# US 11,078,202 B2 · β-lactamase inhibitor and use thereof

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- Number: US 11,078,202 B2
- Document ID: US11078202B2
- Status: Granted
- Kind: B2
- Application number: 16/998,577
- Filed: 2020-08-20
- Published: 2021-02-04
- Granted: 2021-08-03
- Earliest claimed: 2018-01-25
- Assignees: Suzhou Sinovent Pharmaceuticals Co., Ltd.
- Applicants: Suzhou Sinovent Pharmaceuticals Co., Ltd.
- Inventors: Yuchuan Wu; Shaoqiang Huang; Xi Chen; Yonghan Hu; Xiao Liu
- Web page: https://patentgrep.com/patent/US11078202B2

## CPC

- C07D 471/08: Bridged systems
- C07D 471/10: Spiro-condensed systems
- A61K 31/43: Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula [IMAGE cpc-sch-A61K-0952.gif], e.g. penicillins, penems
- A61K 31/4995: Pyrazines or piperazines forming part of bridged ring systems
- A61P 31/04: Antibacterial agents
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Provided are a β-lactamase inhibitor of formula (I), or an ester, a stereoisomer or a pharmaceutically acceptable salt thereof, and a method of preparing the same. Further provided is a pharmaceutical composition comprising the β-lactamase inhibitor of formula (I), or the ester, the stereoisomer or pharmaceutically acceptable salt thereof. In addition, the present invention relates to a method for treating diseases caused by bacterial infection, which comprises administering the β-lactamase inhibitor of formula (I), or the ester, the stereoisomer or the pharmaceutically acceptable salt thereof to a patient or a subject in need.

## Claims

### Claim 1

A compound of formula (I), or an ester, a stereoisomer, or a pharmaceutically acceptable salt thereof:
wherein W1 is selected from an optionally substituted 5- or 6-membered heteroaromatic ring containing O, N, and/or S, and —C(O)—; (i) when W1 is the optionally substituted 5- or 6-membered heteroaromatic ring containing O, N, and/or S, W1 is optionally substituted with C1-C12 alkyl,
W2 is selected from:
(a) H
(b)
wherein R1 is selected from
R2, R3, R4, R4′, R5, and R6 are each independently selected from H, C1-C12 alkyl, amino C1-C12 alkyl, C1-C12 alkylamino C1-C12 alkyl,
Ra and Rb are each independently selected from H, C1-C12 alkyl, C3-C8 cycloalkyl, OH, —OC1-C12 alkyl, —NH2, —NHC1-C12 alkyl, —N(C1-C12 alkyl)2, —SH, —SC1-C12 alkyl, —S(O)C1-C12 alkyl, —S(O2)C1-C12 alkyl, and —SO3H; R7 and R7′ are each independently selected from —NH2, —NHC1-C12 alkyl, —N(C1-C12 alkyl)2, —OC1-C12 alkyl, and —SC1-C12 alkyl; R8 and R8′ are each independently selected from NH, —N(C1-C12 alkyl), O, and S; R9 and R9′ are each independently selected from —NH—, —N(C1-C12 alkyl)-, —O—, and —S—; Z1 is selected from CR10R11, and NR12; R10, R11, and R12 are each independently selected from H, NH2,
R13 and R15 are each independently selected from —NH2, —NHC1-C12 alkyl, —N(C1-C12 alkyl)2, —OC1-C12 alkyl, and —SC1-C12 alkyl; R14 and R16 are each independently selected from NH, NC1-C12 alkyl, O, and S; R17 is selected from —NH—, —N(C1-C12 alkyl)-, —O—, and —S—; i, j, k, l, m, n, p, q, r, and s are each independently selected from 0, 1, 2, 3, 4, 5, and 6, provided that q and r are not both 0; R1′ is selected from H, C1-C12 alkyl, C3-C8 cycloalkyl, OH, —OC1-C12 alkyl, —NH2, —NHC1-C12 alkyl, —N(C1-C12 alkyl)2, —SH, —SC1-C12 alkyl, —S(O)C1-C12 alkyl, —S(O2)C1-C12 alkyl, and —SO3H;
(c)
wherein Z2 is selected from CR18R19, and NR20; R18, R19 and R20 are each independently selected from H, NH2, and
R21 is selected from —NH2, —NHC1-C12 alkyl, —N(C1-C12 alkyl)2, —OC1-C12 alkyl, and —SC1-C12 alkyl; R22 is selected from NH, NC1-C12 alkyl, O, and S; t, u and w are each independently selected from 0, 1, 2, 3, 4, 5, and 6, provided that t and u are not both 0;
(d)
wherein Z3 and Z4 are each independently selected from —NR25—, and —O—; R23 and R24 are each independently selected from H and C1-C12 alkyl, or R23 and R24 together form ═O or ═NH; R25 is selected from H, amino C1-C12 alkyl, and C1-C12 alkylamino C1-C12 alkyl;
(ii) when W1 is selected from —C(O)—,
W2 is selected from —OR26 and —NHR27, wherein R26 and R27 are each independently selected from H, C1-C12 alkyl, and
Z5 is selected from CR28R29, and NR30; R28, R29, and R30 are each independently selected from H, NH2, and
R31 is selected from —NH2, —NHC1-C12 alkyl, —N(C1-C12 alkyl)2, —OC1-C12 alkyl, and —SC1-C12 alkyl; R32 is selected from NH, NC1-C12 alkyl, O, and S; x, y and z are each independently selected from 0, 1, 2, 3, 4, 5, and 6, provided that x and y are not both 0;
W3 is selected from —SO3M, —OSO3M, —OSO2NH2, —OPO3M, —OCR33R34CO2M, —OCR35R36SO3M, and —OCR37R38PO3M; wherein M is selected from H and a pharmaceutically acceptable cation; R33, R34, R35, R36, R37, and R38 are each independently selected from H, C1-C12 alkyl, and halogen.

