A β-lactamase inhibitor and its use

Abstract

The present invention discloses a β-lactamase inhibitor and its use. The β-lactamase inhibitor has a structure represented by the following formula (I) or a pharmaceutically acceptable salt thereof, an isomer thereof, or a deuterated product thereof. The group in the β-lactamase inhibitor that increases the compound's lipid solubility binds to the amide and sulfonic acid groups in the avibactam structure, increasing the lipid solubility of the structure. Furthermore, the inhibitor is able to rapidly and completely release the active metabolite, avibactam, through the action of biological enzymes, resulting in a rapid onset of action. This effectively improves the oral bioavailability of avibactam, enabling oral administration, thereby resolving the issue of avibactam being unable to be administered orally. #imgabs0#

Description

Technical Field

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

[0002] The rapid development of antibiotics has been of great significance in the history of modern medicine. Antibiotics can effectively treat bacterial infections, bringing significant clinical benefits. However, their irrational and even overuse has accelerated the development of bacterial resistance, posing a significant challenge to human health. β-lactam antibiotics, one of the oldest, most widely used, and most commonly used antibiotics in clinical practice, have also faced a growing and increasingly serious problem of resistance.

[0003] β-lactamase produced by bacteria can hydrolyze antibiotics with β-lactam ring structure, making them inactive. This is the most common mechanism of bacterial resistance to β-lactam antibiotics. β-lactamase can be divided into two main categories based on the difference in amino acid sequence in the molecular structure: A, C, and D types with serine as the active site, and metal ions (especially Zn) as the active site. 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 destroyed and 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 compound (DBOs), a class of reversible β-lactamase inhibitors. Compared with classic β-lactamase inhibitors (clavulanic acid, sulbactam, and tazobactam), it has the characteristics of long-lasting effect, reversible covalent binding to the enzyme, and no induction of β-lactamase production. However, because avibactam contains sulfonic acid and formamide structures, it has high water solubility and low lipid solubility, resulting in poor tissue permeability. It cannot be taken orally and can only be used for intravenous injection, which also limits its clinical use.

[0006]

[0007] Chinese invention patent CN110662746 discloses a 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropionate derivative and related compounds as orally administered prodrugs of β-lactamase inhibitors for the treatment of bacterial infections. The structural design of the invention improves the oral bioavailability of avibactam. In an 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 its use. 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 represented by the following formula (I) or a pharmaceutically acceptable salt thereof or an isomer or deuterated product thereof:

[0011]

[0012] Wherein: 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 heterocycloalkylalkyl, C6-8 aryl, C5-8 heteroaryl, C7-10 arylalkyl, C5-10 heteroarylalkyl, substituted C3-8 cycloalkyl, substituted C3-8 heterocycloalkyl, substituted C3-8 cycloalkylalkyl, substituted C3-8 heterocycloalkylalkyl, substituted C6-8 aryl, substituted C5-8 heteroaryl, substituted C7-10 arylalkyl, substituted C5-10 heteroarylalkyl or

[0014] R4 is selected from halogen, hydroxyl, cyano, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C1-8 heteroalkyl, the substituents 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 cycloalkylalkyl, 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 substituents may be halogen, hydroxy, 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 heterocycloalkylalkyl, 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 being halogen, hydroxy, 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 heterocycloalkylalkyl, 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 being halogen, hydroxy, 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 heterocycloalkylalkyl, 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 by 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 is 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, oxetanyl, oxolanyl, oxetanyl, 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, oxetanyl, oxetanyl, oxetanyl, oxetanyl, aryl, heteroaryl, -(CH2) n -R f or R fis selected from isopropyl, isobutyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetanyl, oxolanyl, oxetane, 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, cycloaziridine, oxetanyl, oxacyclopentyl, oxacycloaziridine, 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, oxetane, 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 independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl; in a specific embodiment, 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 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 is 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 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 or 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 carriers" refer to: one or more compatible solid or liquid fillers or gel substances that 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, flavorings, 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 application is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is generally 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 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 drug 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 genera Enterobacter, Citrobacter, Prufidonia, Serratia marcescens and Morganella.

[0049] The beneficial effects of the present invention are as follows: The present invention combines a group capable of increasing the compound's lipid solubility with the amide and sulfonic acid groups in the avibactam structure, thereby increasing the lipid solubility of the structure and rapidly and completely releasing the active metabolite, avibactam, through the action of biological enzymes, leading to rapid onset of action. The compound of the present invention has demonstrated an oral bioavailability of avibactam exceeding 95% in rats and beagle dogs, enabling oral administration without the need for an additional dose increase to achieve the same efficacy as an avibactam injection, thus resolving the issue of avibactam's inability to be administered orally. This provides patients with a broader-spectrum, safer oral β-lactamase inhibitor, effectively overcoming the narrow antibacterial spectrum of existing oral β-lactamase inhibitors. Combined use with antibiotics can effectively avoid antibiotic resistance, thereby enhancing the antibacterial activity of antibiotics. DETAILED DESCRIPTION

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

[0051] Example 1: Synthesis of Compound 1

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

[0053]

[0054] Step 1: Synthesis of compound 1b

[0055] Compound 1a (1.6 g, 5.81 mmol) was dissolved in dichloromethane (16 mL) at room temperature. After 10 minutes, lithium bromide (1.26 g, 14.5 mmol) and triethylamine (1.76 g, 17.4 mmol) were added at -78°C, and the atmosphere was replaced with argon three times. The reaction mixture was allowed to react for another 2 hours at room temperature. Upon completion of the reaction, LCMS was used to quench the reaction mixture. The mixture was then extracted three times with ethyl acetate (150 mL x 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 flash chromatography (petroleum ether:ethyl acetate (v / v = 1 / 1)) to afford 450 mg of compound 1b in a 22.3% yield. 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] At room temperature, compound 1b (450 mg, 1.3 mmol) was dissolved in ethyl acetate (5 mL), and 10% palladium on carbon (140 mg) was added. The resulting mixture was purged with hydrogen three times, and the reaction mixture was allowed to react at room temperature for 1.5 hours. LCMS monitored the reaction completion, and the reaction solution was filtered and the filtrate concentrated to give 290 mg of compound 1c in an 86.8% yield. 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 diethyl ether (300 mL) and cooled to -78°C under nitrogen. A solution of 1d (30.0 g, 205.2 mmol) and pyridine (24.3 g, 307.8 mmol) in diethyl ether (30 mL) was added dropwise. After the addition was complete, the reaction solution was gradually warmed to room temperature and allowed to react for 4 hours. Upon completion of the reaction, the reaction solution was filtered and the filtrate was concentrated to dryness to obtain 40.0 g of compound 1e in a 79.7% yield. 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 equiv) was dissolved in a mixture of tetrahydrofuran (6 mL / well) and N,N-dimethylpropyleneurea (2.4 mL). The mixture was cooled to -78°C under a nitrogen atmosphere. After 10 minutes, sodium bis(trimethylsilyl)amide (0.6 mL, 2 M solution in tetrahydrofuran, 1.24 mmol) was added dropwise to the reaction mixture, which was maintained at -78°C. The reaction mixture was then allowed to react at -78°C for 10 minutes, followed by the addition of compound 1e (552 mg, 2.25 mmol). After 10 minutes, the mixture was allowed to warm to room temperature and allowed to react for 2 hours. After completion of the reaction, as monitored by LCMS, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 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 preparative purification (C18, 10 mmol / L formic acid / water, acetonitrile) to obtain 64.83 mg of compound 1 with a yield of 12.3%. LCMS (ESI): [M+H] + =466.3. 1 H NMR (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), and potassium carbonate (500 mg, 3.63 mmol) and formaldehyde solution (30%, 40 mL) were added sequentially. The reaction mixture was allowed to react overnight at room temperature. After the reaction was completed, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL × 3). 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-oxobutanoate (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 10% palladium on carbon (200 mg) was added. The mixture was then purged with hydrogen three times. The reaction mixture was allowed to react under a hydrogen atmosphere at room temperature for 1.5 hours. Upon completion of the reaction as monitored by LCMS, the reaction solution was filtered and the filtrate concentrated to yield 550 mg of compound 2c, in an 87.6% yield. 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 mixture of dry tetrahydrofuran (11 mL) and N,N-dimethylpropyleneurea (4.4 mL). Sodium bis(trimethylsilyl)amide (0.92 mL, 2 M solution in tetrahydrofuran, 1.84 mmol) was added dropwise to the reaction mixture at -78°C under a nitrogen atmosphere. The reaction was maintained at -78°C for 10 minutes, followed by the addition of compound 1e (846 mg, 3.34 mmol). After 10 minutes, the temperature was slowly raised to room temperature, and the mixture was allowed to react at room temperature for 2 hours. Upon completion of the reaction, the mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase preparative HPLC (C18, 10 mmol / L formic acid / water, acetonitrile) to yield 21.86 mg of compound 2 in a 2.43% yield. 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] Ethyl 3-(((((2S,5R)-2-((((isobutyryloxy)methoxy)carbonyl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate

