Beta-lactamase inhibitor and application thereof

Abstract

The invention discloses a beta-lactamase inhibitor and application thereof, the beta-lactamase inhibitor has a structure as shown in the following formula (I) or a pharmaceutically acceptable salt or an isomer or a deuterated substance of the beta-lactamase inhibitor, and the beta-lactamase inhibitor can increase the combination of a compound fat-soluble group and an amide and a sulfonic group in an avibactam structure and increase the fat solubility of the structure; the active metabolite avibactam can be quickly and completely released under the action of the biological enzyme, so that the oral bioavailability of the avibactam is effectively improved, the avibactam can be orally administrated, and the problem that the avibactam cannot be orally administrated is solved. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry, and specifically relates to a beta-lactamase inhibitor and a pharmaceutical composition thereof and use thereof in treating bacterial infection. Background Art

[0002] The rapid development of antibiotics is of great significance in the history of modern medicine. Antibiotics can effectively treat infectious diseases caused by bacteria, which has brought great convenience to clinical practice. However, the irrational use and even abuse of antibiotics has accelerated the development of bacterial resistance and brought great challenges to human health. As one of the antibiotics with the longest history, the widest range of use, and the most commonly used in clinical practice, the problem of drug resistance of β-lactam antibiotics has also arisen and is becoming increasingly serious.

[0003] β-lactamase produced by bacteria can hydrolyze antibiotics with β-lactam ring structure and inactivate them. This is the most common mechanism of bacterial resistance to β-lactam antibiotics. β-lactamase can be divided into two major categories based on the difference in amino acid sequence in the molecular structure: one is A, C, D type with serine as the active site, and the other is A, C, D type with metal ions (especially Zn 2+ ions) as the active site of metalloenzymes.

[0004] In 1976, the first β-lactamase inhibitor (clavulanic acid) was discovered and later commercialized as an oral / intravenous drug in combination with a β-lactam antibiotic (amoxicillin). β-lactamase inhibitors, while lacking significant antibiotic activity themselves, protect β-lactam antibiotics from being inactivated by enzymes (β-lactamases) produced by microorganisms. β-lactamase inhibitor / antibiotic combinations have become a standard part of treatment since the 1980s.

[0005] In the mid-1990s, a new and important non-β-lactam β-lactamase inhibitor, avibactam, was discovered. It belongs to the diazabicyclic compounds (DBOs), a class of reversible β-lactamase inhibitors. Compared with the classical β-lactamase inhibitors (clavulanic acid, sulbactam, tazobactam), it has the characteristics of long-acting and reversible covalent binding to the enzyme, and will not induce the production of beta-lactamase. However, because avibactam contains sulfonic acid and carboxamide structures in its structure, it has high water solubility and low lipid solubility, resulting in poor tissue permeability, and it cannot be taken orally and can only be used for intravenous injection, which also limits the clinical use of avibactam.

[0006]

[0007] Chinese invention patent CN110662746 discloses a 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropionate derivative and related compounds as orally administered prodrugs of β-lactamase inhibitors for treating bacterial infections. The structural design of the invention improves the oral bioavailability of avibactam. In the oral bioavailability experiment 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%. Likewise, the oral bioavailability (%F) of compounds (36), (37), (42), (53), (57), (58) and (59) was greater than 10%. In these studies, 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%.

[0008] In view of this, providing more structural designs to further improve the oral bioavailability of avibactam and enable oral administration has important clinical value. Summary of the invention

[0009] The object of the present invention is to provide a β-lactamase inhibitor and use thereof. The β-lactamase inhibitor provided by the present invention is a prodrug of avibactam and can significantly improve the oral bioavailability of avibactam.

[0010] The β-lactamase inhibitor of the present invention has a structure as shown in the following formula (I) or a pharmaceutically acceptable salt thereof or an isomer or deuterated product thereof:

[0011]

[0012] Where: R1 is selected from

[0013] R2 and R3 are each independently selected from halogen, hydroxyl, cyano, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C1-8 heteroalkyl, and the substituents may be halogen, hydroxyl, cyano, C1-8 alkyl, C1-8 heteroalkyl, C3-8 cycloalkyl, C3-8 heterocycloalkyl, C3-8 cycloalkylalkyl, C3-8 heterocycloalkylalkylalkyl, C6-8 aryl, C5-8 heteroaryl, C7-10 arylalkyl, C5-10 heteroarylalkyl, substituted C3-8 cycloalkyl, substituted C3-8 heterocycloalkyl, substituted C3-8 cycloalkylalkylalkyl, substituted C3-8 heterocycloalkylalkylalkyl, substituted C6-8 aryl, substituted C5-8 heteroaryl, substituted C7-10 arylalkyl, substituted C5-10 heteroarylalkyl or

[0014] R4 is selected from halogen, hydroxyl, cyano, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C1-8 heteroalkyl, and the substituent can be halogen, hydroxyl, cyano, C1-8 alkyl, C1-8 heteroalkyl, C3-8 cycloalkyl, C3-8 heterocycloalkyl, C3-8 cycloalkylalkyl, C3-8 heterocycloalkylalkylalkyl, C6-8 aryl, C5-8 heteroaryl, C7-10 arylalkyl, C5-10 heteroarylalkyl, substituted C3-8 cycloalkyl, substituted C3-8 heterocycloalkyl, substituted C3-8 cycloalkylalkylalkyl, substituted C3-8 heterocycloalkylalkylalkyl, substituted C6-8 aryl, substituted C5-8 heteroaryl, substituted C7-10 arylalkyl, substituted C5-10 heteroarylalkyl or

[0015] R a , R c , R d Each independently selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, the substituent may be halogen, hydroxyl, cyano, C1-8 alkyl, C1-8 heteroalkyl, C3-8 cycloalkyl, C3-8 heterocycloalkyl, C3-8 cycloalkylalkyl, C3-8 heterocycloalkylalkylalkyl, C6-8 aryl, C5-8 heteroaryl, C7-10 arylalkyl, C5-10 heteroarylalkyl, substituted C3-8 cycloalkyl, substituted C3-8 heterocycloalkyl, substituted C3-8 cycloalkylalkylalkyl, substituted C3-8 heterocycloalkylalkylalkyl, substituted C6-8 aryl, substituted C5-8 heteroaryl, substituted C7-10 arylalkyl, substituted C5-10 heteroarylalkyl;

[0016] R bis selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, the substituents may be halogen, hydroxyl, cyano, C1-8 alkyl, C1-8 heteroalkyl, C3-8 cycloalkyl, C3-8 heterocycloalkyl, C3-8 cycloalkylalkyl, C3-8 heterocycloalkylalkylalkyl, 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 heterocycloalkylalkylalkyl, substituted C6-8 aryl, substituted C5-8 heteroaryl, substituted C7-10 arylalkyl, substituted C5-10 heteroarylalkyl or R e is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, the substituents may be halogen, hydroxyl, cyano, C1-8 alkyl, C1-8 heteroalkyl, C3-8 cycloalkyl, C3-8 heterocycloalkyl, C3-8 cycloalkylalkyl, C3-8 heterocycloalkylalkylalkyl, 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 heterocycloalkylalkylalkyl, substituted C6-8 aryl, substituted C5-8 heteroaryl, substituted C7-10 arylalkyl, substituted C5-10 heteroarylalkyl;

[0017] L1, L2, L3 are each independently selected from unsubstituted or substituted with one or more R 1a Substituted -(CH2) m -or-(CH2) m NH-; wherein m is selected from 1, 2, 3, 4 or 5; R 1a Selected from NH2, C1-C4 alkyl or -NH-Boc.

[0018] In some specific examples, R2 is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclopropyl, oxetanyl, oxacyclopentyl, oxacyclohexyl, aryl, heteroaryl, -(CH2) n -R f R3 is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclopropyl, oxetanyl, oxacyclopentyl, oxacyclohexyl, aryl, heteroaryl, -(CH2) n -R f or R fis selected from isopropyl, isobutyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetanyl, oxolanyl, oxetanyl, aryl, heteroaryl, hydroxy, alkenyl, alkynyl, cyano; wherein n is selected from 1, 2, 3, 4, 5 or 6.

[0019] In some specific examples, R2 is selected from methyl, ethyl, propyl, isopropyl, n-butyl, pentyl, -CH2-R f 、-CH2-CH2-R f 、-(CH2)3-R f ; R3 is selected from methyl, ethyl, propyl, isopropyl, n-butyl, pentyl, -CH2-R f 、-CH2-CH2-R f 、-(CH2)3-R f or

[0020] In some specific examples, R2 is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl; In some specific examples, R3 is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl or

[0021] In some specific examples, R4 is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclopropyl, oxetanyl, oxacyclopentyl, oxacyclohexyl, aryl, heteroaryl, -(CH2) n -R f or R f is selected from isopropyl, isobutyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetanyl, oxolanyl, oxetanyl, aryl, heteroaryl, hydroxy, alkenyl, alkynyl, cyano; wherein n is selected from 1, 2, 3, 4, 5 or 6.

[0022] In some specific examples, R4 is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, -CH2-R f 、-CH2-CH2-R f、 -(CH2)3-R f or

[0023] In some specific examples, R4 is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl or

[0024] In some specific examples, R a , R c , R d Each is independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl; in a specific example, R a In some specific examples, R c , R d Each is independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl and sec-butyl.

[0025] In some specific examples, R b is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl or R e is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl; in some specific examples, R b Selected from methyl or

[0026] In some specific examples, L1, L2, and L3 are each independently selected from unsubstituted or substituted with one or more R 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.

[0027] In some specific examples, L1, L2, and L3 are each independently selected from -CH2-,

[0028] In some specific examples, L1 is selected from

[0029] In some specific examples, L2 is selected from -CH2-,

[0030] In some specific examples, L3 is selected from

[0031] In some specific examples, the β-lactamase inhibitor of the present invention has a structure represented by the following formula (II) or a pharmaceutically acceptable salt thereof:

[0032]

[0033] Among them, R2, R3, R4, L2, R c The definition of can be as mentioned above.

[0034] A β-lactamase inhibitor having a structure represented by the following formula (III) or a pharmaceutically acceptable salt thereof:

[0035]

[0036] Among them, R2, R3, R4, L2, R c The definition is as described above; preferably, R3 is selected from R2, R4, R k Each is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl; preferably, R2 is selected from methyl, ethyl, n-propyl, isopropyl; R4 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl; R k Selected from methyl, ethyl, n-propyl, isopropyl.

[0037] In some specific examples, the present invention also provides a β-lactamase inhibitor or a pharmaceutically acceptable salt thereof as shown in the following specific structure:

[0038]

[0039]

[0040]

[0041] The present invention also provides a pharmaceutical composition comprising the β-lactamase inhibitor of the present invention or a pharmaceutically acceptable salt thereof or an isomer or deuterated product thereof, and a pharmaceutically acceptable carrier.

[0042] The pharmaceutical composition of the present invention further comprises an antibiotic; further, the antibiotic is a β-lactam antibiotic, such as penicillins, cephalosporins, cephamycins and carbapenem antibiotics.

[0043] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the active ingredients of the present invention and with each other without significantly reducing the efficacy of the active ingredients. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, 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 lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0044] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.

[0045] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. The compounds of the present invention can be administered alone or in combination with other therapeutic drugs (such as antibacterial drugs). When using the compounds of the present invention or pharmaceutical compositions, a safe and effective amount of the compounds of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health status, which are all within the skill range of skilled physicians.

[0046] The present invention also provides use of the β-lactamase inhibitor of the present invention or its pharmaceutically acceptable salt or isomer or deuterated product thereof or the composition of the present invention in the preparation of a β-lactamase inhibitor.

[0047] The present invention also provides the use of the β-lactamase inhibitor of the present invention or its pharmaceutically acceptable salt or isomer or deuterated product or the composition of the present invention in the preparation of drugs for treating diseases related to bacterial infection.

[0048] The bacteria described in the present invention are bacteria that can produce β-lactamase, such as bacteria of the genus Enterobacter, Citrobacter, Prufidenella, Serratia marcescens and Morganella.

[0049] Beneficial effects of the present invention: The present invention combines the amide and sulfonic acid groups in the structure of avibactam with a group that can increase the fat solubility of the compound, thereby increasing the fat solubility of the structure, and can quickly and completely release the active metabolite avibactam through the action of biological enzymes, and the compound of the present invention shows that the oral bioavailability of avibactam in rats and beagles is more than 95%, so that it can be orally administered, and the effect of the same dose of avibactam injection can be achieved without additionally increasing the dosage, thus solving the problem that avibactam cannot be orally administered. It provides patients with a more broad-spectrum and safe oral β-lactamase inhibitor, effectively making up for the shortcomings of the narrow antibacterial spectrum of existing oral β-lactamase inhibitors, and can effectively avoid the problem of antibiotic resistance when used in combination with antibiotics, thereby improving the antibacterial activity of antibiotics. DETAILED DESCRIPTION

[0050] The following examples are provided for better understanding of the present invention, but are not intended to limit the present invention. The experimental methods in the following examples are conventional methods unless otherwise specified. The experimental materials used in the following examples are purchased from conventional biochemical reagent stores unless otherwise specified.

