Siderophore-modified vancomycin derivatives as novel repurposed antibiotics to combat Gram-negative bacterial infections

Abstract

The present disclosure provides novel vancomycin derivatives that function as antibacterial agents against Gram-negative bacteria. The disclosed compounds are believed to be useful for treating diseases caused by antibiotic-resistant bacteria, including Acinetobacter baumannii and Escherichia coli. Antimicrobial resistance (AMR) has become a prominent problem. AMR threatens public health and global development and has been named one of the top 10 global public health threats by the World Health Organization (WHO), causing significant morbidity and mortality.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 451,337, filed March 10, 2023, which is incorporated herein by reference in its entirety.

[0002] Federally sponsored research This invention was made with government support under 75N93021C00002 awarded by the National Institutes of Health. The government has certain rights in this invention.

[0003] The present disclosure relates to novel vancomycin-siderophore conjugates and pharmaceutical compositions thereof, as well as methods for treating diseases caused by antimicrobial-resistant pathogens. The pharmaceutical compositions described herein are useful as broad-spectrum antibiotics to combat Gram-negative bacterial infections. [Background technology]

[0004] Antimicrobial resistance (AMR) has become a prominent issue. Threatening public health and global development, AMR has been named one of the top 10 global public health threats by the World Health Organization (WHO) and causes significant morbidity and mortality. See Antimicrobial Resistance: A Top Ten Global Public Health Threat. EClinicalMedicine 2021, 41, 101221. A 2019 CDC report estimated that more than 2.6 million antibiotic-resistant infections occur annually in the United States alone, resulting in nearly 44,000 deaths. See Antibiotic Resistance Threats in The United States. AR Threats Report 2019. Globally, AMR causes an estimated 700,000 deaths each year, and some experts predict that without efforts to stop drug resistance or develop new antibiotics, this number could rise to 10 million by 2050. See Willyard, Drug-Resistant Bacteria Ranked. Nature 2017, 543(7643). In 2017, the WHO published a global priority pathogen threat list that included 12 bacterial species with severe, high, and moderate antibiotic resistance. See, e.g., Asokan, et al., WHO Global Priority Pathogens List: A Bibliometric Analysis of Medline-PubMed for Knowledge Mobilization to Infection Prevention and Control Practices in Bahrain. Oman Medical Journal 2019, 34(3), 184-193, and Kwon, et al., The Post-Antibiotic Era Is Here. Science 2021, 373(6554), 471.Among these, three Gram-negative bacteria—Acinetobacter baumannii (carbapenem), Pseudomonas aeruginosa (carbapenem), and Enterobacteriaceae, extended-spectrum beta-lactamase-producing (carbapenem)—ranked in the top three. In the 2019 Antibiotic Resistance Threats in the United States report, the Gram-negative bacteria carbapenem-resistant Acinetobacter, carbapenem-resistant Enterobacteriaceae, and drug-resistant Neisseria gonorrhoeae ranked first, fourth, and fifth, respectively, on the urgent threat list. Despite currently having 76 clinical antibacterial candidates, relatively few drugs are in late-stage clinical development, especially for key priority pathogens. See, e.g., Butler, et. al., Analysis of the Clinical Pipeline of Treatments for Drug-Resistant Bacterial Infections: Despite Progress, More Action Is Needed. Antimicrobial Agents and Chemotherapy 2022, 66(3), e0199121. Thus, combating antibiotic resistance requires the development of new antibiotics, particularly those directed against critical priority Gram-negative pathogens.

[0005] The Gram-negative bacterial envelope structure has three main layers: the outer membrane, the periplasmic space, and the inner membrane. The outer membrane barrier prevents many antibiotics from effectively penetrating and reaching their targets, complicating the development of new antibiotics for Gram-negative bacteria.

[0006] Vancomycin, the first and most representative member of the glycopeptide antibiotic family, was considered a "last resort" antibiotic for the treatment of severely resistant Gram-positive bacterial infections, such as Staphylococcus aureus, Enterococcus spp., and Clostridium difficile. See, e.g., Binda, et al., Old and New Glycopeptide Antibiotics: Action and Resistance. Antibiotics (Basel) 2014, 3(4), 572-594. Vancomycin binds to the D-Ala-D-Ala moiety of the bacterial cell wall precursor Lipid II, inhibiting subsequent transglycosylation and transpeptidation, resulting in bacterial lysis and death. See, e.g., Nicolaou, et al., Chemistry, Biology, and Medicine of the Glycopeptide Antibiotics. Angewandte Chemie International Edition 1999, 38(15), 2096-2152. After 30 years of widespread use, clinical resistance to vancomycin has emerged, presenting an urgent need for the development of next-generation glycopeptide antibiotics. See, e.g., Uttley, et al., Vancomycin-Resistant Enterococci. Lancet 1988, 1(8575-6), 57-58, and Leclercq, et al., Plasmid-Mediated Resistance to Vancomycin and Teicoplanin in Enterococcus Faecium. New England Journal of Medicine 1988, 319(3), 157-161.

[0007] In recent years, repurposing "old" drugs to treat both common and rare diseases has become an attractive option. See, for example, Pushpakom, et al., Drug Repurposing: Progress, Challenges, and Recommendations. Nature Reviews Drug Discovery 2019, 18(1), 41-58. Vancomycin is a cell wall biosynthesis inhibitor that is only effective against Gram-positive bacteria because it cannot penetrate the outer membrane of Gram-negative bacteria. The peptidoglycan layer, the target of vancomycin, is considered the bacterial "Achilles' heel" because it plays a crucial role in bacterial survival. In Gram-negative bacteria, it is located in the periplasmic space, which has a much thinner peptidoglycan layer compared to Gram-positive bacteria. See, e.g., Sibinelli-Sousa, et. al., Targeting the Achilles' heel of Bacteria: Different Mechanisms to Break Down the Peptidoglycan Cell Wall during Bacterial Warfare. Journal of Bacteriology 2021, 203(7), e00478-20. Facilitating vancomycin penetration of the outer membrane into the periplasmic space appears to be crucial and significant for overcoming resistance in Gram-negative bacteria.

[0008] The "Trojan horse" strategy has been widely and successfully applied in antibiotic design, in which iron-chelating siderophores are conjugated to antibiotics or antimicrobial agents to enhance uptake and antimicrobial activity. See, e.g., Kong, et al., An Overview of Recent Progress in Siderophore-Antibiotic Conjugates. European Journal of Medicinal Chemistry 2019, 182, 111615; Jun, et al., Research Progress of Antibiotics Conjugated with Siderophores. Chinese Journal of Organic Chemistry 2020, 40(10), 3026-3043; and Negash, et al., Siderophore-Antibiotic Conjugate Design: New Drugs for Bad Bugs? Molecules 2019, 24(18), 3314, each of which is incorporated herein by reference for such background teachings. Iron is an essential nutrient for bacterial growth, replication, and metabolism. To maintain their growth and obtain sufficient iron for various physiological activities during infection, bacteria have evolved a series of systems that can uptake iron through the secretion of small organic compounds and function as extracellular iron carriers. These iron carriers, called siderophores, obtain various forms of extracellular iron and translocate them intracellularly via active transport systems. See, for example, Page, "The Role of Iron and Siderophores in Infection," and "The Development of Siderophore Antibiotics." Clinical Infectious Diseases 2019, 69(Suppl 7), S529-S537. The most prominent example of a siderophore antibiotic conjugate is cefiderocol, newly approved by the FDA in 2019.

[0009] As demonstrated in this application, a "Trojan horse" strategy of linking vancomycin to a synthetic siderophore provides a mechanism for vancomycin to penetrate the outer membrane via active uptake by the iron transport system. These vancomycin derivatives can bypass the Gram-negative cell wall and convert vancomycin into a broad-spectrum antibiotic to combat Gram-negative bacteria. This underlies the importance of rationally designing the type and size of siderophores to overcome the Gram-negative outer membrane permeability barrier. Therefore, there remains a need for new antibiotics to combat antimicrobial resistance. [Prior art documents] [Non-patent literature]

[0010] [Non-Patent Document 1] Antimicrobial Resistance:A Top Ten Global Public Health Threat.EClinicalMedicine 2021,41,101221 [Non-patent document 2] Antibiotic Resistance Threats in The United States.AR Threats Report 2019 [Non-patent document 3] Willyard,Drug-Resistant Bacteria Ranked.Nature 2017,543(7643) [Non-patent document 4] Asokan, et al., WHO Global Priority Pathogens List: A Bibliometric Analysis of Medline-PubMed for Knowledge Mobilization to Infection Prevention and Control Practices in Bahrain.Oman Medical Journal 2019,34(3),184-193 [Non-patent document 5] Kwon,et al.,The Post-Antibiotic Era Is Here.Science 2021,373(6554),471 [Non-patent document 6] Butler,et.al.,Analysis of the Clinical Pipeline of Treatments for Drug-Resistant Bacterial Infections:Despite Progress,More Action Is Needed.Antimicrobial Agents and Chemotherapy 2022,66(3),e0199121 [Non-Patent Document 7] Binda,et.al.,Old and New Glycopeptide Antibiotics:Action and Resistance.Antibiotics(Basel)2014,3(4),572-594 [Non-patent document 8] Nicolaou,et.al.,Chemistry,Biology,and Medicine of the Glycopeptide Antibiotics.Angewandte Chemie Internation Edition 1999,38(15),2096-2152 [Non-Patent Document 9] Uttley, et al., Vancomycin-Resistant Enterococci. Lancet 1988, 1(8575-6), 57-58, and Leclercq, et al., Plasmid-Mediated Resistance to Vancomycin and Teicoplanin in Enterococcus Faecium. New England Journal of Medicine 1988, 319(3), 157-161 [Non-Patent Document 10] Pushpakom,et.al.,Drug Repurposing:Progress,Challenges and Recommendations.Nature Reviews Drug Discovery 2019,18(1),41-58 [Non-Patent Document 11] Sibinelli-Sousa,et.al.,Targeting the Achilles 'heel of Bacteria:Different Mechanisms to Break Down the Peptidoglycan Cell Wall during Bacterial Warfare.Journal of Bacteriology 2021,203(7),e00478-20 Summary of the Invention [Means for solving the problem]

[0011] Accordingly, the present disclosure is directed to compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions, and methods useful for treating bacterial infections. The compounds and salts thereof, compositions, and methods described herein are useful for treating or preventing bacterial infections or diseases, including infections caused by Gram-negative and Gram-positive bacteria.

[0012] In one embodiment described herein, the compound of the present disclosure is represented by Formula (I): or a pharmaceutically acceptable salt thereof.

[0013] In one embodiment, the compound of the present disclosure is selected from the group consisting of: [ka] During the ceremony, (i)R 1 teeth, [ka] and R 2 , R 3 , and R 4each of which is H or (ii)R 1 teeth, [ka] and R 2 , R 3 , and R 4 each of which is H or (iii)R 1 teeth, [ka] and R 2 , R 3 , and R 4 each of which is H or (iv)R 1 teeth, [ka] and R 2 , R 3 , and R 4 each of which is H or (v)R 1 is OH and R 2 teeth, [ka] and R 3 and R 4 each of which is H or (vi)R 1 is OH and R 3 teeth, [ka] and R 2 and R 4 each of which is H or or (vii)R 1 is OH and R 4 teeth, [ka] and R 2 and R3 each of which is H; X 1 is a join or [ka] and X 2 is a join or [ka] and X 3 is a join or [ka] and X 4 is a join or [ka] and Y 1 is C(O) or SO2, Y 2 is C(O) or SO2, Y 3 is C(O) or SO2, n1 is 1 to 5, n2 is 1 to 10; n3 is 0 to 5, n4 is 1 to 5, n5 is 1 to 5, n6 is 1 to 10, n7 is 0 to 5, n8 is 0 to 5, n9 is a number between 0 and 5, n 10 is between 0 and 5, n 11 is between 0 and 5, R 5 is selected from the group consisting of hydrogen, halogen, and OH; R 6 is selected from the group consisting of hydrogen, halogen, and OH; R 7is selected from the group consisting of hydrogen, halogen, and OH; R 8 is selected from the group consisting of hydrogen, halogen, and OH; R 9 is selected from the group consisting of hydrogen, halogen, and OH; R 10 is selected from the group consisting of hydrogen, halogen, and OH; R 11 is selected from the group consisting of hydrogen, halogen, and OH; R 12 is selected from the group consisting of hydrogen, halogen, and OH; R 13 is selected from the group consisting of hydrogen, halogen, and OH; R 14 is selected from the group consisting of hydrogen, halogen, and OH; R 15 is selected from the group consisting of hydrogen, halogen, and OH; R 16 is selected from the group consisting of hydrogen, halogen, and OH; R 17 is selected from the group consisting of hydrogen, halogen, and OH; R 18 is selected from the group consisting of hydrogen, halogen, and OH; R 19 is selected from the group consisting of hydrogen, halogen, and OH; R 20 is selected from the group consisting of hydrogen, halogen, and OH; and R 21 is selected from the group consisting of hydrogen, halogen, and OH.

[0014] In another aspect, the compounds described herein, the halogen is Cl.

[0015] In another aspect, in the compounds described herein, R1 is [ka] and each of R2, R3, and R4 is H.

[0016] In another aspect, in the compounds described herein, n1 is 1.

[0017] In another aspect, in the compounds described herein, n1 is 3.

[0018] In another aspect, in the compounds described herein, R1 is [ka] and each of R2, R3, and R4 is H.

[0019] In another aspect, in the compounds described herein, n2 is 1, n3 is 0, X1 is a bond, Y1 is C(O), R5 is Cl, R6 is OH, and R7 is OH.

[0020] In another aspect, in the compounds described herein, n2 is 2, n3 is 0, X1 is a bond, Y1 is C(O), R5 is Cl, R6 is OH, and R7 is OH.

[0021] In another aspect, in the compounds described herein, n2 is 3, n3 is 0, X1 is a bond, Y1 is C(O), R5 is Cl, R6 is OH, and R7 is OH.

[0022] In another aspect, in the compounds described herein, n2 is 4, n3 is 0, and X 1 is a bond, and Y 1 is C(O) and R 5 is Cl and R 6 is OH and R 7 is OH.

[0023] In another aspect, in the compounds described herein, n2 is 5, n3 is 0, X1 is a bond, Y1 is C(O), R5 is Cl, R6 is OH, and R7 is OH.

[0024] In another aspect, in the compounds described herein, n2 is 6, n3 is 0, X1 is a bond, Y1 is C(O), R5 is Cl, R6 is OH, and R7 is OH.

[0025] In another aspect, in the compounds described herein, n2 is 7, n3 is 0, X1 is a bond, Y1 is C(O), R5 is Cl, R6 is OH, and R7 is OH.

[0026] In another aspect, in the compounds described herein, n2 is 2, n3 is 0, X1 is a bond, Y1 is C(O), R5 is OH, R6 is OH, and R7 is H.

[0027] In another aspect, in the compounds described herein, n2 is 3, n3 is 0, X1 is a bond, Y1 is C(O), R5 is OH, R6 is OH, and R7=H.

[0028] In another aspect, in the compounds described herein, n2 is 1, n3 is 1, and X1 is [ka] and Y1 is C(O), R5 is OH, R6 is OH, and R7 is H.

[0029] In another aspect, in the compounds described herein, n2 is 1, n3 is 2, and X1 is [ka] and Y1 is C(O), R5 is OH, R6 is OH, and R7 is H.

[0030] In another aspect, in the compounds described herein, n2 is 2, n3 is 0, X1 is a bond, Y1 is SO2, R5 is H, R6 is OH, and R7 is OH.

[0031] In another aspect, in the compounds described herein, n2 is 3, n3 is 0, X1 is a bond, Y1 is SO2, R5 is H, R6 is OH, and R7 is OH.

[0032] In another aspect, in the compounds described herein, n2 is 2, n3 is 1, and X1 is [ka] wherein Y1 is C(O), R5 is Cl, R6 is OH, and R7 is OH.

[0033] In another aspect, the compounds described herein, R 1 teeth, [ka] and R 2 , R 3 , and R 4 Each of is H.

[0034] In another aspect, in the compounds described herein, n4 is 1, Y2 is C(O), R8 is Cl, R9 is OH, and R10 is OH.

[0035] In another aspect, in the compounds described herein, n4 is 2, Y2 is C(O), R8 is Cl, R9 is OH, and R10 is OH.

[0036] In another aspect, in the compounds described herein, n4 is 2, Y2 is SO2, R8 is H, R9 is OH, and R10 is OH.

[0037] In another aspect, the compounds described herein, R 1 teeth, [ka] and R 2 , R 3 , and R 4 Each of is H.

[0038] In another embodiment, in the compounds described herein, n5 is 2. In another embodiment, in the compounds described herein, n5 is 3.

[0039] In another aspect, the compounds described herein, R 1 is OH and R 2 teeth, [ka] and R 3 and R 4 Each of is H.

[0040] In another aspect, in the compounds described herein, n6 is 2, n7 is 0, X2 is a bond, Y3 is C(O), R11 is Cl, R12 is OH, and R13 is OH.

[0041] In another aspect, in the compounds described herein, n6 is 3, n7 is 0, X2 is a bond, Y3 is C(O), R11 is Cl, R12 is OH, and R13 is OH.

[0042] In another aspect, in the compounds described herein, n6 is 1, n7 is 0, X2 is a bond, Y3 is C(O), R11 is OH, R12 is OH, and R13 is H.

[0043] In another aspect, in the compounds described herein, n6 is 1, n7 is 0, X2 is a bond, Y3 is SO2, R11 is H, R12 is OH, and R13 is OH.

[0044] In another aspect, in the compounds described herein, n6 is 2, n7 is 1, and X 2 teeth, [ka] and Y 3 is C(O) and R 11 is Cl and R 12 is OH and R 13 is H.

[0045] In another aspect, in the compounds described herein, R1 is OH and R3 is [ka] and each of R2 and R4 is H.

[0046] In another aspect, in the compounds described herein, n8 is 1, n9 is 0, X3 is a bond, R14 is Cl, R15 is OH, R16 is OH, R17 is H, and R18 is H.

[0047] In another aspect, in the compounds described herein, n8 is 2, n9 is 0, X3 is a bond, R14 is Cl, R15 is OH, R16 is OH, R17 is H, and R18 is H.

[0048] In another embodiment, in the compounds described herein, n8 is 2, n9 is 3, and X3= [ka] wherein R14 is H, R15 is H, R16 is OH, R17 is OH, and R18 is Cl.

