A β-lactamase inhibitor and its application

Abstract

The present invention discloses an avibactam derivative and a pharmaceutical composition comprising the same, which is used as an orally administered prodrug of a β-lactamase inhibitor for treating bacterial infections, particularly in combination with β-lactam antibiotics for treating bacterial infections. The compound of the present invention can improve the lipid-water partition coefficient, and can better release the original drug, and has good oral bioavailability.

Description

Technical Field

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

[0002] Antibiotics can effectively treat infectious diseases caused by bacteria, which brings great convenience to clinical practice. However, the irrational use and even abuse of antibiotics has accelerated the development of bacterial resistance, posing a great challenge to human health. As one of the antibiotics with the longest history, the widest range of use, and the most commonly used in clinical practice, the problem of drug resistance of β-lactam antibiotics has also emerged and is becoming more and more serious.

[0003] The main mechanism of resistance to β-lactam antibiotics is the production of β-lactamases by bacteria, which covalently bind to the carbonyl group on the β-lactam ring of β-lactam antibiotics, hydrolyzing and inactivating them. 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, can protect β-lactam antibiotics from being destroyed and inactivated by enzymes (β-lactamases) produced by microorganisms. Since the 1980s, β-lactamase inhibitor / antibiotic combinations have become a standard part of treatment.

[0004] In the mid-1990s, a new and important non-β-lactam β-lactamase inhibitor, avibactam, was discovered. It belongs to the diazabicyclic compounds (DBOs), a class of reversible β-lactamase inhibitors. However, at present, due to the presence of sulfonic acid and carboxamide structures in the structure of avibactam, it has high water solubility and low lipid solubility, resulting in poor tissue permeability, and it cannot be taken orally and can only be used for intravenous injection. Prodrug refers to a compound that has no biological activity itself, but can release pharmacologically active metabolites or original drugs through chemical or enzymatic conversion in the body. Prodrug design is a common and effective strategy to improve the lipid solubility of compounds, increase oral absorption, and improve bioavailability.

[0005] Chinese invention patent CN110662746A discloses a 3-(((((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate derivative and related compounds, which are used as orally administered prodrugs of β-lactamase inhibitors for treating bacterial infections. The prodrug design of the invention improves the oral bioavailability of avibactam. In the oral bioavailability experiment in rats, avibactam showed an oral bioavailability (%F) of 1.2%, while the oral bioavailability (%F) of compounds (3), (4), (10), (11), (12), (13), (14), (15), (16), (17), (18) and (19) was greater than 10%. Likewise, the oral bioavailability (%F) of compounds (36), (37), (42), (53), (57), (58) and (59) was greater than 10%. In these studies, the oral bioavailability (%F) of lebactam was 1.8%, while the oral bioavailability (%F) of compounds (20), (22), (23) and (25) was greater than 5%.

[0006] In view of this, providing more prodrug designs of avibactam to further improve the oral bioavailability of avibactam has important clinical value. Summary of the invention

[0007] The present invention aims at the problems existing in the prior art and provides an avibactam derivative to solve the problem of poor oral bioavailability of avibactam.

[0008] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0009] In one aspect, the present invention provides an avibactam derivative, namely a compound represented by general formula I, or a pharmaceutically acceptable salt, metabolite, solvate or hydrate thereof:

[0010]

[0011] Among them, R 1 is C1-6 alkyl, or each R 1 The geminal carbon atom to which it is bonded forms an unsubstituted or substituted C3-6 cycloalkyl group, an unsubstituted or substituted heterocycloalkyl group;

[0012] R 2is a single bond, an unsubstituted or substituted C1-6 alkanediyl, an unsubstituted or substituted C5-6 cycloalkanediyl, an unsubstituted or substituted "heteroatom selected from one or more of N, O and S, with 1 to 3 heteroatoms" C5-6 heterocycloalkanediyl, an unsubstituted or substituted C6 aromatic diyl, or an unsubstituted or substituted "heteroatom selected from one or more of N, O and S, with 1 to 3 heteroaromatic diyl;

[0013] R 3 is C1-6 alkyl, -O(C=O)R 6 、-S(C=O)R 6 、-NH(C=O)R 6 、-O(C=O)OR 6 、-S(C=O)OR 6 、-NH(C=O)OR 6 、-(C=O)OR 6 、-(C=O)OCH 2 O(C=O)R 6 、-(C=O)OCH 2 O(C=O)OR 6 、-(C=O)SR 6 、-(C=O)NHR 6 、-O(C=O)SR 6 , -O(C=O)NHR 6 、-SSR 6 、-SR 6 、-NHR 6 , C3-10 cycloalkyl, "heteroatoms selected from one or more of N, O and S, with 1-3 heteroatoms" heterocycloalkyl, "heteroatoms selected from one or more of N, O and S, with 1-3 heteroatoms" heteroaryl, unsubstituted or substituted C6-10 aryl, -CH=C(R 6 ) 2 ,or

[0014] R 4 -(C=O)R 7 OR -(C=O)OR 7 ;

[0015] R 5 It is hydrogen, C3-6 cycloalkyl or C1-6 alkyl.

[0016] In another aspect, the present invention provides a pharmaceutical composition comprising the above-mentioned avibactam derivative.

[0017] In another aspect, the present invention provides use of the above-mentioned avibactam derivatives as β-lactamase inhibitors.

[0018] In another aspect, the present invention provides the use of the above-mentioned avibactam derivatives and pharmaceutical compositions in the preparation of drugs for treating diseases related to bacterial infections.

[0019] In the present invention, the prodrug principle is adopted to temporarily "mask" the sulfonic acid group and formamide part in the structure of avibactam, thereby improving the fat solubility of the original drug itself and adjusting its lipid-water partition coefficient; the prodrug of the sulfonic acid group part releases the nucleophilic group through the action of esterase in the body, and then releases the original drug through a mild intramolecular cyclization reaction; the prodrug of the formamide part forms an N-hydroxymethyl intermediate under the action of esterase, and then releases the original drug and a molecule of formaldehyde through chemical cleavage.

[0020] The lipid-water partition coefficient of the avibactam prodrug of the present invention is well improved, and the original drug can be well released, and has good oral bioavailability, supports oral administration, and provides a new idea for broadening the administration route of avibactam. DETAILED DESCRIPTION

[0021] Hereinafter, the present invention will be described in detail.

[0022] In one aspect, the present invention provides an avibactam derivative, namely a compound represented by general formula I, or a pharmaceutically acceptable salt, metabolite, solvate or hydrate thereof:

[0023]

[0024]

[0025] Among them, R 1 is C1-6 alkyl, or each R 1 The geminal carbon atom to which it is bonded forms an unsubstituted or R 1-1 Substituted C3-6 cycloalkyl, unsubstituted or R 1-2 substituted heterocycloalkyl;

[0026] R 1-1 and R 1-2 independently selected from hydrogen, halogen, cyano, hydroxy, C1-4 alkyl, C1-4 alkoxy, halo(C1-4 alkyl), halo(C1-4 alkoxy), -NR 1-1-1 R 1-1-2 , or, -(C=O)R 1-1-3 ;

[0027] R 1-1-1 ~R 1-1-3 Independently selected from hydrogen or C1-4 alkyl;

[0028] R 2 is a single bond, unsubstituted or R 2-1 Substituted C1-6 alkanediyl, unsubstituted or R2-2 Substituted C5-6 cycloalkanediyl, unsubstituted or R 2-3 Substituted "heteroatom selected from one or more of N, O and S, with 1 to 3 heteroatoms" C5-6 heterocycloalkanediyl, unsubstituted or R 2-4 Substituted C6 aromatic diyl, unsubstituted or R 2-5 Substituted "heteroatom selected from one or more of N, O and S, with 1 to 3 heteroatoms" C5-6 heteroaromatic diyl;

[0029] R 2-1 ~R 2-5 are independently selected from halogen, cyano, amino, hydroxyl, unsubstituted or R 2-1-1 Substituted C1-4 alkyl, unsubstituted or R 2-1-2 Substituted C1-4 alkoxy, -NR 2-1-3 R 2-1-4 、-(C=O)R 2-1-5 、-(C=O)NR 2-1-6 R 2-1-7 、-(C=O)OR 2 -1-8 , or -S(=O) 2 NR 2-1-9 R 2-1-10 ;

[0030] R 2-1-1 and R 2-1-2 Independently selected from halogen, hydroxy, cyano, amino, or C1-4 alkyl;

[0031] R 2-1-3 ~R 2-1-10 Independently selected from hydrogen or C1-4 alkyl;

[0032] R 3 is C1-6 alkyl, -O(C=O)R 6 、-S(C=O)R 6 、-NH(C=O)R 6 、-O(C=O)OR 6 、-S(C=O)OR 6 、-NH(C=O)OR 6 、-(C=O)OR 6 、-(C=O)OCH 2 O(C=O)R 6 、-(C=O)OCH 2 O(C=O)OR 6 、-(C=O)SR 6 、-(C=O)NHR 6 、-O(C=O)SR 6 , -O(C=O)NHR6 、-SSR 6 、-SR 6 、-NHR 6 , C3-10 cycloalkyl, "heteroatoms selected from one or more of N, O and S, with 1-3 heteroatoms" heterocycloalkyl, "heteroatoms selected from one or more of N, O and S, with 1-3 heteroatoms" heteroaryl, unsubstituted or R 3-1 Substituted C6-10 aryl, -CH=C(R 6 ) 2 ,or

[0033] R 3-1 is deuterium, halogen, cyano, hydroxyl, unsubstituted or R 3-1-1 Substituted C1-6 alkyl, unsubstituted or R 3-1-2 Substituted C1-6 alkoxy, C3-10 cycloalkyl, C3-10 cycloalkyl-(C1-4 alkyl), C3-10 cycloalkyl-oxy, heterocycloalkyl, heterocycloalkyl-(C1-4 alkyl), heterocycloalkyl-oxy, C6-10 aryl, C6-10 aryl-(C1-4 alkyl), (C6-10 aryl)-oxy, heteroaryl, heteroaryl-(C1-4 alkyl), heteroaryl-oxy, -NR 3-1-3 R 3-1-4 、-(C=O)R 3-1-5 、-(C=O)NR 3-1- 6 R 3-1-7 、-(C=O)OR 3-1-8 、-S(=O) 2 NR 3-1-9 R 3-1-10 , or, -O(C=O)R 3-1-11 ; The heterocycloalkyl group is a 4- to 10-membered heterocycloalkyl group "having one or more heteroatoms selected from N, O and S, with 1 to 3 heteroatoms"; the heteroaryl group is a 5- to 10-membered heteroaryl group "having one or more heteroatoms selected from N, O and S, with 1 to 3 heteroatoms";

[0034] R 3-1-1 and R 3-1-2 Independently selected from halogen, cyano, hydroxyl, amino or C1-4 alkyl;

[0035] R 3-1-3 ~R 3-1-11 Independently selected from hydrogen or C1-4 alkyl;

[0036] R 6 is unsubstituted or R 6-1 Substituted C3-10 cycloalkyl, unsubstituted or R 6-2Substituted C3-10 cycloalkyl-(C1-6 alkyl), unsubstituted or R 6-3 Substituted heterocycloalkyl, unsubstituted or R 6-4 Substituted heterocycloalkyl-(C1-6 alkyl), unsubstituted or R 6 -5 Substituted heteroaryl, unsubstituted or R 6-6 Substituted heteroaryl-(C1-6 alkyl), unsubstituted or R 6-7 Substituted C6-10 aryl, unsubstituted or R 6-8 Substituted C6-10 aryl-(C1-6 alkyl), unsubstituted or R 6-9 Substituted C1-10 alkyl, unsubstituted or R 6-10 Substituted C1-10 alkoxy-(C1-10 alkyl) or C1-10 alkylamino-(C1-10 alkyl);

[0037] R 6-1 ~R 6-6 independently selected from halogen, hydroxyl, cyano, amino, C1-6 alkyl, halo(C1-6 alkyl), hydroxy(C1-6 alkyl), C1-6 alkoxy, -NR 6-1-1 R 6-1-2 、-(C=O)R 6-1-3 ;

[0038] R 6-1-1 ~R 6-1-3 Independently selected from hydrogen or C1-4 alkyl;

[0039] R 6-7 and R 6-8 are independently selected from halogen, hydroxy, cyano, nitro, unsubstituted or R 6-7-1 Substituted C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, unsubstituted or R 6-7-2 Substituted C1-6 alkoxy, C6-10 aryl-oxy, heteroaryl-oxy, (C3-10 cycloalkyl)-oxy, C1-6 alkylamino-C1-6 alkoxy-, unsubstituted or R 6-7-3 Substituted C3-10 cycloalkyl, unsubstituted or R 6 -7-4 Substituted C3-10 cycloalkyl-(C1-6 alkyl)-, unsubstituted or R 6-7-5 Substituted heterocycloalkyl, unsubstituted or R 6-7-6 Substituted heterocycloalkyl-(C1-6 alkyl)-, unsubstituted or R 6-7-7 Substituted heteroaryl, unsubstituted or R 6-7-8 Substituted heteroaryl-(C1-6 alkyl)-, unsubstituted or R 6-7-9 Substituted C6-10 aryl, unsubstituted or R 6-7-10Substituted C6-10 aryl-(C1-6 alkyl)-, -NR 6-7-11 R 6-7-12 、-(C=O)R 6-7-13 、-(C=O)NR 6-7-14 R 6-7-15 、-NR 6-7-16 (C=O)R 6-7-17 、-(C=O)OR 6-7-18 、-O(C=O)R 6-7-19 、-(S=O) 2 NR 6-7-20 R 6-7-21 、-NR 6-7-22 (S=O) 2 R 6-7-23 , or, -(S=O) 2 R 6-7-24 ; The heterocycloalkyl group is a 4-10 membered heterocycloalkyl group "wherein the heteroatom is selected from one or more of N, O or S, and the number of heteroatoms is 1-3"; the heteroaryl group is a 5-10 membered heteroaryl group "wherein the heteroatom is selected from one or more of N, O or S, and the number of heteroatoms is 1-3";

[0040] R 6-7-1 and R 6-7-2 Independently selected from C1-4 alkyl, halogen, cyano, hydroxyl or amino;

[0041] R 6-7-3 ~R 6-7-10 independently selected from hydrogen, halogen, cyano, hydroxy, C1-4 alkyl, C1-4 alkoxy, halo(C1-4 alkyl), halo(C1-4 alkoxy), -NR 6-7-3-1 R 6-7-3-2 , or, -(C=O)R 6-7-3-3 ;

[0042] R 6-7-11 ~R 6-7-24 Independently selected from hydrogen or C1-4 alkyl;

[0043] R 6-7-3-1 ~R 6-7-3-3 Independently selected from hydrogen or C1-4 alkyl;

[0044] R 6-9 and R 6-10 independently selected from C1-4 alkyl, halogen, cyano, hydroxyl, -NR 6-9-1 R 6-9-2 ;

[0045] R 6-9-1 and R 6-9-2 Independently selected from hydrogen or C1-4 alkyl;

[0046] R5 is hydrogen, C3-6 cycloalkyl or C1-6 alkyl;

[0047] R 4 -(C=O)R 7 OR -(C=O)OR 7 ;