[0051] Example 1: Synthesis of Compound 1

[0052] 3-(((((2S,5R)-2-((ethoxycarbonyl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoic acid ethyl ester

[0053]

[0054] Step 1: Synthesis of compound 1b

[0055] At room temperature, compound 1a (1.6 g, 5.81 mmol) was dissolved in dichloromethane (16 mL). 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 argon was replaced three times. The reaction solution continued to react for 2 hours at room temperature. LCMS monitored the completion of the reaction, and water (100 mL) was added to the reaction solution to quench the reaction, and 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 separated and purified by flash chromatography (petroleum ether: ethyl acetate (V / V=1 / 1) to obtain 450 mg of compound 1b with a yield of 22.3%. 1H 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).

[0056] Step 2: Synthesis of compound 1c

[0057] Under room temperature, compound 1b (450 mg, 1.3 mmol) was dissolved in ethyl acetate (5 mL), and then 10% palladium on carbon (140 mg) was added thereto. The resulting mixture was replaced with hydrogen three times, and the reaction solution was continued to react at room temperature for 1.5 hours. LCMS monitored the completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated to obtain 290 mg of compound 1c, with a yield of 86.8%. LCMS (ESI): [M+H] + =258.2.

[0058] Step 3: Synthesis of compound 1e

[0059] At room temperature, sulfonyl chloride (41.5 g, 307.8 mmol) was dissolved in ether (300 mL) and cooled to -78 °C in a nitrogen environment; 1d (30.0 g, 205.2 mmol) and pyridine (24.3 g, 307.8 mmol) in ether (30 mL) were added dropwise, and after the addition was complete, the reaction solution was gradually heated to room temperature and reacted at room temperature for 4 hours. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated to dryness to obtain 40.0 g of compound 1e with a yield of 79.7%. 1 H NMR (400MHz, CDCl3) δ4.51 (s, 2H), 4.23-4.17 (m, 2H), 1.32-1.25 (m, 9H).

[0060] Step 4: Synthesis of compound 1

[0061] At room temperature, compound 1c (290 mg, 1.13 mmol, 1.0 equivalent) was dissolved in a mixed solution of tetrahydrofuran (6 mL / ) and N,N-dimethylpropylene urea (2.4 mL), cooled to -78 °C in a nitrogen environment, and sodium bis(trimethylsilyl)amide (0.6 mL, 2M / tetrahydrofuran solution, 1.24 mmol) was added dropwise to the reaction solution and maintained at -78 °C after 10 minutes. The reaction solution was reacted at -78 °C for 10 minutes, and then compound 1e (552 mg, 2.25 mmol) was added. After 10 minutes, the mixture was warmed to room temperature and reacted at room temperature for 2 hours. After the reaction was completed by LCMS monitoring, the reaction solution was poured into water (100 mL) and extracted with ethyl acetate (50 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 reverse phase preparation (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 (400MHz, CDCl3) δ8.50(s,1H),4.71(d,J=9.0Hz,1H),4.61(d,J=9.0Hz,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=12.4Hz,1H),2.93(d,J=12.4Hz,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).

[0062] Example 2: Synthesis of Compound 2

[0063] ((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

[0064]

[0065] Step 1: Synthesis of compound 2a

[0066] At room temperature, compound 1a (8.00 g, 29.06 mmol) was dissolved in acetonitrile (80 mL) solution, and then potassium carbonate (500 mg, 3.63 mmol) and formaldehyde aqueous solution (30%, 40 mL) were added thereto in sequence. The reaction solution was reacted at room temperature overnight. After the reaction was completed, the reaction solution was poured into water (100 mL), extracted with ethyl acetate (100 mL×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(400MHz, Methanol-d4)δ7.47-7.45(m,2H),7.40-7.33(m,3H),5.00(d,J=1 1.2Hz,1H),4.93(d,J=11.3Hz,1H),4.77(d,J=10.2Hz,1H),4.65(d,J=10.2Hz,1 H),3.84(d,J=7.4Hz,1H),3.54(s,1H),3.03-2.99(m,1H),2.89(d,J=11.9Hz,1 H),2.26-2.22(m,1H),2.01-1.94(m,1H),1.91-1.82(m,1H),1.72-1.62(m,1H).

[0067] Step 2: Synthesis of compound 2b

[0068] At room temperature, compound 2a (2.0 g, 6.56 mmol) was added to dry dichloromethane (20 mL), and then pyridine (778 mg, 9.84 mmol) and methyl 4-chloro-4-oxobutyrate (1.48 g, 9.84 mmol) were added thereto in sequence. The reaction solution was reacted 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 the mixture was extracted three times with ethyl acetate (100 mL×3). The organic phases were combined, washed with saturated sodium chloride aqueous 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.

[0069] Step 3: Synthesis of compound 2c

[0070] At room temperature, compound 2b (800 mg, 1.91 mmol) was dissolved in ethyl acetate (8 mL), and then 10% palladium carbon (200 mg) was added thereto, and the mixture was replaced with hydrogen three times. The reaction solution continued to react for 1.5 hours under a hydrogen atmosphere at room temperature. LCMS monitored the completion of the reaction, the reaction solution 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(400MHz,DMSO-d6)δ9.79(s,1H),9.07-8.77(m,1H),5.23-5.06(m,2H),4.13-3.94(m,1H),3.59(s,3H),3.0 9-2.94(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).

[0071] Step 4: Synthesis of compound 2

[0072] At room temperature, compound 2c (550 mg, 1.67 mmol) was added to a mixed solution of dry tetrahydrofuran (11 mL) and N,N-dimethylpropylene urea (4.4 mL). Sodium bis(trimethylsilyl)amide (0.92 mL, 2M / tetrahydrofuran solution, 1.84 mmol) was added dropwise to the reaction solution at -78 °C under a 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 slowly rose to room temperature and the reaction was carried out at room temperature for 2 hours. After the reaction was completed by LCMS monitoring, the reaction solution was poured into water (100 mL) and extracted with ethyl acetate (50 mL×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 / water, acetonitrile) to obtain 21.86 mg of compound 2 with a yield of 2.43%. LCMS(ESI):[M+Na] + =560.1. 1H NMR (400MHz, CDCl3) δ7.60 (t, J = 7.2Hz, 1H), 5.42-5.35 (m, 1H), 5.31-5.24 (m, 1H), 4 .80(d,J=8.8Hz,1H),4.80(d,J=8.8Hz,1H),4.23-4.13(m,3H),4.00(d,J=7.2Hz,1H ),3.70(d,J=9.6Hz,3H),3.20(d,J=12.0Hz,1H),2.80(d,J=12.2Hz,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).

[0073] Example 3: Synthesis of Compound 3

[0074] 3-(((((2S,5R)-2-((((isobutyryloxy)methoxy)carbonyl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoic acid ethyl ester

[0075]

[0076] Step 1: Synthesis of compound 3b

[0077] At room temperature, compound 3a (2.0 g, 15.5 mmol) was added to dichloromethane (20 mL), and triethylamine (1.56 g, 15.5 mmol) and ethanethiol (976 mg, 15.5 mmol) were added thereto in sequence. The reaction solution was continued to react at room temperature for 16 hours. After the reaction was completed by LCMS monitoring, 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 with a yield of 42.0%. 1 H NMR (400MHz, DMSO-d6) δ5.96 (s, 2H), 2.91 (q, J = 7.2Hz, 2H), 1.27 (t, J = 7.2Hz, 3H).

[0078] Step 2: Synthesis of compound 3c

[0079] Compound 3b (1.0 g, 6.49 mmol) was dissolved in isobutyric acid (2.86 g, 32.5 mmol) at room temperature, and then N,N-diisopropylethylamine (2.51 g, 19.5 mmol) was added at room temperature. The reaction solution was continued to react at 60°C for 48 hours. LCMS monitored the completion of the reaction, and water (50 mL) was added to the reaction solution to quench the reaction, and extracted three times with ethyl acetate (100 mL×3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 1.0 g of compound 3c with a yield of 75.2%. 1 H NMR (400MHz, DMSO-d6) δ5.78 (s, 2H), 2.91 (q, J = 7.2Hz, 2H), 2.65-2.56 (m, 1H), 1.25 (t, J = 7.2Hz, 3H), 1.10 (d, J = 7.2Hz, 6H).

[0080] Step 3: Synthesis of compound 3d

[0081] Compound 3c (100 mg, 0.49 mmol) was added to sulfonyl chloride (79 mg, 0.58 mmol) at 0°C. The reaction solution was continued to react for 1 hour at room temperature. LCMS monitored the completion of the reaction, and the reaction solution was concentrated to dryness to obtain 1.4 g of compound 3d with a yield of 78.4%. 1 HNMR (400MHz, CDCl3) δ5.76 (s, 2H), 2.63-2.52 (m, 1H), 1.18-1.11 (m, 6H).

[0082] Step 4: Synthesis of compound 3e

[0083] At room temperature, compound 1a (2,0 g, 7.27 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to -78 ° C in a nitrogen environment, and 10 minutes later, lithium bis(trimethylsilyl)amide (15 mL, 1M / tetrahydrofuran solution, 14.5 mmol) was added dropwise to the reaction solution and maintained at -78 ° C. The reaction solution was reacted at -78 ° C for 30 minutes, and then compound 3d (1.4 g, 8.00 mmol) was added, and the temperature was slowly raised to room temperature. The reaction was reacted at room temperature for 2 hours. After the reaction was completed by LCMS monitoring, the reaction solution was poured into water (100 mL) and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed twice with saturated brine, 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 obtain 450 mg of compound 3e with a yield of 14.7%. LCMS (ESI): [M+H] + =420.1.

[0084] Step 5: Synthesis of compound 3f

[0085] At room temperature, compound 3e (200 mg, 0.48 mmol) was dissolved in ethyl acetate (4 mL), 10% palladium on carbon (20 mg) was added, the mixed solution was replaced with hydrogen three times, and the reaction was stirred at room temperature in a hydrogen atmosphere for 1.5 h. After the reaction was completed, 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(400MHz, CDCl3)δ8.83(s,1H),5.75-5.74(m,2H),3.94-3.83(m,1H),3.74(s,1H),3.20(d ,J=12.0Hz,1H),2.72(d,J=11.6Hz,1H),2.57-2.50(m,1H),2.36(dd,J=15.2,6.8Hz,1H),2.15 -2.06(m,1H),1.70-1.62(m,2H),1.13(d,J=7.2Hz,6H).

[0086] Step 6: Synthesis of compound 3

[0087] At room temperature, compound 3f (120 mg, 0.364 mmol) was dissolved in a mixed solution of tetrahydrofuran (2 mL) and N,N-dimethylpropylene urea (0.8 mL), cooled to -78 ° C in a nitrogen environment, and sodium bis(trimethylsilyl)amide (218 μL, 2M / tetrahydrofuran solution, 1.44 mmol) was added dropwise to the reaction solution and maintained at -78 ° C. The reaction solution was reacted at -78 ° C for 10 minutes, and then compound 1e (178 mg, 0.73 mmol) was added and warmed to room temperature after 10 minutes, and reacted at room temperature for 2 hours. After the reaction was completed by LCMS monitoring, the reaction solution was poured into water (100 mL) and extracted with ethyl acetate (50 mL×3), the organic phases were combined, and concentrated under reduced pressure to obtain a crude product, which was purified by reverse phase preparation (C18, 10 mmol / L formic acid / water, acetonitrile) to obtain 25 mg of compound 3 with a yield of 12.7%. LCMS(ESI):[M+H] + =538.3. 1H NMR (400MHz, CDCl3) δ8.66 (s, 1H), 5.83 (s, 2H), 4.70 (d, J = 8.8Hz, 1H), 4.60 (d, J = 9.2Hz, 1H), 4.21-4.18(m,3H),4.10(d,J=7.2Hz,1H),3.37(d,J=12.0Hz,1H),2.91(d,J=12.0Hz,1H),2.65 -2.61(m,1H),2.44(dd,J=15.6,7.2Hz,1H),2.21-2.02(m,1H),2.04-1.80(m,2H),1.30-1.24(m,9H),1.20(d,J=7.2Hz,6H).

[0088] Example 4: Synthesis of Compound 4

[0089] ((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

[0090]

[0091] Step 1: Synthesis of compound 4a

[0092] At room temperature, compound 2a (1.0 g, 3.28 mmol) was dissolved in dichloromethane (10 mL), 5-chloro-5-oxopentanoic acid methyl ester (1.07 g, 6.56 mmol) and pyridine (778 mg, 9.84 mmol) were added thereto, and the mixture was replaced with argon three times. The reaction solution was continued to react for 3 hours at room temperature. LCMS monitored the completion of the reaction, water (100 mL) was added to the reaction solution to quench the reaction, 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 the filtrate was concentrated to dryness. The 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.