[0049] In another aspect, in the compounds described herein, OH, R4 is [ka] and each of R2 and R3 is H.

[0050] In another aspect, in the compounds described herein, n10 is 1, n11 is 0, X4 is a bond, R19 is Cl, R20 is OH, R21 is OH, R22 is H, and R23 is H.

[0051] In another aspect, in the compounds described herein, n10 is 1, n11 is 3, and X4 is [ka] wherein R19 is H, R20 is H, R21 is OH, R22 is OH, and R23 is Cl.

[0052] In another embodiment, the following: [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] or a pharmaceutically acceptable salt thereof

[0010] Described herein is a compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

[0053] In other aspects, the present disclosure relates to pharmaceutical compositions comprising any of the compounds of the present disclosure, or a pharmaceutically acceptable salt thereof. Another aspect of the present disclosure relates to pharmaceutical compositions comprising any of the compounds of the present disclosure and a pharmaceutically acceptable carrier.

[0054] A further aspect of the present disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.

[0055] According to another aspect, the compounds of the present disclosure or the pharmaceutical compositions of the present disclosure can be used in the treatment of bacterial infectious diseases. Another aspect includes a method of treating a bacterial infection in a patient in need thereof, comprising administering to the patient a compound of the present disclosure or a composition of the present disclosure. A further aspect relates to a method of treating a bacterial infection in a patient in need thereof, comprising administering to the patient a compound of the present disclosure or a composition of the present disclosure in combination with another therapeutic agent.

[0056] In yet another aspect, the method of treating a bacterial infection in a patient in need thereof by administering to the patient a compound of the present disclosure or a composition of the present disclosure in combination with another therapeutic agent further includes where the bacteria is a gram-positive or gram-negative bacterium. In a further aspect, the method of treating a bacterial infection in a patient in need thereof by administering to the patient a compound of the present disclosure or a composition of the present disclosure in combination with another therapeutic agent further includes where the bacteria is a gram-positive bacterium. In another aspect, the method of treating a bacterial infection in a patient in need thereof by administering to the patient a compound of the present disclosure or a composition of the present disclosure in combination with another therapeutic agent further includes where the bacteria is a gram-negative bacterium. An additional aspect includes the method of treating a bacterial infection in a patient in need thereof by administering to the patient a compound of the present disclosure or a composition of the present disclosure in combination with another therapeutic agent further includes where the bacteria is an Acinetobacter baumannii gram-negative bacterium and an Escherichia coli gram-negative bacterium.

[0057] Another aspect of the present disclosure relates to a method of controlling, treating, or reducing the progression, severity, or effects of a bacterial infection in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the disclosure or a pharmaceutical composition of the disclosure.

[0058] In other aspects, the present disclosure relates to methods of reducing or inhibiting bacterial load in a biological sample, comprising contacting the biological sample with a compound of the present disclosure or a composition of the present disclosure.

[0059] In yet another aspect, the present disclosure relates to the use of a compound or pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating a bacterial infectious disease in a patient in need thereof. In a further aspect, the use of a compound or pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating a bacterial infectious disease in a patient in need thereof includes treating a bacterial infectious disease associated with gram-positive or gram-negative bacteria. A further aspect relates to the use of a compound or pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating a bacterial infectious disease in a patient in need thereof, wherein the bacterial infectious disease being treated is associated with gram-positive bacteria. Another aspect relates to the use of a compound or pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating a bacterial infectious disease in a patient in need thereof, wherein the bacterial infectious disease being treated is associated with gram-negative bacteria. Additionally, the use of a compound of the present disclosure or a pharmaceutical composition of the present disclosure in the manufacture of a medicament for the treatment of a bacterial infectious disease in a patient in need thereof includes the treatment of a bacterial infectious disease associated with gram-negative bacteria, including Acinetobacter baumannii and Escherichia coli. DETAILED DESCRIPTION OF THE INVENTION

[0060] overview The present disclosure is directed to compounds and their salts, compositions, and methods that are useful for treating bacterial infections.The term "treatment of bacterial infections," as used herein in its various forms, includes killing bacteria or inhibiting, reducing, or preventing their growth, and is intended to include contacting the bacteria with the compounds described herein.The ability of a compound to treat bacterial infections can be demonstrated by assay (for example, minimum inhibitory concentration).

[0061] In one embodiment described herein, the compound of the present disclosure is represented by formula (I): [ka] In the formula, R 1 teeth, [ka] and OH, R 2 , R 3 , and R 4 Each of is H.

[0062] R 1 If is OH, R 2 teeth, [ka] R may be 3 and R 4 Each of R may be H. Alternatively, R 1 If is OH, R 3 teeth, [ka] R may be 2 and R 4 may each be H. In addition to the above, R 1 If is OH, R 4 teeth, [ka] R may be 2 and R 3 may each be H. X 1 is a join or [ka] is selected from the group consisting of X 2 is a join or [ka] is selected from the group consisting of X 3 is a join or [ka] is selected from the group consisting of X 4 is a join or [ka] is selected from the group consisting of Y 1 is selected from the group consisting of C(O) or SO2; Y 2 is selected from the group consisting of C(O) or SO2; Y 3 is selected from the group consisting of C(O) or SO2; n1 is an integer from 1 to 5 (inclusive); n2 is an integer from 1 to 10, inclusive; n3 is an integer from 0 to 5 (inclusive); n4 is an integer from 1 to 5 (inclusive); n5 is an integer from 1 to 5 (inclusive); n6 is an integer between 1 and 10, inclusive; n7 is an integer between 0 and 5 (inclusive); n8 is an integer between 0 and 5 (inclusive); n9 is an integer between 0 and 5 (inclusive); n 10 is an integer between 0 and 5 (inclusive), n 11 is an integer between 0 and 5 (inclusive), R 5 is selected from the group consisting of hydrogen, halogen, and OH; R 6 is selected from the group consisting of hydrogen, halogen, and OH; R 7 is selected from the group consisting of hydrogen, halogen, and OH; R 8 is selected from the group consisting of hydrogen, halogen, and OH; R 9is selected from the group consisting of hydrogen, halogen, and OH; R 10 is selected from the group consisting of hydrogen, halogen, and OH; R 11 is selected from the group consisting of hydrogen, halogen, and OH; R 12 is selected from the group consisting of hydrogen, halogen, and OH; R 13 is selected from the group consisting of hydrogen, halogen, and OH; R 14 is selected from the group consisting of hydrogen, halogen, and OH; R 15 is selected from the group consisting of hydrogen, halogen, and OH; R 16 is selected from the group consisting of hydrogen, halogen, and OH; R 17 is selected from the group consisting of hydrogen, halogen, and OH; R 18 is selected from the group consisting of hydrogen, halogen, and OH; R 19 is selected from the group consisting of hydrogen, halogen, and OH; R 20 is selected from the group consisting of hydrogen, halogen, and OH; R 21 is selected from the group consisting of hydrogen, halogen, and OH.

[0063] In one aspect of the compounds described herein, the halogen is Cl.

[0064] In one aspect of the compounds described herein, R 1 teeth, [ka] and R 2 , R 3 , and R 4 is H. In another embodiment, n1 is 1. In a further embodiment, n1 is 3.

[0065] In another embodiment of the compounds described herein, R 1 teeth, [ka] and R 2 , R 3 , and R 4 is H. In another embodiment, n3 is 0 and X 1 is a bond, and Y 1 is C(O) and R 5 is Cl and R 6 is OH and R 7 is OH. In further embodiments, n2 is 1, 2, 3, 4, 5, 6, or 7.

[0066] In one aspect of the compounds described herein, R 1 teeth, [ka] and R 2 , R 3 , and R 4 is H. In another embodiment, n3 is 0 and X 1 is a bond, and Y 1 is C(O) and R 5 is OH and R 6 is OH and R 7 is H. In a further embodiment, n2 is 2 or 3.

[0067] In one aspect of the compounds described herein, R 1 teeth, [ka] and R 2 , R 3 , and R 4 is H. In another embodiment, n2 is 1 and X 1 teeth, [ka] and Y 1 is C(O) and R 5 is OH and R 6 is OH and R 7 is H. In a further embodiment, n3 is 1 or 2.

[0068] In another embodiment of the compounds described herein, R 1 teeth, [ka] and R 2 , R 3 , and R 4 is H. In another embodiment, n3 is 0 and X 1 is a bond, and Y 1 is SO2 and R 5 is H and R 6 is OH and R 7 is OH. In a further embodiment, n2 is 2 or 3.

[0069] In one aspect of the compounds described herein, R 1 teeth, [ka] and R 2 , R 3 , and R 4 is H. In another embodiment, n2=2, n3=1, X 1 teeth, [ka] and Y 1 is C(O) and R 5 is Cl and R 6 is OH and R 7 is OH.

[0070] In one aspect of the compounds described herein, R 1 teeth, [ka] and R 2 , R 3 , and R 4 is H. In another embodiment, Y 2 is C(O) and R 8 is Cl and R 9 is OH and R 10 is OH. In a further embodiment, n4=1 or 2.

[0071] In another embodiment of the compounds described herein, R 1 teeth, [ka] and R 2 , R 3 , and R 4 is H. In another embodiment, n4=2 and Y 2 is SO2 and R 8 is H and R 9 is OH and R 10 is OH.

[0072] In one aspect of the compounds described herein, R 1 teeth, [ka] and R 2 , R 3 , and R 4 is H. In a further embodiment, n5=2 or 3.

[0073] In one aspect of the compounds described herein, R 1 is OH and R 2 teeth, [ka] and R 3 and R 4 is H. In another embodiment, n7=0 and X 2 is a bond, and Y 3 is C(O) and R 11 is Cl and R12 is OH and R 13 is OH. In a further embodiment, n6=2 or 3.

[0074] In one aspect of the compounds described herein, R 1 is OH and R 2 teeth, [ka] and R 3 and R 4 is H. In another embodiment, n6=1, n7=0, and X 2 is a bond, and Y 3 is C(O) and R 11 is OH and R 12 is OH and R 13 is H.

[0075] In one aspect of the compounds described herein, R 1 is OH and R 2 teeth, [ka] and R 3 and R 4 is H. In another embodiment, n6=1, n7=0, and X 2 is a bond, and Y 3 is SO2 and R 11 is H and R 12 is OH and R 13 is H.

[0076] In another embodiment of the compounds described herein, R 1 is OH and R 2 teeth, [ka] and R 3 and R 4 is H. In another embodiment, n6=2, n7=1, and X 2 teeth, [ka] and Y 3 is C(O) and R 11 is Cl and R 12 is OH and R 13 is H.

[0077] In one aspect of the compounds described herein, R 1 is OH and R 3 teeth, [ka] and R 2 and R 4 is H. In another embodiment, n9=0 and X 3 is a bond and R 14 is Cl and R 15 is OH and R 16 is OH and R 17 is H and R 18 is H. In a further embodiment, n8=1 or 2.

[0078] In one aspect of the compounds described herein, R 1 is OH and R 3 teeth, [ka] and R 2 and R 4 is H. In another embodiment, n8=2, n9=3, and X 3 teeth, [ka] and R 14 is H and R 15 is H and R 16 is OH and R 17 is OH and R 18 is Cl.

[0079] In another embodiment of the compounds described herein, R 1 is OH and R 4 teeth, [ka] and R 2 and R 3 is H. In another embodiment, n 10 = 1, and n 11 = 0, and X 4 is a bond and R 19 is Cl and R 20 is OH and R 21 is OH and R 22 is H and R 23 is H.

[0080] In one aspect of the compounds described herein, R 1 is OH and R 4 teeth, [ka] and R 2 and R 3 is H. In another embodiment, n 10 = 1, and n 11 = 3, and X 4 teeth, [ka] and R 19 is H and R 20 is H and R 21 is OH and R 22 is OH and R 23 is Cl.

[0081] In one embodiment, the following: [ka] [ka] [ka] [ka] [ka] [ka] 10. A compound of the present disclosure selected from the group consisting of:

[0082] The following definitions are meant to clarify, not limit, the defined terms. If a particular term used herein is not specifically defined, such term should not be considered indefinite. Rather, the term is used within its accepted meaning.

[0083] As used throughout this specification, preferred numbers of atoms, such as carbon atoms, are indicated by, for example, "C x-y The term "alkyl" refers to an alkyl group, as defined herein, containing a specified number of carbon atoms ranging from x to y. Similar terms apply to other preferred terms and ranges. Thus, for example, C 1-4 Alkyl refers to a straight or branched chain hydrocarbon containing 1 to 4 carbon atoms.

[0084] As used herein, the term "alkyl," alone or in combination with any other term, refers to a straight or branched chain hydrocarbon. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, tert-butyl, sec-butyl, iso-pentyl, n-pentyl, n-hexyl, and the like.

[0085] As used herein, the term "aryl" refers to a single benzene ring, a fused, bridged, or spirocyclic benzene ring system, which may be optionally substituted, with multiple degrees of substitution permitted. Examples of "aryl" groups used include, but are not limited to, phenyl, 2-naphthyl, 1-naphthyl, anthracene, and phenanthrene. Preferred aryl rings have 5 to 10 members.

[0086] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0087] Pharmaceutically Acceptable Salts and Compositions As described herein, the present disclosure provides compounds that are antibiotics, and therefore the compounds of the present invention are useful for treating diseases, disorders, and conditions, including but not limited to, killing bacteria or inhibiting, reducing, or preventing the growth of bacteria, by contacting the bacteria with a compound defined herein. Accordingly, in another aspect of the present disclosure, pharmaceutically acceptable compositions are provided, which comprise any of the compounds described herein and optionally include a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

[0088] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio. "Pharmaceutically acceptable salt" means any non-toxic salt or ester salt of a compound of the present disclosure that, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present disclosure.

[0089] It will also be understood that certain compounds of the present disclosure may exist in free form for treatment, or, if desired, as a pharmaceutically acceptable derivative thereof. In accordance with the present disclosure, a pharmaceutically acceptable derivative includes, but is not limited to, a pharmaceutically acceptable salt, ester, salt of such an ester, or any other adduct or derivative that is capable of directly or indirectly providing a compound as otherwise described herein, or a metabolite or residue thereof, upon administration to a subject in need thereof.

[0090] Typically, but not necessarily, the salts of the present disclosure are pharmaceutically acceptable salts. The salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of the present disclosure. The salts of the compounds of the present disclosure may include acid addition salts. Representative salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, calcium edetate, camsylate, carbonate, clavulanate, citrate, dihydrochloride, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolyl arsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, and laurate. , malate, maleate, mandelate, mesylate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, acetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, triethiodide, trimethylammonium, and valerate. Other salts that are not pharmaceutically acceptable may be useful in the preparation of compounds of the present disclosure and these should be considered to form a further aspect of the present disclosure.

[0091] Also included are salts of amino acids such as arginates, and salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge, SM et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66:1-19). Certain compounds of the present disclosure contain both basic and acidic functional groups that allow the compounds to be converted into either base or acid addition salts.

[0092] "Salt thereof" refers to a compound in which a hydrogen of an acid has been replaced by a cation, such as a metal cation or an organic cation. Preferably, the salt is a pharmaceutically acceptable salt, although this is not necessary for salts of intermediate compounds that are not intended for administration to a patient.

[0093] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to the parent form of the compound for purposes of this disclosure.

[0094] In addition to salt forms, the present disclosure provides compounds in the form of prodrugs. Prodrugs of the compounds described herein are compounds that can easily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. Additionally, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment.

[0095] In one aspect, the disclosure features a pharmaceutical composition including a compound of the disclosure and a pharmaceutically acceptable carrier.

[0096] In another aspect, the disclosure features a pharmaceutical composition including a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, of the compound, and one or more pharmaceutically acceptable carriers or vehicles. Uses of compounds and pharmaceutically acceptable salts and compositions

[0097] The present disclosure provides compounds that kill bacteria or inhibit, reduce, or prevent their growth, which includes contacting the bacteria with the compounds defined herein.Bacterial infection refers to bacteria that reside and / or replicate in the body of a subject.Therefore, this term encompasses any disease, disorder, pathology, symptom, clinical state, or syndrome in which bacteria act as a pathogenic agent, or that can be associated with, detected, or involved in infection by one or more bacterial strains.

[0098] As used herein, the term "bacterial infection" is used to define the condition in which a subject is infected with bacteria. Infection can be symptomatic or asymptomatic. In the latter case, a subject can be identified as infected based on various tests, including, for example, biochemical tests, serological tests, microbial culture and / or microscopy.

[0099] One embodiment of the present disclosure relates to a method of controlling, treating, or reducing the progression, severity, or effects of a bacterial infection in a patient, comprising administering to the patient a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof.

[0100] As used herein, the term "patient" refers to a human or animal (more typically a mammalian) subject. A patient may be a patient in need of a composition or method described herein. "In need" may mean that the patient has or has been diagnosed with an infection, such as a bacterial infection, or that the patient is at risk of contracting an infection due to injury, medical or surgical procedure, or microbial exposure, or may be in a position that may expose the patient to such exposure.

[0101] As used herein, "treating" or "treatment" refers to treating or the treatment of a disease or condition (e.g., viral, bacterial, or fungal infections or other infectious diseases, as well as autoimmune or inflammatory conditions) in a patient, e.g., a mammal (particularly a human or companion animal), including ameliorating the disease or condition, i.e., causing elimination or regression of the disease or condition in the patient, inhibiting the disease or condition, i.e., slowing or arresting the onset of the disease or condition in the patient, or alleviating the symptoms of the disease or condition in the patient.

[0102] Additionally, the term "treatment" or "treating" refers to an intervention (e.g., administration of a drug to a subject) that prevents or slows the onset or progression of a disease, or reduces (or eradicates) its occurrence in a treated population. In this instance, the term treatment may be used interchangeably with the term "prophylaxis."

[0103] According to another embodiment, the present disclosure provides a method of reducing or inhibiting bacterial load in a biological sample, the method comprising contacting the biological sample with a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0104] The term "biological sample," as used herein, includes cell cultures or extracts thereof, biopsies or extracts thereof obtained from mammals, and blood, saliva, urine, feces, semen, tears, or other bodily fluids or extracts thereof. The term "biological sample" also includes living organisms, in which case "contacting a compound of the present disclosure with a biological sample" is synonymous with "administering the compound to a mammal for a composition comprising the compound."