[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), followed by the addition of triethylamine (1.56 g, 15.5 mmol) and ethanethiol (976 mg, 15.5 mmol). The reaction mixture was allowed to react for 16 hours at room temperature. Upon completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to dryness. The crude product was purified by flash chromatography (Silica gel, petroleum ether:ethyl acetate (V / V = 10 / 1)) to afford 1.0 g of compound 3b in a 42.0% yield. 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, followed by the addition of N,N-diisopropylethylamine (2.51 g, 19.5 mmol). The reaction mixture was allowed to react at 60°C for 48 hours. Upon completion of the reaction, LCMS was used to quench the reaction mixture. The mixture was then extracted three times with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 1.0 g of compound 3c in a 75.2% yield. 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 was continued at room temperature for 1 hour. LCMS monitoring confirmed the completion of the reaction. The reaction solution was concentrated to dryness to yield 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] Compound 1a (2.0 g, 7.27 mmol) was dissolved in tetrahydrofuran (20 mL) at room temperature and cooled to -78°C under nitrogen. After 10 minutes, lithium bis(trimethylsilyl)amide (15 mL, 1 M solution in tetrahydrofuran, 14.5 mmol) was added dropwise to the reaction mixture and maintained at -78°C. The reaction mixture was allowed to react at -78°C for 30 minutes, followed by compound 3d (1.4 g, 8.00 mmol). The temperature was slowly raised to room temperature and the reaction was continued at room temperature for 2 hours. After completion of the reaction, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The crude product was purified by flash chromatography (Silica gel, petroleum ether:ethyl acetate (V / V = 1 / 1)) to afford 450 mg of compound 3e in a 14.7% yield. LCMS (ESI): [M+H] + =420.1.

[0084] Step 5: Synthesis of compound 3f

[0085] Compound 3e (200 mg, 0.48 mmol) was dissolved in ethyl acetate (4 mL) at room temperature, and 10% palladium on carbon (20 mg) was added. The mixture was replaced with hydrogen three times and stirred at room temperature under a hydrogen atmosphere for 1.5 h. After completion of the reaction, the reaction solution was filtered and the filtrate was concentrated to dryness to obtain 140 mg of compound 3f in an 89.7% yield. 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] Compound 3f (120 mg, 0.364 mmol) was dissolved in a mixture of tetrahydrofuran (2 mL) and N,N-dimethylpropyleneurea (0.8 mL) at room temperature. The mixture was cooled to -78°C under a nitrogen atmosphere. After 10 minutes, sodium bis(trimethylsilyl)amide (218 μL, 2 M solution in tetrahydrofuran, 1.44 mmol) was added dropwise to the reaction mixture, which was maintained at -78°C. The reaction mixture was allowed to react at -78°C for 10 minutes. Compound 1e (178 mg, 0.73 mmol) was then added. After 10 minutes, the mixture was allowed to warm to room temperature and allowed to react at room temperature for 2 hours. After completion of the reaction, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined and concentrated under reduced pressure to obtain the crude product, which was then purified by reverse phase preparative purification (C18, 10 mmol / L formic acid / water, acetonitrile) to afford 25 mg of compound 3 in a 12.7% yield. 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), and methyl 5-chloro-5-oxopentanoate (1.07 g, 6.56 mmol) and pyridine (778 mg, 9.84 mmol) were added thereto. The atmosphere was replaced with argon three times. The reaction mixture was allowed to react for 3 hours at room temperature. LCMS monitored the completion of the reaction. Water (100 mL) was added to the reaction mixture 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] At room temperature, compound 4a (800 mg, 1.85 mmol) was dissolved in ethyl acetate (8 mL), and 10% palladium on carbon (240 mg) was added. The resulting mixture was replaced with hydrogen three times, and the reaction solution was allowed to react under a hydrogen atmosphere at room temperature for 1.5 hours. LCMS monitored the reaction completion, and the reaction solution was filtered and the filtrate 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 mixture of tetrahydrofuran (12 mL) and N,N-dimethylpropyleneurea (4.8 mL). The mixture was cooled to -78°C under a nitrogen atmosphere. After 10 minutes, sodium bis(trimethylsilyl)amide (1.0 mL, 2 M solution in tetrahydrofuran, 1.93 mmol) was added dropwise to the reaction mixture, which was maintained at -78°C. The reaction mixture was allowed to react at -78°C for 10 minutes, followed by the addition of compound 1e (856 mg, 3.5 mmol). After 10 minutes, the mixture was allowed to warm to room temperature and allowed to react for 2 hours. After completion of the reaction, as monitored by LCMS, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were concentrated to dryness under reduced pressure, and the residue was purified by reverse phase preparative purification (C18, 10 mmol / L formic acid / water, acetonitrile) to afford 93.84 mg of compound 4 in a 9.72% yield. 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-dimethylformamide (0.1 mL). Oxalyl chloride (4.16 g, 32.78 mmol) was slowly added to the mixture under an ice bath. The resulting solution was then flushed with argon three times. The reaction mixture was allowed to react at room temperature for 3 hours. Upon completion, the reaction solution was concentrated to yield 3.5 g of compound 5b, which was used directly 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), and compound 2a (1.88 g, 6.16 mmol) and pyridine (1.46 g, 18.48 mmol) were added. The resulting solution was purged with argon three times. The reaction mixture was allowed to react for 3 hours at room temperature. LCMS monitored the reaction completion, and water (100 mL) was added to the reaction mixture to quench the reaction. The mixture was then 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 in 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] At room temperature, compound 5c (1.0 g, 2.23 mmol, 1.0 equivalent) was dissolved in ethyl acetate (10 mL), and 10% palladium on carbon (300 mg) was added. The resulting mixture was replaced with hydrogen three times, and the reaction solution was allowed to react under a hydrogen atmosphere at room temperature for 1.5 hours. LCMS monitored the reaction completion, and the reaction solution was filtered and the filtrate concentrated to dryness to obtain 700 mg of compound 5d in a 90.3% yield. 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 mixture of tetrahydrofuran (14 mL) and N,N-dimethylpropyleneurea (5.6 mL). The mixture was cooled to -78°C under a nitrogen atmosphere. After 10 minutes, sodium bis(trimethylsilyl)amide (1.0 mL, 2 M solution in tetrahydrofuran, 2.16 mmol) was added dropwise to the reaction mixture, which was maintained at -78°C. The reaction mixture was then allowed to react at -78°C for 10 minutes, followed by the addition of compound 1e (962 mg, 3.92 mmol). After 10 minutes, the mixture was allowed to warm to room temperature and allowed to react for 2 hours. After completion of the reaction, as monitored by LCMS, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were concentrated to dryness under reduced pressure, and the residue was purified by reverse phase preparative chromatography (C18, 10 mmol / L formic acid / water, acetonitrile) to afford 71.4 mg of actual compound 5 in a 6.44% yield. 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 mixture of tetrahydrofuran (5 mL) and water (5 mL). Sodium hydroxide (22.47 g, 561.80 mmol) and methyl chloroformate (29.20 g, 309.00 mmol) were then added sequentially. The reaction mixture was allowed to react at room temperature for three hours. After completion of the reaction, the reaction mixture was poured into water (300 mL), the pH was adjusted to 3 with 1 M aqueous hydrochloric acid, and the mixture was extracted with ethyl acetate (100 mL x 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 flash chromatography (silica gel, dichloromethane:methanol (V / V = 5 / 1)) to obtain 11.50 g of compound 8b in a yield of 27.85%. LCMS (ESI) [M+H] + =148.0.

