CEPHALOSPORIN ANTIBACTERIAL COMPOUND AND PHARMACEUTICAL APPLICATION THEREOF

Abstract

Provided are a cephalosporin compound represented by formula I-1, I-2, or I-3, a pharmaceutical composition comprising same, and use thereof as an antibacterial agent.

##STR00001##

Claims

1-10. (canceled)

11. A compound of formula (I-2) or a pharmaceutically acceptable salt, stereoisomer, rotamer, tautomer or deuterated compound thereof, ##STR00159## wherein, X is selected from the group consisting of N, CH and C—Cl; T is selected from the group consisting of S, S═O, CH.sub.2 and O; E is selected from the group consisting of ##STR00160## wherein R.sub.1 and R.sub.2 are each independently selected from the group consisting of hydrogen, halogen, phenyl, alkylthio, and alkyl optionally substituted with carbamoyl; R.sub.11 and R.sub.12 are each independently selected from the group consisting of hydrogen, carboxyl, and alkyl optionally substituted with carbamoyl; and m is an integer from 1 to 5; F is a single bond; A is selected from the group consisting of alkylene, alkenylene and alkynylene; ##STR00161## is a quaternary ammonium group containing one or more N atoms and selected from the group consisting of heterocyclyl, fused heterocyclyl, heteroaryl and fused heteroaryl, wherein the heterocyclyl, fused heterocyclyl, heteroaryl and fused heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, mercapto, —NR.sub.iR.sub.j, oxo, thio, —C(O)R.sub.k, —C(O)OR.sub.k, —C(S)R.sub.k, nitro, cyano, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl and heteroaryl; G.sub.2 is G.sub.1 or alkylene, wherein the alkylene is optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, mercapto, —NR.sub.iR.sub.j, oxo, thio, —C(O)R.sub.k, —C(O)OR.sub.k, —C(S)R.sub.k, nitro, cyano, alkoxy and alkylthio; G.sub.1 is ##STR00162## wherein each x is independently an integer from 1 to 6; A.sub.1 is selected from the group consisting of a single bond, alkylene, alkenylene and alkynylene, wherein the alkylene, alkenylene and alkynylene are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, mercapto, —NR.sub.iR.sub.j, oxo, thio, —C(O)R.sub.k, —C(O)OR.sub.k, —C(S)R.sub.k, nitro, cyano, alkoxy and alkylthio; A.sub.2 is selected from the group consisting of a single bond, alkylene, alkenylene and alkynylene, wherein the alkylene, alkenylene and alkynylene are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, mercapto, —NR.sub.iR.sub.j, oxo, thio, —C(O)R.sub.k, —C(O)OR.sub.k, —C(S)R.sub.k, nitro, cyano, alkoxy and alkylthio; ring D.sub.3 is selected from the group consisting of cycloalkyl, fused cycloalkyl, heterocyclyl and fused heterocyclyl; R.sub.9 is selected from the group consisting of alkyl, halogen, hydroxy, mercapto, oxo, thio, —NR.sub.iR.sub.j, —C(O)R.sub.k, —C(O)OR.sub.k, nitro, cyano, alkoxy and alkylthio, wherein the alkyl, alkoxy and alkylthio are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, mercapto, —NR.sub.iR.sub.j, oxo, thio, —C(O)R.sub.k, —C(O)OR.sub.k, —C(S)R.sub.k, nitro, cyano, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl and heteroaryl; k1 is an integer from 0 to 8; C.sub.2 is selected from the group consisting of —NR.sub.31—C(═O)—, —NR.sub.3—C(═O)—R.sub.33—, —C(═O)—NR.sub.31—, —C(═O)—C(═O)—NR.sub.31—, —C(═N—OR.sub.32)—C(═O)—NR.sub.31—, —NR.sub.31—C(═O)—C(═O)—, —NR.sub.31—C(═O)—C(═N—OR.sub.32)—, —NR.sub.3—C(═NH)—, —C(═NH)—NR.sub.3—, —NR.sub.3—C(═S)—, —C(═S)—NR.sub.3—, —NR.sub.3—C(═S)—NR.sub.3—, —NR.sub.3—C(═NH)—NR.sub.3—, —NR.sub.3— and ##STR00163## wherein each R.sub.3 is independently selected from the group consisting of hydrogen, hydroxy, alkyl and alkoxy, wherein the alkyl and alkoxy are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, mercapto, —NR.sub.iR.sub.j, ##STR00164## oxo, thio, —C(O)R.sub.k, —C(O)OR.sub.k, —C(S)R.sub.k, nitro, cyano, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl and heteroaryl; R.sub.m is selected from the group consisting of hydrogen, alkyl, hydroxy, aryl and heteroaryl, wherein the alkyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, mercapto, —NR.sub.iR.sub.j, carboxyl, nitro, cyano, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl and heteroaryl; each R.sub.31 is independently selected from the group consisting of hydroxy, alkyl and alkoxy, wherein the alkyl and alkoxy are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, mercapto, —NR.sub.iR.sub.j, ##STR00165## oxo, thio, —C(O)R.sub.k, —C(O)OR.sub.k, —C(S)R.sub.k, nitro, cyano, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl and heteroaryl; R.sub.32 is hydrogen or alkyl; R.sub.33 is selected from the group consisting of alkylene, alkenylene and alkynylene, wherein the alkylene, alkenylene and alkynylene are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, mercapto, —NR.sub.iR.sub.j, oxo, thio, —C(O)R.sub.k, —C(O)OR.sub.k, —C(S)R.sub.k, nitro, cyano, alkoxy and alkylthio; and ring D.sub.2 is heterocyclyl or heteroaryl; ring D.sub.1 is selected from the group consisting of aryl, fused cycloaryl, heterocyclyl, fused heterocyclyl, heteroaryl and fused heteroaryl; each R.sub.4 is independently selected from the group consisting of alkyl, halogen, hydroxy, mercapto, oxo, thio, —NR.sub.iR.sub.j, —C(O)R.sub.k, —C(O)OR.sub.k, nitro, cyano, alkoxy and alkylthio, wherein the alkyl, alkoxy and alkylthio are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, mercapto, —NR.sub.iR.sub.j, oxo, thio, —C(O)R.sub.k, —C(O)OR.sub.k, —C(S)R.sub.k, nitro, cyano, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl and heteroaryl; n is an integer from 0 to 8; R.sub.i and R.sub.j are each independently selected from the group consisting of hydrogen, hydroxy, C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 alkoxy; and each R.sub.k is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, hydroxy and —NR.sub.iR.sub.j, wherein the alkyl, haloalkyl and alkoxy are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, mercapto, —NR.sub.iR.sub.j, oxo, thio, carboxyl, nitro, cyano, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl and heteroaryl.

12. The compound or the pharmaceutically acceptable salt, stereoisomer, rotamer, tautomer or deuterated compound thereof according to claim 11, wherein ##STR00166## is selected from the group consisting of: ##STR00167## wherein each R.sub.8 is independently selected from the group consisting of halogen, hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl and C.sub.1-C.sub.6 haloalkoxy; each q is independently an integer from 0 to 5; each r is independently an integer from 0 to 5; and each s is independently an integer from 0 to 3.

13. (canceled)

14. The compound or the pharmaceutically acceptable salt, stereoisomer, rotamer, tautomer or deuterated compound thereof according to claim 11, wherein G.sub.2 is selected from the group consisting of: ##STR00168## wherein each R.sub.9 is independently selected from the group consisting of halogen, hydroxy, alkyl, alkoxy, haloalkyl and haloalkoxy; each k2 is independently an integer from 1 to 6; each k3 is independently an integer from 0 to 3; and each k4 is independently an integer from 0 to 3.

15. The compound or the pharmaceutically acceptable salt, stereoisomer, rotamer, tautomer or deuterated compound thereof according to claim 11, wherein G.sub.2 is selected from the group consisting of: ##STR00169## wherein each R.sub.9 is independently selected from the group consisting of halogen, hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl and C.sub.1-C.sub.6 haloalkoxy; A.sub.1 is a single bond or C.sub.1-C.sub.6 alkylene, wherein the alkylene is optionally substituted with one or more substituents selected from the group consisting of C.sub.1-C.sub.6 alkyl, halogen, hydroxy, mercapto, —NR.sub.iR.sub.j, oxo, thio, —C(O)R.sub.k, —C(O)OR.sub.k, —C(S)R.sub.k, nitro, cyano, C.sub.1-C.sub.6 alkoxy and C.sub.1-C.sub.6 alkylthio; A.sub.2 is a single bond or C.sub.1-C.sub.6 alkylene, wherein the alkylene is optionally substituted with one or more substituents selected from the group consisting of C.sub.1-C.sub.6 alkyl, halogen, hydroxy, mercapto, —NR.sub.iR.sub.j, oxo, thio, —C(O)R.sub.k, —C(O)OR.sub.k, —C(S)R.sub.k, nitro, cyano, C.sub.1-C.sub.6 alkoxy and C.sub.1-C.sub.6 alkylthio; each k2 is independently an integer from 1 to 6; each k3 is independently an integer from 0 to 3; each k4 is independently an integer from 0 to 3; and x is an integer from 1 to 3.