[0093] Step 2: Synthesis of compound 4b

[0094] Under room temperature, compound 4a (800 mg, 1.85 mmol) was dissolved in ethyl acetate (8 mL), and then 10% palladium carbon (240 mg) was added thereto. The resulting mixture was replaced with hydrogen three times, and the reaction solution was continued to react at room temperature in a hydrogen atmosphere for 1.5 hours. LCMS monitored the completion of the reaction, the reaction solution 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.

[0095] Step 3: Synthesis of compound 4

[0096] At room temperature, compound 4b (600 mg, 1.75 mmol) was dissolved in a mixed solution of tetrahydrofuran (12 mL) and N,N-dimethylpropylene urea (4.8 mL), and the temperature was lowered to -78 ° C in a nitrogen environment. After 10 minutes, sodium bis(trimethylsilyl)amide (1.0 mL, 2M / tetrahydrofuran solution, 1.93 mmol) was added dropwise to the reaction solution and maintained at -78 ° C. The reaction solution was reacted at -78 ° C for 10 minutes, and then compound 1e (856 mg, 3.5 mmol) was added. After 10 minutes, the temperature was raised to room temperature and the reaction was carried out at room temperature for 2 hours. After the reaction was completed by LCMS monitoring, the reaction solution was poured into water (100 mL) and extracted with ethyl acetate (50 mL×3). The organic phases were combined and concentrated to dryness under reduced pressure, and the residue was purified by reverse phase preparation (C18, 10 mmol / L formic acid / 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(400MHz, CDCl3)δ7.57(t,J=7.2Hz,1H),5.38-5.25(m,2H),4.71(d,J=9.2H z,1H),4.60(d,J=9.2Hz,1H),4.23-4.14(m,3H),4.03(d,J=7.2Hz,1H),3.68(d ,J=3.2Hz,3H),3.29(d,J=12.0Hz,1H),2.85(d,J=12.0Hz,1H),2.48-2.34(m,5 H),2.20-2.12(m,1H),2.01-1.90(m,3H),1.88-1.80(m,1H),1.30-1.22(m,9H).

[0097] Example 5: Synthesis of Compound 5

[0098] 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-dimethylsuccinate

[0099]

[0100] Step 1: Synthesis of compound 5b

[0101] At room temperature, compound 5a (3.5 g, 21.85 mmol, 1.0 equivalent) was dissolved in dichloromethane (35 mL) and N-N-dimethylformamide (0.1 mL), and oxalyl chloride (4.16 g, 32.78 mmol) was slowly added thereto in an ice bath, and the resulting solution was replaced with argon three times. The reaction solution was continued to react at room temperature for 3 hours. After the reaction was completed, the reaction solution was directly concentrated to obtain 3.5 g of compound 5b, which was directly used in the next step without purification.

[0102] Step 2: Synthesis of compound 5c

[0103] At room temperature, compound 5b (2.2 g, 12.32 mmol) was dissolved in dichloromethane (22 mL), compound 2a (1.88 g, 6.16 mmol) and pyridine (1.46 g, 18.48 mmol) were added thereto, and the resulting solution was replaced with argon three times. The reaction solution was continued to react for 3 hours at room temperature. LCMS monitored the completion of the reaction, water (100 mL) was added to the reaction solution to quench the reaction, and it 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 the filtrate was concentrated to dryness. The crude product was separated and purified by flash chromatography (petroleum ether: ethyl acetate (V / V=1 / 1) to obtain 2.2 g of compound 5c with a yield of 79.7%. LCMS (ESI): [M+H] + =448.2. 1 H NMR (400MHz, CDCl3) δ7.64(t,J=7.2Hz,1H),7.45-7.33(m,5H),5.32-5.28(m,2H),5.26-5.19(m,1H),5.06(d,J=

[0104] 11.2Hz,1H),4.91(d,J=11.2Hz,1H),3.91(d,J=7.2Hz,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=1.6Hz,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).

[0105] Step 3: Synthesis of compound 5d

[0106] Under room temperature, compound 5c (1.0 g, 2.23 mmol, 1.0 equivalent) was dissolved in ethyl acetate (10 mL), and then 10% palladium carbon (300 mg) was added thereto. The resulting mixture was replaced with hydrogen three times, and the reaction solution was continued to react at room temperature in a hydrogen atmosphere for 1.5 hours. LCMS monitored the completion of the reaction, the reaction solution 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.

[0107] Step 5: Synthesis of compound 5

[0108] At room temperature, compound 5d (700 mg, 1.96 mmol) was dissolved in a mixed solution of tetrahydrofuran (14 mL) and N, N-dimethylpropylene urea (5.6 mL), and the temperature was lowered to -78 ° C in a nitrogen environment. After 10 minutes, sodium bis (trimethylsilyl) amide (1.0 mL, 2M / tetrahydrofuran solution, 2.16 mmol) was added dropwise to the reaction solution and maintained at -78 ° C. The reaction solution was reacted at -78 ° C for 10 minutes, and then compound 1e (962 mg, 3.92 mmol) was added. After 10 minutes, the temperature was raised to room temperature and the reaction was carried out at room temperature for 2 hours. After the reaction was completed by LCMS monitoring, the reaction solution was poured into water (100 mL) and extracted with ethyl acetate (50 mL × 3), and the organic phases were combined and concentrated to dryness under reduced pressure. The residue was purified by reverse phase preparation (C18, 10 mmol / L formic acid / water, acetonitrile) to obtain 71.4 mg of real compound 5 with a yield of 6.44%. LCMS(ESI):[M+H] + =566.3. 1HNMR (400MHz, CDCl3) δ7.56 (t, J = 7.2Hz, 1H), 5.38-5.28 (m, 1H), 5.28-5.21 (m, 1H), 4. 71(d,J=9.2Hz,1H),4.60(d,J=9.2Hz,1H),4.25-4.10(m,3H),4.01(d,J=7.2Hz,1H),3. 69(s,3H),3.28(d,J=12.0Hz,1H),2.91(d,J=12.0Hz,1H),2.66-2.54(m,2H),2.50-2.3 9(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).

[0109] Example 6: Synthesis of Compound 6

[0110] Preparation of ethyl 3-(((((2S,5R)-2-((((acetoxymethoxy)carbonyl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate

[0111]

[0112] The synthesis method is the same as in Example 3. LCMS (ESI) [M+H] + =510.3. 1 H NMR (400MHz, CDCl3) δ8.66(s,1H),5.82(s,2H),4.70(d,J=9.2Hz,1H),4.60(d,J=9.2Hz,1H),4.25-4.14(m,3H),4.09(d,J=9.6Hz,1H),3.37(d,J=1 1.6Hz,1H),2.90(d,J=12.4Hz,1H),2.51-2.39(m,1H),2.20(d,J=6.0Hz,1 H),2.14(s,3H),2.01-1.95(m,1H),1.89-1.86(m,1H),1.29-1.26(m,9H).

[0113] Example 7: Synthesis of Compound 7

[0114] 2,2-Dimethyl-3-(((((2S,5R)-7-oxo-2-((((1-(pivaloyloxy)ethoxy)carbonyl)carbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)propanoic acid ethyl ester

[0115]

[0116] The synthesis method is the same as in Example 3. LCMS (ESI): [M+H] + =566.3. 1 H NMR (400MHz, CDCl3) δ8.53 (s, 1H), 6.86-6.83 (m, 1H), 4.70 (d, J = 9.2Hz, 1H), 4 .60(d,J=8.8Hz,1H),4.27-4.13(m,3H),4.09(d,J=11.2Hz,1H),3.37(d,J=12 .0Hz,1H),2.93(t,J=11.6Hz,1H),2.44(d,J=15.2Hz,1H),2.18(d,J=12.0Hz, 1H), 2.04-1.79 (m, 2H), 1.54 (d, J = 5.6Hz, 3H), 1.33-1.25 (m, 9H), 1.21 (s, 9H).

[0117] Example 8: Synthesis of Compound 8

[0118] Preparation of ethyl 3-(2S,5R)-2-(methoxycarbonyl)alanyl)oxy)methyl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy(sulfonyl)oxy)-2,2-dimethylpropanoate

[0119]

[0120] Step 1: Synthesis of compound 8b

[0121] At room temperature, compound 8a (25.00 g, 280.90 mmol) was dissolved in a mixed solution of tetrahydrofuran (5 mL) and water (5 mL), and then sodium hydroxide (22.47 g, 561.80 mmol) and methyl chloroformate (29.20 g, 309.00 mmol) were added in sequence. 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 molar hydrochloric acid aqueous solution, and extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness, and 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.

[0122] Step 2: Synthesis of compound 8c

[0123] At room temperature, compound 8b (4.50 g, 30.59 mmol) was dissolved in tetrahydrofuran (60 mL), and the temperature was lowered to -10°C, and then 4-methylmorpholine (3.40 g, 33.64 mmol) and ethyl chloroformate (3.65 g, 33.64 mmol) were added in sequence. The reaction solution was reacted at -10°C for three hours. After the reaction was completed, the reaction solution 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 (400MHz, CDCl3) δ5.45-5.26(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).

[0124] Step 3: Synthesis of compound 8d

[0125] At room temperature, compound 2a (4.00 g, 13.10 mmol) was dissolved in dichloromethane (40 mL), and pyridine (3.10 g, 39.30 mmol) and compound 8c (4.30 g, 19.6 mmol) were added in sequence. The reaction solution was reacted at room temperature for three hours. After the reaction was completed, the reaction solution 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.

[0126] Step 4: Synthesis of compound 8e

[0127] At room temperature, compound 8d (1.38 g, 3.18 mmol) was dissolved in ethyl acetate (5 mL), and then 10% palladium carbon (414 mg) was added. The reaction solution was reacted at room temperature for 1.5 hours in a hydrogen atmosphere. After the reaction was completed, the reaction solution 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.

[0128] Step 5: Synthesis of Compound 8

[0129] At room temperature, compound 8e (500 mg, 1.45 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and N,N-dimethylpropylene urea (4 mL), and the temperature was lowered to -78°C in a nitrogen environment, and then sodium bis(trimethylsilyl)amide (0.8 mL, 2M / tetrahydrofuran solution, 1.6 mmol) was added dropwise to the reaction solution and maintained at -78°C. The reaction solution was reacted at -78°C for 10 minutes, and 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 was carried out 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×3). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated to dryness, and the residue was purified by reverse phase preparation (C18, 10 mmol / L formic acid / 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(400MHz, CDCl3) δ7.59(t,J=7.6Hz,1H),5.48-5.29(m,2H),5.17-5.06(m,1H),4.71(d,J =9.2Hz,1H),4.60(d,J=9.2Hz,1H),4.41-4.29(m,1H),4.26-4.11(m,3H),4.03(d,J=7.6Hz, 1H),3.69(s,3H),3.28(d,J=12.0Hz,1H),2.89(d,J=12.0Hz,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=7.2Hz,3H),1.30-1.26(m,9H).

[0130] Example 9: Synthesis of Compound 9

[0131] 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-butyloxycarbonyl)-L-aspartate

[0132]

[0133] Step 1: Synthesis of compound 9b

[0134] At room temperature, compound 9a (10.0 g, 80.97 mmol) was added to dry tetrahydrofuran (100 mL), cooled to -10 ° C in a nitrogen environment, and 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 thereto in sequence. The reaction solution was continued to react at -10 ° C for 1 hour. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated to dryness to obtain 10.5 g of compound 9b with a yield of 98.1%. 1 H NMR (400MHz, CDCl3) δ5.50 (d, J = 8.0Hz, 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).

[0135] Step 2: Synthesis of compound 9c

[0136] At room temperature, compound 2a (2.0 g, 6.56 mmol) was added to dry dichloromethane (20 mL), and then pyridine (1.56 g, 19.67 mmol) and compound 9b (2.61 g, 9.83 mmol) were added thereto in sequence. The reaction solution was allowed to react for 3 hours at room temperature. After the reaction was completed, water (50 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, 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 obtain 350 mg of compound 9c, with a yield of 10%). LCMS (ESI): [M+H] + =535.0.

[0137] Step 3: Synthesis of compound 9d

[0138] At room temperature, compound 9c (350 mg, 0.655 mmol) was dissolved in ethyl acetate (5 mL), and then 10% palladium carbon (70 mg) was added thereto, and the mixture was replaced with hydrogen three times. The reaction solution continued to react for 1.5 hours under a hydrogen atmosphere at room temperature. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated to dryness to obtain 250 mg of compound 9d with a yield of 85.9%. LCMS (ESI): [M+Na] + =466.9.