[0048] R 7 is unsubstituted or R 7-1 Substituted C1-10 alkyl, unsubstituted or R 7-2 Substituted C3-10 cycloalkyl, unsubstituted or R 7-3 Substituted C3-10 cycloalkyl-(C1-6 alkyl)-, unsubstituted or R 7-4 Substituted heterocycloalkyl, unsubstituted or R 7-5 Substituted heterocycloalkyl-(C1-6 alkyl)-, unsubstituted or R 7-6 Substituted heteroaryl, unsubstituted or R 7-7 Substituted heteroaryl-(C1-6 alkyl)-, unsubstituted or R 7-8 Substituted C6-10 aryl, unsubstituted or R 7-9 Substituted C6-10 aryl-(C1-6 alkyl)-, C1-10 alkoxy-(C1-10 alkyl), or C1-10 alkylamino-(C1-10 alkyl); the heterocycloalkyl is a 4-10 membered heterocycloalkyl "having one or more heteroatoms selected from N, O or S, with 1 to 3 heteroatoms"; the heteroaryl is a 5-10 membered heteroaryl "having one or more heteroatoms selected from N, O or S, with 1 to 3 heteroatoms";

[0049] R 7-1 Selected from C1-4 alkyl, halogen, cyano, hydroxyl, or -NR 7-1-1 R 7-1-2 ;

[0050] R 7-1-1 and R 7-1-2 Independently selected from hydrogen or C1-4 alkyl;

[0051] R 7-2 ~R 7-5 independently selected from hydrogen, halogen, cyano, hydroxy, C1-4 alkyl, C1-4 alkoxy, halo(C1-4 alkyl), halo(C1-4 alkoxy), -NR 7-2-1 R 7-2-2 , or, -(C=O)R 7-2-3 ;

[0052] R 7-6 ~R 7-9 are independently selected from halogen, hydroxy, cyano, nitro, unsubstituted or R 7-6-1Substituted C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, unsubstituted or R 7-6-2 Substituted C1-6 alkoxy, C6-10 aryl-oxy, heteroaryl-oxy, (C3-10 cycloalkyl)-oxy, C1-6 alkylamino-C1-6 alkoxy-, unsubstituted or R 7-6-3 Substituted C3-10 cycloalkyl, unsubstituted or R 7-6-4 Substituted C3-10 cycloalkyl-(C1-6 alkyl)-, unsubstituted or R 7-6-5 Substituted heterocycloalkyl, unsubstituted or R 7 -6-6 Substituted heterocycloalkyl-(C1-6 alkyl)-, unsubstituted or R 7-6-7 Substituted heteroaryl, unsubstituted or R 7-6-8 Substituted heteroaryl-(C1-6 alkyl)-, unsubstituted or R 7-6-9 Substituted C6-10 aryl, unsubstituted or R 7-6-10 Substituted C6-10 aryl-(C1-6 alkyl)-, -NR 7-6-11 R 7-6-12 、-(C=O)R 7-6-13 、-(C=O)NR 7-6-14 R 7-6-15 、-NR 7-6-16 (C=O)R 7-6-17 、-(C=O)OR 7-6-18 、-O(C=O)R 7-6-19 、-(S=O) 2 NR 7-6-20 R 7-6-21 、-NR 7-6-22 (S=O) 2 R 7-6-23 , or, -(S=O) 2 R 7 -6-24 ; The heterocycloalkyl group is a 4-10 membered heterocycloalkyl group "wherein the heteroatom is selected from one or more of N, O or S, and the number of heteroatoms is 1-3"; the heteroaryl group is a 5-10 membered heteroaryl group "wherein the heteroatom is selected from one or more of N, O or S, and the number of heteroatoms is 1-3";

[0053] R 7-6-1 and R 7-6-2 are independently selected from halogen, hydroxy, cyano, C1-4 alkyl, or -NR 7-6-1-1 R 7-6-1-2 ;

[0054] R 7-6-1-1 and R 7-6-1-2 Independently selected from hydrogen or C1-4 alkyl;

[0055] R 7-6-3~R 7-6-10 independently selected from hydrogen, halogen, cyano, hydroxy, C1-4 alkyl, C1-4 alkoxy, halo(C1-4 alkyl), halo(C1-4 alkoxy), -NR 7-6-3-1 R 7-6-3-2 , or, -(C=O)R 7-6-3-3 ;

[0056] R 7-6-3-1 ~R 7-6-3-3 Independently selected from hydrogen or C1-4 alkyl;

[0057] R 7-6-11 ~R 7-6-24 Independently selected from hydrogen or C1-4 alkyl.

[0058] Further, in the above definitions of the various parts of formula I, the preferred groups of the various parts are as follows:

[0059] R 1 Each R is independently selected from the following groups or 1 It couples with the geminal carbon atom to which it is bonded to form the following group:

[0060]

[0061] R 2 are independently selected from the following groups:

[0062]

[0063] R 3 are independently selected from the following groups:

[0064]

[0065] Among them U 1 is selected from hydrogen, hydroxy, halogen, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, methoxy, trifluoromethoxy or hydroxymethyl;

[0066] R 4 Defined as

[0067] Where R 7 Selected from the following groups:

[0068]

[0069] Among them U 1 is selected from hydrogen, hydroxy, halogen, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, methoxy, trifluoromethoxy or hydroxymethyl;

[0070] R 5 Selected from the following groups:

[0071]

[0072] Furthermore, the compound of formula I is any of the following compounds:

[0073]

[0074]

[0075]

[0076] In another aspect, the present invention provides a pharmaceutical composition comprising the above-mentioned avibactam derivative.

[0077] In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient.

[0078] The pharmaceutical excipients can be those widely used in the field of drug production. Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide methods to dissolve the active ingredient at a desired rate after the subject receives the administration, or promote the effective absorption of the active ingredient after the subject receives the composition. The pharmaceutical excipients can be inert fillers, or provide a certain function, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition. The pharmaceutical excipients can include one or more of the following excipients: adhesives, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents and sweeteners.

[0079] In some embodiments, the pharmaceutical composition of the present invention further comprises a β-lactam antibiotic.

[0080] β-lactam antibiotics include but are not limited to penicillin G, penicillin sodium, amoxicillin, oxacillin, carbenicillin, mecillinam, methicillin, cloxacillin, dicloxacillin, flucloxacillin, ampicillin, epicillin, piperacillin, azlocillin, mezlocillin, apacillin, sulbenicillin, ticarcillin, hetacillin, cephradine, cephalexin, cefazolin, cefmandole, cefuroxime, cefuroxime, ceftriaxone, ceftazidime, cefepime, cefpirome, cefdirox, ceftriaxone, ceftazidime, cefotaxime, cefoxitin, cephalosporins, latamoxef, biapenem, doripenem, ertapenem, faropenem, imipenem, meropenem, panipenem, lazupenem, tebipenem and thiamycin, etc.

[0081] In some embodiments, the pharmaceutical composition of the present invention is in an oral dosage form.

[0082] The pharmaceutical composition of the present invention can be prepared according to the disclosed content using any method known to those skilled in the art, such as conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or lyophilizing processes.

[0083] In another aspect, the present invention provides use of the above-mentioned avibactam derivatives as β-lactamase inhibitors.

[0084] In another aspect, the present invention provides the use of the above-mentioned avibactam derivatives and pharmaceutical compositions in the preparation of drugs for treating diseases related to bacterial infections.

[0085] The bacterial infection includes, but is not limited to, obligate aerobic bacteria, obligate anaerobic bacteria, facultative anaerobic bacteria, and microaerophilic bacteria; obligate aerobic bacteria include, but are not limited to, Gram-negative cocci, for example, Moraxella catarrhalis, Neisseria gonorrhoeae, and Neisseria meningitidi; Gram-positive bacilli, for example, Corynebacterium jeikeium; acid-fast bacilli, for example, Mycobacterium avium complex, M. kansasii, M. leprae, M. tuberculosis, and Nocardia sp; non-fermenting, non-Enterobacteriaceae, for example, Acinetobacter calcoaceticus, Elizabethkingia meningiseptica; meningoseptica) (formerly Flavobacterium meningosepticum), Pseudomonas aeruginosa, P. alcaligenes, other Pseudomonas sp., and Stenotrophomonas maltophilia; strictly Gram-negative cocci and bacilli, for example, Brucella, Bordetella, Francisella, and Legionella spp.; Spirocheteaceae (spiral bacteria), for example, Leptospira sp. Examples of obligate anaerobic bacteria include: Gram-negative bacilli, e.g., Bacteroides fragilis, other Bacteroides sp., Fusobacterium sp., Prevotella sp.; Gram-negative cocci, e.g., Veillonella sp.; Gram-positive cocci, e.g., Peptococcus niger and Peptostreptococcus sp.; non-spore-forming Gram-positive rods, e.g., Clostridium botulinum, C. perfringens, C. tetani.tetani), other Clostridium sp; and endospore-forming Gram-positive rods, for example, Clostridium botulinum, C. perfringens, C. tetani and other Clostridium sp. Facultative anaerobes include, but are not limited to, gram-positive cocci that are catalytically positive, for example, Staphylococcus aureus (coagulase positive), Staphylococcus epidermidis (coagulase negative) and other coagulase-negative staphylococci; gram-positive cocci that are catalytically negative, for example, Enterococcus faecalis, E. faecium, Streptococcus agalactiae (Group B Streptococcus), Streptococcus bovis, Streptococcus pneumoniae, Streptococcus pyogenes (S. pyogenes) (Group A Streptococcus), viridans group streptococci)((S. mutans, S. mitis, S. salivarius, S. sanguis), S. anginosus)((S. anginosus, S. milleri, S.constellatus) and Gemella morbillorum; Gram-positive bacilli, for example, Bacillus anthracis, Erysipelothrix rhusiopathiae and Gardnerella vaginalis (Gram staining is variable); Gram-negative bacilli, for example, Enterobacteriaceae (Citrobacter sp, Enterobacter aerogenes, Escherichia coli, Klebsiella sp, Morganella morganii, Proteus sp, Plesiomonas shigelloides, Providencia rettgeri, Salmonella typhi, other Salmonella sp, Serratia marcescens and Shigella sp, Yersinia enterocolitica, Y. pestis); fermentative non-Enterobacteriaceae, for example, Aeromonas hydrophila, Chromobacterium violaceum and Pasteurella multocida; fastidious Gram-negative cocci and bacilli, for example, Actinobacillus actinomycetemcomitans, Bartonella bacilliformis, B. henselae, B. quintana.quintana), Eikenella corrodens, Haemophilus influenzae and other Haemophilus sp; Mycoplasmas, for example, Mycoplasma pneumoniae; Treponemaceae (spirillae), for example, Borrelia burgdorferi and Treponemapallidum. Examples of microaerophilic bacteria include: Campylobacter, e.g., Campylobacter jejuni, Helicobacter pylori, Vibrio cholerae, and V. vulnificus; obligate intracellular parasites; Chlamydiaceae, e.g., Chlamydia trachomatis, Chlamydophila pneumoniae, and C. psittaci; coxiellaceae, e.g., Coxiella burnetii; Rickettsiae, e.g., Rickettsia prowazekii, R. rickettsii, R. typhi, R. tsutsugamushi, Ehrlichia chaffeensis, and R. sutsugamushi. chaffeensis and Anaplasma phagocytophilum.

[0086] In some embodiments, the bacteria produce β-lactamase. Bacteria that produce β-lactamase include, but are not limited to, Mycobacterium tuberculosis, methicillin-resistant Staphylococcus aureus, Staphylococcus, Enterobacteriaceae, Pseudomonas aeruginosa, Haemophilus influenzae, Klebsiella pneumoniae, Citrobacter, and Morganella.

[0087] Definitions and general terms

[0088] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared from compounds having specific substituents discovered by the present invention with relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the free form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the free form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid (forming carbonate or bicarbonate), phosphoric acid (forming phosphate, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid (forming sulfate or bisulfate), hydroiodic acid, phosphorous acid, and the like; and organic acid salts such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid. Acids such as tartaric acid and methanesulfonic acid; organic acid salts also include salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups, and can be converted into any base or acid addition salt. Preferably, the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the free form of the compound. The free form of the compound differs from its various salt forms in certain physical properties, such as different solubility in polar solvents.

[0089] The "pharmaceutically acceptable salts" of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. In general, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two. In general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.

[0090] The term "metabolite" refers to a pharmaceutically active product produced by the in vivo metabolism of a compound of Formula I or a salt thereof. Such a product may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, glucuronidation, enzymatic cleavage, etc. of the administered compound. Therefore, the present invention includes metabolites of the compounds of the present invention, including compounds produced by a process of contacting a compound of the present invention with a mammal for a period of time sufficient to obtain a metabolite thereof.

[0091] Metabolites are typically identified by preparing radiolabeled isotopes of the compounds of the invention, administering them parenterally to animals, such as rats, mice, guinea pigs, monkeys, or humans, at detectable doses (e.g., greater than about 0.5 mg / kg), allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours), and isolating the conversion products from urine, blood, or other biological samples. These products are easily isolated because they are labeled (others are isolated by using antibodies that can bind to antigenic epitopes present in the metabolites). The metabolite structure is determined in a conventional manner, for example, by MS, LC / MS or NMR analysis. Generally, the analysis of metabolites is performed in the same manner as conventional drug metabolism studies known to those skilled in the art. As long as the metabolite products are not otherwise not found in vivo, they can be used in assays for therapeutic dosing of the compounds of the invention. The compounds of the invention may contain non-natural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, compounds may be labeled with radioisotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0092] The term "solvate" refers to an association formed by one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, methanol, ethanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine or a mixture thereof.

[0093] The term "hydrate" refers to an association formed when the solvent molecule is water. In one embodiment, one molecule of the compound of the present invention can be combined with one water molecule, such as a monohydrate; in another embodiment, one molecule of the compound of the present invention can be combined with more than one water molecule, such as a dihydrate; in yet another embodiment, one molecule of the compound of the present invention can be combined with less than one water molecule, such as a hemihydrate. It should be noted that the hydrates described in the present invention retain the biological effectiveness of the compounds in non-hydrate form.

[0094] The term "bioavailability" refers to the weight percentage of a compound disclosed herein delivered to the systemic circulation of the animal or human being studied. When administered intravenously, the total exposure of the drug (AUC (0-∞)) is usually defined as 100% bioavailability (F%). "Oral bioavailability" refers to the extent to which a compound disclosed herein is absorbed into the systemic circulation when a pharmaceutical composition is taken orally compared to intravenous injection.

[0095] The technical scheme of the present invention will be clearly and completely described below in conjunction with specific embodiments. Obviously, the described embodiments are only a part of embodiments of the present invention, rather than all embodiments. Based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative work are within the scope of protection of the present invention. In addition, it is worth noting that the raw materials involved in the present invention are all common commercial products unless otherwise specified.

[0096] Example 1: Synthesis of Compound 1

[0097] 3-(((((2S,5R)-2-(((acetoxymethyl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoic acid ethyl ester

[0098]

[0099] Step 1: Synthesis of compound S4

[0100] Compound S1 (100 mg, 0.4 mmol) and diisopropylethylamine (77 ul, 0.44 mmol) were dissolved in chlorobenzene (1 ml), and a solution of 9-fluorenylmethyl chloroformate (105 mg, 0.404 mmol) in chlorobenzene (1 ml) was added to the reaction mixture below 35°C, and the mixture was reacted at room temperature for 6 hours to obtain compound S2. The solution was then mixed with carbonyldiimidazole (84.5 mg, 0.52 mmol) and stirred at room temperature for 11 hours to obtain compound S3. Diethylamine (103 ul) was added and stirring was continued at 30°C for 3.5 hours. 3M aqueous hydrochloric acid solution (0.6 ml) was added to adjust the pH to acidic, and the mixture was cooled to 0°C. The solid was separated by filtration, washed twice with water and 1-chlorobutane (5 ml×2), and dried to obtain compound S4 (88 mg, 80%). 1 HNMR(400MHz,DMSO)δ1.65(2H,m),1.86(1H,m),2.10(1H,m),2.91(2H,s),3.63 (1H, s), 3.72 (1H, d, J = 6.7Hz), 4.92 (2H, dd, J = 18.1Hz, J = 11.4Hz), 7.38 (7H, m).

