Β-lactamase inhibitor and use thereof

Abstract

Provided are a β-lactamase inhibitor and the use thereof. The β-lactamase inhibitor has a structure as represented by the below formula (I), or a pharmaceutically acceptable salt thereof, or an isomer thereof or a deuterated substance thereof. A group of the β-lactamase inhibitor capable of enhancing the lipid solubility of the compound binds to the amide and sulfonic acid groups in an avibactam structure, thereby increasing the lipid solubility of the structure. Under the action of biological enzymes, the β-lactamase inhibitor can rapidly and completely release an active metabolite, i.e. avibactam, and enabling the rapid onset of action thereof, which effectively improves the oral bioavailability of avibactam, and enables oral administration of avibactam, thereby solving the problem whereby avibactam cannot be be administered orally.

Description

A beta-lactamase inhibitor and uses thereof TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, and particularly relates to a beta-lactamase inhibitor, a pharmaceutical composition thereof and a use for treating bacterial infection. BACKGROUND

[0002] The rapid development of antibiotics has great significance in the history of modern medicine. Antibiotics can effectively treat infectious diseases caused by bacteria, bringing great convenience to the clinic. However, the unreasonable use and even abuse of antibiotics has accelerated the development process of bacterial drug resistance, bringing great challenges to human health. As one of the oldest, most widely used and most commonly used antibiotics in clinical practice, the problem of drug resistance of beta-lactam antibiotics has also come with it and is becoming more and more serious.

[0003] Beta-lactamase produced by bacteria can hydrolyze antibiotics with beta-lactam ring structure, making the antibiotics inactivated, which is the most common mechanism of bacterial resistance to beta-lactam antibiotics. According to the difference of amino acid sequence in the molecular structure, beta-lactamase can be mainly divided into two categories: one is A, C and D class with serine as active site, and the other is metalloenzyme with metal ion (especially Zn 2+ ion) as active site.

[0004] In 1976, the first beta-lactamase preparation (clavulanic acid) was discovered, and later combined with beta-lactam antibiotics (amoxicillin) as an oral / intravenous drug commercialized. Beta-lactamase inhibitors, although lacking significant antibiotic activity, can protect beta-lactam antibiotics from being inactivated by enzymes (beta-lactamase) produced by microorganisms. Since the 1980s, beta-lactamase inhibitor / antibiotic combinations have become a standard part of treatment.

[0005] In the mid-1990s, a new important non-beta-lactam beta-lactamase inhibitor, avibactam, was discovered. It belongs to the class of diazabicyclic compounds (DBOs), which is a reversible beta-lactamase inhibitor. Compared with classic beta-lactamase inhibitors (clavulanic acid, sulbactam, tazobactam), it has the characteristics of long-acting and reversible covalent binding with enzymes, and does not induce the production of intracellular lactamase. However, due to the presence of sulfonic acid group and formamide structure in the structure of avibactam, its water solubility is large, and its lipid solubility is too low, resulting in poor tissue membrane permeability, which cannot be taken orally, and can only be used for intravenous injection, which also limits the use of avibactam in clinical practice.

[0006] Chinese invention patent CN110662746 discloses a 3-(((((2S,5R)-2-aminocarbonyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate derivative and related compounds as oral prodrugs of beta-lactamase inhibitors for the treatment of bacterial infections. The structural design of the invention improves the oral bioavailability of avibactam. In oral bioavailability experiments in rats, avibactam showed an oral bioavailability (%F) of 1.2%, while the oral bioavailability (%F) of compounds (3), (4), (10), (11), (12), (13), (14), (15), (16), (17), (18) and (19) was greater than 10%. Similarly, the oral bioavailability (%F) of compounds (36), (37), (42), (53), (57), (58) and (59) was greater than 10%. In these experiments, the oral bioavailability (%F) of avibactam was 1.8%, while the oral bioavailability (%F) of compounds (20), (22), (23) and (25) was greater than 5%.

[0007] In view of this, it is of important clinical value to provide more structural designs to further improve the oral bioavailability of avibactam so that it can be orally administered. SUMMARY

[0008] The purpose of the present application is to provide a beta-lactamase inhibitor and its use. The beta-lactamase inhibitor provided by the present application is a prodrug of avibactam, which can significantly improve the oral bioavailability of avibactam.

[0009] The beta-lactamase inhibitor described in the present application has the following structure shown in formula (I) or its pharmaceutically acceptable salt or isomer or deuterated product thereof:

[0010] wherein: R1 is selected from

[0011] R2, R3 are each independently selected from halogen, hydroxyl, cyano, substituted or unsubstituted C1-8alkyl, substituted or unsubstituted C1-8heteroalkyl, the substituent can be halogen, hydroxyl, cyano, C1-8alkyl, C1-8heteroalkyl, C3-8cycloalkyl, C3-8heterocycloalkyl, C3-8cycloalkylalkyl, C3-8heterocycloalkylalkyl, C6-8aryl, C5-8heteroaryl, C7-10arylalkyl, C5-10heteroarylalkyl, substituted C3-8cycloalkyl, substituted C3-8heterocycloalkyl, substituted C3-8cycloalkylalkyl, substituted C3-8heterocycloalkylalkyl, substituted C6-8aryl, substituted C5-8heteroaryl, substituted C7-10arylalkyl, substituted C5-10heteroarylalkyl or

[0012] R4is selected from halogen, hydroxyl, cyano, substituted or unsubstituted C1-8alkyl, substituted or unsubstituted C1-8heteroalkyl, the substituents of which can be halogen, hydroxyl, cyano, C1-8alkyl, C1-8heteroalkyl, C3-8cycloalkyl, C3-8heterocycloalkyl, C3-8cycloalkylalkyl, C3-8heterocycloalkylalkyl, C6-8aryl, C5-8heteroaryl, C7-10arylalkyl, C5-10heteroarylalkyl, substituted C3-8cycloalkyl, substituted C3-8heterocycloalkyl, substituted C3-8cycloalkylalkyl, substituted C3-8heterocycloalkylalkyl, substituted C6-8aryl, substituted C5-8heteroaryl, substituted C7-10arylalkyl, substituted C5-10heteroarylalkyl, or

[0013] R a , R c , R d are each independently selected from substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C1-6heteroalkyl, the substituents of which can be halogen, hydroxyl, cyano, C1-8alkyl, C1-8heteroalkyl, C3-8cycloalkyl, C3-8heterocycloalkyl, C3-8cycloalkylalkyl, C3-8heterocycloalkylalkyl, C6-8aryl, C5-8heteroaryl, C7-10arylalkyl, C5-10heteroarylalkyl, substituted C3-8cycloalkyl, substituted C3-8heterocycloalkyl, substituted C3-8cycloalkylalkyl, substituted C3-8heterocycloalkylalkyl, substituted C6-8aryl, substituted C5-8heteroaryl, substituted C7-10arylalkyl, substituted C5-10heteroarylalkyl;

[0014] R b is selected from substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C1-6heteroalkyl, the substituents of which can be halogen, hydroxyl, cyano, C1-8alkyl, C1-8heteroalkyl, C3-8cycloalkyl, C3-8heterocycloalkyl, C3-8cycloalkylalkyl, C3-8heterocycloalkylalkyl, C6-8aryl, C5-8heteroaryl, C7-10arylalkyl, C5-10heteroarylalkyl, substituted C3-8cycloalkyl, substituted C3-8heterocycloalkyl, substituted C3-8cycloalkylalkyl, substituted C3-8heterocycloalkylalkyl, substituted C6-8aryl, substituted C5-8heteroaryl, substituted C7-10arylalkyl, substituted C5-10heteroarylalkyl, or R eselected from the group consisting of substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C1-6heteroalkyl, the substituents can be halogen, hydroxyl, cyano, C1-8alkyl, C1-8heteroalkyl, C3-8cycloalkyl, C3-8heterocycloalkyl, C3-8cycloalkylalkyl, C3-8heterocycloalkylalkyl, C6-8aryl, C5-8heteroaryl, C7-10arylalkyl, C5-10heteroarylalkyl, substituted C3-8cycloalkyl, substituted C3-8heterocycloalkyl, substituted C3-8cycloalkylalkyl, substituted C3-8heterocycloalkylalkyl, substituted C6-8aryl, substituted C5-8heteroaryl, substituted C7-10arylalkyl, substituted C5-10heteroarylalkyl;

[0015] L1, L2, L3are each independently selected from the group consisting of unsubstituted or substituted with one or more R 1a substituted -(CH2) m substituted -(CH2) m NH-; wherein m is selected from 1, 2, 3, 4, or 5; R 1a is selected from the group consisting of NH2, C1-C4alkyl, or -NH-Boc.

[0016] In some specific examples, R2is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclopropyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, aryl, heteroaryl, -(CH2) n -R f ; R3is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclopropyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, aryl, heteroaryl, -(CH2) n -R f or R f is selected from the group consisting of isopropyl, isobutyl, t-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclopropyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, aryl, heteroaryl, hydroxyl, alkenyl, alkynyl, cyano; wherein n is selected from 1, 2, 3, 4, 5, or 6.

[0017] In some specific examples, R2is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, pentyl, -CH2-R f , -CH2-CH2-R f , -(CH2)3-R f ; R3is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, pentyl, -CH2-R f , -CH2-CH2-R f , -(CH2)3-Rf or

[0018] In some specific examples, R2is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, pentyl; in some specific examples, R3is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, pentyl or

[0019] In some specific examples, R4is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclopopyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, aryl, heteroaryl, -(CH2) n -R f or R f is selected from the group consisting of isopropyl, isobutyl, t-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclopopyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, aryl, heteroaryl, hydroxyl, alkenyl, alkynyl, cyano; wherein n is selected from 1, 2, 3, 4, 5, or 6.

[0020] In some specific examples, R4is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, pentyl, -CH2-R f , -CH2-CH2-R f、 -(CH2)3-R f or

[0021] In some specific examples, R4is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, pentyl or

[0022] In some specific examples, R a , R c , R d are each independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, pentyl; in one specific example, R a is selected from the group consisting of ethyl; in some specific examples, R c , R d are each independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl.

[0023] In some specific examples, R b is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, pentyl or Re selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl; in some specific examples, R b selected from methyl or

[0024] in some specific examples, L1, L2, L3are each independently selected from -CH2-, 1a substituted -(CH2) m - or -(CH2) m NH-; wherein m is selected from 1, 2 or 3; R 1a selected from NH2, methyl, ethyl, propyl, isopropyl or -NH-Boc.

[0025] in some specific examples, L1, L2, L3are each independently selected from -CH2-,

[0026] in some specific examples, L1is selected from

[0027] in some specific examples, L2is selected from -CH2-,

[0028] in some specific examples, L3is selected from

[0029] in some specific examples, the β-lactamase inhibitor according to the present application has the following formula (II) or a pharmaceutically acceptable salt thereof:

[0030] wherein R2, R3, R4, L2, R c are as defined above.

[0031] the β-lactamase inhibitor has the following formula (III) or a pharmaceutically acceptable salt thereof:

[0032] wherein R2, R3, R4, L2, R c are as defined above; preferably, R3is selected from R2, R4, R k are each independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, pentyl; preferably, R2is selected from methyl, ethyl, n-propyl, isopropyl; R4is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl; R k is selected from methyl, ethyl, n-propyl, isopropyl.

[0033] In some embodiments, the present application also provides a beta-lactamase inhibitor or a pharmaceutically acceptable salt thereof as shown in the following specific structures:

[0034] The present application also provides a pharmaceutical composition comprising a beta-lactamase inhibitor or a pharmaceutically acceptable salt thereof or an isomer or deuterated form thereof according to the present application, and a pharmaceutically acceptable carrier.

[0035] The pharmaceutical composition according to the present application further comprises an antibiotic; further, the antibiotic is a beta-lactam antibiotic, such as penicillins, cephalosporins, cephamycins and carbapenems.

[0036] The "pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler or gel materials that are suitable for human use and must have sufficient purity and low toxicity. "Compatible" here means that the components of the composition are capable of being combined with the active ingredient of the present application and with each other in the composition, without any significant degradation of the activity of the active ingredient. Examples of the pharmaceutically acceptable carrier include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers, fillers, wetting agents (such as sodium dodecyl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0037] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.

[0038] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. The compounds of the present application can be administered alone or in combination with other therapeutic agents (such as antibacterial agents). When the compounds of the present application or the pharmaceutical compositions are used, a safe and effective amount of the compounds of the present application is administered to a mammal (such as a human) in need of treatment, wherein the dose is a pharmaceutically effective dose, and for a 60 kg human, the daily dose is usually 1-2000 mg, preferably 20-500 mg. Of course, the specific dose should also take into account the route of administration, the health status of the patient, etc., which are within the skill of a skilled physician.

[0039] The present application also provides the use of a beta-lactamase inhibitor or a pharmaceutically acceptable salt thereof or an isomer or deuterated form thereof according to the present application or a composition according to the present application in the preparation of a beta-lactamase inhibitor.

[0040] The present application also provides the use of the beta-lactamase inhibitor or its pharmaceutically acceptable salt or its isomer or deuterated form described in the present application or the composition described in the present application in the preparation of a medicament for treating diseases related to bacterial infection.

[0041] The bacteria described in the present application are bacteria capable of producing beta-lactamase, such as Enterobacter, Citrobacter, Providencia, Serratia and Morganella, etc.

[0042] The present application has the following beneficial effects: the present application combines a group capable of increasing the liposolubility of the compound with the amide and sulfonic acid group in the structure of avibactam, thereby increasing the liposolubility of the structure, and under the action of biological enzymes, the active metabolite avibactam can be quickly and completely released to quickly take effect. The compound of the present application shows an oral bioavailability of avibactam of more than 95% in rats and beagles, so that it can be orally administered, and the same effect as avibactam injection can be achieved without additional increase in the dosage, thereby solving the problem of the inability of avibactam to be orally administered. The present application provides a more broad-spectrum and safe oral beta-lactamase inhibitor for patients, effectively makes up for the narrow antibacterial spectrum of existing oral beta-lactamase inhibitors, and can be used in combination with antibiotics to effectively avoid the problem of antibiotic resistance, thereby improving the antibacterial activity of antibiotics. DETAILED DESCRIPTION

[0043] The following examples facilitate a better understanding of the present application, but do not limit the present application. In the following examples, the experimental methods are conventional methods unless otherwise specified. The test materials used in the following examples are commercially available from conventional biochemical reagent stores unless otherwise specified.

[0044] Example 1: Synthesis of Compound 1

[0045] 3-(((((2S,5R)-2-((Ethoxycarbonyl)aminoformyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropionic acid ethyl ester

[0046] Step one: Synthesis of compound 1b

[0047] Compound 1a (1.6 g, 5.81 mmol) was dissolved in dichloromethane (16 mL) at room temperature. After 10 minutes, lithium bromide (1.26 g, 14.5 mmol) and triethylamine (1.76 g, 17.4 mmol) were added at -78 °C, and the mixture was purged three times with argon. The reaction mixture was allowed to react for another 2 hours at room temperature. The reaction was monitored by LCMS until completion. Water (100 mL) was added to quench the reaction mixture, and the mixture was extracted three times with ethyl acetate (150 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by rapid chromatography (petroleum ether:ethyl acetate (V / V = 1 / 1) to give 450 mg of compound 1b, yield 22.3%. 1 H NMR(400MHz,DMSO-d6)δ10.50(s,1H),7.49-7.43(m,2H),7.43-7.34(m,3H),5.01-4.84(m,2H),4.10(q,J=7.2Hz,2H), 4.06-3.98(m,1H),3.72-3.60(m,1H),3.01-2.87(m,2H),1.99-1.81(m,2H),1.82-1.64(m,2H),1.21(t,J=7.2Hz,3H).

[0048] Step 2: Synthesis of compound 1c

[0049] Compound 1b (450 mg, 1.3 mmol) was dissolved in ethyl acetate (5 mL) at room temperature, followed by the addition of 10% palladium on carbon (140 mg). The resulting mixture was purged three times with hydrogen, and the reaction was continued at room temperature for 1.5 hours. The reaction was monitored by LCMS until completion. The reaction solution was filtered, and the filtrate was concentrated to give 290 mg of compound 1c, with a yield of 86.8%. LCMS (ESI): [M+H] + =258.2.

