88-4.08 (m, 2H), 4.21 (s, 1H), 4.30-4.50 (m, 2H), 5.18 (br.s., 1H), 5.30 (dd, J = 10.33, 1.41 Hz, 1H), 5.32-5.39 (m, 1H), 6.00 (ddt, J = 17.01, 10.50, 6.36, 6.36 Hz, 1H), 6.14 (d, J = 4.16 Hz, 1H), 9.47 (br.s., 1H); MS (ESI) m / z 411 (M + H) ⁺ .

(B) Using the compound (117 mg) obtained in (a) above, triphenyl (prop-2-en-1-yl) phosphanium ({[(2S, 5R) -2-({3-[(tert-butoxycarbonyl) amino] propoxy} carbamoyl) -3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-ene-6 -Yl] oxydisulfonyl) oxydanide was obtained in an amount of 71 mg.
MS (ESI) m / z 451 (M + H) ⁺

(C) Using the compound (71 mg) obtained in (b) above, 25.4 mg of the title compound was obtained in the same manner as in Example 1 (d).
¹ H-NMR (400 MHz, D ₂ O), δ: 1.68 (s, 3H), 2.01 (dd, J = 7.03, 5.07 Hz, 2H), 3.17 (t, J = 6.85 Hz, 2H), 3.39 ( d, J = 9.78 Hz, 1H), 3.70 (d, J = 11.62 Hz, 1H), 4.04 (t, J = 5.69 Hz, 2H), 4.17-4.30 (m, 2H), 6.25 (br.s., 1H); MS (ESI) m / z 351 (M + H) ⁺ .

（ａ）（２Ｓ，５Ｒ）−２−（ヒドロキシメチル）−３−メチル−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−７−オン（２３８ｍｇ）を用いて実施例１（ａ）で得られた化合物とｔｅｒｔ−ブチル（２Ｓ）−２−［（アミノオキシ）メチル］ピロリジン−１−カルボキシレートを用いて、実施例１（ｂ）と同様の方法でｔｅｒｔ−ブチル（２Ｓ）−２−｛［（｛（２Ｓ，５Ｒ）−３−メチル−７−オキソ−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−２−カルボニル｝アミノ）オキシ］メチル｝ピロリジン−１−カルボキシレートを１４３ｍｇ得た。
¹H-NMR(400 MHz, CDCl₃), δ：1.47 (s, 9H), 1.62 - 1.69 (m, 1H), 1.74 - 1.99 (m, 6H), 3.23 - 3.30 (m, 1H), 3.32 - 3.40 (m, 2H), 3.49 - 3.72 (m, 2H), 3.76 - 3.81 (m, 1H), 3.84 - 3.93 (m, 1H), 4.18 (s, 1H), 4.24 (br s, 1H), 4.33 - 4.47 (m, 2H), 5.26 - 5.31 (m, 1H), 5.32 - 5.38 (m, 1H), 5.92 - 6.06 (m, 1H), 6.13 (d, J = 3.06 Hz, 1H), 10.67 (br s, 1H);MS（ESI） m/z 437 (M+H)⁺. Example 6 (2S, 5R) -3-methyl-7-oxo-N-{[(2S) -pyrrolidin-2-yl] methoxy} -6- (sulfooxy) -1,6-diazabicyclo [3. 2.1] Oct-3-ene-2-carboxamide

(A) (2S, 5R) -2- (hydroxymethyl) -3-methyl-6-[(prop-2-en-1-yl) oxy] -1,6-diazabicyclo [3.2.1] oct Using the compound obtained in Example 1 (a) using -3-en-7-one (238 mg) and tert-butyl (2S) -2-[(aminooxy) methyl] pyrrolidine-1-carboxylate Then, tert-butyl (2S) -2-{[({(2S, 5R) -3-methyl-7-oxo-6-[(prop-2-ene- 143 mg of 1-yl) oxy] -1,6-diazabicyclo [3.2.1] oct-3-en-2-carbonyl {amino) oxy] methyl} pyrrolidine-1-carboxylate was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ), δ: 1.47 (s, 9H), 1.62-1.69 (m, 1H), 1.74-1.99 (m, 6H), 3.23-3.30 (m, 1H), 3.32- 3.40 (m, 2H), 3.49-3.72 (m, 2H), 3.76-3.81 (m, 1H), 3.84-3.93 (m, 1H), 4.18 (s, 1H), 4.24 (br s, 1H), 4.33 -4.47 (m, 2H), 5.26-5.31 (m, 1H), 5.32-5.38 (m, 1H), 5.92-6.06 (m, 1H), 6.13 (d, J = 3.06 Hz, 1H), 10.67 (br s, 1H); MS (ESI) m / z 437 (M + H) ⁺ .

(B) Using the compound (143 mg) obtained in the above (a), triphenyl (prop-2-en-1-yl) phosphanium ({[(2S, 5R) -2-({[(2S) -1- (tert-butoxycarbonyl) pyrrolidin-2-yl] methoxy} carbamoyl) -3-methyl-7-oxo-1,6-diazabicyclo [3.2.1 ] Oct-3-en-6-yl) oxy] sulfonyl oxide anion was obtained in an amount of 154 mg.
MS (ESI) m / z 477 (M + H) ⁺

(C) Using the compound (154 mg) obtained in (b) above, 15.7 mg of the title compound was obtained in the same manner as in Example 1 (d).
¹ H-NMR (400 MHz, D ₂ O), δ: 1.66 (s, 3H), 1.69-1.78 (m, 1H), 1.93-2.09 (m, 2H), 2.10-2.20 (m, 1H), 3.32 (t, J = 6.72 Hz, 2H), 3.38 (dd, J = 11.22, 3.67 Hz, 1H), 3.56 (dd, J = 11.2, 3.55 Hz, 1H), 3.91 (m, 1H), 4.04 (t, J = 10.64 Hz, 1H), 4.16-4.23 (m, 2H), 4.26 (s, 1H), 6.24 (d, J = 5.50 Hz, 1H); MS (ESI) m / z 377 (M + H) ⁺ .

（ａ）（２Ｓ，５Ｒ）−２−（ヒドロキシメチル）−３−メチル−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−７−オン（２３８ｍｇ）を用いて実施例１（ａ）で得られた化合物とｔｅｒｔ−ブチル（３Ｒ）−２−［（アミノオキシ）メチル］ピペリジン−１−カルボキシレートを用いて、実施例１（ｂ）と同様の方法でｔｅｒｔ−ブチル（３Ｒ）−３−｛［（｛（２Ｓ，５Ｒ）−３−メチル−７−オキソ−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−２−カルボニル｝アミノ）オキシ］メチル｝ピロリジン−１−カルボキシレートを１２１ｍｇ得た。
¹H-NMR(400 MHz, CDCl₃), δ：1.46 (s, 9H), 1.53 - 1.55 (m, 1H), 1.59 - 1.65 (m, 2H), 1.84 (s, 4H), 1.87 - 1.99 (m, 1H), 2.70 - 3.06 (m, 2H), 3.21 - 3.31 (br s, 2H), 3.70 - 3.83 (m, 3H), 3.85 - 3.98 (m, 2H), 4.18 - 4.23 (br s, 1H), 4.34 - 4.46 (m, 2H), 5.27 - 5.39 (m, 2H), 5.93 - 6.06 (m, 1H), 6.10 - 6.16 (m, 1H);MS（ESI） m/z 451 (M+H)⁺. Example 7 (2S, 5R) -3-methyl-7-oxo-N-{[(3R) -piperidin-3-yl] methoxy} -6- (sulfooxy) -1,6-diazabicyclo [3. 2.1] Oct-3-ene-2-carboxamide

(A) (2S, 5R) -2- (hydroxymethyl) -3-methyl-6-[(prop-2-en-1-yl) oxy] -1,6-diazabicyclo [3.2.1] oct Using the compound obtained in Example 1 (a) using -3-en-7-one (238 mg) and tert-butyl (3R) -2-[(aminooxy) methyl] piperidine-1-carboxylate Then, tert-butyl (3R) -3-{[({(2S, 5R) -3-methyl-7-oxo-6-[(prop-2-ene- 1-yl) oxy] -1,6-diazabicyclo [3.2.1] oct-3-en-2-carbonyl {amino) oxy] methyl} pyrrolidine-1-carboxylate was obtained in an amount of 121 mg.
¹ H-NMR (400 MHz, CDCl ₃ ), δ: 1.46 (s, 9H), 1.53-1.55 (m, 1H), 1.59-1.65 (m, 2H), 1.84 (s, 4H), 1.87-1.99 ( m, 1H), 2.70-3.06 (m, 2H), 3.21-3.31 (br s, 2H), 3.70-3.83 (m, 3H), 3.85-3.98 (m, 2H), 4.18-4.23 (br s, 1H ), 4.34-4.46 (m, 2H), 5.27-5.39 (m, 2H), 5.93-6.06 (m, 1H), 6.10-6.16 (m, 1H); MS (ESI) m / z 451 (M + H ) ⁺ .

(B) Using the compound (121 mg) obtained in the above (a), triphenyl (prop-2-en-1-yl) phosphanium ({[(2S, 5R) -2-({[(3R) -1- (tert-butoxycarbonyl) piperidin-3-yl] methoxy} carbamoyl) -3-methyl-7-oxo-1,6-diazabicyclo [3.2.1 ] Oct-3-en-6-yl) oxy] sulfonyl oxide anion was obtained in an amount of 104 mg.
MS (ESI) m / z 491 (M + H) ⁺

(C) Using the compound (104 mg) obtained in (b) above, 24.5 mg of the title compound was obtained in the same manner as in Example 1 (d).
¹ H-NMR (400 MHz, D ₂ O), δ: 1.30 (qd, J = 12.6, 3.97 Hz, 1H), 1.64 (s, 3H), 1.66-1.75 (m, 1H), 1.78-1.97 (m , 2H), 2.11-2.23 (m, 1H), 2.80 (t, J = 12.23 Hz, 1H), 2.88 (td, J = 12.6, 3.24 Hz, 1H), 3.30-3.40 (m, 2H), 3.45- 3.52 (m, 1H), 3.57 (d, J = 11.37 Hz, 1H), 3.81-3.81 (m, 1H), 3.90 (q, J = 5.26 Hz, 1H), 4.19-4.25 (m, 2H), 6.21 -6.29 (m, 1H); MS (ESI) m / z 391 (M + H) ⁺ .

