Bacitracin derivative, pharmaceutically acceptable salt of bacitracin derivative, preparation method and application of bacitracin derivative, pharmaceutical composition and application of pharmaceutical composition

Abstract

The invention discloses a bacitracin derivative, a pharmaceutically acceptable salt thereof, a preparation method and application of the bacitracin derivative, a pharmaceutical composition and application of the pharmaceutical composition, and relates to the field of medicines. The invention discloses a bacitracin derivative and a pharmaceutically acceptable salt thereof, the structural general formula of the bacitracin derivative is as follows: the bacitracin derivative and the pharmaceutically acceptable salt thereof provided by the invention can be used for treating and / or preventing diseases or virus infectious diseases caused by bacterial infection.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and more specifically, to a bacitracin derivative and a pharmaceutically acceptable salt thereof, a preparation method and use thereof, a pharmaceutical composition and use thereof. Background Art

[0002] Bacterial infections are a major cause of global health loss. With the misuse and abuse of antibiotics, drug-resistant bacterial strains have gradually increased in recent years. The resulting antibiotic resistance has become a major problem threatening public health for all mankind. Therefore, the development of a new generation of antibiotics that are effective against drug-resistant strains is of great urgency and importance. New drug development is a long, high-risk and high-investment process. Compared with other new drug development strategies, optimizing and modifying existing antibiotic molecules to improve efficacy and overcome drug resistance is currently a relatively fast and low-investment effective approach.

[0003] In 2017, the World Health Organization released a list of antibiotic-resistant "priority pathogens," a catalog of 12 bacterial species that pose the greatest threat to human health, to guide and promote the research and development of new antibiotics. Vancomycin-resistant Enterococcus faecium (VRE), methicillin-resistant and intermediate-vancomycin-resistant Staphylococcus aureus (MRSA, VISA), and penicillin-resistant Streptococcus pneumoniae are among the priority resistance-positive strains on the list, urgently requiring new and effective antibiotics.

[0004] Bacitracin was first reported in 1945 and approved for use by the FDA in 1948. Originally isolated from cultures of Bacillus subtilis and Bacillus licheniformis, it is a complex mixture of structurally similar dodecapeptide homologs, including dozens of analogs such as bacitracin A, B1-B3, C1-C3, and F. Bacitracin A and B1-B3 are particularly active. Bacitracin F, an oxidative metabolite of bacitracin A, is nephrotoxic. Bacitracin is a polypeptide antibiotic highly effective against Gram-positive bacteria, particularly Gram-positive rods and cocci, including Staphylococci, Streptococci, Bacillus, Micrococci, and Clostridium. Its antibacterial mechanism is primarily a triple inhibitory mechanism: (1) inhibition of cell wall synthesis: combining with divalent metal ions (Mn(II), Co(II), Ni(II), Cu(II), Zn(II)) to form complexes that inhibit the dephosphorylation of undecaprenyl pyrophosphate; (2) cell membrane damage: increasing cell membrane permeability, leading to the outflow of various intracellular ions, amino acids, purines, and other substances; (3) interference with intracellular protoplasmic protein synthesis, hindering bacterial growth and reproduction. In the past few decades, chemical research on bacitracin has been limited, with the focus primarily on total synthetic modification. Semisynthetic modification of the active site and corresponding structure-activity relationship studies are lacking.

[0005] Currently, bacitracin is primarily used as a topical medication. Its topical preparations are suitable for acute and chronic localized skin infections. It is also occasionally used for intramuscular injection to treat pediatric streptococcal pneumonia and pulmonary edema. Bacitracin is also formulated with neomycin and polymyxin B into an ointment for over-the-counter use. Bacitracin ointment, formulated with neomycin, polymyxin B, and hydrocortisone, is indicated for the treatment of corticosteroid-responsive skin diseases with secondary infections.

[0006] Schematic diagram of the structure of some components of bacitracin:

[0007]

[0008] Therefore, bacitracin is an attractive candidate antibiotic molecule for modification, and its unique mechanism of action can effectively avoid the occurrence of cross-resistance. Summary of the Invention

[0009] The purpose of the present invention is to provide a bacitracin derivative and a pharmaceutically acceptable salt thereof, a preparation method and use thereof, a pharmaceutical composition and use thereof, so as to solve the above problems.