[0050] Step 3: Synthesis of compound 1e

[0051] At room temperature, sulfonyl chloride (41.5 g, 307.8 mmol) was dissolved in diethyl ether (300 mL), and the solution was cooled to -78 °C under nitrogen atmosphere. A solution of 1d (30.0 g, 205.2 mmol) and pyridine (24.3 g, 307.8 mmol) in diethyl ether (30 mL) was added dropwise. After the addition was complete, the reaction mixture was gradually heated to room temperature and reacted for 4 hours at room temperature. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated to dryness to give 40.0 g of compound 1e, with a yield of 79.7%. 1H NMR (400 MHz, CDC13) δ 4.51 (s, 2H), 4.23-4.17 (m, 2H), 1.32-1.25 (m, 9H).

[0052] Step four: synthesis of compound 1

[0053] Compound 1c (290 mg, 1.13 mmol, 1.0 eq) was dissolved in a mixture of tetrahydrofuran (6 mL) and N,N-dimethylacrylamide (2.4 mL) at room temperature, and cooled to -78 °C under nitrogen. After 10 minutes, sodium bis(trimethylsilyl)amide (0.6 mL, 2M in tetrahydrofuran, 1.24 mmol) was added dropwise to the reaction solution and kept at -78 °C. After 10 minutes, compound 1e (552 mg, 2.25 mmol) was added. After 10 minutes, the reaction solution was warmed to room temperature and reacted for 2 hours at room temperature. After the reaction was completed by LCMS monitoring, the reaction solution was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by reverse phase preparative purification (C18, 10 mmol / L formic acid / water, acetonitrile) to obtain 64.83 mg of compound 1, with a yield of 12.3%. LCMS (ESI): [M+H] + = 466.3. 1 H NMR (400 MHz, CDC13) δ 8.50 (s, 1H), 4.71 (d, J = 9.0 Hz, 1H), 4.61 (d, J = 9.0 Hz, 1H), 4.33-4.24 (m, 2H), 4.24-4.13 (m, 3H), 4.10 (d, J = 7.2 Hz, 1H), 3.36 (d, J = 12.4 Hz, 1H), 2.93 (d, J = 12.4 Hz, 1H), 2.50-2.39 (m, 1H), 2.24-2.13 (m, 1H), 2.04-1.80 (m, 2H), 1.36-1.23 (m, 12H).

[0054] Example 2: synthesis of compound 2

[0055] ((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6- diazabicyclo[3.2.1]octane-2-carboxamido)methyl methyl succinate

[0056] Step one: synthesis of compound 2a

[0057] Compound 1a (8.00 g, 29.06 mmol) was dissolved in acetonitrile (80 mL) at room temperature, and then potassium carbonate (500 mg, 3.63 mmol) and formaldehyde aqueous solution (30%, 40 mL) were added successively. The reaction was allowed to react at room temperature overnight. After the reaction was completed, the reaction solution was poured into water (100 mL), extracted with ethyl acetate (100 mL x 3), and the organic phase was collected and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by flash chromatography (Silica gel, dichloromethane:methanol (V / V = 10 / 1)) to obtain 6.5 g of compound 2a, with a yield of 73.9%. LCMS (ESI) [M+H] + = 305.9. 1 H NMR (400 MHz, Methanol-d4) δ 7.47-7.45 (m, 2H), 7.40-7.33 (m, 3H), 5.00 (d, J = 11.2 Hz, 1H), 4.93 (d, J = 11.3 Hz, 1H), 4.77 (d, J = 10.2 Hz, 1H), 4.65 (d, J = 10.2 Hz, 1H), 3.84 (d, J = 7.4 Hz, 1H), 3.54 (s, 1H), 3.03-2.99 (m, 1H), 2.89 (d, J = 11.9 Hz, 1H), 2.26-2.22 (m, 1H), 2.01-1.94 (m, 1H), 1.91-1.82 (m, 1H), 1.72-1.62 (m, 1H).

[0058] Step two: synthesis of compound 2b

[0059] Compound 2a (2.0 g, 6.56 mmol) was added to dry dichloromethane (20 mL) at room temperature, and then pyridine (778 mg, 9.84 mmol) and 4-chloro-4-oxobutyric acid methyl ester (1.48 g, 9.84 mmol) were added successively. The reaction was allowed to react at room temperature for 3 hours. After the reaction was completed, water (50 mL) was added to the reaction solution to quench the reaction, and extracted with ethyl acetate (100 mL x 3) three times. The organic phase was combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The crude product was separated and purified by flash chromatography (Silica gel, petroleum ether: ethyl acetate (V / V = 1 / 1)) to obtain 1.0 g of compound 2b, with a yield of 36.5%. LCMS (ESI): [M+H] + = 419.9.

[0060] Step three: synthesis of compound 2c

[0061] Compound 2b (800 mg, 1.91 mmol) was dissolved in ethyl acetate (8 mL) at room temperature, then 10% palladium carbon (200 mg) was added thereto, and the mixture was replaced with hydrogen three times. The reaction was continued at room temperature under hydrogen atmosphere for 1.5 hours. The reaction was monitored by LCMS, and the reaction was completed. The reaction was filtered, and the filtrate was concentrated to obtain 550 mg of compound 2c, with a yield of 87.6%. LCMS (ESI): [M+Na] + = 352.1. 1 H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 9.07-8.77 (m, 1H), 5.23-5.06 (m, 2H), 4.13-3.94 (m, 1H), 3.59 (s, 3H), 3.09-2.94 (m, 1H), 2.85-2.72 (m, 1H), 2.52-2.49 (m, 4H), 2.13-2.03 (m, 1H), 2.02-1.87 (m, 2H), 1.80-1.56 (m, 2H).

[0062] Step four: synthesis of compound 2

[0063] Compound 2c (550 mg, 1.67 mmol) was added to a mixture of dry tetrahydrofuran (11 mL) and N,N-dimethylacrylamide (4.4 mL) at room temperature. Sodium bis(trimethylsilyl)amide (0.92 mL, 2M in tetrahydrofuran, 1.84 mmol) was added dropwise to the reaction at -78°C under nitrogen atmosphere, and the reaction was maintained at -78°C for 10 minutes, and then compound 1e (846 mg, 3.34 mmol) was added thereto. After 10 minutes, the temperature was slowly increased to room temperature, and the reaction was continued at room temperature for 2 hours. The reaction was monitored by LCMS, and the reaction was completed. The reaction was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse-phase preparative HPLC (C18, 10 mmol / L formic acid in water, acetonitrile) to obtain 21.86 mg of compound 2, with a yield of 2.43%. LCMS (ESI): [M+Na] + = 560.1. 1H NMR (400 MHz, CDC13) δ 7.60 (t, J = 7.2 Hz, 1H), 5.42-5.35 (m, 1H), 5.31-5.24 (m, 1H), 4.80 (d, J = 8.8 Hz, 1H), 4.80 (d, J = 8.8 Hz, 1H), 4.23-4.13 (m, 3H), 4.00 (d, J = 7.2 Hz, 1H), 3.70 (d, J = 9.6 Hz, 3H), 3.20 (d, J = 12.0 Hz, 1H), 2.80 (d, J = 12.2 Hz, 1H), 2.70-2.59 (m, 4H), 2.50-2.41 (m, 1H), 2.25-2.10 (m, 1H), 2.00-1.93 (m, 1H), 1.30-1.26 (m, 9H).

[0064] Example 3: Synthesis of compound 3

[0065] 3-(((((2S,5R)-2-((((isobutyryloxy)methoxy)carbonyl)aminoformyl)-7-oxo-1,6- diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoic acid ethyl ester

[0066] Step one: Synthesis of compound 3b

[0067] Compound 3a (2.0 g, 15.5 mmol) was added to dichloromethane (20 mL) at room temperature, then triethylamine (1.56 g, 15.5 mmol) and ethanethiol (976 mg, 15.5 mmol) were added to it in turn. The reaction solution was continuously reacted at room temperature for 16 hours. LCMS monitored the completion of the reaction, the reaction solution was filtered and the filtrate was concentrated to dryness. The crude product was separated and purified by flash chromatography (Silica gel, petroleum ether: ethyl acetate (V / V = 10 / 1)) to obtain 1.0 g of compound 3b, yield, 42.0%. 1 H NMR (400 MHz, DMSO-d6) δ 5.96 (s, 2H), 2.91 (q, J = 7.2 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H).

[0068] Step two: Synthesis of compound 3c

[0069] Compound 3b (1.0 g, 6.49 mmol) was dissolved in isobutyric acid (2.86 g, 32.5 mmol) at room temperature, then N,N-diisopropylethylamine (2.51 g, 19.5 mmol) was added at room temperature. The reaction was continued to react at 60 °C for 48 h. LCMS monitoring showed that the reaction was completed. The reaction was quenched by adding water (50 mL) and extracted with ethyl acetate (100 mL x 3) for three times. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to give 1.0 g of compound 3c in a yield of 75.2%. 1 H NMR (400 MHz, DMSO-d6) δ 5.78 (s, 2H), 2.91 (q, J = 7.2 Hz, 2H), 2.65-2.56 (m, 1H), 1.25 (t, J = 7.2 Hz, 3H), 1.10 (d, J = 7.2 Hz, 6H).

[0070] Step three: synthesis of compound 3d

[0071] Compound 3c (100 mg, 0.49 mmol) was added to sulfonyl chloride (79 mg, 0.58 mmol) at 0 °C. The reaction was continued to react at room temperature for 1 h. LCMS monitoring showed that the reaction was completed. The reaction was concentrated to dryness to give 1.4 g of compound 3d in a yield of 78.4%. 1 H NMR (400 MHz, CDCl3) δ 5.76 (s, 2H), 2.63-2.52 (m, 1H), 1.18-1.11 (m, 6H).

[0072] Step four: synthesis of compound 3e

[0073] Compound 1a (2, 0 g, 7.27 mmol) was dissolved in tetrahydrofuran (20 mL) at room temperature, cooled to -78 °C under nitrogen atmosphere, and then lithium bis(trimethylsilyl)amide (15 mL, 1 M in tetrahydrofuran, 14.5 mmol) was added dropwise to the reaction solution and kept at -78 °C. The reaction was continued to react at -78 °C for 30 min, then compound 3d (1.4 g, 8.00 mmol) was added and slowly warmed to room temperature. The reaction was continued to react at room temperature for 2 h. LCMS monitoring showed that the reaction was completed. The reaction was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine twice, dried over anhydrous sodium sulfate and concentrated to dryness. The crude product was separated and purified by flash chromatography (Silica gel, petroleum ether: ethyl acetate (V / V = 1 / 1)) to give 450 mg of compound 3e in a yield of 14.7%. LCMS (ESI): [M+H] + = 420.1.

[0074] Step five: synthesis of compound 3f

[0075] Compound 3e (200 mg, 0.48 mmol) was dissolved in ethyl acetate (4 mL) at room temperature, 10% palladium carbon (20 mg) was added, the mixed solution was replaced with hydrogen gas for three times, and the reaction was stirred at room temperature under hydrogen atmosphere for 1.5 h. After the reaction was monitored to be completed by LCMS, the reaction solution was filtered, and the filtrate was directly concentrated to dryness to obtain 140 mg of compound 3f, with a yield of 89.7%. LCMS (ESI): [M+H] + = 330.2. 1 H NMR (400 MHz, CDCl3) δ 8.83 (s, 1H), 5.75-5.74 (m, 2H), 3.94-3.83 (m, 1H), 3.74 (s, 1H), 3.20 (d, J = 12.0 Hz, 1H), 2.72 (d, J = 11.6 Hz, 1H), 2.57-2.50 (m, 1H), 2.36 (dd, J = 15.2, 6.8 Hz, 1H), 2.15-2.06 (m, 1H), 1.70-1.62 (m, 2H), 1.13 (d, J = 7.2 Hz, 6H).

[0076] Step six: synthesis of compound 3

[0077] Compound 3f (120 mg, 0.364 mmol) was dissolved in a mixed solution of tetrahydrofuran (2 mL) and N, N-dimethylacrylamide (0.8 mL) at room temperature, and the reaction was cooled to -78 °C under nitrogen atmosphere. After 10 minutes, sodium bis(trimethylsilyl)amide (218 μL, 2M in tetrahydrofuran, 1.44 mmol) was added dropwise to the reaction solution, which was kept at -78 °C. After 10 minutes, compound 1e (178 mg, 0.73 mmol) was added, and the reaction was allowed to warm to room temperature. After 2 hours of reaction at room temperature, the reaction was monitored to be completed by LCMS. After the reaction was completed, the reaction solution was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was combined and concentrated under reduced pressure to obtain a crude product, which was purified by reverse phase preparation (C18, 10 mmol / L formic acid in water, acetonitrile) to obtain 25 mg of compound 3, with a yield of 12.7%. LCMS (ESI): [M+H] + = 538.3. 1H NMR (400 MHz, CDC13) δ 8.66 (s, 1H), 5.83 (s, 2H), 4.70 (d, J = 8.8 Hz, 1H), 4.60 (d, J = 9.2 Hz, 1H), 4.21-4.18 (m, 3H), 4.10 (d, J = 7.2 Hz, 1H), 3.37 (d, J = 12.0 Hz, 1H), 2.91 (d, J = 12.0 Hz, 1H), 2.65-2.61 (m, 1H), 2.44 (dd, J = 15.6, 7.2 Hz, 1H), 2.21-2.02 (m, 1H), 2.04-1.80 (m, 2H), 1.30-1.24 (m, 9H), 1.20 (d, J = 7.2 Hz, 6H).

[0078] Example 4: Synthesis of compound 4

[0079] ((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6- diazabicyclo[3.2.1]octane-2-carboxamido)methyl methyl glutarate

[0080] Step one: Synthesis of compound 4a

[0081] Compound 2a (1.0 g, 3.28 mmol) was dissolved in dichloromethane (10 mL) at room temperature, 5-chloro-5-oxopentanoic acid methyl ester (1.07 g, 6.56 mmol), pyridine (778 mg, 9.84 mmol) were added into the solution, which was replaced by argon for three times. The reaction was continued at room temperature for 3 hours. LCMS was used to monitor the completion of the reaction. The reaction was quenched by adding water (100 mL) and extracted by ethyl acetate (150 mL x 3) for three times. The organic phase was washed by saturated sodium chloride solution, dried by anhydrous sodium sulfate, filtered and concentrated to dryness. The obtained crude product was separated and purified by flash chromatography (petroleum ether: ethyl acetate (V / V = 1 / 1) to obtain 800 mg of compound 4a with a yield of 56.3%. LCMS (ESI): [M+H] = 434.2. +

[0082] Step two: Synthesis of compound 4b

[0083] ​Compound 4a (800 mg, 1.85 mmol) was dissolved in ethyl acetate (8 mL) at room temperature, then 10% palladium carbon (240 mg) was added, the resulting mixture was replaced with hydrogen gas for three times, the reaction was continued at room temperature for 1.5 hours in a hydrogen atmosphere. LCMS monitoring showed that the reaction was completed, the reaction was filtered, and the filtrate was concentrated to dryness. 600 mg of compound 4b was obtained, with a yield of 94.5%. LCMS (ESI): [M+H] + = 344.1.

[0084] Step three: synthesis of compound 4

[0085] Compound 4b (600 mg, 1.75 mmol) was dissolved in a mixture of tetrahydrofuran (12 mL) and N,N-dimethylacrylamide (4.8 mL) at room temperature, and cooled to -78°C under nitrogen. After 10 minutes, sodium bis(trimethylsilyl)amide (1.0 mL, 2M in tetrahydrofuran, 1.93 mmol) was added dropwise to the reaction solution and kept at -78°C, and the reaction solution was reacted at -78°C for 10 minutes, then compound 1e (856 mg, 3.5 mmol) was added. After 10 minutes, it was raised to room temperature, and reacted at room temperature for 2 hours. After LCMS monitoring showed that the reaction was completed, the reaction was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was concentrated to dryness under reduced pressure, and the residue was purified by reverse phase preparation (C18, 10 mmol / L formic acid in water, acetonitrile) to obtain 93.84 mg of compound 4, with a yield of 9.72%. LCMS (ESI): [M+Na] + = 574.3. 1 H NMR (400 MHz, CDCl3) δ 7.57 (t, J = 7.2 Hz, 1H), 5.38-5.25 (m, 2H), 4.71 (d, J = 9.2 Hz, 1H), 4.60 (d, J = 9.2 Hz, 1H), 4.23-4.14 (m, 3H), 4.03 (d, J = 7.2 Hz, 1H), 3.68 (d, J = 3.2 Hz, 3H), 3.29 (d, J = 12.0 Hz, 1H), 2.85 (d, J = 12.0 Hz, 1H), 2.48-2.34 (m, 5H), 2.20-2.12 (m, 1H), 2.01-1.90 (m, 3H), 1.88-1.80 (m, 1H), 1.30-1.22 (m, 9H).