（ａ）（２Ｓ，５Ｒ）−２−（ヒドロキシメチル）−３−メチル−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−７−オン（２４８ｍｇ）を用いて実施例１（ａ）で得られた化合物とｔｅｒｔ−ブチル［（２Ｓ）−１−（アミノオキシ）プロパン−２−イル］カルボキシレートを用いて、実施例１（ｂ）と同様の方法でｔｅｒｔ−ブチル｛（２Ｓ）−１−［（｛（２Ｓ，５Ｒ）−３−メチル−７−オキソ−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−２−カルボニル｝アミノ）オキシ］プロパン−２−イル｝カルボキシレートを２０３ｍｇ得た。
¹H-NMR(400 MHz, CDCl₃), δ：1.16 (d, J = 6.80 Hz, 3H), 1.45 (s, 9H), 1.81 (s, 3H), 3.29 (dd, J = 10.51, 2.69 Hz, 1H), 3.42 (d, J = 11.13 Hz, 1H), 3.59 - 3.68 (m, 1H), 3.80 (dd, J = 2.69, 2.69 Hz, 1H), 3.92 (dd, J = 12.10, 3.67 Hz, 1H), 3.95 - 4.03 (m, 1H), 4.20 (s, 1H), 4.34 - 4.47 (m, 2H), 4.74 (d, J = 8.56 Hz, 1H), 5.27 - 5.32 (m, 1H), 5.32 - 5.39 (m, 1H), 5.94-6.06 (m, 1H), 6.10 - 6.17 (m, 1H), 9.89 - 10.09 (m, 1H);MS（ESI） m/z 411 (M+H)⁺. Example 8 (2S, 5R) -N-[(2S) -2-aminopropoxy] -3-methyl-7-oxo-6- (sulfoxy) -1,6-diazabicyclo [3.2.1] Oct-3-ene-2-carboxamide

(A) (2S, 5R) -2- (hydroxymethyl) -3-methyl-6-[(prop-2-en-1-yl) oxy] -1,6-diazabicyclo [3.2.1] oct Using the compound obtained in Example 1 (a) using -3-en-7-one (248 mg) and tert-butyl [(2S) -1- (aminooxy) propan-2-yl] carboxylate Then, tert-butyl {(2S) -1-[({(2S, 5R) -3-methyl-7-oxo-6-[(prop-2-ene- There were obtained 203 mg of 1-yl) oxy] -1,6-diazabicyclo [3.2.1] oct-3-en-2-carbonyl {amino) oxy] propan-2-yl} carboxylate.
¹ H-NMR (400 MHz, CDCl ₃ ), δ: 1.16 (d, J = 6.80 Hz, 3H), 1.45 (s, 9H), 1.81 (s, 3H), 3.29 (dd, J = 10.51, 2.69 Hz) , 1H), 3.42 (d, J = 11.13 Hz, 1H), 3.59-3.68 (m, 1H), 3.80 (dd, J = 2.69, 2.69 Hz, 1H), 3.92 (dd, J = 12.10, 3.67 Hz, 1H), 3.95-4.03 (m, 1H), 4.20 (s, 1H), 4.34-4.47 (m, 2H), 4.74 (d, J = 8.56 Hz, 1H), 5.27-5.32 (m, 1H), 5.32 -5.39 (m, 1H), 5.94-6.06 (m, 1H), 6.10-6.17 (m, 1H), 9.89-10.09 (m, 1H); MS (ESI) m / z 411 (M + H) ⁺ .

(B) Using the compound (203 mg) obtained in (a) above, triphenyl (prop-2-en-1-yl) phosphanium ({[(2S, 5R) -2-({[(2S) -2- (tert-butoxycarbonyl) amino] propoxy} carbamoyl) -3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3 -En-6-yl] oxy] sulfonyl) oxide anion was obtained in an amount of 157 mg.
MS (ESI) m / z 451 (M + H) ⁺

(C) Using the compound (157 mg) obtained in (b) above, 17.9 mg of the title compound was obtained in the same manner as in Example 1 (d).
¹ H-NMR (400 MHz, D ₂ O), δ: 1.26 (s, 3H), 1.66 (s, 3H), 3.38 (dd, J = 11.62, 2.75 Hz, 1H), 3.54 (d, J = 11.62 Hz, 1H), 3.61 (ddq, J = 8.90, 6.72, 3.45, 3.45, 3.45 Hz, 1H), 3.94 (dd, J = 11.49, 8.93 Hz, 1H), 4.10 (dd, J = 11.49, 3.45 Hz, 1H), 4.22 (q, J = 2.75 Hz, 1H), 4.28 (s, 1H), 6.23-6.28 (m, 1H); MS (ESI) m / z 351 (M + H) ⁺ .

（ａ）（２Ｓ，５Ｒ）−２−（ヒドロキシメチル）−３−メチル−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−７−オン（２４８ｍｇ）を用いて実施例１（ａ）で得られた化合物とｔｅｒｔ−ブチル（２Ｒ）−２−［（アミノオキシ）メチル］ピロリジン−１−カルボキシレートを用いて、実施例１（ｂ）と同様の方法でｔｅｒｔ−ブチル（２Ｒ）−２−｛［（｛（２Ｓ，５Ｒ）−３−メチル−７−オキソ−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−２−カルボニル｝アミノ）オキシ］メチル｝ピロリジン−１−カルボキシレートを１６５ｍｇ得た。
¹H-NMR(400 MHz, CDCl₃), δ：1.47 (s, 9H), 1.62 - 1.70 (m, 1H), 1.80 - 1.93 (m, 5H), 1.94 - 2.03 (m, 1H), 3.22 - 3.30 (m, 1H), 3.37 (m, 3H), 3.60 - 3.71 (m, 1H), 3.76 - 3.90 (m, 2H), 4.16 - 4.28 (m, 2H), 4.33 - 4.47 (m, 2H), 5.25 - 5.37 (m, 2H), 5.94 - 6.06 (m, 1H), 6.08 - 6.16 (m, 1H), 10.65 - 10.77 (m, 1H) ;MS（ESI） m/z 437 (M+H)⁺. Example 9 (2S, 5R)-3-methyl-7-oxo -N - {[(2R) - pyrrolidin-2-yl] methoxy} -6- (sulfooxy) -1,6-diazabicyclo [3. 2.1] Oct-3-ene-2-carboxamide

(A) (2S, 5R) -2- (hydroxymethyl) -3-methyl-6-[(prop-2-en-1-yl) oxy] -1,6-diazabicyclo [3.2.1] oct Using the compound obtained in Example 1 (a) using -3-en-7-one (248 mg) and tert-butyl (2R) -2-[(aminooxy) methyl] pyrrolidine-1-carboxylate Then, tert-butyl (2R) -2-{[({(2S, 5R) -3-methyl-7-oxo-6-[(prop-2-ene-) was obtained in the same manner as in Example 1 (b). 165 mg of 1-yl) oxy] -1,6-diazabicyclo [3.2.1] oct-3-en-2-carbonyl {amino) oxy] methyl} pyrrolidine-1-carboxylate was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ), δ: 1.47 (s, 9H), 1.62-1.70 (m, 1H), 1.80-1.93 (m, 5H), 1.94-2.03 (m, 1H), 3.22- 3.30 (m, 1H), 3.37 (m, 3H), 3.60-3.71 (m, 1H), 3.76-3.90 (m, 2H), 4.16-4.28 (m, 2H), 4.33-4.47 (m, 2H), 5.25-5.37 (m, 2H), 5.94-6.06 (m, 1H), 6.08-6.16 (m, 1H), 10.65-10.77 (m, 1H); MS (ESI) m / z 437 (M + H) ⁺ .

(B) Using the compound (165 mg) obtained in (a) above, triphenyl (prop-2-en-1-yl) phosphanium ({[(2S, 5R) -2-({[(2R) -1- (tert-butoxycarbonyl) pyrrolidin-2-yl] methoxy} carbamoyl) -3-methyl-7-oxo-1,6-diazabicyclo [3.2.1 167 mg of [oct-3-en-6-yl) oxy] sulfonyl oxide anion was obtained.
MS (ESI) m / z 477 (M + H) ⁺

(C) Using the compound (167 mg) obtained in the above (b), 6.1 mg of the title compound was obtained in the same manner as in Example 1 (d).
¹ H-NMR (400 MHz, D ₂ O), δ: 1.64 (s, 3H), 1.69-1.78 (m, 1H), 1.93-2.06 (m, 2H), 2.10-2.18 (m, 1H), 3.29 -3.39 (m, 3H), 3.62 (d, J = 11.37 Hz, 1H), 3.93 (m, 1H), 4.02 (t, J = 11.49 Hz, 1H), 4.13-4.24 (m, 3H), 6.20- 6.25 (m, 1H); MS (ESI) m / z 377 (M + H) ⁺ .