[0139] Step 4: Synthesis of compound 9

[0140] At room temperature, compound 9d (250 mg, 0.563 mmol) was added to a mixed solvent of ultra-dry tetrahydrofuran (5 mL) and N,N-dimethylpropylene urea (2 mL). Sodium bis(trimethylsilyl)amide (0.62 mL, 2M / tetrahydrofuran solution, 0.62 mmol) was added dropwise to the reaction solution at -78 °C under a nitrogen atmosphere, and the reaction was maintained at -78 °C for 10 minutes, and then compound 1e (275 mg, 1.12 mmol) was added thereto. After 10 minutes, the temperature slowly rose to room temperature and 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×3), the organic phases were combined and directly concentrated to dryness, and the residue was purified by reverse phase preparative HPLC (C18, 10 mmol / L formic acid / water, acetonitrile) to obtain 21.77 mg of compound 9 with a yield of 5.93%. LCMS (ESI): [M+Na] + =675.5,t R =11.468min. 1 HNMR (400MHz, CDCl3) δ7.56 (t, J = 7.2Hz, 1H), 5.48-5.34 (m, 2H), 5.31-5.23 (m, 1H), 4.71 (d,J=9.2Hz,1H),4.60(d,J=9.2Hz,2H),4.23-4.13(m,3H),4.03(d,J=7.2Hz,1H),3.29( d,J=12.0Hz,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).

[0141] Example 10: Synthesis of Compound 10

[0142] ((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)succinate

[0143]

[0144] Step 1: Synthesis of compound 10b

[0145] At room temperature, compound 10a (10.0 g, 48.07 mmol) was added to N, N-dimethylformamide (100 mL), and 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 thereto in sequence. The reaction solution was allowed to react for 16 hours at room temperature. After the reaction was completed, a saturated aqueous solution of NaHCO3 (200 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with a 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=5 / 1)) to obtain 11.0 g of compound 10b, with a yield of 74.3%. LCMS (ESI): [M+Na] + =330.9. 1 H NMR (400MHz, DMSO-d6) δ7.42-7.24(m,5H),5.69(s,2H),5.09(s,2H),3.34(s,4H),2.52(q,J=7.2Hz,1H),1.08(d,J=7.2Hz,6H).

[0146] Step 2: Synthesis of 4-((isobutyryloxy)methoxy)-4-oxobutyric acid

[0147] At room temperature, compound 10b (10.0 g, 32.47 mmol) was dissolved in methanol (100 mL), and then 10% palladium carbon (1.5 g) was added thereto, and the mixture was replaced with hydrogen three times. The reaction solution continued to react for 1 hour under hydrogen atmosphere at room temperature. 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, with a yield of 85.7%. LCMS (ESI): [M+Na] + =240.9.

[0148] Step 3: Synthesis of methyl (isobutyryloxy) 4-chloro-4-oxobutyrate

[0149] At room temperature, compound 10c (2.3 g, 10.55 mmol) was dissolved in dry dichloromethane (23 mL), cooled to 0°C in a nitrogen environment, and then N,N-dimethylformamide (77 mg, 1.06 mmol) and oxalyl chloride (1.34 g, 10.55 mmol) were added thereto in sequence. The reaction solution was continued to react 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 with a yield of 92.7%. 1H NMR (400MHz, DMSO-d6) δ5.70 (s, 2H), 2.84-2.64 (m, 1H), 2.60-2.54 (m, 2H), 2.53-2.47 (m, 2H), 1.10 (d, J = 7.2Hz, 6H).

[0150] Step 4: Synthesis of compound 10e

[0151] At room temperature, compound 2a (2.0 g, 6.56 mmol) was dissolved in dry dichloromethane (20 mL), and then pyridine (1.556 g, 19.67 mmol) and compound 10d (2.32 g, 9.84 mmol) were added thereto in sequence. The reaction solution was allowed to react for 16 hours at room temperature. After the reaction was completed, water (50 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, 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 = 1 / 1)) to obtain 2.0 g of compound 10e with a yield of 60.6%. LCMS (ESI): [M+H] + =505.9.

[0152] Step 5: Synthesis of compound 10f

[0153] At room temperature, compound 10e (2.0 g, 3.96 mmol) was dissolved in ethyl acetate (20 mL), and then 10% palladium carbon (400 mg) was added thereto, and the mixture was replaced with hydrogen three times. The reaction solution continued to react for 1.5 hours under a hydrogen atmosphere at room temperature. 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.

[0154] Step 6: Synthesis of compound 10

[0155] At room temperature, compound 10f (1.53 g, 3.69 mmol) was added to a mixed solution of dry tetrahydrofuran (25 mL) and N,N-dimethylpropylene urea (10 mL). Sodium bis(trimethylsilyl)amide (2.03 mL, 2M / tetrahydrofuran solution, 4.06 mmol) was added dropwise to the reaction solution at -78°C in a nitrogen atmosphere. The reaction was maintained at -78°C for 10 minutes, and then compound 1e (1.80 g, 7.37 mmol) was added thereto. After 10 minutes, the temperature was slowly raised to room temperature and the reaction was continued 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×3). The organic phases were combined and directly concentrated to dryness. The residue was purified by reverse phase preparative HPLC (C18, 10 mmol / L formic acid / water, acetonitrile) to obtain 42.96 mg of compound 10 with a yield of 1.87%. LCMS (ESI): [M+H] + =624.4. 1 H NMR (400MHz, CDCl3) δ7.61 (t, J = 7.2Hz, 1H), 5.75 (s, 2H), 5.43-5.35 (m, 1H), 5.33-5.22 (m, 1H) ,4.71(d,J=8.8Hz,1H),4.60(d,J=8.8Hz,1H),4.24-4.12(m,3H),4.03(d,J=7.2Hz,1H),3.29(d ,J=12.4Hz,1H),2.89(d,J=12.0Hz,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 = 7.2Hz, 6H).

[0156] Example 11: Synthesis of Compound 11

[0157] 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-dimethylglutarate

[0158]

[0159] Step 1: Synthesis of compound 11b

[0160] At room temperature, compound 11a (10.0 g, 70.34 mmol) was dissolved in methanol (100 mL), and then triethylamine (7.12 g, 70.34 mmol) and N,N-dimethylformamide (0.86 g, 7.03 mmol) were added, and the reaction solution 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.

[0161] Step 2: Synthesis of compound 11c

[0162] At room temperature, compound 11b (3.0 g, 17.2 mmol) was dissolved in dichloromethane (300 mL), and 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 (400MHz, DMSO) δ3.52 (d, J = 3.4 Hz, 3H), 2.34 (s, 2H), 2.23 (s, 2H), 1.00 (d, J = 7.1 Hz, 6H).

[0163] Step 3: Synthesis of compound 11d

[0164] At room temperature, compound 2a (2.0 g, 6.6 mmol) was dissolved in dichloromethane (200 mL), 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 × 3), the organic phases were combined, washed with saturated brine (100 mL × 2), the organic phases were dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. It was 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.

[0165] Step 4: Synthesis of compound 11e

[0166] At room temperature, compound 11d (1.1 g, 2.39 mmol) was dissolved in ethyl acetate (11 mL), 10% palladium on carbon (200 mg) was added to the mixed solution, and the mixed solution was replaced with hydrogen three times. The reaction solution was reacted at room temperature for 2 h in a hydrogen atmosphere. After 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 (400MHz, CDCl3) δ7.69(t,J=7.2Hz,1H),5.36-5.24(m,2H),4.12(q,J=7.1Hz,1H),3.91(d,J=7.6Hz,1H),3.77(s,1H),3.65(s,3H),3.18(d,J= 11.8Hz,1H),2.73(d,J=11.8Hz,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).

[0167] Step 5: Synthesis of compound 11

[0168] At room temperature, compound 11e (900 mg, 2.43 mmol) was dissolved in a mixed solution of ultra-dry tetrahydrofuran (9 mL) and N,N-dimethylpropylene urea (8 mL). Under nitrogen protection, the temperature was lowered to -78 ° C, and sodium bis(trimethylsilyl)amide (1.3 mL, 2.67 mmol) was slowly added thereto. The reaction was continued to stir at -78 ° C for 10-15 min, and compound 1e (651 g, 2.67 mmol) was slowly added. After 10 minutes, the temperature was slowly raised to room temperature and 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×3). The organic phases were combined and 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. 1HNMR (400MHz, CDCl3) δ7.57-7.52(m,1H),5.37-5.26(m,2H),4.71(d,J=9.0Hz ,1H),4.60(d,J=9.0Hz,1H),4.26-4.09(m,3H),4.01(d,J=7.6Hz,1H),3.65(s, 3H),3.27(d,J=12.4Hz,1H),2.86(d,J=12.1Hz,1H),2.48-2.38(m,5H),2.16( d,J=14.2Hz,1H),1.99-1.86(m,2H),1.58-1.56(m,9H),1.11(d,J=3.3Hz,6H).

[0169] Example 12: Synthesis of Compound 12

[0170] 3-(((((2S,5R)-2-((((1-acetoxyethoxy)carbonyl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoic acid ethyl ester

[0171]

[0172] The synthesis method is the same as in Example 3. LCMS (ESI): [M+H] + =524.2. 1 H NMR (400MHz, CDCl3) δ8.56 (s, 1H), 6.95-6.77 (m, 1H), 4.70 (d, J = 9.2Hz, 1H), 4. 60(d,J=9.2Hz,1H),4.24-4.14(m,3H),4.11-4.03(m,1H),3.37(d,J=12.0Hz,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=5.2,1.6Hz,3H),1.31-1.24(m,9H).

[0173] Example 13: Synthesis of Compound 13

[0174] 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 2,2-dimethylsuccinate

[0175]

[0176] Step 1: Synthesis of compound 13b

[0177] At room temperature, compound 13a (10.0 g, 78.12 mmol) was dissolved in dry dichloromethane (100 mL), and then methanol (5.0 g, 156.25 mmol) and triethylamine (31.56 g, 312.5 mmol) were added thereto in sequence. The reaction solution was allowed to react at room temperature for 16 hours. After the reaction was completed, 1M dilute hydrochloric acid (200 mL) was added to the reaction solution to quench the reaction, and the resulting solution was extracted three times with ethyl acetate (100 mL×3). The organic phases were combined, 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.

[0178] Step 2: Synthesis of compound 13c

[0179] At room temperature, compound 13b (1.75 g, 10.93 mmol) was dissolved in dry dichloromethane (20 mL), cooled to 0°C under nitrogen protection, and then N,N-dimethylformamide (80 mg, 1.09 mmol) and oxalyl chloride (1.39 g, 10.93 mmol) were added in sequence. The reaction solution was continued to react 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 (400MHz, DMSO-d6) δ3.56(s,3H),2.89(s,1H),2.73(s,1H),1.16(s,6H).

[0180] Step 3: Synthesis of compound 13d

[0181] At room temperature, compound 2a (2.0 g, 6.56 mmol) was dissolved in dry dichloromethane (20 mL), and then pyridine (1.556 g, 19.67 mmol) and compound 13c (1.75 g, 9.84 mmol, 1.5 equivalents) were added thereto in sequence. The reaction solution continued 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 it was extracted with ethyl acetate (100 mL×3). The organic phases were combined, 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.

[0182] Step 4: Synthesis of compound 13e

[0183] At room temperature, compound 13d (1.4 g, 3.13 mmol) was dissolved in ethyl acetate (8 mL), and then 10% palladium carbon (280 mg) was added thereto, and the mixture was replaced with hydrogen three times. The reaction solution continued to react for 1.5 hours under a hydrogen atmosphere at room temperature. After the reaction was completed, the reaction solution 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(400MHz,DMSO-d6)δ9.74(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).

[0184] Step 5: Synthesis of compound 13

[0185] At room temperature, compound 13e (650 mg, 1.82 mmol) was dissolved in dry tetrahydrofuran (13 mL) and N,N-dimethylpropylene urea (5.2 mL). Sodium bis(trimethylsilyl)amide (1.0 mL, 2M / tetrahydrofuran solution, 2.0 mmol) was added dropwise to the reaction solution at -78°C in a nitrogen atmosphere. The reaction was maintained at -78°C for 10 minutes, and then compound 1e (888 mg, 3.64 mmol) was added thereto. After 10 minutes, the mixture was warmed to room temperature and 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 (50 mL×3). The organic phases were combined and directly concentrated to dryness. The residue was purified by reverse phase preparative HPLC (C18, 10 mmol / L formic acid / water, acetonitrile) to obtain 83.47 mg of compound 13 with a yield of 8.12%. LCMS (ESI): [M+Na] + =566.31. 1H NMR (400MHz, CDCl3) δ7.69-7.52(m,1H),5.42-5.31(m,1H),5.27-5.21(m,1H),4.72(d, J=9.2Hz,1H),4.60(d,J=9.2Hz,1H),4.23-4.13(m,3H),4.02(t,J=6.8Hz,1H),3.69(s,1 H),3.63(s,1H),3.29(d,J=12.0Hz,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).