[0105] The compound of the present disclosure, or its pharmaceutical salt, can be formulated into pharmaceutical compositions for administration to animals or humans.Therefore, another embodiment described herein is a pharmaceutical composition that is effective for treating or preventing bacterial infection, and can comprise a compound of formula (I) in an amount sufficient to measurably reduce bacterial load, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.The term "measurably reduce bacterial load" as used herein refers to the measurable change in bacterial count between a sample containing any one of the compounds described herein and a sample that does not contain the compound.

[0106] According to another embodiment, the method of the present disclosure is useful for treating patients in the field of veterinary medicine, including but not limited to zoo, laboratory, human companion, and farm animals, including primates, rodents, reptiles, and birds, including but not limited to guinea pigs, hamsters, otters, rats, mice, rabbits, dogs, cats, horses, pigs, sheep, cows, goats, deer, rhesus monkeys, monkeys, tamarinds, apes, baboons, gorillas, chimpanzees, orangutans, gibbons, ostriches, chickens, turkeys, ducks, and geese.

[0107] According to another embodiment, the present disclosure provides a method for reducing or inhibiting the bacterial load of Acinetobacter baumannii and Escherichia coli in a biological sample, comprising contacting the biological sample with a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0108] The pharmaceutical compositions and methods of the present disclosure may be useful for controlling bacterial infections in vivo. Examples of bacterial organisms that may be controlled by the compositions and methods of the present disclosure include, but are not limited to, the following organisms: Staphylococcus aureus, Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumonia, Escherichia coli, and Neisseria gonorrhoeae.

[0109] Without intending to be bound by any particular theory, it is believed that the compounds provided herein are bacteriostatic or bactericidal in nature. The terms "bacteriostatic" and "bactericidal" are technical terms used to define the ability to prevent (or reduce the rate of) bacterial growth and the ability to mediate (directly or indirectly) the cell destruction of bacterial cells, respectively. These terms are not mutually exclusive, and many agents exert both bacteriostatic and bactericidal effects (in some cases, in a dose-specific or target-specific manner). Compounds contemplated by the present disclosure include, but are not limited to, the exemplary compounds provided herein and their salts.

[0110] For example, compounds of the present disclosure can act as potent antibacterial agents, and this activity can be further confirmed in minimum inhibitory concentration assays. Thus, the compounds provided herein are useful in pharmaceutical compositions, in methods for treating bacterial infections, and as controls in assays for identifying antibacterial compounds.

[0111] The term "minimum inhibitory concentration" or "MIC" defines the lowest concentration of a test compound required to inhibit the growth of a bacterial isolate in vitro. A common method for determining the MIC of an antibiotic is to prepare several tubes containing serial dilutions of the test compound and then inoculate them with the bacterial isolate of interest. After incubation at the appropriate atmosphere and temperature, the MIC of the antibiotic can be determined from the tube with the lowest concentration that does not exhibit turbidity.

[0112] Therapeutic Compositions In another aspect, the present disclosure provides compositions that exhibit antibacterial activity. Generally, compositions for antibacterial use in humans and animals include a pharmaceutically acceptable excipient or diluent and a compound having formula (I).

[0113] The term "composition," as used herein, is intended to encompass a product containing the specified ingredients in the specified amounts, and any product resulting, directly or indirectly, from combining the specified ingredients in the specified amounts. "Pharmaceutically acceptable" means the carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0114] The pharmaceutical composition for administering the compound of the present disclosure can be conveniently presented in unit dosage form and can be prepared by any method known in the art of pharmacy.All methods include the step of associating active ingredient with carrier that constitutes one or more accessory ingredients.Generally, pharmaceutical composition is prepared by associating active ingredient with liquid carrier or finely divided solid carrier or both uniformly and intimately, and then, if necessary, shaping product into desired formulation.Pharmaceutical composition contains the active target compound in an amount sufficient to produce the desired effect on disease process or condition.

[0115] The pharmaceutical composition containing the active ingredient can be in a form suitable for oral use, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions and self-emulsifying formulations such as those described in U.S. Patent No. 6,451,339, hard or soft capsules, or in the form of syrups or elixirs.Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions.Such compositions can contain one or more agents selected from sweeteners, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically attractive and palatable preparation.Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients can be, for example, inert diluents such as cellulose, silicon dioxide, aluminum hydroxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as PVP, cellulose, PEG, starch, gelatin, or acacia, and lubricants such as magnesium stearate, stearic acid, or talc. Tablets can be uncoated or enteric-coated or otherwise coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period of time. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate can be used. They can also be coated by the techniques described in U.S. Patent Nos. 4,256,108, 4,166,452, and 4,265,874 to form osmotic therapeutic tablets for controlled release.

[0116] The preparation for oral use can also be presented as hard gelatin capsule, and active ingredient is mixed with inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or presented as soft gelatin capsule, and active ingredient is mixed with water or oil medium such as peanut oil, liquid paraffin or olive oil.In addition, emulsion can be prepared with non-water-miscible ingredients such as oil, and stabilized with surfactant such as mono-diglyceride, PEG ester.

[0117] Aqueous suspensions contain the active substance in admixture with excipients suitable for the manufacture of aqueous suspensions.Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents can be naturally occurring phosphatides, for example, lecithin, or condensation products of alkylene oxides with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with fatty acids and partial esters derived from hexitol, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with fatty acids and partial esters derived from hexitol anhydrides, for example, polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0118] Oily suspension can be prepared by suspending active ingredients in vegetable oil, such as peanut oil, olive oil, sesame oil or coconut oil, or mineral oil such as liquid paraffin.Oily suspension can contain thickening agent, such as beeswax, hard paraffin or cetyl alcohol.Sweetener, such as the above-mentioned sweetener, and flavoring agent can be added to provide a pleasant oral preparation.These compositions can be preserved by adding antioxidants such as ascorbic acid.

[0119] Dispersible powders and granules suitable for preparing an aqueous suspension by adding water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives.Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.Additional excipients, such as sweeteners, flavoring agents, and coloring agents, may also be present.

[0120] The pharmaceutical composition of the present disclosure can also be in the form of an oil-in-water emulsion.The oily phase can be vegetable oil, such as olive oil or peanut oil, or mineral oil, such as liquid paraffin, or their mixture.Suitable emulsifiers can be naturally occurring gums, such as gum acacia or gum tragacanth, naturally occurring phosphatides, such as soybean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and the condensation products of this partial ester with ethylene oxide, such as polyoxyethylene sorbitan monooleate.Emulsions can also contain sweeteners and flavoring agents.

[0121] Syrups and elixirs can be formulated with sweeteners, such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations can also contain one or more of a demulcent, a preservative, a flavoring agent, and a coloring agent. Oral solutions can be prepared in combination with, for example, cyclodextrin, PEG, and a surfactant.

[0122] The pharmaceutical composition may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to known techniques using the above-mentioned suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland fixed oil, including synthetic monoglycerides or diglycerides, may be used. In addition, fatty acids such as oleic acid are useful in the preparation of injectables.

[0123] The compound of the present disclosure can be administered in the form of suppositories for rectal administration of drugs.These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at normal temperature but liquid at rectal temperature, so that it melts in the rectum and releases the drug.Such materials are cocoa butter and polyethylene glycol.In addition, the compound can be administered via ocular delivery using a solution or ointment.In addition, transdermal delivery of the target compound can be achieved using iontophoretic patches, etc.

[0124] For topical use, creams, ointments, jellies, solutions or suspensions containing the compounds of the present disclosure are used.As used herein, topical application is also intended to include the use of mouthwashes and gargles.

[0125] The pharmaceutical compositions and methods of the present disclosure may further include other therapeutically active compounds as described herein, such as those applied in the treatment of the pathological conditions mentioned above.

[0126] In one embodiment, the disclosure provides a composition comprising a pharmaceutically acceptable carrier and a compound of the disclosure.

[0127] Pharmaceutical manufacturing In one aspect, the present disclosure provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating a bacterial infectious disease, hi another aspect, the bacterial infection can be from a gram-negative or gram-positive bacterium.

[0128] In yet another aspect, the disclosure provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or reducing the severity of a bacterial infection in a subject having such an infection.

[0129] Administration of pharmaceutically acceptable salts and compositions. In yet another aspect, the present disclosure provides a method for treating a bacterial infection, comprising administering any of the compounds or compositions of the present disclosure to a patient in need thereof. This method finds broad applicability in the treatment of any Gram-positive or Gram-negative bacterial infection or disease. The terms Gram-positive and Gram-negative bacteria are terms of art that define specific classes of bacteria that are grouped together based on certain cell wall staining characteristics.

[0130] In one embodiment, the bacteria include gram-positive or gram-negative bacteria. Exemplary gram-negative bacteria include, but are not limited to, Acinetobacter baumannii, Escherichia coli, Klebsiella pneumonia, Haemophilus influenza, Helicobacter pylori, Bordatella pertussis, Pseudomonas aeruginosa, Neisseria gonorrhoeae, or Chlamydia trachomatis. Exemplary gram-positive bacteria include, but are not limited to, Staphylococcus aureus, Group A streptococcus, Mycobacterium tuberculosis, Bacillus coagulans, Listeria monoctyogenes, Clostridium botulinum, or Lactobacillus acidophilus. In one embodiment, the gram-negative bacteria include Acinetobacter baumannii or Escherichia coli.

[0131] For use in therapy, a therapeutically effective amount of the compounds of formula (I), and salts or solvates thereof, may be administered as the raw chemical. Additionally, the active ingredient may be presented as a pharmaceutical composition.

[0132] In certain embodiments of the present disclosure, an "effective amount" of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition is an amount effective to kill, inhibit, reduce, or prevent the growth of bacteria, which involves contacting the bacteria with a compound as defined herein.

[0133] As used herein, the term "effective amount" refers to an amount of a drug or agent that will elicit the biological or medical response in a tissue, system, animal, or human that is being sought, for example, by a researcher or clinician. The term "therapeutically effective amount" refers to any amount that results in the treatment, cure, prevention, or amelioration of a disease, disorder, or side effect, or a reduction in the rate of progression of a disease or disorder, compared to a corresponding subject not receiving such amount. The term also includes within its scope an amount effective to enhance normal physiological function.

[0134] Accordingly, the present disclosure further provides pharmaceutical compositions comprising an effective amount of one or more compounds of formula (I), or salts or solvates thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The compounds of formula (I), or salts or solvates thereof, are as described herein. The carrier(s), diluent(s), or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the composition and not harmful to the recipient of the pharmaceutical composition.

[0135] The therapeutically effective amount of a compound of the present disclosure will depend on many factors. For example, the recipient's species, age, and weight, the exact condition requiring treatment and its severity, the nature of the composition, and the route of administration are all factors to be considered. The therapeutically effective amount can be at the discretion of the attending physician or veterinarian. Nevertheless, an effective amount of a compound of Formula (I) for treating a human suffering from a bacterial infection or disease will generally be within the range of 0.1 to 100 mg / kg of recipient (mammal) body weight per day. An effective amount can also be within the range of 0.1 to 20 mg / kg of recipient (mammal) body weight per day. Thus, for a 70 kg adult mammal, an example of an actual amount per day would be 10 mg to 2000 mg. This amount can be given in a single dose per day or in multiple (2, 3, 4, 5, or more, etc.) partial doses per day that provide the same total daily dose. An effective amount of a salt or solvate thereof can be determined as a percentage of the effective amount of the compound of Formula (I) itself. Similar dosages should be appropriate for treating other conditions mentioned herein. Pharmaceutical compositions can be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such units can contain, by way of non-limiting example, 1 mg to 2 g of a compound of formula (I), depending on the condition being treated, the route of administration, and the age, weight, and condition of the patient. Preferred unit dosage compositions are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of the active ingredient, as recited herein above. Such pharmaceutical compositions can be prepared by any method well known in the art of pharmacy.

[0136] The compound of the present disclosure or its salt or solvate can be used alone or in combination with other therapeutic agents.Exemplary additional therapeutic agents include but are not limited to one or more of the active pharmaceutical ingredients of cold, cough, allergy, nasal decongestant, antitussive, expectorant, antihistamine, stimulant, sedative, anti-inflammatory, antibiotic, antiviral, antiasthma, antimigraine, hypnotic, narcotic analgesic or narcotic antagonist, or further combinations thereof.

[0137] As used herein, the term "combination," when applied to two or more compounds and / or agents (also referred to herein as components), is intended to define a material in which the two or more compounds / agents are associated. The terms "combined" and "combining" in this context should be interpreted accordingly.

[0138] As used herein, the term "combination therapy" is intended to define a therapy that includes the use of a combination of two or more compounds / agents. Accordingly, references in this application to "combination therapy," "combination," and the use of "combined" compounds / agents may refer to compounds / agents administered as part of the same overall treatment regimen. As such, the posology of each of the two or more compounds / agents may differ, and each may be administered simultaneously or at different times. Therefore, it should be understood that the compounds / agents of a combination may be administered sequentially (e.g., before or after) or simultaneously, either in the same pharmaceutical formulation (i.e., together) or in different pharmaceutical formulations (i.e., separately). Simultaneous administration in the same formulation is a single formulation, while simultaneous administration in different pharmaceutical formulations is a non-single formulation. The posology of each of the two or more compounds / agents in a combination therapy may also differ with respect to the route of administration.

[0139] The compound of formula (I) and other pharmaceutically active agent(s) can be administered together or separately, and when administered separately, administration can be simultaneous or sequential in any order. The amounts of the compound of formula (I) and other pharmaceutically active agent(s) and the relative timing of administration can be selected to achieve the desired combined therapeutic effect. The combined administration of the compound of formula (I) or its salt or solvate and other therapeutic agents can be a combination by simultaneous administration in: (1) a single pharmaceutical composition containing the combination of compounds, or (2) separate pharmaceutical compositions each containing one of the compounds. Alternatively, the combination can be administered separately in a sequential manner, where one therapeutic agent is administered first and the other is administered second, or vice versa. Such sequential administration can be close in time or distant in time.

[0140] The compounds and compositions of the present disclosure can be combined with other compounds and compositions or therapeutic agents with related utility to prevent and treat target conditions or diseases, such as bacterial infections and diseases.The selection of appropriate therapeutic agents for use in combination therapy can be performed by those skilled in the art.The combination of therapeutic agents can act synergistically to treat or prevent various disorders.Using this approach, it may be possible to achieve therapeutic efficacy with lower dosages of each drug, thereby reducing the possibility of adverse side effects.

[0141] The compounds of Formula (I) can be administered with other antibiotics to enhance the therapeutic or prophylactic effects against various bacterial infections. When the compounds of the present disclosure are administered in combination with other drugs, they can be administered sequentially or simultaneously to patients. Alternatively, pharmaceutical or prophylactic compositions according to the present disclosure include a combination of a compound of Formula (I) and another therapeutic or prophylactic agent. Exemplary additional therapeutic agents include, but are not limited to, antibiotics selected from natural penicillins, penicillinase-resistant penicillins, antipseudomonal penicillins, aminopenicillins, first-generation cephalosporins, second-generation cephalosporins, third-generation cephalosporins, fourth-generation cephalosporins, carbapenems, cephamycins, quinolones, fluoroquinolones, aminoglycosides, macrolides, ketolides, polymyxins, tetracyclines, glycopeptides, streptogramins, oxazolidinones, rifamycins, or sulfonamides.

[0142] Probiotic therapy has been suggested to improve immune system responses in patients with intestinal infections, for example, intravenous immunoglobulin (J. Antimicrob. Chem., 2004, 53, 882-884) can be used to treat patients, especially recurrent cases where any additional antimicrobial treatment further exacerbates intestinal dysbiosis. Thus, the compounds of the present disclosure can be used adjunctively with various immunoglobulins.

[0143] In some embodiments, compounds of formula (I) may be used prophylactically to prevent bacterial infections. In some embodiments, compounds of formula (I) may be used before, during, or after dental or surgical procedures to prevent opportunistic infections.

[0144] The term "preventing bacterial infection," as used herein, unless otherwise specified, refers to the prophylactic use of antibiotics and other compounds of the present disclosure to prevent bacterial infection. Antibiotic treatment can be administered prophylactically to prevent infections caused by organisms susceptible to the antibiotics of formula (I). One common set of conditions for which prophylactic treatment may be considered is when an individual is more vulnerable to infection due to, for example, a weakened immune system, surgery, trauma, the presence of an artificial device in the body (temporary or permanent), an anatomical defect, exposure to high levels of bacteria, or potential exposure to disease-causing pathogens. Examples of factors that may lead to a weakened immune system include chemotherapy, radiation therapy, diabetes, elderly people, HIV infection, and transplants. An example of an anatomical defect is a defective heart valve, which increases the risk of bacterial endocarditis. Examples of artificial devices include artificial joints, surgical pins, catheters, etc. Another set of situations in which the prophylactic use of antibiotics may be appropriate is to prevent the spread of pathogens between individuals (directly or indirectly).

[0145] One embodiment of the present disclosure includes a method of treating a bacterial infection comprising administering to a subject an effective amount of any compound described herein or a pharmaceutically acceptable salt thereof, or a composition described herein. An aspect of the embodiment includes a method wherein the bacterial infection being treated results from a gram-positive or gram-negative bacterium. A further aspect of this embodiment includes a method wherein the bacterial infection results from Acinetobacter baumannii and Escherichia coli.

[0146] One embodiment of the present disclosure includes a method of treating a bacterial infection comprising administering to a subject an effective amount of any compound described herein or a pharmaceutically acceptable salt thereof, or a composition described herein, in combination with another therapeutic agent. [Example]

[0147] chemistry The synthesis of the siderophore building blocks is shown in Scheme 1. Five siderophore groups were selected, each classified into two types: catecholates and 3-hydroxypyridones. Generally, amide bonds with different aliphatic or PEGylated linkers were formed via coupling reactions (i, iii, iv, vi), followed by removal of the protecting group with BBr3 or HCl (ii, v). For the azide-containing building blocks, the NH2 functionality was converted to an azide using imidazole-1-sulfonyl azide (vii). For the synthesis of the aldehyde building blocks, the alcohol was oxidized to the aldehyde with Dess-Martin periodinane (viii), followed by treatment with BBr3 to remove the methyl group on the phenol (ii). [ka]

[0148] Scheme 1. Synthesis of siderophore building blocks. Reagents and conditions: i) N-Boc-diamine, HATU, DIPEA, DCM; ii) BBr3, DCM, -78 °C, 30 min, then warmed to room temperature, 30 min; iii) N-Boc-diamine, toluene, microwave irradiation, 170 °C, 10 min; iv) N-Boc-1,2-diaminoethane, HOBT, EDC-HCl, TEA, THF, room temperature, 24 h; v) 4 M HCl in dioxane, room temperature, 40 min; vi) N-Boc-diamine, DIPEA, DCM; vii) imidazole-1-sulfonyl azide HCl salt, CuSO4·5H2O, K2CO3, MeOH; viii) Dess-Martin periodinane, DCM, room temperature, 2 h.