[0086] Example 5: synthesis of compound 5

[0087] 4-(((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo- 1,6-diazabicyclo[3.2.1]octane-2-carboxamido)methyl) 1-methyl 2,2-dimethyl succinate

[0088] Step one: synthesis of compound 5b

[0089] Compound 5a (3.5 g, 21.85 mmol, 1.0 eq) was dissolved in dichloromethane (35 mL) and N-N dimethylformamide (0.1 mL) at room temperature, oxalyl chloride (4.16 g, 32.78 mmol) was added slowly under ice-bath, the resulting solution was replaced by argon for three times. The reaction was continued at room temperature for 3 hours. The reaction was directly concentrated to get 3.5 g of compound 5b, which was used for the next step without purification.

[0090] Step two: synthesis of compound 5c

[0091] Compound 5b (2.2 g, 12.32 mmol) was dissolved in dichloromethane (22 mL) at room temperature, compound 2a (1.88 g, 6.16 mmol), pyridine (1.46 g, 18.48 mmol) were added, the resulting solution was replaced by argon for three times. The reaction was continued at room temperature for 3 hours. The reaction was monitored by LCMS, the reaction was quenched by adding water (100 mL) and extracted by ethyl acetate (150 mL x 3) for three times. The organic phase was washed by saturated sodium chloride solution, dried by anhydrous sodium sulfate, filtered and concentrated to dryness. The crude product was purified by flash chromatography (petroleum ether: ethyl acetate (V / V = 1 / 1) to get 2.2 g of compound 5c with a yield of 79.7%. LCMS (ESI): [M+H] = 448.2. + 1 ​H NMR (400 MHz, CDC13) δ 7.64 (t, J = 7.2 Hz, 1H), 7.45-7.33 (m, 5H), 5.32-5.28 (m, 2H), 5.26-5.19 (m, 1H), 5.06 (d, J = 11.2 Hz, 1H), 4.91 (d, J = 11.2 Hz, 1H), 3.91 (d, J = 7.2 Hz, 1H), 3.69 (s, 3H), 3.34-3.29 (m, 1H), 3.05-2.94 (m, 1H), 2.68-2.60 (m, 1H), 2.57 (d, J = 1.6 Hz, 2H), 2.40-2.31 (m, 1H), 2.01-1.89 (m, 2H), 2.02-1.89 (m, 2H), 1.64-1.55 (m, 1H), 1.27-1.24 (m, 6H).

[0092] Step three: synthesis of compound 5d

[0093] Compound 5c (1.0 g, 2.23 mmol, 1.0 eq) was dissolved in ethyl acetate (10 mL) at room temperature, then 10% palladium-carbon (300 mg) was added, the resulting mixture was replaced with hydrogen three times, and the reaction was continued at room temperature in a hydrogen atmosphere for 1.5 hours. The reaction was monitored by LCMS to be completed, the reaction was filtered, and the filtrate was concentrated to dryness to obtain 700 mg of compound 5d, with a yield of 90.3%. LCMS (ESI): [M+H] + = 357.9.

[0094] Step five: synthesis of compound 5

[0095] Compound 5d (700 mg, 1.96 mmol) was dissolved in a mixed solution of tetrahydrofuran (14 mL) and N,N-dimethylacrylurea (5.6 mL) at room temperature, and was cooled to -78°C under nitrogen. After 10 minutes, sodium bis(trimethylsilyl)amide (1.0 mL, 2M in tetrahydrofuran, 2.16 mmol) was added dropwise to the reaction, and the reaction was kept at -78°C. After 10 minutes, compound 1e (962 mg, 3.92 mmol) was added, and the reaction was allowed to warm to room temperature. After 2 hours at room temperature, the reaction was monitored by LCMS to be completed, and the reaction was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was combined, concentrated to dryness under reduced pressure, and the residue was purified by reverse phase preparation (C18, 10 mmol / L formic acid in water, acetonitrile) to obtain 71.4 mg of compound 5, with a yield of 6.44%. LCMS (ESI): [M+H] + = 566.3. 1H NMR (400 MHz, CDC13) δ 7.56 (t, J = 7.2 Hz, 1H), 5.38-5.28 (m, 1H), 5.28-5.21 (m, 1H), 4.71 (d, J = 9.2 Hz, 1H), 4.60 (d, J = 9.2 Hz, 1H), 4.25-4.10 (m, 3H), 4.01 (d, J = 7.2 Hz, 1H), 3.69 (s, 3H), 3.28 (d, J = 12.0 Hz, 1H), 2.91 (d, J = 12.0 Hz, 1H), 2.66-2.54 (m, 2H), 2.50-2.39 (m, 1H), 2.22-2.09 (m, 1H), 2.00-1.92 (m, 1H), 1.90-1.81 (m, 1H), 1.31-1.21 (m, 15H).

[0096] Example 6: Synthesis of compound 6

[0097] Preparation of ethyl 3-(((((2S,5R)-2-((((acetyloxy)methoxy)carbonyl)carbamoyl)-7-oxo- 1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate

[0098] Synthetic method as in Example 3. LCMS (ESI) [M+H] + = 510.3. 1 H NMR (400 MHz, CDC13) δ 8.66 (s, 1H), 5.82 (s, 2H), 4.70 (d, J = 9.2 Hz, 1H), 4.60 (d, J = 9.2 Hz, 1H), 4.25-4.14 (m, 3H), 4.09 (d, J = 9.6 Hz, 1H), 3.37 (d, J = 11.6 Hz, 1H), 2.90 (d, J = 12.4 Hz, 1H), 2.51-2.39 (m, 1H), 2.20 (d, J = 6.0 Hz, 1H), 2.14 (s, 3H), 2.01-1.95 (m, 1H), 1.89-1.86 (m, 1H), 1.29-1.26 (m, 9H).

[0099] Example 7: Synthesis of compound 7

[0100] Ethyl 2,2-dimethyl-3-(((((2S,5R)-7-oxo-2-((((1-(neopentanoyloxy)ethoxy)carbonyl)carbamoyl)- 1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)propanoate

[0101] Synthesis method as in Example 3. LCMS (ESI): [M+H] + = 566.3. 1 H NMR (400 MHz, CDC13) δ 8.53 (s, 1H), 6.86-6.83 (m, 1H), 4.70 (d, J = 9.2 Hz, 1H), 4.60 (d, J = 8.8 Hz, 1H), 4.27-4.13 (m, 3H), 4.09 (d, J = 11.2 Hz, 1H), 3.37 (d, J = 12.0 Hz, 1H), 2.93 (t, J = 11.6 Hz, 1H), 2.44 (d, J = 15.2 Hz, 1H), 2.18 (d, J = 12.0 Hz, 1H), 2.04-1.79 (m, 2H), 1.54 (d, J = 5.6 Hz, 3H), 1.33-1.25 (m, 9H), 1.21 (s, 9H).

[0102] Example 8: Synthesis of compound 8

[0103] Preparation of ethyl 3-(2S,5R)-2-(methoxycarbonyl)alaninyl)oxy)methyl)aminocarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl)oxy(sulfonyl)oxy)-2,2-dimethylpropanoate

[0104] Step one: synthesis of compound 8b

[0105] Compound 8a (25.00 g, 280.90 mmol) was dissolved in a mixture of tetrahydrofuran (5 mL) and water (5 mL) at room temperature, then sodium hydroxide (22.47 g, 561.80 mmol) and methyl chloroformate (29.20 g, 309.00 mmol) were added in turn. The reaction solution was reacted at room temperature for three hours. After the reaction was completed, the reaction solution was poured into water (300 mL), the pH value was adjusted to 3 with 1 mol hydrochloric acid aqueous solution, and extracted with ethyl acetate (100 mL x 3). The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was separated and purified by flash chromatography (Silica gel, dichloromethane:methanol (V / V = 5 / 1)) to obtain 11.50 g of compound 8b, with a yield of 27.85%. LCMS (ESI) [M+H] + = 148.0.

[0106] Step two: synthesis of compound 8c

[0107] Compound 8b (4.50 g, 30.59 mmol) was dissolved in tetrahydrofuran (60 mL) at room temperature, and the temperature was reduced to -10 °C, then 4-methylmorpholine (3.40 g, 33.64 mmol) and ethyl chloroformate (3.65 g, 33.64 mmol) were added successively. The reaction was reacted at -10 °C for three hours. After the reaction was completed, the reaction was filtered, and the filtrate was concentrated to dryness to obtain 4.50 g of compound 8c with a yield of 67.3%. 1 H NMR (400 MHz, CDC13) δ 5.45-5.26 (m, 1H), 4.55-4.42 (m, 1H), 4.39-4.31 (m, 2H), 3.70 (s, 3H), 1.52-1.48 (m, 3H), 1.41-1.35 (m, 3H).

[0108] Step three: synthesis of compound 8d

[0109] Compound 2a (4.00 g, 13.10 mmol) was dissolved in dichloromethane (40 mL) at room temperature, and pyridine (3.10 g, 39.30 mmol) and compound 8c (4.30 g, 19.6 mmol) were added successively. The reaction was reacted at room temperature for three hours. After the reaction was completed, the reaction was directly concentrated to dryness, and the residue was separated and purified by flash chromatography (Silica gel, petroleum ether: ethyl acetate (V / V = 1 / 1)) to obtain 1.38 g of compound 8d with a yield of 24.25%. LCMS (ESI) [M+H] + = 435.2.

[0110] Step four: synthesis of compound 8e

[0111] Compound 8d (1.38 g, 3.18 mmol) was dissolved in ethyl acetate (5 mL) at room temperature, and then 10% palladium-carbon (414 mg) was added. The reaction was reacted at room temperature for 1.5 hours in a hydrogen atmosphere. After the reaction was completed, the reaction was filtered, and the filtrate was concentrated to dryness to obtain 500 mg of compound 8e with a yield of 45.72%. LCMS (ESI) [M+Na] + = 367.2.

[0112] Step five: synthesis of compound 8

[0113] Compound 8e (500 mg, 1.45 mmol) was dissolved in a mixture of tetrahydrofuran (10 mL) and N,N-dimethylacrylamide (4 mL) at room temperature, and then sodium bis(trimethylsilyl)amide (0.8 mL, 2M in tetrahydrofuran, 1.6 mmol) was added dropwise to the reaction solution under nitrogen at -78 °C. The reaction solution was kept at -78 °C for 10 minutes, and then compound 1e (533 mg, 2.18 mmol) was added dropwise to the reaction solution. After 10 minutes, the temperature was raised to room temperature, and the reaction solution was kept at room temperature for 2 hours. After the reaction was completed, the reaction solution was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by reverse phase preparative purification (C18, 10 mmol / L formic acid in water, acetonitrile) to obtain 48.25 mg of compound 8, with a yield of 6.01%. LCMS (ESI) [M+Na] = 575.4. + 1 H NMR (400 MHz, CDCl3) δ 7.59 (t, J = 7.6 Hz, 1H), 5.48-5.29 (m, 2H), 5.17-5.06 (m, 1H), 4.71 (d, J = 9.2 Hz, 1H), 4.60 (d, J = 9.2 Hz, 1H), 4.41-4.29 (m, 1H), 4.26-4.11 (m, 3H), 4.03 (d, J = 7.6 Hz, 1H), 3.69 (s, 3H), 3.28 (d, J = 12.0 Hz, 1H), 2.89 (d, J = 12.0 Hz, 1H), 2.50-2.39 (m, 1H), 2.20-2.13 (m, 1H), 2.00-1.93 (m, 1H), 1.90-1.80 (m, 1H), 1.41 (d, J = 7.2 Hz, 3H), 1.30-1.26 (m, 9H).

[0114] Example 9: Synthesis of compound 9

[0115] 4-(((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6- diazabicyclo[3.2.1]octane-2-carboxamido)methyl) 1-methyl (tert-butoxycarbonyl)-L- aspartate

[0116] Step one: Synthesis of compound 9b

[0117] ​Compound 9a (10.0 g, 80.97 mmol) was added to dry tetrahydrofuran (100 mL) at room temperature, and the mixture was cooled to -10 °C under nitrogen. Then N-methylmorpholine (4.50 g, 44.5 mmol), methyl 2-chloroacetate (4.37 g, 80.97 mmol), and methyl 4-chloro-4-oxobutyrate (1.48 g, 9.84 mmol) were added successively. The reaction was continued at -10 °C for 1 h. Upon completion, the reaction was filtered and the filtrate was concentrated to dryness to give 10.5 g of compound 9b in 98.1% yield. 1 H NMR (400 MHz, CDC13) δ 5.50 (d, J = 8.0 Hz, 1H), 4.68-4.54 (m, 1H), 3.78 (s, 3H), 3.22-3.06 (m, 1H), 3.06-2.95 (m, 1H), 1.45 (s, 9H).

[0118] Step two: synthesis of compound 9c

[0119] Compound 2a (2.0 g, 6.56 mmol) was added to dry dichloromethane (20 mL) at room temperature, and then pyridine (1.56 g, 19.67 mmol) and compound 9b (2.61 g, 9.83 mmol) were added successively. The reaction was continued at room temperature for 3 h. Upon completion, the reaction was quenched by adding water (50 mL) and extracted with dichloromethane (50 mL x 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was separated and purified by flash chromatography (Silica gel, petroleum ether: ethyl acetate (V / V = 1 / 1)) to give 350 mg of compound 9c in 10% yield. LCMS (ESI): [M+H] + = 535.0.

[0120] Step three: synthesis of compound 9d

[0121] Compound 9c (350 mg, 0.655 mmol) was dissolved in ethyl acetate (5 mL) at room temperature, and then 10% palladium-carbon (70 mg) was added. The mixture was replaced with hydrogen three times. The reaction was continued at room temperature under hydrogen atmosphere for 1.5 h. Upon completion, the reaction was filtered, and the filtrate was concentrated to dryness to give 250 mg of compound 9d in 85.9% yield. LCMS (ESI): [M+Na] + = 466.9.

[0122] Step four: synthesis of compound 9

[0123] Compound 9d (250 mg, 0.563 mmol) was added to a mixture of super dry tetrahydrofuran (5 mL) and N,N-dimethylacrylamide (2 mL) at room temperature. Sodium bis(trimethylsilyl)amide (0.62 mL, 2M in tetrahydrofuran, 0.62 mmol) was added dropwise to the reaction mixture at -78 °C under nitrogen atmosphere. The reaction was kept at -78 °C for 10 minutes, then compound 1e (275 mg, 1.12 mmol) was added. The temperature was slowly increased to room temperature after 10 minutes, and the reaction was kept at room temperature for 2 hours. The reaction was completed, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3), the organic phase was concentrated to dryness directly, the residue was purified by reverse phase preparative HPLC (C18, 10 mmol / L formic acid in water, acetonitrile) to give 21.77 mg of compound 9, yield 5.93%. LCMS (ESI): [M+Na] = 675.5, tR= 11.468 min. + R = 11.468 min. 1 HNMR (400 MHz, CDCl3) δ 7.56 (t, J = 7.2 Hz, 1H), 5.48-5.34 (m, 2H), 5.31-5.23 (m, 1H), 4.71 (d, J = 9.2 Hz, 1H), 4.60 (d, J = 9.2 Hz, 2H), 4.23-4.13 (m, 3H), 4.03 (d, J = 7.2 Hz, 1H), 3.29 (d, J = 12.0 Hz, 1H), 3.02-2.94 (m, 1H), 2.92-2.80 (m, 2H), 2.49-2.41 (m, 1H), 2.21-2.12 (m, 1H), 2.01-1.93 (m, 1H), 1.90-1.83 (m, 1H), 1.72 (s, 2H), 1.45 (s, 9H), 1.30-1.25 (m, 9H).