[0186] Example 14: Synthesis of Compound 14

[0187] 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(tert-butyloxycarbonyl)-L-aspartic acid

[0188]

[0189] The synthesis method is the same as in Example 9. LCMS (ESI) [M+Na] + =675.5. 1 H NMR (400MHz, CDCl3) δ7.68-7.58(m,1H),5.49-5.38(m,2H),5.36-5.24(m,1H),4.71(d, J=9.2Hz,1H),4.60(d,J=9.2Hz,1H),4.58-4.50(m,1H),4.26-4.13(m,3H),4.02(d,J=7 .6Hz,1H),3.68(s,3H),3.28(d,J=11.6Hz,1H),3.05-2.94(m,1H),2.92-2.78(m,2H),2 .51-2.37(m,1H),2.21-2.08(m,1H),2.04-1.78(m,2H),1.45(s,9H),1.30-1.26(m,9H).

[0190] Example 15: Synthesis of Compound 15

[0191] ((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)glutarate

[0192]

[0193] The synthesis method is the same as in Example 10. LCMS (ESI): [M+H] + =638.3. 1 H NMR (400MHz, CDCl3) δ7.56 (t, J = 7.6Hz, 1H), 5.75 (d, J = 4.4Hz, 2H), 5.37-5.25 (m, 2H), 4.71 (d, J = 9. 2Hz,1H),4.60(d,J=9.2Hz,1H),4.19-4.15(m,2H),4.03(d,J=7.2Hz,1H),3.30(d,J=11.6Hz,1H),2 .85(d,J=12.0Hz,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=7.2Hz,6H).

[0194] Example 16: Synthesis of Compound 16

[0195] 2,2-Dimethyl-3-(((2S,5R)-7-oxo-2-((((pivaloyloxy)methoxy)carbonyl)carbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)propanoic acid ethyl ester

[0196]

[0197] The synthesis method is as in Example 3. LCMS (ESI): [M+Na] + =574.3. 1H NMR (400MHz, CDCl3) δ8.64(s,1H),5.83(q,J=5.6Hz,2H),4.70(d,J=9.0Hz,1H),4.60(d,J=9.0Hz,1H),4.25-4.04(m,4H),3.37(d,J=11.6 Hz,1H),2.90(d,J=12.2Hz,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=5.8Hz,9H),1.23(s,9H).

[0198] Example 17: Synthesis of Compound 17

[0199] 3-(((((2S,5R)-2-(((2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)methyl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoic acid ethyl ester

[0200]

[0201] Step 1: Synthesis of compound 17b

[0202] At room temperature, compound 17a (5.0 g, 30.43 mmol) was dissolved in dichloromethane (50 mL), and 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 solution was concentrated to dryness to obtain 6.0 g of crude compound 17b, which was directly subjected to the next step of reaction. 1 H NMR (400MHz, CDCl3) δ4.69 (dd, J = 6.5, 3.5 Hz, 1H), 3.51 (dd, J = 18.1, 3.5 Hz, 1H), 3.35 (dd, J = 18.1, 6.4 Hz, 1H), 1.65 (s, 3H), 1.58 (s, 3H).

[0203] Step 2: Synthesis of compound 17c

[0204] At room temperature, compound 2a (4.0 g, 13.11 mmol) was dissolved in dichloromethane (40 mL), pyridine (1.6 g, 19.67 mmol) and compound 17b (3.8 g, 19.67 mmol, 1.5 equivalents) 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 × 3), the organic phases were combined, washed with saturated brine (100 mL × 2), dried with 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 2.7 g of compound 17c, with a yield of 45.0%. LCMS (ESI): [M+H] + =462.0.

[0205] Step 3: Synthesis of compound 17d

[0206] At room temperature, compound 17c (3.5 g, 7.59 mmol) was dissolved in ethyl acetate (35 mL), 10% palladium on carbon (400 mg) was added to the mixed solution, and the mixed solution was replaced with hydrogen three times. The reaction solution was reacted in a hydrogen atmosphere at room temperature for 1.5 h. After the reaction was completed, the reaction solution was filtered and the filtrate was directly concentrated to dryness to obtain 2.7 g of compound 17d with a yield of 96.4%. LCMS (ESI): [M+H] + =372.1.

[0207] Step 4: Synthesis of compound 17

[0208] At room temperature, 17d (2.2 g, 5.93 mmol) was dissolved in ultra-dry tetrahydrofuran (22 mL) and N,N-dimethylpropyleneurea (18 mL). Under nitrogen protection, sodium bis(trimethylsilyl)amide (3.3 mL, 6.53 mmol) was added at -78°C. The reaction was continued to stir at -78°C for 10 min, and compound 1e (2.9 g, 11.86 mmol) was slowly added thereto. After 10 minutes, the mixture was warmed to room temperature and 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×3). The organic phases were combined, washed with saturated brine (200 mL×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 obtain 41.69 mg of compound 17, with a yield of 1.2%. LCMS (ESI): [M+H] + =580.3. 1H NMR(400MHz, CDCl3)δ7.65(t,J=7.2Hz,1H),5.50-5.38(m,1H),5.30(dd,J=10.2,7.0Hz, 1H),4.71(d,J=8.2Hz,2H),4.60(d,J=9.0Hz,1H),4.21-4.17(m,3H),4.02(d,J=7.6Hz,1 H),3.31(d,J=12.5Hz,1H),2.92-2.85(m,3H),2.44(dd,J=15.1,7.2Hz,1H),2.16(d,J=1 6.3Hz,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).

[0209] Example 18: Synthesis of Compound 18

[0210] 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

[0211]

[0212] The synthesis method is the same as in Example 3. LCMS (ESI) [M+Na] + =574.3. 1 H NMR (400MHz, DMSO-d6) δ11.03(s,1H),6.72(q,J=5.6Hz,1H),4.63(d,J=9.2Hz,1H),4.55(d,J=9.2Hz,1H),4.26-4.22(m,1H),4.13-4.08(m,3H),3 .23(d,J=5.2Hz,2H),2.58-2.51(m,1H),2.01-1.91(m,3H),1.84-1.78(m ,1H),1.45(dd,J=5.2,1.2Hz,3H),1.23-1.15(m,9H),1.12-1.02(m,6H).

[0213] Example 19: Synthesis of Compound 19

[0214] 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

[0215]

[0216] Step 1: Synthesis of compound 19b

[0217] At room temperature, compound 19a (20.0 g, 143.0 mmol) was dissolved in N, N-dimethylformamide (100 mL), and the temperature was lowered to 0°C, and then sodium carbonate (45.4 g, 471.0 mmol) and 2-bromo-1-ethanol (19.6 g, 157.0 mmol) were added in sequence. The reaction solution was reacted at room temperature for 2 hours. After the reaction was completed, the reaction mixture was also poured into water (500 mL), and the resulting solution was extracted with ethyl acetate (300 mL×2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. Flash chromatography separation and purification (Silica gel, petroleum ether: ethyl acetate (V / V=5 / 1)) gave 24.0 g of compound 19b with a yield of 91.6%. LCMS (ESI) [M+H] + =185.2. 1 H NMR (400MHz, CDCl3) δ7.43-7.35 (m, 2H), 6.91-6.81 (m, 2H), 3.79 (s, 3H), 3.71-3.61 (m, 2H), 2.99 (t, J = 6.0Hz, 2H).

[0218] Step 2: Synthesis of compound 19c

[0219] At room temperature, compound 19b (22.0 g, 119.6 mmol) was dissolved in methanol (440 mL) and water (44 mL), and then potassium peroxymonosulfonate (124.1 g, 358.7 mmol) was added. The reaction solution was reacted at 70°C for 15 minutes. After the reaction was completed, the reaction mixture was also poured into water (1000 mL), and the resulting solution was extracted with ethyl acetate (200 mL×2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. Flash chromatography separation and purification (Silica gel, petroleum ether: ethyl acetate (V / V=1 / 1)) gave 24.0 g of compound 19c with a yield of 96.5%. LCMS (ESI): [M+H] + =217.0. 1 H NMR (400MHz, CDCl3) δ7.90-7.75(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).

[0220] Step 3: Synthesis of compound 19d

[0221] At room temperature, compound 19c (2.0 g, 9.26 mmol) was dissolved in tetrahydrofuran (20 mL), and triethylamine (1.4 g, 13.9 mmol) and triphosgene (4.00 g, 13.5 mmol) were added in sequence 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 step.

[0222] Step 4: Synthesis of compound 19e

[0223] At room temperature, 1a (2.0 g, 7.27 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to -78 °C in a nitrogen environment, and then lithium bis(trimethylsilyl)amide (14.5 mL, 1M / tetrahydrofuran solution, 14.5 mmol) was added dropwise to the reaction solution and maintained at -78 °C. The reaction solution was reacted at -78 °C for 10 min, and then 2-((4-methoxyphenyl)sulfonyl)ethylphosgene (2.4 g, 8.72 mmol) was added dropwise to the reaction solution. After 10 minutes, the temperature was raised to room temperature and the reaction was carried out 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×3). The organic phases were combined, washed with saturated brine (200 mL×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 1.0 g of compound 19e with a yield of 26.4%. LCMS (ESI): [M+H] + =518.2.

[0224] Step 5: Synthesis of compound 19f

[0225] At room temperature, compound 19e (1.0 g, 1.93 mmol) was dissolved in ethyl acetate (30 mL), and then 10% palladium carbon (500 mg) was added. The reaction solution was replaced with hydrogen three times, and the reaction solution was reacted in a hydrogen atmosphere at room temperature 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%.

[0226] LCMS(ESI):[M+H] + =428.2.

[0227] Step 6: Synthesis of compound 19

[0228] At room temperature, compound 19f (150 mg, 0.35 mmol) was dissolved in tetrahydrofuran (3 mL) and N,N-dimethylpropylene urea (1.1 mL), and the temperature was cooled to -78 ° C in a nitrogen environment. Then, sodium bis(trimethylsilyl)amide (0.2 mL, 2M / tetrahydrofuran solution, 0.38 mmol) was added dropwise to the reaction solution and maintained at -78 ° C. The reaction solution was reacted at -78 ° C for 10 minutes, and compound 1e (214 mg, 0.88 mmol) was added dropwise to the reaction solution. After 10 minutes, the temperature was raised to room temperature and the reaction was carried out 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 × 2). The organic phases were combined, washed with saturated brine (50 mL × 2), 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 14.08 mg of compound 19, with a yield of 6.31%. LCMS (ESI) [M+H] + =636.3. 1 H NMR (400MHz, DMSO-d6) δ10.66(s,1H),7.83(d,J=8.4Hz,2H),7.16(d,J=8.4Hz,2H),4.63(d,J=8.8Hz,1H),4.55(d,J=9.2Hz,1H),4.33-4.3 2(m,2H),4.19(d,J=6.0Hz,1H),4.13-4.07(m,3H),3.85(s,3H),3.67(t,J=6.0Hz,2H),3.21(s,2H),1.93-1.79(m,4H),1.19-1.18(m,9H).

[0229] Example 20: Synthesis of Compound 20

[0230] 3-(((((2S,5R)-2-(((2-(butyldisulfanyl)ethoxy)carbonyl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoic acid ethyl ester

[0231]

[0232] Step 1: Synthesis of compound 20a

[0233] At room temperature, 1a (20.0 g, 72.6 mmol) was dissolved in ethyl acetate (200 mL), and then 10% palladium on carbon (5.60 g) was added thereto. The resulting mixture was replaced with hydrogen three times, and the reaction solution was reacted in a hydrogen atmosphere at room temperature for 3 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was directly concentrated to dryness to obtain 13.0 g of compound 20a with a yield of 96.6%. LCMS (ESI): [M+H] + =186.2. 1 H NMR (400MHz, DMSO-d6) δ9.70 (s, 1H), 7.49-7.15 (m, 2H), 3.64 (d, J = 7.2Hz, 1H), 3.17 (d, J = 3.2Hz, 1H), 3.00-2. 99(m,1H),2.87(d,J=11.6Hz,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).