[0149] The synthesis of target compounds 1–18, 20, and 21 is shown in Scheme 2. Site-specific amide coupling was utilized for C-terminal modification of the vancomycin scaffold after obtaining the above amine building blocks, which afforded the targeted vancomycin-siderophore conjugates and the corresponding alkynyl intermediates. [ka]

[0150] Scheme 2. Synthesis of targets 1–18, 20, 21 and C-terminally modified alkynyl intermediates. Reagents and conditions: i) HATU, DIPEA, DMF / DMSO, room temperature, 30 min–2 h.

[0151] The synthesis of target compounds 22–25 is shown in Scheme 3. Using the Mannich reaction, the resorcinol (R) position was selectively modified to give the corresponding vancomycin-siderophore conjugates as well as alkynyl-containing intermediates. [ka]

[0152] Scheme 3. Synthesis of targets 22-25 and R-modified alkynyl intermediates. Reagents and conditions: i) HCHO, DIPEA, H2O / CH3CN, -10 °C, 12-24 h.

[0153] The synthesis of target compounds 28–29 is shown in Scheme 4. The specific vancosamine (V) position modification was achieved by a two-step reductive amination reaction, first forming the imine of the C–N double bond under basic conditions, followed by reduction with NaCNBH3 under acidic conditions. [ka]

[0154] Scheme 4. Synthesis of targets 28-29 and alkynyl intermediates modified at the V position. Reagents and conditions: i) (a) DIPEA, DMF, 50 °C, 1 h, (b) NaCNBH3, MeOH, TFA, DMF, room temperature, 3 h.

[0155] The synthesis of target compound 30 is shown in Scheme 5. The N-terminus was specifically modified by aqueous acid reductive amination reaction to give vancomycin conjugate 30 and an N-terminally modified alkynyl intermediate. [ka]

[0156] Scheme 5. Synthesis of target 30 and N-terminally modified alkynyl intermediates. Reagents and conditions: i) NaCNBH3, AcOH-H2O-CH3CN (1:2:2), 70 °C, 7 h.

[0157] The synthesis of target compounds 14, 15, 19, 26, 27, 31, and 32 is shown in Scheme 6. Click reaction was applied to generate triazole linkages to give the corresponding vancomycin-siderophore conjugates. The linker length and siderophore moiety were varied for each target compound. [ka]

[0158] Scheme 6. Synthesis of targets 14, 15, 19, 26, 27, 31, and 32 bearing triazole linkages. Reagents and conditions: i) Azide building block, NaHCO3, CuSO5·5H2O, sodium ascorbate, H2O / t-BuOH, room temperature, 2 h.

[0159] experiment All solvents and chemicals were reagent grade. Unless otherwise stated, all reagents and solvents were purchased from commercial vendors and used as received. Flash column chromatography was performed on a Teledyne ISCO CombiFlash® Rf system using pre-packed silica gel columns to obtain the required intermediates or building blocks. Analytical RP-HPLC was used to monitor reaction progress, which was carried out on a VARIAN ProStar HPLC instrument (photodiode array detector) with a C18 column (XBridge®, 5 μm, 4.6 mm × 250 mm). The column was eluted with a gradient of 2 to 58.8% (or 2 to 90%) CH3CN containing 0.1% TFA over 20 min (or 30 min) at a flow rate of 1 mL / min. Preparative RP-HPLC was performed on a VARIAN ProStar HPLC instrument equipped with a photodiode array detector. An XBridge® Prep C18 5 μm OBD™ column (19 × 250 mm) was used with a gradient elution method of 2 → 58.8% (or 2 → 90%) CH3CN containing 0.1% TFA in 20 min (or 30 min) at a flow rate of 7 mL / min.

[0160] Compound purity and characterization was established by a combination of NMR, mass spectrometry, TLC, and HPLC analysis. 1 H and 13C NMR spectra were recorded on a Bruker Avance DPX-300 (300 MHz) spectrometer and determined in CDCl3, DMSO-d6, or CD3OD with tetramethylsilane (TMS) (0.00 ppm) or the solvent peak as the internal reference. 20 μL of DO was added to exchange the active hydrogen of the target product when the solvent was DMSO-d6. Chemical shifts are reported in ppm relative to the reference signal, and coupling constant (J) values ​​are reported in hertz (Hz). High-resolution mass spectrometry (HRMS) was obtained using an Agilent 1290 Infinity UHPLC-6230 TOF mass spectrometer (ESI). Nominal mass spectra were obtained using an Agilent InfinityLab MSD single quadrupole mass spectrometer system (ESI). Thin-layer chromatography (TLC) was performed on EMD-precoated silica gel 60 F254 plates, and spots were visualized with UV light or iodine staining.

[0161] All final compounds were greater than 95% pure as determined by HPLC on a Waters 2695 Separation Module equipped with a Waters 2996 Photodiode Array Detector and a Phenomenex Synergi 4 mm Hydro-RP 80A C18 250 × 4.6 mm column using a 1 mL / min flow rate starting with 5% solvent B, followed by a 15 min gradient of 5 to 95% solvent B, followed by 9 min of 95% solvent B (Solvent A, water with 0.1% TFA; Solvent B, acetonitrile with 0.1% TFA and 5% water; absorbance monitored at 280 nm).

[0162] Example 1: Synthesis of Compounds 33-50 (Scheme 1) To a mixture of 2-chloro-3,4-dimethoxybenzoic acid (650 mg, 3 mmol) and N-Boc-diamine (3.3 mmol) in DCM (20 mL), DIPEA (1 mL, 6 mmol) and HATU (1.5 g, 3.9 mmol) were added sequentially. The mixture was stirred at room temperature for 2 h until no progress was observed by TLC. DCM (30 mL) was then added and washed with HO (50 mL) to remove hydrophilic by-products. The collected DCM layers were concentrated and purified by flash chromatography to give the corresponding intermediates 33–41. Deprotection was carried out using BBr3 in DCM. To a stirred solution of the above intermediate (1 g) in 10 mL of anhydrous DCM at −78 °C, 3 equivalents of a BBr3 solution (1 M in DCM) was added dropwise. The mixture was stirred at −78 °C for 30 min. It was then warmed to room temperature and stirred for another 30 min. After completion of the reaction, as detected by TLC and LCMS, the reaction was quenched with MeOH (20 mL) at 0 °C. The resulting mixture was concentrated. Ether was added to the residue, and the solution was left for 48 h. If no crystals precipitated, vacuum drying was used to obtain the deprotected product. The HBr salts of siderophore components 42–49 were obtained as off-white solids or light brown hygroscopic residues. Compound 50 was purified by RP-C18 Prep-HPLC to obtain the corresponding TFA salt.

[0163] compound 33 [ka] 1 H NMR(300MHz,CDCl3)δ 7.41(d,J=8.7Hz,1H),6.84(d,J=8.7Hz,1H),6.79(s,1H),5.01(s,1H),3.90 (s,3H),3.85(s,3H),3.64-3.47(m,2H),3.38(q,J=5.9Hz,2H),1.43(s,9H).

[0164] compound 42 [ka] 1H NMR(300MHz,CD3OD)δ 6.96(d,J=8.3Hz,1H),6.77(d,J=8.3Hz,1H),3.62(t,J=6.2Hz,2H),3.16(t,J=6.3Hz,2H).

[0165] Compound 34

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[0166] Compound 43

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[0167] Compound 35

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[0168] Compound 44

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[0169] Compound 36

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[0170] Compound 45

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[0171] Compound 37

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[0172] Compound 46

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[0173] Compound 38

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[0174] Compound 47

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[0175] Compound 39

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[0176] Compound 48

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[0177] Compound 40

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[0178] Compound 49

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[0179] Compound 41

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[0180] Compound 50

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[0181] Synthesis of compounds 51-54 (Scheme 1) 5,6-Dimethoxyisobenzofuran-1,3-dione (300 mg, 1.44 mmol) and the respective N-Boc-diamine (1.1 equiv.) were mixed in 8 mL of toluene in a sealed tube, which was stirred and irradiated in a microwave reactor at 170 °C for 10 min. After cooling to room temperature, the solvent was removed under reduced pressure, followed by purification by flash chromatography (0 → 90% EtOAc in hexanes) to give the corresponding intermediates 51 and 52. The intermediates were then deprotected with BBr in DCM according to the procedure described above to give compounds 53 and 54 without further purification.

[0182] compound 51 [ka] 1 H NMR(300MHz,CDCl3)δ 7.30(s,2H),5.08(s,1H),3.72(t,J=6.5Hz,2H),3.13(q,J=6.4Hz,2H),1.82(p,J=6.4Hz,2H),1.44(s,9H).

[0183] compound 53 [ka] 1 H NMR(300MHz,D2O)δ 6.86(s,2H),3.77-3.37(m,2H),3.03(t,J=7.0Hz,2H),2.22-1.47(m,2H).

[0184] compound 52 [ka] 1 H NMR(300MHz,CDCl3)δ 7.30(s,2H),4.56(s,1H),3.65(t,J=7.0Hz,2H),3.16(q,J=6.6Hz,2H),1.80-1.63(m,2H),1.60-1.46(m,2H),1.43(s,9H).

[0185] compound 54 [ka] 1 H NMR(300MHz,CD3OD)δ 7.17(s,2H),3.64(t,J=6.2Hz,2H),2.99(t,J=7.0Hz,2H),1.90-1.40(m,4H).

[0186] Synthesis of compounds 55-60 (Scheme 1) compound 55 [ka] A solution of N-Boc-1,2-diaminoethane (1.27 mL, 8 mmol), 2,3-dihydroxybenzoic acid (616 mg, 4 mmol), and HOBT (648 mg, 4.8 mmol) in THF (10 mL) was stirred under N2 until homogeneous. After 5 min, TEA (1.67 mL, 12 mmol) was added, followed by EDC-HCl (2.3 g, 12 mmol). The reaction mixture was stirred for 24 h, and the solvent was removed under reduced pressure. The remaining residue was dissolved in 50 mL of DCM and washed with 1 N HCl, saturated NaHCO3, and brine. The DCM solution was concentrated, and the residue was purified by flash chromatography (0 → 5% MeOH in DCM) to give 55 as a white solid (300 mg, 25% yield).

[0187] 1 H NMR(300MHz,CDCl3)δ 12.88(s,1H),7.80(s,1H),7.07-6.92(m,2H),6.75(dd,J=9.4,6.6Hz,1H),4.99(s,1H),3.63-3.48(m,2H),3.43(q,J=5.9Hz,2H),1.44(s,9H).

[0188] compound 58 [ka] To compound 55 (300 mg, 1 mmol) was added 4 M HCl / dioxane (10 mL, 40 mmol). After stirring at room temperature for 40 min, the solvent was removed under reduced pressure to give compound 58 (190 mg, 97% yield) as an off-white powder solid.

[0189] 1 H NMR(300MHz,CD3OD)δ 7.17(d,J=8.0Hz,1H),6.86(d,J=7.8Hz,1H),6.64(t,J=7.9Hz,1H),3.64-3.57(m,2H),3.08(t,J=5.9Hz,2H).

[0190] Other members of this series with different aliphatic chain lengths were synthesized using the same procedure.

[0191] compound 56 [ka] 1 H NMR(300MHz,CDCl3)δ 7.91(s,1H),7.12(d,J=8.0Hz,1H),7.04(dd,J=7.9,1.4Hz,1H),6.88-6.65(m,1H),4.83 (s,1H),3.49(q,J=6.1Hz,2H),3.26(q,J=6.3Hz,2H),1.70(p,J=6.1Hz,2H),1.47(s,9H).

[0192] compound 59 [ka] 1 H NMR(300MHz,CD3OD)δ 7.24(dd,J=8.1,1.8Hz,1H),6.94(dd,J=7.9,1.8Hz,1H),6.73(td,J=8.0,2. 0Hz,1H),3.51(t,J=6.6Hz,2H),3.00(t,J=7.4Hz,2H),1.97(p,J=6.8Hz,2H).

[0193] compound 57 [ka] 1 H NMR(300MHz,CDCl3)δ 7.82(s,1H),7.26(dd,J=8.1,1.5Hz,1H),7.02(dd,J=7.9,1.5Hz,1H),6.78-6.52(m,1H) ,4.88(s,1H),3.53-3.36(m,2H),3.14(q,J=6.5Hz,2H),1.71-1.51(m,4H),1.43(s,9H).

[0194] compound 60 [ka] 1 H NMR(300MHz,CD3OD)δ 7.28(d,J=8.0Hz,1H),6.96(d,J=7.8Hz,1H),6.73(t,J=8.0Hz,1H),3.52-3.36(m,2H),3.24-2.80(m,2H),1.90-1.50(m,4H).

[0195] Synthesis of compounds 61-68 (Scheme 1) To a solution of 3,4-dimethoxybenzene-1-sulfonyl chloride (710 mg, 3 mmol) in DCM (10 mL), N-Boc-diamine (3.3 mmol, 1.1 equiv.) and DIPEA (950 μL, 6 mmol) were added sequentially and stirred at room temperature for 1 h until the reaction was complete by TLC detection. The mixture was then diluted with DCM, followed by washing with 1 N HCl, saturated NaHCO3, and brine, respectively. The resulting mixture was then dried over Na2SO4, concentrated, purified by flash chromatography, and finally dried in vacuo to give 61–63 and 67 in over 80% yield. The deprotection procedure was the same as described above for compounds 42–50 with BBr3 in DCM to give compounds 64–66 and 68.

[0196] compound 61 [ka] 1H NMR (300MHz, CDCl3)δ 7.47(dd,J=8.5,2.2Hz,1H),7.33(d,J=2.2Hz,1H),6.93(d,J=8.5Hz,1H),5.19(s,1H),4 .86(s,1H),3.94(s,3H),3.93(s,3H),3.26-3.17(m,2H),3.10-3.01(m,2H),1.42(s,9H).

[0197] Compound 64

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[0198] Compound 62

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[0199] Compound 65

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[0200] Compound 63

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[0201] Compound 66

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[0202] Compound 67

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[0203] Synthesis of Compounds 69~72 (スキーム1) A solution of N-Boc-diamine (1.2 mmol), 5-(benzyloxy)-4-oxo-1,4-dihydropyridine-2-carboxylic acid (245 mg, 1 mmol), and HOBT (648 mg, 4.8 mmol) in THF (10 mL) was stirred under N2 until homogeneous. After 5 min, TEA (418 μL, 3 mmol) was added, followed by EDC-HCl (383 mg, 2 mmol). The reaction mixture was stirred for 24 h, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (0→10% MeOH in DCM) to give intermediates 69 (12% yield) and 70 (14% yield). Deprotection was carried out using BBr3 (3 equiv.) in DCM and stirred at -78 °C for 30 min, then at room temperature for 30 min. After completion of the reaction as determined by LC-MS, the reaction was quenched with MeOH at 0 °C. The mixture was concentrated and dried under vacuum overnight to give siderophore components 71 and 72 as HBr salts.

[0204] compound 69 [ka] 1 H NMR(300MHz,CD3OD)δ 7.53-7.40(m,3H),7.43-7.23(m,4H),5.23(s,2H),3.39(t,J=6.8Hz,2H),3.10(t,J=6.7Hz,2H),1.73(p,J=6.9Hz,2H),1.42(s,9H).

[0205] compound 71 [ka] 1 H NMR(300MHz,D2O)δ 8.12(s,1H),7.63(s,1H),3.53(t,J=6.8Hz,2H),3.08(t,J=7.7Hz,2H),2.01(p,J=7.3Hz,2H).

[0206] compound 70 [ka] 1 H NMR(300MHz,CDCl3)δ 8.08(s,1H),7.93(d,J=6.4Hz,1H),7.81(s,1H),7.51-7.31(m,5H),5.23(s,2H),4.61 (s,1H),3.45(q,J=6.5Hz,2H),3.15(q,J=6.5Hz,2H),1.64-1.59(m,4H),1.43(s,9H).

[0207] compound 72 [ka] 1 H NMR(300MHz,CD3OD)δ 8.08(s,1H),7.85(s,1H),3.47(t,J=6.0Hz,2H),2.98(t,J=6.1Hz,2H),1.91-1.40(m,4H).

[0208] Synthesis of compounds 73-74 (Scheme 1) To a solution of siderophore building block 58 or 43 (0.4 mmol, 1 equiv.) in methanol (10 mL), imidazole-1-sulfonyl azide HCl salt (101 mg, 1.2 equiv.), CuSO 5HO (10 mg, 0.1 equiv.), and KCO (166 mg, 3 equiv.) were added sequentially. The mixture was stirred at room temperature for 2 h until reaction completion was detected by analytical HPLC and LCMS. The resulting cloudy gray mixture was quenched with TFA and purified by Prep-RP-HPLC to give the corresponding azidosiderophore building block 73 (10% yield) or 74 (55% yield). Note: Intermediate 73 was not pure enough for characterization and was used in the next step without further purification.

[0209] compound 74 [ka] 1H NMR(300MHz,CDCl3)δ 7.12(d,J=8.5Hz,1H),6.84(dd,J=8.4,0.9Hz,1H),6.34(s,1H),3.56(q,J=6.4Hz,2H),3.47(t,J=6.5Hz,2H),1.92(p,J=6.6Hz,2H).

[0210] Synthesis of compounds 75-80 (Scheme 1) To a stirred mixture of 2-chloro-3,4-dimethoxybenzoic acid (3 mmol, 1 equiv.) and amine (3.3 mmol, 1.1 equiv.) in DCM (20 mL), DIPEA (6 mmol, 2 equiv.) and HATU (3.9 mmol, 1.3 equiv.) were added. The mixture was stirred at room temperature for 2 h. After the reaction was complete, the mixture was concentrated and purified by flash chromatography to give compounds 75 and 76 (yield >80%). Next, Dess-Martin periodinane (2.5 equiv.) was added to a solution of primary alcohol (1 equiv.) in DCM (20 mL), followed by the addition of 100 μL of HO to accelerate the oxidation reaction. After the reaction was complete or had not progressed, the mixture was filtered to remove the resulting insoluble by-product and subsequently washed with a saturated aqueous NaHCO3 and NaSO3 mixture to remove any residual iodine by-product. The resulting DCM layer was dried over anhydrous NaSO and purified by flash chromatography to give compounds 77 and 78. Finally, demethylation was carried out using BBr (3 equiv.) in DCM and stirred at −78° C. for 30 min, then at room temperature for 30 min. The reaction was quenched with methanol, concentrated, and dried under vacuum to give crude components 79 and 80, which were used in the next step without purification.