### Claim 2 (depends on 1)

The compound, or the ester, the stereoisomer, or the pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) is:
wherein W1, W2, and W3 are defined in formula (I).

### Claim 3 (depends on 2)

The compound, or the ester, the stereoisomer, or the pharmaceutically acceptable salt thereof according to claim 2, wherein,
W1 is selected from an optionally substituted 5- or 6-membered heteroaromatic ring containing O, N, and/or S;
W2 is selected from:
(a) H
(b)
wherein R1 is selected from
R2, R3, R4, R4′, R5, and R6 are each independently selected from H, C1-C12 alkyl, amino C1-C12 alkyl, C1-C12 alkylamino C1-C12 alkyl,
Ra and Rb are each independently selected from H, C1-C12 alkyl, OH, —OC1-C12 alkyl, —NH2, —NHC1-C12 alkyl, —N(C1-C12 alkyl)2, —SH, —SC1-C12 alkyl, —S(O)C1-C12 alkyl, —S(O2)C1-C12 alkyl, and —SO3H; R7 and R7′ are each independently selected from —NH2, —NHC1-C12 alkyl, —N(C1-C12 alkyl)2, —OC1-C12 alkyl, and —SC1-C12 alkyl; R8 and R8′ are each independently selected from NH, —NC1-C12 alkyl, O, and S; R9 and R9′ are each independently selected from —NH—, —N(C1-C12 alkyl)-, —O—, and —S—; Z1 is selected from CR10R11 and NR12; R10, R11 and R12 are each independently selected from H, NH2,
R13 and R15 are each independently selected from —NH2, —NHC1-C12 alkyl, —N(C1-C12 alkyl)2, —OC1-C12 alkyl, and —SC1-C12 alkyl; R14 and R16 are each independently selected from NH, NC1-C12 alkyl, O, and S; R17 is selected from —NH—, —N(C1-C12 alkyl)-, —O—, and —S—; and i, j, k, l, m, n, p, q, r, and s are each independently selected from 0, 1, 2, 3, 4, 5, and 6, provided that q and r are not both 0;
R1′ is selected from H, C1-C12 alkyl, C3-C8 cycloalkyl, OH, —OC1-C12 alkyl, —NH2, —NHC1-C12 alkyl, —N(C1-C12 alkyl)2, —SH, —SC1-C12 alkyl, —S(O)C1-C12 alkyl, —S(O2)C1-C12 alkyl, and —SO3H;
(c)
wherein Z2 is selected from CR18R19, and NR20; R18, R19 and R20 are each independently selected from H, NH2, and
R21 is selected from —NH2, —NHC1-C12 alkyl, —N(C1-C12 alkyl)2, —OC1-C12 alkyl, and —SC1-C12 alkyl; R22 is selected from NH, NC1-C12 alkyl, O, and S; t, u and w are each independently selected from 0, 1, 2, 3, 4, 5, and 6, provided that t and u are not both 0;
(d)
wherein Z3 and Z4 are each independently selected from —NR25—, and —O—; R23 and R24 are each independently selected from H and C1-C12 alkyl, or R23 and R24 together form ═O or ═NH; R25 is selected from H, amino C1-C12 alkyl, and C1-C12 alkylamino C1-C12 alkyl.