[0010] According to the first aspect of the present invention, a bacitracin derivative and a pharmaceutically acceptable salt thereof are provided. The general structural formula of the bacitracin derivative is as follows:

[0011]

[0012] wherein R1 and R2 are each independently selected from substituted or unsubstituted C1-C 20 Straight chain or branched alkyl, substituted or unsubstituted C4-C 20 Straight chain or branched chain alkanoyl, substituted or unsubstituted C4-C 20 Straight chain or branched alkenyl, substituted or unsubstituted C4-C 20 Straight chain or branched alkynyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 20 Aryl, 3-10 membered non-aromatic heterocyclic group containing one or more heteroatoms selected from N, O and S in the substituted or unsubstituted ring, 5-10 membered heteroaryl group containing one or more heteroatoms selected from N, O and S in the substituted or unsubstituted ring; the substitution refers to substitution by one or more substituents selected from the following: halogen, -OH, -NH2, cyano, C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Alkylamino, C1-C 10 Alkanoyl, C3-C 10 Cycloalkyl, halogenated C1-C 10Alkyl, C2-C6 straight-chain or branched alkynyl, phenylethynyl, trimethylsilylethynyl, pyridyl, phenyl, cyanophenyl, C1-C6 alkylphenyl, trifluoromethylphenyl, chlorophenyl, biphenyl, methylbiphenyl, trifluoromethylbiphenyl, halogen-substituted biphenyl.

[0013] Preferably, the bacitracin derivatives and pharmaceutically acceptable salts thereof include compounds of the following structural formula:

[0014]

[0015]

[0016]

[0017]

[0018]

[0019] The second aspect of the present application provides a method for preparing the bacitracin derivative and a pharmaceutically acceptable salt thereof, comprising:

[0020] The bacitracin derivative is obtained by subjecting bacitracin to one or more of reductive amination reaction, acylation reaction, substitution reaction and epoxy ring-opening reaction.

[0021] The third aspect of the present application provides a use of the bacitracin derivative and a pharmaceutically acceptable salt thereof for preparing a medicament for treating and / or preventing diseases related to bacterial infection.

[0022] The bacteria are Gram-negative bacteria and / or Gram-positive bacteria.

[0023] Optionally, the disease includes one or more of bacteremia, sepsis, pneumonia, meningitis, urinary tract infection, impetigo, erysipelas, cellulitis, skin infection, and Clostridium difficile infection.

[0024] The fourth aspect of the present application provides a pharmaceutical composition comprising the bacitracin derivative and a pharmaceutically acceptable salt thereof.

[0025] The fifth aspect of the present application provides a use of the pharmaceutical composition for preparing a drug for treating and / or preventing diseases related to bacterial infection, wherein the bacteria are Gram-negative bacteria and / or Gram-positive bacteria.

[0026] Optionally, the disease includes one or more of bacteremia, sepsis, pneumonia, meningitis, urinary tract infection, impetigo, erysipelas, cellulitis, skin infection, and Clostridium difficile infection.

[0027] The technical content disclosed in the present invention has the following beneficial effects:

[0028] The bacitracin derivatives and pharmaceutically acceptable salts and pharmaceutical compositions provided herein can be used to treat and / or prevent diseases caused by bacterial infections or viral infections.

[0029] Further features and advantages of the present invention will become apparent from the following detailed description of exemplary embodiments of the present invention with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and, together with the description, serve to explain the principles of the invention.

[0031] Figure 1 This is a bar graph of cell viability in the kidney cell toxicity experiment in biological test example 2;

[0032] Figure 2 This is a bar graph of the antiviral activity of biological test example 3. DETAILED DESCRIPTION

[0033] Various exemplary embodiments of the present invention will now be described in detail with reference to the accompanying drawings. It should be noted that unless otherwise specifically stated, the relative arrangement of components and steps, numerical expressions and numerical values ​​set forth in these embodiments do not limit the scope of the present invention.

[0034] The following description of at least one exemplary embodiment is merely illustrative in nature and is in no way intended to limit the invention, its application, or uses.

[0035] Technologies, methods, and equipment known to ordinary technicians in the relevant art may not be discussed in detail, but where appropriate, the technologies, methods, and equipment should be considered part of the specification.

[0036] In all examples shown and discussed herein, any specific values ​​should be interpreted as merely exemplary and not limiting. Therefore, other examples of the exemplary embodiments may have different values.

[0037] It should be noted that like reference numerals and letters refer to like items in the following figures, and therefore, once an item is defined in one figure, it need not be further discussed in subsequent figures.