[0122] Step 2: Synthesis of compound 8c

[0123] Compound 8b (4.50 g, 30.59 mmol) was dissolved in tetrahydrofuran (60 mL) at room temperature and the temperature was lowered to -10°C. 4-Methylmorpholine (3.40 g, 33.64 mmol) and ethyl chloroformate (3.65 g, 33.64 mmol) were then added sequentially. The reaction mixture was allowed to react at -10°C for three hours. Upon completion of the reaction, the reaction mixture 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 sequentially. The reaction mixture was allowed to react at room temperature for three hours. After completion of the reaction, the reaction mixture was directly concentrated to dryness, and the residue was purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (V / V = 1 / 1)) to obtain 1.38 g of compound 8d in a yield of 24.25%. LCMS (ESI) [M+H] + =435.2.

[0126] Step 4: Synthesis of compound 8e

[0127] Compound 8d (1.38 g, 3.18 mmol) was dissolved in ethyl acetate (5 mL) at room temperature, followed by the addition of 10% palladium on carbon (414 mg). The reaction mixture was allowed to react at room temperature under a hydrogen atmosphere for 1.5 hours. After completion of the reaction, the reaction mixture 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-dimethylpropyleneurea (4 mL). The mixture was cooled to -78°C under nitrogen. Sodium bis(trimethylsilyl)amide (0.8 mL, 2 M / tetrahydrofuran solution, 1.6 mmol) was then added dropwise to the reaction mixture, which was maintained at -78°C for 10 minutes. Compound 1e (533 mg, 2.18 mmol) was then added dropwise to the reaction mixture. After 10 minutes, the mixture was allowed to warm to room temperature and allowed to react at room temperature for 2 hours. Upon completion of the reaction, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic 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 preparative purification (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). The mixture was cooled to -10°C under nitrogen. N-methylmorpholine (4.50 g, 44.5 mmol), methyl 2-chloroacetate (4.37 g, 80.97 mmol), and methyl 4-chloro-4-oxobutanoate (1.48 g, 9.84 mmol) were then added sequentially. The reaction mixture was allowed to react at -10°C for 1 hour. Upon completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to dryness to obtain 10.5 g of compound 9b in a 98.1% yield. 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), followed by the addition of pyridine (1.56 g, 19.67 mmol) and compound 9b (2.61 g, 9.83 mmol). The reaction mixture was allowed to react for 3 hours at room temperature. Upon completion, water (50 mL) was added to the reaction mixture 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 10% palladium on carbon (70 mg) was added. The mixture was then purged with hydrogen three times. The reaction mixture was allowed to react under a hydrogen atmosphere at room temperature for 1.5 hours. After the reaction was complete, the reaction solution was filtered and the filtrate was concentrated to dryness to obtain 250 mg of compound 9d in an 85.9% yield. 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 mixture of ultra-dry tetrahydrofuran (5 mL) and N,N-dimethylpropyleneurea (2 mL). Sodium bis(trimethylsilyl)amide (0.62 mL, 2M solution in tetrahydrofuran, 0.62 mmol) was added dropwise to the reaction mixture under a nitrogen atmosphere at -78°C. The reaction was maintained at -78°C for 10 minutes, followed by the addition of compound 1e (275 mg, 1.12 mmol). After 10 minutes, the temperature was slowly raised to room temperature, and the mixture was allowed to react at room temperature for 2 hours. Upon completion of the reaction, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were concentrated to dryness, and the residue was purified by reverse-phase preparative HPLC (C18, 10 mmol / L formic acid / water, acetonitrile) to yield 21.77 mg of compound 9 in a 5.93% yield. 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), followed by the addition of 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). The reaction mixture was allowed to react for 16 hours at room temperature. Upon completion, the reaction mixture was quenched with saturated aqueous NaHCO₃ (200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (v / v = 5 / 1)) to afford 11.0 g of compound 10b in a 74.3% yield. 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-oxobutanoic acid

[0147] At room temperature, compound 10b (10.0 g, 32.47 mmol) was dissolved in methanol (100 mL), and 10% palladium on carbon (1.5 g) was added. The mixture was then purged with hydrogen three times. The reaction mixture was allowed to react under a hydrogen atmosphere at room temperature for 1 hour. After the reaction was complete, the reaction solution was filtered and the filtrate was concentrated to dryness to obtain 6.0 g of compound 10c in an 85.7% yield. LCMS (ESI): [M+Na] + =240.9.