16. The compound or the pharmaceutically acceptable salt, stereoisomer, rotamer, tautomer or deuterated compound thereof according to claim 11, wherein C.sub.2 is selected from the group consisting of —NR.sub.31—C(O)—, —NR.sub.3—C(S)—, —NR.sub.3—C(═NH)—, —NR.sub.3—C(═NH)—NR.sub.3—, —NR.sub.3—C(═S)—NR.sub.3—, ##STR00170## and —NR.sub.3.

17. The compound or the pharmaceutically acceptable salt, stereoisomer, rotamer, tautomer or deuterated compound thereof according to claim 11, wherein R.sub.3 is selected from the group consisting of hydrogen, hydroxy, C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6 alkoxy, wherein the alkyl and alkoxy are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, —NR.sub.iR.sub.j, ##STR00171## oxo, —C(O)OR.sub.k and cyano; each R.sub.n is independently selected from the group consisting of C.sub.1-C.sub.6 alkyl, hydroxy and halogen; and k5 is an integer from 0 to 5.

18. The compound or the pharmaceutically acceptable salt, stereoisomer, rotamer, tautomer or deuterated compound thereof according to claim 11, wherein R.sub.31 is selected from the group consisting of hydroxy, C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 alkoxy, wherein the alkyl and alkoxy are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, —NR.sub.iR.sub.j, ##STR00172## oxo, —C(O)OR.sub.k and cyano; each R.sub.n is independently selected from the group consisting of C.sub.1-C.sub.6 alkyl, hydroxy and halogen; and k5 is an integer from 0 to 5.

19. (canceled)

20. The compound or the pharmaceutically acceptable salt, stereoisomer, rotamer, tautomer or deuterated compound thereof according to claim 11, wherein ##STR00173## each R.sub.n is independently selected from the group consisting of C.sub.1-C.sub.6 alkyl, hydroxy and halogen, and k5 is an integer from 0 to 5.

21. The compound or the pharmaceutically acceptable salt, stereoisomer, rotamer, tautomer or deuterated compound thereof according to claim 11, wherein ring D.sub.1 is phenyl or naphthyl.

22. The compound or the pharmaceutically acceptable salt, stereoisomer, rotamer, tautomer or deuterated compound thereof according to claim 11, wherein G.sub.2 is C.sub.1-C.sub.6 alkylene optionally substituted with one or more substituents selected from the group consisting of C.sub.1-C.sub.6 alkyl, halogen, hydroxy, mercapto, —NR.sub.iR.sub.j, oxo, thio, —C(O)R.sub.k, —C(O)OR.sub.k, —C(S)R.sub.k, nitro, cyano, C.sub.1-C.sub.6 alkoxy and C.sub.1-C.sub.6 alkylthio.

23. The compound or the pharmaceutically acceptable salt, stereoisomer, rotamer, tautomer or deuterated compound thereof according to claim 11, wherein the compound of formula (I-2) is ##STR00174## wherein A, ##STR00175## G.sub.2, C.sub.2, D.sub.1, R.sub.4 and n are as described in claim 11.

24-33. (canceled)

34. The compound or the pharmaceutically acceptable salt, stereoisomer, rotamer, tautomer or deuterated compound thereof according to claim 11, wherein the compound is selected from the group consisting of ##STR00176## ##STR00177## ##STR00178## ##STR00179## ##STR00180##

35. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt, stereoisomer, rotamer, tautomer or deuterated compound thereof according to claim 11, and a pharmaceutically acceptable carrier, diluent, or excipient.

36. A method of treating or preventing a disease caused by gram-negative bacteria or pathogenic bacteria in a subject in need thereof, the method comprising administering to the subject the compound or the pharmaceutically acceptable salt, stereoisomer, rotamer, tautomer or deuterated compound thereof according to claim 11.

37. (canceled)

38. The method according to claim 36, wherein the disease is selected from the group consisting of airway infectious diseases, urinary system infectious diseases, respiratory system infectious diseases, septicemia, nephritis, cholecystitis, oral infectious diseases, endocarditis, pneumonia, bone marrow membrane myelitis, otitis media, enteritis, empyema, traumatic infectious diseases and opportunistic infections.

39. The method according to claim 36, wherein the gram-negative bacteria is selected from the group consisting of E. coli, Klebsiella, Serratia, Enterobacter, Citrobacter, Morganella, Providencia, Proteus, Haemophilus, Moraxella, Pseudomonas aeruginosa and Pseudomonas other than P. aeruginosa, Stenotrophomonas, Burkholderia or Acinetobacter.

40. The compound or the pharmaceutically acceptable salt, stereoisomer, rotamer, tautomer or deuterated compound thereof according to claim 11, wherein ##STR00181## wherein k5 is an integer from 0 to 3.

41. The compound or the pharmaceutically acceptable salt, stereoisomer, rotamer, tautomer or deuterated compound thereof according to claim 11, wherein ##STR00182##

Description

DETAILED DESCRIPTION

[0269] The preparation of the compound described herein and a pharmaceutically acceptable salt thereof is further described below in conjunction with the examples, which are not intended to limit the scope of the present disclosure.

[0270] Experimental procedures without conditions specified in the examples of the present disclosure, are generally conducted according to conventional conditions, or according to conditions recommended by the manufacturer of the starting materials or commercial products. Reagents without specific origins indicated are commercially available conventional reagents.

[0271] The structures of the compounds are determined by nuclear magnetic resonance (NMR) spectroscopy and/or mass spectrometry (LCMS). NMR shift (δ) is given in a unit of 10.sup.−6 (ppm). NMR spectra are measured using a Bruker AVANCE-400 nuclear magnetic resonance instrument, with deuterated dimethyl sulfoxide (DMSO-d.sub.6), deuterated chloroform (CDCl.sub.3) and deuterated methanol (CD.sub.3OD) as determination solvents, and tetramethylsilane (TMS) as an internal standard. The spatial configurations of the optical isomers (isomers) of the compounds can be further confirmed by determining single crystal parameters.

[0272] HPLC analysis is performed using a Waters ACQUITY ultra high performance LC, Shimadzu LC-20A systems, Shimadzu LC-2010HT series, or Agilent 1200 LC high performance liquid chromatograph (ACQUITY UPLC BEH C18 1.7 μm 2.1×50 mm column, Ultimate XB-C18 3.0×150 mm column, or Xtimate C18 2.1×30 mm column).

[0273] MS analysis is performed by Waters SQD2 mass spectrometer in positive/negative ion mode with a mass scan range of 100 to 1200.

[0274] Chiral HPLC analytical determination is performed using a Chiralpak IC-3 100×4.6 mm I.D., 3 μm, Chiralpak AD-3 150×4.6 mm I.D., 3 μm, Chiralpak AD-3 50×4.6 mm I.D., 3 μm, Chiralpak AS-3 150×4.6 mm I.D., 3 μm, Chiralpak AS-3 100×4.6 mm I.D., 3 μm, ChiralCel OD-3 150×4.6 mm I.D., 3 μm, ChiralCel OD-3 100×4.6 mm I.D., 3 μm, ChiralCel OJ-H 150×4.6 mm I.D., 5 μm, or ChiralCel OJ-3 150×4.6 mm I.D., 3 μm chromatographic column.

[0275] Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate is adopted as a thin layer chromatography (TLC) silica gel plate. The specification of the silica gel plate is 0.15-0.2 mm for the thin layer chromatography (TLC), and 0.4-0.5 mm for the separation and purification of products by the TLC.

[0276] The flash column purification is performed using a Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage) system.

[0277] The forward column chromatography is generally performed using 100-200 mesh, 200-300 mesh or 300-400 mesh Yantai Huanghai silica gel as a carrier, or using a Changzhou Santai pre-fill ultrapure forward phase silica gel column (40-63 μm, 60 g, 12 g, 25 g, 40 g, 80 g or other specifications).

[0278] Reverse phase column chromatography is generally performed using a Changzhou Santai pre-fill ultrapure C18 silica gel column (20-45 μm, 100 Å, 40 g, 80 g, 120 g, 220 g or other specifications).

[0279] The high pressure column purification is performed using a Waters AutoP system in combination with Waters XBridge BEH C18 OBD Prep Column, 130 Å, 5 μm, 19×150 mm or Atlantis T3 OBD Prep Column, 100 Å, 5 μm, 19×150 mm.

[0280] The chiral preparation is performed using a DAICEL CHIRALPAK IC (250×30 mm, 10 μm) or Phenomenex-Amylose-1 (250×30 mm, 5 μm) column.

[0281] Starting materials known in the present disclosure may be synthesized using or according to methods known in the art, or may be purchased from Shanghai Titan Scientific, ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., Darui Chemicals, and other companies.

[0282] In the example, all reactions can be performed under nitrogen atmosphere unless otherwise specified.

[0283] An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to a balloon containing about 1 L of argon or nitrogen.

[0284] A hydrogen atmosphere means that the reaction flask is connected to a balloon containing about 1 L of hydrogen.

[0285] The pressurized hydrogenation reaction is performed using a Parr 3916EKX hydrogenator, a Qinglan QL-500 hydrogenator or a HC2-SS hydrogenator.

[0286] The hydrogenation reaction usually involves 3 cycles of vacuumization and hydrogen purge.

[0287] The microwave reaction is performed in a CEM Discover-S 908860 microwave reactor.