[0038] First, an overall introduction to the technical solution provided by this application is given:

[0039] The general structural formula of the bacitracin derivative provided in this application is shown in the following formula (I):

[0040]

[0041] wherein R1 and R2 are each independently selected from substituted or unsubstituted C1-C 20 Straight chain or branched alkyl, substituted or unsubstituted C4-C 20 Straight chain or branched chain alkanoyl, substituted or unsubstituted C4-C 20 Straight chain or branched alkenyl, substituted or unsubstituted C4-C 20 Straight chain or branched alkynyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 20 Aryl, 3-10 membered non-aromatic heterocyclic group containing one or more heteroatoms selected from N, O and S in the substituted or unsubstituted ring, 5-10 membered heteroaryl group containing one or more heteroatoms selected from N, O and S in the substituted or unsubstituted ring; the substitution refers to substitution by one or more substituents selected from the following: halogen, -OH, -NH2, cyano, C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Alkylamino, C1-C 10 Alkanoyl, C3-C 10 Cycloalkyl, halogenated C1-C 10 Alkyl, C2-C6 straight-chain or branched alkynyl, phenylethynyl, trimethylsilylethynyl, pyridyl, phenyl, cyanophenyl, C1-C6 alkylphenyl, trifluoromethylphenyl, chlorophenyl, biphenyl, methylbiphenyl, trifluoromethylbiphenyl, halogen-substituted biphenyl.

[0042] Some of the bacitracin derivatives provided in this application are listed and their structural formulas are numbered, as shown in Table 1 below:

[0043] Table 1 Structural formula list

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050]

[0051] In general, exemplary, the above substances can be obtained by the following method:

[0052] The bacitracin derivatives of the present invention are obtained by reductive amination, acylation, substitution, and epoxy ring-opening reaction of bacitracin. The preparation of specific compounds can be carried out according to the specific reaction conditions in the examples.

[0053] The reductive amination reaction can be carried out at room temperature to 50° C., preferably at 37° C. In the SN2 ring-opening substitution reaction of the bacitracin derivative intermediate with the epoxide, the equivalent ratio of the epoxide can be 10-40 times that of the bacitracin intermediate, and the reaction solvent can be glacial acetic acid.

[0054] Specifically, the reductive amination reaction method can be the following three preparation methods:

[0055] Method 1: Selectively reductively aminating the amino group of ornithine at position 7 of bacitracin to obtain a bacitracin derivative represented by formula (I) (taking bacitracin A component as an example):

[0056]

[0057] Wherein, R3 is selected from substituted or unsubstituted C2-C 18 Straight chain or branched alkyl; substituted or unsubstituted C2-C 18 Straight chain or branched alkenyl, substituted or unsubstituted C2-C 18 Straight or branched alkynyl; the above substitution means being substituted by one or more substituents selected from the following: halogen, -OH, -NH2, cyano, C1-C 10 Alkyl (preferably C1-C6 alkyl, more preferably C1-C4 alkyl, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, etc.), C1-C 10 Alkoxy (preferably C1-C6 alkoxy, more preferably C1-C4 alkoxy, for example, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, etc.), C1-C 10 Alkylamino (preferably C1-C6 alkylamino, more preferably C1-C4 alkylamino, for example, methylamino, ethylamino, propylamino, butylamino, pentylamino, hexylamino, heptylamino, etc.), C1-C 10 Alkanoyl (preferably C1-C6 alkanoyl, more preferably C1-C4 alkanoyl, for example, formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl, heptanoyl, etc.), C3-C 10 Cycloalkyl, halogenated C1-C 10 Alkyl (preferably halogenated C1-C6 alkyl, more preferably halogenated C1-C4 alkyl, such as trifluoromethyl), C2-C6 straight-chain or branched alkynyl, phenylethynyl, trimethylsilylethynyl, pyridyl, phenyl, cyanophenyl, C1-C6 alkylphenyl, trifluoromethylphenyl, chlorophenyl, biphenyl, methylbiphenyl, trifluoromethylbiphenyl, halogen-substituted biphenyl.

[0058] The reductive amination reaction is carried out in a reaction solvent, which may be DMF.

[0059] The reducing agent required for the reductive amination reaction is preferably sodium acetate borohydride.

[0060] Method 2: Selectively reductively aminating the amino group of the amino acid at position 1 of bacitracin to obtain a bacitracin derivative represented by formula (I) (taking bacitracin A component as an example):

[0061]