[0101] Step 2: Synthesis of compound S6

[0102] Compound S4 (88 mg, 0.32 mmol) was dissolved in acetonitrile, and aqueous formaldehyde solution (37%, 270 ul) and potassium carbonate (5 mg, 0.04 mmol) were added to the above solution in sequence, and the mixture was reacted at room temperature for 12 h. After the reaction was completed, the mixture was extracted with ethyl acetate 3 times (10 ml × 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound S5.

[0103] The compound S5 obtained above was dissolved in pyridine (2 ml), acetic anhydride (50 ul, 0.5 mmol) was added, and the mixture was reacted at room temperature for 3 h. After the reaction was completed, the mixture was extracted with ethyl acetate 3 times (10 ml × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound S6 (78 mg, 70%). 1 HNMR(400MHz,Chloroform-d)δ7.35(dddd,J=13.5,5.3,2.2,1.4Hz,5H),6.48(t,J=4.5Hz,1H),5.03-4.93( m,2H),4.79(dt,J=11.7,0.9Hz,1H),4.72(dt,J=11.7,1.0Hz,1H),4.40(dd,J=6.7,4.4Hz,1H),3.83(dtd,J= 6.4,4.0,2.5Hz,1H),3.78(dd,J=10.1,2.4Hz,1H),3.54(dd,J=10.1,3.8Hz,1H),2.19(dddd,J=12.4,8.2,6 .8,5.9Hz,1H),2.15-2.05(m,1H),2.09(s,3H),1.95-1.84(m,1H),1.78(dddd,J=12.4,8.1,5.9,4.3Hz,1H).

[0104] Step 3: Synthesis of compound S7

[0105] The above-obtained compound S6 (78 mg, 0.23 mmol), palladium / carbon (10% weight, 8 mg), was dissolved in a methanol (1 ml) solution and hydrogenated at 1 atm (balloon) until thin layer chromatography analysis indicated that the reaction was complete (about 30 minutes). The mixture was filtered through a diatomaceous earth pad and then the pad was thoroughly rinsed with 20 mL of methanol. The filtrate was concentrated under vacuum (water bath temperature not exceeding 25°C) to give a transparent colorless oil. The oil was dried under vacuum for 1 hour to obtain compound S7 (52 mg, 90%), and the residue was immediately used in the next step without further purification. 1HNMR(400MHz,Chloroform-d)δ6.46(t,J=4.4Hz,1H),5.91(s,1H),4.96(dd,J=4.5,1.0Hz,2H),4.38-4.31(m,1H),3.81-3.70(m,2H),3. 69(dd,J=9.8,3.9Hz,1H),2.16-2.04(m,2H),2.08(s,3H),1.99(ddt,J=12.5,8.0,6.2Hz,1H),1.80(dddd,J=11.4,9.0,6.0,4.4Hz,1H).

[0106] Step 4: Synthesis of compound 1a

[0107] Under an argon atmosphere, a solution of sulfuryl chloride (0.11 mL, 1.5 mmol) in diethyl ether (1 ml) was cooled to -78 °C. Then, 3-hydroxy-2,2-dimethylpropionic acid ethyl ester and pyridine in diethyl ether were added dropwise to the above reaction solution for more than 1 hour. The reaction solution was slowly warmed to room temperature and then stirred at room temperature until TLC analysis showed that the reaction was complete. The mixture was filtered, the filtrate was collected, and concentrated to obtain compound 1a, which can be used directly in the next step without further purification. 1 HNMR (400MHz, CDCl 3 ): δ4.50(s,2H),4.19(q,J=6.9Hz,2H),1.31(s,6H),1.28(t,J=6.9Hz,3H).

[0108] Step 5: Synthesis of compound 1

[0109] The above-obtained compound S7 (52 mg, 0.2 mmol) and 1,3-dimethyltetrahydropyrimidine-2(1H)-1 (3.01 mL) were dissolved in THF (3.0 mL) and cooled to -78°C under an argon atmosphere. A tetrahydrofuran solution of sodium bis(trimethylsilyl)amide (2M; 0.12 mL, 0.24 mmol) was added dropwise and stirred at -78°C for 10 minutes. Then, a THF (0.5 mL) solution of ethyl 3-(chlorosulfonyl)oxyethyl-2,2-dimethylpropanoate (59 mg, 0.24 mmol) was quickly added to the reaction mixture via a syringe. After reacting at -78°C for 10 minutes, the mixture was heated to room temperature and stirred at room temperature until the reaction was completed as determined by TLC analysis (approximately 2 hours). After the reaction was completed, the mixture was extracted with ethyl acetate three times (10 ml×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 1 (18 mg, 20%). 1HNMR(400MHz,Chloroform-d)δ6.19(t,J=4.5Hz,1H),5.02-4.91(m,2H),4.42-4.34(m,1H),4. 26(d,J=9.9Hz,1H),4.24-4.14(m,1H),4.18-4.08(m,2H),3.83(dtd,J=6.4,3.8,2.5Hz,1H),3 .77(dd,J=10.1,2.6Hz,1H),3.71(dd,J=10.1,3.8Hz,1H),2.19-2.07(m,2H),2.07(s,2H),2.0 1(ddt,J=12.3,8.1,6.2Hz,1H),1.91-1.81(m,2H),1.30-1.21(m,9H).MS(EI,m / z):466(M++1).

[0110] Example 2: Synthesis of Compound 2

[0111] 2,2-Dimethyl-3-(((((2S,5R)-7-oxo-2-(((propionyloxy)methyl)carbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)propionic acid ethyl ester

[0112]

[0113] The synthesis method is the same as in Example 1. 1 HNMR(400MHz,Chloroform-d)δ6.35(t,J=4.4Hz,1H),5.01-4.88(m,2H),4.40-4.31(m,2H) ,4.24-4.08(m,2H),3.98(d,J=9.9Hz,2H),3.87-3.80(m,2H),3.76-3.70(m,2H),2.36(dq,J =10.1,7.8Hz,2H),2.12-1.95(m,2H),1.84(dddd,J=12.3,7.9,6.0,4.4Hz,1H),1.71(dddd ,J=12.6,8.1,6.8,5.9Hz,1H),1.29-1.20(m,7H),1.13(t,J=7.9Hz,3H).MS(EI,m / z):480(M + +1).

[0114] Example 3: Synthesis of Compound 3

[0115] ((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)methylbutyrate

[0116]

[0117] The synthesis method is the same as in Example 1. 1 HNMR(400MHz,Chloroform-d)δ6.33(t,J=4.5Hz,1H),5.01-4.73(m,2H),4.40(dd,J=6.8,4.4Hz,2H),4.25(d,J=9.9 Hz,1H),4.25-4.16(m,1H),4.14(dq,J=10.1,7.0Hz,2H),3.87-3.76(m,2H),3.57(dd,J=10.1,3.8Hz,1H),2.41-2.26 (m,2H),2.20(dddd,J=12.5,8.2,6.8,5.9Hz,1H),2.09(dddd,J=12.4,8.2,5.9,4.1Hz,1H),1.97-1.87(m,1H),1.77 (dddd,J=12.5,8.2,5.9,4.4Hz,1H),1.73-1.55(m,2H),1.30-1.21(m,8H),0.97(t,J=7.5Hz,3H).MS(EI,m / z):494(M + +1).

[0118] Example 4: Synthesis of Compound 4

[0119] ((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide)pentanoic acid methyl ester

[0120]

[0121] The synthesis method is the same as in Example 1. 1HNMR(400MHz,Chloroform-d)δ6.24(t,J=4.4Hz,1H),5.01-4.89(m,2H),4.38(dd,J=6.8,4.4Hz,2H),4.17(d,J=9.9Hz,1H),4.23( dq,J=10.1,7.0Hz,1H),4.19-4.08(m,2H),3.87-3.76(m,2H),3.63(dd,J=10.0,3.9Hz,1H),2.33(td,J=7.0,3.8Hz,2H),2.20(ddd d,J=12.4,8.1,6.7,5.9Hz,1H),2.07(dddd,J=12.4,8.2,5.9,4.1Hz,1H),1.93(ddt,J=12.4,8.2,6.1Hz,1H),1.78(dddd,J=12.4, 8.1,5.9,4.4Hz,1H),1.64(pd,J=6.9,2.5Hz,2H),1.48-1.30(m,2H),1.34-1.21(m,8H),0.94(t,J=7.6Hz,3H).MS(EI,m / z):508(M + +1).

[0122] Example 5: Synthesis of Compound 5

[0123] 2,2-Dimethyl-3-(((((2S,5R)-7-oxo-2-(((pivaloyloxy)methyl)carbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)propanoic acid ethyl ester

[0124]

[0125] The synthesis method is the same as in Example 1. 1H NMR(400MHz,Chloroform-d)δ6.33(t,J=4.5Hz,1H),5.01-4.91(m,2H),4.39(dd,J=6.7,4.3Hz,2H),4.25 (d,J=9.9Hz,1H),4.25-4.16(m,1H),4.19-4.08(m,2H),3.87-3.78(m,2H),3.59(dd,J=10.0,3.9Hz,1H),2 .17(dddd,J=12.4,8.1,6.7,5.9Hz,1H),2.08(dddd,J=12.3,8.1,5.9,4.0Hz,1H),1.91(ddt,J=12.5,8.2 ,6.1Hz,1H),1.77(dddd,J=12.4,8.0,5.9,4.4Hz,1H),1.30-1.21(m,8H),1.17(s,9H).MS(EI,m / z):508(M + +1).

[0126] Example 6: Synthesis of Compound 6

[0127] 3-(((((2S,5R)-2-((((isobutenyloxy)methyl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate

[0128]

[0129] The synthesis method is the same as in Example 1. 1H NMR(400MHz,Chloroform-d)δ6.37(t,J=4.4Hz,1H),5.02-4.91(m,2H),4.39(dd,J=6.8,4.4Hz,2H),4.25(d,J=9.9Hz, 1H),4.23-4.16(m,1H),4.17(dd,J=9.9,7.1Hz,2H),3.87-3.79(m,2H),3.60(dd,J=10.1,3.8Hz,1H),2.55(hept,J=7.1 Hz,1H),2.19(dddd,J=12.4,8.1,6.7,5.9Hz,1H),2.09(dddd,J=12.4,8.2,5.9,4.1Hz,1H),1.92(ddt,J=12.5,8.2,6. 2Hz,1H),1.77(dddd,J=12.4,8.2,5.9,4.4Hz,1H),1.30-1.22(m,8H),1.16(dd,J=25.1,7.2Hz,6H).MS(EI,m / z):494(M + +1).

[0130] Example 7: Synthesis of Compound 7

[0131] ((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide) 2-methylbutanoic acid methyl ester

[0132]

[0133] The synthesis method is the same as in Example 1. 1H NMR(400MHz,Chloroform-d)δ6.29(t,J=4.4Hz,1H),5.03–4.93(m,2H),4.39(dd,J=6.8,4.4Hz,2H),4.28(d,J=9.9Hz,1H),4.25–4.12(m,2H) ,4.03(d,J=9.9Hz,1H),3.86(dtd,J=6.5,3.9,2.5Hz,1H),3.77(dd,J=10.1,2.6Hz,1H),3.59(dd,J=10.1,3.8Hz,1H),2.33(dtd,J=13.6,7.3, 6.3Hz,1H),2.19(dddd,J=12.5,8.1,6.8,5.9Hz,1H),2.09(dddd,J=12.4,8.2,5.9,4.2Hz,1H),1.96–1.85(m,1H),1.77(dddd,J=12.4,8.1,5. 9,4.3Hz,1H),1.67(dddd,J=23.2,14.0,13.3,6.9Hz,2H),1.29–1.20(m,8H),1.13(d,J=7.2Hz,3H),0.92(t,J=7.0Hz,3H).MS(EI,m / z):508(M + +1).

[0134] Example 8: Synthesis of Compound 8

[0135] ((2S,5R)-6-(((3-Ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide)methyl cyclopropanecarboxylate

[0136]

[0137] The synthesis method is the same as in Example 1. 1H NMR(400MHz,Chloroform-d)δ6.40(t,J=4.5Hz,1H),5.04–4.94(m,2H),4.43(d,J=9.9Hz,1H),4.30(d d,J=6.6,4.4Hz,1H),4.25–4.10(m,2H),4.07(d,J=9.7Hz,1H),3.92–3.82(m,2H),3.67(dd,J=10.0,3 .9Hz,1H),2.22–2.00(m,3H),1.88(dddd,J=12.3,8.2,6.0,4.4Hz,1H),1.61(p,J=6.4Hz,1H),1.29–1 .20(m,9H),1.06(tdd,J=10.1,6.4,0.8Hz,2H),0.88(tdd,J=10.1,6.5,1.0Hz,2H).MS(EI,m / z):492(M + +1).

[0138] Example 9: Synthesis of Compound 9

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

[0140]

[0141] The synthesis method is the same as in Example 1. 1 H NMR(400MHz,Chloroform-d)δ6.22(t,J=4.5Hz,1H),4.99(d,J=4.4Hz,2H),4.43–4.35(m,2H),4.29(d ,J=9.9Hz,1H),4.25–4.08(m,2H),4.07(d,J=9.7Hz,1H),3.84(dtd,J=6.4,4.0,2.4Hz,1H),3.78(dd, J=10.1,2.6Hz,1H),3.62(dd,J=10.1,3.8Hz,1H),2.62–2.53(m,1H),2.20–2.10(m,1H),2.10–2.00(m ,1H),1.97–1.84(m,3H),1.78–1.66(m,4H),1.66–1.54(m,3H),1.29–1.20(m,8H).MS(EI,m / z):520(M + +1).

[0142] Example 10: Synthesis of Compound 10

[0143] ((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide)methyl cyclohexanecarboxylate

[0144]

[0145] The synthesis method is the same as in Example 1. 1 H NMR(400MHz,Chloroform-d)δ6.27(t,J=4.5Hz,1H),4.97(d,J=4.4Hz,2H),4.36(dd,J=6.6,4.4Hz,1H),4.27(d,J= 9.9Hz,1H),4.24–4.16(m,1H),4.18–4.08(m,2H),3.84(dtd,J=6.4,4.0,2.5Hz,1H),3.74(dd,J=10.1,2.4Hz,1H), 3.66(dd,J=10.1,3.8Hz,1H),2.28(dq,J=9.5,6.3Hz,1H),2.16–1.95(m,3H),1.97–1.90(m,1H),1.94–1.85(m,1H) ,1.88–1.79(m,1H),1.71–1.59(m,4H),1.58–1.46(m,1H),1.43–1.31(m,3H),1.28–1.19(m,9H).MS(EI,m / z):534(M + +1).