[0288] In the examples, a solution refers to an aqueous solution unless otherwise specified.

[0289] In the examples, the reaction temperature was room temperature, i.e., 20° C. to 30° C., unless otherwise specified.

[0290] The reaction progress in the examples is monitored by thin layer chromatography (TLC). The developing solvent for reactions, the eluent system for column chromatography purification and the developing solvent system for thin layer chromatography include: A: dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, D: petroleum ether/ethyl acetate/methanol system, and E: petroleum ether/tetrahydrofuran system. The volume ratio of the solvents is adjusted according to the polarity of the compound, or by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.

Example 1

[0291] ##STR00089## ##STR00090##

[0292] Compound 1-1 (2.46 g, 10 mmol) was dissolved in 5% aqueous sodium bicarbonate solution (86 mL), and the solution was stirred until it was clarified, followed by the addition of Fmoc-OSu (3.37 g, 10 mmol, dissolved in 24 mL of dioxane). After the addition, the mixture was reacted overnight. The reaction mixture was concentrated under reduced pressure to remove most of the dioxane, added with hydrochloric acid to adjust the pH, extracted with ethyl acetate for liquid separation, dried over magnesium sulfate, filtered and evaporated to dryness to give compound 1-2 (5.2 g), which was directly used in the next step.

[0293] LC/MS (ESI): m/z 469.1 [M+H].sup.+

Step 2

[0294] ##STR00091##

[0295] Compound 1-2 (2.08 g, 4 mmol), EDCI (1.15 g, 6 mmol) and DMAP (49 mg, 0.4 mmol) were dissolved in dichloromethane (20 mL), followed by the addition of p-methoxybenzyl alcohol (828 mg, 6 mmol), and the mixture was stirred. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, slurried with methyl tert-butyl ether, filtered, and concentrated in vacuum to remove the solvent to give compound 1-3 (1.31 g, 2.23 mmol, yield 56%).

[0296] LC/MS (ESI): m/z 589.1 [M+H].sup.+

Step 3

[0297] ##STR00092##

[0298] Compound 1-3 (945 mg, 1.6 mmol) were dissolved with dichloromethane (10 mL), followed by the addition of DBU (243 mg, 1.6 mmol), and the mixture was stirred. After the reaction was completed, the reaction was quenched with aqueous citric acid solution, and the reaction mixture was diluted with MTBE for liquid separation. The aqueous phase was adjusted to pH 8 with 1 N NaOH solution, extracted with dichloromethane, dried, filtered and concentrated to give compound 1-4 (562 mg, yield 96%).

[0299] LC/MS (ESI): m/z 367.1 [M+H].sup.+

Step 4

[0300] ##STR00093##

[0301] Compound 1-4 (534 mg, 1.46 mmol) was dissolved with acetonitrile (20 mL), followed by the addition of 1,4-dibromobutane (330 mg, 1.53 mmol) and N,N-diisopropylethylamine (395 mg, 3.06 mmol), and the mixture was heated to reflux for 6 h. After the reaction was completed, the reaction was quenched with aqueous citric acid solution, and the reaction mixture was diluted with methyl tert-butyl ether for liquid separation. The aqueous phase was extracted with dichloromethane, evaporated to dryness under reduced pressure, adjusted to pH 8 with saturated aqueous sodium bicarbonate solution, and extracted with methyl tert-butyl ether. The organic phases were combined, dried over anhydrous MgSO.sub.4, filtered and concentrated to give compound 1-5 (400 mg, yield 66%).

[0302] LC/MS (ESI): m/z 421.1 [M+H].sup.+

Step 5

[0303] ##STR00094##

[0304] Compound 1-5 (211 mg, 0.5 mmol), compound 1-6 (synthesized by the method described in the patent WO2016035847, 360 mg, 0.45 mmol) and sodium iodide (225 mg, 1.5 mmol) were dissolved with N,N-dimethylformamide (0.8 mL), and the solution was stirred. After the reaction was completed, the reaction mixture was cooled to 0° C., added with potassium iodide (523 mg, 3.15 mmol), N,N-dimethylformamide (1.6 mL) and acetyl chloride (177 mg, 2.25 mmol), and stirred. After the reaction was completed, the reaction mixture was added to a 5% aqueous Na.sub.2S.sub.2O.sub.5, stirred, filtered, and concentrated under reduced pressure to remove the solvent to give compound 1-7 (540 mg).

[0305] LC/MS (ESI): m/z 1164.2 [M].sup.+

##STR00095##

[0306] Compound 1-7 (233 mg) was dissolved with anisole (0.5 mL) and trifluoroacetic acid (2 mL), and the solution was stirred. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was dissolved with methyl tert-butyl ether, and washed with dilute hydrochloric acid. The aqueous phases were combined and concentrated under reduced pressure to give a crude product (110 mg), which was purified by HPLC to give compound 1 (4 mg).

[0307] LC/MS (ESI): m/z 668.0 [M+H].sup.+

[0308] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ: 1.27-1.38 (m, 1H), 1.44 (s, 3H), 1.45 (s, 3H), 1.56-1.80 (m, 4H), 1.82-1.96 (m, 1H), 1.97-2.15 (m, 4H), 3.04-3.20 (m, 3H), 3.27-3.71 (m, 5H), 3.92 (d, 1H), 3.96-4.10 (m, 2H), 4.65-4.88 (m, 1H), 5.27 (d, 1H), 5.90-5.93 (m, 1H), 6.71 (s, 1H), 7.32 (s, 2H), 8.06-8.56 (m, 2H), 9.50 (d, 1H), 12.62 (brs, 1H).

Example 2

[0309] ##STR00096##

Step 1

[0310] ##STR00097##

[0311] Compound 2-1 (2.0 g, 10.69 mmol, 1 eq) was dissolved with dichloromethane (10 mL), and triethylamine (3.24 g, 32.07 mmol, 3 eq) was added, followed by the dropwise addition of methanesulfonyl chloride (2.43 g, 21.38 mmol, 2 eq). The mixture was reacted at room temperature. After the reaction was completed, the reaction mixture was diluted with dichloromethane, washed with water, dried, filtered and concentrating to give a crude product. The crude product (2.6 g, about 8.96 mmol) was dissolved in acetonitrile (20 mL), followed by the addition of potassium carbonate (2.76 g, 20 mmol, 2.23 eq), tetrahydropyrrole (1.06 g, 15 mmol, 1.67 eq), and the mixture was stirred at 40° C. overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to remove the solvent, dissolved with dichloromethane, washed with water, dried, filtered and concentrated under reduced pressure, and the residue was separated by column chromatography to give compound 2-2 (1.7 g, yield 79%).

Step 2

[0312] ##STR00098##

[0313] Compound 2-2 (300 mg, 1.25 mmol) was dissolved with dichloromethane (4 mL), followed by the addition of trifluoroacetic acid (1 mL), and the mixture was stirred. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, diluted with methanol, neutralized with potassium carbonate, filtered and concentrated to give crude compound 2-3, which was directly used in the next step.

[0314] LC/MS (ESI): m/z 141.1 [M+H].sup.+

Step 3

[0315] ##STR00099##

[0316] The crude compound 2-3 obtained from the previous step, compound 2-4 (synthesized by the method described in the patent CN106661052A, 1.07 g, 2.5 mmol) and HATU (1.43 g, 3.75 mmol) were dissolved in N,N-dimethylformamide (10 mL), followed by the addition of DIPEA (1.1 mL, 6.25 mmol), and the reaction mixture was stirred overnight. After the reaction was completed, the reaction mixture was added with aqueous sodium hydroxide, stirred and filtered, and the filter cake was washed with water and concentrated in vacuum to remove the solvent to give a crude product, which was separated by column chromatography to give compound 2-5 (600 mg, 1.09 mmol, yield 87% over two steps).

[0317] LC/MS (ESI): m/z 555.1 [M+H].sup.+

Step 4

[0318] ##STR00100##

[0319] Compound 2-5 (219 mg, 0.4 mmol), compound 1-6 (398 mg, 0.5 mmol), sodium iodide (180 mg, 1.2 mmol) and boric acid (7.5 mg, 0.12 mmol) were dissolved with N-methylpyrrolidone (1 mL), and the solution was stirred. After the reaction was completed, the reaction mixture was cooled with ice water, added with KI (465 mg, 2.8 mmol), N-methylpyrrolidone (2 mL) and acetyl chloride (188 mg, 2.4 mmol), and stirred. After the reaction was completed, the reaction mixture was directly added into a large amount of aqueous sodium metabisulfite solution in an ice bath, stirred and filtered, and the filter cake was washed with water and concentrated in vacuum to remove the solvent to give compound 2-6 (635 mg).

[0320] LC/MS (ESI): m/z 1294.4 [M].sup.+

Step 5

[0321] ##STR00101##

[0322] Compound 2-6 (200 mg) was dissolved with anisole (0.4 mL) and trifluoroacetic acid (1.6 mL), and the solution was stirred. After the reaction was completed, the reaction mixture was added with MTBE (4 mL) to precipitate a solid and filtered, and the solid was rinsed with MTBE, and dried to give a crude product (170 mg), which was purified by HPLC to give compound 2 (4.2 mg).