[0062] Wherein, R4 is selected from substituted or unsubstituted C2-C 18 Straight chain or branched alkyl; substituted or unsubstituted C2-C 18 Straight chain or branched alkenyl, substituted or unsubstituted C2-C 18 Straight or branched alkynyl; the above substitution means being substituted by one or more substituents selected from the following: halogen, -OH, -NH2, cyano, C1-C 10 Alkyl (preferably C1-C6 alkyl, more preferably C1-C4 alkyl, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, etc.), C1-C 10 Alkoxy (preferably C1-C6 alkoxy, more preferably C1-C4 alkoxy, for example, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, etc.), C1-C 10 Alkylamino (preferably C1-C6 alkylamino, more preferably C1-C4 alkylamino, for example, methylamino, ethylamino, propylamino, butylamino, pentylamino, hexylamino, heptylamino, etc.), C1-C 10 Alkanoyl (preferably C1-C6 alkanoyl, more preferably C1-C4 alkanoyl, for example, formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl, heptanoyl, etc.), C3-C 10 Cycloalkyl, halogenated C1-C 10 Alkyl (preferably halogenated C1-C6 alkyl, more preferably halogenated C1-C4 alkyl, such as trifluoromethyl), C2-C6 straight-chain or branched alkynyl, phenylethynyl, trimethylsilylethynyl, pyridyl, phenyl, cyanophenyl, C1-C6 alkylphenyl, trifluoromethylphenyl, chlorophenyl, biphenyl, methylbiphenyl, trifluoromethylbiphenyl, halogen-substituted biphenyl.

[0063] The reductive amination reaction is carried out in a reaction solvent, which may be a mixed solvent of water and acetonitrile.

[0064] The reducing agent required for the reductive amination reaction is preferably sodium cyanoborohydride.

[0065] Method 3: Perform a double-site reductive amination reaction on the amino group of amino acid 1 and amino acid 7 of bacitracin to obtain a bacitracin derivative represented by formula (I) (taking bacitracin A component as an example):

[0066]

[0067] Wherein, R5 is selected from substituted or unsubstituted C2-C 18 Straight chain or branched alkyl; substituted or unsubstituted C2-C 18 Straight chain or branched alkenyl, substituted or unsubstituted C2-C 18 Straight or branched alkynyl; the above substitution means being substituted by one or more substituents selected from the following: halogen, -OH, -NH2, cyano, C1-C 10 Alkyl (preferably C1-C6 alkyl, more preferably C1-C4 alkyl, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, etc.), C1-C 10 Alkoxy (preferably C1-C6 alkoxy, more preferably C1-C4 alkoxy, for example, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, etc.), C1-C 10 Alkylamino (preferably C1-C6 alkylamino, more preferably C1-C4 alkylamino, for example, methylamino, ethylamino, propylamino, butylamino, pentylamino, hexylamino, heptylamino, etc.), C1-C 10 Alkanoyl (preferably C1-C6 alkanoyl, more preferably C1-C4 alkanoyl, for example, formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl, heptanoyl, etc.), C3-C 10 Cycloalkyl, halogenated C1-C 10 Alkyl (preferably halogenated C1-C6 alkyl, more preferably halogenated C1-C4 alkyl, such as trifluoromethyl), C2-C6 straight-chain or branched alkynyl, phenylethynyl, trimethylsilylethynyl, pyridyl, phenyl, cyanophenyl, C1-C6 alkylphenyl, trifluoromethylphenyl, chlorophenyl, biphenyl, methylbiphenyl, trifluoromethylbiphenyl, halogen-substituted biphenyl.

[0068] The reductive amination reaction is carried out in a reaction solvent, which may be a mixed solvent of water and acetonitrile.

[0069] The reducing agent required for the reductive amination reaction is preferably sodium cyanoborohydride.

[0070] The reductive amination reaction requires an excess of the aldehyde reagent, which may be 2 to 3 equivalents.

[0071] The present invention also provides the use of a bacitracin derivative represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing diseases or conditions associated with Gram-positive bacteria, Gram-negative bacteria or viral infection.

[0072] The present invention also provides a pharmaceutical composition comprising the bacitracin derivative represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0073] The present invention also provides use of the pharmaceutical composition in preparing a drug for treating and / or preventing diseases or conditions related to Gram-positive bacteria infection or Gram-negative bacteria infection or viral infection.

[0074] The diseases or conditions associated with Gram-positive or Gram-negative bacterial infection include bacteremia, sepsis, pneumonia, meningitis, urinary tract infection, impetigo, erysipelas, cellulitis, skin infection, Clostridium difficile infection, etc.

[0075] The virus is preferably respiratory syncytial virus.

[0076] The viral infection disease is preferably a respiratory tract infection disease.

[0077] In the present invention, the term "aryl" refers to an aromatic ring group containing no heteroatoms, such as phenyl, naphthyl, biphenyl and the like.

[0078] In the present invention, the term "heteroaryl" refers to an aromatic group containing one or more heteroatoms in the ring, such as pyrrolyl, imidazolyl, oxazolyl, thiazolyl, furanyl, thienyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, etc.

[0079] In the present invention, the term "non-aromatic heterocyclic group" refers to tetrahydrofuran, 1,4-dioxane, tetrahydropyrrole and the like.

[0080] In the present invention, the term "cycloalkyl" refers to a saturated alicyclic hydrocarbon group, such as cyclohexane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane and the like.