[0124] Example 10: Synthesis of compound 10

[0125] ((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6- diazabicyclo[3.2.1]octane-2-carboxamido)methyl((isobutyryloxy)methyl) butanedioate

[0126] Step one: Synthesis of compound 10b

[0127] ​Compound 10a (10.0 g, 48.07 mmol) was added into N,N-dimethylformamide (100 mL) at room temperature, then sodium carbonate (20.38 g, 192.3 mmol), sodium iodide (7.2 g, 48.07 mmol) and chloromethyl isobutyrate (9.81 g, 72.1 mmol) were added into the mixture in turn. The reaction was continued at room temperature for 16 hours. After the reaction was completed, saturated NaHCO3 aqueous solution (200 mL) was added into the reaction solution to quench the reaction, and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was separated and purified by flash chromatography (Silica gel, petroleum ether: ethyl acetate (V / V = 5 / 1)) to obtain 11.0 g of compound 10b, yield, 74.3%. LCMS (ESI): [M+Na] + = 330.9. 1 H NMR (400 MHz, DMSO-d6) δ 7.42-7.24 (m, 5H), 5.69 (s, 2H), 5.09 (s, 2H), 3.34 (s, 4H), 2.52 (q, J = 7.2 Hz, 1H), 1.08 (d, J = 7.2 Hz, 6H).

[0128] Step two: synthesis of 4-((isobutyryloxy)methoxy)-4-oxobutanoic acid

[0129] Compound 10b (10.0 g, 32.47 mmol) was dissolved in methanol (100 mL) at room temperature, then 10% palladium-carbon (1.5 g) was added into the mixture, and the mixture was replaced with hydrogen gas for three times. The reaction was continued at room temperature under hydrogen atmosphere for 1 hour. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to dryness to obtain 6.0 g of compound 10c, yield, 85.7%. LCMS (ESI): [M+Na] + = 240.9.

[0130] Step three: synthesis of (isobutyryloxy) 4-chloro-4-oxobutanoate

[0131] Compound 10c (2.3 g, 10.55 mmol) was dissolved in dry dichloromethane (23 mL) at room temperature, and the mixture was cooled to 0°C under nitrogen atmosphere, then N,N-dimethylformamide (77 mg, 1.06 mmol) and oxalyl chloride (1.34 g, 10.55 mmol) were added into the mixture in turn. The reaction was continued at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly concentrated to dryness to obtain 2.3 g of compound 10d, yield 92.7%. 1H NMR (400 MHz, DMSO-d6) δ 5.70 (s, 2H), 2.84-2.64 (m, 1H), 2.60-2.54 (m, 2H), 2.53-2.47 (m, 2H), 1.10 (d, J = 7.2 Hz, 6H).

[0132] Step four: synthesis of compound 10e

[0133] Compound 2a (2.0 g, 6.56 mmol) was dissolved in dry dichloromethane (20 mL) at room temperature, then pyridine (1.556 g, 19.67 mmol) and compound 10d (2.32 g, 9.84 mmol) were added successively. The reaction solution was continuously reacted at room temperature for 16 hours. After the reaction was completed, water (50 mL) was added to quench the reaction, and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was separated and purified by flash chromatography (Silica gel, petroleum ether: ethyl acetate (V / V = 1 / 1)) to obtain 2.0 g of compound 10e, with a yield of 60.6%. LCMS (ESI): [M+H] + = 505.9.

[0134] Step five: synthesis of compound 10f

[0135] Compound 10e (2.0 g, 3.96 mmol) was dissolved in ethyl acetate (20 mL) at room temperature, then 10% palladium-carbon (400 mg) was added, and the mixture was replaced with hydrogen three times. The reaction solution was continuously reacted under hydrogen atmosphere at room temperature for 1.5 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was directly concentrated to dryness to obtain 1.3 g of compound 10f, with a yield of 79.3%. LCMS (ESI): [M+H] + = 415.8.

[0136] Step six: synthesis of compound 10

[0137] Compound 10f (1.53 g, 3.69 mmol) was added to a mixture of dry tetrahydrofuran (25 mL) and N,N-dimethylacrylamide (10 mL) at room temperature. Sodium bis(trimethylsilyl)amide (2.03 mL, 2M in tetrahydrofuran, 4.06 mmol) was added dropwise to the reaction mixture at -78 °C under nitrogen atmosphere. After 10 minutes, compound le (1.80 g, 7.37 mmol) was added to the reaction mixture. The temperature was slowly increased to room temperature after 10 minutes and the reaction was allowed to proceed at room temperature for 2 hours. Upon completion of the reaction, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was concentrated to dryness directly and the residue was purified by reverse phase preparative HPLC (C18, 10 mmol / L formic acid in water, acetonitrile) to give 42.96 mg of compound 10 in 1.87% yield. LCMS (ESI): [M+H] + = 624.4. 1 H NMR (400 MHz, CDCl3) δ 7.61 (t, J = 7.2 Hz, 1H), 5.75 (s, 2H), 5.43-5.35 (m, 1H), 5.33-5.22 (m, 1H), 4.71 (d, J = 8.8 Hz, 1H), 4.60 (d, J = 8.8 Hz, 1H), 4.24-4.12 (m, 3H), 4.03 (d, J = 7.2 Hz, 1H), 3.29 (d, J = 12.4 Hz, 1H), 2.89 (d, J = 12.0 Hz, 1H), 2.71-2.62 (m, 3H), 2.62-2.54 (m, 1H), 2.50-2.41 (m, 1H), 2.14 (s, 1H), 2.01-1.91 (m, 1H), 1.87-1.85 (m, 1H), 1.29-1.25 (m, 9H), 1.19 (d, J = 7.2 Hz, 6H).

[0138] Example 11: Synthesis of compound 11

[0139] 1-(((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6- diazabicyclo[3.2.1]octane-2-carboxamido)methyl) 5-methyl 3,3-dimethylpentanedioate

[0140] Step one: Synthesis of compound 11b

[0141] Compound 11a (10.0 g, 70.34 mmol) was dissolved in methanol (100 mL) at room temperature, then triethylamine (7.12 g, 70.34 mmol) and N,N-dimethylformamide (0.86 g, 7.03 mmol) were added, and the reaction was heated to 69 °C for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness, and the residue was separated and purified by flash chromatography (Silica gel, petroleum ether: ethyl acetate (V / V = 1 / 1)) to obtain 10.0 g of compound 11b, with a yield of 81.6%. LCMS (ESI): [M+H] + = 175.0.

[0142] Step two: synthesis of compound 11c

[0143] Compound 11b (3.0 g, 17.2 mmol) was dissolved in dichloromethane (300 mL) at room temperature, then oxalyl chloride (3.3 g, 25.8 mmol) and 1 drop of N,N-dimethylformamide were added, and the mixture was reacted at room temperature for 3 h. After the reaction was completed, the reaction solution was concentrated to dryness to obtain 3.0 g of compound 11c, with a yield of 90.7%. 1 H NMR (400 MHz, DMSO) δ 3.52 (d, J = 3.4 Hz, 3H), 2.34 (s, 2H), 2.23 (s, 2H), 1.00 (d, J = 7.1 Hz, 6H).

[0144] Step three: synthesis of compound 11d

[0145] Compound 2a (2.0 g, 6.6 mmol) was dissolved in dichloromethane (200 mL) at room temperature, pyridine (778 mg, 9.8 mmol) and compound 11c (1.9 g, 9.8 mmol) were added at 0 °C, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, water (50 mL) was added to the reaction solution to quench the reaction, and the resulting solution was extracted with ethyl acetate (100 mL x 3), the combined organic phases were washed with saturated brine (100 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness, and separated and purified by flash chromatography (Silica gel, petroleum ether: ethyl acetate (V / V = 1 / 1)) to obtain 2.6 g of compound 11d, with a yield of 86.7%. LCMS (ESI): [M+H] + = 462.2.

[0146] Step four: synthesis of compound 11e

[0147] Compound 11d (1.1 g, 2.39 mmol) was dissolved in ethyl acetate (11 mL) at room temperature, 10% palladium carbon (200 mg) was added to the mixed solution, and the mixture was replaced with hydrogen three times. The reaction solution was reacted at room temperature for 2 h in a hydrogen atmosphere, the reaction was completed, the reaction solution was filtered, and the filtrate was directly concentrated to dryness to obtain 800 mg of compound 11e, with a yield of 90.4%. LCMS (ESI): [M+H] + = 372.1. 1 H NMR (400 MHz, CDCl3) δ 7.69 (t, J = 7.2 Hz, 1H), 5.36-5.24 (m, 2H), 4.12 (q, J = 7.1 Hz, 1H), 3.91 (d, J = 7.6 Hz, 1H), 3.77 (s, 1H), 3.65 (s, 3H), 3.18 (d, J = 11.8 Hz, 1H), 2.73 (d, J = 11.8 Hz, 1H), 2.45-2.43 (m, 2H), 2.42-2.40 (m, 2H), 2.15-2.13 (m, 1H), 2.02-1.88 (m, 1H), 1.77-1.66 (m, 1H), 1.11 (s, 6H).

[0148] Step five: synthesis of compound 11

[0149] Compound 11e (900 mg, 2.43 mmol) was dissolved in a mixed solution of super dry tetrahydrofuran (9 mL) and N, N-dimethylacrylurea (8 mL) at room temperature, and sodium bis-trimethylsilyl amide (1.3 mL, 2.67 mmol) was slowly added thereto under nitrogen protection and cooled to -78°C. Stirring was continued at -78°C for 10-15 min, and compound 1e (651 g, 2.67 mmol) was slowly added. After 10 min, the temperature was slowly raised to room temperature, and the reaction was reacted at room temperature for 2 h. After the reaction was completed, the reaction solution was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3), and the combined organic phase was directly concentrated to dryness. The residue was purified by preparative HPLC (0.1% FA, ACN) to obtain 41.69 mg of compound 11 with a yield of 1.2%. LCMS (ESI): [M+Na] + = 602.4. 1H NMR (400 MHz, CDC13) δ 7.57 - 7.52 (m, 1H), 5.37 - 5.26 (m, 2H), 4.71 (d, J = 9.0 Hz, 1H), 4.60 (d, J = 9.0 Hz, 1H), 4.26 - 4.09 (m, 3H), 4.01 (d, J = 7.6 Hz, 1H), 3.65 (s, 3H), 3.27 (d, J = 12.4 Hz, 1H), 2.86 (d, J = 12.1 Hz, 1H), 2.48 - 2.38 (m, 5H), 2.16 (d, J = 14.2 Hz, 1H), 1.99 - 1.86 (m, 2H), 1.58 - 1.56 (m, 9H), 1.11 (d, J = 3.3 Hz, 6H).

[0150] Example 12: Synthesis of compound 12

[0151] 3-(((((2S,5R)-2-((((1-acetyloxyethoxy)carbonyl)aminocarbonyl)-7-oxo-1,6- diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoic acid ethyl ester

[0152] Synthetic procedure as in example 3. LCMS (ESI): [M+H] + = 524.2. 1 H NMR (400 MHz, CDC13) δ 8.56 (s, 1H), 6.95 - 6.77 (m, 1H), 4.70 (d, J = 9.2 Hz, 1H), 4.60 (d, J = 9.2 Hz, 1H), 4.24 - 4.14 (m, 3H), 4.11 - 4.03 (m, 1H), 3.37 (d, J = 12.0 Hz, 1H), 2.96 - 2.86 (m, 1H), 2.54 - 2.36 (m, 1H), 2.25 - 2.13 (m, 1H), 2.09 (s, 3H), 2.02 - 1.90 (m, 1H), 1.92 - 1.79 (m, 1H), 1.54 (dd, J = 5.2, 1.6 Hz, 3H), 1.31 - 1.24 (m, 9H).

[0153] Example 13: Synthesis of compound 13

[0154] 1-(((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6- diazabicyclo[3.2.1]octan-2-carboxamido)methyl) 4-methyl 2,2-dimethylsuccinate

[0155] Step one: synthesis of compound 13b

[0156] Compound 13a (10.0 g, 78.12 mmol) was dissolved in dry dichloromethane (100 mL) at room temperature, then methanol (5.0 g, 156.25 mmol) and triethylamine (31.56 g, 312.5 mmol) were added successively. The reaction solution was continuously reacted at room temperature for 16 hours. After the reaction was completed, 1M dilute hydrochloric acid (200 mL) was added to quench the reaction, and the obtained solution was extracted with ethyl acetate (100 mL x 3) for three times. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain 12.0 g of compound 13b, with a yield of 96.0%. LCMS (ESI): [M+H] + = 161.0.

[0157] Step two: synthesis of compound 13c

[0158] Compound 13b (1.75 g, 10.93 mmol) was dissolved in dry dichloromethane (20 mL) at room temperature, and then N,N-dimethylformamide (80 mg, 1.09 mmol) and oxalyl chloride (1.39 g, 10.93 mmol) were added successively under nitrogen protection and cooling to 0°C. The reaction solution was continuously reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was directly concentrated to dryness to obtain 1.75 g of compound 13c, with a yield of 90.2%. 1 H NMR (400 MHz, DMSO-d6) δ 3.56 (s, 3H), 2.89 (s, 1H), 2.73 (s, 1H), 1.16 (s, 6H).

[0159] Step three: synthesis of compound 13d

[0160] Compound 2a (2.0 g, 6.56 mmol) was dissolved in dry dichloromethane (20 mL) at room temperature, and then pyridine (1.556 g, 19.67 mmol) and compound 13c (1.75 g, 9.84 mmol, 1.5 equivalents) were added successively. The reaction solution was continuously reacted at room temperature for 3 hours. After the reaction was completed, water (50 mL) was added to quench the reaction, and extraction was performed with ethyl acetate (100 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was separated and purified by flash chromatography (Silica gel, petroleum ether: ethyl acetate (V / V = 1 / 1)) to obtain 1.4 g of compound 13d, with a yield of 47.7%. LCMS (ESI): [M+H] + = 447.9.

[0161] Step four: synthesis of compound 13e

[0162] Compound 13d (1.4 g, 3.13 mmol) was dissolved in ethyl acetate (8 mL) at room temperature, then 10% palladium carbon (280 mg) was added to the solution, and the mixture was replaced with hydrogen three times. The reaction was continued at room temperature under hydrogen atmosphere for 1.5 hours. After the reaction was completed, the reaction was filtered, and the filtrate was concentrated to dryness to obtain 950 mg of compound 13e, with a yield of 84.9%. LCMS (ESI): [M+Na] + = 357.9. 1 H NMR (400 MHz, DMSO-d6) δ 9.74 (s, 1H), 9.00-8.77 (m, 1H), 5.20-5.04 (m, 2H), 3.56-3.54 (m, 2H), 3.32 (s, 3H), 3.10-2.90 (m, 1H), 2.58-2.54 (m, 2H), 2.12-2.03 (m, 1H), 1.96-1.51 (m, 4H), 1.18-1.16 (m, 6H).

[0163] Step five: synthesis of compound 13

[0164] Compound 13e (650 mg, 1.82 mmol) was dissolved in dry tetrahydrofuran (13 mL) and N,N-dimethylacrylamide (5.2 mL) at room temperature, and sodium bis(trimethylsilyl)amide (1.0 mL, 2M in tetrahydrofuran, 2.0 mmol) was added dropwise to the reaction solution at -78°C under nitrogen atmosphere, and the reaction was maintained at -78°C for 10 minutes, then compound 1e (888 mg, 3.64 mmol) was added. After 10 minutes, the temperature was raised to room temperature, and the reaction was continued at room temperature for 2 hours. After the reaction was completed, the reaction was poured into water (100 mL), and the resulting solution was extracted with ethyl acetate (50 mL x 3), and the combined organic phase was directly concentrated to dryness, and the residue was purified by reverse phase preparative HPLC (C18, 10 mmol / L formic acid in water, acetonitrile) to obtain 83.47 mg of compound 13, with a yield of 8.12%. LCMS (ESI): [M+Na] + = 566.31. 1H NMR (400 MHz, CDC13) δ 7.69 - 7.52 (m, 1H), 5.42 - 5.31 (m, 1H), 5.27 - 5.21 (m, 1H), 4.72 (d, J = 9.2 Hz, 1H), 4.60 (d, J = 9.2 Hz, 1H), 4.23 - 4.13 (m, 3H), 4.02 (t, J = 6.8 Hz, 1H), 3.69 (s, 1H), 3.63 (s, 1H), 3.29 (d, J = 12.0 Hz, 1H), 3.06 - 2.88 (m, 1H), 2.67 - 2.57 (m, 2H), 2.49 - 2.40 (m, 1H), 2.19 - 2.10 (m, 1H), 2.04 - 1.88 (m, 2H), 1.87 - 1.80 (m, 1H), 1.30 - 1.24 (m, 15H).