[0323] LC/MS (ESI): m/z 777.9 [M+H].sup.+

[0324] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ: 1.00-1.08 (m, 4H), 1.44 (s, 3H), 1.45 (s, 3H), 1.91-2.14 (m, 4H), 3.36-3.44 (m, 2H), 3.48-3.60 (m, 3H), 3.60-3.74 (m, 3H), 3.80 (d, 1H), 4.18 (d, 1H), 5.01 (d, 1H), 5.18-5.24 (m, 1H), 5.67-5.82 (m, 1H), 6.66-6.84 (m, 3H), 7.29 (s, 2H), 8.76 (s, 1H), 9.24-9.55 (m, 2H), 10.26 (br s, 1H).

Example 3

[0325] ##STR00102##

Step 1

[0326] ##STR00103##

[0327] Compound 3-1 (5 g, 29.40 mmol) and compound 3-2 (3.68 g, 44.10 mmol) were dissolved in methanol (30 mL) and water (15 mL), and the solution was stirred. After potassium carbonate (14.22 g, 102.89 mmol) was added, the mixture was heated to reflux. After the reaction was completed, the reaction mixture was cooled to room temperature and added with MTBE and aqueous NaOH solution for liquid separation, and the aqueous phase was extracted with MTBE. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give compound 3-3 (0.7 g).

[0328] LC/MS (ESI): m/z 145.1 [M+H].sup.+

Step 2

[0329] ##STR00104##

[0330] Compound 2-4 (1.9 g, 4.43 mmol) was added to tetrahydrofuran (30 mL) and stirred in an ice water bath, and triethylamine (0.98 mL, 7.09 mmol) was added, followed by the dropwise addition of methanesulfonyl chloride (0.45 mL, 5.80 mmol). After the addition, the mixture was reacted in an ice water bath. Compound 3-3 was dissolved in THE (10 mL), and the solution was added dropwise to the above reaction mixture. After the addition, the resulting reaction mixture was heated to room temperature and reacted. Ethyl acetate was added, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give a crude product. The crude product was purified by HPLC to give compound 3-4 (220 mg).

[0331] LC/MS (ESI): m/z 555.1 [M+H].sup.+

Step 3

[0332] ##STR00105##

[0333] Compound 1-6 (315 mg, 0.395 mmol), compound 3-4 (220 mg, 0.395 mmol) and sodium iodide (178 mg, 1.19 mmol) were added to N,N-dimethylformamide (0.9 mL), and the mixture was stirred. After the reaction was completed, the flask was cooled in an ice water bath, followed by the addition of PBr.sub.3 (751 mg, 2.77 mmol), and the mixture was stirred. After the reaction was completed, the reaction mixture was added dropwise to aqueous NaHSO.sub.3 solution and filtered, and the filter cake was washed with clear water and dried in vacuum to obtain crude compound 3-5 (623 mg).

[0334] LC/MS (ESI): m/z 1298.1 [M].sup.+

Step 4

[0335] ##STR00106##

[0336] Compound 3-5 (200 mg, 0.154 mmol) was added to anisole (0.4 mL) and trifluoroacetic acid (1.6 mL), and the mixture was reacted at room temperature. The reaction mixture was added with methyl tert-butyl ether, stirred and filtered. The filter cake was rinsed with MTBE and dried to give a crude product (112 mg). The crude product was purified by HPLC to give compound 3 (7.1 mg).

[0337] LC/MS (ESI): m/z 781.9 [M+H].sup.+

[0338] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ: 1.43 (s, 3H), 1.46 (s, 3H), 1.94-2.09 (m, 3H), 2.10-2.21 (m, 1H), 3.43-3.56 (m, 8H), 3.57-3.67 (m, 3H), 3.67-3.83 (m, 2H), 3.92-4.06 (m, 1H), 4.07-4.36 (m, 3H), 5.03-5.11 (m, 1H), 5.15 (d, 1H), 5.69-5.75 (m, 1H), 6.71-6.82 (m, 3H), 7.27 (s, 2H), 8.15 (s, 1H).

Example 4

[0339] ##STR00107##

Step 1

[0340] ##STR00108##

[0341] Compound 2-4 (3.0 g, 7.0 mmol) and triethylamine (0.85 g, 8.39 mmol) were added to toluene (50 mL), and diphenyl phosphoryl azide (2.31 g, 8.39 mmol) was slowly added dropwise. After the addition, the mixture was stirred overnight, heated to 110° C. and reacted, added with 9-fluorenylmethanol (2.06 g, 10.49 mmol), and reacted at 110° C. After the reaction was completed, the reaction mixture was cooled to room temperature, added with piperidine (2.98 g, 34.97 mmol) and stirred overnight. The heating was stopped, and the reaction mixture was concentrated to remove toluene, added with dichloromethane and water, and stirred for liquid separation. The aqueous phase was extracted with dichloromethane, and the organic phases were combined, dried, filtered and concentrated to give a crude product. The crude product was directly purified by column chromatography to give compound 4-1 (462 mg, yield 17%).

[0342] LC/MS(ESI): m/z 400.0 [M+H].sup.+

Step 2

[0343] ##STR00109##

[0344] Compound 4-1 (0.46 g, 1.15 mmol) was dissolved with dichloromethane (8 mL), and thiophosgene (0.40 g, 3.45 mmol) was added, followed by the addition of DMAP (0.70 g, 5.73 mmol) at 0° C. The mixture was heated to room temperature and stirred. After the reaction was completed, the reaction was directly purified by column chromatography to give compound 4-2 (432 mg, yield 85%).

Step 3

[0345] ##STR00110##

[0346] Compound 4-2 (0.43 g, 1.01 mmol), compound 4-3 (0.13 g, 1.1 mmol) and DMAP (0.61 g, 5.0 mmol) were added to a reaction flask, followed by the addition of DMF (0.5 mL). The mixture was stirred at room temperature overnight. The reaction mixture was added with water to precipitate a solid and filtered, and the filter cake was collected purified by column chromatography to give compound 4-4 (467 mg, yield 83%).

[0347] LC/MS(ESI):m/z 556.0 [M+H].sup.+

Step 4

[0348] ##STR00111##

[0349] Compound 4-4 (200 mg, 0.36 mmol), compound 1-6 (315 mg, 0.4 mmol) and sodium iodide (180 mg, 1.2 mmol) were dissolved with NMP (0.9 mL), and the mixture was stirred. After the reaction was completed, the reaction mixture was cooled to 0° C., added with PBr.sub.3 (650 mg, 2.4 mmol) and stirred. After the reaction was completed, the reaction solution was added to aqueous Na.sub.2S.sub.2O.sub.5 solution in an ice bath, stirred and filtered, and the filter cake was with water and concentrated in vacuum to remove the solvent to give compound 4-5 (515 mg).

[0350] LC/MS (ESI): m/z 1299.0 [M].sup.+

Step 5

[0351] ##STR00112##

[0352] Compound 4-5 (200 mg, 0.154 mmol) was added to a reaction flask, followed by the addition of anisole (0.4 mL) and trifluoroacetic acid (1.6 mL), and the mixture was stirred. After the reaction was completed, the reaction mixture was added with MTBE and filtered, and the filter cake was rinsed with MTBE and dried to give a crude product (68 mg). The crude product was purified by HPLC to give compound 4 (4.4 mg).

[0353] LC/MS (ESI): m/z 782.9 [M+H].sup.+

[0354] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ: 1.43 (s, 3H), 1.44 (s, 3H), 1.46-1.57 (m, 1H), 1.78-2.11 (m, 4H), 2.96 (d, 1H), 3.41 (d, 2H), 3.48-3.93 (m, 9H), 4.57 (s, 1H), 5.26 (s, 1H), 5.38-5.45 (m, 1H), 6.57 (d, 1H), 6.64 (d, 1H), 6.88 (s, 1H), 7.22-7.51 (m, 2H), 9.05 (s, 1H), 9.22-9.34 (m, 1H), 9.36 (s, 1H), 9.77 (brs, 1H).

Example 5

[0355] ##STR00113##

Step 1

[0356] ##STR00114##

[0357] Compound 3-1 (50.0 g, 0.294 mol), hydroxylamine hydrochloride (40.8 g, 0.59 mol), sodium carbonate (62.3 g, 0.59 mol), ethanol (300 mL) and water (150 mL) were added to a three-necked flask. The mixture was reacted in an oil bath at 50° C. After the reaction was completed, the reaction mixture was concentrated, added with isopropyl ether and water and stirred for liquid separation. The organic phase was washed with saturated brine, dried and concentrated to give a crude product, which was distilled under reduced pressure to give compound 5-1 (12.5 g, yield 33%).

[0358] LC/MS (ESI): m/z 131.1 [M+H].sup.+

Step 2

[0359] ##STR00115##

[0360] Compound 5-1 (1.0 g, 7.7 mmol), acetonitrile (10 mL) and sodium bicarbonate (1.3 g, 15.4 mmol) were added to a single-necked flask, and the mixture was cooled in an ice water bath, added dropwise with acetyl chloride (0.66 g, 8.5 mmol), and reacted in an ice water bath. After the reaction was completed, the reaction mixture was added with dichloromethane and water for liquid separation. The aqueous phase was extracted with dichloromethane, dried and concentrated to give compound 5-2 (0.9 g, yield 68%).