[0081] In the present invention, the term "C4-C 20 "Alkyl" refers to a straight or branched chain alkyl group having 4 to 20 carbon atoms in the main chain.

[0082] In the present invention, the term "C4-C 20 The term "straight-chain or branched-chain alkenyl" refers to a straight-chain or branched-chain alkenyl group having 4 to 20 carbon atoms in the main chain.

[0083] In the present invention, the term "C4-C 20 The term "straight-chain or branched-chain alkynyl group" refers to a straight-chain or branched-chain alkynyl group having 4 to 20 carbon atoms in the main chain.

[0084] The term "pharmaceutically acceptable salt" in the present invention refers to a salt formed with an inorganic acid such as phosphoric acid, sulfuric acid, or hydrochloric acid, or an organic acid such as acetic acid, tartaric acid, citric acid, malic acid, or trifluoroacetic acid, or an acidic amino acid such as aspartic acid or glutamic acid, or a salt formed with the above-mentioned acid after forming an ester or amide and then with an inorganic base, such as sodium, potassium, calcium, aluminum salt, and ammonium salt.

[0085] For the following examples, standard operations and purification methods known to those skilled in the art can be used. Unless otherwise specified, raw materials are generally available from commercial sources, such as Aldrich Chemicals Co. and Acros Organics. Commercially available solvents and reagents are generally used without further purification, anhydrous solvents are treated by standard methods, and other reagents are commercially available analytical grade. Unless otherwise stated, all temperatures are expressed in degrees Celsius, and room temperature or ambient temperature refers to 20-25°C. The structures of the compounds are determined by nuclear magnetic resonance spectroscopy (NMR) and / or mass spectrometry (MS).

[0086] H NMR shifts (δ) are given in parts per million (ppm). H NMR spectra were measured using a Mercury-600 MHz and a Bruker (AV-400) 400 MHz NMR spectra, using deuterated dimethyl sulfoxide (DMSO-d6) and deuterated water (D2O) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0087] High-resolution mass spectra were measured using an Agilent 6230 series TOF LC-MS. When describing the intensity of ions containing chloride or bromide, the expected intensity ratio was observed (approximately 3:1 for ions containing 35Cl / 37Cl and 1:1 for ions containing 79Br / 81Br), and only the intensity of the lower mass ions was given.

[0088] HPLC: -3030 analytical high performance liquid chromatography system (Shanghai Tongwei Analytical Technology Co., Ltd.) and -3050 preparative HPLC system (Shanghai Tongwei Analytical Technology Co., Ltd.). Analytical HPLC conditions: C18 column (Welch 5μm, 4.6×250mm), UV detection band at 214 and 254nm, elution condition 2-80% acetonitrile (containing 0.1% v / v TFA) gradient elution over 20 minutes. Preparative HPLC conditions: C18 column (Welch 5 μm, 21.2×250 mm), the UV detection bands were 254 and 280 nm, and the elution conditions were 2-90% acetonitrile (containing 0.1% v / v TFA) gradient washing over 30 min.

[0089] In the above discussion and the following examples, the following abbreviations have the following meanings. If an abbreviation is not defined, it has the generally accepted meaning.

[0090] DMF is N,N-dimethylformamide;

[0091] TFA is trifluoroacetic acid;

[0092] DIPEA is diisopropylethylamine;

[0093] MTBE is methyl tert-butyl ether.

[0094] Example 1:

[0095]

[0096] Commercially available bacitracin (71 mg, 0.05 mmol) was dissolved in 2 mL of DMF in a single-necked reaction flask and stirred. Propionaldehyde (4.3 μL, 0.06 mmol) was pipetted into the reaction mixture and stirred for 2 minutes at room temperature. Sodium acetate borohydride (21 mg, 0.1 mmol) was then weighed and added to the reaction mixture. Stirring was continued, and the reaction progress was monitored by analytical reverse-phase high-performance liquid chromatography (RP-HPLC). When the reaction ceased, the reaction mixture was pipetted and added dropwise to a 50 mL centrifuge tube containing 30 mL of MTBE. After centrifugation, the supernatant was discarded, and the precipitated solid was collected and purified by preparative reverse-phase HPLC. The collected target fraction was lyophilized to yield Bac001 (16 mg, 22% yield) as a white, fluffy solid.