[0165] Example 14: Synthesis of compound 14

[0166] 1-(((2S,5R)-6-((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6- diazabicyclo[3.2.1]octane-2-carboxamido)methyl)-4-methyl(benzyl)-L-aspartic acid

[0167] Synthetic method as in example 9. LCMS (ESI) [M+Na] + = 675.5. 1 H NMR (400 MHz, CDC13) δ 7.69 - 7.52 (m, 1H), 5.42 - 5.31 (m, 1H), 5.27 - 5.21 (m, 1H), 4.72 (d, J = 9.2 Hz, 1H), 4.60 (d, J = 9.2 Hz, 1H), 4.23 - 4.13 (m, 3H), 4.02 (t, J = 6.8 Hz, 1H), 3.69 (s, 1H), 3.63 (s, 1H), 3.29 (d, J = 12.0 Hz, 1H), 3.06 - 2.88 (m, 1H), 2.67 - 2.57 (m, 2H), 2.49 - 2.40 (m, 1H), 2.19 - 2.10 (m, 1H), 2.04 - 1.88 (m, 2H), 1.87 - 1.80 (m, 1H), 1.30 - 1.24 (m, 15H).

[0168] Example 15: Synthesis of compound 15

[0169] ((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6- diazabicyclo[3.2.1]octane-2-carboxamido)methyl ((isobutyryloxy)methyl)pentanedioate

[0170] Synthetic procedure as Example 10. LCMS (ESI): [M+H] + = 638.3. 1 H NMR (400 MHz, CDC13) δ 7.56 (t, J = 7.6 Hz, 1H), 5.75 (d, J = 4.4 Hz, 2H), 5.37 - 5.25 (m, 2H), 4.71 (d, J = 9.2 Hz, 1H), 4.60 (d, J = 9.2 Hz, 1H), 4.19 - 4.15 (m, 2H), 4.03 (d, J = 7.2 Hz, 1H), 3.30 (d, J = 11.6 Hz, 1H), 2.85 (d, J = 12.0 Hz, 1H), 2.64 - 2.55 (m, 1H), 2.50 - 2.44 (m, 2H), 2.44 - 2.37 (m, 4H), 2.23 - 2.11 (m, 1H), 1.99 - 1.95 (m, 2H), 1.95 - 1.90 (m, 1H), 1.89 - 1.85 (m, 1H), 1.30 - 1.26 (m, 9H), 1.19 (d, J = 7.2 Hz, 6H).

[0171] Example 16: Synthesis of compound 16

[0172] 2,2-dimethyl-3-(((2S,5R)-7-oxo-2-((((tert-butoxy)methoxy)carbonyl)carbamoyl)- 1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)propanoic acid ethyl ester

[0173] Synthetic procedure as Example 3. LCMS (ESI): [M+Na] + = 574.3. 1H NMR (400 MHz, CDC13) δ 8.64 (s, 1H), 5.83 (q, J = 5.6 Hz, 2H), 4.70 (d, J = 9.0 Hz, 1H), 4.60 (d, J = 9.0 Hz, 1H), 4.25 - 4.04 (m, 4H), 3.37 (d, J = 11.6 Hz, 1H), 2.90 (d, J = 12.2 Hz, 1H), 2.47 - 2.38 (m, 1H), 2.17 (s, 1H), 2.02 - 1.91 (m, 1H), 1.91 - 1.81 (m, 1H), 1.27 (t, J = 5.8 Hz, 9H), 1.23 (s, 9H).

[0174] Example 17: Synthesis of compound 17

[0175] 3-(((((2S,5R)-2-(((2-(2,2-dimethyl-5-oxo-l,3-dioxolan-4-yl)acetyloxy)methyl)amino- carbonyl)-7-oxo-l,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoic acid ethyl ester

[0176] Step one: Synthesis of compound 17b

[0177] Compound 17a (5.0 g, 30.43 mmol) was dissolved in dichloromethane (50 mL) at room temperature, then oxalyl chloride (5.8 g, 45.65 mmol) and a catalytic amount of N,N- dimethylformamide were added, and the mixture was reacted at room temperature for 3 h. After the reaction was completed, the reaction liquid was concentrated to dryness to obtain 6.0 g of crude compound 17b, which was directly subjected to the next step reaction. 1 H NMR (400 MHz, CDC13) δ 8.64 (s, 1H), 5.83 (q, J = 5.6 Hz, 2H), 4.70 (d, J = 9.0 Hz, 1H), 4.60 (d, J = 9.0 Hz, 1H), 4.25 - 4.04 (m, 4H), 3.37 (d, J = 11.6 Hz, 1H), 2.90 (d, J = 12.2 Hz, 1H), 2.47 - 2.38 (m, 1H), 2.17 (s, 1H), 2.02 - 1.91 (m, 1H), 1.91 - 1.81 (m, 1H), 1.27 (t, J = 5.8 Hz, 9H), 1.23 (s, 9H).

[0178] Step two: Synthesis of compound 17c

[0179] Compound 2a (4.0 g, 13.11 mmol) was dissolved in dichloromethane (40 mL) at room temperature, pyridine (1.6 g, 19.67 mmol) and compound 17b (3.8 g, 19.67 mmol, 1.5 eq) were added at 0 °C, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, water (50 mL) was added to quench the reaction, and the resulting solution was extracted with ethyl acetate (100 mL x 3), the combined organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was separated and purified by flash chromatography (silica gel, petroleum ether: ethyl acetate (V / V = 1 / 1)) to give 2.7 g of compound 17c, with a yield of 45.0%. LCMS (ESI): [M+H] + = 462.0.

[0180] Step three: synthesis of compound 17d

[0181] Compound 17c (3.5 g, 7.59 mmol) was dissolved in ethyl acetate (35 mL) at room temperature, 10% palladium-carbon (400 mg) was added to the mixture, and the mixture was replaced with hydrogen three times. The reaction solution was reacted in a hydrogen atmosphere at room temperature for 1.5 h, and after the reaction was completed, the reaction solution was filtered, and the filtrate was directly concentrated to dryness to give 2.7 g of compound 17d, with a yield of 96.4%. LCMS (ESI): [M+H] + = 372.1.

[0182] Step four: synthesis of compound 17

[0183] Compound 17d (2.2 g, 5.93 mmol) was dissolved in super dry tetrahydrofuran (22 mL) and N,N-dimethylacrylamide (18 mL) at room temperature, and sodium bis(trimethylsilyl)amide (3.3 mL, 6.53 mmol) was added at -78 °C under nitrogen protection. The reaction was continued to be stirred at -78 °C for 10 min, and compound 1e (2.9 g, 11.86 mmol) was slowly added. After 10 min, the temperature was raised to room temperature, and the reaction was reacted at room temperature for 2 h. After the reaction was completed, the reaction solution was poured into water (100 mL), and the resulting solution was extracted with ethyl acetate (200 mL x 3), the combined organic phase was washed with saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by Pre-HPLC (0.1% FA, ACN) to give 41.69 mg of compound 17, with a yield of 1.2%. LCMS (ESI): [M+H] + = 580.3. 1H NMR (400 MHz, CDC13) δ 7.65 (t, J = 7.2 Hz, 1H), 5.50-5.38 (m, 1H), 5.30 (dd, J = 10.2, 7.0 Hz, 1H), 4.71 (d, J = 8.2 Hz, 2H), 4.60 (d, J = 9.0 Hz, 1H), 4.21-4.17 (m, 3H), 4.02 (d, J = 7.6 Hz, 1H), 3.31 (d, J = 12.5 Hz, 1H), 2.92-2.85 (m, 3H), 2.44 (dd, J = 15.1, 7.2 Hz, 1H), 2.16 (d, J = 16.3 Hz, 1H), 2.03-1.91 (m, 1H), 1.80-1.78 (m, 1H), 1.63-1.57 (m, 6H), 1.29-1.23 (m, 9H).

[0184] Example 18: Synthesis of compound 18

[0185] 3-(((((2S,5R)-2-((((1-(isobutyryloxy)ethoxy)carbonyl)carbamoyl)-7-oxo-1,6- diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoic acid ethyl ester

[0186] Synthetic method as in example 3. LCMS (ESI) [M+Na] + = 574.3. 1 H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 6.72 (q, J = 5.6 Hz, 1H), 4.63 (d, J = 9.2 Hz, 1H), 4.55 (d, J = 9.2 Hz, 1H), 4.26-4.22 (m, 1H), 4.13-4.08 (m, 3H), 3.23 (d, J = 5.2 Hz, 2H), 2.58-2.51 (m, 1H), 2.01-1.91 (m, 3H), 1.84-1.78 (m, 1H), 1.45 (dd, J = 5.2, 1.2 Hz, 3H), 1.23-1.15 (m, 9H), 1.12-1.02 (m, 6H).

[0187] Example 19: Synthesis of compound 19

[0188] 3-(((((2S,5R)-2-(((2-((4-methoxyphenyl)sulfonyl)ethoxy)carbonyl)carbamoyl)-7-oxo- 1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoic acid ethyl ester

[0189] Step one: synthesis of compound 19b

[0190] Compound 19a (20.0 g, 143.0 mmol) was dissolved in N,N-dimethylformamide (100 mL) at room temperature, and the temperature was lowered to 0 °C, then sodium carbonate (45.4 g, 471.0 mmol) and 2-bromo-1-ethanol (19.6 g, 157.0 mmol) were added successively. The reaction was reacted at room temperature for 2 hours. After the reaction was completed, the reaction was poured into water (500 mL), and the resulting solution was extracted with ethyl acetate (300 mL x 2), the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness, and purified by flash chromatography (Silica gel, petroleum ether: ethyl acetate (V / V = 5 / 1)) to give 24.0 g of compound 19b, with a yield of 91.6%. LCMS (ESI) [M+H] + = 185.2. 1 H NMR (400 MHz, CDCl3) δ 7.43-7.35 (m, 2H), 6.91-6.81 (m, 2H), 3.79 (s, 3H), 3.71-3.61 (m, 2H), 2.99 (t, J = 6.0 Hz, 2H).

[0191] Step two: synthesis of compound 19c

[0192] Compound 19b (22.0 g, 119.6 mmol) was dissolved in methanol (440 mL) and water (44 mL) at room temperature, then potassium peroxymonosulfate (124.1 g, 358.7 mmol) was added. The reaction was reacted at 70 °C for 15 minutes. After the reaction was completed, the reaction was poured into water (1000 mL), and the resulting solution was extracted with ethyl acetate (200 mL x 2), the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness, and purified by flash chromatography (Silica gel, petroleum ether: ethyl acetate (V / V = 1 / 1)) to give 24.0 g of compound 19c, with a yield of 96.5%. LCMS (ESI): [M+H] + = 217.0. 1 H NMR (400 MHz, CDCl3) δ 7.90-7.75 (m, 2H), 7.05-7.01 (m, 2H), 3.96-3.94 (m, 2H), 3.89-3.87 (m, 3H), 3.33-3.31 (m, 2H).

[0193] Step three: synthesis of compound 19d

[0194] Compound 19c (2.0 g, 9.26 mmol) was dissolved in tetrahydrofuran (20 mL) at room temperature, and triethylamine (1.4 g, 13.9 mmol) and triphosgene (4.00 g, 13.5 mmol) were added successively at 0 °C. The reaction solution was reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was directly concentrated to dryness to obtain 2.5 g of crude compound 19d, which was directly used in the next reaction.

[0195] Step four: synthesis of compound 19e

[0196] Compound 1a (2.0 g, 7.27 mmol) was dissolved in tetrahydrofuran (20 mL) at room temperature, and the reaction solution was cooled to -78 °C under nitrogen, and then lithium bis(trimethylsilyl)amide (14.5 mL, 1 M in tetrahydrofuran, 14.5 mmol) was added dropwise to the reaction solution while maintaining the temperature at -78 °C, and the reaction solution was reacted at -78 °C for 10 minutes, and then 2-((4-methoxyphenyl)sulfonyl)ethyl carbonyl chloride (2.4 g, 8.72 mmol) was added dropwise to the reaction solution, and after 10 minutes, the temperature was raised to room temperature, and the reaction solution was reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was poured into water (100 mL), and the resulting solution was extracted with ethyl acetate (200 mL x 3), and the combined organic phase was washed with saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness, and the residue was separated and purified by flash chromatography (silica gel, petroleum ether: ethyl acetate (V / V = 3 / 1)) to obtain 1.0 g of compound 19e, with a yield of 26.4%. LCMS (ESI): [M+H] + = 518.2.

[0197] Step five: synthesis of compound 19f

[0198] Compound 19e (1.0 g, 1.93 mmol) was dissolved in ethyl acetate (30 mL) at room temperature, and then 10% palladium-carbon (500 mg) was added. The reaction solution was replaced with hydrogen three times, and the reaction solution was reacted at room temperature under a hydrogen atmosphere for 1 hour. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to dryness to obtain 500 mg of compound 19f, with a yield of 60.5%.

[0199] LCMS (ESI): [M+H] + = 428.2.

[0200] Step six: synthesis of compound 19

[0201] Compound 19f (150 mg, 0.35 mmol) was dissolved in tetrahydrofuran (3 mL) and N,N-dimethylacrylamide (1.1 mL) at room temperature, and then sodium bis(trimethylsilyl)amide (0.2 mL, 2M in tetrahydrofuran, 0.38 mmol) was added dropwise to the reaction solution under nitrogen at -78 °C, and the reaction solution was kept at -78 °C for 10 minutes. Compound 1e (214 mg, 0.88 mmol) was added dropwise to the reaction solution, and the reaction solution was kept at room temperature for 10 minutes, and then the reaction solution was kept at room temperature for 2 hours. After the reaction was completed, the reaction solution was poured into water (20 mL), and the resulting solution was extracted with ethyl acetate (50 mL x 2), and the combined organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by reverse phase preparative purification (C18, 10 mmol / L formic acid in water, acetonitrile) to obtain 14.08 mg of compound 19, a yield of 6.31%. LCMS (ESI) [M+H] + = 636.3. 1 H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 4.63 (d, J = 8.8 Hz, 1H), 4.55 (d, J = 9.2 Hz, 1H), 4.33-4.32 (m, 2H), 4.19 (d, J = 6.0 Hz, 1H), 4.13-4.07 (m, 3H), 3.85 (s, 3H), 3.67 (t, J = 6.0 Hz, 2H), 3.21 (s, 2H), 1.93-1.79 (m, 4H), 1.19-1.18 (m, 9H).

[0202] Example 20: Synthesis of compound 20

[0203] 3-(((((2S,5R)-2-(((2-(Butyl disulfanyl)ethoxy)carbonyl)aminoformyl)-7-oxo-1,6- diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoic acid ethyl ester

[0204] Step one: Synthesis of compound 20a

[0205] Compound 20a (10.0 g, 54.0 mmol) was dissolved in tetrahydrofuran (200 mL) and N,N-dimethyl acrylamide (80 mL) at room temperature, and the mixture was cooled to -78 °C under nitrogen. Then sodium bis(trimethylsilyl)amide (29.5 mL, 2 M in tetrahydrofuran, 59.4 mmol) was added dropwise to the mixture, which was kept at -78 °C. After 10 min, compound 1e (26.4 g, 108 mmol) was added dropwise to the mixture, which was allowed to warm to room temperature. After 2 h, the reaction was quenched by pouring the mixture into water (300 mL). The mixture was extracted with ethyl acetate (300 mL x 3). The combined organic phase was concentrated directly to dryness. The residue was purified by reverse-phase preparative purification (C18, 10 mmol / L formic acid in water, acetonitrile) to give a crude product, which was further purified by flash chromatography (petroleum ether: ethyl acetate (V / V = 3 / 1)) to give compound 20c (3.51 g, 16.5% yield). LCMS (ESI) [M+H] + = 186.2. 1 H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 7.49-7.15 (m, 2H), 3.64 (d, J = 7.2 Hz, 1H), 3.17 (d, J = 3.2 Hz, 1H), 3.00-2.99 (m, 1H), 2.87 (d, J = 11.6 Hz, 1H), 2.10-2.07 (m, 1H), 2.10-2.05 (m, 1H), 1.79-1.67 (m, 1H), 1.66-1.55 (m, 1H).