[0234] Step 2: Synthesis of compound 20c

[0235] At room temperature, 20a (10.0 g, 54.0 mmol) was dissolved in tetrahydrofuran (200 mL) and N,N-dimethylpropylene urea (80 mL), and the temperature was cooled to -78 °C in a nitrogen environment. Then, sodium bis(trimethylsilyl)amide (29.5 mL, 2M / tetrahydrofuran solution, 59.4 mmol) was added dropwise to the reaction solution and maintained at -78 °C. The reaction solution was reacted at -78 °C for 10 minutes, and compound 1e (26.4 g, 108 mmol) was added dropwise to the reaction solution. After 10 minutes, the temperature was raised to room temperature and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, the reaction solution was poured into water (300 mL) and extracted with ethyl acetate (300 mL×3). The organic phases were combined and directly concentrated to dryness. The residue was purified by reverse phase preparation (C18, 10 mmol / L formic acid / water, acetonitrile) to obtain a crude product, which was further separated and purified by flash chromatography (petroleum ether: ethyl acetate (V / V=3 / 1) to obtain 3.51 g of compound 20c with a yield of 16.5%. LCMS (ESI) [M+H] + =394.2. 1H NMR (400MHz, CDCl3) δ6.47(s,1H),5.57(s,1H),4.72(d,J=9.2Hz,1H),4.61(d,J=8.8Hz,1H),4.20-4.07(m,3H),4.06(d,J=7.2Hz ,1H),3.33(d,J=12.4Hz,1H),3.02(d,J=12.0Hz,1H),2.46-2.42(m,1H),2.16-1.96(m,1H),1.95-1.89(m,2H),1.29-1.26(m,9H).

[0236] Step 3: Synthesis of compound 20e

[0237] Under argon protection, compound 20d (10.0 g, 0.111 mol) was added to a solution of sodium hydride (4.5 g, 0.111 mol) in THF (100 mL) at -20 ° C. One minute later, 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 quickly added. The reaction mixture was stirred at -20 ° C for 1 hour. After the reaction was completed, the solvent 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 10. g of compound 20e with a yield of 55.5%. 1 H NMR (400MHz, CDCl3) δ3.89 (t, J = 6.0 Hz, 2H), 2.85 (t, J = 6.0 Hz, 3H), 2.77-2.67 (m, 2H), 1.67-1.65 (m, 2H), 1.43-1.41 (m, 2H), 0.93 (t, J = 7.2Hz, 3H).

[0238] Step 4: Preparation of compound 20f

[0239] At -0°C, compound 20e (2.2 g, 13.3 mmol) was dissolved in dichloromethane (20 mL), and triethylamine (2.0 g, 19.9 mmol) and triphosgene (1.4 g, 4.64 mmol) were added thereto in sequence. 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 to obtain 2.0 g of compound 20f with a yield of 66.1%. 1 H NMR (400MHz, CDCl3) δ4.57-4.54(m,2H),2.96(t,J=6.8Hz,2H),2.72(t,J=7.2Hz,2H),1.66-1.65(m,2H),1.43-1.41(m,2H),0.93(t,J=7.2Hz,3H).

[0240] Step 5: Synthesis of compound 20

[0241] At room temperature, compound 20c (320 mg, 0.76 mmol) was dissolved in tetrahydrofuran (3 mL) solution, cooled to -78 °C in a nitrogen environment, and 10 minutes later, lithium bis(trimethylsilyl)amide (1.53 mL, 1M / tetrahydrofuran solution, 1.52 mmol) was added dropwise to the reaction solution and maintained at -78 °C. The reaction solution was reacted at -78 °C for 30 minutes, and then compound 20f (209 g, 0.92 mmol) was added, slowly warmed to room temperature, and reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was poured into water (100 mL) and extracted three times with ethyl acetate (50 mL×3). The organic phase was collected, washed twice with saturated brine, 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 (400MHz, CDCl3) δ8.56(s,1H),4.70(d,J=9.2Hz,1H),4.61(d,J=9.2Hz,1H),4.47(t,J=8 .0Hz,2H),4.27-4.16(m,3H),4.10(d,J=11.1Hz,1H),3.37(t,J=12.0Hz,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=7.2Hz,3H).

[0242] Example 21: Synthesis of Compound 21

[0243] 2,2-Dimethyl-3-(2S,5R)-7-oxo-2-(((2-(propyldisulfanyl)ethoxy)carbonyl)carbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxypropanoic acid ethyl ester

[0244]

[0245] The synthesis method is the same as Example 20. LCMS (ESI): [M+H] + =572.2.1 H NMR (400MHz, CDCl3) δ8.55(s,1H),4.71(d,J=9.2Hz,1H),4.61(d,J=9.2Hz,1H),4.47(t ,J=8.0Hz,2H),4.27-4.16(m,3H),4.10(d,J=11.1Hz,1H),3.38(t,J=12.0Hz,1H),2.93 (t,J=8.8Hz,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=7.2Hz,3H).

[0246] Example 22: Synthesis of Compound 22

[0247] Acetoxymethyl 3-(((((2S,5R)-2-((((acetoxymethoxy)carbonyl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate

[0248]

[0249] Step 1: Synthesis of compound 22a

[0250] At room temperature, compound 3b (11.0 g, 71.5 mmol) was dissolved in acetic acid (21.5 g, 697 mmol), and then N, N-diisopropylethylamine (27.7 g, 540 mmol) was added thereto. The reaction solution was continued to react 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 it was extracted with ethyl acetate (300 mL×3). The organic phases were combined, 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 HNMR (400MHz, CDCl3) δ5.73 (s, 2H), 2.83 (q, J = 7.2Hz, 2H), 2.06 (s, 3H), 5.93 (t, J = 7.2Hz, 3H).

[0251] Step 2: Synthesis of compound 22b

[0252] At -10°C, sulfonyl chloride (4.5 g, 25.3 mmol) was added to compound 22a (4.5 g, 25.3 mmol), and the reaction solution was reacted at -10°C for 20 minutes, then warmed to room temperature and reacted at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure to obtain 4.5 g of compound 22b, which was directly used in the next step. 1 HNMR (400MHz, CDCl3) δ1.07 (s, 2H), 2.57 (s, 3H).

[0253] Step 3: Synthesis of compound 22c

[0254] At room temperature, compound 1a (2.0 g, 7.27 mmol) was added to tetrahydrofuran (20 mL), cooled to -78 ° C in a nitrogen environment, and then lithium bis(trimethylsilyl)amide (14.5 mL, 1M / tetrahydrofuran solution, 14.5 mmol) was added dropwise to the reaction solution and maintained at -78 ° C. The reaction solution was reacted at -78 ° C for 10 minutes, and compound 22b (2.2 g, 14.5 mmol) was added dropwise to the reaction solution and reacted at -78 ° C for 2 hours. After the reaction was completed, water (100 mL) was added to the reaction solution to quench the reaction, and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, 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 obtain 950 mg of compound 22c, with a yield of 35.7%). LCMS(ESI):[M+H] + =392.2.

[0255] Step 4: Synthesis of compound 22d

[0256] At room temperature, compound 22c (350 mg, 0.90 mmol) was dissolved in ethyl acetate (10 mL), and then 10% palladium carbon (300 mg) was added. The resulting solution was replaced with hydrogen three times, and the reaction solution was reacted at room temperature for 1 hour in a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated to dryness to obtain 250 mg of compound 22d with a yield of 92.6%. LCMS (ESI): [M+H] + =302.1.

[0257] Step 5: Synthesis of compound 22f

[0258] Compound 22e (15.0 g, 126.9 mmol) was dissolved in acetonitrile (150 mL) at room temperature, and 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 then 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 the reaction solution to quench the reaction, and the mixture was extracted three times with ethyl acetate (100 mL x 3). The organic phases were combined, 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(400MHz, CDCl3) δ5.67(s,2H),3.40(s,2H),2.06(s,3H),1.10(s,6H).

[0259] Step 6: Synthesis of compound 22g

[0260] At room temperature, sulfonyl chloride (532 mg, 3.9 mmol) was dissolved in ether (5 mL), the mixture was replaced with argon three times, and stirred at -78 ° C for 10 min. Compound 22f (500 mg, 2.6 mmol) and pyridine (311 mg, 3.9 mmol) in ether (0.5 mL) were 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(400MHz, CDCl3) δ5.70(s,2H),3.71(s,2H),2.06(s,3H),1.21(s,6H).

[0261] Step 7: Synthesis of compound 26

[0262] At room temperature, compound 22d (400 mg, 1.33 mmol) was dissolved in ultra-dry tetrahydrofuran (12 mL) and N,N-dimethylpropylene urea (3.2 mL). The reaction solution was cooled to -78 ° C under nitrogen protection, and sodium bis(trimethylsilyl)amide (0.8 mL, 1.46 mmol) was added dropwise. The reaction was stirred at -78 ° C for 10 min, and compound 22g (1.1 g, 4.00 mmol) was slowly added to the reaction solution. The temperature of the reaction solution gradually rose to room temperature. , react at room temperature for 2 hours. The reaction was monitored by LCMS to complete. After the reaction was completed, water (20 mL) was added to the reaction solution to quench the reaction, and extracted three times with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was 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 (400MHz, CDCl3) δ8.65 (s, 1H), 5.83-5.75 (m, 4H), 4.71 (d, J = 9.2Hz, 1H) ,4.59(d,J=9.2Hz,1H),4.19(s,1H),4.09(d,J=6.4Hz,1H),3.39(d,J=11.6H z,1H),2.90(d,J=12.0Hz,1H),2.50-2.39(m,1H),2.18-2.17(m,1H),2.14(d ,J=8.8Hz,6H),2.00-1.95(m,1H),1.88-1.82(m,1H),1.30(d,J=4.0Hz,6H).

[0263] Example 23: Synthesis of Compound 23

[0264] Diisopropyl 2-((((((2S,5R)-2-((((acetoxymethoxy)carbonyl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonate

[0265]

[0266] Step 1: Synthesis of compound 23b

[0267] At room temperature, compound 23a (10.0 g, 84.68 mmol) was dissolved in dichloromethane (100 mL), and isopropanol (11.2 g, 186.3 mmol) and 4-dimethylaminopyridine (1.03 g, 8.468 mmol) were added in sequence. The reaction solution was cooled to 0°C, and N,N'-dicyclohexylcarbodiimide (38.44 g, 186.3 mmol) was added thereto. The mixed solution 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 with a yield of 81.8%.

[0268] 1 H NMR (400MHz, CDCl3) δ5.14-5.00 (m, 2H), 3.83 (q, J = 7.2Hz, 1H), 1.42 (d, J = 7.2Hz, 3H), 1.30-1.17 (m, 12H).

[0269] Step 2: Synthesis of compound 23c

[0270] At room temperature, compound 23b (7.0 g, 34.61 mmol) was dissolved in ethanol (35 mL) and water (35 mL), and formaldehyde aqueous solution (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 × 3), and the combined organic phases were washed with saturated brine (100 mL × 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 with a yield of 46.1%. 1 H NMR (400MHz, CDCl3) δ5.13-5.02 (m, 2H), 3.83 (d, J = 7.2Hz, 2H), 1.42 (s, 3H), 1.30-1.19 (m, 12H).

[0271] Step 3: Synthesis of compound 23d

[0272] At room temperature, sulfonyl chloride (698 mg, 5.17 mmol) was dissolved in ether (10 mL), the mixture was replaced with argon three times, and a solution of compound 23c (1.0 g, 4.31 mmol) and pyridine (375 mg, 4.74 mmol, 1.1 equivalent) in ether (1 mL) was added at -78°C. The mixture was stirred at -78°C for 0.5 hours and then gradually warmed to room temperature. The reaction was continued at room temperature for 2 hours. After the reaction was completed, the reaction solution was directly concentrated to dryness to obtain 1.0 g of compound 23d with a yield of 96.4%. 1 H NMR (400MHz, CDCl3) δ5.12-5.06 (m, 2H), 4.79 (s, 2H), 1.57 (s, 3H), 1.26 (d, J = 7.2Hz, 12H).

[0273] Step 4: Synthesis of compound 23

[0274] At room temperature, compound 22d (400 mg, 1.3 mmol) was dissolved in tetrahydrofuran (12 mL) and N,N-dimethylpropylene urea (3.2 mL). Under argon protection, sodium bis(trimethylsilyl)amide (0.7 mL, 2M / tetrahydrofuran solution, 1.43 mmol) was added thereto at -78°C. The reaction was continued to stir at -78°C for 10 min, and compound 23d (877 mg, 2.6 mmol) was slowly added thereto. After the addition was completed, the reaction temperature was gradually raised to room temperature, and the reaction was continued at room temperature for 2 h. After the reaction was completed, water (100 mL) was added to the reaction solution to quench the reaction. The resulting solution was extracted with ethyl acetate (200 mL×3), the organic phases were combined, washed with saturated brine (200 mL×2), dried over anhydrous sodium sulfate, filtered, and 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, with a yield of 6.6%. LCMS(ESI)[M+H] + =596.4. 1 H NMR (400MHz, CDCl3) δ8.63 (s, 1H), 5.82 (s, 2H), 5.11-5.06 (m, 2H), 4.99 (d, J = 9.6 Hz,1H),4.90(d,J=9.6Hz,1H),4.19(d,J=3.2Hz,1H),4.09(d,J=6.4Hz,1H),3.36( d,J=11.6Hz,1H),2.90(d,J=12.4Hz,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).