[0097] Retention time (RT) = 14.668 min, 1H NMR(600MHz,DMSO-d6 with 20μLD2O)δ9.00–8.88(m,1H),8.63(d,J=9.1Hz,1H),8.38(d,J=8.9Hz,1H),8.27(d,J=8.2Hz,1H),8.07(d,J=8.9Hz,1H),7.8 5(d,J=8.8Hz,1H),7.82(d,J=8.4Hz,1H),7.30(s,1H),7.26–7.19(m,4H),7.14(t,J=6.7Hz,1H),4.89–4.80(m,1H),4.73(dd ,J=8.6,5.0Hz,1H),4.67(dd,J=11.2,4.0Hz,1H),4.51(dd,J=7.9,5.5Hz,1H),4.49–4.42(m,2H),4.38(dd,J=8.8,4.9Hz,1H ),4.31–4.23(m,2H),4.23–4.17(m,1H),4.16(dd,J=9.5,4.9Hz,1H),3.70(t,J=10.6Hz,1H),3.56(dd,J=11.3,7.7Hz,1H),3. 10–2.98(m,2H),2.98–2.91(m,1H),2.89–2.81(m,3H),2.81–2.70(m,3H),2.70–2.58(m,1H),2.50–2.42(m,3H),2.40–2.34( m,1H),2.20(td,J=13.1,11.1,6.8Hz,2H),1.96–1.85(m,2H),1.83–1.70(m,2H),1.66–1.59(m,2H),1.59–1.53(m,2H),1.53 –1.39(m,9H),1.39–1.28(m,3H),1.27–1.16(m,3H),1.13–1.02(m,1H),0.97(d,J=6.9Hz,3H),0.95–0.91(m,1H),0.91–0.86(m,9H),0.84(d,J=5.9Hz,3H),0.82–0.75(m,6H),0.75–0.64(m,1H),0.50(t,J=7.5Hz,3H),0.48(d,J=6.7Hz,3H). High resolution mass spectrometry (ESI) + )C 69 H 109 N 17 O 16 S[M+2H] 2+ The theoretical value is m / z 732.9053, and the measured value is m / z 732.9065.

[0098] Example 2:

[0099]

[0100] The propionaldehyde in Example 1 was replaced with butyraldehyde, and the remaining raw materials, reagents, and preparation method were the same as in Example 1 to obtain Bac002 (19 mg, yield 26%). RT = 14.912 min (analytical RP-HPLC). 11H NMR (600 MHz, DMSO-d6) δ 8.96 (d, J = 1.4 Hz, 1H), 8.63 (d, J = 9.1 Hz, 1H), 8.38 (d, J = 8.9 Hz, 1H), 8.27 (d, J = 8.1 Hz, 1H), 8.07 (d, J = 8.9 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.30 (s, 1H), 7.26–7.18 (m, 4H), 7.17–7.10 (m, 1H), 5.17 (ddd, J = 9.8, 7.7, 1.8 Hz, 1H), 4.91–4.79 (m, 1H), 4.73 (dd, J = 8.6, 5.0 Hz, 1H), 4.67 (dd, J = 11.3, 3.9 Hz, 1H), 4.51 (dd, J = 7.9, 5.5 Hz, 1H), 4.47 (td, J = 6.6, 5.9, 2.6 Hz, 2H), 4.38 (dd, J = 8.8, 5.0 Hz, 1H), 4.31–4.23 (m, 2H), 4.20 (t, J = 6.8 Hz, 1H), 4.16 (dd, J = 9.5, 4.8 Hz, 1H), 3.70 (t, J = 10.7 Hz, 1H), 3.56 (dd, J = 11.3, 7.7 Hz, 1H), 3.02 (ddd, J = 16.1, 11.9, 5.9 Hz, 2H), 2.94 (p, J = 6.6 Hz, 1H), 2.92–2.79 (m, 5H), 2.80–2.73 (m, 1H), 2.69–2.59 (m, 1H), 2.51–2.40 (m, 3H), 2.41–2.31 (m, 1H), 2.20 (td, J = 13.0, 11.0, 6.8 Hz, 2H), 1.91 (qd, J = 11.8, 9.8, 5.4 Hz, 2H), 1.83–1.71 (m, 2H), 1.68–1.57 (m, 2H), 1.56–1.40 (m, 12H), 1.39–1.25 (m, 5H), 1.25–1.17 (m, 3H), 1.14– 1.02 (m, 1H), 0.97 (d, J = 6.9 Hz, 3H), 0.91–0.85 (m, 9H), 0.84 (d, J = 6.0 Hz, 3H), 0.82–0.75 (m, 6H), 0.75–0.64 (m, 1H), 0.50 (t, J = 7.4 Hz, 3H), 0.48 (d, J = 6.7 Hz, 3H). High resolution mass spectrometry (ESI + ) C 70 H 111 N 17 O 16 S [M+2H] 2+The theoretical value is m / z 739.9131, and the measured value is m / z 739.9144.