### Claim 4 (depends on 2)

The compound, or the ester, the stereoisomer, or the pharmaceutically acceptable salt thereof according to claim 2, wherein,
W1 is —C(O)—;
W2 is selected from —OR26, and —NHR27, wherein R26 and R27 are each independently selected from H, C1-C12 alkyl, and
Z5 is selected from CR28R29, and NR30; R28, R29, and R30 are each independently selected from H, NH2, and
R31 is selected from —NH2, —NHC1-C12 alkyl, —N(C1-C12 alkyl)2, —OC1-C12 alky, and —SC1-C12 alkyl; R32 is selected from NH, NC1-C12 alkyl, O, and S; and x, y and z are each independently selected from 0, 1, 2, 3, 4, 5, and 6, provided that x and y are not both 0.

### Claim 5 (depends on 1)

The compound, or the ester, the stereoisomer, or the pharmaceutically acceptable salt thereof according to claim 1, wherein W1 is selected from:
X is selected from O, S, and NH; Y and Z are each independently selected from CH and N; and W1 is optionally substituted with C1-C12 alkyl.

### Claim 6 (depends on 1)

The compound, or the ester, the stereoisomer, or the pharmaceutically acceptable salt thereof according to claim 1, wherein W1 is selected from a furan ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a triazole ring, a thiophene ring, a thiazole ring, an isothiazole ring, an oxazole ring, an isoxazole ring, a 1,2,4-oxadiazole ring, a 1,3,4-oxadiazole ring, a pyridine ring, pyrimidyl, a triazine ring, a pyrazine ring, a tetrazole ring, a pyridazine ring, and a thiadiazole ring;
M is selected from H, sodium ion, potassium ion, calcium ion, magnesium ion, NH4+, and N(C1-C12 alkyl)4+.

### Claim 7 (depends on 6)

The compound or the pharmaceutically acceptable salt thereof according to claim 6, wherein W1 is selected from an oxazole ring, an isoxazole ring, a 1,2,4-oxadiazole ring, and a 1,3,4-oxadiazole ring.

### Claim 8 (depends on 7)

The compound or the pharmaceutically acceptable salt thereof according to claim 7, wherein W1 is selected from