[0361] LC/MS (ESI): m/z 173.1 [M+H].sup.+

Step 3

[0362] ##STR00116##

[0363] Compound 5-2 (510 g, 3 mmol), DCM (10 mL) and imidazole (410 mg, 6 mmol) were added to a single-necked flask, followed by the dropwise addition of tert-butyldiphenylchlorosilane (910 mg, 3.3 mmol). After the reaction was completed, the reaction was added with DCM and H.sub.2O and stirred for liquid separation. The aqueous phase was extracted with DCM. The organic phase was washed with saturated brine, dried, concentrated and purified by column chromatography to give compound 5-3 (1.1 g, yield 92%).

[0364] LC/MS (ESI): m/z 411.1 [M+H].sup.+

Step 4

[0365] ##STR00117##

[0366] Compound 5-4 (synthesized by the method described in the patent WO2016035847, 330 mg, 0.43 mmol), compound 5-3 (210 mg, 0.5 mmol), sodium iodide (194 mg, 1.3 mmol) and NMP (1.0 mL) were added to a single-necked flask, and the mixture was reacted at room temperature. After the reaction was completed, the reaction mixture was added dropwise to a 5% aqueous sodium bisulfite solution and filtered, and the filter cake was washed with water and concentrated in vacuum to remove the solvent to give compound 5-5 (230 mg).

[0367] LC/MS (ESI): m/z 1154.1 [M].sup.+

Step 5

[0368] ##STR00118##

[0369] Compound 5-5 (200 mg, 0.164 mmol) was dissolved with anisole (0.4 mL) and trifluoroacetic acid (1.6 mL), and the solution was stirred. After the reaction was completed, the reaction mixture was added with MTBE and filtered, and the filter cake was rinsed with MTBE and dried to give a crude product (66 mg). The crude product was purified by HPLC to give compound 5 (1.9 mg).

[0370] LC/MS (ESI): m/z 640.0 [M+H].sup.+

[0371] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ: 1.39 (s, 3H), 1.45 (s, 3H), 1.89-2.16 (m, 4H), 2.00 (s, 3H), 3.41-3.90 (m, 12H), 3.93-4.25 (m, 2H), 5.13-5.17 (m, 1H), 5.70-5.80 (m, 1H), 6.73 (s, 1H), 7.22 (s, 2H), 8.20 (s, 1H).

Example 6

[0372] ##STR00119##

Step 1

[0373] ##STR00120##

[0374] Compound 5-1 (0.5 g, 3.8 mmol), dichloromethane and imidazole (0.8 g, 11.5 mmol) were added to a reaction flask, and the mixture was cooled in an ice water bath, added dropwise with tert-butyldiphenylchlorosilane (1.15 g, 4.3 mmol), and stirred. After the reaction was completed, the reaction mixture was added with dichloromethane and water and stirred for liquid separation, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, dried, concentrated and purified by column chromatography to give compound 6-1 (1.2 g, yield 85%).

[0375] LC/MS (ESI): m/z 369.1 [M+H].sup.+

Step 2

[0376] ##STR00121##

[0377] Compound 2-4 (428 mg, 1.0 mmol) and N,N-dimethylacetamide (4 mL) were added to a three-necked flask, and the mixture was cooled in an ice salt bath, added dropwise with MsCl (126 mg, 1.1 mmol) and TEA (111 mg, 1.1 mmol), and stirred. Compound 6-1 (410 mg, 1.0 mmol) was added and N-methylmorpholine (172 mg, 1.7 mmol) was added dropwise. After the reaction was completed, the reaction was quenched and the aqueous phase was extracted with EA. The organic phases were combined, dried, concentrated and purified by column chromatography to give compound 6-2 (240 mg, yield 30.8%).

[0378] LC/MS (ESI): m/z 779.0 [M+H].sup.+

Step 3

[0379] ##STR00122##

[0380] Compound 5-4 (270 mg, 0.35 mmol), compound 6-2 (240 mg, 0.31 mmol), sodium iodide (157 mg, 1.05 mmol) and NMP (0.81 mL) were added to a single-necked flask, and the mixture was reacted at room temperature overnight. The reaction mixture was added dropwise to a 5% aqueous sodium metabisulfite solution, filtered, and concentrated in vacuum to remove the solvent to give compound 6-3 (501 mg).

[0381] LC/MS (ESI): m/z 1523.1 [M].sup.+

Step 4

[0382] ##STR00123##

[0383] Compound 6-3 (501 mg) was added to a reaction flask, followed by the addition of TFA (4 mL) and anisole (1 mL), and the mixture was stirred. After the reaction was completed, the reaction mixture was added dropwise with MTBE and filtered, and the filter cake was washed with MTBE to give a crude product (210 mg), which was purified by reverse phase column chromatography to give compound 6 (10 mg).

[0384] LC/MS (ESI): m/z 767.8 [M+H].sup.+

[0385] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ: 1.42 (s, 3H), 1.48 (s, 3H), 1.85-2.25 (m, 4H), 3.40-3.86 (m, 11H), 3.88-4.07 (m, 2H), 4.17-4.39 (m, 1H), 4.91-5.06 (m, 1H), 5.14-5.20 (m, 1H), 5.74-5.83 (m, 1H), 6.58-6.91 (m, 3H), 7.22 (s, 2H), 10.65 (br s, 1H), 11.60 (br s, 1H).

Example 7

[0386] ##STR00124##

Step 1

[0387] ##STR00125##

[0388] Compound 7-1 (0.40 g, 0.76 mmol) was weighed in a reaction flask (synthesized according to known document European Journal of Medicinal Chemistry, 2018, 155, 847-868), and under nitrogen atmosphere, anhydrous dichloromethane (4 mL) was added. The mixture was cooled to −40° C., added dropwise with pyridine (0.20 g, 2.5 mmol) and trifluoromethanesulfonic anhydride (0.28 g, 0.99 mmol), heated to −5° C. and reacted for 2 h. Then the reaction mixture was reacted at room temperature for 2 h, cooled to −5° C., added dropwise with ammonium sulfide, and reacted at room temperature. After the reaction, the reaction mixture was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent, and the residue was separated and purified by silica gel column chromatography to give compound 7-2 (0.35 g, 0.65 mmol, yield 85%).

[0389] LC/MS (ESI): m/z 541.0 [M+H].sup.+

Step 2

[0390] ##STR00126##

[0391] Compound 7-2 (350 mg, 0.65 mmol), compound 1-6 (647 mg, 0.81 mmol) and sodium iodide (369 mg, 2.46 mmol) were added to N,N-dimethylformamide (2 mL), and the mixture was stirred. After the reaction was completed, the flask was cooled in an ice water bath, followed by the addition of PBr.sub.3 (360 mg, 1.33 mmol), and the mixture was stirred. After the reaction was completed, the reaction mixture was added dropwise to aqueous NaHSO.sub.3 solution and filtered, and the filter cake was washed with clear water and dried in vacuum to give crude compound 7-3 (1.1 g).

Step 3

[0392] ##STR00127##

[0393] Compound 7-3 (1.06 g, 0.824 mmol) was added to anisole (2 mL) and trifluoroacetic acid (8 mL), and the mixture was reacted at room temperature. The reaction mixture was added with methyl tert-butyl ether, stirred and filtered. The filter cake was rinsed with MTBE and dried to give a crude product (550 mg). 50 mg of the crude product was purified by HPLC to give compound 7 (4.8 mg).

[0394] HRMS: 768.1334 [M+H].sup.+

Example 8

[0395] ##STR00128##

Step 1

[0396] ##STR00129##

[0397] To a solution of compound 8-1 (200 mg, 0.92 mmol) (synthesized according to known document J. Med. Chem. 1997, 40, 1186-1194) in DMF (10 mL) were added PMBCl (503 mg, 3.21 mmol), K.sub.2CO.sub.3 (509 mg, 3.68 mmol) and NaI (138 mg, 0.92 mmol). The mixture was heated to 50° C. and stirred. The reaction mixture was added with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine sequentially, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give a crude product. The crude product was purified by reverse phase silica gel column chromatography to give compound 8-2 (105 mg, yield 25%).

[0398] .sup.1H-NMR (400 MHz, DMSO-d6) δ: 3.76 (s, 6H), 3.18 (s, 3H), 5.18 (s, 2H), 5.19 (s, 2H), 6.96 (d, 4H), 7.44 (d, 4H), 7.53 (s, 1H), 7.67 (s, 1H), 7.81 (s, 2H), 8.44 (s, 1H).

Step 2

[0399] ##STR00130##

[0400] To a mixed solution of compound 8-2 (105 mg, 0.23 mmol) in THF (3 mL) and MeOH (1.5 mL) was added a solution of LiOH.H.sub.2O (20 mg, 0.46 mmol) in H.sub.2O (1.5 mL). The mixture was stirred at room temperature. The reaction mixture was cooled to room temperature in an ice bath, adjusted to neutrality with 2 M HCl, and extracted with ethyl acetate. The organic phase was washed with water and saturated brine sequentially, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give crude compound 8-3 (100 mg).