（ａ）（２Ｓ，５Ｒ）−２−（ヒドロキシメチル）−３−メチル−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−７−オン（３０４ｍｇ）を用いて実施例１（ａ）で得られた化合物とｔｅｒｔ−ブチル ［２−（アミノオキシ）エチル］エチルカルバメートを用いて、実施例１（ｂ）と同様の方法でｔｅｒｔ−ブチル エチル｛２−［（｛（２Ｓ，５Ｒ）−３−メチル−７−オキソ−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−２−カルボニル｝アミノ）オキシ］エチル｝カーバメートを１１８ｍｇ得た。
¹H-NMR(400 MHz, CDCl₃), δ：1.13 (t, J = 7.09 Hz, 3H), 1.48 (s, 9H), 1.83 (s, 3H), 3.28 (br d, J = 11.49 Hz, 3H), 3.38 - 3.54 (m, 3H), 3.80 (br s, 1H), 3.96 (br s, 2H), 4.23 (s, 1H), 4.41 (qd, J = 12.31, 6.24 Hz, 2H), 5.26 - 5.41 (m, 2H), 6.01 (ddt, J = 16.93, 10.51, 6.45, 6.45 Hz, 1H), 6.14 (br s, 1H), 10.41 (br s, 1H) ;MS（ESI） m/z 425 (M+H)⁺. Example 10 (2S, 5R) -N- [2- (ethylamino) ethoxy] -3-methyl-7-oxo-6- (sulfoxy) -1,6-diazabicyclo [3.2.1] oct -3-ene-2-carboxamide

(A) (2S, 5R) -2- (hydroxymethyl) -3-methyl-6-[(prop-2-en-1-yl) oxy] -1,6-diazabicyclo [3.2.1] oct Example 1 (b) using the compound obtained in Example 1 (a) using -3-en-7-one (304 mg) and tert-butyl [2- (aminooxy) ethyl] ethyl carbamate. Tert-butyl ethyl} 2-[({(2S, 5R) -3-methyl-7-oxo-6-[(prop-2-en-1-yl) oxy] -1,6- 118 mg of diazabicyclo [3.2.1] oct-3-en-2-carbonyl {amino) oxy] ethyl} carbamate were obtained.
¹ H-NMR (400 MHz, CDCl ₃ ), δ: 1.13 (t, J = 7.09 Hz, 3H), 1.48 (s, 9H), 1.83 (s, 3H), 3.28 (br d, J = 11.49 Hz, 3H), 3.38-3.54 (m, 3H), 3.80 (br s, 1H), 3.96 (br s, 2H), 4.23 (s, 1H), 4.41 (qd, J = 12.31, 6.24 Hz, 2H), 5.26 -5.41 (m, 2H), 6.01 (ddt, J = 16.93, 10.51, 6.45, 6.45 Hz, 1H), 6.14 (br s, 1H), 10.41 (br s, 1H); MS (ESI) m / z 425 (M + H) ⁺ .

(B) Using the compound (118 mg) obtained in (a) above, triphenyl (prop-2-en-1-yl) phosphanium ({[(2S, 5R) -2-({2-[(tert-butoxycarbonyl) (ethyl) amino] ethoxy} carbamoyl) -3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3- 138 mg of [en-6-yl] oxydisulfonyl) oxydanide were obtained.
MS (ESI) m / z 465 (M + H) ⁺

(C) Using the compound (138 mg) obtained in the above (b), 10 mg of the title compound was obtained in the same manner as in Example 1 (d).
¹ H-NMR (400 MHz, D ₂ O), δ: 1.28 (t, J = 7.27 Hz, 3H), 1.64 (s, 3H), 3.10 (q, J = 7.34 Hz, 2H), 3.15-3.29 ( m, 2H), 3.32 (br d, J = 8.68 Hz, 1H), 3.88 (d, J = 11.37 Hz, 1H), 4.01-4.10 (m, 3H), 4.21 (dd, J = 5.14, 2.57 Hz, 1H), 6.13 (br s, 1H); MS (ESI) m / z 365 (M + H) ⁺ .

（ａ）（２Ｓ，５Ｒ）−２−（ヒドロキシメチル）−３−メチル−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−７−オン（３２７ｍｇ）を用いて実施例１（ａ）で得られた化合物とｔｅｒｔ−ブチル ［２−（アミノオキシ）エチル］メチルカルバメートを用いて、実施例１（ｂ）と同様の方法でｔｅｒｔ−ブチル メチル｛２−［（｛（２Ｓ，５Ｒ）−３−メチル−７−オキソ−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−２−カルボニル｝アミノ）オキシ］エチル｝カーバメートを２０４ｍｇ得た。
¹H-NMR(400 MHz, CDCl₃), δ：1.47 (s, 9H), 1.82 (s, 3H), 2.89 (s, 3H), 3.23 - 3.32 (m, 1H), 3.40 - 3.60 (m, 3H), 3.76 - 3.83 (m, 1H), 3.89 - 4.06 (m, 2H), 4.22 (s, 1H), 4.35 - 4.48 (m, 2H), 5.26 - 5.38 (m, 2H), 5.95 - 6.07 (m, 1H), 6.08 - 6.17 (m, 1H), 10.32(br s, 1H) ;MS（ESI） m/z 411 (M+H)⁺. Example 11 (2S, 5R) -3-methyl-N- [2- (methylamino) ethoxy] -7-oxo-6- (sulfoxy) -1,6-diazabicyclo [3.2.1] oct -3-ene-2-carboxamide

(A) (2S, 5R) -2- (hydroxymethyl) -3-methyl-6-[(prop-2-en-1-yl) oxy] -1,6-diazabicyclo [3.2.1] oct Example 1 (b) using the compound obtained in Example 1 (a) using -3-en-7-one (327 mg) and tert-butyl [2- (aminooxy) ethyl] methylcarbamate. Tert-butyl methyl} 2-[({(2S, 5R) -3-methyl-7-oxo-6-[(prop-2-en-1-yl) oxy] -1,6- 204 mg of diazabicyclo [3.2.1] oct-3-en-2-carbonyl {amino) oxy] ethyl} carbamate were obtained.
¹ H-NMR (400 MHz, CDCl ₃ ), δ: 1.47 (s, 9H), 1.82 (s, 3H), 2.89 (s, 3H), 3.23-3.32 (m, 1H), 3.40-3.60 (m, 3H), 3.76-3.83 (m, 1H), 3.89-4.06 (m, 2H), 4.22 (s, 1H), 4.35-4.48 (m, 2H), 5.26-5.38 (m, 2H), 5.95-6.07 ( m, 1H), 6.08-6.17 (m, 1H), 10.32 (brs, 1H); MS (ESI) m / z 411 (M + H) ⁺ .

(B) Using the compound (204 mg) obtained in the above (a), triphenyl (prop-2-en-1-yl) phosphanium ({[(2S, 5R) -2-({2-[(tert-butoxycarbonyl) (methyl) amino] ethoxy} carbamoyl) -3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3- 130 mg of [en-6-yl] oxy {sulfonyl) oxydanide were obtained.
MS (ESI) m / z 451 (M + H) ⁺

(C) Using the compound (130 mg) obtained in (b) above, 14.9 mg of the title compound was obtained in the same manner as in Example 1 (d).
¹ H-NMR (400 MHz, D ₂ O), δ: 1.65 (s, 3H), 3.46 (s, 3H), 3.23-3.30 (m, 2H), 3.32-3.41 (m, 1H), 3.56-3.63 (m, 1H), 4.14-4.25 (m, 4H), 6.21-6.24 (m, 1H); MS (ESI) m / z 351 (M + H) ⁺ .

（ａ）（２Ｓ，５Ｒ）−２−（ヒドロキシメチル）−３−メチル−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−７−オン（２６７ｍｇ）を用いて実施例１（ａ）で得られた化合物とｔｅｒｔ−ブチル（３Ｓ）−３−（アミノオキシ）ピロリジン−１−カルボキシレートを用いて、実施例１（ｂ）と同様の方法でｔｅｒｔ−ブチル（３Ｓ）−３−［（｛（２Ｓ，５Ｒ）−３−メチル−７−オキソ−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−２−カルボニル｝アミノ）オキシ］ピロリジン−１−カルボキシレートを１７８ｍｇ得た。
¹H-NMR(400 MHz, CDCl₃), δ：1.47 (s, 9H), 1.83 (br s, 3H), 1.92 - 2.03 (m, 1H), 2.15 - 2.24 (m, 1H), 3.25 (br s, 2H), 3.32 - 3.75 (m, 4H), 3.78 - 3.85 (m, 1H), 4.21 - 4.28 (m, 1H), 4.40 (dd, J = 10.70, 6.30 Hz, 2H), 4.57 - 4.68 (m, 1H), 5.27 - 5.39 (m, 2H), 5.93 - 6.06 (m, 1H), 6.15 (br s, 1H), 9.22 - 9.44 (br s, 1H) ;MS（ESI） m/z 423 (M+H)⁺. Example 12 (2S, 5R) -3-methyl-7-oxo-N-{[(3S) -pyrrolidin-3-yl] oxy} -6- (sulfooxy) -1,6-diazabicyclo [3. 2.1] Oct-3-ene-2-carboxamide

(A) (2S, 5R) -2- (hydroxymethyl) -3-methyl-6-[(prop-2-en-1-yl) oxy] -1,6-diazabicyclo [3.2.1] oct Using the compound obtained in Example 1 (a) using -3-en-7-one (267 mg) and tert-butyl (3S) -3- (aminooxy) pyrrolidine-1-carboxylate Tert-Butyl (3S) -3-[({(2S, 5R) -3-methyl-7-oxo-6-[(prop-2-en-1-yl)] in the same manner as in Example 1 (b). Oxy] -1,6-diazabicyclo [3.2.1] oct-3-ene-2-carbonyl {amino) oxy] pyrrolidine-1-carboxylate was obtained in an amount of 178 mg.
¹ H-NMR (400 MHz, CDCl ₃ ), δ: 1.47 (s, 9H), 1.83 (br s, 3H), 1.92-2.03 (m, 1H), 2.15-2.24 (m, 1H), 3.25 (br s, 2H), 3.32-3.75 (m, 4H), 3.78-3.85 (m, 1H), 4.21-4.28 (m, 1H), 4.40 (dd, J = 10.70, 6.30 Hz, 2H), 4.57-4.68 ( m, 1H), 5.27-5.39 (m, 2H), 5.93-6.06 (m, 1H), 6.15 (br s, 1H), 9.22-9.44 (br s, 1H); MS (ESI) m / z 423 ( (M + H) ⁺ .