[0206] Step two: synthesis of compound 20c

[0207] Compound 20a (10.0 g, 54.0 mmol) was dissolved in tetrahydrofuran (200 mL) and N,N-dimethyl acrylamide (80 mL) at room temperature, and the mixture was cooled to -78 °C under nitrogen. Then sodium bis(trimethylsilyl)amide (29.5 mL, 2 M in tetrahydrofuran, 59.4 mmol) was added dropwise to the mixture, which was kept at -78 °C. After 10 min, compound 1e (26.4 g, 108 mmol) was added dropwise to the mixture, which was allowed to warm to room temperature. After 2 h, the reaction was quenched by pouring the mixture into water (300 mL). The mixture was extracted with ethyl acetate (300 mL x 3). The combined organic phase was concentrated directly to dryness. The residue was purified by reverse-phase preparative purification (C18, 10 mmol / L formic acid in water, acetonitrile) to give a crude product, which was further purified by flash chromatography (petroleum ether: ethyl acetate (V / V = 3 / 1)) to give compound 20c (3.51 g, 16.5% yield). LCMS (ESI) [M+H] + = 394.2. 1H NMR (400 MHz, CDCI3) δ 6.47 (s, 1 H), 5.57 (s, 1 H), 4.72 (d, J = 9.2 Hz, 1 H), 4.61 (d, J = 8.8 Hz, 1 H), 4.20-4.07 (m, 3 H), 4.06 (d, J = 7.2 Hz, 1 H), 3.33 (d, J = 12.4 Hz, 1 H), 3.02 (d, J = 12.0 Hz, 1 H), 2.46-2.42 (m, 1 H), 2.16-1.96 (m, 1 H), 1.95-1.89 (m, 2 H), 1.29-1.26 (m, 9 H).

[0208] Step three: synthesis of compound 20e

[0209] To a solution of sodium hydride (4.5 g, 0.111 mol) in THF (100 mL) was added compound 20d (10.0 g, 0.111 mol) at -20 °C under argon atmosphere, after one minute, a solution of 2-mercaptoethanol (8.7 g, 0.111 mol) and trichloroisocyanuric acid (9.0 g, 0.0390 mol) in acetonitrile (30 mL) was added quickly. The reaction mixture was kept stirring at -20 °C for 1 h. The reaction was completed, the solvent was concentrated to dryness, the residue was purified by flash chromatography (Silica gel, petroleum ether: ethyl acetate (V / V = 3 / 1)) to give 10. g compound 20e, yield 55.5%. 1 H NMR (400 MHz, CDCI3) δ 3.89 (t, J = 6.0 Hz, 2 H), 2.85 (t, J = 6.0 Hz, 3 H), 2.77-2.67 (m, 2 H), 1.67-1.65 (m, 2 H), 1.43-1.41 (m, 2 H), 0.93 (t, J = 7.2 Hz, 3 H).

[0210] Step four: preparation of compound 20f

[0211] Compound 20e (2.2 g, 13.3 mmol) was dissolved in dichloromethane (20 mL) at -0 °C, to which was added triethylamine (2.0 g, 19.9 mmol) and triphosgene (1.4 g, 4.64 mmol) successively, the mixture was reacted at room temperature for 16 h, the reaction was completed, the reaction liquid was filtered, the filtrate was concentrated to dryness to give 2.0 g of compound 20f, yield 66.1%. 1 H NMR (400 MHz, CDCI3) δ 3.89 (t, J = 6.0 Hz, 2 H), 2.85 (t, J = 6.0 Hz, 3 H), 2.77-2.67 (m, 2 H), 1.67-1.65 (m, 2 H), 1.43-1.41 (m, 2 H), 0.93 (t, J = 7.2 Hz, 3 H).

[0212] Step five: synthesis of compound 20

[0213] Compound 20c (320 mg, 0.76 mmol) was dissolved in tetrahydrofuran (3 mL) at room temperature, and cooled to -78 °C under nitrogen atmosphere. After 10 minutes, lithium bis(trimethylsilyl)amide (1.53 mL, 1 M in tetrahydrofuran, 1.52 mmol) was added dropwise to the reaction solution and kept at -78 °C. The reaction solution was reacted at -78 °C for 30 minutes, then compound 20f (209 g, 0.92 mmol) was added, and slowly warmed to room temperature. The reaction was reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3) three times. The organic phase was collected, washed with saturated brine twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by reverse phase preparation (C18, 10 mmol / L formic acid / water, acetonitrile) to obtain 81.1 mg of compound 20, with a yield of 12.7%. LCMS (ESI): [M+Na] + = 608.5. 1 H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 4.70 (d, J = 9.2 Hz, 1H), 4.61 (d, J = 9.2 Hz, 1H), 4.47 (t, J = 8.0 Hz, 2H), 4.27-4.16 (m, 3H), 4.10 (d, J = 11.1 Hz, 1H), 3.37 (t, J = 12.0 Hz, 1H), 2.93 (t, J = 8.8 Hz, 2H), 2.73-2.70 (m, 1H), 2.47-2.42 (m, 1H), 2.20-2.16 (m, 1H), 2.02-1.97 (m, 3H), 1.90-1.81 (m, 1H), 1.68-1.66 (m, 2H), 1.44-1.40 (m, 2H), 1.29-1.26 (m, 9H), 0.93 (t, J = 7.2 Hz, 3H).

[0214] Example 21: synthesis of compound 21

[0215] 2,2-dimethyl-3-(2S,5R)-7-oxo-2-(((2-(propyldisulfanyl)ethoxy)carbonyl)aminocarbamoyl)-1,6-diazabicyclo[3.2.1]oct-6-yl)oxy)sulfonyl)oxypropanoic acid ethyl ester

[0216] Synthetic method as in example 20. LCMS (ESI): [M+H] + = 572.2. 1H NMR (400 MHz, CDC13) δ 8.55 (s, 1H), 4.71 (d, J = 9.2 Hz, 1H), 4.61 (d, J = 9.2 Hz, 1H), 4.47 (t, J = 8.0 Hz, 2H), 4.27-4.16 (m, 3H), 4.10 (d, J = 11.1 Hz, 1H), 3.38 (t, J = 12.0 Hz, 1H), 2.93 (t, J = 8.8 Hz, 2H), 2.73-2.71 (m, 1H), 2.47-2.42 (m, 1H), 2.20-2.16 (m, 1H), 2.02-1.97 (m, 3H), 1.90-1.81 (m, 1H), 1.35-1.41 (m, 2H), 1.28-1.25 (m, 9H), 0.94 (t, J = 7.2 Hz, 3H).

[0217] Example 22: Synthesis of compound 22

[0218] Acetyloxymethyl 3-(((((2S,5R)-2-((((acetyloxy)methoxy)carbonyl)aminomethyl)-7-oxo- 1,6-diazabicyclo[3.2.1]oct-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate

[0219] Step one: Synthesis of compound 22a

[0220] Compound 3b (11.0 g, 71.5 mmol) was dissolved in acetic acid (21.5 g, 697 mmol) at room temperature, and then N,N-diisopropyl ethylamine (27.7 g, 540 mmol) was added thereto. The reaction solution was continuously reacted at room temperature for 48 hours. After the reaction was completed, water (300 mL) was added to the reaction solution to quench the reaction, and extracted with ethyl acetate (300 mL x 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was separated and purified by flash chromatography (Silica gel, petroleum ether: ethyl acetate (V / V = 10 / 1)) to obtain 6.5 g of compound 22a, with a yield of 51.2%. 1 H NMR (400 MHz, CDC13) δ 5.73 (s, 2H), 2.83 (q, J = 7.2 Hz, 2H), 2.06 (s, 3H), 5.93 (t, J = 7.2 Hz, 3H).

[0221] Step two: Synthesis of compound 22b

[0222] Sulfonyl chloride (4.5 g, 25.3 mmol) was added to compound 22a (4.5 g, 25.3 mmol) at -10 °C. The reaction was allowed to react at -10 °C for 20 min and then was allowed to react at room temperature for 1 h. After the reaction was completed, the reaction was concentrated to dryness under reduced pressure to obtain 4.5 g of compound 22b, which was used directly in the next reaction. 1 HNMR (400 MHz, CDC13) δ 1.07 (s, 2H), 2.57 (s, 3H).

[0223] Step three: synthesis of compound 22c

[0224] Compound 1a (2.0 g, 7.27 mmol) was added to tetrahydrofuran (20 mL) at room temperature, and the reaction was cooled to -78 °C under nitrogen. Then, lithium bis(trimethylsilyl)amide (14.5 mL, 1 M in tetrahydrofuran, 14.5 mmol) was added dropwise to the reaction at -78 °C, and the reaction was allowed to react at -78 °C for 10 min. Compound 22b (2.2 g, 14.5 mmol) was added dropwise to the reaction at -78 °C, and the reaction was allowed to react at -78 °C for 2 h. After the reaction was completed, water (100 mL) was added to the reaction to quench the reaction, and the reaction was extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was separated and purified by flash chromatography (silica gel, petroleum ether: ethyl acetate (V / V = 1 / 1)) to obtain 950 mg of compound 22c at a yield of 35.7%. LCMS (ESI): [M+H] + = 392.2.

[0225] Step four: synthesis of compound 22d

[0226] Compound 22c (350 mg, 0.90 mmol) was dissolved in ethyl acetate (10 mL) at room temperature, and then 10% palladium-carbon (300 mg) was added. The resulting solution was replaced with hydrogen three times, and the reaction was allowed to react at room temperature for 1 h under a hydrogen atmosphere. After the reaction was completed, the reaction was filtered, and the filtrate was concentrated to dryness to obtain 250 mg of compound 22d at a yield of 92.6%. LCMS (ESI): [M+H] + = 302.1.

[0227] Step five: synthesis of compound 22f

[0228] Compound 22e (15.0 g, 126.9 mmol) was dissolved in acetonitrile (150 mL) at room temperature, then potassium carbonate (17.5 g, 127.0 mmol), chloromethyl acetate (16.5 g, 152.3 mmol) and potassium iodide (10.5 g, 63.5 mmol) were added at room temperature. The mixture was reacted at 45 °C for 16 h. After the reaction was completed, water (100 mL) was added to quench the reaction, and extracted with ethyl acetate (100 mL x 3) three times. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was separated and purified by flash chromatography (Silica gel, petroleum ether: ethyl acetate (V / V = 3 / 1)) to obtain 2.1 g of compound 22f, with a yield of 8.71%. 1 HNMR (400 MHz, CDC13) δ 5.67 (s, 2H), 3.40 (s, 2H), 2.06 (s, 3H), 1.10 (s, 6H).

[0229] Step six: synthesis of compound 22g

[0230] Sulfonyl chloride (532 mg, 3.9 mmol) was dissolved in diethyl ether (5 mL) at room temperature, and the mixture was replaced with argon three times and stirred at -78 °C for 10 min. A solution of compound 22f (500 mg, 2.6 mmol) and pyridine (311 mg, 3.9 mmol) in diethyl ether (0.5 mL) was slowly added dropwise at -78 °C, and the mixture was stirred at -78 °C for 2 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to dryness to obtain 580 mg of compound 22g, with a yield of 77.3%. 1 HNMR (400 MHz, CDC13) δ 5.67 (s, 2H), 3.40 (s, 2H), 2.06 (s, 3H), 1.10 (s, 6H).

[0231] Step seven: synthesis of compound 26

[0232] Compound 22d (400 mg, 1.33 mmol) was dissolved in super dry tetrahydrofuran (12 mL) and N,N-dimethylacrylamide (3.2 mL) at room temperature, the reaction solution was cooled to -78 °C under nitrogen protection, and sodium bis-trimethylsilylamide (0.8 mL, 1.46 mmol) was added dropwise. Keep -78 °C and continue to stir the reaction for 10 min, slowly add compound 22g (1.1 g, 4.00 mmol) to the reaction solution. The temperature of the reaction solution gradually rises to room temperature, and the reaction is carried out at room temperature for 2 hours. Monitor the completion of the reaction by LCMS. After the reaction is completed, water (20 mL) is added to quench the reaction, and extracted with ethyl acetate (50 mL x 3) three times. The organic phase is combined, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to dryness. The residue is purified by preparative HPLC (0.1% formic acid / water, acetonitrile) to obtain 30.41 mg of compound 22, with a yield of 4.1%. LCMS (ESI): [M+H] + = 554.4. 1 H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 5.83-5.75 (m, 4H), 4.71 (d, J = 9.2 Hz, 1H), 4.59 (d, J = 9.2 Hz, 1H), 4.19 (s, 1H), 4.09 (d, J = 6.4 Hz, 1H), 3.39 (d, J = 11.6 Hz, 1H), 2.90 (d, J = 12.0 Hz, 1H), 2.50-2.39 (m, 1H), 2.18-2.17 (m, 1H), 2.14 (d, J = 8.8 Hz, 6H), 2.00-1.95 (m, 1H), 1.88-1.82 (m, 1H), 1.30 (d, J = 4.0 Hz, 6H).

[0233] Example 23: Synthesis of compound 23

[0234] 2-((((((2S,5R)-2-((((acetyloxy methoxy)carbonyl)amino methyl)carbonyl)-7-oxo-1,6- diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methyl malonic acid diisopropyl ester

[0235] Step one: synthesis of compound 23b

[0236] Compound 23a (10.0 g, 84.68 mmol) was dissolved in dichloromethane (100 mL) at room temperature, isopropyl alcohol (11.2 g, 186.3 mmol) and 4-dimethylaminopyridine (1.03 g, 8.468 mmol) were added successively, the reaction solution was lowered to 0 °C, N,N'-dicyclohexylcarbodiimide (38.44 g, 186.3 mmol) was added thereto, and the mixture was reacted at room temperature for 16 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to dryness. The residue was separated and purified by flash chromatography (Silica gel, petroleum ether: ethyl acetate (V / V = 10 / 1)) to obtain 14.0 g of compound 23b at a yield of 81.8%.

[0237] 1 H NMR (400 MHz, CDCl3) δ 5.14-5.00 (m, 2H), 3.83 (q, J = 7.2 Hz, 1H), 1.42 (d, J = 7.2 Hz, 3H), 1.30-1.17 (m, 12H).

[0238] Step two: synthesis of compound 23c

[0239] Compound 23b (7.0 g, 34.61 mmol) was dissolved in ethanol (35 mL) and water (35 mL) at room temperature, aqueous formaldehyde (3.12 g, 38.07 mmol) and sodium bicarbonate (291 mg, 3.46 mmol, 0.1 equivalent) were added at room temperature, and the mixture was stirred at room temperature for 16 h. After the reaction was completed, the reaction solution was extracted with ethyl acetate (100 mL x 3), the combined organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was separated and purified by flash chromatography (Silica gel, petroleum ether: ethyl acetate (V / V = 3 / 1)) to obtain 3.7 g of compound 23c at a yield of 46.1%. 1 H NMR (400 MHz, CDCl3) δ 5.14-5.00 (m, 2H), 3.83 (q, J = 7.2 Hz, 1H), 1.42 (d, J = 7.2 Hz, 3H), 1.30-1.17 (m, 12H).

[0240] Step three: synthesis of compound 23d

[0241] Sulfonyl chloride (698 mg, 5.17 mmol) was dissolved in ether (10 mL) at room temperature, the mixture was replaced with argon for three times, compound 23c (1.0 g, 4.31 mmol) and pyridine (375 mg, 4.74 mmol, 1.1 eq) in ether (1 mL) were added at -78 °C, the mixture was stirred at -78 °C for 0.5 h, then gradually increased to room temperature. Continue to react at room temperature for 2 h, the reaction was completed, the reaction solution was directly concentrated to dryness to obtain 1.0 g of compound 23d, yield 96.4%. 1 H NMR (400 MHz, CDCl3) δ 5.12-5.06 (m, 2H), 4.79 (s, 2H), 1.57 (s, 3H), 1.26 (d, J = 7.2 Hz, 12H).

[0242] Step four: synthesis of compound 23

[0243] Compound 22d (400 mg, 1.3 mmol) was dissolved in tetrahydrofuran (12 mL) and N, N-dimethylacrylurea (3.2 mL) at room temperature, under argon protection, sodium bis (trimethylsilyl) amide (0.7 mL, 2M in tetrahydrofuran solution, 1.43 mmol) was added at -78 °C. Continue to stir at -78 °C for 10 min, slowly add compound 23d (877 mg, 2.6 mmol) to it. After adding, the reaction temperature was gradually increased to room temperature, continue to react at room temperature for 2 h, the reaction was completed, water (100 mL) was added to the reaction solution to quench the reaction, the obtained solution was extracted with ethyl acetate (200 mL x 3), the combined organic phase was washed with saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, the residue was purified by preparative HPLC (0.1% FA, ACN) to obtain 52.47 mg of compound 23, yield 6.6%. LCMS (ESI) [M+H] + = 596.4. 1 H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 5.82 (s, 2H), 5.11-5.06 (m, 2H), 4.99 (d, J = 9.6 Hz, 1H), 4.90 (d, J = 9.6 Hz, 1H), 4.19 (d, J = 3.2 Hz, 1H), 4.09 (d, J = 6.4 Hz, 1H), 3.36 (d, J = 11.6 Hz, 1H), 2.90 (d, J = 12.4 Hz, 1H), 2.45-2.41 (m, 1H), 2.21-2.19 (m, 1H), 2.14 (s, 3H), 2.01-1.93 (m, 1H), 1.89-1.81 (m, 1H), 1.53 (s, 3H), 1.27-1.24 (m, 12H).