[0146] Example 11: Synthesis of Compound 11

[0147] (2S,5R)-6-(((3-Ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide)methyl benzoate

[0148]

[0149] The synthesis method is as in Example 1. 1H NMR (400 MHz, Chloroform-d) δ7.86–7.78 (m, 2H), 7.59–7.50 (m, 1H), 7.48–7.40 (m, 2H), 6.34 (t, J = 4.4 Hz, 1H), 5.16–5.02 (m, 2H), 4.36 (dd, J = 6.7, 4.3 Hz, 2H), 4.28 (d, J = 9.7 Hz, 1H), 4.24–4.09 (m, 3H), 3.87–3.75 (m, 2H), 3.70 (dd,J=10.1,3.7Hz,1H),2.14(dddd,J=12.5,8.0,6.7,6.0Hz,1H),2.06(dddd,J=12.4,8.0,5.9,4.1Hz,1H),1.9 7(ddt,J=12.6,8.0,6.2Hz,1H),1.84(dddd,J=12.4,8.1,5.9,4.3Hz,1H),1.30–1.20(m,8H).MS(EI,m / z):528(M + +1).

[0150] Example 12: Synthesis of Compound 12

[0151] ((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide)methyltetrahydrofuran-3-carboxylate

[0152]

[0153] The synthesis method is the same as in Example 1. 1H NMR(400MHz,Chloroform-d)δ6.19(t,J=4.5Hz,1H),4.99(d,J=4.4Hz,2H),4.43–4.33(m,2H),4.25–4.08(m,3H),4.03(dd,J=10.5,6.5Hz,1H ),3.91–3.85(m,1H),3.88–3.83(m,1H),3.87–3.76(m,2H),3.74(dd,J=10.1,2.5Hz,1H),3.60(dd,J=10.1,3.8Hz,1H),2.84(p,J=6.5Hz,1H), 2.36(dddd,J=13.4,6.6,5.7,4.8Hz,1H),2.22(dddd,J=13.2,6.4,5.5,4.6Hz,1H),2.10(dddd,J=12.4,8.2,6.7,5.8Hz,1H),2.00(ddt,J=12 .4,8.2,6.2Hz,1H),1.86(dddd,J=12.4,8.2,6.0,4.4Hz,1H),1.75(dddd,J=12.4,8.2,5.8,4.1Hz,2H),1.29–1.20(m,8H).MS(EI,m / z):522(M + +1).

[0154] Example 13: Synthesis of Compound 13

[0155] ((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide)methyltetrahydrothiophene-3-carboxylate

[0156]

[0157] The synthesis method is the same as in Example 1. 1H NMR(400MHz,Chloroform-d)δ6.24(t,J=4.5Hz,1H),4.96(d,J=4.6Hz,2H),4.43-4.33(m,2H),4.24-4.08(m,3H),3.87-3.77(m,2 H),3.64(dd,J=10.1,3.8Hz,1H),3.26(dd,J=13.3,5.2Hz,1H),3.17(tt,J=6.4,5.2Hz,1H),3.12-3.00(m,3H),2.70(dddd,J=12. 6,6.4,4.2,3.5Hz,1H),2.21(dddd,J=12.6,8.2,6.8,5.9Hz,1H),2.07(dddd,J=12.3,8.1,5.9,4.0Hz,1H),2.00(ddt,J=12.7,6. 4,3.8Hz,1H),1.91(ddt,J=12.5,8.1,6.1Hz,1H),1.78(dddd,J=12.5,8.2,5.9,4.4Hz,1H),1.28-1.19(m,9H).MS(EI,m / z):538(M + +1).

[0158] Example 14: Synthesis of Compound 14

[0159] 3-(((((2S,5R)-2-(((2-cyclopentylacetoxy)methyl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoic acid ethyl ester

[0160]

[0161] The synthesis method is the same as in Example 1. 1H NMR(400MHz,Chloroform-d)δ6.28(t,J=4.5Hz,1H),4.97(d,J=4.4Hz,2H),4.40(dd,J=6.8,4.2Hz,1H),4.29(d,J=9.9H z,2H),4.24-4.09(m,2H),4.10(d,J=9.9Hz,1H),3.88(dtd,J=6.3,3.9,2.5Hz,1H),3.78(dd,J=10.1,2.6Hz,1H),3.61( dd,J=10.1,3.8Hz,1H),2.51(dd,J=15.9,7.5Hz,1H),2.29(dd,J=15.8,7.6Hz,1H),2.26-2.14(m,2H),2.09(dddd,J=12 .4,8.2,5.9,4.1Hz,1H),1.98-1.85(m,3H),1.72-1.50(m,5H),1.41-1.30(m,2H),1.29-1.20(m,8H).MS(EI,m / z):534(M + +1).

[0162] Example 15: Synthesis of Compound 15

[0163] 3-(((((2S,5R)-2-((((3-cyclopropylpropionyl)oxy)methyl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate

[0164]

[0165] The synthesis method is the same as in Example 1. 1H NMR(400MHz,Chloroform-d)δ6.28(t,J=4.4Hz,1H),4.97(d,J=4.4Hz,2H),4.39-4.30(m,2H),4.20(dq,J= 10.1,7.0Hz,1H),4.19-4.08(m,2H),3.87-3.76(m,2H),3.72(dd,J=10.1,3.8Hz,1H),2.36(dt,J=15.6,7.9 Hz,1H),2.28(dt,J=15.3,8.0Hz,1H),2.18-2.02(m,2H),1.97(ddt,J=12.5,7.9,6.2Hz,1H),1.90-1.75(m ,2H),1.52(dtd,J=12.5,7.9,6.2Hz,1H),1.34-1.18(m,14H),1.01(hept,J=6.1Hz,1H).MS(EI,m / z):520(M + +1).

[0166] Example 16: Synthesis of Compound 16

[0167] ((2S,5R)-6-((((3-methyl-2-oxotetrahydro-2H-pyran-3-yl)methoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide)methyl propanoate

[0168]

[0169] The synthesis method is the same as in Example 1. 1 H NMR(400MHz,Chloroform-d)δ6.27(t,J=4.4Hz,1H),5.01-4.91(m,2H),4.40(dd,J=6.8,4.4Hz,1H),4. 32(d,J=9.7Hz,2H),4.08(d,J=9.7Hz,1H),4.08-3.97(m,2H),3.88(dtd,J=6.5,4.0,2.6Hz,1H),3.77(d d,J=10.1,2.6Hz,1H),3.57(dd,J=10.1,3.8Hz,1H),2.45-2.27(m,2H),2.19(dddd,J=12.5,8.4,6.8,5 .9Hz,1H),2.00-1.72(m,6H),1.75-1.65(m,1H),1.20(s,2H),1.13(t,J=7.9Hz,3H).MS(EI,m / z):478(M + +1).

[0170] Example 17: Synthesis of Compound 17

[0171] 3-((((((2S,5R)-2-((((methoxycarbonyl)oxy)methyl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octyl-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoic acid ethyl ester

[0172]

[0173] The synthesis method of compound S5 is as described in Example 1.

[0174] Step 3: Synthesis of compound S8

[0175] Compound S5 (89 mg, 0.29 mmol) was added to dichloromethane solvent (1 ml), and pyridine (36 ul, 0.44 mmol) and methyl chloroformate (42 ul, 0.44 mmol) were added in sequence at room temperature, and the mixture was reacted at room temperature until TLC showed that the reaction was complete (about 4 h). After the reaction was completed, the mixture was extracted with ethyl acetate 3 times (10 ml × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound S8 (84 mg, 80%). 1 H NMR(400MHz,Chloroform-d)δ7.38-7.28(m,5H),6.60(t,J=4.5Hz,1H),5.03(d,J =4.4Hz,2H),4.79(dt,J=11.8,1.0Hz,1H),4.72(dt,J=11.9,0.9Hz,1H),4.42(dd ,J=6.8,4.3Hz,1H),3.81(s,3H),3.86-3.75(m,2H),3.55(dd,J=10.1,3.8Hz,1H) ,2.21(dddd,J=12.5,8.2,6.7,5.9Hz,1H),1.92-1.81(m,1H),1.83-1.67(m,2H).

[0176] Step 4: Synthesis of compound S9

[0177] The above obtained compound S8 (84 mg, 0.23 mmol), palladium / carbon (10% weight, 9 mg), was dissolved in a methanol (1 ml) solution and hydrogenated at 1 atm (balloon) until thin layer chromatography analysis indicated that the reaction was complete (about 30 minutes). The mixture was filtered through a celite pad and then the pad was thoroughly rinsed with 20 mL of methanol. The filtrate was concentrated under vacuum (water bath temperature not exceeding 25°C) to give a transparent colorless oil. The oil was dried under vacuum for 1 hour to obtain compound S9 (57 mg, 90%), and the residue was immediately used in the next step without further purification. 1 H NMR(400MHz,Chloroform-d)δ6.64(t,J=4.4Hz,1H),5.90(s,1H),5.00(d,J=4.4Hz,2H),4.43(dd,J=6.7,4.3Hz,1H),3.81(s,3H) ,3.83-3.70(m,2H),3.56(dd,J=10.0,3.9Hz,1H),2.24-2.07(m,2H),1.97-1.86(m,1H),1.80(dddd,J=12.4,8.2,5.9,4.4Hz,1H).

[0178] Step 5: Synthesis of compound 17

[0179] The above-obtained compound S9 (57 mg, 0.2 mmol) and 1,3-dimethyltetrahydropyrimidine (1 mL) were dissolved in THF (3.0 mL) and cooled to -78 ° C under an argon atmosphere. A tetrahydrofuran solution of sodium bis(trimethylsilyl)amide (2M; 0.12 mL, 0.24 mmol) was added dropwise and stirred at -78 ° C for 10 minutes. Then, a solution of 3-(chlorosulfonyl)oxyethyl-2,2-dimethylpropionic acid ethyl ester (59 mg, 0.24 mmol) in THF (0.5 mL) was quickly added to the reaction mixture via a syringe. After reacting at -78 ° C for 10 minutes, the mixture was heated to room temperature and stirred at room temperature until the reaction was completed as determined by TLC analysis (about 2 h). After the reaction was completed, the mixture was extracted with ethyl acetate 3 times (10 ml × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 17 (19 mg, 20%). 1H NMR(400MHz,Chloroform-d)δ6.33(t,J=4.5Hz,1H),5.02(d,J=4.4Hz,2H),4.44(dd,J=6.8,4.4Hz,1 H),4.24-4.14(m,2H),4.14-4.08(m,1H),3.99(d,J=9.9Hz,1H),3.87-3.78(m,5H),3.60(dd,J=10.0 ,3.9Hz,1H),2.23(dddd,J=12.4,8.1,6.6,5.9Hz,1H),2.08(dddd,J=12.4,8.2,5.9,4.1Hz,1H),1.9 7-1.86(m,1H),1.77(dddd,J=12.4,8.1,5.9,4.4Hz,1H),1.29-1.20(m,9H).MS(EI,m / z):482(M++1).

[0180] Example 18: Synthesis of Compound 18

[0181] Benzyl 3-((((((2S,5R)-2-((((ethoxycarbonyl)oxy)methyl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octyl-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate

[0182]

[0183] The synthesis method is the same as Example 17. 1 H NMR(400MHz,Chloroform-d)δ7.33(s,3H),7.37–7.27(m,2H),6.28(t,J=4.4Hz,1H),5.18(d,J=11.8 Hz,1H),5.07–5.02(m,3H),4.44–4.38(m,2H),4.30–4.19(m,2H),4.14(dq,J=10.1,7.0Hz,1H),4.02( d,J=9.7Hz,1H),3.87–3.80(m,1H),3.78(dd,J=10.1,2.6Hz,1H),3.69(dd,J=10.1,3.8Hz,1H),2.12 –2.01(m,1H),1.89–1.72(m,3H),1.35(t,J=7.0Hz,3H),1.26(s,2H),1.21(s,3H).MS(EI,m / z):558(M + +1).

[0184] Example 19: Synthesis of Compound 19

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

[0186]

[0187] The synthesis method is the same as Example 17. 1 H NMR(400MHz,Chloroform-d)δ6.23(t,J=4.5Hz,1H),5.03(d,J=4.4Hz,2H),4.91(p,J=5.5Hz,1H),4.43(dd,J= 6.7,4.3Hz,2H),4.25(d,J=9.9Hz,1H),4.22–4.06(m,3H),3.84(dtd,J=6.4,3.9,2.5Hz,1H),3.79(dd,J=10.1, 2.4Hz,1H),3.62(dd,J=10.1,3.8Hz,1H),2.22(dddd,J=12.5,8.1,6.8,5.9Hz,1H),2.07(dddd,J=12.4,8.2,5 .9,4.2Hz,1H),1.97–1.86(m,3H),1.87–1.65(m,5H),1.67–1.55(m,2H),1.29–1.20(m,8H).MS(EI,m / z):536(M + +1).

[0188] Example 20: Synthesis of Compound 20

[0189] 3-(((((2S,5R)-2-(((2-ethoxyacetoxy)methyl)carbamoyl)-7-carbonyl-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoic acid ethyl ester

[0190]

[0191] The synthesis method is the same as in Example 1. 1H NMR(400MHz,Chloroform-d)δ6.31(t,J=4.5Hz,1H),5.05–4.94(m,2H),4.41(d,J=9. 9Hz,1H),4.36–4.29(m,2H),4.25–4.09(m,4H),4.04(d,J=15.4Hz,1H),3.84(dtd,J= 6.4,3.9,2.5Hz,1H),3.77(dd,J=10.1,2.6Hz,1H),3.68(dd,J=10.1,3.8Hz,1H),3.4 1(s,2H),2.14–2.01(m,2H),1.99–1.81(m,2H),1.29–1.20(m,9H).MS(EI,m / z):496(M + +1).

[0192] Example 21: Synthesis of Compound 21

[0193] 3-(((((2S,5R)-7-oxo-2-(((propionyloxy)methyl)carbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)sulfonyl)oxy)-2,2-dimethyl-propionic acid benzyl ester

[0194]

[0195] The synthesis method is the same as in Example 1. 1 H NMR(400MHz,Chloroform-d)δ7.37–7.25(m,5H),6.26(t,J=4.5Hz,1H),5.12(s,2H),4.95(d,J =4.4Hz,2H),4.47(d,J=9.9Hz,2H),4.44–4.37(m,1H),4.11(d,J=9.7Hz,1H),3.87–3.77(m,2H) ,3.58(dd,J=10.0,3.9Hz,1H),2.37(ddt,J=25.4,15.6,7.7Hz,2H),2.28–2.17(m,1H),1.99–1 .88(m,2H),1.80–1.70(m,1H),1.27(s,2H),1.22(s,3H),1.17–1.10(m,3H).MS(EI,m / z):542(M + +1).

[0196] Example 22: Synthesis of Compound 22

[0197] 3-(((((2S,5R)-2-(((acetoxymethyl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)oxy)sulfonyl)-2,2-dimethylpropanoic acid ethyl ester

[0198]

[0199] The synthesis method is the same as in Example 1. 1 H NMR(400MHz,Chloroform-d)δ6.27(t,J=4.4Hz,1H),5.01–4.91(m,2H),4.38(dd,J=6.7,4.3Hz,1H),4.23(d,J=9.9 Hz,2H),4.12(d,J=9.7Hz,1H),3.96–3.77(m,4H),3.58(dd,J=10.1,3.8Hz,1H),2.37(qd,J=7.8,6.7Hz,2H),2.20(d dddd,J=12.5,8.1,6.8,5.9Hz,1H),2.08(dddd,J=12.4,8.2,5.9,4.2Hz,1H),1.97–1.83(m,2H),1.78(dddd,J=12.3, 8.0,5.9,4.4Hz,1H),1.28(s,2H),1.23(s,3H),1.17–1.10(m,3H),0.91(dd,J=25.1,6.9Hz,6H).MS(EI,m / z):508(M + +1).