[0401] .sup.1H-NMR (400 MHz, DMSO-d6) δ: 3.76 (s, 6H), 5.18 (s, 2H), 5.19 (s, 2H), 6.96 (d, 4H), 7.44 (d, 4H), 7.52 (s, 1H), 7.64 (s, 1H), 7.79 (s, 2H), 8.40 (s, 1H), 12.85 (br s, 1H).

Step 3

[0402] ##STR00131##

[0403] A solution of compound 8-3 (100 mg, 0.23 mmol) in THE (3 mL) was cooled in an ice water bath, and under argon atmosphere, MsCl (53 mg, 0.46 mmol) and Et.sub.3N (70 mg, 0.69 mmol) were added. The mixture was stirred at this temperature. A solution of compound 8-A (40 mg, 0.35 mmol) in THE (1 mL) was added to the above mixture, and the resulting mixture was heated to room temperature and stirred. The reaction mixture was added with water and extracted with EA. The organic phase was washed with water and saturated brine sequentially, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give a crude product. The crude product was purified by flash silica gel column chromatography to give compound 8-4 (70 mg, yield 57%).

[0404] LC/MS (ESI): m/z 541.1 [M+H].sup.+

Step 4

[0405] ##STR00132##

[0406] Compound 8-4 (86 mg, 0.16 mmol), compound 1-6 (139 mg, 0.18 mmol) and sodium iodide (81 mg, 0.54 mmol) were added to N,N-dimethylformamide (0.5 mL), and the mixture was stirred. After the reaction was completed, the flask was cooled in an ice water bath, followed by the addition of PBr.sub.3 (72 mg, 0.26 mmol), and the mixture was stirred. After the reaction was completed, the reaction mixture was added dropwise to aqueous NaHSO.sub.3 solution and filtered, and the filter cake was washed with clear water and dried in vacuum to give crude compound 8-5 (150 mg).

[0407] LC/MS (ESI): m/z 1284.1 [M].sup.+

Step 5

[0408] ##STR00133##

[0409] Compound 8-5 (150 mg, 0.117 mmol) was added to a single-necked flask, followed by the addition of anisole (0.3 mL) and TFA (1.2 mL), and the mixture was stirred. The reaction mixture was added with MTBE and filtered to give a crude product (78 mg). The crude product was purified by HPLC to give compound 8 (11.21 mg).

[0410] HRMS: 768.2109 [M+H].sup.+

Example 9

[0411] ##STR00134##

Step 1

[0412] ##STR00135##

[0413] To a solution of compound 2-4 (500 mg, 1.17 mmol) in DMF (12 mL) was added iodomethane (5 g, 35.1 mmol) and potassium carbonate (323 mg, 2.34 mmol), and the mixture was stirred at room temperature. After the reaction was completed, the reaction mixture was added with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give a crude product. The crude product was purified by flash silica gel column chromatography to give compound 9-2 (505 mg, yield 97%).

[0414] LC/MS (ESI): m/z 465.0 [M+Na].sup.+

##STR00136##

[0415] A solution of LiAlH.sub.4 (1.1 mL, 1.14 mmol) in 1 M THF was added dropwise to a solution of compound 9-2 (505 mg, 1.14 mmol) in THF (4.2 mL) cooled in ice water. The mixture was slowly heated to room temperature and reacted until the reaction was completed. The reaction mixture was cooled in an ice water bath, added with Na.sub.2SO.sub.4.10 H.sub.2O, stirred at room temperature and filtered to remove a solid, and the filtrated was concentrated under reduced pressure to give crude compound 9-3. The crude product was directly used in the next step (465 mg, yield 98%).

[0416] LC/MS (ESI): m/z 437.1 [M+Na].sup.+

Step 3

[0417] ##STR00137##

[0418] Dess-Martin reagent (712 mg, 1.68 mmol) was added to a solution of compound 9-3 (465 mg, 1.12 mmol) in DCM (23 mL) cooled in an ice/water. The mixture was slowly heated to room temperature and reacted until the reaction was completed. H.sub.2O was added to quench the reaction, and the reaction mixture was extracted with DCM. The organic phase was washed with water and saturated brine sequentially, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give a crude product. The crude product was purified by flash silica gel column chromatography to give compound 9-4 (440 mg, yield 95%).

[0419] LC/MS (ESI): m/z 412.9 [M+H].sup.+

Step 4

[0420] ##STR00138##

[0421] A solution of a mixture of NH.sub.2OH HCl (82 mg, 1.18 mmol) and Et.sub.3N (199 mg, 197 mmol) in CH.sub.3CN (5 mL) was stirred at room temperature, followed by the dropwise addition of a solution of compound 9-4 (405 mg, 0.98 mmol) in CH.sub.3CN (5 mL), and the resulting mixture was stirred at room temperature. To the reaction mixture were added MsCl (280 mg, 2.45 mmol) and Et.sub.3N (104 mg, 1.03 mmol). The mixture was stirred at room temperature until the reaction was completed. H.sub.2O was added to quench the reaction, and the reaction mixture was washed with saturated brine sequentially, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give a crude product. The crude product was purified by flash silica gel column chromatography to give compound 9-5 (290 mg, yield 72%).

[0422] LC/MS (ESI): m/z 432.0 [M+Na].sup.+

Step 5

[0423] ##STR00139##

[0424] n-BuLi (0.64 mL, 1.02 mmol) was slowly added dropwise to a solution of compound 9-5 (210 mg, 0.51 mmol) in THE (5 mL) cooled in ice water. A solution of compound 8-A (88 mg, 0.77 mmol) in THE (1 mL) was added to the above mixture, and the resulting mixture was heated to room temperature and stirred. After the reaction was completed, saturated NH.sub.4Cl solution was added to quench the reaction, and the reaction mixture was extracted with EA. The organic phase was washed with water and saturated brine sequentially, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give a crude product. The crude product was purified by flash silica gel column chromatography to give compound 9-6 (147 mg, yield 54%).

[0425] LC/MS (ESI): m/z 524.2 [M+H].sup.+

Step 6

[0426] ##STR00140##

[0427] Compound 9-6 (140 mg, 0.267 mmol), compound 1-6 (265 mg, 0.334 mmol) and sodium iodide (150 mg, 1 mmol) were added to N,N-dimethylformamide (0.8 mL), and the mixture was stirred. After the reaction was completed, the flask was cooled in an ice water bath, followed by the addition of PBr.sub.3 (144 mg, 0.52 mmol), and the mixture was stirred. After the reaction was completed, the reaction mixture was added dropwise to aqueous NaHSO.sub.3 solution and filtered, and the filter cake was washed with clear water and dried in vacuum to obtain crude compound 9-7 (400 mg).

[0428] LC/MS (ESI): m/z 1267.1 [M].sup.+

Step 7

[0429] ##STR00141##

[0430] Compound 9-7 (100 mg, 0.0788 mmol) was added to a single-necked flask, followed by the addition of anisole (0.3 mL) and TFA (1.2 mL), and the mixture was reacted at room temperature. After the reaction was completed, the reaction mixture was added with MTBE and filtered, and the crude product was purified by HPLC to give compound 9 (4.4 mg).

[0431] HRMS: 751.1716 [M+H].sup.+

Example 10

[0432] ##STR00142##

Step 1

[0433] ##STR00143##

[0434] To a solution of compound 2-4 (1.5 g, 3.50 mmol) in DMF (35 mL) was added DMTMM (1.55 g, 5.26 mmol) and DIEA (905 mg, 7.0 mmol). After purging with argon three times, compound 10-A (525 mg, 7.0 mmol) was added to the above mixture, and the resulting mixture was stirred at room temperature for 2 h. The reaction solution was slowly added to water, and a solid product was gradually precipitated. The solid product obtained by filtration was dissolved in DCM, and extracted, followed by liquid separation. The organic phase was washed with water and saturated brine sequentially, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give compound 10-2 (1.6 g, yield 94%).

[0435] LC/MS (ESI): m/z 486.1 [M+H].sup.+

Step 2

[0436] ##STR00144##

[0437] A solution of oxalyl chloride (1.05 g, 8.24 mmol) in DCM (10 mL) was cooled to −78° C. in a dry ice/acetone bath, DMSO (1.29 g, 16.5 mmol) was added dropwise under argon atmosphere, and the mixture was stirred. A solution of compound 10-2 (1.6 g, 3.30 mmol) in DCM (6 mL) was added dropwise slowly to the above mixture, and the resulting mixture was stirred at −78° C. The reaction mixture was added with Et.sub.3N (3.34 g, 33.0 mmol), stirred at −78° C., and slowly heated to 0° C. until the reaction was completed. H.sub.2O was added to quench the reaction, and the reaction mixture was extracted with DCM. The organic phase was washed with water and saturated brine sequentially, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give a crude product. The crude product was purified by flash silica gel column chromatography to give compound 10-3 (1.28 g, yield 80%).

[0438] LC/MS (ESI): m/z 484.0 [M+H].sup.+

Step 3

[0439] ##STR00145##

[0440] To a solution of compound 10-3 (1.28 g, 2.65 mmol) in DCM (26 mL) was added compound 8-A (605 mg, 5.30 mmol), and the mixture was cooled in an ice water bath, added with NaBH(OAc).sub.3 (1.68 g, 7.95 mmol), and heated to room temperature and stirred. After the reaction was completed, NaHCO.sub.3 solution was added to quench the reaction, and the reaction mixture was extracted with DCM. The organic phase was washed with water and saturated brine sequentially, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give a crude product. The crude product was purified by flash silica gel column chromatography to give compound 10-4 (735 mg, yield 48%).