[0244] Example 24: Synthesis of compound 24

[0245] 2-((((((2S,5R)-2-((((acetyloxy)methoxy)carbonyl)amino methyl)-7-oxo-1,6- diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonic acid-1- ethyl-3-isopropyl ester

[0246] Step one: Synthesis of compound 24b

[0247] Compound 24a (10 g, 75.7 mmol) was dissolved in dichloromethane (100 mL) at 0 °C, and isopropanol (4.6 g, 75.7 mmol), N,N'-dicyclohexylcarbodiimide (17.2 g, 83.3 mmol) and 4-dimethylaminopyridine (924 mg, 7.58 mmol) were added under nitrogen protection. After the addition was completed, the reaction solution was warmed to 25 °C and the reaction was continued for 12 hours. After the reaction was completed, water (200 mL) was added to the reaction mixture to quench the reaction, and dichloromethane (300 mL x 3) was used for extraction. The organic phase was combined, washed with saturated brine (300 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 10 / 1 V / V) to obtain 13 g of compound 24b with a yield of 98.6%. 1 H NMR (400 MHz, CDCl3) δ 5.10-5.04 (m, 1H), 4.21 (q, J = 7.2 Hz, 2H), 3.33 (s, 2H), 1.31-1.23 (m, 9H).

[0248] Step two: Synthesis of compound 24c

[0249] Compound 24b (10.0 g, 57.5 mmol) was dissolved in tetrahydrofuran (100 mL) at 0 °C, and sodium hydride (2.53 g, 63.2 mmol, 60% in mineral oil) was slowly added under nitrogen protection. After the addition was completed, the reaction solution was kept at 0 °C and stirred for 30 minutes, and then methyl iodide (8.16 g, 57.2 mmol) was added. After the addition was completed, the reaction solution was allowed to react at room temperature overnight. After the reaction was completed, saturated aqueous ammonium chloride solution (100 mL) was added to the reaction mixture at 0 °C to quench the reaction, and ethyl acetate (100 mL x 3) was used for extraction. The organic phase was combined, backwashed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain 6.0 g of compound 24c, which was directly used in the next step reaction.

[0250] Step three: Synthesis of compound 24d

[0251] Compound 24c (6.00 g, 31.9 mmol) was dissolved in a mixture of ethanol (30 mL) and water (10 mL) at 0 °C, and sodium bicarbonate (268 mg, 3.19 mmol) and 37% aqueous formaldehyde solution (3.16 g, 35.1 mmol) were added successively under nitrogen protection. After the addition was completed, the reaction was allowed to react at room temperature for 16 hours. After the reaction was completed, water (100 mL) was added to the reaction mixture at 25 °C to quench the reaction, and extracted with ethyl acetate (100 mL x 3). The organic phase was combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 10 / 1 V / V) to obtain 3.5 g of compound 24d, with a yield of 50.7%. 1 H NMR (400 MHz, CDCl3) δ 5.12-5.08 (m, 1H), 4.08 (s, 2H), 4.24 (dd, J = 6.8, 1.6 Hz, 2H), 1.58 (s, 3H), 1.30-1.25 (m, 9H).

[0252] Step four: synthesis of compound 24e

[0253] Sulfonyl chloride (728 mg, 5.43 mmol) was dissolved in diethyl ether (10 mL) at room temperature, and a solution of 1-tert-butyl-3-ethyl-2-(hydroxymethyl)-2-methylmalonate (500 mg, 3.62 mmol) and pyridine (429 mg, 5.43 mmol) in diethyl ether (2 mL) was slowly added to it under nitrogen protection, and the temperature was gradually increased to room temperature. After the dropwise addition was completed, the reaction was allowed to react at room temperature for 4 hours. After the reaction was completed, the reaction liquid was filtered, the filtrate was collected and concentrated under reduced pressure to obtain 0.5 g of compound 24e, which was directly used in the next step reaction.

[0254] Step five: synthesis of compound 24

[0255] Compound 22d (300 mg, 0.996 mmol) was dissolved in a mixture of tetrahydrofuran (3 mL) and N,N-dimethylacrylamide (1 mL) at room temperature, and then sodium bis(trimethylsilyl)amide (59.8 uL, 2M in tetrahydrofuran) was added dropwise to the reaction solution under nitrogen at -78 °C. After the addition was completed, the reaction solution was reacted at -78 °C for 10 minutes, and then compound 24e (380 mg, 1.19 mmol) was added dropwise to the reaction solution. After the addition was completed, the reaction solution was gradually warmed to room temperature and reacted at room temperature for 3 hours. After the reaction was completed, the reaction solution was poured into a 0 °C saturated aqueous sodium bicarbonate solution (20 mL), extracted with ethyl acetate (50 mL x 2), and the combined organic phases were concentrated to dryness. The residue was purified by preparative HPLC (0.1% FA, ACN) to obtain 17.4 mg of compound 24, a yield of 3.0%. LCMS (ESI) [M+H] + = 582.4. 1 H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 5.82 (s, 2H), 5.16-5.04 (m, 1H), 5.00 (d, J = 9.6 Hz, 1H), 4.90 (d, J = 9.6 Hz, 1H), 4.26-4.10 (m, 3H), 4.10 (d, J = 7.2 Hz, 1H), 3.36 (d, J = 12.0 Hz, 1H), 2.90 (d, J = 11.6 Hz, 1H), 2.50-2.39 (m, 1H), 2.16-2.15 (m, 1H), 2.14 (s, 3H), 2.04-1.94 (m, 1H), 1.88-1.86 (m, 1H), 1.54 (s, 3H), 1.26 (d, J = 8.6 Hz, 9H).

[0256] Example 25: Synthesis of compound 25

[0257] 2-((((((2S,5R)-2-((((acetyloxymethoxy)carbonyl)aminoformyl)-7-oxo-1,6- diazabicyclo[3.2.1]oct-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylmalonic acid-1- isopropyl-3-methyl ester

[0258] Step one: Synthesis of compound 25b

[0259] Compound 25a (10 g, 84.7 mmol) was dissolved in dichloromethane (100 mL) at 0 °C, and isopropyl alcohol (7.63 g, 127 mmol), N,N'-dicyclohexylcarbodiimide (26.2 g, 127 mmol) and 4-dimethylaminopyridine (1.03 g, 8.47 mmol) were added successively under nitrogen protection. After the addition was completed, the reaction solution was warmed to 25 °C and the reaction was continued for 12 hours. After the reaction was completed, water (200 mL) was added to the reaction mixture to quench the reaction, and dichloromethane (300 mL x 3) was used for extraction. The organic phase was combined, washed with saturated brine (300 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 10 / 1 V / V) to obtain 11.0 g of compound 25b. 1 H NMR (400 MHz, CDCl3) δ 5.27-4.99 (m, 1H), 3.71 (s, 3H), 3.33 (s, 2H), 1.24 (s, 3H), 1.22 (s, 3H).

[0260] Step two: synthesis of compound 25c

[0261] Compound 25b (10.0 g, 62.5 mmol) was dissolved in tetrahydrofuran (100 mL) at 0 °C, and sodium hydride (2.75 g, 68.7 mmol, 60% in mineral oil) was slowly added under nitrogen protection. After the addition was completed, the stirring was continued for 30 minutes, and then iodomethane (8.87 g, 62.5 mmol) was added to the above reaction solution. After the addition was completed, the reaction solution was allowed to react at room temperature overnight. After the reaction was completed, saturated aqueous ammonium chloride solution (100 mL) was added to the reaction mixture at 0 °C to quench the reaction, and ethyl acetate (100 mL x 3) was used for extraction. The organic phase was combined, backwashed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain 5.0 g of compound 25c, which was directly used in the next step reaction.

[0262] Step three: synthesis of compound 25d

[0263] Compound 25c (5.00 g, 26.5 mmol) was dissolved in a mixture of ethanol (30 mL) and water (10 mL) at 0 °C, and sodium bicarbonate (223 mg, 2.65 mmol) and 37% aqueous formaldehyde solution (2.63 g, 29.2 mmol) were added successively under nitrogen protection. After the addition was completed, the reaction was allowed to react at room temperature for 16 hours. After the reaction was completed, water (100 mL) was added to the reaction mixture at 25 °C to quench the reaction, and extracted with ethyl acetate (100 mL x 3). The organic phase was combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 10 / 1 V / V) to obtain 3.5 g of compound 25d, with a yield of 60.7%. 1 H NMR (400 MHz, CDC13) δ 5.12-5.08 (m, 1H), 4.86 (s, 2H), 3.78 (s, 3H), 2.10 (q, J = 12.4 Hz, 2H), 1.26 (d, J = 6.4, 6H), 0.93 (t, J = 7.6, 3H).

[0264] Step four: synthesis of compound 25e

[0265] Sulfonyl chloride (462 mg, 3.44 mmol) was dissolved in diethyl ether (10 mL) at room temperature, and a solution of compound 25d (500 mg, 2.29 mmol) and pyridine (271 mg, 3.44 mmol) in diethyl ether (2 mL) was slowly added thereto under nitrogen protection and cooled to -78 °C. After the dropwise addition was completed, the temperature was gradually increased to room temperature, and the reaction was allowed to react at room temperature for 4 hours. After the reaction was completed, the reaction liquid was filtered, the filtrate was collected and concentrated under reduced pressure to obtain 0.5 g of compound 25e, which was directly used in the next step reaction.

[0266] Step five: synthesis of compound 25

[0267] Compound 22d (300 mg, 0.996 mmol) was dissolved in a mixture of tetrahydrofuran (3 mL) and N,N-dimethylacrylamide (1 mL) at room temperature, and then sodium bis(trimethylsilyl)amide (59.8 uL, 2M tetrahydrofuran solution) was added dropwise to the reaction solution under nitrogen protection at -78 °C. After the dropwise addition was completed, the reaction solution was reacted at -78 °C for 10 minutes, and then compound 24e (378 mg, 1.19 mmol) was added dropwise into the reaction solution. After the dropwise addition was completed, the reaction solution was gradually warmed to room temperature and reacted at room temperature for 3 hours. After the reaction was completed, the reaction solution was poured into a 0 °C saturated aqueous sodium bicarbonate solution (20 mL), extracted with ethyl acetate (50 mL x 2), and the combined organic phases were concentrated to dryness. The residue was purified by preparative HPLC (0.1% FA, ACN) to obtain 13.2 mg of compound 25, with a yield of 2.5%. LCMS (ESI) [M+H] + = 582.4. 1 H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 5.82 (s, 2H), 5.12-5.04 (m, 2H), 4.94 (dd, J = 10.0, 5.2 Hz, 1H), 4.18 (s, 1H), 4.09 (d, J = 7.6 Hz, 1H), 3.77 (d, J = 4.8 Hz, 3H), 3.36 (d, J = 12.4 Hz, 1H), 2.90 (d, J = 12.0 Hz, 1H), 2.48-2.40 (m, 1H), 2.16 -2.15 (m, 1H), 2.14 (s, 3H), 2.13-2.11 (m, 1H), 2.09-2.01 (m, 2H), 1.87 (s, 1H), 1.25-1.23 (m, 6H), 0.92 (t, J = 7.6 Hz, 3H).

[0268] Example 26: Synthesis of compound 26

[0269] 2-((((((2S,5R)-2-((((acetyloxymethoxy)carbonyl)aminoformyl)-7-oxo-1,6- diazabicyclo[3.2.1]oct-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonic acid-1-tert-butyl-3- ethyl ester

[0270] Step one: Synthesis of compound 26b

[0271] Compound 26a (50.0 g, 0.312 mol) was dissolved in dichloromethane (500 mL) at room temperature, and then ethanol (21.5 g, 0.468 mol), 4-dimethylaminopyridine (3.81 g, 31.2 mmol) were added successively. After the addition was completed, the reaction solution was cooled to 0 °C, and N,N'-dicyclohexylcarbodiimide (70.8 g, 0.343 mol) was added thereto. After the addition was completed, the reaction was carried out at room temperature for 16 h. After the reaction was completed, the reaction solution was directly filtered, and the filtrate was concentrated to dryness. The residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 10 / 1 V / V) to obtain 40.0 g of compound 26b. 1 H NMR (400 MHz, DMSO-d6) δ 4.11-4.09 (m, 2H), 3.40-3.19 (m, 2H), 1.41 (s, 9H), 1.19 (t, J = 7.2 Hz, 3H).

[0272] Step two: synthesis of compound 26c

[0273] Compound 26b (40.0 g, 0.212 mol) was dissolved in tetrahydrofuran (400 mL) at 0 °C, and sodium hydride (9.36 g, 0.234 mol, 60% in mineral oil) was slowly added thereto under nitrogen protection. After the addition was completed, the reaction was carried out at room temperature for 30 min, and then methyl iodide (31.7 g, 0.21 mol) was added to the above reaction solution. After the addition was completed, the reaction was carried out at room temperature overnight. After the reaction was completed, saturated aqueous ammonium chloride solution (200 mL) was added to the reaction mixture at 0 °C to quench, and extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain 20.0 g of compound 26c, which was directly used in the next reaction.

[0274] Step three: synthesis of compound 26d

[0275] Compound 26c (20.0 g, 99.1 mmol) was dissolved in a mixed solution of ethanol (200 mL) and water (100 mL) at 0 °C, and sodium bicarbonate (831 mg, 9.91 mmol) and 37% formaldehyde aqueous solution (9.80 g, 108 mol) were added thereto successively under nitrogen protection. After the addition was completed, the reaction was carried out at room temperature for 16 h. After the reaction was completed, water (200 mL) was added to the reaction mixture at 25 °C to quench, and extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 10 / 1 V / V) to obtain 11.1 g of compound 26d with a yield of 48.0%.1 H NMR (400 MHz, CDC13) δ 4.27-4.15 (m, 2H), 3.79 (d, J = 18.0 Hz, 2H), 1.47 (s, 9H), 1.40 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H).

[0276] Step four: synthesis of compound 26e

[0277] Sulfonyl chloride (6.93 g, 51.7 mmol) was dissolved in ether (30 mL) at room temperature, and the solution was cooled to -78 °C under nitrogen protection. A solution of compound 26c (8.00 g, 34.5 mmol) and pyridine (4.08 g, 51.7 mmol) in ether (5 mL) was added dropwise, and the solution was gradually warmed to room temperature. The reaction was carried out at room temperature for 4 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was collected and concentrated under reduced pressure to obtain 10.0 g of compound 26e, which was directly used in the next step.

[0278] Step five: synthesis of compound 26

[0279] Compound 22d (8.00 g, 26.5 mmol) was dissolved in a mixed solution of tetrahydrofuran (80 mL) and N,N-dimethylacrylamide (35 mL) at room temperature, and the solution was cooled to -78 °C under nitrogen protection. Sodium bis(trimethylsilyl)amide (15.9 mL, 2M tetrahydrofuran solution) was then added dropwise to the reaction solution, and the solution was gradually warmed to room temperature. After the addition was completed, the reaction was carried out at -78 °C for 10 minutes. Compound 26e (10.5 g, 31.9 mmol) was then added dropwise to the reaction solution, and the solution was gradually warmed to room temperature. The reaction was carried out at room temperature for 3 hours. After the reaction was completed, the reaction solution was poured into a 0 °C saturated aqueous sodium bicarbonate solution (20 mL), and extracted with ethyl acetate (50 mL x 2). The organic phases were combined and concentrated to dryness. The residue was purified by preparative HPLC (0.1% FA, ACN) to obtain 1.03 g of compound 26, with a yield of 6.6%. LCMS (ESI) [M+H] = 596.2. + 1 H NMR (400 MHz, CDC13) δ 8.65 (s, 1H), 5.82 (s, 2H), 5.02-4.83 (m, 2H), 4.30-4.14 (m, 3H), 4.09 (d, J = 7.6 Hz, 1H), 3.44-3.28 (m, 1H), 2.91-2.88 (m, 1H), 2.44-2.42 (m, 1H), 2.24-2.09 (m, 4H), 1.99-1.96 (m, 1H), 1.90-1.78 (m, 1H), 1.51 (d, J = 2.0 Hz, 3H), 1.46 (d, J = 3.6 Hz, 9H), 1.28 (t, J = 7.2 Hz, 3H).​

[0280] Example 27: Synthesis of compound 27 2-((((((2S,5R)-2-((((acetyloxy methoxy)carbonyl)amino)methyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethyl propanedioic acid-1-ethyl-3-isopropyl ester

[0281] Step one: Synthesis of compound 27a

[0282] Compound 24b (10.0 g, 57.5 mmol) was dissolved in tetrahydrofuran (100 mL) at 0 °C, sodium hydride (2.53 g, 63.2 mmol, 60% in mineral oil) was added slowly under nitrogen protection, after the addition was completed, the reaction was stirred for 30 minutes, then iodomethane (8.93 g, 57.2 mmol) was added to the above reaction solution. After the addition was completed, the reaction was allowed to react at room temperature overnight. After the reaction was completed, saturated aqueous ammonium chloride solution (200 mL) was added to the reaction mixture at 0 °C to quench, extracted with ethyl acetate (100 mL x 3). The organic phase was combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give 6.1 g of compound 27a, which was used directly in the next step.