[0211] compound 75 [ka] 1H NMR(300MHz,DMSO-d6)δ 8.22(t,J=5.5Hz,1H),7.17(d,J=8.5Hz,1H),7.06(d,J=8.6Hz,1H),3.85(s,3H),3.74(s,3H),3.48(t,J=6.3Hz,2H),3.26(q,J=6.2Hz,2H).

[0212] Compound 76

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[0213] Compound 77

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[0214] Compound 78

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[0215] Synthesis of target compounds 1–13, 16–18, 20–21 and intermediates 81–82 (Scheme 2). To a mixture of vancomycin hydrochloride (1 eq.) and a siderophore amine or alkynylamine (1.5 eq.) in DMF / DMSO (1:1) was added DIPEA (3 eq.). The mixture was stirred overnight at room temperature until clear and homogeneous. HATU (1 eq.) dissolved in DMF / DMSO (1:1) was then added dropwise to the mixture. The amount of HATU was optimized to avoid uronium byproducts. The reaction was monitored by analytical RP-HPLC. After approximately 1-2 h, the reaction was quenched with TFA until no progress was detected by HPLC analysis. The mixture was precipitated by dropwise addition of cold ether and then centrifuged. The upper ether layer was removed, and the precipitate was dissolved in CH3CN-HO for RP-HPLC purification. The target peak eluate was collected and lyophilized to obtain the target compound TFA salt as a white fluffy solid.

[0216] compound 1 [ka] Yield: 49%. HPLC R =8.719 minutes.

[0217] 1H NMR (300MHz, 20μL of D2O containing DMSO-d6)δ 8.70(s,1H),8.51(s,1H),7.97(s,1H),7.86(s,1H),7.61-7.51(m,3H),7.46(d ,J=8.4Hz,1H),7.33(d,J=8.4Hz,1H),7.24-7.18(m,2H),7.16(s,2H),6.84-6.6 2(m,3H),6.37(d,J=2.3Hz,1H),6.21(d,J=2.3Hz,1H),5.76(d,J=7.8Hz,1H),5. 60(s,1H),5.33-5.23(m,3H),5.18(s,2H),4.93(s,1H),4.68(d,J=6.8Hz,1H),4 .45(s,1H),4.35(d,J=5.3Hz,1H),4.29-4.11(m,2H),3.97(s,1H),3.68(d,J=10 .9Hz,1H),3.27(d,J=5.1Hz,2H),3.21-3.07(m,3H),3.06(s,1H),2.91(s,1H),2 .64(s,3H),2.15(d,J=12.9Hz,1H),1.91(d,J=12.0Hz,1H),1.80-1.54(m,6H),1 .30(s,3H),1.07(d,J=6.3Hz,3H),0.92(d,J=5.6Hz,3H),0.87(d,J=5.6Hz,3H);

[0218] C 77 H 85 Cl2N 11 O 27 [M+2H] 2+ The calculated HRMS (ESI) m / z value is 833.7570 and the measured value is 833.7566.

[0219] Compound 2

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[0220] 1H NMR (300MHz, 20μL of D2O containing DMSO-d6)δ 8.70(s,1H),8.44(s,1H),7.86(s,1H),7.63-7.49(m,2H),7.46(d,J=8.6Hz,1H ),7.40-7.31(m,1H),7.26-7.16(m,2H),7.15(s,2H),6.86-6.63(m,3H),6.52(d ,J=16.5Hz,1H),6.37(d,J=2.3Hz,1H),6.24(d,J=2.3Hz,1H),5.76(d,J=7.7Hz ,1H),5.60(s,1H),5.32-5.21(m,3H),5.19(d,J=4.6Hz,2H),4.93(s,1H),4.68( d,J=6.8Hz,1H),4.45(s,1H),4.38(d,J=5.6Hz,1H),4.31-4.10(m,2H),3.97(s ,1H),3.68(d,J=10.9Hz,1H),3.27(d,J=5.1Hz,2H),3.21-3.10(m,3H),2.64(s, 3H),2.16(d,J=11.2Hz,1H),1.91(d,J=11.4Hz,1H),1.77-1.51(m,6H),1.51-1 .35(m,2H),1.07(d,J=6.3Hz,3H),0.92(d,J=5.5Hz,3H),0.87(d,J=5.5Hz,3H);

[0221] C 78 H 87 Cl2N 11 O 27 [M+2H] 2+ The calculated value of HRMS (ESI) m / z is 840.7648, and the measured value is 840.7642.

[0222] Compound 3

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[0223] 1H NMR(300MHz,DMSO-d6)δ 8.71(s,1H),8.47(s,1H),8.35(s,1H),8.04(s,1H),7.86(s,1H),7.60-7.50(m,2 H),7.46(d,J=8.5Hz,1H),7.33(d,J=8.3Hz,1H),7.23-7.14(m,2H),6.85-6.69(m ,4H),6.37(d,J=2.3Hz,1H),6.25(d,J=2.3Hz,1H),5.76(d,J=7.8Hz,1H),5.60(s ,1H),5.30(s,1H),5.28-5.22(m,2H),5.22-5.15(m,2H),4.97-4.87(m,1H),4.68( d,J=6.7Hz,1H),4.45(s,1H),4.37(d,J=5.3Hz,1H),4.23(s,2H),4.03-3.91(m,1 H),3.68(d,J=10.9Hz,1H),3.37-3.21(m,5H),3.18(s,1H),2.94-2.83(m,1H),2.6 4(s,3H),2.16(dd,J=16.2,6.6Hz,1H),1.91(d,J=11.2Hz,1H),1.81-1.50(m,4H) ,1.30(s,3H),1.07(d,J=6.3Hz,3H),0.92(d,J=5.4Hz,3H),0.87(d,J=5.6Hz,3H);

[0224] C 75 H 84 Cl3N 11 O 26 [M+2H] 2+ The calculated HRMS (ESI) m / z value is 830.7401 and the measured value is 830.7401.

[0225] Compound 4

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[0226] 1H NMR (300MHz, DMSO-d6)δ 8.69(s,1H),8.49(s,1H),7.86(s,1H),7.60-7.49(m,2H),7.45(d,J=8.1Hz,1 H),7.33(d,J=8.3Hz,1H),7.19(d,J=8.1Hz,2H),6.83-6.59(m,5H),6.37(d,J= 2.3Hz,1H),6.27(d,J=2.3Hz,1H),5.76(d,J=7.8Hz,1H),5.60(s,1H),5.35-5. 22(m,3H),5.19(s,2H),4.93(s,1H),4.68(d,J=6.8Hz,1H),4.45(s,1H),4.37( d,J=5.3Hz,1H),4.29-4.14(m,2H),4.02-3.85(m,1H),3.68(d,J=10.8Hz,1H), 3.32-3.24(m,5H),3.23-3.12(m,2H),3.08-2.98(m,1H),2.98-2.82(m,1H),2. 64(s,3H),2.16(d,J=9.3Hz,1H),1.90(d,J=10.8Hz,1H),1.82-1.48(m,6H),1. 30(s,3H),1.07(d,J=6.3Hz,3H),0.91(d,J=5.4Hz,3H),0.86(d,J=5.6Hz,3H);

[0227] C 76 H 86 Cl3N 11 O 26 [M+2H] 2+ The calculated value of HRMS (ESI) m / z is 837.7479, and the measured value is 837.7480.

[0228] Compound 5

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[0229] 1H NMR(300MHz,DMSO-d6)δ 8.70(s,1H),8.45(s,1H),7.86(s,1H),7.60-7.50(m,2H),7.47(d,J=8.7H z,1H),7.34(d,J=8.3Hz,1H),7.26-7.12(m,2H),6.83-6.66(m,5H),6.37( d,J=2.2Hz,1H),6.27(d,J=2.3Hz,1H),5.76(d,J=7.8Hz,1H),5.60(s,1H) ,5.31-5.22(m,3H),5.19(s,2H),5.00-4.85(m,1H),4.68(d,J=6.7Hz,1H), 4.45(s,1H),4.40(d,J=5.5Hz,1H),4.29-4.10(m,2H),4.04-3.91(m,1H), 3.68(d,J=10.8Hz,1H),3.30-3.24(m,2H),3.25-3.07(m,5H),2.64(s,3H) ,2.15(d,J=12.7Hz,1H),1.91(d,J=12.1Hz,1H),1.83-1.44(m,8H),1.30( s,3H),1.07(d,J=6.3Hz,3H),0.92(d,J=5.6Hz,3H),0.87(d,J=5.7Hz,3H);

[0230] C 77 H 88 Cl3N 11 O 26 [M+2H] 2+ The calculated value of HRMS (ESI) m / z is 844.7557, and the measured value is 844.7558.

[0231] Compound 6

change

[0232] 1H NMR (300MHz, DMSO-d6)δ 8.70(s,1H),8.44(s,1H),7.86(s,1H),7.61-7.50(m,2H),7.47(d,J=9.5Hz ,1H),7.34(d,J=8.3Hz,1H),7.25-7.10(m,2H),6.82-6.65(m,5H),6.37(d,J =2.3Hz,1H),6.26(d,J=2.3Hz,1H),5.76(d,J=7.7Hz,1H),5.60(s,1H),5.31 -5.22(m,3H),5.19(s,2H),4.94(d,J=3.8Hz,1H),4.68(d,J=6.7Hz,1H),4.4 8-4.40(m,1H),4.39(d,J=5.5Hz,1H),4.30-4.12(m,2H),4.03-3.86(m,1H), 3.68(d,J=10.8Hz,1H),3.32-3.23(m,2H),3.23-3.08(m,5H),2.64(s,3H),2 .16(d,J=10.6Hz,1H),1.91(d,J=11.6Hz,1H),1.82-1.42(m,8H),1.40-1.21 (m,5H),1.07(d,J=6.3Hz,3H),0.91(d,J=5.5Hz,3H),0.86(d,J=5.5Hz,3H);

[0233] C 78 H 90 Cl3N 11 O 26 [M+2H] 2+ The calculated value of HRMS (ESI) m / z is 851.7635, and the measured value is 851.7645.

[0234] Compound 7

change

[0235] 1H NMR (300MHz, DMSO-d6)δ 8.71(s,1H),8.44(s,1H),7.86(s,1H),7.61-7.50(m,2H),7.47(d,J=8.6Hz ,1H),7.33(d,J=8.3Hz,1H),7.24-7.15(m,2H),6.82-6.63(m,5H),6.38(d, J=2.3Hz,1H),6.25(d,J=2.3Hz,1H),5.75(d,J=7.7Hz,1H),5.60(s,1H),5. 32-5.22(m,3H),5.22-5.15(m,3H),4.93(s,1H),4.68(d,J=6.8Hz,1H),4.45 (d,J=5.2Hz,1H),4.38(d,J=5.4Hz,1H),4.28-4.11(m,2H),4.05-3.88(m,1 H),3.49-3.38(m,1H),3.31-3.24(m,2H),3.22-3.06(m,5H),2.64(s,3H),2 .15(d,J=10.5Hz,1H),1.91(d,J=7.6Hz,1H),1.84-1.40(m,8H),1.41-1.22 (m,7H),1.07(d,J=6.2Hz,3H),0.92(d,J=5.5Hz,3H),0.87(d,J=5.5Hz,3H);

[0236] C 79 H 92 Cl3N 11 O 26 [M+2H] 2+ The calculated value of HRMS (ESI) m / z is 858.7714 and the measured value is 858.7719.

[0237] Compound 8

change

[0238] 1H NMR (300MHz, DMSO-d6)δ 8.70(s,1H),8.44(s,1H),7.86(s,1H),7.56(d,J=8.7Hz,1H),7.52(s,1H),7.4 7(d,J=8.7Hz,1H),7.33(d,J=8.4Hz,1H),7.23-7.14(m,2H),6.82-6.60(m,5H) ,6.38(d,J=2.3Hz,1H),6.25(d,J=2.3Hz,1H),5.76(d,J=7.7Hz,1H),5.60(s,1 H),5.37-5.22(m,3H),5.20(s,2H),4.93(d,J=4.0Hz,1H),4.68(d,J=6.7Hz,1H) ,4.45(s,1H),4.38(d,J=5.6Hz,1H),4.22(s,2H),4.02-3.89(m,1H),3.68(d,J =10.9Hz,1H),3.33-3.21(m,2H),3.22-2.99(m,5H),2.64(s,3H),2.12(d,J=30. 0Hz,0H),1.91(d,J=11.3Hz,1H),1.82-1.54(m,4H),1.57-1.39(m,4H),1.38-1 .17(m,9H),1.07(d,J=6.3Hz,3H),0.92(d,J=5.4Hz,3H),0.87(d,J=5.3Hz,3H);

[0239] C 80 H 94 Cl3N 11 O 26 [M+2H] 2+ The calculated value of HRMS (ESI) m / z is 865.7792, and the measured value is 865.7786.

[0240] Compound 9

change

[0241] 1H NMR(300MHz,DMSO-d6)δ 8.70(s,1H),8.44(s,1H),7.86(s,1H),7.56(d,J=8.9Hz,1H),7.52(s,1H),7.47(d ,J=8.7Hz,1H),7.33(d,J=8.4Hz,1H),7.25-7.14(m,2H),6.81-6.61(m,5H),6.38( d,J=2.3Hz,1H),6.25(d,J=2.3Hz,1H),5.76(d,J=7.5Hz,1H),5.60(s,1H),5.27(d ,J=7.2Hz,3H),5.22-5.11(m,2H),4.93(d,J=3.7Hz,1H),4.68(d,J=6.7Hz,1H),4. 45(d,J=5.0Hz,1H),4.38(d,J=5.5Hz,1H),4.30-4.07(m,2H),4.03-3.88(m,1H),3 .68(d,J=10.6Hz,1H),3.34-3.23(m,2H),3.22-3.05(m,5H),2.64(s,3H),2.15(d, J=10.1Hz,1H),1.91(d,J=11.5Hz,1H),1.81-1.55(m,4H),1.54-1.41(m,4H),1.39 -1.22(m,11H),1.07(d,J=6.2Hz,3H),0.92(d,J=5.4Hz,3H),0.87(d,J=5.4Hz,3H);

[0242] C 81 H 96 Cl3N 11 O 26 [M+2H] 2+ The calculated value of HRMS (ESI) m / z is 872.7870 and the measured value is 872.7873.

[0243] Compound 10

change

[0244] 1H NMR(300MHz, 20μLのCD3ODおよびD2OをcontainingむDMSO-d6)δ 8.71(s,1H),8.47(s,1H),7.96(t,J=4.7Hz,1H),7.87(s,1H),7.56(d,J=8.8Hz, 1H),7.53(s,1H),7.47(d,J=8.7Hz,1H),7.34(d,J=8.4Hz,1H),7.26-7.15(m,2H ),6.82-6.62(m,5H),6.39(d,J=2.3Hz,1H),6.27(d,J=2.3Hz,1H),5.76(d,J=7. 8Hz,1H),5.61(s,1H),5.35-5.22(m,3H),5.20(s,2H),4.94(d,J=4.0Hz,1H),4.6 9(q,J=6.7Hz,1H),4.46(d,J=5.3Hz,1H),4.41(d,J=5.5Hz,1H),4.30-4.14(m,2 H),4.04-3.91(m,1H),3.41-3.33(m,4H),3.29-3.24(m,2H),3.19(s,1H),2.64( s,3H),2.16(dd,J=16.1,7.5Hz,1H),1.92(d,J=12.3Hz,1H),1.80-1.47(m,4H), 1.31(s,3H),1.08(d,J=6.3Hz,3H),0.92(d,J=5.5Hz,3H),0.87(d,J=5.6Hz,3H);

[0245] C 77 H 88 Cl3N 11 O 27 [M+2H] 2+ The calculated value of HRMS (ESI) m / z is 852.7532, and the measured value is 853.7530.

[0246] Compound 11

change

[0247] 1H NMR (300MHz, 20μL of D2O containing DMSO-d6)δ 8.64(s,1H),8.39(s,1H),7.84-7.73(m,1H),7.49(d,J=8.9Hz,1H),7.45(s ,1H),7.40(d,J=8.7Hz,1H),7.27(d,J=8.4Hz,1H),7.19-7.02(m,2H),6.83- 6.56(m,5H),6.32(d,J=2.2Hz,1H),6.19(d,J=2.3Hz,1H),5.69(d,J=7.7Hz, 1H),5.54(s,1H),5.25-5.16(m,3H),5.13(s,2H),4.87(s,1H),4.62(d,J=6. 8Hz,1H),4.50-4.37(m,1H),4.33(d,J=5.5Hz,1H),4.25-4.04(m,2H),3.98 -3.82(m,1H),3.28(t,J=6.2Hz,2H),3.24-3.15(m,2H),3.12(s,1H),2.58(s ,3H),2.09(d,J=8.9Hz,1H),1.85(d,J=12.3Hz,1H),1.73-1.41(m,4H),1.24 (s,3H),1.01(d,J=6.3Hz,3H),0.85(d,J=5.6Hz,3H),0.80(d,J=5.5Hz,3H);

[0248] C 79 H 92 Cl3N 11 O 28 [M+2H] 2+ The calculated value of HRMS (ESI) m / z is 874.7663 and the measured value is 874.7659.