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

[0149] At room temperature, compound 10c (2.3 g, 10.55 mmol) was dissolved in dry dichloromethane (23 mL). The mixture was cooled to 0°C under a nitrogen atmosphere, and then N,N-dimethylformamide (77 mg, 1.06 mmol) and oxalyl chloride (1.34 g, 10.55 mmol) were added sequentially. The reaction mixture was allowed to react at room temperature for 1 hour. Upon completion of the reaction, the solution was concentrated to dryness to obtain 2.3 g of compound 10d in a 92.7% yield. 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 pyridine (1.556 g, 19.67 mmol) and compound 10d (2.32 g, 9.84 mmol) were added sequentially. The reaction mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, water (50 mL) was added to the reaction mixture to quench the reaction, and the mixture was extracted 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 = 1 / 1)) to obtain 2.0 g of compound 10e in a 60.6% yield. 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 10% palladium on carbon (400 mg) was added. The mixture was then purged with hydrogen three times. The reaction mixture was allowed to react under a hydrogen atmosphere at room temperature for 1.5 hours. Upon completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated to dryness to obtain 1.3 g of compound 10f in 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 mixture of dry tetrahydrofuran (25 mL) and N,N-dimethylpropyleneurea (10 mL). Sodium bis(trimethylsilyl)amide (2.03 mL, 2 M / tetrahydrofuran solution, 4.06 mmol) was added dropwise to the reaction mixture at -78°C under a nitrogen atmosphere. The reaction was maintained at -78°C for 10 minutes, followed by the addition of compound 1e (1.80 g, 7.37 mmol). After 10 minutes, the temperature was slowly raised to room temperature, and the mixture was allowed to react at room temperature for 2 hours. Upon completion of the reaction, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were concentrated to dryness, and the residue was purified by reverse-phase preparative HPLC (C18, 10 mmol / L formic acid / water, acetonitrile) to afford 42.96 mg of compound 10 in a 1.87% yield. 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] Compound 11a (10.0 g, 70.34 mmol) was dissolved in methanol (100 mL) at room temperature, followed by the addition of triethylamine (7.12 g, 70.34 mmol) and N,N-dimethylformamide (0.86 g, 7.03 mmol). The reaction mixture was heated to 69°C for 16 hours. After the reaction was complete, the reaction mixture was concentrated to dryness, and the residue was purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (V / V = 1 / 1)) to afford 10.0 g of compound 11b in an 81.6% yield. LCMS (ESI): [M+H] + =175.0.

[0161] Step 2: Synthesis of compound 11c

[0162] Compound 11b (3.0 g, 17.2 mmol) was dissolved in dichloromethane (300 mL) at room temperature. Oxalyl chloride (3.3 g, 25.8 mmol) and 1 drop of N,N-dimethylformamide were then added. The mixture was allowed to react at room temperature for 3 h. After the reaction, the reaction mixture was concentrated to dryness to obtain 3.0 g of compound 11c in a 90.7% yield. 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] Compound 2a (2.0 g, 6.6 mmol) was dissolved in dichloromethane (200 mL) at room temperature. Pyridine (778 mg, 9.8 mmol) and compound 11c (1.9 g, 9.8 mmol) were added at 0°C, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, water (50 mL) was added to the reaction solution to quench the reaction. The resulting solution was extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed with saturated brine (100 mL × 2). The organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (V / V = 1 / 1)) to obtain 2.6 g of compound 11d in an 86.7% yield. LCMS (ESI): [M+H] + =462.2.

[0165] Step 4: Synthesis of compound 11e

[0166] Compound 11d (1.1 g, 2.39 mmol) was dissolved in ethyl acetate (11 mL) at room temperature. 10% palladium on carbon (200 mg) was added to the mixture, and the mixture was purged with hydrogen three times. The reaction mixture was allowed to react at room temperature under a hydrogen atmosphere for 2 h. Upon completion of the reaction, the reaction mixture was filtered and the filtrate was directly concentrated to dryness to obtain 800 mg of compound 11e in a 90.4% yield. 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 mixture of ultra-dry tetrahydrofuran (9 mL) and N,N-dimethylpropyleneurea (8 mL). Under nitrogen, the temperature was lowered to -78°C, and sodium bis(trimethylsilyl)amide (1.3 mL, 2.67 mmol) was slowly added. The reaction was stirred at -78°C for 10-15 minutes, and compound 1e (651 g, 2.67 mmol) was slowly added. After 10 minutes, the temperature was slowly raised to room temperature, and the reaction was continued at room temperature for 2 hours. Upon completion of the reaction, the reaction solution was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were directly concentrated to dryness, and the residue was purified by preparative HPLC (0.1% FA, ACN) to yield 41.69 mg of compound 11 in a 1.2% yield. 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] Ethyl 3-(((((2S,5R)-2-((((1-acetoxyethoxy)carbonyl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate

[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 methanol (5.0 g, 156.25 mmol) and triethylamine (31.56 g, 312.5 mmol) were added sequentially. The reaction mixture was allowed to react at room temperature for 16 hours. Upon completion, 1M dilute hydrochloric acid (200 mL) was added to the reaction mixture to quench the reaction. The resulting solution was extracted three times with ethyl acetate (100 mL x 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). The mixture was cooled to 0°C under nitrogen. N,N-dimethylformamide (80 mg, 1.09 mmol) and oxalyl chloride (1.39 g, 10.93 mmol) were then added sequentially. The reaction mixture was allowed to react at room temperature for 2 hours. Upon completion, the reaction mixture was concentrated to dryness to obtain 1.75 g of compound 13c in a 90.2% yield. 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 pyridine (1.556 g, 19.67 mmol) and compound 13c (1.75 g, 9.84 mmol, 1.5 equivalents) were added sequentially. The reaction mixture was allowed to react at room temperature for 3 hours. Upon completion, water (50 mL) was added to the reaction mixture to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL x 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 in a 47.7% yield. 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 10% palladium on carbon (280 mg) was added. The mixture was then purged with hydrogen three times. The reaction mixture was allowed to react under a hydrogen atmosphere at room temperature for 1.5 hours. After the reaction was complete, 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-dimethylpropyleneurea (5.2 mL). Sodium bis(trimethylsilyl)amide (1.0 mL, 2 M / tetrahydrofuran solution, 2.0 mmol) was added dropwise to the reaction mixture under a nitrogen atmosphere at -78°C. The reaction was maintained at -78°C for 10 minutes, followed by the addition of compound 1e (888 mg, 3.64 mmol). After 10 minutes, the mixture was warmed to room temperature and allowed to react for 2 hours. Upon completion of the reaction, the reaction mixture was poured into water (100 mL), and the resulting solution was extracted with ethyl acetate (50 mL x 3). The organic phases were combined and concentrated to dryness. The residue was purified by reverse-phase preparative HPLC (C18, 10 mmol / L formic acid / water, acetonitrile) to afford 83.47 mg of compound 13 in an 8.12% yield. 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 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] ethyl 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)propanoate

[0196]