### Claim 9 (depends on 1)

The compound or the pharmaceutically acceptable salt thereof according to claim 1, which is selected from:
(1R,4S)-4-(1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(aminomethyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(guanidinomethyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(2-aminoethyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(2-guanidinoethyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
sodium (1R,4S)-4-(5-(3-aminopropyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(4-aminobutyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(2-iminoimidazolidin-4-yl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro [bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(2-amino-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(2-guanidyl-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro [bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-((R)-2-guanidyl-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro [bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-((S)-2-guanidyl-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro [bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(1-(guanidinomethyl)cyclopropyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-((azetidin-3-ylamino)methyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro [bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(isoxazol-3-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(guanidinomethyl)isoxazol-3-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-((1-methylguanidino)methyl)isoxazol-3-yl)-6-oxo-5,7-diazaspiro[bicycle [3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(aminomethyl)-isoxazol-3-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-((methylamino)methyl)isoxazol-3-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(2-guanidinoethyl)isoxazol-3-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(2-(1-methylguanidino)ethyl)isoxazol-3-yl)-6-oxo-5,7-diazaspiro[bicycle [3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(2-guanidyl-1-hydroxyethyl)isoxazol-3-yl)-6-oxo-5,7-diazaspiro[bicycle [3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-((S)-2-guanidyl-1-hydroxyethyl)isoxazol-3-yl)-6-oxo-5,7-diazaspiro[bicycle [3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-((R)-2-guanidyl-1-hydroxyethyl)isoxazol-3-yl)-6-oxo-5,7-diazaspiro[bicycle [3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(2-aminoethyl)isoxazol-3-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(2-(methylamino)ethyl)isoxazol-3-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-6-oxo-4-(5-(piperidin-4-yl)isoxazol-3-yl)-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-6-oxo-4-(5-(piperidin-3-yl)isoxazol-3-yl)-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-6-oxo-4-(5-(pyrrolidin-3-yl)isoxazol-3-yl)-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-6-oxo-4-(5-(2-(piperidin-4-ylamino)ethyl)isoxazol-3-yl)-5,7-diazaspiro[bicycle [3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(2-((1-amidinopiperidin-4-yl)amino)ethyl)isoxazol-3-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-((1S,3R)-3-aminocyclobutyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro [bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-((1R,3S)-3-aminocyclobutyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro [bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-((1R,3S)-3-aminocyclopentyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro [bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-((1R,3R)-3-aminocyclopentyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro [bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(((1R,3R)-3-aminocyclobutyl)methyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(((1S,3S)-3-aminocyclobutyl)methyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-((1-aminocyclopropyl)methyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro [bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-((1-(methylamino)cyclopropyl)methyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(azetidin-3-ylmethyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicycle [3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(2-(methylamino)ethyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicycle [3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-((azetidin-3-ylamino)methyl)isoxazol-3-yl)-6-oxo-5,7-diazaspiro[bicycle [3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(azetidin-3-ylmethyl)isoxazol-3-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-((azetidin-3-yloxy)methyl)isoxazol-3-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(((1-amidinoazetidin-3-yl)amino)methyl)isoxazol-3-yl)-6-oxo-5,7-diazaspiro [bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(3-aminocyclobutyl)isoxazol-3-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-((1S,3S)-3-aminocyclobutyl)isoxazol-3-yl)-6-oxo-5,7-diazaspiro[bicycle [3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-((1R,3R)-3-aminocyclobutyl)isoxazol-3-yl)-6-oxo-5,7-diazaspiro[bicycle [3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(2-((2-guanidinoethyl)amino)ethyl)isoxazol-3-yl)-6-oxo-5,7-diazaspiro [bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-6-oxo-4-(piperidin-4-ylaminoformyl)-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-6-oxo-4-(pyrrolidin-3-ylaminoformyl)-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(azetidin-3-ylaminoformyl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-((S)-1-hydroxy-2-((2-(methylamino)ethyl)amino)ethyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-((S)-2-((2-aminoethyl)amino)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-((S)-2-iminoimidazolidin-4-yl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro [bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-((R)-2-iminoimidazolidin-4-yl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro [bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
2-(((1R,4S)-4-(5-(aminomethyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl)oxy)acetate;
2-(((1R,4S)-4-(5-(((tert-butoxycarbonyl)amino)methyl)isoxazol-3-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl)oxy)acetate;