[0441] LC/MS (ESI): m/z 582.1 [M+H].sup.+

Step 4

[0442] ##STR00146##

[0443] To a solution of compound 2-4 (650 mg, 1.51 mmol) in DMF (13 mL) was added HATU (961 mg, 2.52 mmol) and DIEA (490 mg, 3.78 mmol). The mixture was stirred at room temperature under argon atmosphere. Compound 10-4 (735 mg, 1.26 mmol) was added to the above reaction mixture, and the resulting mixture was stirred at room temperature. The reaction mixture was slowly added to water, filtered and dried in vacuum to give compound 10-5 (1.2 g, yield 96%).

[0444] LC/MS (ESI): m/z 992.1 [M+H].sup.+

Step 5

[0445] ##STR00147##

[0446] Compound 10-5 (546 mg, 0.55 mmol), compound 1-6 (398 mg, 0.5 mmol) and sodium iodide (225 mg, 1.5 mmol) were added to N,N-dimethylformamide (1.5 mL), and the mixture was stirred. After the reaction was completed, the flask was cooled in an ice water bath, followed by the addition of PBr.sub.3 (360 mg, 1.33 mmol), and the mixture was stirred. After the reaction was completed, the reaction mixture was added dropwise to aqueous NaHSO.sub.3 solution and filtered, and the filter cake was washed with clear water and dried in vacuum to obtain crude compound 10-6 (1.13 g).

[0447] LC/MS (ESI): m/z 1737.1 [M].sup.+

Step 6

[0448] ##STR00148##

[0449] Compound 10-6 (1.13 g, 0.5 mmol) was added to anisole (2 mL) and trifluoroacetic acid (8 mL), and the mixture was reacted at room temperature. The reaction mixture was added with methyl tert-butyl ether, stirred and filtered. The filter cake was rinsed with MTBE and dried to give a crude product (600 mg). The crude product was purified by HPLC to give compound 10 (4 mg).

[0450] HRMS: 979.1874 [M+H].sup.+

[0451] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ: 1.44 (s, 3H), 1.46 (s, 3H), 1.66-2.06 (m, 6H), 2.93-3.88 (m, 14H), 3.04-3.05 (m, 2H), 4.00-4.03 (m, 2H), 4.82-5.13 (m, 1H), 5.18 (d, 1H), 5.74 (dd, 1H), 6.54 (d, 1H), 6.60 (d, 1H), 6.73-6.85 (m, 3H), 7.28 (s, 2H), 8.05-8.33 (m, 1H), 9.46 (br s, 2H), 10.26 (br s, 2H).

Example 11

[0452] ##STR00149##

Step 1

[0453] ##STR00150##

[0454] To a reaction flask were added compound 11-1 (30.3 g, 174.1 mmol, 1.0 eq), 2,4-dimethoxybenzaldehyde (29.5 g, 177.6 mmol, 1.02 eq), methanol (300 mL) and anhydrous sodium sulfate (24.7 g, 174.1 mmol, 1.0 eq), and the mixture was stirred at room temperature. The reaction mixture was cooled in an ice water bath, added with sodium borohydride (3.3 g, 87.0 mmol, 0.5 eq.) in portions, stirred for 5 min, and then stirred at room temperature until the reaction was completed. The reaction mixture was added with glacial acetic acid (3.3 mL), stirred, filtered, and washed with ethyl acetate. The filtrate was concentrated, and the residue was added with water and ethyl acetate and stirred for liquid separation. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give compound 11-2 (58.0 g, yield 102.8%). MS m/z 325.1 [M+H].sup.+

Step 2

[0455] ##STR00151##

[0456] Compound 11-2 (2.0 g, 6.2 mmol, 1.0 eq), S-propylene oxide (0.54 g, 9.3 mmol, 1.5 eq) and EtOH (20 mL) were added to a reaction flask, and the mixture was heated to 60° C. After the starting material was consumed completely as detected by LC-MS, the reaction mixture was concentrated, and the crude product was purified by column chromatography to give compound 11-3 (1.2 g, yield 51.1%).

[0457] MS m/z 383.2 [M+H].sup.+

Step 3

[0458] ##STR00152##

[0459] Compound 11-3 (1.2 g, 3.2 mmol, 1.0 eq), DCM (20 mL) and TEA (0.65 g, 6.4 mmol, 2.0 eq) were added to a reaction flask, and the mixture was cooled in an ice water bath, slowly added dropwise with MsCl (0.54 g, 4.7 mmol, 1.5 eq), and stirred. After the starting material was consumed completely as detected by LC-MS, the reaction mixture was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give crude compound 11-4 (1.34 g), which was directly used in the next reaction.

[0460] MS m/z 461.1 [M+H].sup.+

Step 4

[0461] ##STR00153##

[0462] The crude compound 11-4 (1.34 g, 3.2 mmol, 1.0 eq), tetrahydropyrrole (0.56 g, 8.0 mmol, 2.5 eq), MeCN (15 mL) and potassium carbonate (0.66 g, 4.8 mmol, 1.5 eq) were added to a reaction flask, and the mixture was heated to 40° C. and stirred. After the starting material was consumed completely as detected by LC-MS, the reaction mixture was added with water (30 mL) and EA (30 mL) and stirred for liquid separation. The aqueous phase was washed with EA. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography to give compound 11-5 (0.66 g, yield 48.5% over two steps).

[0463] MS m/z 436.1 [M+H].sup.+

Step 5

[0464] ##STR00154##

[0465] Compound 11-5 (600 mg, 1.38 mmol) and TFA (10 mL) were dissolved in a reaction flask, and the solution was heated to 60° C. and reacted until the reaction was completed. The reaction mixture was concentrated to dryness, added with MTBE (10 mL) and slurried, and the supernatant was removed. The resulting oil was concentrated in vacuum to remove most of the solvent, and directly used in the next step.

[0466] MS m/z 186.1 [M+H].sup.+

Step 6

[0467] ##STR00155##

[0468] The crude compound 11-6 and compound 2-4 (1.31 g, 3.05 mmol) were dissolved in DCM (15 mL), and the mixture was stirred at 0° C. DIPEA (2.02 mL, 12.22 mmol) and HATU (1.39 g, 3.67 mmol) were added. The resulting mixture was warmed to room temperature and reacted until the reaction was completed. The reaction mixture was added with water (10 mL), followed by the liquid separation. The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was separated by column chromatography (DCM:MeOH=10:1) to give compound 11-7 (0.85 g).

[0469] MS m/z 1006.3 [M+H].sup.+

Step 7

[0470] ##STR00156##

[0471] Compound 1-6 (720 mg, 0.904 mmol), compound 11-7 (650 mg, 0.645 mmol), sodium iodide (0.406 g, 2.71 mmol) and boric acid (17 mg, 0.271 mmol) were added to a reaction flask, and after purging with argon three times, NMP (2.1 mL) was added. The reaction mixture was reacted at room temperature until the reaction was completed. The reaction solution was directly used in the next step without further treatment.

[0472] MS m/z 1767.5 [M].sup.+

Step 8

[0473] ##STR00157##

[0474] NMP (0.7 mL) was added to the above reaction mixture, and the resulting reaction mixture was cooled to 0° C., added with phosphorus trichloride (0.103 mL, 1.17 mmol), and reacted at 0° C. until the reaction was completed. The reaction mixture was added with 5% aqueous sodium hydrogen sulfite solution (20 mL), slurried in an ice water bath and filtered, and the filter cake was dissolved with DCM (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give compound 11-9 (1.21 g).

[0475] MS m/z 1751.4 [M].sup.+

Step 9

[0476] ##STR00158##

[0477] Compound 11-9 (1.21 g, 0.69 mmol) was dissolved in anisole (0.2 mL) and trifluoroacetic acid (0.8 mL), and the solution was reacted at room temperature until the reaction was completed. The reaction mixture was cooled to 0° C., added with MTBE (20 mL), slurried in an ice water bath and filtered, the filter cake was rinsed with MTBE and dried to give a crude product (0.82 g). The crude product was purified by reverse HPLC to give compound 11 (107 mg).

[0478] MS m/z 993.1 [M+H].sup.+

Biological Evaluation

[0479] The present disclosure is further described and explained below with reference to test examples, which are not intended to limit the scope of the present disclosure.

Test Example 1: Antibacterial Activity Test

[0480] The test compounds were diluted in a gradient and used for an MIC assay on the test strains. The test compounds at an initial assay concentration of 32 μg/mL were diluted in a 2-fold gradient (11 concentration points in total), and two duplicate wells were set for each concentration. Additional wells without drug dosing were set as growth controls. The minimum inhibitory concentration (MIC) assay was performed with reference to the Clinical and Laboratory Standards Institute (CLSI) guidelines.

1. Preparation of Bacterial Inoculation Liquid

[0481] After the frozen strains were subcultured, a single colony was picked and re-suspended in normal saline or sterile water in a tube. The bacterial suspension was vortexed and adjusted to 0.5 McF using a spectrophotometer at the wavelength of 530 nm. The bacterial solution was taken by a pipette, added to a culture medium, diluted and mixed well, and seeded to a bacterial assay plate.