[0200] Example 23: Synthesis of Compound 23

[0201] 3-(((((2S,5R)-7-oxo-2-(((propionyloxy)methyl)carbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)-2,2-dimethyl-propionic acid butyl ester

[0202]

[0203] The synthesis method is the same as in Example 1. 1H NMR(400MHz,Chloroform-d)δ6.27(t,J=4.4Hz,1H),5.01–4.91(m,2H),4.42(dd,J=6.7,4.2 Hz,1H),4.28(d,J=9.9Hz,2H),4.14–4.01(m,3H),3.83(dtd,J=6.3,3.9,2.4Hz,1H),3.78(dd ,J=10.1,2.6Hz,1H),3.57(dd,J=10.1,3.8Hz,1H),2.41(dd,J=15.4,7.7Hz,1H),2.35(dd,J= 15.6,7.8Hz,1H),2.23–2.10(m,1H),1.97–1.84(m,2H),1.75(dddd,J=12.0,8.7,5.8,4.1Hz, 1H), 1.72-1.60 (m, 1H),1.62-1.50 (m, 1H),1.47 -1.34 (m, 1H),1.37–1.21(m,6H),1.14(t,J=7.9Hz,3H),0.90(t,J=7.6Hz,3H).MS(EI,m / z):508(M + +1).

[0204] Example 24: Synthesis of Compound 24

[0205] 3-Hexane-2,2-dimethyl-3-(((((2S,5R)-7-oxo-2-(((propionyloxy)methyl)carbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)propionate

[0206] The synthesis method is the same as in Example 1. 1H NMR(400MHz,Chloroform-d)δ6.29(t,J=4.5Hz,1H),5.17(p,J=5.5Hz,1H),5.06–4.91(m,2H),4.44–4.36( m,2H),3.96(d,J=9.9Hz,1H),3.90–3.80(m,5H),3.74(dd,J=10.1,2.6Hz,1H),3.57(dd,J=10.1,3.8Hz,1H) ,2.46–2.35(m,1H),2.39–2.27(m,2H),1.98(ddt,J=12.4,8.1,6.2Hz,1H),1.87(dddd,J=12.5,8.2,5.9,4 .4Hz,1H),1.75(dddd,J=12.3,8.2,5.8,4.1Hz,1H),1.25(s,4H),1.14(t,J=7.9Hz,3H).MS(EI,m / z):508(M + +1).

[0207] Example 25: Synthesis of Compound 25

[0208] (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl 2,2-dimethyl-3-(((((2S,5R)-7-oxo-2-(((propionyloxy)methyl)carbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)propanoate

[0209]

[0210] The synthesis method is the same as in Example 1. 1H NMR(400MHz,Chloroform-d)δ6.27(t,J=4.4Hz,1H),4.98(d,J=4.4Hz,2H),4.84(dq,J=14.7,1.0Hz,1H),4.75(dq,J=14 .5,1.0Hz,2H),4.35(dd,J=6.7,4.4Hz,1H),4.23(d,J=9.9Hz,1H),4.12(d,J=9.9Hz,1H),3.87–3.76(m,2H),3.75(dd,J= 10.1,3.7Hz,1H),2.44–2.28(m,2H),2.15(dddd,J=12.5,7.9,6.7,6.0Hz,1H),2.11–2.00(m,4H),1.96(ddt,J=12.4,7. 9,6.2Hz,1H),1.84(dddd,J=12.3,8.2,6.0,4.4Hz,1H),1.28(s,2H),1.23(s,3H),1.17–1.10(m,3H).MS(EI,m / z):564(M + +1).

[0211] Example 26: Synthesis of Compound 26

[0212] 1-((((((2S,5R)-7-oxo-2-(((propionyloxy)methyl)carbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)methyl)cyclohexane-1-carboxylic acid ethyl ester

[0213]

[0214] The synthesis method is the same as in Example 1. 1H NMR(400MHz,Chloroform-d)δ6.28(t,J=4.4Hz,1H),4.95(d,J=4.4Hz,2H),4.38–4.29(m,2H),4.24–4.05(m,2H),4.07(d,J=9.7Hz ,1H),3.88(dtd,J=6.5,4.0,2.6Hz,1H),3.75(dd,J=10.1,2.6Hz,1H),3.66(dd,J=10.1,3.8Hz,1H),2.37(qd,J=7.8,4.3Hz,2H),2. 13(dddd,J=12.4,7.9,6.7,5.9Hz,1H),2.05(dddd,J=12.4,8.1,6.0,4.2Hz,1H),2.00–1.89(m,3H),1.83(dddd,J=12.3,8.1,5.9, 4.3Hz,1H),1.71(ddd,J=12.7,6.8,4.8Hz,2H),1.62–1.39(m,6H),1.23(t,J=6.9Hz,3H),1.14(t,J=7.9Hz,3H).MS(EI,m / z):520(M + +1).

[0215] Example 27: Synthesis of Compound 27

[0216] 1-((((((2S,5R)-7-oxo-2-(((propionyloxy)methyl)carbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)methyl)cyclopentane-1-carboxylic acid ethyl ester

[0217]

[0218] The synthesis method is the same as in Example 1. 1H NMR(400MHz,Chloroform-d)δ6.28(t,J=4.4Hz,1H),5.05–4.91(m,2H),4.40(dd,J=6.6,4.4Hz,1H),4.31(d,J=9.7Hz,2H), 4.20(dq,J=10.1,6.9Hz,1H),4.19–4.07(m,2H),3.87–3.75(m,2H),3.59(dd,J=10.0,3.9Hz,1H),2.45–2.29(m,2H),2.20(d ddd,J=12.5,8.2,6.8,5.9Hz,1H),2.06(dddd,J=12.4,8.2,5.9,4.1Hz,1H),1.97(ddt,J=6.5,2.9,2.0Hz,1H),1.97–1.86(m ,2H),1.83–1.74(m,1H),1.78–1.67(m,3H),1.71–1.63(m,2H),1.23(t,J=7.0Hz,3H),1.17–1.10(m,3H).MS(EI,m / z):506(M + +1).

[0219] Example 28: Synthesis of Compound 28

[0220]

[0221] Step 1: Synthesis of compound 28a

[0222] At 0°C, in an argon atmosphere, 2,6-dimethylbenzoyl chloride (0.13 g, 0.74 mmol), pyridine (0.12 mL, 3.0 mmol) and N,N-4-dimethylaminopyridine (catalytic amount) were added to a stirred solution of 2,2-dimethylbutane-1,4-diol (105 mg, 0.9 mmol) in DCM (1 mL). The reaction mixture was gradually warmed to room temperature, and the mixture was stirred overnight. 1N HCl (3 mL) was added, quenched, the organic layer and the aqueous layer were separated, and the aqueous layer was extracted with DCM (10 ml × 3). The combined organic layer was washed with saturated NaHCO3, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 28a (94 mg, 50%). 1H NMR(400MHz,Chloroform-d)δ8.08–8.02(m,2H),7.54(ddt,J=8.0,6.9,1.5Hz,1H),7.4 8–7.40(m,2H),4.05(s,2H),3.29(d,J=6.8Hz,2H),3.06(t,J=6.9Hz,1H),1.01(s,6H).

[0223] Step 2: Synthesis of compound 28b

[0224] In an argon atmosphere, a solution of freshly distilled sulfonyl chloride (122 μL, 1.7 mmol) in Et2O (1.0 mL) was cooled to -78 °C. A solution of 4-hydroxy-3,3-dimethylbutyl 2,6-dimethylbenzoate (28a) (94 mg, 0.45 mmol) and pyridine (136 μL, 1.7 mmol) in Et2O (1.5 mL) was added dropwise to the sulfonyl chloride solution over 15 minutes. The flask was rinsed with Et2O (2×20 mL) and the rinse was added to the reaction mixture. The mixture was stirred at -78 °C for 10 minutes, then warmed to room temperature and stirred for 1 hour. Filtered and concentrated to give compound 28b, which was used directly in the next step without further purification. 1 H NMR (500MHz, Chloroform-d) δ8.08–8.02(m,2H),7.58–7.51(m,1H),7.48–7.40(m,2H),4.02(s,2H),3.76(s,2H),1.05(s,6H).

[0225] Step 3: Synthesis of compound 28

[0226] The above-obtained compound S7 (52 mg, 0.2 mmol) and 1,3-dimethyltetrahydropyrimidine-2(1H)-1 (3.01 mL) were dissolved in THF (3.0 mL) and cooled to -78°C under an argon atmosphere. A tetrahydrofuran solution of sodium bis(trimethylsilyl)amide (2M; 0.12 mL, 0.24 mmol) was added dropwise and stirred at -78°C for 10 minutes. Then a THF (0.5 mL) solution of compound 28b was quickly added to the reaction mixture via a syringe. After reacting at -78°C for 10 minutes, the mixture was heated to room temperature and stirred at room temperature until the reaction was completed as determined by TLC analysis (about 2 h). After the reaction was completed, the mixture was extracted with ethyl acetate 3 times (10 ml × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 28 (21 mg, 20%). 1HNMR(400MHz,Chloroform-d)δ8.08–8.02(m,2H),7.55(ddt,J=8.0,6.9,1.5Hz,1H),7.48–7.41(m,2H),6.12(t,J =4.5Hz,1H),4.97(d,J=4.6Hz,2H),4.39(dd,J=6.8,4.2Hz,1H),4.14(dd,J=25.6,10.4Hz,2H),3.99(d,J=11.0Hz, 1H),3.87–3.77(m,2H),3.70(d,J=10.1Hz,1H),3.58(dd,J=10.1,3.8Hz,1H),2.26–2.16(m,1H),2.07(s,2H),1.98 –1.87(m,1H),1.77(ddddd,J=20.2,12.1,8.2,6.1,4.1Hz,2H),1.10(s,2H),1.05(s,2H).MS(EI,m / z):528(M++1).

[0227] Example 29: Synthesis of Compound 29

[0228] 2,2-Dimethyl-3-(((((2S,5R)-7-oxo-2-(((propionyloxy)methyl)carbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)2-methylbenzoic acid propyl ester

[0229]

[0230] The synthesis method is the same as Example 28. 1 H NMR(400MHz,Chloroform-d)δ7.89–7.83(m,1H),7.40(ddd,J=7.9,4.9,3.7Hz,1H),7.34–7.26(m,2H), 6.27(t,J=4.4Hz,1H),4.96(d,J=4.4Hz,2H),4.45–4.35(m,2H),4.12(d,J=11.0Hz,1H),3.97(d,J=11. 2Hz,1H),3.89–3.78(m,3H),3.69–3.58(m,2H),2.52(s,3H),2.36(ddq,J=31.4,15.7,7.8Hz,2H),2.21 –2.10(m,1H),2.11–2.01(m,1H),1.96–1.84(m,2H),1.17–1.06(m,5H),1.03(s,3H).MS(EI,m / z):556(M + +1).

[0231] Example 30: Synthesis of Compound 30

[0232] 2,2-Dimethyl-3-(((((2S,5R)-7-oxo-2-(((propionyloxy)methyl)carbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)2,6-dimethylbenzoic acid propyl ester

[0233]

[0234] The synthesis method is the same as Example 28. 1 H NMR (400MHz, Chloroform-d) δ7.32(dd,J=8.2,7.5Hz,1H),7.14(d,J=7.7Hz,2H),6.25(t,J=4.4Hz,1H),4.96(d,J=4.4Hz,2H),4.37(dd,J=6.7 ,4.4Hz,2H),4.13(d,J=11.0Hz,1H),4.03(d,J=10.0Hz,1H),3.98(d,J=11.0Hz,1H),3.87–3.5(m,2H),3.71(dd,J=10.2,3.8Hz,2H),3.65(d,J =9.9Hz,1H),2.42(dd,J=15.6,7.8Hz,1H),2.39(s,5H),2.33(dq,J=15.7,7.9Hz,1H),2.18–2.07(m,1H),2.06(tdd,J=8.1,6.0,4.0Hz,1H),1. 98(ddt,J=12.5,7.9,6.2Hz,1H),1.84(dddd,J=12.4,8.2,6.0,4.4Hz,1H),1.14(t,J=7.9Hz,3H),1.02(s,2H),0.97(s,3H).MS(EI,m / z):570(M + +1).

[0235] Example 31: Synthesis of Compound 31

[0236] 2,2-Dimethyl-3-(((((2S,5R)-7-oxo-2-(((propionyloxy)methyl)carbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)2-fluoro-6-methoxybenzoic acid propyl ester

[0237]

[0238] The synthesis method is the same as Example 28. 1H NMR (400MHz, Chloroform-d) δ7.41(td,J=7.9,4.9Hz,1H),6.92(td,J=7.9,1.2Hz,1H),6.73(dd,J=7.8,1.3Hz,1H),6.28(t,J=4.4Hz,1H),4.96( d,J=4.4Hz,2H),4.40(dd,J=6.6,4.4Hz,2H),4.23(d,J=11.0Hz,2H),4.1 5(d,J=9.9Hz,1H),4.00(d,J=11.0Hz,1H),3.88–3.77(m,4H),3.72(d,J= 9.9Hz,1H),3.57(dd,J=10.1,3.8Hz,1H),2.36(ddt,J=21.1,15.6,7.7Hz,2H),2.19(dddd,J=12.5,8.1,6.7,5.9Hz,1H),2.09(dddd,J=12.4,8.2, 5.9,4.2Hz,1H),1.92(ddt,J=12.5,8.2,6.1Hz,1H),1.79(dddd,J=12.5,8.2,5.9,4.4Hz,1H),1.17–1.08(m,5H),1.05(s,3H).MS(EI,m / z):590(M + +1).

[0239] Example 32: Synthesis of Compound 32

[0240] 2,2-Dimethyl-3-(((((2S,5R)-7-oxo-2-(((propionyloxy)methyl)carbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)2,6-dimethoxybenzoic acid propyl ester

[0241]

[0242] The synthesis method is the same as Example 28. 1H NMR (400MHz, Chloroform-d) δ7.41(td,J=7.9,4.9Hz,1H),6.92(td,J=7.9,1.2Hz,1H),6.75(dd,J=7.8,1.3Hz,1H),6.28(t,J=4.4Hz,1H),4.96(d,J =4.4Hz,2H),4.40(dd,J=6.6,4.4Hz,1H),4.23(d,J=11.0Hz,2H),4.15(d, J=9.9Hz,2H),4.00(d,J=11.0Hz,1H),3.86(s,3H)3.88–3.77(m,4H),3.72 (d,J=9.9Hz,1H),3.57(dd,J=10.1,3.8Hz,1H),2.36(ddt,J=21.1,15.6,7.7Hz,2H),2.19(dddd,J=12.5,8.1,6.7,5.9Hz,1H),2.09(dddd,J=12.4,8 .2,5.9,4.2Hz,1H),1.92(ddt,J=12.5,8.2,6.1Hz,1H),1.79(dddd,J=12. 5,8.2,5.9,4.4Hz,1H),1.17–1.08(m,5H),1.05(s,3H).MS(EI,m / z):602(M + +1).