(B) Using the compound (178 mg) obtained in (a) above, triphenyl (prop-2-en-1-yl) phosphanium {[(2S, 5R) in the same manner as in Example 1 (c). ) -2-({[(3S) -1- (tert-butoxycarbonyl) pyrrolidin-3-yl] oxy} carbamoyl) -3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] 222 mg of oct-3-en-6-yl) oxy] sulfonyl peroxide were obtained.
MS (ESI) m / z 463 (M + H) ⁺

(C) Using the compound (222 mg) obtained in the above (b), 22.5 mg of the title compound was obtained in the same manner as in Example 1 (d).
¹ H-NMR (400 MHz, D ₂ O), δ: 1.64 (s, 3H), 2.12-2.23 (m, 1H), 2.23-2.33 (m, 1H), 3.30-3.47 (m, 5H), 3.54 -3.63 (m, 2H), 4.20-4.23 (m, 1H), 4.25 (s, 1H), 6.23-6.25 (m, 1H); MS (ESI) m / z 363 (M + H) ⁺ .

（ａ）（２Ｓ，５Ｒ）−２−（ヒドロキシメチル）−３−メチル−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−７−オン（３０７ｍｇ）を用いて実施例１（ａ）で得られた化合物とｔｅｒｔ−ブチル−３−［（アミノオキシ）メチル］アゼチジン−１−カルボキシレートを用いて、実施例１（ｂ）と同様の方法でｔｅｒｔ−ブチル−３−｛［（｛（２Ｓ，５Ｒ）−３−メチル−７−オキソ−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−２−カルボニル｝アミノ）オキシ］メチル｝アゼチジン−１−カルボキシレートを２０３ｍｇ得た。
¹H-NMR(400 MHz, CDCl₃), δ：1.44 (s, 9H), 1.85 (s, 3H), 2.88 (br d, J = 5.75 Hz, 1H), 3.18 - 3.33 (m, 2H), 3.70 - 3.86 (m, 3H), 3.99 - 4.19 (m, 4H), 4.22 (s, 1H), 4.33 - 4.51 (m, 2H), 5.27 - 5.43 (m, 2H), 6.00 (ddt, J = 17.07, 10.56, 6.36, 6.36 Hz, 1H), 6.15 (br s, 1H), 9.30 (s, 1H) ;MS（ESI） m/z 423 (M+H)⁺. Example 13 (2S, 5R) -N-{[azetidin-3-yl] methoxy} -3-methyl-7-oxo-6- (sulfooxy) -1,6-diazabicyclo [3.2.1] Oct-3-ene-2-carboxamide

(A) (2S, 5R) -2- (hydroxymethyl) -3-methyl-6-[(prop-2-en-1-yl) oxy] -1,6-diazabicyclo [3.2.1] oct Using the compound obtained in Example 1 (a) with -3-en-7-one (307 mg) and tert-butyl-3-[(aminooxy) methyl] azetidine-1-carboxylate In the same manner as in Example 1 (b), tert-butyl-3-{[({(2S, 5R) -3-methyl-7-oxo-6-[(prop-2-en-1-yl) oxy]] 203 mg of -1,6-diazabicyclo [3.2.1] oct-3-ene-2-carbonyl {amino) oxy] methyl} azetidine-1-carboxylate was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ), δ: 1.44 (s, 9H), 1.85 (s, 3H), 2.88 (br d, J = 5.75 Hz, 1H), 3.18-3.33 (m, 2H), 3.70-3.86 (m, 3H), 3.99-4.19 (m, 4H), 4.22 (s, 1H), 4.33-4.51 (m, 2H), 5.27-5.43 (m, 2H), 6.00 (ddt, J = 17.07 , 10.56, 6.36, 6.36 Hz, 1H), 6.15 (br s, 1H), 9.30 (s, 1H); MS (ESI) m / z 423 (M + H) ⁺ .

(B) Using the compound (203 mg) obtained in (a) above, triphenyl (prop-2-en-1-yl) phosphanium ({[(2S, 5R) -2-({[1- (tert-butoxycarbonyl) azetidin-3-yl] methoxy} carbamoyl) -3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3 -En-6-yl] oxy {sulfonyl) oxide anion was obtained in an amount of 243 mg.
MS (ESI) m / z 463 (M + H) ⁺ .

(C) Using the compound (243 mg) obtained in (b) above, 65 mg of the title compound was obtained in the same manner as in Example 1 (d).
¹ H-NMR (400 MHz, D ₂ O), δ: 1.70 (s, 3H), 3.23-3.34 (m, 1H), 3.43 (dd, J = 11.43, 2.02 Hz, 1H), 3.61 (d, J = 11.49 Hz, 1H), 4.07 (dd, J = 11.62, 7.09 Hz, 2H), 4.15 (d, J = 5.99 Hz, 2H), 4.19-4.28 (m, 3H), 4.30 (s, 1H), 6.30 (br dd, J = 3.48, 1.53 Hz, 1H); MS (ESI) m / z 363 (M + H) ⁺ .

（ａ）（２Ｓ，５Ｒ）−２−（ヒドロキシメチル）−３−メチル−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−７−オン（３３０ｍｇ）を用いて実施例１（ａ）で得られた化合物とｔｅｒｔ−ブチル［（２Ｓ）−１−ヒドラジニル−１−オキシプロパン−２−イル）カーバメートを用いて、実施例２（ａ）と同様の方法でｔｅｒｔ−ブチル［（２Ｓ）−１−（２−｛（２Ｓ，５Ｒ）−３−メチル−７−オキソ−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−２−カルボニル｝ヒドラジニル）−１−オキソプロパン−２−イル］カーバメートを２５５ｍｇ得た。
¹H-NMR(400 MHz, CDCl₃), δ：1.40 (d, J = 7.09 Hz, 3H), 1.46 (s, 9H), 1.88 (s, 3H), 3.34 (s, 2H), 3.76 - 3.84 (m, 1H), 4.22 - 4.33 (m, 1H), 4.34 - 4.47 (m, 2H), 4.88 - 4.97 (m, 1H), 5.27 - 5.40 (m, 2H), 5.94 - 6.06 (m, 1H), 6.09 - 6.14 (m, 1H), 8.49 (br s, 1H), 8.74 (br s, 1H) ;MS（ESI） m/z 424 (M+H)⁺. [Example 14] (2S, 5R) -N '-[(2S) -2-aminopropanoyl] -3-methyl-7-oxo-6- (sulfooxy) -1,6-diazabicyclo [3.2. 1] Oct-3-ene-2-carbohydrazide

(A) (2S, 5R) -2- (hydroxymethyl) -3-methyl-6-[(prop-2-en-1-yl) oxy] -1,6-diazabicyclo [3.2.1] oct Using the compound obtained in Example 1 (a) using -3-en-7-one (330 mg) and tert-butyl [(2S) -1-hydrazinyl-1-oxypropan-2-yl) carbamate And tert-butyl [(2S) -1- (2-{(2S, 5R) -3-methyl-7-oxo-6-[(prop-2-ene)] in the same manner as in Example 2 (a). 255 mg of -1-yl) oxy] -1,6-diazabicyclo [3.2.1] oct-3-en-2-carbonyl {hydrazinyl) -1-oxopropan-2-yl] carbamate was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ), δ: 1.40 (d, J = 7.09 Hz, 3H), 1.46 (s, 9H), 1.88 (s, 3H), 3.34 (s, 2H), 3.76-3.84 (m, 1H), 4.22-4.33 (m, 1H), 4.34-4.47 (m, 2H), 4.88-4.97 (m, 1H), 5.27-5.40 (m, 2H), 5.94-6.06 (m, 1H) , 6.09-6.14 (m, 1H), 8.49 (br s, 1H), 8.74 (br s, 1H); MS (ESI) m / z 424 (M + H) ⁺ .

(B) Using the compound (255 mg) obtained in the above (a), triphenyl (prop-2-en-1-yl) phosphanium {[(2S, 5R)] in the same manner as in Example 2 (b). ) -2- (2-{(2S) -2-[(tert-butoxycarbonyl) amino] propanoyl} hydrazinecarbonyl) -3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct 264 mg of (-3-en-6-yl] oxy} sulfonyl) oxide anion was obtained.
MS (ESI) m / z 464 (M + H) ⁺ .

(C) Using the compound (264 mg) obtained in the above (b), 17.3 mg of the title compound was obtained in the same manner as in Example 2 (c).
¹ H-NMR (400 MHz, D ₂ O), δ: 1.50 (d, J = 7.20 Hz, 3H), 1.71 (s, 3H), 3.40 (dd, J = 11.56, 3.18 Hz, 1H), 3.51 ( d, J = 11.56 Hz, 1H), 4.07-4.17 (m, 1H), 4.19-4.24 (m, 1H), 4.47 (m, 1H), 6.20-6.28 (m, 1H); MS (ESI) m / z 364 (M + H) ⁺ .