[0275] Example 24: Synthesis of Compound 24

[0276] 2-((((((2S,5R)-2-((((acetyloxymethoxy)carbonyl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonic acid, 1-ethyl-3-isopropyl ester

[0277]

[0278] Step 1: Synthesis of compound 24b

[0279] At 0°C, compound 24a (10 g, 75.7 mmol) was dissolved in dichloromethane (100 mL), 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, the reaction solution was heated 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 the mixture was extracted with dichloromethane (300 mL × 3). The organic phases were combined, washed with saturated brine (300 mL × 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 13 g of compound 24b with a yield of 98.6%. 1 H NMR (400MHz, CDCl3) δ5.10-5.04 (m, 1H), 4.21 (q, J = 7.2Hz, 2H), 3.33 (s, 2H), 1.31-1.23 (m, 9H).

[0280] Step 2: Synthesis of compound 24c

[0281] At 0°C, compound 24b (10.0 g, 57.5 mmol) was dissolved in tetrahydrofuran (100 mL), and sodium hydrogen sulfide (2.53 g, 63.2 mmol, 60% in mineral oil) was slowly added under nitrogen protection. After the addition was completed, the mixture was stirred at 0°C for 30 minutes, and then iodomethane (8.16 g, 57.2 mmol) was added to the above reaction solution. After the addition was completed, the reaction solution was reacted 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, and the mixture was extracted with ethyl acetate (100 mL×3). The organic phases were combined, backwashed with saturated brine (100 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain 6.0 g of compound 24c, which was directly used in the next step.

[0282] Step 3: Synthesis of compound 24d

[0283] At 0°C, compound 24c (6.00 g, 31.9 mmol) was dissolved in a mixed solution of ethanol (30 mL) and water (10 mL). Under nitrogen protection, sodium bicarbonate (268 mg, 3.19 mmol) and 37% aqueous formaldehyde solution (3.16 g, 35.1 mol) were added thereto in sequence. After the addition was completed, the mixture was reacted 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 the mixture was extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with saturated brine (100 mL×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 / 1V / V) to obtain 3.5 g of compound 24d with a yield of 50.7%. 1 H NMR (400MHz, CDCl3) δ5.12-5.08(m,1H),4.08(s,2H),4.24(dd,J=6.8,1.6Hz,2H),1.58(s,3H),1.30-1.25(m,9H).

[0284] Step 4: Synthesis of compound 24e

[0285] At room temperature, sulfonyl chloride (728 mg, 5.43 mmol) was dissolved in ether (10 mL), cooled to -78 °C under nitrogen protection, and 1-tert-butyl-3-ethyl-2-(hydroxymethyl)-2-methylmalonate (500 mg, 3.62 mmol) and pyridine (429 mg, 5.43 mmol) in ether (2 mL) were slowly added thereto. After the addition was complete, the temperature was gradually raised to room temperature and the mixture was reacted at room temperature for 4 hours. After the reaction was completed, the reaction solution 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.

[0286] Step 5: Synthesis of compound 24

[0287] At room temperature, compound 22d (300 mg, 0.996 mmol) was dissolved in a mixed solution of tetrahydrofuran (3 mL) and N,N-dimethylpropylene urea (1 mL), cooled to -78°C in a nitrogen environment, and then sodium bis(trimethylsilyl)amide (59.8 uL, 2M in tetrahydrofuran solution) was added dropwise to the reaction solution. After the addition was complete, 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 complete, the temperature was gradually raised to room temperature and the reaction was carried out at room temperature for 3 hours. After the reaction was completed, the reaction solution was poured into a saturated aqueous solution of sodium bicarbonate (20 mL) at 0°C, extracted with ethyl acetate (50 mL×2), the organic phases were combined and concentrated to dryness, and the residue was purified by preparative HPLC (0.1% FA, ACN) to obtain 17.4 mg of compound 24 with a yield of 3.0%. LCMS (ESI) [M+H] + =582.4. 1 H NMR (400MHz, CDCl3) δ8.64 (s, 1H), 5.82 (s, 2H), 5.16-5.04 (m, 1H), 5.00 (d, J = 9.6 Hz,1H),4.90(d,J=9.6Hz,1H),4.26-4.10(m,3H),4.10(d,J=7.2Hz,1H),3.36(d,J =12.0Hz,1H),2.90(d,J=11.6Hz,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=8.6Hz,9H).

[0288] Example 25: Synthesis of Compound 25

[0289] 2-((((((2S,5R)-2-((((acetyloxymethoxy)carbonyl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylmalonic acid-1-isopropyl-3-methyl ester

[0290]

[0291] Step 1: Synthesis of compound 25b

[0292] At 0°C, compound 25a (10 g, 84.7 mmol) was dissolved in dichloromethane (100 mL), and isopropanol (7.63 g, 127 mmol), N,N'-dicyclohexylcarbodiimide (26.2 g, 127 mmol) and 4-dimethylaminopyridine (1.03 g, 8.47 mmol) were added in sequence under nitrogen protection. After the addition was completed, the reaction solution was heated 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 the mixture was extracted with dichloromethane (300 mL × 3). The organic phases were combined, washed with saturated brine (300 mL × 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 11.0 g of compound 25b. 1 H NMR (400MHz, CDCl3) δ5.27-4.99(m,1H),3.71(s,3H),3.33(s,2H),1.24(s,3H),1.22(s,3H).

[0293] Step 2: Synthesis of compound 25c

[0294] At 0°C, compound 25b (10.0 g, 62.5 mmol) was dissolved in tetrahydrofuran (100 mL). Under nitrogen protection, sodium hydrogen sulfide (2.75 g, 68.7 mmol, 60% in mineral oil) was slowly added. After the addition was completed, stirring was continued for 30 minutes, and then iodoethane (8.87 g, 62.5 mmol) was added to the above reaction solution. After the addition was completed, the reaction solution was reacted 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, and extracted with ethyl acetate (100 mL×3). The organic phases were combined, backwashed with saturated brine (100 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain 5.0 g of compound 25c, which was directly used in the next step.

[0295] Step 3: Synthesis of compound 25d

[0296] At 0°C, compound 25c (5.00 g, 26.5 mmol) was dissolved in a mixed solution of ethanol (30 mL) and water (10 mL), and sodium bicarbonate (223 mg, 2.65 mmol) and 37% aqueous formaldehyde solution (2.63 g, 29.2 mol) were added thereto in sequence under nitrogen protection. After the addition was completed, the mixture was reacted 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 the mixture was extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with saturated brine (100 mL×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 (400MHz, CDCl3) δ 5.12-5.08 (m, 1H), 4.86 (s, 2H), 3.78 (s, 3H), 2.10 (q, J = 12.4Hz, 2H), 1.26 (d, J = 6.4, 6H), 0.93 (t, J = 7.6, 3H).

[0297] Step 4: Synthesis of compound 25e

[0298] At room temperature, sulfonyl chloride (462 mg, 3.44 mmol) was dissolved in ether (10 mL), cooled to -78 °C under nitrogen protection, and a solution of compound 25d (500 mg, 2.29 mmol) and pyridine (271 mg, 3.44 mmol) in ether (2 mL) was slowly added thereto. After the addition was complete, the temperature was gradually raised to room temperature and the mixture was reacted 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 0.5 g of compound 25e, which was directly used in the next step.

[0299] Step 5: Synthesis of compound 25

[0300] At room temperature, compound 22d (300 mg, 0.996 mmol) was dissolved in a mixed solution of tetrahydrofuran (3 mL) and N,N-dimethylpropylene urea (1 mL), and the mixture was cooled to -78°C under nitrogen protection. Then sodium bis(trimethylsilyl)amide (59.8 uL, 2M tetrahydrofuran solution) was added dropwise to the reaction solution. After the addition was complete, the reaction solution was reacted at -78°C for 10 minutes. Compound 24e (378 mg, 1.19 mmol) was added dropwise to the reaction solution. After the addition was complete, the mixture 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 saturated aqueous solution of sodium bicarbonate (20 mL) at 0°C, extracted with ethyl acetate (50 mL×2), the organic phases were combined and concentrated to dryness, and 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 (400MHz, CDCl3) δ8.65 (s, 1H), 5.82 (s, 2H), 5.12-5.04 (m, 2H), 4.94 (dd, J = 10.0, 5.2Hz, 1H), 4.18 (s, 1H), 4.0 9(d,J=7.6Hz,1H),3.77(d,J=4.8Hz,3H),3.36(d,J=12.4Hz,1H),2.90(d,J=12.0Hz,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=7.6Hz,3H).

[0301] Example 26: Synthesis of Compound 26

[0302] 2-((((((2S,5R)-2-((((acetyloxymethoxy)carbonyl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonic acid-1-tert-butyl-3-ethyl ester

[0303]

[0304] Step 1: Synthesis of compound 26b

[0305] At room temperature, compound 26a (50.0 g, 0.312 mol) was dissolved in dichloromethane (500 mL), and then ethanol (21.5 g, 0.468 mol) and 4-dimethylaminopyridine (3.81 g, 31.2 mmol) were added in sequence. 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 mixture was reacted at room temperature for 16 hours. 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 (400MHz, DMSO-d6) δ4.11-4.09(m,2H),3.40-3.19(m,2H),1.41(s,9H),1.19(t,J=7.2Hz,3H).

[0306] Step 2: Synthesis of compound 26c

[0307] At 0°C, compound 26b (40.0 g, 0.212 mol) was dissolved in tetrahydrofuran (400 mL). Under nitrogen protection, sodium hydrogen sulfide (9.36 g, 0.234 mol, 60% in mineral oil) was slowly added. After the addition, stirring was continued for 30 minutes, and then iodomethane (31.7 g, 0.21 mol) was added to the above reaction solution. After the addition, the reaction solution was reacted 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×3). The organic phases were combined, backwashed with saturated brine (200 mL×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 step.

[0308] Step 3: Synthesis of compound 26d

[0309] At 0°C, compound 26c (20.0 g, 99.1 mmol) was dissolved in a mixed solution of ethanol (200 mL) and water (100 mL), and sodium bicarbonate (831 mg, 9.91 mmol) and 37% formaldehyde aqueous solution (9.80 g, 108 mol) were added in sequence 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 (200 mL) was added to the reaction mixture at 25°C to quench the reaction, and the mixture was extracted with ethyl acetate (200 mL×3). The organic phases were combined, washed with saturated brine (200 mL×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 (400MHz, CDCl3) δ4.27-4.15(m,2H),3.79(d,J=18.0Hz,2H),1.47(s,9H),1.40(s,3H),1.28(t,J=7.2Hz,3H).

[0310] Step 4: Synthesis of compound 26e

[0311] At room temperature, sulfonyl chloride (6.93 g, 51.7 mmol) was dissolved in ether (30 mL), cooled to -78 °C under nitrogen protection, and 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. After the addition was complete, the temperature was gradually raised to room temperature and the mixture was reacted 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.

[0312] Step 5: Synthesis of compound 26

[0313] At room temperature, compound 22d (8.00 g, 26.5 mmol) was dissolved in a mixed solution of tetrahydrofuran (80 mL) and N,N-dimethylpropylene urea (35 mL), cooled to -78°C under nitrogen protection, and then sodium bis(trimethylsilyl)amide (15.9 mL, 2M tetrahydrofuran solution) was added dropwise to the reaction solution. After the addition was complete, the reaction was carried out at -78°C for 10 minutes. Compound 26e (10.5 g, 31.9 mmol) was added dropwise to the reaction solution. After the addition was complete, the temperature was gradually raised to room temperature and the reaction was carried out at room temperature for 3 hours. After the reaction was completed, the reaction solution was poured into a saturated aqueous solution of sodium bicarbonate (20 mL) at 0°C, extracted with ethyl acetate (50 mL×2), the organic phases were combined and concentrated to dryness, and 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 (400MHz, CDCl3) δ8.65(s,1H),5.82(s,2H),5.02-4.83(m,2H),4.30-4.14(m,3H),4.09(d,J=7.6Hz,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 = 2.0Hz, 3H), 1.46 (d, J = 3.6Hz, 9H), 1.28 (t, J = 7.2Hz, 3H).

[0314] Example 27: Synthesis of Compound 27 Isopropyl 2-((((((2S,5R)-2-((((acetyloxymethoxy)carbonyl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylmalonate

[0315]

[0316] Step 1: Synthesis of compound 27a

[0317] At 0°C, compound 24b (10.0 g, 57.5 mmol) was dissolved in tetrahydrofuran (100 mL). Under nitrogen protection, sodium hydrogen sulfide (2.53 g, 63.2 mmol, 60% in mineral oil) was slowly added. After the addition was completed, stirring was continued for 30 minutes, and then iodoethane (8.93 g, 57.2 mmol) was added to the above reaction solution. After the addition was completed, the reaction solution was reacted 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 (100 mL×3). The organic phases were combined, backwashed with saturated brine (100 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain 6.1 g of compound 27a, which was directly used in the next step.