2-(((1R,4S)-4-(5-(aminomethyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl)oxy)-2,2-difluoroacetate;
2-(((1R,4S)-4-(5-(((tert-butoxycarbonyl)amino)methyl)isoxazol-3-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl)oxy)-2,2-difluoroacetate;
(1R,4S)-4-(5-((1S,3R)-3-guanidinocyclobutyl)isoxazol-3-yl)-6-oxo-5,7-diazaspiro[bicycle [3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(1-hydroxy-2-((2-(methylamino)ethyl)amino)ethyl)isoxazol-3-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-((S)-1-hydroxy-2-((2-(methylamino)ethyl)amino)ethyl)isoxazol-3-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-((R)-1-hydroxy-2-((2-(methylamino)ethyl)amino)ethyl)isoxazol-3-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(2-((2-aminoethyl)amino)-1-hydroxyethyl)isoxazol-3-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-((S)-2-((2-aminoethyl)amino)-1-hydroxyethyl)isoxazol-3-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-((R)-2-((2-aminoethyl)amino)-1-hydroxyethyl)isoxazol-3-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(2-((2-guanidinoethyl)amino)-1-hydroxyethyl)isoxazol-3-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-((S)-2-((2-guanidinoethyl)amino)-1-hydroxyethyl)isoxazol-3-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-((R)-2-((2-guanidinoethyl)amino)-1-hydroxyethyl)isoxazol-3-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-((1-hydroxy-2-((2-methylamino)ethyl)amino)ethyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-((R)-1-hydroxy-2-((2-(methylamino)ethyl)amino)ethyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(2-((2-aminoethyl)amino)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-((R)-2-((2-aminoethyl)amino)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(2-((2-guanidinoethyl)amino)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-((S)-2-((2-guanidinoethyl)amino)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-((R)-2-((2-guanidinoethyl)amino)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(2-(azetidin-3-ylamino)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(1-hydroxy-2-(methylamino)ethyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(1-hydroxy-2-(pyrrolidin-3-ylamino)ethyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(2-(dimethylamino)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(hydroxy(pyrrolidin-2-yl)methyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro [bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
2-hydroxy-N,N,N-trimethyl-2-(5-((1R,4S)-6-oxo-7-(sulfooxy)-5,7-diazaspiro[bicycle [3.2.1]octane-2,1′-cyclopropane]-4-yl)-1,3,4-oxadiazol-2-yl)ethan-1-ammonium;
(1R,4S)-4-(5-(1-hydroxy-2-(piperidin-4-ylamino)ethyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(4-hydroxypiperidin-4-yl)isoxazol-3-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(1-amidinopiperidin-4-yl)isoxazol-3-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-6-oxo-4-(5-(piperazin-1-yl)isoxazol-3-yl)-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-6-oxo-4-(5-(2-oxopiperazine-1-yl)isoxazol-3-yl)-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(L-prolyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-((S)-2-((2-(dimethylamino)ethyl)amino)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
2-(((2S)-2-hydroxy-2-(5-((1R,4S)-6-oxo-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropane]-4-yl)-1,3,4-oxadiazol-2-yl)ethyl)amino)-N,N,N-trimethylethan-1-ammonium;
(1R,4S)-6-oxo-4-(5-(2-oxoimidazolidine-4-yl)-1,3,4-oxadiazol-2-yl)-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-6-oxo-4-(5-(2-oxooxazolidine-5-yl)-1,3,4-oxadiazol-2-yl)-5,7-diazaspiro[bicycle [3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-6-oxo-4-(5-(2-oxooxazolidine-4-yl)-1,3,4-oxadiazol-2-yl)-5,7-diazaspiro[bicycle [3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(2-imino-1-((methylamino)methyl)imidazolidin-4-yl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-(1-((dimethylamino)methyl)-2-iminoimidazolidin-4-yl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
1-(2-imino-4-(5-((1R,4S)-6-oxo-7-(sulfooxy)-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropane]-4-yl)-1,3,4-oxadiazol-2-yl)imidazolidin-1-yl)-N,N,N-trimethylmethylammonium;
(1R,4S)-4-(5-(2-imino-1-((methylamino)methyl)-5-oxoimidazolidin-4-yl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropane]-7-yl sulfate;
(1R,4S)-4-(5-(5-hydroxy-2-imino-1-((methylamino)methyl)imidazolidin-4-yl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropane]-7-yl sulfate;
(1R,4S)-4-(5-(3-((methylamino)methyl)-2-oxooxazolidine-4-yl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropane]-7-yl sulfate;
(1R,4S)-4-(5-(1-(aminomethyl)-2-iminoimidazolidin-4-yl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropane]-7-yl sulfate;
(1R,4S)-4-(5-(5-amino-2-iminoimidazolidin-4-yl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropane]-7-yl sulfate;
(1R,4S)-4-(5-(2-imino-5-(methylamino)imidazolidin-4-yl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropane]-7-yl sulfate;
(1R,4S)-4-(5-(5-(dimethylamino)-2-iminoimidazolidin-4-yl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl sulfate;
(1R,4S)-4-(5-((R)-2-amino-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro [bicyclo[3.2.1]octane-2,1′-cyclopropane]-7-yl sulfate;
(1R,4S)-4-(5-((S)-2-amino-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro [bicyclo[3.2.1]octane-2,1′-cyclopropane]-7-yl sulfate;
(1R,4S)-4-(5-((S)-1-hydroxy-2-(methylamino)ethyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropane]-7-yl sulfate;
(1R,4S)-4-(5-((S)-2-(dimethylamino)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropane]-7-yl sulfate;
2-(((1R,4S)-4-(5-(aminomethyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl)oxy)acetate;
2-(((1R,4S)-4-(5-(((tert-butoxycarbonyl)amino)methyl)isoxazol-3-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl)oxy)acetate;
2-(((1R,4S)-4-(5-(aminomethyl)-1,3,4-oxadiazol-2-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl)oxy)-2,2-difluoroacetate;
2-(((1R,4S)-4-(5-(((tert-butoxycarbonyl)amino)methyl)isoxazol-3-yl)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1′-cyclopropan]-7-yl)oxy)-2,2-difluoroacetate.