[0101] Example 3:

[0102]

[0103] The propionaldehyde in Example 1 was replaced by valeraldehyde, and the remaining raw materials, reagents, and preparation method were the same as in Example 1 to obtain Bac003 (19 mg, yield 25%). RT = 15.263 min (analytical RP-HPLC). 1H NMR (600MHz, DMSO-d6) δ8.95(s,1H),8.63(d,J=9.1Hz,1H),8.38(d,J=8.8Hz,1H),8.27(d,J=8.1Hz,1H),8.07(d,J=8.9Hz,1H ),7.85(d,J=8.6Hz,1H),7.82(d,J=8.3Hz,1H),7.30(s,1H),7.27–7.17(m,4H),7.17–7.10(m,1H),5.17(ddd,J=9.8,7.7,1.8H z,1H),4.87–4.80(m,1H),4.73(dd,J=8.6,5.1Hz,1H),4.67(dd,J=11.3,3.8Hz,1H),4.51(dd,J=7.9,5.5Hz,1H),4.49–4.41(m ,2H),4.38(dd,J=8.8,5.0Hz,1H),4.31–4.24(m,2H),4.24–4.17(m,1H),4.17–4.14(m,1H),3.74–3.65(m,1H),3.56(dd,J=11. 3,7.7Hz,1H),3.07–2.98(m,2H),2.98–2.91(m,1H),2.82(ddq,J=28.9,20.7,11.1,9.7Hz,6H),2.69–2.58(m,1H),2.50–2.41( m,2H),2.41–2.32(m,1H),2.20(td,J=13.1,11.1,6.7Hz,2H),1.96–1.84(m,2H),1.83–1.70(m,2H),1.66–1.57(m,2H),1.57–1 .40(m,12H),1.39–1.31(m,3H),1.31–1.24(m,4H),1.24–1.15(m,3H),1.13–1.02(m,1H),0.97(d,J=6.9Hz,3H),0.91–0.85(m,10H),0.84(d,J=6.0Hz,3H),0.79(q,J=7.3Hz,6H),0.74–0.65(m,1H),0.51(t,J=7.3Hz,3H),0.48(d,J=6.8Hz,3H). High resolution mass spectrometry (ESI + )C 71 H 113 N 17 O 16 S[M+2H] 2+ The theoretical value is m / z746.9209, and the measured value is m / z746.9210.

[0104] Example 4:

[0105]

[0106] The propionaldehyde in Example 1 was replaced with methylthiopropionaldehyde, and the remaining raw materials, reagents, and preparation method were the same as in Example 1 to obtain Bac004 (18 mg, yield 23%). RT = 14.852 min (analytical RP-HPLC). 11H NMR (600 MHz, DMSO-d6) δ 8.99–8.89 (m, 1H), 8.63 (d, J = 9.1 Hz, 1H), 8.37 (dd, J = 8.4, 3.4 Hz, 1H), 8.27 (d, J = 8.1 Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 8.9 Hz, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.30 (s, 1H), 7.26–7.19 (m, 4H), 7.14 (t, J = 6.7 Hz, 1H), 5.17 (t, J = 9.7 Hz, 1H), 4.87–4.80 (m, 1H), 4.73 (dd, J = 8.6, 5.0 Hz, 1H), 4.70–4.62 (m, 1H), 4.51 (dd, J = 7.9, 5.5 Hz, 1H), 4.49–4.42 (m, 2H), 4.38 (dd, J = 8.8, 5.1 Hz, 1H), 4.31–4.24 (m, 2H), 4.24–4.18 (m, 1H), 4.19–4.11 (m, 1H), 3.70 (t, J = 10.6 Hz, 1H), 3.56 (dd, J = 11.3, 7.7 Hz, 1H), 3.07–2.97 (m, 2H), 2.98–2.88 (m, 4H), 2.89–2.80 (m, 2H), 2.80–2.73 (m, 1H), 2.65 (dd, J = 16.2, 4.8 Hz, 1H), 2.49–2.41 (m, 2H), 2.37 (dd, J = 15.1, 8.0 Hz, 1H), 2.20 (td, J = 13.5, 11.3, 6.9 Hz, 2H), 2.04 (s, 3H), 1.96–1.86 (m, 2H), 1.82 (p, J = 7.2 Hz, 2H), 1.80–1.70 (m, 2H), 1.68–1.56 (m, 2H), 1.57–1.39 (m, 10H), 1.39–1.29 (m, 3H), 1.28–1.15 (m, 3H), 1.13–1.02 (m, 1H), 0.97 (d, J = 6.9 Hz, 3H), 0.91–0.85 (m, 6H), 0.84 (d, J = 5.9 Hz, 3H), 0.82–0.76 (m, 6H), 0.70 (ddd, J = 20.7, 13.9, 7.4 Hz, 1H), 0.50 (t, J = 7.5 Hz, 3H), 0.48 (d, J = 6.7 Hz, 3H). High resolution mass spectrometry (ESI + ) C 70 H 111 N 17 O 16 S2[M + 2H] 2+The theoretical value is m / z 755.8991, and the measured value is m / z 755.8974.