（ａ）（２Ｓ，５Ｒ）−２−（ヒドロキシメチル）−３−メチル−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−７−オン（２４１ｍｇ）を用いて実施例１（ａ）で得られた化合物とｔｅｒｔ−ブチル（２Ｓ）−２−（ヒドラジンカルボニル）ピロリジン−１−カルボキシレートを用いて、実施例２（ａ）と同様の方法でｔｅｒｔ−ブチル（２Ｓ）−２−（２−｛（２Ｓ，５Ｒ）−３−メチル−７−オキソ−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−２−カルボニル｝ヒドラジンカルボニル）ピロリジン−１−カルボキシレートを１３４ｍｇ得た。
¹H-NMR(400 MHz, CDCl₃), δ：1.46 (s, 9H), 1.83 (s, 3H), 1.85 - 2.03 (m, 2H), 2.10 - 2.38 (m, 2H), 3.26 - 3.43 (m, 2H), 3.44 - 3.58 (m, 2H), 3.76 - 3.83 (m, 1H), 4.33 - 4.50 (m, 4H), 5.26 - 5.40 (m, 2H), 5.94 - 6.06 (m, 1H), 6.12 (br s, 1H), 9.19 (br s, 2H) ;MS（ESI） m/z 450 (M+H)⁺. [Example 15] (2S, 5R) -3-Methyl-7-oxo-N '-[(2S) -pyrrolidine-2-carbonyl] -6- (sulfooxy) -1,6-diazabicyclo [3.2. 1] Oct-3-ene-2-carbohydrazide

(A) (2S, 5R) -2- (hydroxymethyl) -3-methyl-6-[(prop-2-en-1-yl) oxy] -1,6-diazabicyclo [3.2.1] oct Using the compound obtained in Example 1 (a) using -3-en-7-one (241 mg) and tert-butyl (2S) -2- (hydrazinecarbonyl) pyrrolidine-1-carboxylate In a similar manner to Example 2 (a), tert-butyl (2S) -2- (2-{(2S, 5R) -3-methyl-7-oxo-6-[(prop-2-en-1-yl) 134) mg)) oxy] -1,6-diazabicyclo [3.2.1] oct-3-en-2-carbonyl {hydrazinecarbonyl) pyrrolidine-1-carboxylate.
¹ H-NMR (400 MHz, CDCl ₃ ), δ: 1.46 (s, 9H), 1.83 (s, 3H), 1.85-2.03 (m, 2H), 2.10-2.38 (m, 2H), 3.26-3.43 ( m, 2H), 3.44-3.58 (m, 2H), 3.76-3.83 (m, 1H), 4.33-4.50 (m, 4H), 5.26-5.40 (m, 2H), 5.94-6.06 (m, 1H), 6.12 (br s, 1H), 9.19 (br s, 2H); MS (ESI) m / z 450 (M + H) ⁺ .

(B) Using the compound (134 mg) obtained in the above (a), triphenyl (prop-2-en-1-yl) phosphanium ({[(2S, 5R) -2- {2-[(2S) -1- (tert-butoxycarbonyl) pyrrolidine-2-carbonyl] hydrazinecarbonyl} -3-methyl-7-oxo-1,6-diazabicyclo [3.2.1 [Oct-3-en-6-yl] oxy} sulfonyl) oxide anion was obtained in an amount of 129 mg.
MS (ESI) m / z 490 (M + H) ⁺ .

(C) Using the compound (129 mg) obtained in (b) above, 20.4 mg of the title compound was obtained in the same manner as in Example 2 (c).
¹ H-NMR (400 MHz, D ₂ O), δ: 1.71 (s, 3H), 1.98-2.18 (m, 3H), 2.39-2.52 (m, 1H), 3.29-3.44 (m, 3H), 3.45 -3.52 (m, 1H), 4.21-4.24 (m, 1H), 4.40-4.49 (m, 2H), 6.19-6.27 (m, 1H); MS (ESI) m / z 390 (M + H) ⁺ .

（ａ）（２Ｓ，５Ｒ）−２−（ヒドロキシメチル）−３−メチル−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−７−オン（２６２ｍｇ）を用いて実施例１（ａ）で得られた化合物とＯ−エトキシヒドロキシルアミンを用いて、実施例１（ｂ）と同様の方法で（２Ｓ，５Ｒ）−Ｎ−エトキシ−３−メチル−７−オキソ−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−２−カルボキサミドを１３３ｍｇ得た。
¹H-NMR(400 MHz, CDCl₃), δ：1.29 (t, J = 7.03 Hz, 3H), 1.85 (s, 3H), 3.23 - 3.29 (m, 2H), 3.80 - 3.82 (m, 1H), 3.94 - 4.07 (m, 2H), 4.19 - 4.25 (m, 1H), 4.34 - 4.46 (m, 2H), 5.28 - 5.33 (m, 1H), 5.33 - 5.39 (m, 1H), 5.91 - 6.07 (m, 1H), 6.10 - 6.19 (m, 1H), 9.12 - 9.21 (m, 1H) ;MS（ESI） m/z 283 (M+H)⁺. Example 16 Sodium ({[(2S, 5R) -2- (ethoxycarbamoyl) -3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6 Yl] oxy} sulfonyl) oxydanide

(A) (2S, 5R) -2- (hydroxymethyl) -3-methyl-6-[(prop-2-en-1-yl) oxy] -1,6-diazabicyclo [3.2.1] oct Using the compound obtained in Example 1 (a) using -3-en-7-one (262 mg) and O-ethoxyhydroxylamine, (2S, 5R ) -N-Ethoxy-3-methyl-7-oxo-6-[(prop-2-en-1-yl) oxy] -1,6-diazabicyclo [3.2.1] oct-3-en-2 -133 mg of carboxamide were obtained.
¹ H-NMR (400 MHz, CDCl ₃ ), δ: 1.29 (t, J = 7.03 Hz, 3H), 1.85 (s, 3H), 3.23-3.29 (m, 2H), 3.80-3.82 (m, 1H) , 3.94-4.07 (m, 2H), 4.19-4.25 (m, 1H), 4.34-4.46 (m, 2H), 5.28-5.33 (m, 1H), 5.33-5.39 (m, 1H), 5.91-6.07 ( m, 1H), 6.10-6.19 (m, 1H), 9.12-9.21 (m, 1H); MS (ESI) m / z 283 (M + H) ⁺ .

(B) Using the compound (133 mg) obtained in (a) above, triphenyl (prop-2-en-1-yl) phosphanium ({[(2S, 160 mg of 5R) -2- (ethoxycarbamoyl) -3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yl] oxy {sulfonyl) oxide anion was obtained. .
MS (ESI) m / z 322 (M + H) ⁺ .

(C) Using the compound (160 mg) obtained in (b) above, 18.4 mg of the title compound was obtained in the same manner as in Example 3 (c).
¹ H-NMR (400 MHz, D ₂ O), δ: 1.21 (t, J = 7.06 Hz, 3H), 1.64 (s, 3H), 3.36 (dd, J = 11.48, 2.60 Hz, 1H), 3.62 ( d, J = 1.48 Hz, 1H), 3.94 (q, J = 7.06 Hz, 2H), 4.21 (dd, J = 2.60, 2.60 Hz, 1H), 4.23 (s, 1H), 6.19-6.28 (m, 1H ); MS (ESI) m / z 320 (MH) ^- .

（ａ）（２Ｓ，５Ｒ）−２−（ヒドロキシメチル）−３−メチル−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−７−オン（２６０ｍｇ）を用いて実施例１（ａ）で得られた化合物と２−（アミノオキシ）−Ｎ，Ｎ‘−ジメチルアセタミドを用いて、実施例１（ｂ）と同様の方法で（２Ｓ，５Ｒ）−Ｎ−［ ２−(ジメチルアミノ) −２−オキソエトキシ］−３−メチル−７−オキソ−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−２−カルボキサミドを１４８．９ｍｇ得た。
¹H-NMR(400 MHz, CDCl₃), δ：1.84 (s, 3H), 2.95 - 3.01 (m, 6H), 3.26 - 3.30 (m, 2H), 3.77 - 3.82 (m, 1H), 4.18 - 4.23 (m, 1H), 4.33 - 4.48 (m, 2H), 4.57 - 4.63 (m, 2H), 5.26 - 5.33 (m, 1H), 5.34 - 5.39 (m, 1H), 5.93 - 6.07 (m, 1H), 6.10 - 6.17 (m, 1H), 10.15 - 10.24 (m, 1H);MS（ESI） m/z 339 (M+H)⁺. Example 17 Sodium ({[(2S, 5R) -2-{[2- (dimethylamino) -2-oxoethoxy] carbamoyl} -3-methyl-7-oxo-1,6-diazabicyclo [3. 2.1] Oct-3-en-6-yl] oxy {sulfonyl) oxydanide

(A) (2S, 5R) -2- (hydroxymethyl) -3-methyl-6-[(prop-2-en-1-yl) oxy] -1,6-diazabicyclo [3.2.1] oct Using the compound obtained in Example 1 (a) using -3-en-7-one (260 mg) and 2- (aminooxy) -N, N′-dimethylacetamide, Example 1 ( In the same manner as in b), (2S, 5R) -N- [2- (dimethylamino) -2-oxoethoxy] -3-methyl-7-oxo-6-[(prop-2-en-1-yl ) Oxy] -1,6-diazabicyclo [3.2.1] oct-3-en-2-carboxamide was obtained in 148.9 mg.
¹ H-NMR (400 MHz, CDCl ₃ ), δ: 1.84 (s, 3H), 2.95-3.01 (m, 6H), 3.26-3.30 (m, 2H), 3.77-3.82 (m, 1H), 4.18- 4.23 (m, 1H), 4.33-4.48 (m, 2H), 4.57-4.63 (m, 2H), 5.26-5.33 (m, 1H), 5.34-5.39 (m, 1H), 5.93-6.07 (m, 1H ), 6.10-6.17 (m, 1H), 10.15-10.24 (m, 1H); MS (ESI) m / z 339 (M + H) ⁺ .