### Claim 10 (depends on 1)

A method of preparation for the compound of formula (I) of claim 1, wherein W1 in the compound of formula (I) is selected from a 1,3,4-oxadiazole ring; the method comprising:
step 1: the intermediate 1 and hydrazide are subjected to condensation under a basic condition to give the intermediate 2;
Step 2: the intermediate 2 is subjected to cyclization to give the intermediate 3;
step 3: the protecting group P in the intermediate 3 is selectively removed to give the intermediate 4;
step 4: the intermediate 4 reacts with SO3 under a basic condition to give the intermediate 5;
step 5: the protecting group P′ in the intermediate 5 is removed to give the product 6;
wherein, P is a hydroxyl protecting group, P′ is a hydroxyl or amine protecting group, and W2 is defined in formula (I).

### Claim 11 (depends on 1)

A pharmaceutical composition comprising the compound according to claim 1, and a pharmaceutically acceptable excipient.

### Claim 12 (depends on 11)

The pharmaceutical composition according to claim 11, further comprising one or more β-lactam antibiotics.

### Claim 13 (depends on 12)

The pharmaceutical composition according to claim 12, wherein the β-lactam antibiotic is selected from a penicillin antibiotic, a cephalosporin antibiotic, a monobactam antibiotic, a carbapenem antibiotic, and a penemase inhibitor.

### Claim 14 (depends on 1)

A method of treating a disease caused by a bacterial infection in a subject, comprising administration of a therapeutically effective amount of the compound according to claim 1.

### Claim 15 (depends on 14)

The method according to claim 14, wherein the method further comprises administration of a β-lactam antibiotic.

### Claim 16 (depends on 14)

The method according to claim 14, wherein the bacterium is selected from one or more of Citrobacter spp., Citrobacter freundii, Enterobacter cloacae, Klebsiella pneumoniae, Escherichia coli, Proteus vulgaris, Salmonella spp., Serratia marcescens, Shigella spp., Pseudomonas aeruginosa, Moraxella mucositis, Neisseria gonorrhoeae, Neisseria meningitidis, Acinetobacter spp., Burkholderia spp., Campylobacter spp., Helicobacter pylori, Vibrio cholerae, Klebsiella pneumoniae, Haemophilus influenzae, Mycobacterium avium complex, Mycobacterium abscessus, Mycobacterium kansasii, Mycobacterium ulcerosa, Chlamydophila pneumoniae, Chlamydia trachomatis, β-hemolytic Streptococcus, Acinetobacter baumannii, Pseudomonas pyocyaneum, Pseudomonas aeruginosa, Bacteroides fragilis, Bacillus cereus, and Stenotrophomonas maltophilia.

### Claim 17 (depends on 14)

The method according to claim 14, wherein the disease is selected from one or more of respiratory tract infection, urinary tract infection, central nervous system infection, ear infection, pleuropneumoniae and bronchial infection, intra-abdominal infection, cardiovascular infection, skin or soft tissue infections, bone and joint infections, genital infection, eye infection, pharyngeal infection, and oral infection.

### Claim 18 (depends on 17)

The method according to claim 17, wherein the disease is selected from one or more of upper respiratory tract infection, lower respiratory tract infection, tracheitis, bronchitis, pneumonia, pulmonary tuberculosis, pharyngitis, complicated urinary tract infection, non-complicated urinary tract infections, cystitis, pyelonephritis, encephalitis, meningitis, brain abscess, otitis externa, otitis media, blood infection, endocarditis, myocarditis, pericarditis, arthritis, osteomyelitis, genital ulceration, vaginitis, cervicitis, conjunctivitis, keratitis, endophthalmitis, pharyngitis, and gingivitis.

### Claim 19 (depends on 18)

The method according to claim 18, wherein the blood infection is sepsis or bacteremia.