[0197] The synthesis method is the same 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] Compound 17a (5.0 g, 30.43 mmol) was dissolved in dichloromethane (50 mL) at room temperature. Oxalyl chloride (5.8 g, 45.65 mmol) and a catalytic amount of N,N-dimethylformamide were then added. The mixture was allowed to react at room temperature for 3 h. Upon completion of the reaction, the reaction solution was concentrated to dryness to yield 6.0 g of crude compound 17b, which was directly used for the next step. 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] Compound 2a (4.0 g, 13.11 mmol) was dissolved in dichloromethane (40 mL) at room temperature. Pyridine (1.6 g, 19.67 mmol) and compound 17b (3.8 g, 19.67 mmol, 1.5 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. The resulting solution was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, 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 = 1 / 1)) to obtain 2.7 g of compound 17c in a 45.0% yield. 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 hydrogen atmosphere was replaced three times. The reaction mixture was allowed to react at room temperature under a hydrogen atmosphere for 1.5 h. Upon completion of the reaction, the reaction solution was filtered and the filtrate was directly concentrated to dryness to obtain 2.7 g of compound 17d in a 96.4% yield. 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, sodium bis(trimethylsilyl)amide (3.3 mL, 6.53 mmol) was added at -78°C. The reaction was stirred at -78°C for 10 minutes, and compound 1e (2.9 g, 11.86 mmol) was slowly added. After 10 minutes, the mixture was warmed to room temperature and allowed to react for 2 hours. Upon completion of the reaction, the reaction solution was poured into water (100 mL), and the resulting solution was extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to dryness. The residue was purified by Pre-HPLC (0.1% FA, ACN) to obtain 41.69 mg of compound 17 in a 1.2% yield. 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] Ethyl 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-dimethylpropanoate

[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] Ethyl 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-dimethylpropanoate

[0215]

[0216] Step 1: Synthesis of compound 19b

[0217] Compound 19a (20.0 g, 143.0 mmol) was dissolved in N,N-dimethylformamide (100 mL) at room temperature and cooled to 0°C. Sodium carbonate (45.4 g, 471.0 mmol) and 2-bromo-1-ethanol (19.6 g, 157.0 mmol) were then added sequentially. The reaction mixture was allowed to react at room temperature for 2 hours. Upon completion, the reaction mixture was poured into water (500 mL) and the resulting solution was extracted with ethyl acetate (300 mL x 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 (silica gel, petroleum ether:ethyl acetate (V / V = 5 / 1)) afforded 24.0 g of compound 19b in a 91.6% yield. 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] Compound 19b (22.0 g, 119.6 mmol) was dissolved in methanol (440 mL) and water (44 mL) at room temperature, followed by the addition of potassium peroxymonosulfate (124.1 g, 358.7 mmol). The reaction mixture was incubated at 70°C for 15 minutes. Upon completion, the mixture was poured into water (1000 mL), and the resulting solution was extracted with ethyl acetate (200 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. Flash chromatography (silica gel, petroleum ether:ethyl acetate (V / V = 1 / 1)) afforded 24.0 g of compound 19c in a 96.5% yield. 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] Compound 19c (2.0 g, 9.26 mmol) was dissolved in tetrahydrofuran (20 mL) at room temperature. Triethylamine (1.4 g, 13.9 mmol) and triphosgene (4.00 g, 13.5 mmol) were added sequentially at 0°C. The reaction mixture was allowed to react at room temperature for 2 hours. Upon completion of the reaction, the mixture was concentrated to dryness to yield 2.5 g of crude compound 19d, which was used directly in the next reaction.

[0222] Step 4: Synthesis of compound 19e

[0223] At room temperature, 1a (2.0 g, 7.27 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled to -78°C under nitrogen. Then, lithium bistrimethylsilylamide (14.5 mL, 1 M / 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. 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 continued 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, and filtered. The filtrate was concentrated to dryness, and the residue was separated and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (v / v = 3 / 1)) to obtain 1.0 g of compound 19e in a yield of 26.4%. LCMS (ESI): [M+H] + =518.2.

[0224] Step 5: Synthesis of compound 19f

[0225] Compound 19e (1.0 g, 1.93 mmol) was dissolved in ethyl acetate (30 mL) at room temperature, followed by the addition of 10% palladium on carbon (500 mg). The reaction mixture was purged with hydrogen three times and allowed to react under a hydrogen atmosphere at room temperature for 1 hour. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to dryness to yield 500 mg of compound 19f in a 60.5% yield.

[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 under 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 continued at room temperature for 2 hours. After the reaction, 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 preparative purification (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] Ethyl 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-dimethylpropanoate

[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 10% palladium on carbon (5.60 g) was added. The resulting mixture was replaced with hydrogen three times, and the reaction solution was reacted under 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 under nitrogen. Then, sodium bis(trimethylsilyl)amide (29.5 mL, 2M / tetrahydrofuran solution, 59.4 mmol) was added dropwise to the reaction solution and the temperature was maintained at -78°C. The reaction solution was reacted at -78°C for 10 min, 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 continued at room temperature for 2 h. After the reaction was completed, the reaction solution was poured into water (300 mL) and extracted with ethyl acetate (300 mL × 3). The combined organic phases were directly concentrated to dryness. The residue was purified by reverse phase preparative purification (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, 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 purified by flash chromatography (Silica gel, petroleum ether:ethyl acetate (V / V = 3 / 1)) to give 10. g of compound 20e in 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] Compound 20e (2.2 g, 13.3 mmol) was dissolved in dichloromethane (20 mL) at -0°C. Triethylamine (2.0 g, 19.9 mmol) and triphosgene (1.4 g, 4.64 mmol) were added sequentially. 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 in 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] Compound 20c (320 mg, 0.76 mmol) was dissolved in tetrahydrofuran (3 mL) at room temperature and cooled to -78°C under nitrogen. After 10 minutes, lithium bis(trimethylsilyl)amide (1.53 mL, 1 M solution in tetrahydrofuran, 1.52 mmol) was added dropwise to the reaction mixture, which was maintained at -78°C. The reaction mixture was then allowed to react at -78°C for 30 minutes. Compound 20f (209 g, 0.92 mmol) was then added, and the mixture was slowly warmed to room temperature. The reaction mixture was allowed to react at room temperature for 2 hours. Upon completion of the reaction, the reaction mixture was poured into water (100 mL) and extracted three times with ethyl acetate (50 mL x 3). The organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to dryness. The residue was purified by reverse phase preparative purification (C18, 10 mmol / L formic acid / water, acetonitrile) to obtain 81.1 mg of compound 20 in a 12.7% yield. 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] Ethyl 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)oxypropanoate

[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 N,N-diisopropylethylamine (27.7 g, 540 mmol) was added. The reaction mixture was allowed to react at room temperature for 48 hours. Upon completion, water (300 mL) was added to the reaction mixture to quench the reaction, and the mixture was extracted with ethyl acetate (300 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 purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (v / v = 10 / 1)) to obtain 6.5 g of compound 22a in a 51.2% yield. 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] Sulfonyl chloride (4.5 g, 25.3 mmol) was added to compound 22a (4.5 g, 25.3 mmol) at -10°C. The reaction mixture was allowed to react at -10°C for 20 minutes, then warmed to room temperature and allowed to react for 1 hour. Upon completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure to yield 4.5 g of compound 22b, which was used directly 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) and cooled to -78°C under nitrogen. Lithium bistrimethylsilylamide (14.5 mL, 1 M solution in tetrahydrofuran, 14.5 mmol) was then added dropwise to the reaction mixture and maintained at -78°C. The reaction mixture was allowed to react at -78°C for 10 minutes. Compound 22b (2.2 g, 14.5 mmol) was then added dropwise to the reaction mixture and allowed to react at -78°C for 2 hours. After completion of the reaction, the reaction mixture was quenched by the addition of water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to dryness. The residue was purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (v / v = 1 / 1)) to afford 950 mg of compound 22c in a 35.7% yield. LCMS(ESI):[M+H] + =392.2.