[0249] Compound 12

change

[0250] 1H NMR (300MHz, 20μL of D2O containing DMSO-d6)δ 8.71(s,1H),8.52(s,1H),8.08(s,1H),7.89-7.75(m,1H),7.60-7.51(m,2H),7.46( d,J=9.4Hz,1H),7.34(d,J=8.3Hz,1H),7.27(dd,J=8.1,1.5Hz,1H),7.23-7.10(m,2 H),6.94(dd,J=7.8,1.5Hz,1H),6.85-6.62(m,4H),6.38(d,J=2.3Hz,1H),6.25(d,J =2.3Hz,1H),5.76(d,J=7.8Hz,1H),5.60(s,1H),5.33-5.21(m,3H),5.21-5.10(m,2 H),4.93(s,1H),4.68(d,J=6.8Hz,1H),4.46(d,J=5.1Hz,1H),4.37(d,J=5.3Hz,1H) ,4.22(s,1H),4.03-3.88(m,1H),3.68(d,J=10.8Hz,1H),3.35-3.21(m,4H),3.20-3 .10(m,2H),2.64(s,3H),2.23-2.06(m,1H),1.91(d,J=11.4Hz,1H),1.80-1.46(m,6 H),1.30(s,3H),1.07(d,J=6.2Hz,3H),0.92(d,J=5.4Hz,3H),0.87(d,J=5.5Hz,3H);

[0251] C 76 H 87 Cl2N 11 O 26 [M+2H] 2+ The calculated value of HRMS (ESI) m / z is 820.7674, and the measured value is 820.7674.

[0252] Compound 13

change

[0253] 1H NMR (300MHz, 20μL of D2O containing DMSO-d6)δ 8.71(s,1H),8.45(s,1H),7.89-7.83(m,1H),7.62-7.50(m,2H),7.47(d,J=8.6Hz, 1H),7.34(d,J=8.3Hz,1H),7.30-7.24(m,1H),7.24-7.13(m,2H),6.92(dd,J=7.8, 1.5Hz,1H),6.82-6.62(m,4H),6.38(d,J=2.3Hz,1H),6.26(d,J=2.3Hz,1H),5.76( d,J=7.7Hz,1H),5.60(s,1H),5.34-5.21(m,3H),5.23-5.11(m,2H),4.99-4.81(m, 1H),4.68(d,J=6.8Hz,1H),4.45(d,J=5.0Hz,1H),4.39(d,J=5.5Hz,1H),4.30-4.1 1(m,2H),4.02-3.90(m,1H),3.68(d,J=10.9Hz,1H),3.36-3.23(m,4H),3.22-3.06 (m,3H),2.64(s,3H),2.23-2.08(m,1H),1.91(d,J=11.6Hz,1H),1.82-1.38(m,8H) ,1.30(s,3H),1.07(d,J=6.2Hz,3H),0.92(d,J=5.4Hz,3H),0.87(d,J=5.7Hz,3H);

[0254] C 77 H 89 Cl2N 11 O 26 [M+2H] 2+ The calculated value of HRMS (ESI) m / z is 827.7752, and the measured value is 827.7754.

[0255] Compound 16

change

[0256] 1H NMR (300MHz, 20μL of D2O containing DMSO-d6)δ 8.71(s,1H),8.45(s,1H),7.86(s,1H),7.59-7.51(m,2H),7.47(d,J=8.6Hz,1H),7. 34(d,J=8.4Hz,1H),7.25-7.15(m,3H),7.11(dd,J=8.3,2.3Hz,1H),6.89(d,J=8.3Hz ,1H),6.81-6.63(m,2H),6.37(d,J=2.3Hz,1H),6.21(d,J=2.3Hz,1H),5.76(d,J=7. 6Hz,1H),5.60(s,1H),5.34-5.21(m,3H),5.22-5.14(m,2H),4.93(s,1H),4.68(d,J= 6.8Hz,1H),4.45(s,1H),4.37(d,J=5.4Hz,1H),4.21(s,2H),3.96(d,J=7.1Hz,1H), 3.74-3.64(m,1H),3.27(d,J=4.9Hz,2H),3.18(s,1H),3.16-2.98(m,2H),2.72(t,J= 6.7Hz,2H),2.64(s,3H),2.23-2.06(m,1H),1.91(d,J=11.8Hz,1H),1.84-1.47(m,6 H),1.30(s,3H),1.07(d,J=6.2Hz,3H),0.92(d,J=5.5Hz,3H),0.87(d,J=5.5Hz,3H);

[0257] C 75 H 87 Cl2N 11 O 27 S[M+2H] 2+ The calculated value of HRMS (ESI) m / z is 838.7509, and the measured value is 838.7510.

[0258] Compound 17

change

[0259] 1H NMR (300MHz, 20μL of D2O containing DMSO-d6)δ 8.71(s,1H),8.43(s,1H),7.91(s,1H),7.85(s,1H),7.60-7.50(m,2H),7.46(d,J=8.5H z,1H),7.33(d,J=8.3Hz,1H),7.23-7.17(m,2H),7.16(d,J=2.2Hz,1H),7.10(dd,J=8.3, 2.3Hz,1H),6.88(d,J=8.3Hz,1H),6.81-6.66(m,3H),6.37(d,J=2.3Hz,1H),6.23(d,J=2 .3Hz,1H),5.76(d,J=7.8Hz,1H),5.60(s,1H),5.30-5.22(m,3H),5.18(s,2H),4.93(s,1 H),4.68(d,J=6.8Hz,1H),4.44(s,1H),4.37(d,J=5.4Hz,1H),4.28-4.13(m,2H),4.04- 3.91(m,1H),3.73-3.60(m,2H),3.32-3.22(m,2H),3.18(s,1H),3.14-3.00(m,2H),2.74 -2.58(m,5H),2.24-2.06(m,1H),1.91(d,J=10.8Hz,1H),1.82-1.51(m,4H),1.50-1.34( m,4H),1.30(s,3H),1.07(d,J=6.2Hz,3H),0.92(d,J=5.5Hz,3H),0.87(d,J=5.6Hz,3H);

[0260] C 76 H 89 Cl2N 11 O 27 S[M+2H] 2+ The calculated value of HRMS (ESI) m / z is 845.7587, and the measured value is 845.7591.

[0261] Compound 18

change

[0262] 1H NMR (300MHz, 20μL of D2O containing DMSO-d6)δ 8.71(s,1H),8.45(s,1H),7.97(s,1H),7.86(s,1H),7.58-7.51(m,2H),7.47(d,J=8.6 Hz,1H),7.34(d,J=8.4Hz,1H),7.23-7.14(m,3H),7.11(dd,J=8.3,2.2Hz,1H),6.88(d ,J=8.3Hz,1H),6.81-6.64(m,3H),6.38(d,J=2.2Hz,1H),6.25(d,J=2.3Hz,1H),5.76( d,J=7.7Hz,1H),5.60(s,1H),5.31-5.22(m,3H),5.18(s,2H),4.93(s,1H),4.68(d,J= 6.7Hz,1H),4.45(s,1H),4.39(d,J=5.4Hz,1H),4.26-4.15(m,2H),4.02-3.92(m,1H), 3.68(d,J=11.0Hz,1H),3.38(t,J=6.0Hz,2H),3.34-3.21(m,4H),3.18(s,1H),2.83(t ,J=6.0Hz,2H),2.64(s,3H),2.24-2.09(m,1H),1.91(d,J=11.9Hz,1H),1.79-1.47(m, 4H),1.30(s,3H),1.07(d,J=6.2Hz,3H),0.92(d,J=5.4Hz,3H),0.87(d,J=5.5Hz,3H);

[0263] C 78 H 93 Cl2N 11 O 29 S[M+2H] 2+ The calculated value of HRMS (ESI) m / z is 875.7692, and the measured value is 875.7692.

[0264] Compound 20

change

[0265] 1H NMR (300MHz, DMSO-d6)δ 8.72(s,1H),8.49(s,1H),7.96(s,1H),7.86(d,J=5.3Hz,1H),7.59-7.51(m, 2H),7.49(s,1H),7.46(s,1H),7.33(d,J=8.4Hz,1H),7.26-7.11(m,2H),6.8 5-6.61(m,3H),6.38(d,J=2.3Hz,1H),6.27(d,J=2.6Hz,1H),5.76(d,J=7.7H z,1H),5.60(s,1H),5.34-5.22(m,3H),5.22-5.12(m,2H),4.93(s,1H),4.68 (d,J=6.8Hz,1H),4.45(t,J=5.2Hz,1H),4.37(d,J=5.4Hz,1H),4.31-4.15(m ,2H),3.97(t,J=6.5Hz,1H),3.33-3.22(m,4H),3.18(s,1H),3.03(s,1H),2. 64(s,3H),2.22-2.08(m,1H),1.91(d,J=11.9Hz,1H),1.80-1.47(m,6H),1.3 0(s,3H),1.07(d,J=6.3Hz,3H),0.92(d,J=5.6Hz,3H),0.87(d,J=5.6Hz,3H);

[0266] C 75 H 86 Cl2N 12 O 26 [M+2H] 2+ The calculated value of HRMS (ESI) m / z is 821.2650, and the measured value is 821.2652.

[0267] Compound 21

change

[0268] 1H NMR (300MHz, DMSO-d6)δ 8.71(d,J=5.0Hz,1H),8.44(s,1H),7.93(s,1H),7.86(s,1H),7.61-7.49(m,2H ),7.50-7.43(m,2H),7.34(dd,J=8.4,4.4Hz,1H),7.20(d,J=7.4Hz,2H),6.84-6 .63(m,3H),6.37(d,J=2.3Hz,1H),6.26(d,J=2.6Hz,1H),5.76(d,J=7.2Hz,1H) ,5.60(s,1H),5.29-5.21(m,3H),5.21-5.13(m,2H),4.93(d,J=4.2Hz,1H),4.68 (q,J=6.7Hz,1H),4.45(t,J=4.4Hz,1H),4.38(d,J=5.5Hz,1H),4.30-4.16(m,2 H),3.97(t,J=6.3Hz,1H),3.34-3.22(m,4H),3.22-3.07(m,2H),2.64(s,3H),2. 24-2.07(m,1H),1.91(d,J=12.4Hz,1H),1.81-1.57(m,4H),1.58-1.42(m,4H),1 .30(s,3H),1.07(d,J=6.3Hz,3H),0.92(d,J=5.5Hz,3H),0.87(d,J=5.5Hz,3H);

[0269] C 76 H 88 Cl2N 12 O 26 [M+2H] 2+ The calculated value of HRMS (ESI) m / z is 828.2728, and the measured value is 828.2727.

[0270] Compound 81

change

[0271] 1H NMR (300MHz, 20μL of D2O containing DMSO-d6)δ 8.72(s,1H),8.51-8.37(m,2H),7.86(s,1H),7.60-7.51(m,2H),7.47(d ,J=8.5Hz,1H),7.34(d,J=8.3Hz,1H),7.24-7.15(m,2H),6.39(d,J=2.3 Hz,1H),6.23(d,J=2.3Hz,1H),5.76(d,J=7.8Hz,1H),5.60(s,1H),5.30 -5.22(m,3H),5.18(s,2H),4.93(s,1H),4.68(d,J=6.8Hz,1H),4.50-4. 38(m,1H),4.21(d,J=10.7Hz,2H),4.06-3.80(m,3H),3.68(d,J=11.0Hz ,1H),3.31-3.20(m,2H),3.18(s,1H),3.11(t,J=2.5Hz,1H),2.64(s,3H ),2.22-2.05(m,1H),1.91(d,J=8.2Hz,1H),1.77-1.50(m,4H),1.30(s, 3H),1.07(d,J=6.3Hz,3H),0.92(d,J=5.5Hz,3H),0.87(d,J=5.4Hz,3H).

[0272] C 69 H 78 Cl2N 10 O 23 [M+2H] 2+ The calculated MS (ESI) m / z value is 743.2 and the measured value is 743.4.

[0273] Compound 82

change

[0274] 1H NMR (300MHz, 20μL of D2O containing DMSO-d6)δ 8.71(s,1H),8.47(s,1H),8.08(s,1H),7.86(s,1H),7.60-7.51(m,2H),7.47(d ,J=8.5Hz,1H),7.34(d,J=8.3Hz,1H),7.23-7.15(m,2H),6.82-6.63(m,3H),6. 37(d,J=2.3Hz,1H),6.26(d,J=2.3Hz,1H),5.76(d,J=7.8Hz,1H),5.60(s,1H), 5.31-5.21(m,3H),5.18(s,2H),4.92(s,1H),4.68(d,J=6.8Hz,1H),4.44(s,1H ),4.37(d,J=5.5Hz,1H),4.29-4.09(m,2H),4.02-3.87(m,1H),3.68(d,J=10.9 Hz,1H),3.37-3.21(m,4H),3.18(s,1H),2.85(t,J=2.6Hz,1H),2.64(s,3H),2. 45-2.30(m,2H),2.25-2.05(m,1H),1.91(d,J=7.9Hz,1H),1.82-1.46(m,4H),1 .30(s,3H),1.07(d,J=6.2Hz,3H),0.92(d,J=5.5Hz,3H),0.87(d,J=5.4Hz,3H);

[0275] C 70 H 80 Cl2N 10 O 23 [M+2H] 2+ The calculated MS (ESI) m / z value is 750.2 and the measured value is 750.4.

[0276] The target compounds 22~25 were synthesized from intermediates 83~84 (スキーム3). For modification at the R position, the Mannich reaction was applied. DIPEA (20 equiv.) was added to a solution of vancomycin hydrochloride (1 equiv.) and an amine (siderophore component or alkynylamine, 10 equiv.) in CH3OH-HO (1:1 or 1:2). The mixture was stirred at room temperature for 5 min and then cooled to -10 °C. After stirring for another 5 min, 37% formaldehyde solution (1.2 equiv. for the intermediate or 1.08 equiv. for the final target) was added to the mixture and stirred for 12–24 h. The reaction was monitored by analytical RP-HPLC and quenched with TFA. The resulting solution was directly purified by preparative RP-HPLC. The target peak collections were combined and lyophilized to give target compounds 22–25 and intermediates 83–84 bearing alkynyl groups. Note: Intermediates 83 and 84 were not pure enough for characterization and were used in the click reaction without further purification.

[0277] compound 22 [ka] Yield: 33%. HPLC R =7.850 minutes.

[0278] 1H NMR (300MHz, 20μL of D2O containing DMSO-d6)δ 7.84(s,1H),7.63(s,1H),7.55-7.40(m,2H),7.33(d,J=8.3Hz,1H),7.22(d,J=8.4Hz,1H),7.12(s,1H),6.87(d,J=8.9Hz,1 H),6.80(d,J=8.4Hz,1H),6.77-6.68(m,2H),6.56(s,1H),5.74(s,1H),5.70(s,1H),5.26(d,J=6.9Hz,2H),5.20-5.07(m,3 H),4.83(s,1H),4.67(d,J=6.7Hz,1H),4.45(d,J=5.0Hz,1H),4.18-3.90(m,4H),3.68(d,J=10.9Hz,1H),3.33-3.21(m,4H) ,3.04-2.95(m,2H),2.60(s,3H),2.11(d,J=20.8Hz,1H),1.91(d,J=11.0Hz,2H),1.82-1.44(m,5H),1.07(d,J=6.3Hz,3H);

[0279] C 77 H 88 Cl3N 11 O 27 [M+2H] 2+ The calculated value of HRMS (ESI) m / z is 852.7532, and the measured value is 852.7525.

[0280] Compound 23

change

[0281] 1H NMR (300MHz, 20μL of D2O containing DMSO-d6)δ 8.79(s,1H),8.67(s,1H),7.83(s,1H),7.78-7.64(m,1H),7.61(s,1H),7.58-7.42(m,2 H),7.33(dd,J=8.4,3.6Hz,1H),7.22(d,J=8.2Hz,1H),7.13(s,1H),6.87(d,J=8.9Hz,1H ),6.80(d,J=8.4Hz,1H),6.78-6.69(m,2H),6.56(s,1H),5.74(d,J=6.0Hz,1H),5.69(s, 1H),5.27(d,J=7.7Hz,2H),5.17(d,J=11.0Hz,2H),5.14-5.07(m,1H),4.84(s,1H),4.68 (d,J=6.7Hz,1H),4.45(d,J=5.1Hz,1H),4.19-4.07(m,2H),4.07-3.94(m,1H),3.70(d, 1H),3.27(d,J=5.1Hz,2H),3.23-3.18(m,2H),3.00-2.89(m,1H),2.85-2.72(m,1H),2.6 0(s,3H),2.10(d,J=21.2Hz,1H),1.91(d,J=11.8Hz,1H),1.82-1.61(m,4H),1.61-1.41( m,4H),1.32(s,3H),1.07(d,J=6.2Hz,3H),0.93(d,J=5.8Hz,3H),0.87(d,J=6.0Hz,3H);

[0282] C 78 H 90 Cl3N 11 O 27 [M+2H] 2+ The calculated value of HRMS (ESI) m / z is 859.7610 and the measured value is 859.7611.

[0283] Compound 24

change

[0284] 1H NMR (300MHz, 20μL of D2O containing DMSO-d6)δ 8.89(s,0H),8.80(s,1H),8.67(s,1H),7.83(s,1H),7.63(s,1H),7.50(t,J=1 0.1Hz,2H),7.33(d,J=8.4Hz,1H),7.24(t,J=7.6Hz,2H),7.12(s,1H),6.96(dd ,J=7.8,1.4Hz,1H),6.87(d,J=8.6Hz,1H),6.83-6.64(m,3H),6.56(s,1H),5.7 4(d,J=7.5Hz,1H),5.69(s,1H),5.30-5.21(m,2H),5.15(s,2H),5.14-5.07(m, 1H),4.83(s,1H),4.68(d,J=6.7Hz,1H),4.44(d,J=5.9Hz,2H),4.26-3.95(m,5 H),3.73-3.61(m,3H),3.31-3.22(m,2H),3.22-3.07(m,3H),2.81-2.64(m,1H) ,2.60(s,3H),2.24-2.03(m,1H),1.91(d,J=10.9Hz,1H),1.81-1.45(m,4H),1. 31(s,3H),1.07(d,J=6.3Hz,3H),0.93(d,J=5.9Hz,3H),0.88(d,J=5.9Hz,3H);

[0285] C 76 H 87 Cl2N 11 O 27 [M+2H] 2+ The calculated value of HRMS (ESI) m / z is 828.7648, and the measured value is 828.7646.