(B) Using the compound (149 mg) obtained in (a) above, triphenyl (prop-2-en-1-yl) phosphanium ({[(2S, 5R) -2-{[2- (Dimethylamino) -2-oxoethoxy] carbamoyl} -3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-ene-6 141 mg of [yl] oxy} sulfonyl) oxide anion were obtained.
MS (ESI) m / z 379 (M + H) ⁺ .

(C) Using the compound (141 mg) obtained in (b) above, 22.1 mg of the title compound was obtained in the same manner as in Example 3 (c).
¹ H-NMR (400 MHz, D ₂ O), δ: 1.62 (s, 3H), 2.89 (s, 3H), 2.95 (s, 3H), 3.34 (dd, J = 11.49, 2.93 Hz, 1H), 3.65 (d, J = 10.51 Hz, 1H), 4.14-4.23 (m, 2H), 4.56-4.66 (m, 2H), 6.16-6.26 (m, 1H); MS (ESI) m / z 379 (M + H) ⁺ .

（ａ）（２Ｓ，５Ｒ）−２−（ヒドロキシメチル）−３−メチル−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−７−オン（２５０ｍｇ）を用いて実施例１（ａ）で得られた化合物とＯ−メトキシヒドロキシルアミン塩酸塩を用いて、実施例１（ｂ）と同様の方法で（２Ｓ，５Ｒ）−Ｎ−メトキシ−３−メチル−７−オキソ−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−２−カルボキサミドを１０２ｍｇ得た。
¹H-NMR(400 MHz, CDCl₃), δ：1.85 (s, 3H), 3.26 (s, 2H), 3.76-3.85 (m, 4H), 4.22 (s, 1H), 4.34 - 4.46 (m, 2H), 5.28 - 5.33 (m, 1H), 5.33 - 5.40 (m, 1H), 5.94 - 6.04 (m, 1H), 6.11 - 6.17 (m, 1H), 9.18 - 9.29 (br s, 1H) ;MS（ESI） m/z 268 (M+H)⁺. Example 18 Sodium ({[(2S, 5R) -2- (methoxycarbamoyl) -3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6 Yl] oxy} sulfonyl) oxydanide

(A) (2S, 5R) -2- (hydroxymethyl) -3-methyl-6-[(prop-2-en-1-yl) oxy] -1,6-diazabicyclo [3.2.1] oct (2S) using the compound obtained in Example 1 (a) using -3-en-7-one (250 mg) and O-methoxyhydroxylamine hydrochloride in the same manner as in Example 1 (b). , 5R) -N-Methoxy-3-methyl-7-oxo-6-[(prop-2-en-1-yl) oxy] -1,6-diazabicyclo [3.2.1] oct-3-ene 102 mg of -2-carboxamide was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ), δ: 1.85 (s, 3H), 3.26 (s, 2H), 3.76-3.85 (m, 4H), 4.22 (s, 1H), 4.34-4.46 (m, 2H), 5.28-5.33 (m, 1H), 5.33-5.40 (m, 1H), 5.94-6.04 (m, 1H), 6.11-6.17 (m, 1H), 9.18-9.29 (brs, 1H); MS (ESI) m / z 268 (M + H) ⁺ .

(B) Using the compound (102 mg) obtained in (a) above, triphenyl (prop-2-en-1-yl) phosphanium ({[(2S, 172 mg of 5R) -2- (ethoxycarbamoyl) -3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yl] oxy {sulfonyl) oxide anion was obtained. .
MS (ESI) m / z 308 (M + H) ⁺ .

(C) Using the compound (172 mg) obtained in the above (b), 23 mg of the title compound was obtained in the same manner as in Example 3 (c).
¹ H-NMR (400 MHz, D ₂ O), δ: 1.65 (s, 3H), 3.37 (m, J = 11.50, 2.69 Hz, 1H), 3.59 (d, J = 11.50 Hz, 1H), 3.72 ( s, 3H), 4.19-4.25 (m, 2H), 6.19-6.28 (m, 1H); MS (ESI) m / z 306 (MH) ^- .

（ａ）（２Ｓ，５Ｒ）−２−（ヒドロキシメチル）−３−メチル−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−７−オン（３０３ｍｇ）を用いて実施例１（ａ）で得られた化合物とＯ−（シクロプロピルメチル）ヒドロキシルアミンを用いて、実施例１（ｂ）と同様の方法で（２Ｓ，５Ｒ）−Ｎ−（シクロプロピルメトキシ）−３−メチル−７−オキソ−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−２−カルボキサミドを１２５ｍｇ得た。
¹H-NMR(400 MHz, CDCl₃), δ：0.33 (br s, 2H), 0.56 - 0.68 (m, 2H), 1.07 - 1.22 (m, 1H), 1.86 (s, 3H), 3.26 (s, 2H), 3.72 - 3.87 (m, 3H), 4.23 (s, 1H), 4.32 - 4.53 (m, 2H), 5.25 - 5.43 (m, 2H), 6.01 (ddt, J = 17.04, 10.56, 6.37, 6.37 Hz, 1H), 6.15 (br s, 1H), 9.19 (br s, 1H);MS（ESI） m/z 308 (M+H)⁺. Example 19 Sodium [({(2S, 5R) -2-[(cyclopropylmethoxy) carbamoyl] -3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3- [En-6-yl} oxy) sulfonyl] oxydanide

(A) (2S, 5R) -2- (hydroxymethyl) -3-methyl-6-[(prop-2-en-1-yl) oxy] -1,6-diazabicyclo [3.2.1] oct Using the compound obtained in Example 1 (a) with -3-en-7-one (303 mg) and O- (cyclopropylmethyl) hydroxylamine, in the same manner as in Example 1 (b). (2S, 5R) -N- (cyclopropylmethoxy) -3-methyl-7-oxo-6-[(prop-2-en-1-yl) oxy] -1,6-diazabicyclo [3.2.1] 125 mg of oct-3-ene-2-carboxamide was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ), δ: 0.33 (br s, 2H), 0.56-0.68 (m, 2H), 1.07-1.22 (m, 1H), 1.86 (s, 3H), 3.26 (s , 2H), 3.72-3.87 (m, 3H), 4.23 (s, 1H), 4.32-4.53 (m, 2H), 5.25-5.43 (m, 2H), 6.01 (ddt, J = 17.04, 10.56, 6.37, 6.37 Hz, 1H), 6.15 (br s, 1H), 9.19 (br s, 1H); MS (ESI) m / z 308 (M + H) ⁺ .

(B) Using the compound (125 mg) obtained in (a) above, triphenyl (prop-2-en-1-yl) phosphanium [({(2S, 5R) -2-[(Cyclopropylmethoxy) carbamoyl] -3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yl {oxy) sulfonyl] oxide anion 183 mg was obtained.
MS (ESI) m / z 348 (M + H) ⁺ .

(C) Using the compound (183 mg) obtained in the above (b), 23.4 mg of the title compound was obtained in the same manner as in Example 3 (c).
¹ H-NMR (400 MHz, D ₂ O), δ: -0.05-0.04 (m, 2H), 0.26-0.31 (m, 2H), 0.78-0.89 (m, 1H), 1.40 (s, 3H), 3.13 (dd, J = 11.40, 2.75 Hz, 1H), 3.35 (d, J = 11.40 Hz, 1 H), 3.48 (d, J = 6.27 Hz, 2H), 3.97 (dd, J = 6.27, 2.75 Hz, 1H), 3.99-4.02 (m, 1H), 5.96-6.03 (m, 1H); MS (ESI) m / z 348 (M + H) ⁺ .

（ａ）（２Ｓ，５Ｒ）−２−（ヒドロキシメチル）−３−メチル−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−７−オン（３３０ｍｇ）を用いて実施例１（ａ）で得られた化合物とＯ−フェニルヒドロキシルアミン塩酸塩を用いて、実施例１（ｂ）と同様の方法で（２Ｓ，５Ｒ）−３−メチル−７−オキソ−Ｎ−フェノキシ−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−２−カルボキサミドを１９６ｍｇ得た。
¹H-NMR(400 MHz, CDCl₃), δ：1.84 (br s, 3H), 3.33 - 3.43 (m, 2H), 3.80 - 3.89 (m, 1H), 4.35 - 4.48 (m, 3H), 5.26 - 5.40 (m, 2H), 5.92 - 6.06 (m, 1H), 6.15 - 6.21 (m, 1H), 7.01 - 7.14 (m, 3H), 7.28 - 7.38 (m, 2H), 9.59 - 9.79 (m, 1H) ;MS（ESI） m/z 330 (M+H)⁺. Example 20 Sodium ({[(2S, 5R) -3-methyl-7-oxo-2- (phenoxycarbamoyl) -1,6-diazabicyclo [3.2.1] oct-3-ene-6 Yl] oxy} sulfonyl) oxydanide

(A) (2S, 5R) -2- (hydroxymethyl) -3-methyl-6-[(prop-2-en-1-yl) oxy] -1,6-diazabicyclo [3.2.1] oct Using the compound obtained in Example 1 (a) using -3-en-7-one (330 mg) and O-phenylhydroxylamine hydrochloride, the compound (2S) was prepared in the same manner as in Example 1 (b). , 5R) -3-Methyl-7-oxo-N-phenoxy-6-[(prop-2-en-1-yl) oxy] -1,6-diazabicyclo [3.2.1] oct-3-ene 196 mg of -2-carboxamide was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ), δ: 1.84 (br s, 3H), 3.33-3.43 (m, 2H), 3.80-3.89 (m, 1H), 4.35-4.48 (m, 3H), 5.26 -5.40 (m, 2H), 5.92-6.06 (m, 1H), 6.15-6.21 (m, 1H), 7.01-7.14 (m, 3H), 7.28-7.38 (m, 2H), 9.59-9.79 (m, 1H); MS (ESI) m / z 330 (M + H) ⁺ .