[0283] Step two: Synthesis of compound 27b

[0284] Compound 27a (6.00 g, 29.7 mmol) was dissolved in a mixture of ethanol (30 mL) and water (10 mL) at 0 °C, sodium bicarbonate (249 mg, 2.97 mmol) and 37% formaldehyde aqueous solution (2.94 g, 32.6 mol) were added sequentially under nitrogen protection. After the addition was completed, the reaction was allowed to react at room temperature for 16 hours. After the reaction was completed, water (100 mL) was added to the reaction mixture at 25 °C to quench the reaction, extracted with ethyl acetate (100 mL x 3). The organic phase was combined, washed with saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was separated and purified by flash chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 10 / 1 V / V) to give 3.9 g of compound 27b, with a yield of 56.6%. 1 H NMR (400 MHz, CDCl3) δ 5.12-5.08 (m, 1H), 4.08 (s, 2H), 4.24 (q, J = 3.2 Hz, 2H), 2.10 (q, J = 3.2 Hz, 2H), 1.30-1.25 (m, 9H), 0.94 (t, J = 7.2 Hz, 3H).

[0285] Step three: Synthesis of compound 27c

[0286] Sulfonyl chloride (433 mg, 3.23 mmol) was dissolved in diethyl ether (10 mL) at room temperature, and the solution was cooled to -78 °C under nitrogen protection. A solution of compound 27b (500 mg, 2.16 mmol) and pyridine (255 mg, 3.23 mmol) in diethyl ether (2 mL) was added dropwise. After the addition was completed, the solution was gradually warmed to room temperature and reacted for 4 hours at room temperature. After the reaction was completed, the reaction solution was filtered, and the filtrate was collected and concentrated under reduced pressure to obtain 0.6 g of compound 27c, which was directly used in the next step.

[0287] Step four: synthesis of compound 27

[0288] Compound 22d (300 mg, 0.996 mmol) was dissolved in a mixed solution of tetrahydrofuran (3 mL) and N,N-dimethylacrylurea (1 mL) at room temperature, and the solution was cooled to -78 °C under nitrogen protection. Sodium bis(trimethylsilyl)amide (59.8 uL, 2M tetrahydrofuran solution) was added dropwise. After the addition was completed, the solution was reacted for 10 minutes at -78 °C, and then compound 27c (392 mg, 1.19 mmol) was added dropwise. After the addition was completed, the solution was gradually warmed to room temperature and reacted for 3 hours at room temperature. After the reaction was completed, the reaction solution was poured into a 0 °C saturated aqueous sodium bicarbonate solution (20 mL), extracted with ethyl acetate (50 mL x 2), and the organic phases were combined and concentrated to dryness. The residue was purified by preparative HPLC (0.1% FA, ACN) to obtain 10.5 mg of compound 27, with a yield of 2.8%. LCMS (ESI) [M+H] + = 596.3. 1 H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 5.82 (s, 2H), 5.16-5.04 (m, 2H), 4.95 (d, J = 10.0 Hz, 1H), 4.30-4.15 (m, 4H), 4.09 (d, J = 7.2 Hz, 1H), 3.36 (d, J = 12.4 Hz, 1H), 2.90 (d, J = 12.0 Hz, 1H), 2.46-2.43 (m, 1H), 2.16-2.15 (m, 1H), 2.14 (s, 3H), 2.09-1.96 (m, 2H), 1.88-1.82 (m, 1H), 1.33-1.19 (m, 9H), 0.92 (t, J = 7.6 Hz, 3H).

[0289] Test Example 1: Liver microsomal stability test

[0290] 1.1 Liver microsomes

[0291] Human liver microsomes (source Bioreclamation IVT).

[0292] 1.2 Compound solution preparation

[0293] Weigh a certain amount of the compound of the example, add DMSO to prepare a 0.1 mM intermediate solution A, and then add PBS to prepare a 3 μΜ intermediate solution B.

[0294] 1.3 Sample incubation

[0295] Take 15 μL of human liver microsomal protein and 15 μL of NADPH solution and dispense into a 96-well plate at different time points (0, 5, 15, 30, 60 min), and take 15 μL of human liver microsomal protein and 15 μL of PBS solution and dispense into a 96-well plate at different time points (0 and 60 min) as a negative control; for 0 min, add acetonitrile:methanol (1:1) containing an internal standard and intermediate solution B, and for other time points, add intermediate solution B to start the reaction. Incubate all samples in a 37 °C incubator for 5 min, add acetonitrile:methanol (1:1) containing an internal standard to stop the reaction; shake the samples at 600 rpm for 10 min, centrifuge at 4000 rpm for 15 min, collect the supernatant and analyze by LC-MS.

[0296] 2. Results

[0297] The conversion of the compound of the example in human liver microsomes is as follows, and the data are shown in Tables 1 and 2:

[0298] Table 1 Metabolic data of the compound in human liver microsomes

[0299] Table 2 Data of the conversion of the compound in human liver microsomes to release avibactam

[0300] The compounds of Examples 6, 7, 16, 23, 24, 25, 26, and 27 are all rapidly converted to the parent drug avibactam in human liver microsomes, with a half-life T 1 / 2 <5 min.

[0301] Test Example 2: Oral bioavailability in rats

[0302] After intravenous (IV) and oral (PO) administration of avibactam to male Sprague-Dawley (SD) rats and oral (PO) administration of the test compound, a pharmacokinetic (PK) study was performed, and the oral bioavailability of avibactam (%F) was determined by comparing the AUC after oral administration and the AUC after IV administration.

[0303] 1.1 Drug preparation

[0304] Avibactam was dissolved in phosphate buffered saline (PBS) (pH 7.5) to make a 0.4 mg / mL solution for intravenous injection. Avibactam and the compounds of Examples 6, 23, 24, 25, 26, 27 were dissolved in 2% DMSO + 10% Solutol + 88% Saline to make a 1.0 mg / mL solution for oral administration.

[0305] 1.2 Dosing

[0306] The intravenous dose was 2 mg / kg and the oral dose was 10 mg / kg. The dose volume for intravenous and oral administration was 5 mL / kg and 10 mL / kg, respectively.

[0307] 1.3 Procedure

[0308] Blood samples were collected via jugular sinus puncture at 0 h, 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h post-dose and anticoagulated with sodium heparin. Blood samples were placed on ice after collection and plasma was separated (centrifugation conditions: 6800 g, 6 minutes, 2-8°C) within 30 minutes of collection. The supernatant was removed and analyzed for avibactam concentration by LC / MS / MS.

[0309] 1.3 Pharmacokinetic parameter results

[0310] The oral bioavailability of the parent drug in male rats after equimolar conversion of the compound to the parent drug is shown in Table 3 below, where A indicates (%F) > 95%, B indicates 50 < (%F) < 95%, C indicates 20 < (%F) < 50%, and D indicates (%F) < 20%.

[0311] Examples 23, 26, and 27 show that the oral bioavailability of avibactam is greater than 95%, Examples 6 and 24 show that the oral bioavailability of avibactam is greater than 50% and less than 95%, and Example 25 shows that the oral bioavailability of avibactam is greater than 20% and less than 50%. The results show that the compounds of the present application greatly improve the oral bioavailability of avibactam and solve the problem of the inability to orally administer avibactam.

[0312] Table 3

Claims

1. A β-lactamase inhibitor having the structure shown in formula (I) below, or a pharmaceutically acceptable salt thereof, or an isomer or deuterated thereof: wherein: R1is selected from R2, R3are each independently selected from the group consisting of halogen, hydroxyl, cyano, substituted or unsubstituted C1-8alkyl, substituted or unsubstituted C1-8heteroalkyl, the substituents can be halogen, hydroxyl, cyano, C1-8alkyl, C1-8heteroalkyl, C3-8cycloalkyl, C3-8heterocycloalkyl, C3-8cycloalkylalkyl, C3-8heterocycloalkylalkyl, C6-8aryl, C5-8heteroaryl, C7-10arylalkyl, C5-10heteroarylalkyl, substituted C3-8cycloalkyl, substituted C3-8heterocycloalkyl, substituted C3-8cycloalkylalkyl, substituted C3-8heterocycloalkylalkyl, substituted C6-8aryl, substituted C5-8heteroaryl, substituted C7-10arylalkyl, substituted C5-10heteroarylalkyl or R4is selected from halogen, hydroxyl, cyano, substituted or unsubstituted C1-8alkyl, substituted or unsubstituted C1-8heteroalkyl, the substituents of which can be halogen, hydroxyl, cyano, C1-8alkyl, C1-8heteroalkyl, C3-8cycloalkyl, C3-8heterocycloalkyl, C3-8cycloalkylalkyl, C3-8heterocycloalkylalkyl, C6-8aryl, C5-8heteroaryl, C7-10arylalkyl, C5-10heteroarylalkyl, substituted C3-8cycloalkyl, substituted C3-8heterocycloalkyl, substituted C3-8cycloalkylalkyl, substituted C3-8heterocycloalkylalkyl, substituted C6-8aryl, substituted C5-8heteroaryl, substituted C7-10arylalkyl, substituted C5-10heteroarylalkyl, or R a , R c , R d each independently is selected from substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C1-6heteroalkyl, the substituent can be halogen, hydroxyl, cyano, C1-8alkyl, C1-8heteroalkyl, C3-8cycloalkyl, C3-8heterocycloalkyl, C3-8cycloalkylalkyl, C3-8heterocycloalkylalkyl, C6-8aryl, C5-8heteroaryl, C7-10arylalkyl, C5-10heteroarylalkyl, substituted C3-8cycloalkyl, substituted C3-8heterocycloalkyl, substituted C3-8cycloalkylalkyl, substituted C3-8heterocycloalkylalkyl, substituted C6-8aryl, substituted C5-8heteroaryl, substituted C7-10arylalkyl, substituted C5-10heteroarylalkyl; R b selected from substituted or unsubstituted Ci-6alkyl, substituted or unsubstituted Ci-6heteroalkyl, the substituent can be halogen, hydroxyl, cyano, Ci-8alkyl, Ci-8heteroalkyl, C3-8 cycloalkyl, C3-8 heterocycloalkyl, C3-8 cycloalkylalkyl, C3-8 heterocycloalkylalkyl, C6-8 aryl, C5-8 heteroaryl, C7-10 arylalkyl, C5-10 heteroarylalkyl, substituted C3-8 cycloalkyl, substituted C3-8 heterocycloalkyl, substituted C3-8 cycloalkylalkyl, substituted C3-8 heterocycloalkylalkyl, substituted C6-8 aryl, substituted C5-8 heteroaryl, substituted C7-10 arylalkyl, substituted C5-10 heteroarylalkyl or R e selected from substituted or unsubstituted Ci-6alkyl, substituted or unsubstituted Ci-6heteroalkyl, the substituent can be halogen, hydroxyl, cyano, Ci-8alkyl, Ci-8heteroalkyl, C3-8cycloalkyl, C3-8heterocycloalkyl, C3-8cycloalkylalkyl, C3-8heterocycloalkylalkyl, C6-8aryl, C5-8heteroaryl, C7-10arylalkyl, C5-10heteroarylalkyl, substituted C3-8cycloalkyl, substituted C3-8heterocycloalkyl, substituted C3-8cycloalkylalkyl, substituted C3-8heterocycloalkylalkyl, substituted C6-8aryl, substituted C5-8heteroaryl, substituted C7-10arylalkyl, substituted C5-10heteroarylalkyl; L1, L2, L3are each independently selected from the group consisting of unsubstituted or substituted -(CH2) 1a -(CH2) m -(CH2) m NH-; wherein m is selected from 1, 2, 3, 4 or 5; R 1a is selected from the group consisting of NH2, C1-C4 alkyl or -NH-Boc.

2. The β-lactamase inhibitor according to claim 1, characterized in that, R2is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, oxolanyl, oxepanyl, aryl, heteroaryl, -(CH2) n R f ; preferably, R3is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, oxolanyl, oxepanyl, aryl, heteroaryl, -CH2-R f , -CH2-CH2-R f , -(CH2)3-R f or R f is selected from the group consisting of isopropyl, isobutyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, oxolanyl, oxepanyl, aryl, heteroaryl, hydroxy, alkenyl, alkynyl, cyano; preferably, R2is selected from the group consisting of methyl, ethyl, propyl, n-butyl, pentyl, -CH2-R f , -CH2-CH2-R f , -(CH2)3-R f ; preferably, R3is selected from the group consisting of methyl, ethyl, propyl, n-butyl, pentyl, -CH2-R f , -CH2-CH2-R f , -(CH2)3-R f or wherein n is selected from 1, 2, 3, 4, 5 or 6; preferably, R2is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl; preferably, R3is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl or 3. The β-lactamase inhibitor according to claim 1, characterized in that, R4is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, oxepanyl, oxanyl, aryl, heteroaryl, -(CH2) n -R f , or R f is selected from the group consisting of isopropyl, isobutyl, t-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, oxepanyl, oxanyl, aryl, heteroaryl, hydroxy, alkenyl, alkynyl, cyano; preferably, R4is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, pentyl, -CH2-R f , -CH2-CH2-R f、 -(CH2)3-R f or wherein n is selected from 1, 2, 3, 4, 5 or 6; preferably, R4is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, pentyl or preferably, R a , R c , R d are each independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, pentyl; preferably, R a is selected from ethyl; preferably, R c , R d are each independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl; preferably, R b is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, pentyl or preferably, R e is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl; preferably, R b is selected from the group consisting of methyl or 4. The β-lactamase inhibitor according to claim 1, characterized in that, L1, L2, and L3 are each independently selected from those that are unsubstituted or have been replaced by one or more R... 1a Substituted -(CH2) m -or-(CH2) m NH-; where m is selected from 1, 2, or 3; R 1a Selected from NH2, methyl, ethyl, propyl, isopropyl, or -NH-Boc; preferably, L1, L2, and L3 are each independently selected from -CH2-, More preferably, L1 is selected from More preferably, L2 is selected from -CH2-, More preferably, L3 is selected from 5. A β-lactamase inhibitor having the following formula (II) or a pharmaceutically acceptable salt thereof: ###0002### (II) wherein R2, R3, R4, L2, R c The definitions can be as in any of claims 1 to 4.

6. A β-lactamase inhibitor having the following formula (III) or a pharmaceutically acceptable salt thereof: wherein R2, R3, R4, L2, R c are as defined in any one of claims 1 to 4; preferably R3is selected from R2, R4, R k each independently selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, pentyl; preferably, R2is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl; R4is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl; R k is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl.

7. A β-lactamase inhibitor or a pharmaceutically acceptable salt thereof as shown in the following specific structures:

8. A pharmaceutical composition, characterized by, A pharmaceutical composition comprising the beta-lactamase inhibitor according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or an isomer or deuterated form thereof, and a pharmaceutically acceptable carrier; preferably, the pharmaceutical composition further comprises an antibiotic; more preferably, the antibiotic is a beta-lactam antibiotic, preferably a penicillin, a cephalosporin, a cephamycin, and a carbapenem antibiotic.

9. Use of the beta-lactamase inhibitor according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8, for the manufacture of a beta-lactamase inhibitor.

10. Use of the beta-lactamase inhibitor according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8, for the manufacture of a medicament for the treatment of a disease associated with a bacterial infection; preferably, the bacteria is a beta-lactamase producing bacteria, more preferably a bacteria of the Enterobacter, Citrobacter, Providencia, Serratia, or Morganella genus.

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