2. Culture

[0482] The bacterial assay plate was placed in an incubator, incubated at 35° C. with 85% humidity for 24 h, and read for the MIC values.

3. MIC interpretation

[0483] The 96-well plate was affixed with a disposable sealing film, shaken and mixed well, and visually observed using a plate reader. The minimum concentration of the compounds capable of inhibiting the growth of bacteria was defined as MIC as compared to the growth controls.

[0484] MIC Results

TABLE-US-00001 Strain MIC (μg/mL) Strain No. Meropenem Cefiderocol Compound 1 Compound 2 Compound 3 Compound 4 Compound 6 Carbapenem- 110390 12 0.5 >32 0.5 2 >32 2 resistant 110358 4 1 >32 1 2 >32 4 Pseudomonas 110163 24 1 >32 0.5 1 >32 0.5 aeruginosa 110224 16 0.75 32 0.75 1 >32 0.625 (CRPA) (n = 5) 100110 32 0.047 16 0.031 0.5625 16 0.063 Carbapenem- 311277 32 5 >32 1.5 8 >32 8 resistant 110525 32 6 >32 2 16 >32 4 Enterobacteriaceae 110502 32 12 >32 6 >32 >32 32 (CRE) (n = 5) 100186 >32 0.5 >32 1.5 6 >32 1.5 100109 >32 1 >32 1 3 >32 2 Carbapenem- 110517 32 0.5 >32 0.5 1 >32 1 resistant 110477 >32 1 >32 2 4 >32 3 Acinetobacter 110440 32 1.5 >32 3 4 >32 4 baumannii 100333 >32 2 >32 2 6 >32 6 (CRAB) (n = 5) 100085 32 0.5 >32 0.5 3 >32 3

[0485] As shown above, the compounds of the present disclosure have a broad antibacterial spectrum, specifically an effective antibacterial spectrum against gram-negative bacteria, and/or have efficacy against multidrug-resistant bacteria, and further exhibit high stability in its activity against gram-negative bacteria producing β-lactamases.

Test Example 2: Antibacterial Activity Test

[0486] 1. The test compounds were dissolved in sterile normal saline, vortexed for uniformly mixing, and diluted in a 2-fold dilution with the sterile normal saline (11 concentration points in total). The test concentration range was 32-0.031 μg/mL, and two duplicate wells were set for each concentration. Additional wells without drug dosing were set as growth controls.
2. 4 μL of the diluent was added to 196 μL of the bacterial suspension in a 96-well plate (the bacterial count in the bacterial suspension was 2-8×10.sup.5 colony forming units/mL).
3. The plate was incubated at 36° C. for 24 h, and read for the MIC values by visual observation.

[0487] The minimum inhibitory concentration (MIC) assay was performed with reference to the Clinical and Laboratory Standards Institute (CLSI) guidelines.

TABLE-US-00002 Strain ID-CAMHB, MIC, μg/mL (gram-negative Compound Compound Compound bacteria) Strain ID AMR gene Cefiderocol 2 7 5 Carbapenem- FDA-CDC strB, OXA-65, 0.25 0.5 2 >32 resistant AR-BANK #0036 OXA-24, strA, sul2 Acinetobacter FDA-CDC OXA-58, OXA- 0.0625 0.0625 0.25 >32 baumannii AR-BANK #0052 100, sul2 (CRAB, FDA-CDC OXA-23, OXA-65, 8 16 >32 >32 Acinetobacter AR-BANK #0063 OXA-24, sul2 baumannii) FDA-CDC OXA-58, OXA- 0.125 0.0625 0.125 >32 AR-BANK #0070 100, sul2 FDA-CDC strB, OXA-65, 1 0.5 4 >32 AR-BANK #0101 OXA-24, strA, sul2 Carbapenem- FDA-CDC TEM-1; SHV- 2 1 1 >32 resistant AR-BANK #0361 12; KPC-2 Enterobacteriaceae FDA-CDC TEM-1; SHV- 0.5 0.5 1 >32 (CRE, Klebsiella AR-BANK #0362 11; KPC-2 pneumoniae) FDA-CDC TEM-1; SHV- 0.25 0.5 0.5 >32 AR-BANK #0363 12; KPC-2 FDA-CDC aph(3′)-Ia, dfrA12, 2 1 2 >32 AR-BANK #0438 KPC-3, OmpK35, oqxA, oqxB, SHV-11 FDA-CDC KPC-3, OmpK35, 1 2 4 >32 AR-BANK #0453 oqxA, oqxB, SHV-11, TEM-1B Carbapenem- FDA-CDC aac(6′)-Il, 0.25 0.5 8 >32 resistant AR-BANK #0439 aadA1b, BCR1, Pseudomonas IMP-18, OXA-50 aeruginosa (CRPA, FDA-CDC KPC-2 1 2 8 >32 Pseudomonas AR-BANK #0441 aeruginosa) FDA-CDC aac(6′)-Il, 2 4 32 >32 AR-BANK #0444 dfrB5, OXA-4, tet(G), VIM-2 FDA-CDC aadA6, VIM-2 0.125 0.125 1 >32 AR-BANK #0457 Control ATCC 25922 — 0.0625 0.125 0.125 >32 strain* Escherichia coli Control ATCC 27853 — 0.0625 0.0625 0.125 >32 Strain* Pseudomonas aeruginosa Strain ID-CAMHB, MIC, μg/mL CAMHB (gram-negative Compound Compound Compound Compound MIC, μg/mL bacteria) 9 8 10 11 Meropenem Carbapenem- >32 0.25 0.125 0.5 >32 resistant Acinetobacter >32 0.0625 0.0625 0.125 16 baumannii (CRAB, >32 8 >32 4 >32 Acinetobacter baumannii) >32 0.125 0.125 0.25 8 >32 2 0.5 1 >32 Carbapenem- >32 2 0.25 1 16 resistant Enterobacteriaceae 16 1 0..25 0.25 >32 (CRE, Klebsiella pneumoniae) >32 0.25 0.125 0.5 32 >32 2 0.5 1 >32 >32 2 2 1 >32 Carbapenem- >32 1 0.25 0.5 >32 resistant Pseudomonas aeruginosa (CRPA, >32 4 1 8 >32 Pseudomonas aeruginosa) >32 4 16 4 >32 >32 0.25 0.0625 0.25 >32 Control 16 0.25 0.0625 0.125 ≤0.03125 strain* Escherichia coli Control >32 0.25 0.0625 0.0625 0.5 Strain* Pseudomonas aeruginosa

[0488] As shown above, the compounds of the present disclosure have a broad antibacterial spectrum, specifically an effective antibacterial spectrum against gram-negative bacteria, and/or have efficacy against multidrug-resistant bacteria, and further exhibit high stability in its activity against gram-negative bacteria producing β-lactamases.

Test Example 3: Pharmacokinetic Study in Cynomolgus Monkeys

1. Sample Preparation

[0489] An appropriate amount of a test compound was weighed precisely and added to a container, and 0.9% sodium chloride injection and 0.2 M NaOH solution were added thereto in an ice bath until the test compound was completely dissolved, so that a sample solution at a concentration of 2 mg/mL was obtained followed by storage at 2-8° C. for later use.

2. Test Animal

[0490] Species and strain: cynomolgus monkey
Animal grade: general grade
Animal source: Guangxi Xiongsen Primate Experimental Animal Breeding Development Co., Ltd.
Number of the using of laboratory animal: SYXK (Su) 2019-0012

3. Test Method

[0491] 6 cynomolgus monkeys (half male and half female) were selected and randomly divided into 3 groups with 1 animal/sex in each group. The cynomolgus monkeys were administered with the test sample at a dose of 10 mg/kg by the single intravenous infusion. Blood samples were collected from each group of animals at the following time points: before administration, and 5 min, 15 min, 0.5 h, 1 h, 2 h, 4 h, 6 h, and 8 h after administration. In the test, the concentration of each test compound in the plasma of the cynomolgus monkey was detected by the LC-MS/MS method, and the lower limit of quantification of the analysis methods for the plasma samples were all 1 μg/mL. The plasma concentration data were analyzed by the non-compartmental analysis (NCA) of the analysis software for pharmacokinetic data, WinNonlin, pharmacokinetic parameters were calculated, and pharmacokinetic characteristics of the test compounds in cynomolgus monkeys after administration were investigated, with the results shown in the following table

TABLE-US-00003 t.sub.1/2 T.sub.max C.sub.max AUC last AUC.sub.inf Vd CL MRT Sample Animal No. (h) (h) (ug/mL) (h*ug/mL) (h*ug/mL) (mL/kg) (mL/h/kg) (h) Compound 2073541 0.62 0.08 35.48 29.29 32.94 270.05 303.57 0.64 10 2073542 0.56 0.08 30.64 23.44 25.64 313.34 390.01 0.62 Cefiderocol 2073545 0.86 0.08 30.53 26.21 32.39 380.98 308.70 0.70 2073546 0.75 0.08 24.33 23.94 28.35 379.63 352.76 0.70

[0492] The compounds of the present disclosure are superior in terms of C.sub.max as compared to cefiderocol.