[0243] Example 33: Synthesis of Compound 33

[0244] 2,2-Dimethyl-3-(((((2S,5R)-7-oxo-2-(((propionyloxy)methyl)carbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)3-fluoro-2,6-dimethoxybenzoate

[0245]

[0246] The synthesis method is the same as Example 28. 1H NMR(400MHz,Chloroform-d)δ7.18–7.11(m,1H),6.82(dd,J=8.4,5.1Hz,1H),6.26(t,J=4.5Hz,1H),4.96(d,J=4.5Hz,2H), 4.39(dd,J=6.7,4.4Hz,1H),4.25–4.15(m,2H),4.04(d,J=11.0Hz,2H),3.89(s,3H),3.87–3.77(m,5H),3.75(d,J=9.9Hz,1H ),3.57(dd,J=10.0,3.9Hz,1H),2.46–2.29(m,2H),2.18(dddd,J=12.5,8.1,6.7,5.9Hz,1H),2.08(dddd,J=12.4,8.2,5.9, 4.1Hz,1H),1.97–1.87(m,1H),1.79(dddd,J=12.3,8.1,5.9,4.3Hz,1H),1.17–1.08(m,5H),1.05(s,3H).MS(EI,m / z):620(M + +1).

[0247] Example 34: Synthesis of Compound 34

[0248] 2-Ethyl-2-((((((2S,5R)-7-oxo-2-(((propyloxy)methyl)carbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)butyl propionate

[0249]

[0250] The synthesis method is the same as Example 28. 1H NMR(400MHz,Chloroform-d)δ6.28(t,J=4.5Hz,1H),4.96(d,J=4.4Hz,2H),4.43(dd,J=6.6,4.4Hz,1H),4.11(d,J=10.8Hz,1H) ,3.96–3.89(m,2H),3.87–3.74(m,3H),3.57(dd,J=10.1,3.8Hz,1H),2.38(dq,J=8.9,7.9Hz,4H),2.33(dddd,J=12.5,8.1,6.8, 5.9Hz,1H),2.07(dddd,J=12.4,8.1,5.9,4.1Hz,1H),1.92(ddt,J=12.5,8.1,6.1Hz,1H),1.80(dddd,J=12.5,8.2,5.9,4.4Hz,1 H),1.57(dq,J=13.2,7.2Hz,2H),1.47(dq,J=13.2,7.2Hz,2H),1.15(q,J=7.8Hz,6H),0.84(t,J=7.1Hz,6H).MS(EI,m / z):522(M + +1).

[0251] Example 35: Synthesis of Compound 35

[0252] 3,3-Dimethyl-4-(((((2S,5R)-7-oxo-2-(((propionyloxy)methyl)carbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)butyl propionate

[0253]

[0254] The synthesis method is the same as Example 28. 1H NMR(400MHz,Chloroform-d)δ6.28(t,J=4.4Hz,1H),5.01–4.91(m,2H),4.41(dd,J=6.7,4.1Hz,1H),4.25(dt,J=11.7,6.5 Hz,2H),4.00(dt,J=11.7,6.4Hz,1H),3.87–3.75(m,3H),3.68(d,J=9.9Hz,1H),3.59(dd,J=10.1,3.9Hz,1H),2.47–2.25( m,4H),2.17(dddd,J=11.7,8.6,6.6,5.9Hz,1H),2.08(dddd,J=12.4,8.3,6.0,4.1Hz,1H),1.97–1.84(m,2H),1.73(dt,J= 13.9,6.4Hz,1H),1.45(dt,J=13.7,6.5Hz,1H),1.14(td,J=7.8,3.0Hz,6H),1.03(s,2H),0.98(s,3H).MS(EI,m / z):508(M + +1).

[0255] Example 36: Synthesis of Compound 36

[0256] ((2S,5R)-7-Oxo-6-(((2,2,3,3-tetramethyl-4-(propyloxy)butoxy)sulfonyl)oxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide)methyl propanoate

[0257]

[0258] The synthesis method is the same as Example 28. 1H NMR(400MHz,Chloroform-d)δ6.28(t,J=4.5Hz,1H),4.96(d,J=4.4Hz,2H),4.38(dd,J=6.7,4.4Hz,1H),4.13–4.0 4(m,2H),3.96–3.85(m,3H),3.78(dd,J=10.1,2.6Hz,1H),3.71(dd,J=10.1,3.8Hz,1H),2.43(dq,J=15.6,7.8Hz, 1H),2.41–2.35(m,1H),2.38–2.27(m,2H),2.18–2.01(m,2H),1.96(ddt,J=12.4,7.8,6.2Hz,1H),1.84(dddd,J=1 2.5,8.2,6.0,4.4Hz,1H),1.17(q,J=7.9Hz,6H),1.01(d,J=1.2Hz,6H),0.96(d,J=1.3Hz,6H).MS(EI,m / z):536(M + +1).

[0259] Example 37: Synthesis of Compound 37

[0260] 3,3-Dimethyl-4-(((((2S,5R)-7-oxo-2-(((propionyloxy)methyl)carbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)octanoic acid butyl ester

[0261]

[0262] The synthesis method is the same as Example 28. 1H NMR (400MHz, Chloroform-d) δ6.27(t,J=4.5Hz,1H),4.96(d,J=4.4Hz,2H),4.41(dd,J=6.7,4.3Hz,1H),4.23(dt,J=11.7,6.6Hz,2H),4.02(d t,J=11.7,6.4Hz,1H),3.90–3.80(m,2H),3.78(dd,J=10.1,2.5Hz,2H),3.68(d,J=9.9Hz,1H),3.58(dd,J=10.1,3.8Hz,1H),2.44–2.35(m,1H ),2.38–2.29(m,2H),2.31–2.12(m,2H),2.08(dddd,J=12.4,8.1,5.9,4.1Hz,1H),1.96–1.79(m,2H),1.57(dt,J=12.9,6.9Hz,1H),1.55–1.4 2(m,2H),1.39(dt,J=13.7,6.4Hz,1H),1.35–1.16(m,6H),1.17–1.10( m,3H),1.03(s,3H),0.98(s,3H),0.94–0.84(m,3H).MS(EI,m / z):578(M + +1).

[0263] Example 38: Synthesis of Compound 38

[0264] 3,3-Dimethyl-4-(((((2S,5R)-7-oxo-2-(((propionyloxy)methyl)carbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)3-methoxypropanoic acid butyl ester

[0265]

[0266] The synthesis method is the same as Example 28. 1H NMR(400MHz,Chloroform-d)δ6.28(t,J=4.4Hz,1H),4.97(d,J=4.4Hz,2H),4.36(dd,J=6.7,4.4Hz,1H),4.17(dt,J=11.7,6.4Hz,2H ),4.08(dt,J=11.7,6.4Hz,2H),4.02–3.88(m,2H),3.84(dtd,J=6.4,4.0,2.5Hz,1H),3.82–3.74(m,2H),3.74–3.67(m,2H),3.33(s, 3H),2.64–2.48(m,2H),2.44–2.27(m,2H),2.18–2.01(m,2H),1.97(ddt,J=12.5,7.9,6.2Hz,1H),1.84(dddd,J=12.3,8.2,6.0,4.4 Hz,1H),1.47(dt,J=13.9,6.5Hz,1H),1.39(dt,J=13.7,6.5Hz,1H),1.17–1.10(m,3H),1.03(s,2H),0.98(s,2H).MS(EI,m / z):538(M + +1).

[0267] Example 39: Synthesis of Compound 39

[0268] 3,3-Dimethyl-4-(((((2S,5R)-7-oxo-2-(((propionyloxy)methyl)carbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)butyl 5-acetoxypentyl ester

[0269]

[0270] The synthesis method is the same as Example 28. 1H NMR(400MHz,Chloroform-d)δ6.28(t,J=4.4Hz,1H),4.98(d,J=4.4Hz,2H),4.38(dd,J=6.8,4.4Hz,1H),4.21–4.03(m,3H),4.02(dt,J=11.7,6 .5Hz,2H),3.83(dtd,J=6.5,4.0,2.6Hz,1H),3.79–3.72(m,2H),3.63(d,J=10.1Hz,1H),3.57(dd,J=10.1,3.8Hz,1H),2.49(dq,J=15.8,7.9Hz, 1H),2.42(dd,J=8.1,4.0Hz,1H),2.42–2.32(m,2H),2.20(dddd,J=12.5,8.1,6.6,5.9Hz,1H),2.07(dddd,J=12.4,8.2,5.9,4.2Hz,1H),2.02( s,3H),1.96–1.85(m,1H),1.86–1.61(m,6H),1.55(dt,J=13.9,6.4Hz,1 H),1.14(t,J=7.9Hz,3H),1.04(s,2H),0.99(s,3H).MS(EI,m / z):594(M + +1).

[0271] Example 40: Synthesis of Compound 40

[0272] 4,4-Dimethyl-5-(((((2S,5R)-7-oxo-2-(((propionyloxy)methyl)carbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)propanoic acid pentyl ester

[0273]

[0274] The synthesis method is the same as Example 28. 1H NMR(400MHz,Chloroform-d)δ6.28(t,J=4.4Hz,1H),4.95(d,J=4.4Hz,2H),4.42(dd,J=6.8,4.1Hz,1H),4.13(dt,J=11.3,6 .0Hz,2H),4.05(dt,J=11.5,6.0Hz,1H),3.87–3.80(m,1H),3.81–3.72(m,2H),3.68(d,J=9.9Hz,1H),3.57(dd,J=10.1,3.8H z,1H),2.43–2.31(m,4H),2.21–2.11(m,1H),2.08(dddd,J=12.3,8.4,5.9,4.1Hz,1H),1.98–1.86(m,2H),1.72–1.53(m,2H) ,1.39(dt,J=12.8,6.3Hz,1H),1.36–1.27(m,1H),1.14(td,J=7.9,4.0Hz,6H),1.01(s,2H),0.96(s,3H).MS(EI,m / z):522(M + +1).

[0275] Example 41: Synthesis of Compound 41

[0276] ((2S,5R)-6-(((2,2-dimethyl-4-(2-phenylacetyloxy)butoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide)methyl propanoate

[0277]

[0278] The synthesis method is the same as Example 28. 1H NMR(400MHz,Chloroform-d)δ7.33–7.22(m,3H),7.16–7.10(m,2H),6.27(t,J=4.4Hz,1H),4.97(d,J=4.4Hz,2H),4.40(dd,J=6.8,4.4Hz,2H),4 .21(dt,J=11.7,6.4Hz,1H),4.06(dt,J=11.7,6.5Hz,1H),3.87–3.74(m ,3H),3.73–3.56(m,3H),3.50(dt,J=13.7,1.1Hz,1H),2.44–2.27(m,2H ),2.18(dddd,J=12.5,8.1,6.8,5.9Hz,1H),2.09(dddd,J=12.4,8.1,5.9,4.1Hz,1H),1.92(ddt,J=12.4,8.1,6.1Hz,1H),1.80(dddd,J=12.4,8 .1,5.9,4.3Hz,1H),1.47(dt,J=13.9,6.5Hz,1H),1.39(dt,J=13.9,6.4 Hz,1H),1.17–1.10(m,3H),1.03(s,2H),0.98(s,3H).MS(EI,m / z):570(M + +1).

[0279] Example 42: Synthesis of Compound 42

[0280] 2,2-Dimethyl-5-(((((2S,5R)-7-oxo-2-(((propionyloxy)methyl)carbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)propanoic acid pentyl ester

[0281]

[0282] The synthesis method is the same as Example 28. 1H NMR(400MHz,Chloroform-d)δ6.24(t,J=4.5Hz,1H),4.96(d,J=4.4Hz,2H),4.45(dd,J=6.6,4.4Hz ,1H),4.11–4.00(m,3H),3.96(d,J=1.3Hz,2H),3.53–3.41(m,2H),2.37(qd,J=7.9,2.2Hz,4H),1. 95(dddd,J=12.3,7.9,6.1,4.4Hz,1H),1.86–1.76(m,2H),1.76–1.70(m,2H),1.69–1.58(m,1H),1 .42(hept,J=6.6Hz,2H),1.15(td,J=7.9,3.5Hz,6H),1.06(s,3H),1.01(s,3H).MS(EI,m / z):522(M + +1).

[0283] Example 43: Synthesis of Compound 43

[0284] 2,2,4,4-Tetramethyl-5-(((((2S,5R)-7-oxo-2-(((propionyloxy)methyl)carbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)benzoic acid pentyl ester

[0285]

[0286] The synthesis method is the same as Example 28. 1 H NMR(400MHz,Chloroform-d)δ8.05–7.99(m,2H),7.59–7.52(m,1H),7.50–7.40(m,2H),6.24(t,J=4.5Hz ,1H),4.96(d,J=4.4Hz,2H),4.47(dd,J=6.7,4.4Hz,1H),4.07–3.99(m,3H),3.90(d,J=0.7Hz,2H),3.53– 3.41(m,2H),2.36(q,J=7.8Hz,2H),1.95(dddd,J=12.3,7.9,6.1,4.3Hz,1H),1.86–1.70(m,2H),1.70–1 .56(m,1H),1.49–1.39(m,2H),1.15(t,J=7.9Hz,3H),1.00(dd,J=25.0,11.8Hz,12H).MS(EI,m / z):598(M + +1).

[0287] Example 44: Synthesis of Compound 44

[0288] 2,2,4,4-Tetramethyl-5-(((((2S,5R)-7-oxo-2-(((propionyloxy)methyl)carbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)pentyl 2,6-dimethoxybenzoate

[0289]

[0290] The synthesis method is the same as Example 28. 1 H NMR(400MHz,Chloroform-d)δ7.42(t,J=8.3Hz,1H),6.85(d,J=8.3Hz,2H),6.30(t,J=4.4Hz,1H),4.96(d, J=4.5Hz,2H),4.45(dd,J=6.7,4.4Hz,1H),4.10–4.00(m,3H),3.93–3.85(m,8H),3.50(dd,J=10.1,3.8Hz, 1H),3.45(dd,J=10.1,2.6Hz,1H),2.37(q,J=7.9Hz,2H),1.93(dddd,J=12.3,7.9,6.2,4.4Hz,1H),1.86–1 .71(m,2H),1.69–1.58(m,1H),1.44(s,2H),1.15(t,J=7.9Hz,3H),1.06–0.94(m,12H).MS(EI,m / z):658(M + +1).

[0291] Example 45: Synthesis of Compound 45

[0292] 2,2,4,4-Tetramethyl-5-(((((2S,5R)-7-oxo-2-(((propionyloxy)methyl)carbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)pentyl 2-methoxybenzoate

[0293]

[0294] The synthesis method is the same as Example 28. 1H NMR(400MHz,Chloroform-d)δ7.81(dd,J=8.1,1.6Hz,1H),7.43(td,J=8.1,1.6Hz,1H),7.22(td,J=8.1,1.3Hz,1H),7.00(dd ,J=8.3,1.3Hz,1H),6.30(t,J=4.4Hz,1H),4.96(d,J=4.5Hz,2H),4.45(dd,J=6.7,4.4Hz,1H),4.09–4.00(m,3H),3.90(d,J= 5.1Hz, 5H), 3.50 (dd, J=10.1, 3.8Hz, 1H), 3.45 (dd, J=10.1, 2.6Hz, 1H), 2.37 (q, J=7.9Hz, 2H), 1.95 (dddd, J=12.3, 7.9, 6.1, 4.3Hz,1H),1.86–1.71(m,2H),1.70–1.59(m,1H),1.44(s,2H),1.15(t,J=7.9Hz,3H),1.07–0.95(m,12H).MS(EI,m / z):628(M + +1).