[0255] Step 4: Synthesis of compound 22d

[0256] Compound 22c (350 mg, 0.90 mmol) was dissolved in ethyl acetate (10 mL) at room temperature, followed by the addition of 10% palladium on carbon (300 mg). The resulting solution was replaced with hydrogen three times, and the reaction mixture was allowed to react at room temperature under a hydrogen atmosphere for 1 hour. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated to dryness to obtain 250 mg of compound 22d in a 92.6% yield. 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, followed by the addition of 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). The mixture was reacted at 45°C for 16 h. Upon 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 (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 purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (v / v = 3 / 1)) to afford 2.1 g of compound 22f in an 8.71% yield. 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] Sulfonyl chloride (532 mg, 3.9 mmol) was dissolved in diethyl ether (5 mL) at room temperature. The mixture was purged with argon three times and stirred at -78°C for 10 min. A solution of compound 22f (500 mg, 2.6 mmol) and pyridine (311 mg, 3.9 mmol) in diethyl ether (0.5 mL) was slowly added dropwise at -78°C. The mixture was stirred at -78°C for 2 h. After the reaction was complete, the reaction mixture was filtered and the filtrate was concentrated to dryness to obtain 580 mg of compound 22g, 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 minutes, and compound 22g (1.1 g, 4.00 mmol) was slowly added to the reaction solution. The reaction temperature was gradually raised to room temperature. , reacted at room temperature for 2 hours. The reaction was monitored for completion by LCMS. 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] Compound 23a (10.0 g, 84.68 mmol) was dissolved in dichloromethane (100 mL) at room temperature. Isopropyl alcohol (11.2 g, 186.3 mmol) and 4-dimethylaminopyridine (1.03 g, 8.468 mmol) were added sequentially. The reaction mixture was cooled to 0°C, and N,N'-dicyclohexylcarbodiimide (38.44 g, 186.3 mmol) was added. The mixture was allowed to react at room temperature for 16 h. After the reaction was complete, the reaction mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by flash chromatography (Silica gel, petroleum ether:ethyl acetate (v / v = 10 / 1)) to obtain 14.0 g of compound 23b in an 81.8% yield.

[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] Compound 23b (7.0 g, 34.61 mmol) was dissolved in ethanol (35 mL) and water (35 mL) at room temperature. Aqueous formaldehyde (3.12 g, 38.07 mmol) and sodium bicarbonate (291 mg, 3.46 mmol, 0.1 equivalent) were added at room temperature, and the mixture was stirred at room temperature for 16 h. After the reaction, the reaction solution was extracted with ethyl acetate (100 mL × 3). 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 isolated and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate (v / v = 3 / 1)) to obtain 3.7 g of compound 23c in 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] Sulfonyl chloride (698 mg, 5.17 mmol) was dissolved in diethyl ether (10 mL) at room temperature. The mixture was purged 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 equivalents) in diethyl ether (1 mL) was added at -78°C. The mixture was stirred at -78°C for 0.5 hour and then gradually warmed to room temperature. The reaction was continued at room temperature for 2 hours. Upon completion, the reaction solution was concentrated to dryness to obtain 1.0 g of compound 23d in 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] Compound 22d (400 mg, 1.3 mmol) was dissolved in tetrahydrofuran (12 mL) and N,N-dimethylpropyleneurea (3.2 mL) at room temperature. Under argon, sodium bis(trimethylsilyl)amide (0.7 mL, 2M / tetrahydrofuran solution, 1.43 mmol) was added at -78°C. The reaction was stirred at -78°C for 10 min, and compound 23d (877 mg, 2.6 mmol) was slowly added. After the addition, the reaction temperature was gradually raised to room temperature and the reaction was continued at room temperature for 2 h. Upon completion, water (100 mL) was added to quench the reaction. The resulting solution was extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to dryness. The residue was purified by preparative HPLC (0.1% FA, ACN) to afford 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] 3-Isopropyl 2-((((((2S,5R)-2-((((acetyloxymethoxy)carbonyl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonate

[0277]

[0278] Step 1: Synthesis of compound 24b

[0279] Compound 24a (10 g, 75.7 mmol) was dissolved in dichloromethane (100 mL) at 0°C. Isopropyl alcohol (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 to the solution under nitrogen. After addition, the reaction mixture was warmed to 25°C and allowed to react for 12 hours. After completion of the reaction, water (200 mL) was added to the reaction mixture to quench the reaction, followed by extraction with dichloromethane (300 mL x 3). The organic phases were combined, washed with saturated brine (300 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to dryness. The residue was purified by flash chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 10 / 1 v / v) to afford 13 g of compound 24b in a 98.6% yield. 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] Compound 24b (10.0 g, 57.5 mmol) was dissolved in tetrahydrofuran (100 mL) at 0°C. Sodium hydroxide (2.53 g, 63.2 mmol, 60% in mineral oil) was slowly added under nitrogen. Stirring was continued at 0°C for 30 minutes. Then, iodomethane (8.16 g, 57.2 mmol) was added to the reaction mixture. After the addition was complete, the reaction mixture was allowed to react at room temperature overnight. After completion of the reaction, saturated aqueous ammonium chloride (100 mL) was added to the reaction mixture at 0°C and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, backwashed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to dryness to yield 6.0 g of compound 24c, which was used directly in the next step.

[0282] Step 3: Synthesis of compound 24d

[0283] Compound 24c (6.00 g, 31.9 mmol) was dissolved in a mixture of ethanol (30 mL) and water (10 mL) at 0°C. Under nitrogen, sodium bicarbonate (268 mg, 3.19 mmol) and 37% aqueous formaldehyde (3.16 g, 35.1 mol) were added sequentially. The mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, water (100 mL) was added to the reaction mixture at 25°C to quench the reaction. The mixture was then extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to dryness. The residue was purified by flash chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 10 / 1 v / v) to afford 3.5 g of compound 24d in a 50.7% yield. 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 diethyl ether (10 mL). The mixture was cooled to -78°C under nitrogen. 1-tert-butyl-3-ethyl-2-(hydroxymethyl)-2-methylmalonate (500 mg, 3.62 mmol) and pyridine (429 mg, 5.43 mmol) dissolved in diethyl ether (2 mL) were slowly added dropwise. The mixture was gradually warmed to room temperature and allowed to react for 4 hours. After the reaction, the reaction mixture was filtered, and the filtrate was collected and concentrated under reduced pressure to obtain 0.5 g of compound 24e, which was used directly 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 mixture of tetrahydrofuran (3 mL) and N,N-dimethylpropyleneurea (1 mL). The mixture was cooled to -78°C under a nitrogen atmosphere. Sodium bis(trimethylsilyl)amide (59.8 μL, 2 M in tetrahydrofuran) was then added dropwise to the reaction mixture. The reaction mixture was allowed to react at -78°C for 10 minutes. Compound 24e (380 mg, 1.19 mmol) was then added dropwise to the reaction mixture. The mixture was gradually warmed to room temperature and allowed to react for 3 hours. Upon completion of the reaction, the reaction mixture was poured into a saturated aqueous sodium bicarbonate solution (20 mL) at 0°C and extracted with ethyl acetate (50 mL x 2). The organic phases were combined and concentrated to dryness. The residue was purified by preparative HPLC (0.1% FA, ACN) to yield 17.4 mg of compound 24 in a 3.0% yield. 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] 1-Isopropyl-3-methyl 2-((((((2S,5R)-2-((((acetyloxymethoxy)carbonyl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylmalonate

[0290]

[0291] Step 1: Synthesis of compound 25b

[0292] Compound 25a (10 g, 84.7 mmol) was dissolved in dichloromethane (100 mL) at 0°C. Isopropyl alcohol (7.63 g, 127 mmol), N,N'-dicyclohexylcarbodiimide (26.2 g, 127 mmol), and 4-dimethylaminopyridine (1.03 g, 8.47 mmol) were added sequentially under nitrogen. After the addition was complete, the reaction mixture was warmed to 25°C and allowed to react for 12 hours. After completion of the reaction, water (200 mL) was added to the reaction mixture to quench the reaction, followed by extraction with dichloromethane (300 mL x 3). The organic phases were combined, washed with saturated brine (300 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to dryness. The residue was purified by flash chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 10 / 1 v / v) to yield 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] Compound 25b (10.0 g, 62.5 mmol) was dissolved in tetrahydrofuran (100 mL) at 0°C. Under nitrogen, sodium hydroxide (2.75 g, 68.7 mmol, 60% in mineral oil) was slowly added. After addition, stirring was continued for 30 minutes. Then, iodoethane (8.87 g, 62.5 mmol) was added to the reaction mixture. After addition, the reaction mixture was allowed to react at room temperature overnight. After completion of the reaction, saturated aqueous ammonium chloride (100 mL) was added to the reaction mixture at 0°C to quench the reaction mixture. The mixture was then extracted with ethyl acetate (100 mL x 3). The organic phases were combined, backwashed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to dryness to yield 5.0 g of compound 25c, which was used directly in the next step.

[0295] Step 3: Synthesis of compound 25d

[0296] Compound 25c (5.00 g, 26.5 mmol) was dissolved in a mixture of ethanol (30 mL) and water (10 mL) at 0°C. Sodium bicarbonate (223 mg, 2.65 mmol) and 37% aqueous formaldehyde (2.63 g, 29.2 mol) were added sequentially under nitrogen. The mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, water (100 mL) was added to the reaction mixture at 25°C to quench the reaction. The mixture was then extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to dryness. The residue was purified by flash chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 10 / 1 v / v) to afford 3.5 g of compound 25d in a 60.7% yield. 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 diethyl ether (10 mL). The mixture was cooled to -78°C under nitrogen. A solution of compound 25d (500 mg, 2.29 mmol) and pyridine (271 mg, 3.44 mmol) in diethyl ether (2 mL) was slowly added dropwise. The mixture was gradually warmed to room temperature and allowed to react for 4 hours. Upon completion of the reaction, the reaction mixture was filtered, and the filtrate was collected and concentrated under reduced pressure to yield 0.5 g of compound 25e, which was used directly 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 mixture of tetrahydrofuran (3 mL) and N,N-dimethylpropyleneurea (1 mL). The mixture was cooled to -78°C under nitrogen. Sodium bis(trimethylsilyl)amide (59.8 μL, 2 M solution in tetrahydrofuran) was then added dropwise to the reaction mixture. The reaction mixture was allowed to react at -78°C for 10 minutes. Compound 24e (378 mg, 1.19 mmol) was then added dropwise to the reaction mixture. The mixture was gradually warmed to room temperature and allowed to react for 3 hours. Upon completion of the reaction, the reaction mixture was poured into a 0°C saturated aqueous sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (50 mL x 2). The organic phases were combined and concentrated to dryness. The residue was purified by preparative HPLC (0.1% FA, ACN) to afford 13.2 mg of compound 25 in a 2.5% yield. 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] 1-tert-Butyl-3-ethyl 2-((((((2S,5R)-2-((((acetyloxymethoxy)carbonyl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonate

[0303]

[0304] Step 1: Synthesis of compound 26b

[0305] Compound 26a (50.0 g, 0.312 mol) was dissolved in dichloromethane (500 mL) at room temperature. Ethanol (21.5 g, 0.468 mol) and 4-dimethylaminopyridine (3.81 g, 31.2 mmol) were then added sequentially. After completion of the addition, the reaction solution was cooled to 0°C and N,N'-dicyclohexylcarbodiimide (70.8 g, 0.343 mol) was added. The mixture was allowed to react at room temperature for 16 hours. Upon completion of the reaction, the reaction solution was filtered and the filtrate was concentrated to dryness. The residue was purified by flash chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 10 / 1 v / v) to yield 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] Compound 26b (40.0 g, 0.212 mol) was dissolved in tetrahydrofuran (400 mL) at 0°C. Under nitrogen, sodium hydroxide (9.36 g, 0.234 mol, 60% in mineral oil) was slowly added. Stirring was continued for 30 minutes after the addition was complete. Then, iodomethane (31.7 g, 0.21 mol) was added to the reaction mixture. The reaction mixture was allowed to react at room temperature overnight. After the reaction was complete, saturated aqueous ammonium chloride (200 mL) was added to the reaction mixture at 0°C to quench the reaction mixture. The mixture was then extracted with ethyl acetate (200 mL x 3). The organic phases were combined, backwashed with saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to dryness to yield 20.0 g of compound 26c, which was used directly in the next step.