[0286] Compound 25

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[0287] 1H NMR (300MHz, 20μL of D2O containing DMSO-d6)δ 8.80(s,1H),8.66(s,1H),7.83(s,1H),7.63(s,1H),7.56-7.39(m,2H),7. 33(d,J=8.4Hz,1H),7.24(s,1H),7.21(s,1H),7.17(d,J=2.3Hz,1H),7.14- 7.03(m,2H),6.91(d,J=8.3Hz,1H),6.86-6.65(m,2H),6.55(s,1H),5.74( d,J=7.6Hz,1H),5.69(s,1H),5.30-5.21(m,2H),5.20-5.06(m,3H),4.83(s ,1H),4.68(d,J=6.8Hz,1H),4.44(d,J=5.2Hz,1H),4.18-3.97(m,4H),3.6 8(d,J=11.2Hz,1H),3.27(d,J=5.3Hz,2H),3.18(s,1H),3.01(s,3H),2.60( s,3H),2.22-2.04(m,1H),1.91(d,J=10.9Hz,1H),1.81-1.44(m,4H),1.31( s,3H),1.07(d,J=6.3Hz,3H),0.93(d,J=5.9Hz,3H),0.88(d,J=5.8Hz,3H);

[0288] C 75 H 87 Cl2N 11 O 28 S[M+2H] 2+ The calculated value of HRMS (ESI) m / z is 846.7483, and the measured value is 846.7482.

[0289] The target compound 28~29 was synthesized from intermediate 85 (スキーム4). A reductive amination reaction was applied to the conjugation of siderophore components at the V position. To a mixture of vancomycin HCl salt (75 mg, 0.05 mmol) and siderophore aldehyde (2 equiv.) in DMF (3 mL) was added DIPEA (6 equiv.). The reaction mixture was stirred at 50 °C for 2 h to form the corresponding imine intermediate, which could be detected by analytical HPLC. The mixture was then allowed to cool to room temperature, and subsequently, methanol (1 mL) and a solution of NaCNBH3 (3 equiv.) in TFA were added to adjust the pH to 3-4, reducing the imine C-N double bond to a C-N single bond. After stirring for 3 h, no further progress was detected. The mixture was added dropwise to cold ether (30 mL) in a 50 mL centrifuge tube. A white precipitate immediately collapsed, which was centrifuged to obtain the precipitated crude product. The crude product was dissolved in HO and subsequently purified by Prep-RP-HPLC. After lyophilization of the collected target fractions, the final compounds 28, 29 and intermediate 85 were obtained as white fluffy solids.

[0290] compound 28 [ka] Yield: 40%. HPLC R =8.206 minutes.

[0291] 1H NMR(300MHz,DMSO-d6)δ 8.73(s,1H),8.57(d,J=5.8Hz,1H),8.34(t,J=5.6Hz,1H),7.85(s,1H),7.55(d,J=8 .2Hz,2H),7.48(d,J=8.6Hz,1H),7.34(d,J=8.3Hz,1H),7.20(d,J=8.5Hz,1H),7.16( s,1H),6.82(d,J=8.3Hz,1H),6.79-6.62(m,4H),6.41(d,J=2.3Hz,1H),6.26(d,J=2 .2Hz,1H),5.76(d,J=7.7Hz,1H),5.62(s,1H),5.34-5.23(m,2H),5.20-5.14(m,2H), 5.12(s,1H),4.92(d,J=3.8Hz,1H),4.67(q,J=6.6Hz,1H),4.51-4.35(m,2H),4.19( d,J=10.7Hz,2H),3.97(t,J=6.5Hz,1H),3.69(d,J=10.9Hz,1H),3.34-3.22(m,3H),3 .07-2.81(m,3H),2.63(s,3H),2.23-2.08(m,1H),2.00-1.80(m,2H),1.74-1.50(m,3 H),1.36(s,3H),1.10(d,J=6.3Hz,3H),0.92(d,J=5.6Hz,3H),0.87(d,J=5.7Hz,3H);

[0292] C 75 H 83 Cl3N 10 O 27 [M+2H] 2+ The calculated value of HRMS (ESI) m / z is 831.2321 and the measured value is 831.2313.

[0293] Compound 29

change

[0294] 1H NMR (300MHz, DMSO-d6)δ 8.73(s,1H),8.57(s,1H),8.30(t,J=5.9Hz,1H),7.85(s,1H),7.62-7.51(m,2 H),7.47(d,J=8.6Hz,1H),7.33(d,J=8.3Hz,1H),7.20(d,J=8.6Hz,1H),7.17(s ,1H),6.84-6.61(m,5H),6.41(d,J=2.3Hz,1H),6.26(d,J=2.3Hz,1H),5.76(d, J=7.8Hz,1H),5.62(s,1H),5.36-5.25(m,2H),5.22-5.05(m,3H),4.93(s,1H), 4.65(d,J=6.9Hz,1H),4.51-4.38(m,2H),4.26-4.10(m,2H),3.96(s,1H),3.68 (d,J=10.8Hz,1H),3.34-3.18(m,4H),2.95-2.75(m,2H),2.63(s,3H),2.16(d, J=9.3Hz,1H),2.00(d,J=10.6Hz,1H),1.89-1.73(m,2H),1.73-1.49(m,3H),1. 35(s,3H),1.10(d,J=6.3Hz,3H),0.92(d,J=5.5Hz,3H),0.87(d,J=5.6Hz,3H);

[0295] C 76 H 85 Cl3N 16 O 27 [M+2H] 2+ The calculated value of HRMS (ESI) m / z is 838.2399 and the measured value is 838.2392.

[0296] Compound 85

change

[0297] 1H NMR(300MHz,DMSO-d6)δ 8.72(s,1H),8.56(s,1H),7.85(d,J=1.9Hz,1H),7.59-7.50(m,2H),7.47(dd,J=8.3, 1.8Hz,1H),7.33(d,J=8.3Hz,1H),7.20(d,J=8.5Hz,1H),7.17(s,1H),6.82-6.66(m,3 H),6.41(d,J=2.3Hz,1H),6.26(d,J=2.3Hz,1H),5.75(d,J=7.8Hz,1H),5.61(s,1H),5 .34-5.24(m,2H),5.19(d,J=3.6Hz,1H),5.17(d,J=1.9Hz,1H),5.12(s,1H),4.93(d,J =4.1Hz,1H),4.64(q,J=6.6Hz,1H),4.52-4.38(m,2H),4.28-4.11(m,2H),3.96(t,J=7 .2Hz,1H),3.68(d,J=10.9Hz,1H),3.34-3.21(m,3H),2.95-2.71(m,3H),2.64(s,3H), 2.27(td,J=7.2,2.7Hz,2H),2.21-2.08(m,1H),1.98(d,J=10.3Hz,1H),1.87-1.48(m, 6H),1.34(s,3H),1.09(d,J=6.3Hz,3H),0.92(d,J=5.5Hz,3H),0.87(d,J=5.6Hz,3H);

[0298] C 71 H 81 Cl2N9O 24 [M+2H] 2+ The calculated MS (ESI) m / z value is 757.7 and the measured value is 757.6.

[0299] The target compound 30および intermediate 86 was synthesized (スキーム5). The N-terminal modification of vancomycin was performed by selective reductive amination. To a stirred mixture of vancomycin hydrochloride (200 mg, 135 μmol) and 2-chloro-3,4-dihydroxy-N-(2-oxoethyl)benzamide (3 equiv.) in HO (3 mL), CHCN (3 mL) and acetic acid (1.5 mL) were added and stirred for 5 min to homogenize the mixture. NaCNBH (10 equiv.) was then added to the reaction mixture and stirred for 2 days. A stream of N was then used to blow off most of the acetic acid and CHCN, followed by prep-RP-HPLC purification to give compound 30 (5.5 mg, 2% yield) as a fluffy white solid. Intermediate 86 was also prepared according to the above procedure.

[0300] compound 30 [ka] Yield: 2%. HPLC R =8.695 minutes.

[0301] 1H NMR(300MHz,DMSO-d6)δ 8.76(s,1H),8.56(s,1H),7.85(d,J=1.8Hz,1H),7.54(d,J=8.9Hz,2H),7.47(d,J=8. 6Hz,1H),7.35(d,J=8.3Hz,1H),7.20(d,J=8.3Hz,1H),7.16(s,1H),6.77(ddd,J=15. 3,11.2,7.9Hz,5H),6.41(d,J=2.3Hz,1H),6.26(d,J=2.4Hz,1H),5.77(d,J=7.6Hz,1 H),5.63(s,1H),5.25(d,J=7.3Hz,2H),5.22-5.16(m,2H),5.12(s,1H),4.89(s,1H), 4.68(d,J=6.8Hz,1H),4.44(d,J=5.5Hz,1H),4.26-4.06(m,3H),3.68(d,J=11.1Hz,2 H),3.33-3.21(m,3H),3.18(s,1H),2.94(s,2H),2.90(s,1H),2.74(s,1H),2.64(s,1 H),2.28-2.05(m,1H),1.90(d,J=9.9Hz,1H),1.81-1.67(m,1H),1.54(d,J=21.7Hz,1 H),1.29(s,3H),1.07(d,J=6.2Hz,3H),0.94(d,J=6.0Hz,3H),0.88(d,J=5.7Hz,3H);

[0302] C 75 H 83 Cl3N 10 O 27 [M+2H] 2+ The calculated MS (ESI) m / z value is 831.23, and the measured value is 831.20.

[0303] Compound 86

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[0304] 1H NMR(300MHz,DMSO-d6)δ 8.79(s,2H),8.57(d,J=5.5Hz,1H),7.85(s,1H),7.61(s,1H),7.53(d,J=8.5Hz,1 H),7.47(d,J=8.6Hz,1H),7.35(d,J=8.4Hz,1H),7.20(d,J=8.4Hz,1H),7.15(s,1H ),6.84-6.67(m,3H),6.41(d,J=2.3Hz,1H),6.26(d,J=2.3Hz,1H),5.78(d,J=7.7 Hz,1H),5.66(d,J=10.5Hz,1H),5.25(d,J=6.7Hz,2H),5.21-5.15(m,2H),5.12(s, 1H),4.89(s,1H),4.68(q,J=7.3,6.5Hz,1H),4.52-4.35(m,2H),4.27-3.94(m,3H ),3.68(d,J=10.9Hz,1H),3.33-3.21(m,3H),3.18(s,2H),2.94(s,1H),2.87(s,3H ),2.37-2.23(m,2H),2.21-2.06(m,1H),1.97-1.65(m,4H),1.60(d,J=11.7Hz,1H) ,1.29(s,3H),1.07(d,J=6.4Hz,3H),0.95(d,J=6.0Hz,3H),0.88(d,J=6.1Hz,3H);

[0305] C 71 H 81 Cl2N9O 24 [M+2H] 2+ The calculated MS (ESI) m / z value is 757.75 and the measured value is 757.60.

[0306] The target compounds 14, 15, 19, 26, 27, 31 and 32 were synthesized (スキーム6). To a solution of the alkynylvancomycin intermediate (0.025 mmol, 1 equiv.) and the azide-containing siderophore component (0.025 mmol, 1 equiv.) in HO / t-BuOH (1:1, 3 mL), NaHCO (0.2 mmol, 8 equiv.), CuSO 5HO (0.05 mmol, 2 equiv.), and sodium ascorbate (0.375 mmol, 15 equiv.) were added sequentially. After completion of the reaction, monitored by analytical RP-HPLC, the mixture was stirred at room temperature for 2 h. The reaction was quenched with TFA, and the mixture was subsequently purified by prep-RP-HPLC to give the target compounds 14, 15, 19, 26, 27, 31, and 32.

[0307] compound 14 [ka] Yield: 75%. HPLC R =8.701 minutes.

[0308] 1H NMR (300MHz, 20 μL of D2O containing 20 μL of D2O containing DMSO-d6) δ 8.91(s,1H),8.72(s,1H),8.47(d,J=10.8Hz,2H),7.87(d,J=13.0Hz,2H),7.60- 7.50(m,2H),7.47(d,J=8.6Hz,1H),7.34(d,J=8.3Hz,1H),7.27-7.10(m,3H),6. 93(dd,J=7.8,1.4Hz,1H),6.84-6.61(m,4H),6.38(d,J=2.4Hz,1H),6.22(d,J=2 .4Hz,1H),5.76(d,J=7.9Hz,1H),5.60(s,1H),5.36-5.20(m,3H),5.20-5.10(m, 2H),4.93(s,1H),4.68(d,J=6.8Hz,1H),4.60-4.49(m,1H),4.48-4.35(m,3H),4 .31-4.13(m,2H),3.96(s,1H),3.79-3.61(m,3H),3.27(d,J=5.1Hz,2H),3.18(s ,1H),2.64(s,3H),2.26-2.06(m,1H),1.90(d,J=8.4Hz,1H),1.78-1.49(m,4H), 1.30(s,3H),1.07(d,J=6.2Hz,3H),0.92(d,J=5.3Hz,3H),0.87(d,J=5.6Hz,4H);

[0309] C 78 H 88 Cl2N 14 O 26 [M+2H] 2+ The calculated value of HRMS (ESI) m / z is 854.2759, and the measured value is 854.2753.

[0310] Compound 15

change

[0311] 1H NMR (300MHz, 20μL of D2O containing DMSO-d6)δ 8.73(s,1H),8.48(s,1H),8.14(s,1H),7.89(s,1H),7.85(s,1H),7.59-7.51(m ,2H),7.48(d,J=8.5Hz,1H),7.34(d,J=8.3Hz,1H),7.26-7.14(m,3H),6.93(d, J=7.7Hz,1H),6.78(d,J=8.6Hz,1H),6.74-6.64(m,2H),6.37(s,1H),6.25(s,1 H),5.76(d,J=8.4Hz,1H),5.61(s,1H),5.27(d,J=10.1Hz,2H),5.19(s,2H),4.9 2(s,1H),4.58-4.42(m,3H),4.42-4.34(m,1H),4.29-4.12(m,2H),4.03-3.89( m,1H),3.81-3.63(m,4H),3.32-3.21(m,2H),3.18(s,1H),2.91-2.81(m,2H),2. 80-2.71(m,2H),2.63(s,3H),2.25-2.05(m,1H),1.90(d,J=9.4Hz,1H),1.80-1 .47(m,4H),1.07(d,J=6.2Hz,3H),0.92(d,J=5.5Hz,3H),0.87(d,J=5.4Hz,3H);

[0312] C 79 H 90 Cl2N 14 O 26 [M+2H] 2+ The calculated value of HRMS (ESI) m / z is 861.2837, and the measured value is 861.2837.

[0313] Compound 19

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[0314] 1H NMR (300MHz, 20μL of D2O containing DMSO-d6)δ 8.81(s,1H),8.68(s,1H),7.99(s,1H),7.83(s,1H),7.64(s,1H),7.50(t,J=9.3Hz,2H),7.33 (d,J=8.3Hz,1H),7.23(d,J=8.5Hz,1H),7.19(dd,J=8.1,1.5Hz,1H),7.15-7.07(m,1H),6.93 (dd,J=7.9,1.5Hz,1H),6.87(d,J=8.7Hz,1H),6.80(d,J=8.6Hz,2H),6.70(t,J=8.0Hz,1H),6 .56(s,1H),5.75(d,J=7.6Hz,1H),5.70(s,1H),5.31-5.21(m,2H),5.19-5.06(m,3H),4.82(s ,1H),4.67(d,J=6.7Hz,1H),4.60-4.50(m,2H),4.49-4.35(m,2H),4.24-3.94(m,4H),3.78-3 .68(m,2H),3.66(s,1H),3.31-3.23(m,2H),3.24-3.13(m,3H),3.13-2.95(m,3H),2.76(d,J= 14.0Hz,1H),2.59(s,3H),2.23-2.04(m,1H),1.90(d,J=8.3Hz,1H),1.79-1.60(m,3H),1.59- 1.48(m,1H),1.30(s,3H),1.07(d,J=6.2Hz,3H),0.93(d,J=5.8Hz,3H),0.88(d,J=5.7Hz,3H);

[0315] C 80 H 92 Cl2N 14 O 27 [M+2H] 2+ The calculated value of HRMS (ESI) m / z is 876.2890 and the measured value is 876.2881.

[0316] Compound 26

change

[0317] 1 H NMR (300MHz, DMSO-d6)δ 8.72(s,1H),8.49(s,2H),8.31(t,J=5.5Hz,1H),7.89(s,1H),7.85(s,1H),7 .55(d,J=9.0Hz,2H),7.47(d,J=8.5Hz,1H),7.34(d,J=8.4Hz,1H),7.20(d,J =8.6Hz,2H),6.84-6.65(m,5H),6.38(d,J=2.3Hz,1H),6.22(d,J=2.3Hz,1H) ,5.76(d,J=7.8Hz,1H),5.60(s,1H),5.26(d,J=6.7Hz,3H),5.19(s,2H),4.93 (s,1H),4.68(d,J=6.8Hz,1H),4.51-4.33(m,6H),4.31-4.11(m,2H),3.96(s ,1H),3.68(d,J=12.5Hz,1H),3.33-3.11(m,6H),2.64(s,3H),2.15(d,J=10.0 Hz,1H),2.05(q,J=7.2Hz,2H),1.91(d,J=8.1Hz,1H),1.80-1.46(m,4H),1.3 0(s,3H),1.07(d,J=6.2Hz,3H),0.92(d,J=5.5Hz,3H),0.87(d,J=5.6Hz,3H);

[0318] C 79 H 89 Cl3N 14 O 26 [M+2H] 2+ The calculated value of HRMS (ESI) m / z is 878.2642, and the measured value is 878.2632.

[0319] Compound 27

change

[0320] 1H NMR (300MHz, 20μL of D2O containing DMSO-d6)δ 8.73(s,1H),8.59(s,1H),8.20(s,1H),7.76(s,1H),7.55(s,1H),7.50-7.36( m,2H),7.27(d,J=8.4Hz,1H),7.15(d,J=8.4Hz,1H),7.06(s,1H),6.80(d,J=8 .8Hz,1H),6.73(d,J=8.4Hz,1H),6.70-6.60(m,2H),6.48(s,1H),5.67(d,J=7 .8Hz,1H),5.62(s,1H),5.23-5.13(m,2H),5.06(d,J=7.5Hz,3H),4.77(s,1H) ,4.61(d,J=6.7Hz,1H),4.47-4.27(m,4H),4.18(s,2H),4.14-3.99(m,2H),3. 99-3.84(m,1H),3.61(d,J=11.0Hz,1H),3.25-3.17(m,2H),3.17-3.00(m,3H) ,2.53(s,3H),2.14-1.89(m,1H),1.84(d,J=7.7Hz,1H),1.74-1.39(m,4H),1. 23(s,3H),1.00(d,J=6.3Hz,3H),0.86(d,J=5.9Hz,3H),0.81(d,J=6.1Hz,3H);

[0321] C 80 H 91 Cl3N 14 O 27 [M+2H] 2+ The calculated value of HRMS (ESI) m / z is 893.2695 and the measured value is 893.2686.