[0318] Step 2: Synthesis of compound 27b

[0319] At 0°C, compound 27a (6.00 g, 29.7 mmol) was dissolved in a mixed solution of ethanol (30 mL) and water (10 mL). Under nitrogen protection, sodium bicarbonate (249 mg, 2.97 mmol) and 37% formaldehyde aqueous solution (2.94 g, 32.6 mol) were added thereto in sequence. After the addition was completed, the mixture was reacted 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 the mixture was extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with saturated brine (200 mL×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 / 1V / V) to obtain 3.9 g of compound 27b with a yield of 56.6%. 1 H NMR (400MHz, CDCl3) δ5.12-5.08(m,1H),4.08(s,2H),4.24(q,J=3.2Hz,2H),2.10(q,J=3.2Hz,2H),1.30-1.25(m,9H),0.94(t,J=7.2Hz,3H).

[0320] Step 3: Synthesis of compound 27c

[0321] At room temperature, sulfonyl chloride (433 mg, 3.23 mmol) was dissolved in ether (10 mL), cooled to -78 °C under nitrogen protection, and a solution of compound 27b (500 mg, 2.16 mmol) and pyridine (255 mg, 3.23 mmol) in ether (2 mL) was added dropwise. After the addition was complete, the temperature was gradually raised to room temperature and the mixture was reacted 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 0.6 g of compound 27c, which was directly used in the next step.

[0322] Step 4: Synthesis of compound 27

[0323] At room temperature, compound 22d (300 mg, 0.996 mmol) was dissolved in a mixed solution of tetrahydrofuran (3 mL) and N,N-dimethylpropylene urea (1 mL), cooled to -78°C under nitrogen protection, and sodium bis(trimethylsilyl)amide (59.8 uL, 2M tetrahydrofuran solution) was added dropwise. After the addition was complete, the mixture was reacted at -78°C for 10 minutes. Compound 27c (392 mg, 1.19 mmol) was then added dropwise to the reaction solution. After the addition was complete, the mixture 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 saturated aqueous solution of sodium bicarbonate (20 mL) at 0°C, extracted with ethyl acetate (50 mL×2), the organic phases were combined and concentrated to dryness, and 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 (400MHz, CDCl3) δ8.65 (s, 1H), 5.82 (s, 2H), 5.16-5.04 (m, 2H), 4.95 (d, J= 10.0Hz,1H),4.30-4.15(m,4H),4.09(d,J=7.2Hz,1H),3.36(d,J=12.4Hz,1H) ,2.90(d,J=12.0Hz,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=7.6Hz,3H).

[0324] Test Example 1: Liver microsome stability test

[0325] 1.1 Liver microsomes

[0326] Human liver microsomes (source: BioreclamationIVT).

[0327] 1.2 Preparation of compound solution

[0328] A certain amount of the example compound was weighed, and DMSO was added to prepare a 0.1 mM intermediate solution A, which was then added to PBS to prepare a 3 μM intermediate solution B.

[0329] 1.3 Sample incubation

[0330] 15 μL human liver microsomal protein and 15 μL NADPH solution were dispensed into 96-well plates at different time points (0, 5, 15, 30, 60 min), and 15 μL human liver microsomal protein and 15 μL PBS solution were dispensed into 96-well plates at different time points (0 and 60 min) as negative controls; for 0 min, acetonitrile:methanol (1:1) containing internal standard and intermediate solution B were added, and for samples at other time points, intermediate solution B was added to start the reaction. All samples were pre-incubated in a 37°C incubator for 5 min, and acetonitrile:methanol (1:1) containing internal standard was added to stop the reaction; the samples were shaken at 600 rpm for 10 min, centrifuged at 4000 rpm for 15 min, and the supernatant was collected for LC-MS analysis.

[0331] 2. Results

[0332] The transformation of the compounds of the present invention in human liver microsomes is as follows, and the data are shown in Table 1 and Table 2:

[0333] Table 1 Metabolism data of compounds in human liver microsomes

[0334]

[0335] Table 2 Data on the conversion and release of avibactam by compounds in human liver microsomes

[0336]

[0337] The compounds of Examples 6, 7, 16, 23, 24, 25, 26, and 27 were rapidly converted into the parent drug avibactam in human liver microsomes with a half-life of T 1 / 2 <5min.

[0338] Test Example 2: Oral Bioavailability in Rats

[0339] Pharmacokinetic (PK) studies were conducted in male Sprague-Dawley (SD) rats following intravenous (IV) and oral (PO) administration of avibactam and oral (PO) administration of test compound. The oral bioavailability (%F) of avibactam was determined by comparing the AUC after oral administration with the AUC after IV administration.

[0340] 1.1 Drug preparation

[0341] Avibactam was dissolved in phosphate buffered saline (PBS) (pH 7.5) to prepare 0.4 mg / mL for intravenous injection, and avibactam and the compounds of Examples 6, 23, 24, 25, 26, and 27 were respectively prepared with 2% DMSO + 10% Solutol + 88% Saline to prepare 1.0 mg / mL solutions for oral administration.

[0342] 1.2 Administration

[0343] The intravenous dose is 2 mg / kg and the oral dose is 10 mg / kg; the intravenous and oral dose volumes are 5 mL / kg and 10 mL / kg, respectively.

[0344] 1.3 Operation

[0345] Blood was collected by jugular sinus puncture at 0h, 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, and 24h after administration, and heparin sodium was used for anticoagulation. Blood samples were placed on ice after collection, and plasma separation was completed within 30 minutes after collection (centrifugation conditions: 6800g, 6 minutes, 2-8°C), and the supernatant was removed for LC / MS / MS analysis to determine the concentration of avibactam.

[0346] 1.3 Pharmacokinetic parameter results

[0347] In male rats, after the compound and the original drug were converted to equimolar, the oral bioavailability of the original drug is shown in Table 3 below, where A represents (%F)>95%, B represents 50<(%F)≤95%, C represents 20<(%F)≤50%, and D represents (%F)≤20%.

[0348] 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 invention can greatly improve the oral bioavailability of avibactam, solving the problem that avibactam cannot be orally administered.

[0349] Table 3

[0350]

Claims

1. A β-lactamase inhibitor having a structure as shown in the following formula (I) or a pharmaceutically acceptable salt thereof or an isomer or deuterated product thereof: in: R1 is selected from R2 and R3 are each independently selected from halogen, hydroxyl, cyano, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C1-8 heteroalkyl, and the substituents may be halogen, hydroxyl, cyano, C1-8 alkyl, C1-8 heteroalkyl, C3-8 cycloalkyl, C3-8 heterocycloalkyl, C3-8 cycloalkylalkyl, C3-8 heterocycloalkylalkylalkyl, C6-8 aryl, C5-8 heteroaryl, C7-10 arylalkyl, C5-10 heteroarylalkyl, substituted C3-8 cycloalkyl, substituted C3-8 heterocycloalkyl, substituted C3-8 cycloalkylalkylalkyl, substituted C3-8 heterocycloalkylalkylalkyl, substituted C6-8 aryl, substituted C5-8 heteroaryl, substituted C7-10 arylalkyl, substituted C5-10 heteroarylalkyl or R4 is selected from halogen, hydroxyl, cyano, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C1-8 heteroalkyl, and the substituent can be halogen, hydroxyl, cyano, C1-8 alkyl, C1-8 heteroalkyl, C3-8 cycloalkyl, C3-8 heterocycloalkyl, C3-8 cycloalkylalkyl, C3-8 heterocycloalkylalkylalkyl, C6-8 aryl, C5-8 heteroaryl, C7-10 arylalkyl, C5-10 heteroarylalkyl, substituted C3-8 cycloalkyl, substituted C3-8 heterocycloalkyl, substituted C3-8 cycloalkylalkylalkyl, substituted C3-8 heterocycloalkylalkylalkyl, substituted C6-8 aryl, substituted C5-8 heteroaryl, substituted C7-10 arylalkyl, substituted C5-10 heteroarylalkyl or R a , R c , R d Each independently selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, the substituent may be halogen, hydroxyl, cyano, C1-8 alkyl, C1-8 heteroalkyl, C3-8 cycloalkyl, C3-8 heterocycloalkyl, C3-8 cycloalkylalkyl, C3-8 heterocycloalkylalkylalkyl, C6-8 aryl, C5-8 heteroaryl, C7-10 arylalkyl, C5-10 heteroarylalkyl, substituted C3-8 cycloalkyl, substituted C3-8 heterocycloalkyl, substituted C3-8 cycloalkylalkylalkyl, substituted C3-8 heterocycloalkylalkylalkyl, substituted C6-8 aryl, substituted C5-8 heteroaryl, substituted C7-10 arylalkyl, substituted C5-10 heteroarylalkyl; R b is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, the substituents may be halogen, hydroxyl, cyano, C1-8 alkyl, C1-8 heteroalkyl, C3-8 cycloalkyl, C3-8 heterocycloalkyl, C3-8 cycloalkylalkyl, C3-8 heterocycloalkylalkylalkyl, 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 heterocycloalkylalkylalkyl, substituted C6-8 aryl, substituted C5-8 heteroaryl, substituted C7-10 arylalkyl, substituted C5-10 heteroarylalkyl or R e is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, the substituents may be halogen, hydroxyl, cyano, C1-8 alkyl, C1-8 heteroalkyl, C3-8 cycloalkyl, C3-8 heterocycloalkyl, C3-8 cycloalkylalkyl, C3-8 heterocycloalkylalkylalkyl, 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 heterocycloalkylalkylalkyl, substituted C6-8 aryl, substituted C5-8 heteroaryl, substituted C7-10 arylalkyl, substituted C5-10 heteroarylalkyl; L1, L2, L3 are each independently selected from unsubstituted or substituted with one or more R 1a Substituted -(CH2) m -or-(CH2) m NH-; wherein m is selected from 1, 2, 3, 4 or 5; R 1a Selected from NH2, C1-C4 alkyl or -NH-Boc.

2. The β-lactamase inhibitor according to claim 1, characterized in that R2 is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclopropyl, oxetanyl, oxacyclopentyl, oxacyclohexyl, aryl, heteroaryl, -(CH2) n -R f ,; Preferably, R3 is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclopropyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, aryl, heteroaryl, -CH2-R f 、-CH2-CH2-R f 、-(CH2)3-R f or R f is selected from isopropyl, isobutyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclopropyl, oxetanyl, oxacyclopentyl, oxacyclohexyl, aryl, heteroaryl, hydroxy, alkenyl, alkynyl, cyano; Preferably, R2 is selected from methyl, ethyl, propyl, n-butyl, pentyl, -CH2-R f 、-CH2-CH2-R f 、-(CH2)3-R f Preferably, R3 is selected from 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, R2 is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl; preferably, R3 is selected from 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 R4 is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclopropyl, oxetanyl, oxacyclopentyl, oxacyclohexyl, aryl, heteroaryl, -(CH2) n -R f ,or R f is selected from isopropyl, isobutyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclopropyl, oxetanyl, oxacyclopentyl, oxacyclohexyl, aryl, heteroaryl, hydroxyl, alkenyl, alkynyl, cyano; preferably, R4 is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-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, R4 is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl or Preferably, R a , R c , R d Each is independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl; preferably, R a Selected from ethyl; preferably, R c , R d Each independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl; preferably, R b is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl or Preferably, R e is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl and sec-butyl; preferably, R b Selected from methyl or 4. The β-lactamase inhibitor according to claim 1, characterized in that L1, L2, L3 are each independently selected from unsubstituted or substituted with one or more R 1a Substituted -(CH2) m -or-(CH2) m NH-; wherein m is selected from 1, 2 or 3; R 1a is selected from NH2, methyl, ethyl, propyl, isopropyl or -NH-Boc; preferably, L1, L2, 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 a structure represented by the following formula (II) or a pharmaceutically acceptable salt thereof: Among them, R2, R3, R4, L2, R c The definition may be as described in any one of claims 1 to 4.

6. A β-lactamase inhibitor having a structure represented by the following formula (III) or a pharmaceutically acceptable salt thereof: Among them, R2, R3, R4, L2, R c The definition is as described in any one of claims 1 to 4; preferably, R3 is selected from R2, R4, R k Each is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl; preferably, R2 is selected from methyl, ethyl, n-propyl, isopropyl; R4 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl; R k Selected from methyl, ethyl, n-propyl, isopropyl.

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

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

9. Use of the β-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 in the preparation of a β-lactamase inhibitor.

10. Use of the β-lactamase inhibitor or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating diseases related to bacterial infection; preferably, the bacteria are bacteria capable of producing β-lactamase, more preferably bacteria of the genus Enterobacter, Citrobacter, Prufidenella, Serratia marcescens or Morganella.

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