[0295] Example 46: Synthesis of Compound 46

[0296] 2,2,4,4-Tetramethyl-5-(((((2S,5R)-7-oxo-2-(((propionyloxy)methyl)carbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)pentyl 2,3-dimethylbenzoate

[0297]

[0298] The synthesis method is the same as Example 28. 1H NMR (400MHz, Chloroform-d) δ7.80 (dd, J=7.8, 1.2Hz, 1H), 7.20 (t, J=7.9Hz, 1H), 7.13 (ddq, J=7.8, 1.5, 0.8Hz, 1H), 6.30 (t, J= 4.4Hz,1H),4.97(d,J=4.5Hz,2H),4.45(dd,J=6.7,4.4Hz,1H),4.07–4.00(m,3H),3.90(d,J=0.7Hz,2H),3.50(dd,J=10.1,3.8 Hz,1H),3.45(dd,J=10.1,2.6Hz,1H),2.41–2.32(m,5H),2.23(d,J=0.7Hz,3H),1.95(dddd,J=12.3,7.9,6.1,4.3Hz,1H),1.86 –1.71(m,2H),1.70–1.59(m,1H),1.50–1.39(m,2H),1.15(t,J=7.9Hz,3H),1.00(dd,J=24.9,11.9Hz,12H).MS(EI,m / z):626(M + +1).

[0299] Example 47: Synthesis of Compound 47

[0300] 2,2,4,4-Tetramethyl-5-(((((2S,5R)-7-oxo-2-(((propionyloxy)methyl)carbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)pentyl 2,6-dimethylbenzoate

[0301]

[0302] The synthesis method is the same as Example 28. 1H NMR(400MHz,Chloroform-d)δ7.24–7.16(m,3H),6.30(t,J=4.4Hz,1H),4.96(d,J=4.5Hz,2H),4.45(dd,J=6.7,4. 4Hz,1H),4.12(d,J=11.0Hz,1H),4.09–4.00(m,2H),3.90(d,J=0.7Hz,2H),3.50(dd,J=10.1,3.8Hz,1H),3.45(dd, J=10.1,2.6Hz,1H),2.44–2.32(m,8H),1.95(dddd,J=12.3,7.9,6.1,4.3Hz,1H),1.86–1.71(m,2H),1.70–1.59(m, 1H),1.50–1.39(m,2H),1.15(t,J=7.9Hz,3H),1.04(s,3H),0.99(d,J=3.3Hz,6H),0.95(s,3H).MS(EI,m / z):626(M + +1).

[0303] Example 48: Synthesis of Compound 48

[0304] 2,2,4,4-Tetramethyl-5-(((((2S,5R)-7-oxo-2-(((propionyloxy)methyl)carbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)pentyl 2-acetoxybenzoate

[0305]

[0306] The synthesis method is the same as Example 28. 1H NMR(400MHz,Chloroform-d)δ7.89(dd,J=8.0,1.6Hz,1H),7.55(td,J=8.1,1.6Hz,1H),7.27(td,J=8.0,1.2Hz,1H),7.13(dd,J=8.2,1.3Hz,1H) ,6.30(t,J=4.4Hz,1H),4.96(d,J=4.5Hz,2H),4.45(dd,J=6.7,4.4Hz,1H),4.14(d,J=11.0Hz,1H),4.08–4.00(m,2H),3.90(d,J=0.7Hz,2H),3. 50(dd,J=10.1,3.8Hz,1H),3.45(dd,J=10.1,2.6Hz,1H),2.37(q,J=7.9Hz,2H),2.24(s,3H),1.93(dddd,J=12.3,7.9,6.2,4.4Hz,1H),1.86–1. 70(m,2H),1.69–1.58(m,1H),1.45(d,J=2.4Hz,2H),1.15(t,J=7.9Hz,3H),1.04(s,3H),1.00(d,J=2.4Hz,6H),0.95(s,3H).MS(EI,m / z):656(M + +1).

[0307] Example 49: Synthesis of Compound 49

[0308] ((2S,5R)-6-((((2,2-dimethyl-6-(2-phenylacetoxy)hexyl)oxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide)methyl propanoate

[0309]

[0310] The synthesis method is the same as Example 28. 1H NMR(400MHz,Chloroform-d)δ7.35–7.24(m,3H),7.16(ddtd,J=6.6,4.4,2.1,1.0Hz,2H),6.24(t,J=4.5Hz,1H) ,4.96(d,J=4.4Hz,2H),4.45(dd,J=6.7,4.4Hz,1H),4.12(t,J=6.1Hz,2H),4.03(dtd,J=6.4,4.0,2.5Hz,1H),3. 92(s,2H),3.57(t,J=1.0Hz,2H),3.53–3.41(m,2H),2.36(q,J=7.8Hz,2H),1.95(dddd,J=12.3,7.9,6.1,4.3Hz ,1H),1.86–1.59(m,5H),1.52–1.32(m,4H),1.15(t,J=7.9Hz,3H),1.00(s,3H),0.95(s,3H).MS(EI,m / z):598(M + +1).

[0311] Example 50: Synthesis of Compound 50

[0312] 4,4-Dimethyl-5-(((((2S,5R)-7-oxo-2-(((propionyloxy)methyl)carbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)pentane-1,2-diol dipropionate

[0313]

[0314] The synthesis method is the same as Example 28. 1 H NMR (400MHz, Chloroform-d) δ6.24(t,J=4.5Hz,1H),5.06(tt,J=6.4,5.5Hz,1H),4.97(d,J=4. 4Hz,2H),4.45(dd,J=6.7,4.4Hz,1H),4.27(d,J=5.7Hz,2H),4.03(dtd,J=6.3,4.0,2.5Hz,1H) ,3.98(s,2H),3.53–3.41(m,2H),2.36(qdd,J=7.9,6.8,1.1Hz,6H),2.00–1.89(m,3H),1.86–1 .71(m,2H),1.70–1.59(m,1H),1.19–1.12(m,9H),1.10(s,3H),1.05(s,3H).MS(EI,m / z):594(M + +1).

[0315] Example 51: Synthesis of Compound 51

[0316] 4-Methyl-5-(((((2S,5R)-7-oxo-2-(((propionyloxy)methyl)carbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)pentane-1,2-diol dipropionate

[0317]

[0318] The synthesis method is the same as Example 28. 1 H NMR(400MHz,Chloroform-d)δ6.24(t,J=4.5Hz,1H),4.99–4.90(m,3H),4.45(d d,J=6.8,4.4Hz,1H),4.33(d,J=5.6Hz,2H),4.07–3.97(m,3H),3.53–3.41(m,2H ),2.41–2.30(m,6H),2.07–1.97(m,1H),2.00–1.90(m,3H),1.86–1.70(m,2H), 1.70–1.59(m,1H),1.19–1.11(m,9H),1.06(d,J=6.9Hz,3H).MS(EI,m / z):580(M + +1).

[0319] Example 52: Synthesis of Compound 52

[0320] 5-(((((2S,5R)-2-(((acetoxymethyl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)-4-methylpentane-1,2-diylbis(2-phenylacetic acid)

[0321]

[0322] The synthesis method is the same as Example 28. 1H NMR(400MHz,Chloroform-d)δ7.32–7.22(m,6H),7.22(tdp,J=4.0,2.9,1.0Hz,4H),6.14(t,J=4.4Hz, 1H),5.06–4.95(m,3H),4.43(dd,J=6.7,4.3Hz,1H),4.37–4.25(m,2H),4.07–3.97(m,3H),3.58(q,J= 0.8Hz,4H),3.50(dd,J=10.1,3.8Hz,1H),3.45(dd,J=10.1,2.6Hz,1H),2.08(s,3H),2.07–1.94(m,1H ),1.98–1.90(m,3H),1.86–1.70(m,2H),1.69–1.58(m,1H),1.06(d,J=6.9Hz,3H).MS(EI,m / z):690(M + +1).

[0323] Example 53: Synthesis of Compound 53

[0324] ((2S,5R)-6-((((2,2-dimethyl-6-(propionylthio)hexyl)oxy)sulfonyl)oxy)-7-carbonyl-1,6-diazabicyclo[3.2.1]octane-2-carbazylamino<oxalylamino>)methyl propionate

[0325]

[0326] The synthesis method is the same as Example 28. 1 H NMR(400MHz,Chloroform-d)δ6.24(t,J=4.5Hz,1H),4.96(d,J=4.4Hz,2H),4.45(dd,J=6.8,4.4Hz,1H),4.03(dtd, J=6.4,4.0,2.5Hz,1H),3.92(s,3H),3.53–3.40(m,2H),2.87(t,J=6.4Hz,2H),2.65(q,J=7.9Hz,2H),2.36(q,J=7.8 Hz,2H),1.95(dddd,J=12.3,7.9,6.1,4.3Hz,1H),1.86–1.70(m,2H),1.70–1.60(m,1H),1.64–1.55(m,2H),1.54–1 .45(m,2H),1.42(td,J=6.4,1.1Hz,2H),1.17(dt,J=15.7,7.9Hz,6H),1.01(s,2H),0.96(s,3H).MS(EI,m / z):552(M+ +1).

[0327] Example 54: Synthesis of Compound 54

[0328] 2-Methoxyethyl 2,2-dimethyl-3-(((((2S,5R)-7-oxo-2-(((propionyloxy)methyl)carbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)propionate

[0329]

[0330] The synthesis method is the same as in Example 1. 1 H NMR(400MHz,Chloroform-d)δ6.24(t,J=4.5Hz,1H),5.01–4.91(m,2H),4.45(dd,J=6.6,4.4Hz,1H ),4.26(d,J=9.9Hz,1H),4.24–4.14(m,3H),4.02(dtd,J=6.5,4.0,2.6Hz,1H),3.68–3.54(m,2H),3 .53–3.41(m,2H),3.39(s,3H),2.36(q,J=7.9Hz,2H),1.92(dddd,J=12.3,7.9,6.1,4.3Hz,1H),1.8 6–1.70(m,2H),1.66–1.58(m,1H),1.28(s,3H),1.23(s,3H),1.19–1.12(m,3H).MS(EI,m / z):510(M + +1).

[0331] Example 55: Synthesis of Compound 55

[0332] 2,2-Difluoroethyl 2,2-dimethyl-3-(((((2S,5R)-7-oxo-2-(((propionyloxy)methyl)carbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)propionate

[0333]

[0334] The synthesis method is the same as in Example 1. 1H NMR(400MHz,Chloroform-d)δ6.51(t,J=2.2Hz,1H),6.24(t,J=4.5Hz,1H),5.01–4.91(m,2H),4. 45(dd,J=6.6,4.4Hz,1H),4.26(d,J=9.9Hz,1H),4.22–4.18(m,3H),4.02(dtd,J=6.5,4.0,2.6Hz, 1H),3.53–3.41(m,2H),2.36(q,J=7.9Hz,2H),1.95(dddd,J=12.3,7.9,6.1,4.3Hz,1H),1.86–1. 70(m,2H),1.71–1.61(m,1H),1.27(s,2H),1.22(s,2H),1.15(t,J=7.9Hz,3H).MS(EI,m / z):516(M + +1).

[0335] Example 56: Synthesis of Compound 56

[0336] 3,5-Dimethyl-2-(2-methyl-1-(((((2S,5R)-7-oxo-2-(((propionyloxy)methyl)carbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)propan-2-yl)benzoic acid methyl ester

[0337]

[0338] The synthesis method is the same as in Example 1. 1 H NMR(400MHz,Chloroform-d)δ7.53(d,J=2.0Hz,1H),7.02–6.97(m,1H),6.24(t,J=4.5Hz,1H),4. 96(d,J=4.4Hz,2H),4.45(d,J=4.2Hz,3H),4.03(dtd,J=6.4,4.0,2.5Hz,1H),3.89(s,3H),3.55– 3.41(m,2H),2.41–2.28(m,5H),2.20(s,3H),1.96(dddd,J=12.3,7.9,6.1,4.3Hz,1H),1.86–1.7 0(m,2H),1.70–1.59(m,1H),1.42(s,3H),1.37(s,3H),1.15(t,J=7.9Hz,3H).MS(EI,m / z):570(M + +1).

[0339] Example 57: Synthesis of Compound 57

[0340] ((2S,5R)-7-Oxo-6-((((3,5,5-trimethyl-2-oxotetrahydrofuran-3-yl)methoxy)sulfonyl)oxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide)methyl propanoate

[0341]

[0342] The synthesis method is the same as in Example 1. 1 H NMR(400MHz,Chloroform-d)δ6.35(t,J=4.5Hz,1H),5.01–4.93(m,2H),4.45(dd,J=6.8,4.4H z,1H),4.30–4.22(m,2H),4.02(dtd,J=6.4,4.0,2.6Hz,2H),3.45(qd,J=10.1,3.2Hz,2H),2. 33(q,J=7.9Hz,2H),2.14(d,J=0.7Hz,2H),1.92(dddd,J=12.2,7.7,6.1,4.4Hz,1H),1.87–1. 72(m,2H),1.69–1.58(m,1H),1.34(s,2H),1.29(s,2H),1.23–1.12(m,6H).MS(EI,m / z):492(M + +1).

[0343] Example 58: Synthesis of Compound 58

[0344] ((2S,5R)-6-(((4-(Acetylthio)-2,2-dimethylbutyloxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide)methyl propanoate

[0345]

[0346] The synthesis method is the same as Example 28. 1H NMR(400MHz,Chloroform-d)δ6.34(t,J=4.5Hz,1H),5.03–4.91(m,2H),4.43(dd,J=6.6,4.4Hz,1 H),4.03(dtd,J=6.4,4.0,2.6Hz,1H),3.97(d,J=10.1Hz,1H),3.91(d,J=9.9Hz,1H),3.53–3.41( m,2H),2.93(t,J=5.1Hz,2H),2.41–2.32(m,5H),1.92(dddd,J=12.2,7.7,6.1,4.4Hz,1H),1.87– 1.72(m,2H),1.69–1.58(m,3H),1.20–1.12(m,3H),1.05(s,3H),1.00(s,3H).MS(EI,m / z):510(M + +1).

[0347] Example 59: Synthesis of Compound 59

[0348] ((2S,5R)-6-(((3-(Acetylthio)-2,2-dimethylpropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide)methyl propanoate

[0349]

[0350] The synthesis method is the same as Example 28. 1 H NMR(400MHz,Chloroform-d)δ6.33(t,J=4.5Hz,1H),5.01–4.92(m,2H),4.45 (dd,J=6.8,4.4Hz,1H),4.10–3.99(m,3H),3.53–3.42(m,2H),2.87(s,3H),2. 41–2.32(m,5H),1.92(dddd,J=12.2,7.8,6.1,4.3Hz,1H),1.88–1.71(m,2H) ,1.69–1.55(m,1H),1.19–1.10(m,5H),1.08(s,3H).MS(EI,m / z):496(M++1).

[0351] Example 60: Synthesis of Compound 60

[0352] Cyclopropyl 3-(((((2S,5R)-2-(((acetoxymethyl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate

[0353]

[0354] The synthesis method is the same as in Example 1. 1 H NMR(400MHz,Chloroform-d)δ6.08(t,J=4.5Hz,1H),5.02–4.91(m,2H),4.45(d d,J=6.8,4.4Hz,1H),4.33(p,J=5.5Hz,2H),4.23(s,1H),4.02(dtd,J=6.4,4.0 ,2.6Hz,1H),3.53–3.41(m,2H),2.07(s,3H),1.95(dddd,J=12.3,7.9,6.1,4.4 Hz,1H),1.88–1.71(m,2H),1.68–1.55(m,5H),1.26(s,6H).MS(EI,m / z):478(M + +1).