(B) Using the compound (196 mg) obtained in the above (a), triphenyl (prop-2-en-1-yl) phosphanium ({[(2S, 293 mg of 5R) -3-methyl-7-oxo-2- (phenoxycarbamoyl) -1,6-diazabicyclo [3.2.1] oct-3-en-6-yl] oxy {sulfonyl) oxide anion was obtained. .
MS (ESI) m / z 370 (M + H) ⁺ .

(C) Using the compound (293 mg) obtained in (b) above, 18.7 mg of the title compound was obtained in the same manner as in Example 3 (c).
¹ H-NMR (400 MHz, D ₂ O), δ: 1.69-1.73 (s, 3H), 3.35 (dd, J = 11.32, 2.77 Hz, 1H), 3.85 (d, J = 11.32 Hz, 1H), 4.20 (q, J = 2.77 Hz, 1H), 4.23 (m, 1H), 6.11-6.16 (m, 1H), 6.99 (t, J = 7.34 Hz, 1H), 7.03-7.04 (m, 1H), 7.04 -7.07 (m, 1H), 7.27-7.34 (m, 2H); MS (ESI) m / z 370 (M + H) ⁺ .

（ａ）（２Ｓ，５Ｒ）−２−（ヒドロキシメチル）−３−メチル−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−７−オン（２６０ｍｇ）を用いて実施例１（ａ）で得られた化合物とＯ−［（オキセタン−３−イル）メチル］ヒドロキシルアミンを用いて、実施例１（ｂ）と同様の方法で（２Ｓ，５Ｒ）−３−メチル−Ｎ−［(オキセタン−３−イル)メトキシ］−７−オキソ−６−［（プロパ−２−エン−１−イル）オキシ］−１，６−ジアザビシクロ［３．２．１］オクト−３−エン−２−カルボキサミドを６７．４ｍｇ得た。
¹H-NMR(400 MHz, CDCl₃), δ：1.75 (s, 3H), 3.17 - 3.28 (m, 1H), 3.27 - 3.41 (m, 1H), 3.47 - 3.59 (m, 1H), 3.79 - 3.89 (m, 1H), 4.09 - 4.28 (m, 3H), 4.33 - 4.46 (m, 2H), 4.48 - 4.59 (m, 2H), 4.74 - 4.90 (m, 2H), 5.26 - 5.41 (m, 2H), 5.91 - 6.07 (m, 1H), 6.16 (m, 1H), 9.91 - 10.18 (m, 1H);MS（ESI） m/z 324 (M+H)⁺. Example 21 Sodium ({[(2S, 5R) -3-methyl-2 - {[(oxetan-3-yl) methoxy] carbamoyl} -7-oxo-1,6-diazabicyclo [3.2.1 ] Oct-3-en-6-yl] oxy {sulfonyl) oxydanide

(A) (2S, 5R) -2- (hydroxymethyl) -3-methyl-6-[(prop-2-en-1-yl) oxy] -1,6-diazabicyclo [3.2.1] oct Example 1 (b) using the compound obtained in Example 1 (a) using -3-en-7-one (260 mg) and O-[(oxetan-3-yl) methyl] hydroxylamine. (2S, 5R) -3-methyl-N-[(oxetan-3-yl) methoxy] -7-oxo-6-[(prop-2-en-1-yl) oxy] -1 , 6-Diazabicyclo [3.2.1] oct-3-en-2-carboxamide was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ), δ: 1.75 (s, 3H), 3.17-3.28 (m, 1H), 3.27-3.41 (m, 1H), 3.47-3.59 (m, 1H), 3.79- 3.89 (m, 1H), 4.09-4.28 (m, 3H), 4.33-4.46 (m, 2H), 4.48-4.59 (m, 2H), 4.74-4.90 (m, 2H), 5.26-5.41 (m, 2H ), 5.91-6.07 (m, 1H), 6.16 (m, 1H), 9.91-10.18 (m, 1H); MS (ESI) m / z 324 (M + H) ⁺ .

(B) Using the compound (67.4 mg) obtained in (a) above, triphenyl (prop-2-en-1-yl) phosphanium (｛[( 2S, 5R) -3-Methyl-2-{[(oxetan-3-yl) methoxy] carbamoyl} -7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yl 50.7 mg of [oxy] sulfonyl) oxide anion was obtained.
MS (ESI) m / z 364 (M + H) ⁺ .

(C) Using the compound (293 mg) obtained in (b) above, 18.7 mg of the title compound was obtained in the same manner as in Example 3 (c).
¹ H-NMR (400 MHz, D ₂ O), δ: 1.64 (s, 3H), 3.24-3.39 (m, 2H), 3.58 (d, J = 11.25 Hz, 1H), 4.18 (d, J = 7.09 Hz, 2H), 4.19-4.24 (m, 2H), 4.51 (dd, J = 6.60, 6.60 Hz, 2H), 4.83 (dd, J = 6.60, 6.60 Hz, 2H), 6.21-6.27 (m, 1H) ; MS (ESI) m / z 362 (MH) ^- .

[Test Example 1 Measurement of β-lactamase inhibitory activity]
Preparation of β -lactamase enzyme DNAs encoding regions excluding the signal peptides of AmpC, CTX-M-15, KPC-2 and OXA-48, which are β-lactamases, were isolated from P. lactamase, respectively. aeruginosa, Escherichia coli produced by CTX-M-15 and Klebsiella pneumoniae ATCCBAA-1705 were used as templates to amplify by PCR, and OXA-48 was used for E. coli. An artificial gene was synthesized based on the base sequence of OXA-48 derived from E. coli. AmpC, CTX-M-15 and KPC-2 were used to introduce PCR products into pET-28b (+) vector (Merck), OXA-48 was introduced with an artificial gene, and introduced into Escherichia coli BL21 (DE3) (Merck). Was cultured overnight at 20 ° C under the induction of Isopropyl-β-D-(-)-thiogalactopyranoside (Nacalai Tesque) to express AmpC, CTX-M-15, KPC-2 and OXA-48. After recovering the cells, AmpC was purified from the cell extract obtained by sonication at 4 ° C. using CM Sepharose Fast Flow (GE Healthcare) and HiTrap Heparin HP (GE Healthcare). CTX-M-15 was purified using HiTrap SPHP (GE Healthcare), and KPC-2 was purified using HiTrap SPHP. OXA-48 was purified using HiTrap Q (GE Healthcare).

β -lactamase inhibitory activity For the measurement of β-lactamase inhibitory activity, nitrosefin (Oxoid) having a final concentration of 100 μM was used as a substrate, and 10 μg / mL bovine serum-derived albumin (Sigma-Aldrich), 50 mM phosphate buffer at pH 7.0. Was used as a reaction solution. In each well of a 96-well plate, a test substance (Example compound, Avibactam (MedChem Express) as a comparative drug) and AmpC, KPC-2, CTX-M-15 or OXA-48 (the final concentration was 0.5 nM, respectively) (0.5 nM, 0.25 nM or 0.2 nM) and reacted at 30 ° C. for 10 minutes. Nitrocefin was added to each well, mixed, reacted at 30 ° C. for 20 minutes, and measured for the wavelength of 492 nm using a Multiscan Ascent (Thermo Fisher Scientific) to measure the nitrosefin hydrolysis activity of β-lactamase, The enzyme inhibitory activity was used. As a control, a reaction solution without β-lactamase was prepared, and the concentration of the test substance showing 50% inhibition was defined as the IC ₅₀ value. Inhibitory activity of less than _{(IC 50} value) of 0.03 [mu] M A, less than 0.1 [mu] M B, Table 1 the results of the inhibitory activity of the test substance than 0.3 [mu] M C, less than 1 [mu] M D, the above 1 [mu] M as E It was shown to.
Class A β-lactamase: KPC-2, CTX-M-15
Class C β-lactamase: AmpC
Class D β-lactamase: OXA-48

[Test Example 2 Single antibacterial activity and combined effect]
P. aeruginosa AmpC constitutive expression strain, Escherichia coli producing CTX-M-15, and KPC-2 producing strain KPC-2. pneumoniae ATCCBAA-1705 was used to evaluate the combined effect of the avibactam with a β-lactam drug against bacteria as an example compound and a comparative drug, and the single antibacterial activity. Cefepime (CF United States Pharmacopeial Convention) was used as a β-lactam drug, and the minimum inhibitory concentration (MIC) of CFPM was measured according to a plate method based on a plate obtained by dilution with a Clinical and Laboratory Standards Institute (CLSI method). That is, an agar plate containing each concentration of CFPM adjusted to a two-fold stoichiometric dilution series in Mueller-Hinton agar (MHA, Becton, Dickinson and Company) and a 1/1 concentration of each of the example compound or the comparative drug in CFPM was used. Bacteria produced and cultured overnight in a cation-adjusted Mueller-Hinton broth (CAMHB, Becton, Dickinson and Company) were adjusted to 10 ⁴ CFU / spot in the same medium and inoculated on a drug-containing plate. This drug-containing plate was cultured overnight at 35 ° C., and the minimum drug concentration at which no growth of bacteria was observed was defined as the MIC. P.A., which is an AmpC constitutive expression. aeruginosa, KPC-2 producing K. aeruginosa. pneumoniae, CTX-M-15 (ESBL) production The antibacterial activity of CFPM alone against E. coli was 8 μg / mL, 16 μg / mL, and 8 μg / mL, respectively. The antibacterial activity of CFPM recovered to 1/16 or less due to the combined effect of the example compound or the comparative drug was A, The results of the combined effect are shown in Table 2, where B was 1/4 or less, C was 1/1 or less, and D was not recovered. The single antibacterial activity of the compound of the present invention or the comparative drug is A of 1 μg / mL or less, B of 10 μg / mL or more exceeding 1, B of C exceeding 10 μg / mL and 32 μg / mL or more, exceeding 32 μg / mL. Table 3 shows the results of the single antibacterial activity, where D is D.
Class A β-lactamase: KPC-2, CTX-M-15 (ESBL)
Class C β-lactamase: AmpC

  According to the present invention, a β-lactam antibiotic resistant bacterium that produces a class A, class C, or class D β-lactamase is used in combination with an existing β-lactam antibiotic. The present invention provides treatment of bacterial infections by strongly restoring the antibacterial activity of β-lactam antibiotics.