[0322] Compound 31

change

[0323] 1H NMR(300MHz,DMSO-d6)δ 8.74(s,1H),8.57(s,1H),8.29(t,J=5.8Hz,1H),7.90(s,1H),7.85(s,1H),7.59-7.51( m,2H),7.48(d,J=8.5Hz,1H),7.33(d,J=8.3Hz,1H),7.20(d,J=8.7Hz,1H),7.17(s,1H), 6.83-6.68(m,5H),6.41(d,J=2.2Hz,1H),6.26(d,J=2.3Hz,1H),5.76(d,J=7.8Hz,1H),5 .62(s,1H),5.35-5.25(m,2H),5.19(d,J=3.5Hz,1H),5.16(s,1H),5.12(s,1H),4.92(s, 1H),4.64(d,J=6.8Hz,1H),4.48-4.42(m,2H),4.42-4.33(m,2H),4.27-4.11(m,2H),3.9 7(s,1H),3.69(d,J=10.8Hz,1H),3.32-3.24(m,3H),3.18(d,J=6.0Hz,2H),3.00-2.78(m ,2H),2.76-2.66(m,2H),2.63(s,3H),2.22-2.09(m,1H),2.09-1.76(m,6H),1.75-1.48( m,3H),1.35(s,3H),1.09(d,J=6.2Hz,3H),0.92(d,J=5.6Hz,3H),0.87(d,J=5.6Hz,3H);

[0324] C 81 H 92 Cl3N 13 O 27 [M+2H] 2+ The calculated value of HRMS (ESI) m / z is 892.7719, and the measured value is 892.7720.

[0325] Compound 32

change

[0326] 1H NMR (300MHz, DMSO-d6)δ 8.77(s,1H),8.57(s,1H),8.30(t,J=5.5Hz,1H),7.96(s,1H),7.85(s,1H),7 .54(d,J=8.3Hz,1H),7.47(d,J=8.4Hz,1H),7.35(d,J=8.4Hz,1H),7.21(d,J= 8.4Hz,1H),7.16(s,1H),6.82-6.64(m,5H),6.41(d,J=2.3Hz,1H),6.26(d,J =2.4Hz,2H),5.78(d,J=7.6Hz,1H),5.63(s,1H),5.25(d,J=7.5Hz,2H),5.21- 5.14(m,2H),5.12(s,1H),4.89(s,1H),4.68(d,J=6.9Hz,1H),4.50-4.34(m, 4H),4.24-4.02(m,3H),3.68(d,J=10.8Hz,1H),3.32-3.24(m,3H),3.23-3.07 (m,3H),2.87(s,2H),2.74(s,2H),2.23-1.85(m,5H),1.62-1.47(m,1H),1.2 9(s,3H),1.07(d,J=6.3Hz,4H),0.92(d,J=5.0Hz,3H),0.86(d,J=4.8Hz,3H);

[0327] C 81 H 92 Cl3N 13 O 27 [M+2H] 2+ The calculated value of HRMS (ESI) m / z is 892.7719, and the measured value is 892.7714.

[0328] Neo-Confucianism The MICs of target compounds were tested at JMI Laboratories (North Liberty, Iowa, US) as shown in Table 1. Test compounds, including vancomycin hydrochloride, were supplied as a 6.4 mg / mL solution in 100% dimethyl sulfoxide (DMSO), aliquoted into individual wells of a 96-well plate (50 μL per well). Each compound was diluted and tested in a 12-point, two-fold dilution series ranging from 0.03 to 64 μg / mL. A standardized inoculum was added to the MIC test plate, which was then incubated at 35°C for the indicated time. N. gonorrhoeae strains were cultured in an atmosphere containing 5% CO2.

[0329] The final optical density of each well at 600 nm was measured using a Tecan Spark plate reader. Compound concentration versus OD600 data was then curve-fitted using custom software. MIC values ​​were defined as the lowest compound concentration that resulted in an OD600 value ≤ 0.15 for E. coli, K. pneumoniae, P. aeruginosa, A. baumannii, or S. aureus strains. For N. gonorrhoeae strains, an OD600 value ≤ 0.19 was used as the cutoff to define MIC values. This higher cutoff was necessary because the N. gonorrhoeae MIC plates were covered with plastic seals, which increased background OD600 values. These OD600 cutoff values ​​produced MIC values ​​that were consistent with corresponding MIC values ​​read by eye.

[0330] JMI Laboratories followed current CLSI quality assurance practices when conducting susceptibility testing. MIC values ​​were verified by simultaneously testing the CLSI-recommended ATCC QC reference strains S. aureus ATCC 29213 and K. pneumoniae ATCC 700603. Inoculum density during susceptibility testing was monitored by bacterial colony counts. Where applicable, the QC ranges for the reference strains tested were the ranges approved or published by CLSI for testing at CAMHB. MIC values ​​for erythromycin and tetracycline were identical or nearly identical when tested in the original strain validation and during testing of this compound set. Importantly, the CLSI reference method for testing N. gonorrhoeae is the agar dilution MIC method, which was not used here. Therefore, the CLSI MIC QC ranges for N. gonorrhoeae were not applicable to the antimicrobials studied here.

[0331] The specific pharmacological response observed may vary according to and depending on the particular active compound selected, or whether a pharmaceutical carrier is present, as well as the type of composition and method of administration used, and such expected variations or differences in results are contemplated in accordance with the practice of the present disclosure.

[0332] [Table 1]

[0333] Abbreviation: EC, E. coli (wild type) BW25113; EC leakage -, E. coli (tolC) JW5503-1; KPN, K. pneumoniae ATCC 700603; PSA, P. aeruginosa PAO1; PSA efflux-, P. aeruginosa (multipump gene mutant) PAM1626; ACB, A. baumannii JMI #1186154; GC, N. gonorrhoeae WHO-Z; SA, S. aureus ATCC 29213. Broth microdilution MIC values ​​were determined in iron-depleted CAMHB for all strains except GC, which was tested in selective broth.

[0334] Although specific embodiments of the present disclosure are illustrated and described in detail herein, the present disclosure is not limited thereto. The above detailed description is provided as an example of the present disclosure and should not be construed as constituting any limitation of the present disclosure. Modifications will be apparent to those skilled in the art, and all modifications that do not depart from the spirit of the present disclosure are intended to be included within the scope of the appended claims.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, 【Chemistry 149】 During the ceremony, (i) R １ but, [Chemical 150] and R ２ , R ３ , and R ４ each of which is H, or (ii) R １ but, 【Chemistry 151】 and R ２ , R ３ , and R ４ each of which is H, or (iii) R １ but, 【Chemistry 152】 and R ２ , R ３ , and R ４ each of which is H, or (iv) R １ but, 【Chemistry 153】 and R ２ , R ３ , and R ４ each of which is H, or (v) R １ is OH and R ２ but, 【Chemistry 154】 and R ３ and R ４ each of which is H, or (vi) R １ is OH and R ３ but, 【Chemistry 155】 and R ２ and R ４ each of which is H, or or (vii) R １ is OH and R ４ but, 【Chemistry 156】 and R ２ and R ３ each of which is H; X １ but a bond or 【Chemistry 157】 and X ２ but a bond or 【Chemistry 158】 and X ３ but a bond or 【Chemistry 159】 and X ４ but a bond or [Chemical 160] and Y １ is C(O) or SO ２ and Y ２ is C(O) or SO ２ and Y ３ is C(O) or SO ２ and n １ is 1 to 5, n ２ is 1 to 10, n ３ is 0 to 5, n ４ is 1 to 5, n ５ is 1 to 5, n ６ is 1 to 10, n ７ is 0 to 5, n ８ is 0 to 5, n ９ is 0 to 5, n １０ is 0 to 5, n １１ is 0 to 5, R ５ is selected from the group consisting of hydrogen, halogen, and OH; R ６ is selected from the group consisting of hydrogen, halogen, and OH; R ７ is selected from the group consisting of hydrogen, halogen, and OH; R ８ is selected from the group consisting of hydrogen, halogen, and OH; R ９ is selected from the group consisting of hydrogen, halogen, and OH; R １０ is selected from the group consisting of hydrogen, halogen, and OH; R １１ is selected from the group consisting of hydrogen, halogen, and OH; R １２ is selected from the group consisting of hydrogen, halogen, and OH; R １３ is selected from the group consisting of hydrogen, halogen, and OH; R １４ is selected from the group consisting of hydrogen, halogen, and OH; R １５ is selected from the group consisting of hydrogen, halogen, and OH; R １６ is selected from the group consisting of hydrogen, halogen, and OH; R １７ is selected from the group consisting of hydrogen, halogen, and OH; R １８ is selected from the group consisting of hydrogen, halogen, and OH; R １９ is selected from the group consisting of hydrogen, halogen, and OH; R ２０ is selected from the group consisting of hydrogen, halogen, and OH; and R ２１ is selected from the group consisting of hydrogen, halogen, and OH, or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein the halogen is Cl.

3. R １ but, 【Chemistry 161】 and R ２ , R ３ , and R ４ 2. The compound of claim 1, wherein each of

4. n １ The compound according to claims 1 and 3, wherein is 1.

5. n １ The compound according to claims 1 and 3, wherein is 3.

6. R １ but, 【Chemistry 162】 and R ２ , R ３ , and R ４ 2. The compound of claim 1, wherein each of

7. n ２ is 1, and n ３ is 0, and X １ is a bond, and Y １ is C(O) and R ５ is Cl, and R ６ is OH and R ７ The compound according to claims 1 and 6, wherein is OH.

8. n ２ is 2, and n ３ is 0, and X １ is a bond, and Y １ is C(O) and R ５ is Cl, and R ６ is OH and R ７ The compound according to claims 1 and 6, wherein is OH.

9. n ２ is 3, and n ３ is 0, and X １ is a bond, and Y １ is C(O) and R ５ is Cl, and R ６ is OH and R ７ The compound according to claims 1 and 6, wherein is OH.

10. n ２ is 4, and n ３ is 0, and X １ is a bond, and Y １ is C(O) and R ５ is Cl, and R ６ is OH and R ７ The compound according to claims 1 and 6, wherein is OH.

11. n ２ is 5, and n ３ is 0, and X １ is a bond, and Y １ is C(O) and R ５ is Cl, and R ６ is OH and R ７ The compound according to claims 1 and 6, wherein is OH.

12. n ２ is 6, and n ３ is 0, and X １ is a bond, and Y １ is C(O) and R ５ is Cl, and R ６ is OH and R ７ The compound according to claims 1 and 6, wherein is OH.

13. n ２ is 7, and n ３ is 0, and X １ is a bond, and Y １ is C(O) and R ５ is Cl, and R ６ is OH and R ７ The compound according to claims 1 and 6, wherein is OH.

14. n ２ is 2, and n ３ is 0, and X １ is a bond, and Y １ is C(O) and R ５ is OH and R ６ is OH and R ７ The compound of claims 1 and 6, wherein is H.

15. n ２ is 3, and n ３ is 0, and X １ is a bond, and Y １ is C(O) and R ５ is OH and R ６ is OH and R ７ 7. The compound of claims 1 and 6, wherein: =H.

16. n ２ is 1, and n ３ is 1, and X １ but, 【Chemical 163】 and Y １ is C(O) and R ５ is OH and R ６ is OH and R ７ The compound of claims 1 and 6, wherein is H.

17. n ２ is 1, and n ３ is 2, and X １ but, 【Chemistry 164】 and Y １ is C(O) and R ５ is OH and R ６ is OH and R ７ The compound of claims 1 and 6, wherein is H.

18. n ２ is 2, and n ３ is 0, and X １ is a bond, and Y １ But SO ２ and R ５ is H and R ６ is OH and R ７ The compound according to claims 1 and 6, wherein is OH.

19. n ２ is 3, and n ３ is 0, and X １ is a bond, and Y １ But SO ２ and R ５ is H and R ６ is OH and R ７ The compound according to claims 1 and 6, wherein is OH.

20. n ２ is 2, and n ３ is 1, and X １ but, 【Chemistry 165】 and Y １ is C(O) and R ５ is Cl, and R ６ is OH and R ７ The compound according to claims 1 and 6, wherein is OH.

21. R １ but, 【Chemistry 166】 and R ２ , R ３ , and R ４ 2. The compound of claim 1, wherein each of

22. n ４ is 1, and Y ２ is C(O) and R ８ is Cl, and R ９ is OH and R １０ 21. The compound of claims 1 and 20, wherein is OH.

23. n ４ is 2, and Y ２ is C(O) and R ８ is Cl, and R ９ is OH and R １０ 21. The compound of claims 1 and 20, wherein is OH.

24. n ４ is 2, and Y ２ But SO ２ and R ８ is H and R ９ is OH and R １０ 21. The compound of claims 1 and 20, wherein is OH.

25. R １ but, 【Chemistry 167】 and R ２ , R ３ , and R ４ 2. The compound of claim 1, wherein each of

26. n ５ 26. The compound of claims 1 and 25, wherein is 2.

27. n ５ 26. The compound of claims 1 and 25, wherein is 3.

28. R １ is OH and R ２ but, 【Chemical 168】 and R ３ and R ４ 2. The compound of claim 1, wherein each of

29. n ６ is 2, and n ７ is 0, and X ２ is a bond, and Y ３ is C(O) and R １１ is Cl, and R １２ is OH and R １３ 30. The compound of claim 1 and 28, wherein is OH.

30. n ６ is 3, and n ７ is 0, and X ２ is a bond, and Y ３ is C(O) and R １１ is Cl, and R １２ is OH and R １３ 30. The compound of claim 1 and 28, wherein is OH.

31. n ６ is 1, and n ７ is 0, and X ２ is a bond, and Y ３ is C(O) and R １１ is OH and R １２ is OH and R １３ 30. The compound of claim 1 and 28, wherein is H.

32. n ６ is 1, and n ７ is 0, and X ２ is a bond, and Y ３ But SO ２ and R １１ is H and R １２ is OH and R １３ 30. The compound of claim 1 and 28, wherein is OH.

33. n ６ is 2, and n ７ is 1, and X ２ but, 【Chemistry 169】 and Y ３ is C(O) and R １１ is Cl, and R １２ is OH and R １３ 30. The compound of claim 1 and 28, wherein is H.

34. R １ is OH and R ３ but, 【Chemistry 170】 and R ２ and R ４ 2. The compound of claim 1, wherein each of

35. n ８ is 1, and n ９ is 0, and X ３ is a bond, and R １４ is Cl, and R １５ is OH and R １６ is OH and R １７ is H and R １８ 35. The compound of claims 1 and 34, wherein is H.

36. n ８ is 2, and n ９ is 0, and X ３ is a bond, and R １４ is Cl, and R １５ is OH and R １６ is OH and R １７ is H and R １８ 35. The compound of claims 1 and 34, wherein is H.

37. n ８ is 2, and n ９ is 3, and X ３ = but, 【Chemistry 171】 and R １４ is H and R １５ is H and R １６ is OH and R １７ is OH and R １８ 35. The compound of claims 1 and 34, wherein is Cl.

38. R １ is OH and R ４ but, 【Chemistry 172】 and R ２ and R ３ 2. The compound of claim 1, wherein each of

39. n １０ is 1, and n １１ is 0, and X ４ is a bond, and R １９ is Cl, and R ２０ is OH and R ２１ is OH and R ２２ is H and R ２３ 40. The compound of claims 1 and 39, wherein is H.

40. n １０ is 1, and n １１ is 3, and X ４ but, 【Chemistry 173】 and R １９ is H and R ２０ is H and R ２１ is OH and R ２２ is OH and R ２３ 40. The compound of claims 1 and 39, wherein is Cl.

41. below Table 3-1 Table 3-2 Table 3-3 Table 3-4 Table 3-5 Table 3-6 Table 3-7 Table 3-8 Table 3-9 Table 3-10 or a pharmaceutically acceptable salt thereof 1. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

42. 42. A pharmaceutical composition comprising any of the compounds of claims 1 to 41, or a pharmaceutically acceptable salt thereof.

43. A pharmaceutical composition comprising any of the compounds of claims 1 to 41 and a pharmaceutically acceptable carrier.

44. 42. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claims 1-41, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.

45. A compound according to claims 1 to 41 or a pharmaceutical composition according to claims 42 to 44 for use in the treatment of a bacterial infectious disease.

46. 46. ​​A method of treating a bacterial infection in a patient in need thereof, comprising administering to said patient a compound of claims 1-41 or a composition of claims 42-44.

47. 46. ​​A method of treating a bacterial infection in a patient in need thereof, comprising administering to said patient a compound of claims 1-41 or a composition of claims 42-44 in combination with another therapeutic agent.

48. 46. ​​A method of controlling, treating, or reducing the progression, severity, or effects of a bacterial infection in a patient, comprising administering to said patient a therapeutically effective amount of a compound of claims 1-41 or a pharmaceutical composition of claims 42-44.

49. 45. A method of reducing or inhibiting bacterial load in a biological sample, comprising contacting said biological sample with a compound according to claims 1-41 or a composition according to claims 42-44.

50. 48. The method of claim 47, wherein the bacteria comprises a gram-positive or gram-negative bacterium.

51. 48. The method of claim 47, wherein the bacteria comprises a gram-positive bacterium.

52. 48. The method of claim 47, wherein the bacteria comprises a gram-negative bacterium.

53. 53. The method of claim 52, wherein the gram-negative bacteria include Acinetobacter baumannii and Escherichia coli.

54. 46. ​​Use of a compound according to any one of claims 1 to 41 or a pharmaceutical composition according to claims 42 to 44 in the manufacture of a medicament for the treatment of a bacterial infectious disease in a patient in need thereof.

55. Use of a compound according to any one of claims 1 to 41 or a pharmaceutical composition according to claims 42 to 44 for the treatment of a bacterial infectious disease associated with Gram-positive bacteria.

56. Use of a compound according to any one of claims 1 to 41 or a pharmaceutical composition according to claims 42 to 44 for the treatment of a bacterial infectious disease associated with gram-negative bacteria.

57. Use of a compound according to any one of claims 1 to 41 or a pharmaceutical composition according to claims 42 to 44 for the treatment of bacterial infectious diseases associated with gram-negative bacteria, including Acinetobacter baumannii and Escherichia coli.

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