[0308] Step 3: Synthesis of compound 26d

[0309] Compound 26c (20.0 g, 99.1 mmol) was dissolved in a mixture of ethanol (200 mL) and water (100 mL) at 0°C. Sodium bicarbonate (831 mg, 9.91 mmol) and 37% aqueous formaldehyde (9.80 g, 108 mol) were added sequentially under nitrogen. After completion of the addition, the mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, water (200 mL) was added to the reaction mixture at 25°C to quench the reaction mixture, which was then extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to dryness. The residue was purified by flash chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 10 / 1 v / v) to afford 11.1 g of compound 26d in a 48.0% yield.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 diethyl ether (30 mL). The mixture was cooled to -78°C under nitrogen. A solution of compound 26c (8.00 g, 34.5 mmol) and pyridine (4.08 g, 51.7 mmol) in diethyl ether (5 mL) was added dropwise. After the addition was complete, the mixture was gradually warmed to room temperature and allowed to react for 4 hours. After the reaction was complete, 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 used directly 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 mixture of tetrahydrofuran (80 mL) and N,N-dimethylpropyleneurea (35 mL). The mixture was cooled to -78°C under nitrogen. Sodium bis(trimethylsilyl)amide (15.9 mL, 2 M solution in tetrahydrofuran) was then added dropwise to the reaction mixture. The mixture was allowed to react at -78°C for 10 minutes. Compound 26e (10.5 g, 31.9 mmol) was then added dropwise to the reaction mixture. The mixture was gradually warmed to room temperature and allowed to react for 3 hours. Upon completion of the reaction, the reaction mixture was poured into a 0°C saturated aqueous sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (50 mL x 2). The organic phases were combined and concentrated to dryness. The residue was purified by preparative HPLC (0.1% FA, ACN) to afford 1.03 g of compound 26 in a 6.6% yield. 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 1-ethyl-3-((((((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] Compound 24b (10.0 g, 57.5 mmol) was dissolved in tetrahydrofuran (100 mL) at 0°C. Under nitrogen, sodium hydroxide (2.53 g, 63.2 mmol, 60% in mineral oil) was slowly added. After addition, stirring was continued for 30 minutes. Then, iodoethane (8.93 g, 57.2 mmol) was added to the reaction mixture. After addition, the reaction mixture was allowed to react overnight at room temperature. After completion of the reaction, saturated aqueous ammonium chloride (200 mL) was added to the reaction mixture at 0°C and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, backwashed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to yield 6.1 g of compound 27a, which was used directly in the next step.

[0318] Step 2: Synthesis of compound 27b

[0319] Compound 27a (6.00 g, 29.7 mmol) was dissolved in a mixture of ethanol (30 mL) and water (10 mL) at 0°C. Under nitrogen, sodium bicarbonate (249 mg, 2.97 mmol) and 37% aqueous formaldehyde (2.94 g, 32.6 mol) were added sequentially. The mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, water (100 mL) was added to the reaction mixture at 25°C to quench the reaction. The mixture was then extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to dryness. The residue was purified by flash chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 10 / 1 v / v) to afford 3.9 g of compound 27b in a 56.6% yield. 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 diethyl ether (10 mL). The mixture was cooled to -78°C under nitrogen. A solution of compound 27b (500 mg, 2.16 mmol) and pyridine (255 mg, 3.23 mmol) in diethyl ether (2 mL) was added dropwise. After the addition was complete, the mixture was gradually warmed to room temperature and allowed to react for 4 hours. After the reaction was complete, the reaction solution was filtered, and the filtrate was collected and concentrated under reduced pressure to yield 0.6 g of compound 27c, which was used directly 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 mixture of tetrahydrofuran (3 mL) and N,N-dimethylpropyleneurea (1 mL). The mixture was cooled to -78°C under nitrogen. Sodium bis(trimethylsilyl)amide (59.8 μL, 2 M tetrahydrofuran solution) was added dropwise. The mixture was allowed to react at -78°C for 10 minutes. Compound 27c (392 mg, 1.19 mmol) was then added dropwise. The mixture was gradually warmed to room temperature and allowed to react for 3 hours. Upon completion of the reaction, the reaction mixture was poured into a 0°C saturated aqueous sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (50 mL x 2). The organic phases were combined and concentrated to dryness. The residue was purified by preparative HPLC (0.1% FA, ACN) to afford 10.5 mg of compound 27 in a 2.8% yield. 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: Bioreclamation IVT).

[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 of human liver microsomal protein and 15 μL of NADPH solution were aliquoted into 96-well plates at different time points (0, 5, 15, 30, and 60 min). 15 μL of human liver microsomal protein and 15 μL of PBS solution were aliquoted into 96-well plates at different time points (0 and 60 min) as negative controls. For samples at 0 min, acetonitrile:methanol (1:1) containing the internal standard and intermediate solution B were added. For samples at other time points, intermediate solution B was added to initiate the reaction. All samples were preincubated in a 37°C incubator for 5 min and stopped by adding acetonitrile:methanol (1:1) containing the internal standard. The samples were shaken at 600 rpm for 10 min and centrifuged at 4000 rpm for 15 min. The supernatant was collected and analyzed by LC-MS.

[0331] 2. Results

[0332] The conversion of the compounds of the present invention in human liver microsomes is as follows, as shown in Tables 1 and 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 the 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. Avibactam and the compounds of Examples 6, 23, 24, 25, 26, and 27 were each prepared in 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 samples were collected via jugular sinus puncture at 0, 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after dosing and anticoagulated with sodium heparin. Blood samples were placed on ice and plasma separated within 30 minutes of collection (centrifugation conditions: 6800 g, 6 minutes, 2-8°C). The supernatant was removed and analyzed by LC / MS / MS to determine the avibactam concentration.

[0346] 1.3 Pharmacokinetic parameter results

[0347] In male rats, after the compound and the original drug were converted to equimolar ratios, 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 all showed that the oral bioavailability of avibactam was greater than 95%. Examples 6 and 24 showed that the oral bioavailability of avibactam was greater than 50% and less than 95%. Example 25 showed that the oral bioavailability of avibactam was greater than 20% and less than 50%. These results demonstrate that the compounds of the present invention can significantly improve the oral bioavailability of avibactam, resolving the issue of avibactam's inability to be administered orally.

[0349] Table 3

[0350]

Claims

1. A β-lactamase inhibitor or a pharmaceutically acceptable salt thereof, wherein the β-lactamase inhibitor has a structure represented by the following formula (II): R2 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl; R3 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl or R a Selected from methyl, ethyl, n-propyl, isopropyl; R4 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl or R e Selected from methyl, ethyl, n-propyl, isopropyl; L2 is selected from -CH2-, R c Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl.

2. The β-lactamase inhibitor or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R2 is selected from methyl.

3. The β-lactamase inhibitor or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R3 is selected from methyl or R a Selected from methyl, ethyl, n-propyl, isopropyl.

4. The β-lactamase inhibitor or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R4 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl or R e Selected from methyl.

5. The β-lactamase inhibitor or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: wherein L2 is selected from -CH2-, 6. A β-lactamase inhibitor or a pharmaceutically acceptable salt thereof, wherein the β-lactamase inhibitor has the structure represented by the following formula (III): wherein 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, and pentyl.

7. The β-lactamase inhibitor or a pharmaceutically acceptable salt thereof according to claim 6, characterized in that: 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.

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

9. A pharmaceutical composition, characterized in that The invention comprises the β-lactamase inhibitor according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. The pharmaceutical composition according to claim 9, characterized in that The pharmaceutical composition also comprises an antibiotic.

11. The pharmaceutical composition according to claim 10, characterized in that The antibiotic is a β-lactam antibiotic.

12. The pharmaceutical composition according to claim 11, characterized in that The antibiotics are penicillins, cephalosporins, cephamycins and carbapenems.

13. Use of the β-lactamase inhibitor according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 9 to 12 in the preparation of a β-lactamase inhibitor.

14. Use of the β-lactamase inhibitor according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 9 to 12, in the preparation of a medicament for treating diseases related to bacterial infection.

15. The use according to claim 14, characterized in that The bacteria are bacteria that can produce beta-lactamase.

16. The use according to claim 15, characterized in that The bacteria are bacteria of the genus Enterobacter, Citrobacter, Prufidonia, Serratia marcescens or Morganella.

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