[0355] Example 61: Synthesis of Compound 61

[0356] Cyclobutylmethyl 3-(((((2S,5R)-2-((acetoxymethyl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxysulfonyl)oxy)-2,2-dimethylpropanoate

[0357]

[0358] The synthesis method is the same as in Example 1. 1 H NMR(400MHz,Chloroform-d)δ6.09(t,J=4.5Hz,1H),5.05–4.93(m,2H),4.45(dd,J=6.6,4.4Hz,1H),4.26(d,J=9.9Hz,1H),4.21(d,J=9.9Hz,1H),4.06–3 .98(m,3H),3.53–3.41(m,2H),2.07(s,3H),2.01–1.86(m,2H),1.86–1.76(m ,1H),1.80–1.72(m,2H),1.75–1.48(m,8H),1.25(s,4H).MS(EI,m / z):506(M + +1).

[0359] Example 62: Synthesis of Compound 62

[0360] Pyridin-3-ylmethyl 3-(((((2S,5R)-2-((acetyloxymethyl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxysulfonyl)oxy)-2,2-dimethylpropanoate

[0361]

[0362] The synthesis method is the same as in Example 1. 1 H NMR(400MHz,Chloroform-d)δ8.60(t,J=1.8Hz,1H),8.46(dt,J=3.7,1.8Hz,1H),7.77(dt,J=7.9,2.0Hz,1H),7.30(dd ,J=7.9,3.5Hz,1H),6.09(t,J=4.5Hz,1H),5.32(d,J=4.2Hz,2H),4.97(d,J=4.6Hz,2H),4.45(dd,J=6.8,4.4Hz,1H),4 .28(d,J=9.9Hz,1H),4.21(d,J=9.9Hz,1H),4.03(dtd,J=6.5,4.0,2.6Hz,1H),3.53–3.41(m,2H),2.07(s,2H),1.94(d ddd,J=12.3,7.9,6.0,4.3Hz,1H),1.86–1.70(m,2H),1.69–1.59(m,2H),1.27(s,3H),1.22(s,3H).MS(EI,m / z):529(M + +1).

[0363] Example 63: Synthesis of Compound 63

[0364] Methyl ((2S,5R)-6-(((3-((ethoxycarbonyl)oxy)-2,2-dimethylpropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide)acetate

[0365]

[0366] The synthesis method is the same as Example 17. 1H NMR(400MHz,Chloroform-d)δ6.16(t,J=4.5Hz,1H),5.05–4.97(m,2H),4.47(dd,J=6.7, 4.4Hz,1H),4.26(q,J=7.0Hz,2H),4.11–3.99(m,5H),3.6–3.41(m,2H),2.09(s,2H),1.97 (dddd,J=12.2,7.7,6.1,4.4Hz,1H),1.85(dddd,J=12.6,6.3,1.7Hz,1H),1.81–1.73(m,1H ),1.72–1.58(m,2H),1.36(t,J=7.0Hz,3H),1.13(s,3H),1.06(s,3H).MS(EI,m / z):496(M + +1).

[0367] Example 64: Synthesis of Compound 64

[0368] Methyl ((2S,5R)-6-(((neopentyloxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide)acetate

[0369]

[0370] The synthesis method is the same as in Example 1. 1 H NMR(400MHz,Chloroform-d)δ6.13(t,J=4.5Hz,1H),5.04–4.94(m,2H),4.45(dd,J=6.8,4.4Hz,1H),4.03(dtd,J=6.4,4.1,2.6Hz,1H),3.89(d,J=0.9H z,2H),3.52–3.41(m,2H),2.08(s,2H),1.92(dddd,J=12.2,7.7,6.2,4.3Hz ,1H),1.84–1.70(m,2H),1.64–1.53(m,2H),1.03(s,3H).MS(EI,m / z):408(M + +1).

[0371] Example 65: Synthesis of Compound 65

[0372] 3-(((((2S,5R)-2-(((acetyloxymethyl)(methyl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxysulfonyl)oxy)-2,2-dimethylpropanoate

[0373]

[0374] The synthesis of compound S6 is as in Example 1.

[0375] Step 4: Synthesis of compound S10

[0376] Compound S6 (80 mg, 0.23 mmol) in tetrahydrofuran (1 ml) was added to a solution of sodium hydride (11 mg, 0.46 mmol) in tetrahydrofuran at 0 degrees in an ice bath and stirred for 1 hour. Iodomethane (98 mg, 0.69 mmol) was added at 0 degrees in an ice bath and refluxed overnight. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with ethyl acetate 3 times (10 ml × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound S10 (50 mg, 60%). 1H NMR(400MHz,Chloroform-d)δ7.38–7.28(m,5H),5.54(d,J=9.3Hz,1H),5.34( d,J=9.3Hz,1H),4.79(dt,J=11.8,1.0Hz,1H),4.75–4.66(m,2H),3.82(dtd,J =6.5,4.0,2.5Hz,1H),3.70(dd,J=10.1,2.6Hz,1H),3.52(dd,J=10.1,3.8Hz, 1H), 2.96 (s, 3H), 2.14–1.93 (m, 6H), 1.77 (dddd, J = 12.4, 8.1, 6.1, 4.4Hz, 1H).

[0377] Step 5: Synthesis of compound S11

[0378] Reference to the synthesis of compound S8. 1H NMR (400 MHz, Chloroform-d) δ 5.93 (s, 1H), 5.70 (d, J = 9.3 Hz, 1H), 5.59 (d, J = 9.3 Hz, 1H), 4.71 (dd, J = 6.6, 4.5 Hz, 1H), 3.79–3.71 (m, 2H), 3.57–3.50 (m, 1H), 2.97 (s, 3H), 2.13–1.94 (m, 5H), 1.91–1.74 (m, 2H).

[0379] Step 6: Synthesis of compound 65

[0380] Synthesis of reference compound 1. 1H NMR(400MHz,Chloroform-d)δ5.70(d,J=9.3Hz,1H),5.59(d,J=9.3Hz,1H),4.73–4.66(m,1H) ,4.23–4.16(m,1H),4.20–4.10(m,2H),4.08(d,J=9.9Hz,1H),3.83(dtd,J=6.2,4.0,2.6Hz,1H ),3.77(dd,J=10.1,2.6Hz,1H),3.55(dd,J=10.1,3.8Hz,1H),2.97(s,3H),2.09(s,3H),2.15 –1.99(m,2H),1.78(dddd,J=12.2,8.0,6.5,4.4Hz,2H),1.29–1.20(m,8H).MS(EI,m / z):480(M + +1).

[0381] Example 66: Synthesis of Compound 66

[0382] 3-(((((2S,5R)-2-(cyclopropyl((propionyloxy)methyl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoic acid ethyl ester

[0383]

[0384] The synthesis method is the same as Example 65. 1 H NMR (400MHz, Chloroform-d) δ5.33 (s, 1H), 4.73 (dd, J=6.8, 4.4Hz, 1H), 4.28 (d, J= 9.9Hz,1H),4.24–4.14(m,3H),4.03(dtd,J=6.5,4.0,2.6Hz,1H),3.54–3.43(m,2H) ,3.13(p,J=5.8Hz,1H),2.37(q,J=7.9Hz,2H),1.93(dddd,J=12.3,7.9,6.0,4.4Hz ,2H),1.89–1.71(m,2H),1.68–1.57(m,2H),1.30–1.12(m,15H).MS(EI,m / z):520(M + +1).

[0385] Example 67: In vitro enzyme activity assay and IC 50 Determination

[0386] Enzyme inhibition assays were performed in 96-well enzyme plates using clinically relevant purified β-lactamase: KPC-2 (10 ng / well) in 10 mM HEPES buffer (pH 7.5) in 96-well microtiter plates, nitrophenol (Sigma-Aldrich, St Louis, MS), chromogenic cephalosporin (λ, 482 nm; εM (15000 M-1 cm-1) as reporter substrate, and KPC-2 at 100 M.

[0387] The enzyme was preincubated in the presence of different concentrations of inhibitor (0.006 to 3000 nM, compounds dissolved in DMSO and subsequently diluted in reaction buffer, maximum residual DMSO concentration not exceeding 1%) for 10 min (to allow for the formation of a covalent complex between the enzyme and the inhibitor). Nitrophenol was then added and hydrolyzed by the uninhibited enzyme fraction at 30°C for 10 min using an Envision UV fluorescence plate reader (Perkin Elmer, Waltham, Mass.). The hydrolysis rate data were used to determine the inhibitory activity, as IC 50 Values ​​are expressed as (corresponding to the concentration of compound required to inhibit 50% of the enzymatic reaction (M)).

[0388] In this trial, avibactam showed IC 50 The value is 8nM.

[0389] Example 68: Minimum Inhibitory Concentration

[0390] The clinically isolated sbl-positive strains were Enterobacter cloacae KPC-2 / TEM-1, Klebsiella pneumoniae SHV-11 / TEM-1 / KPC-3, Klebsiella pneumoniae SHV-11 / OXA-181, Acinetobacter baumannii OXA-23, and Klebsiella pneumoniae TEMOSBL / CTX-M-14 / OXA-48. The first four isolates were provided by P. Nordmann, and the last isolate was purchased from the International Health Management Association (IHMA).

[0391] Minimum inhibitory concentrations (MICs) for MEM and MEM / ANT3310 were determined by broth microdilution according to the Clinical and Laboratory Standards Institute (CLSI) guidelines using a cation-adjusted Mueller-Hinton (CAMBH; NE). Colonies were removed directly from the culture plates and resuspended in saline to a volume equivalent to 0.5 McFarland standard S10. Microplates were inoculated within 15 minutes of adjusting the suspension, and incubated at 37°C for 16 to 20 h. Quality control (QC) testing was performed daily in accordance with CLSI using the following isolates: Escherichia coli designated ATCC 25922 and Pseudomonas aeruginosa designated ATCC 27853.

[0392] In this trial, avibactam showed an MIC value of 16 μg / mL.

[0393] Example 69: Oral Bioavailability in Rats

[0394] Pharmacokinetic (PK) studies were performed on 3 male Sprague-Dawley (SD) rats after intravenous (IV) and oral (OP) administration of avibactam (5 mg / kg) and test compound (10 mg / kg), and avibactam in plasma was measured. Avibactam (dissolved in phosphate buffered saline (PBS) (pH 7.5) to 0.4 mg / ml was used for intravenous injection.

[0395] Oral compounds were formulated at 1 mg / ml in 10% ethanol / 40% polyethylene glycol (PEG) 400 / 50% water for injection (WFI), pH 6.5.

[0396] The rats were catheterized and blood samples (300 μL to 400 μL) were collected from the jugular vein at various time points. The blood samples were collected into K2EDTA anticoagulant tubes and stored on ice until centrifugation. The plasma was centrifuged within 60 minutes after blood collection (at 8000 rpm for 5 minutes at 2-8°C). After centrifugation, the plasma was transferred to a 96-well plate or centrifuge tube. For animals in the control group, blood was collected by cardiac puncture, plasma was harvested, and frozen at -70°C until further analysis.

[0397] Plasma samples were processed using acetonitrile precipitation and analyzed by LC-MS / MS. Aliquots of drug-free plasma were spiked with the test substances at the specified concentration levels to generate plasma standard curves. Spiked plasma samples were processed with unknown plasma samples using the same method. The processed plasma samples were stored at -70°C until subjected to LC-MS / MS analysis, at which time the peak areas were recorded and the corresponding standard curves were used to determine the concentration of the test substance in the unknown plasma samples.

[0398] Watson LIMS (Thermo Fisher Scientific, version 7.6, ThermoFisher, USA) was used to manage biological samples, and the standard curve, QC and sample concentration data were calculated and summarized based on the sample peak area collected by the mass spectrometry workstation. Non-partition analysis (NCA) of plasma data was performed using WinNonlin.Certara LPPharsight, St.Louis, MO, to obtain the pharmacokinetic parameters (AUClast, AUCINF, T1 / 2, Tmax and Cmax) of the compounds after IV and PO administration.

[0399] In this study, avibactam showed an oral bioavailability (%F) of 1.4%.

[0400] Table 1 shows the inhibitory activity, minimum inhibitory concentration and oral bioavailability of the compounds of the present invention against β-lactamase: A:IC 50 <8nM,B:IC 50 =8nM-16nM; MIC: m:MIC>16μg / mL, n:MIC=10μg / mL-16μg / mL; α: F>50%, β: 50%>F>40%, γ: 40%>F>20%.

[0401] As shown in Table 1, 1) the example compounds have significant inhibitory activity against β-lactamase, and the inhibitory activity is better than or equivalent to avibactam. 2) The example compounds have significant inhibitory activity (MIC) against the tested strains, and the inhibitory activity is better than or equivalent to avibactam. 3) The example compounds show excellent oral bioavailability in rats, which is significantly better than avibactam, supporting oral administration.

[0402] Table 1 Inhibitory activity (IC50), minimum inhibitory concentration (MIC) and oral bioavailability (%F) of compounds 1-66 against β-lactamase

[0403]

[0404]

[0405] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A compound as shown in formula I or a pharmaceutically acceptable salt thereof, characterized in that: I Among them, R 1 Each R is independently selected from the following groups or 1 It couples with the geminal carbon atom to which it is bonded to form the following groups: R 2 Selected from the following groups: R 3 Selected from the following groups: R 4 Selected from R 5 Each independently selected from the following groups: Where R 6 is unsubstituted or R 6-1 Substituted C3-10 cycloalkyl, unsubstituted or R 6-2 Substituted C3-10 cycloalkyl-(C1-6 alkyl), unsubstituted or R 6-3 Substituted heterocycloalkyl, unsubstituted or R 6-4 Substituted heterocycloalkyl-(C1-6 alkyl), unsubstituted or R 6 -5 Substituted heteroaryl, unsubstituted or R 6-6 Substituted heteroaryl-(C1-6 alkyl), unsubstituted or R 6-7 Substituted C6-10 aryl, unsubstituted or R 6-8 Substituted C6-10 aryl-(C1-6 alkyl); the heterocycloalkyl is a 4-10 membered heterocycloalkyl with 1 to 3 heteroatoms selected from one or more of N, O or S; the heteroaryl is a 5-10 membered heteroaryl with 1 to 3 heteroatoms selected from one or more of N, O or S; R 6-1 ~R 6-6 Independently selected from halogen, hydroxy, cyano, amino, C1-6 alkyl, halo(C1-6 alkyl), hydroxy(C1-6 alkyl), C1-6 alkoxy; R 6-7 and R 6-8 Independently selected from halogen, hydroxy, cyano, nitro; R 7 Selected from the following groups: wherein U1 is selected from hydrogen, hydroxy, halogen, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, methoxy, trifluoromethoxy or hydroxymethyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The compound of formula I is any of the following compounds:

3. A pharmaceutical composition, characterized in that Contains a therapeutically effective amount of one or more compounds according to any one of claims 1 to 2 or pharmaceutically acceptable salts thereof as an active ingredient.

4. The pharmaceutical composition according to claim 3, characterized in that Further comprising a pharmaceutically acceptable carrier.

5. The pharmaceutical composition according to claim 3, characterized in that Further comprising antibiotics.

6. The pharmaceutical composition according to claim 5, characterized in that The antibiotic is selected from β-lactam antibiotics.

7. The pharmaceutical composition according to any one of claims 4 to 6, characterized in that The pharmaceutical composition includes an oral dosage form.

8. Use of the compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to any one of claims 3 to 7 in the preparation of a medicament for treating bacterial infection.

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