Claims (12)

A compound represented by the following formula (1), a pharmaceutically acceptable salt thereof, or a solvate thereof.

[In the above formula (1), R ¹ is —NHCOR ² or —OR ³ ;
R ² is C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, amino, phenyl, heterocyclyl, or heteroaryl;
R ² is a halogen atom, hydroxy, phenyl, C _1-6 alkyl optionally substituted with a halogen atom, C _3-6 cycloalkyl optionally substituted with a halogen atom, substituted with a halogen atom. also a _{C 1-6} alkoxy, optionally _{C 3-6} cycloalkoxy optionally substituted with halogen atoms selected _{amino, C 1-6} alkylamino, _{di-C 1-6} alkylamino, from the group consisting of heterocyclyl and heteroaryl May be substituted with 1 to 4 groups represented by
R ³ is C _1-6 alkyl, C _3-6 cycloalkyl, phenyl, heterocyclyl, or heteroaryl;
R ³ is a halogen atom, hydroxy, phenyl, C _1-6 alkyl optionally substituted with a halogen atom, C _3-6 cycloalkyl optionally substituted with a halogen atom, substituted with a halogen atom. C _1-6 alkoxy, C _3-6 cycloalkoxy optionally substituted with a halogen atom, carboxy, aminocarbonyl, heterocyclylaminocarbonyl, sulfamoyl, amino, C _1-6 alkylamino, diC _1-6 alkyl Amino, C _3-6 cycloalkylamino, di C _1-6 alkylaminocarbonyl, C _1-6 alkylsulfonyl, a group represented by the following formula: —NHCOR ⁴ , 1 selected from the group consisting of heterocyclyl and heteroaryl May be substituted with 4 groups,
R ⁴ is C _1-6 alkyl, C _3-6 cycloalkyl, phenyl, amino, heterocyclyl or heteroaryl;
R ⁴ is substituted with 1 to 4 groups selected from the group consisting of a halogen atom, hydroxy, amino, phenyl, C _1-6 alkylamino, diC _1-6 alkylamino and C _1-6 alkyl. May be
M represents a hydrogen atom, a sodium atom or a potassium atom. ] In the formula (1), R ² is a C _1-6 alkyl group,
R ² may be substituted with an amino group,
The compound according to claim 1, wherein R ³ is a heterocyclyl group, a pharmaceutically acceptable salt thereof, or a solvate thereof. The compound represented by the formula (1) is
(2S, 5R) -N- (2-aminoethoxy) -3-methyl-7-oxo-6- (sulfoxy) -1,6-diazabicyclo [3.2.1] oct-3-en-2-carboxamide ,
(2S, 5R) -3-Methyl-7-oxo-N '-[(3R) -piperidine-3-carbonyl] -6- (sulfoxy) -1,6-diazabicyclo [3.2.1] oct-3 -En-2-carbohydrazide,
Sodium [({(2S, 5R) -2-[(2-methoxyethoxy) carbamoyl] -3-methyl-7-oxo-6- (sulfoxy) -1,6-diazabicyclo [3.2.1] oct- 3-en-6-yl {oxy) sulfonyl] oxydanide,
(2S, 5R) -N-{[(2S) -azetidin-2-yl] methoxy} -3-methyl-7-oxo-6- (sulfooxy) -1,6-diazabicyclo [3.2.1] oct -3-en-2-carboxamide,
(2S, 5R) -N- (3-aminopropoxy) -3-methyl-7-oxo-6- (sulfoxy) -1,6-diazabicyclo [3.2.1] oct-3-en-2-carboxamide ,
(2S, 5R) -3-methyl-7-oxo-N-{[(2S) -pyrrolidin-2-yl] methoxy} -6- (sulfooxy) -1,6-diazabicyclo [3.2.1] oct -3-en-2-carboxamide,
(2S, 5R) -3-methyl-7-oxo-N-{[(3R) -piperidin-3-yl] methoxy} -6- (sulfooxy) -1,6-diazabicyclo [3.2.1] oct -3-en-2-carboxamide,
(2S, 5R) -N-[(2S) -2-aminopropoxy] -3-methyl-7-oxo-6- (sulfoxy) -1,6-diazabicyclo [3.2.1] oct-3-ene -2-carboxamide,
(2S, 5R) -3-methyl-7-oxo-N-{[(2R) -pyrrolidin-2-yl] methoxy} -6- (sulfooxy) -1,6-diazabicyclo [3.2.1] oct -3-en-2-carboxamide,
(2S, 5R) -N- [2- (ethylamino) ethoxy] -3-methyl-7-oxo-6- (sulfoxy) -1,6-diazabicyclo [3.2.1] oct-3-ene- 2-carboxamide,
(2S, 5R) -3-methyl-N- [2- (methylamino) ethoxy] -7-oxo-6- (sulfooxy) -1,6-diazabicyclo [3.2.1] oct-3-ene- 2-carboxamide,
(2S, 5R) -3-methyl-7-oxo-N-{[(3S) -pyrrolidin-3-yl] oxy} -6- (sulfooxy) -1,6-diazabicyclo [3.2.1] oct -3-en-2-carboxamide,
(2S, 5R) -N-{[azetidin-3-yl] methoxy} -3-methyl-7-oxo-6- (sulfoxy) -1,6-diazabicyclo [3.2.1] oct-3-ene -2-carboxamide,
(2S, 5R) -N '-[(2S) -2-aminopropanoyl] -3-methyl-7-oxo-6- (sulfoxy) -1,6-diazabicyclo [3.2.1] oct-3 -Ene-2-carbohydrazide (2S, 5R) -3-methyl-7-oxo-N '-[(2S) -pyrrolidine-2-carbonyl] -6- (sulfooxy) -1,6-diazabicyclo [3. 2.1] Oct-3-en-2-carbohydrazide,
Sodium ({[(2S, 5R) -2- (ethoxycarbamoyl) -3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yl] oxy} sulfonyl ) Oxidanid,
Sodium ({[(2S, 5R) -2-{[2- (dimethylamino) -2-oxoethoxy] carbamoyl} -3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct -3-en-6-yl] oxy} sulfonyl) oxydanide,
Sodium ({[(2S, 5R) -2- (methoxycarbamoyl) -3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yl] oxy} sulfonyl ) Oxidanid,
Sodium [({(2S, 5R) -2-[(cyclopropylmethoxy) carbamoyl] -3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yl [｝ Oxy) sulfonyl] oxydanide,
Sodium ({[(2S, 5R) -3-methyl-7-oxo-2- (phenoxycarbamoyl) -1,6-diazabicyclo [3.2.1] oct-3-en-6-yl] oxy} sulfonyl ) Oxanidide or sodium ({[(2S, 5R) -3-methyl-2-{[(oxetan-3-yl) methoxy] carbamoyl} -7-oxo-1,6-diazabicyclo [3.2.1] The compound according to claim 1 or 2, which is oct-3-en-6-yl] oxy {sulfonyl) oxydanide, a pharmaceutically acceptable salt thereof, or a solvate thereof. The compound represented by the formula (1) is represented by the following formula:

The compound according to claim 1 or 2, a pharmaceutically acceptable salt thereof, or a solvate thereof.   It contains at least one selected from the group consisting of the compound according to any one of claims 1 to 4, a pharmaceutically acceptable salt thereof, and a solvate thereof, as an active ingredient. Is a pharmaceutical composition comprising a medically acceptable carrier.   The pharmaceutical composition according to claim 5, which is administered in combination with a β-lactam antibiotic.   The pharmaceutical composition according to claim 5 or 6, for treating a bacterial infection.   A β-lactamase containing as an active ingredient at least one selected from the group consisting of the compound according to any one of claims 1 to 4, a pharmaceutically acceptable salt thereof, and a solvate thereof. Inhibitors.   A pharmaceutical composition comprising the β-lactamase inhibitor according to claim 8, a β-lactam antibiotic, and optionally a medically acceptable carrier.   The β-lactam antibiotic is ampicillin, amoxicillin, piperacillin, ticarcillin, flomoxef, cefotaxime, ceftriaxone, ceftazidime, cefepime, ceftaroline, ceftrozan, cefiderocol, imipenem, meropenem, biapenem, or doripeneum Item 10. The pharmaceutical composition according to Item 9.   A method for treating bacterial infection, which comprises administering the β-lactamase inhibitor according to claim 8 and a β-lactam antibiotic in combination. The β-lactam antibiotic is ampicillin, amoxicillin, piperacillin, ticarcillin, flomoxef, cefotaxime, ceftriaxone, ceftazidime, cefepime, ceftaroline, ceftrozan, cefiderocol, imipenem, meropenem, biapenem, or doripeneum Item 12. The method for treating a bacterial infection according to Item 11.