[0107] Example 5:

[0108]

[0109] The propionaldehyde in Example 1 was replaced by hexanal, and the remaining raw materials, reagents and preparation method were the same as in Example 1 to obtain Bac005 (20 mg, yield 27%). RT = 15.523 min (analytical RP-HPLC). 1H NMR (600MHz, DMSO-d6) δ8.96(s,1H),8.63(d,J=9.1Hz,1H),8.37(d,J=8.6Hz,1H),8.26(d,J=8.0Hz,1H),8.06(d,J=8. 8Hz,1H),7.84(dd,J=12.1,8.3Hz,1H),7.30(s,1H),7.26–7.19(m,4H),7.14(t,J=6.8Hz,1H),5.17(ddd,J=9.8,7.7,1 .8Hz,1H),4.83(td,J=8.9,4.4Hz,1H),4.73(dd,J=8.6,5.1Hz,1H),4.70–4.63(m,1H),4.51(dd,J=7.9,5.5Hz,1H),4. 49–4.42(m,2H),4.38(dd,J=8.8,5.0Hz,1H),4.32–4.24(m,2H),4.23–4.18(m,1H),4.18–4.11(m,1H),3.70(t,J=10.6 Hz,1H),3.56(dd,J=11.3,7.6Hz,1H),3.07–2.98(m,2H),2.98–2.91(m,1H),2.82(ddt,J=27.3,19.1,9.8Hz,6H),2.69 –2.61(m,1H),2.49–2.43(m,2H),2.37(dd,J=15.2,8.0Hz,1H),2.24–2.15(m,2H),1.97–1.85(m,2H),1.84–1.70(m,2H ),1.66–1.57(m,2H),1.57–1.39(m,12H),1.39–1.31(m,3H),1.31–1.15(m,10H),1.14–1.01(m,1H),0.97(d,J=6.9Hz,3H),0.91–0.82(m,13H),0.82–0.75(m,7H),0.75–0.65(m,1H),0.51(d,J=7.2Hz,3H),0.48(d,J=6.8Hz,3H). High resolution mass spectrometry (ESI + )C 72 H 115 N 17 O 16 S[M+2H] 2+ The theoretical value is m / z 753.9287, and the measured value is m / z 753.9293.

[0110] Example 6:

[0111]

[0112] The propionaldehyde in Example 1 was replaced by hexanal, and the remaining raw materials, reagents and preparation method were the same as in Example 1 to obtain Bac006 (8 mg, yield 10%). RT = 17.178 min (analytical RP-HPLC). 1 H NMR (600MHz, DMSO-d6) δ8.95(s,1H),8.64(d,J=9.1Hz,1H),8.36(d,J=8.1Hz,1H),8.26(d,J=8.0Hz,1H),8.09(d, J=9.1Hz,1H),7.87(d,J=8.4Hz,1H),7.84(d,J=8.2Hz,1H),7.30(s,1H),7.24–7.18(m,4H),7.16–7.10(m,1H),5. 17(ddd,J=9.8,7.7,1.7Hz,1H),4.89–4.80(m,1H),4.77–4.64(m,2H),4.54–4.42(m,3H),4.38(dd,J=8.7,5.0Hz, 1H), 4.32 (q, J=4.7, 3.3Hz, 1H), 4.27 (dd, J=3.9, 1.7Hz, 1H), 4.18 (t, J=6.6Hz, 1H), 4.13 (td, J=8.1, 7.7, 3.7Hz, 1H ),3.72–3.64(m,1H),3.56(dd,J=11.2,7.7Hz,1H),3.08(q,J=10.4,10.0Hz,1H),3.04–2.90(m,8H),2.84(dd,J=1 5.2,9.2Hz,1H),2.76(d,J=12.6Hz,1H),2.67–2.59(m,1H),2.49–2.43(m,2H),2.41–2.32(m,1H),2.20(td,J=13. 0,10.9,6.7Hz,2H),1.99–1.85(m,2H),1.83–1.71(m,2H),1.66–1.40(m,16H),1.40–1.32(m,3H),1.24–1.14(m,3H),1.14–1.02(m,1H),0.97(d,J=6.9Hz,3H),0.91–0.75(m,26H),0.75–0.64(m,1H),0.52–0.46(m,7H). High resolution mass spectrometry (ESI + )C 78 H 127 N 17 O 16 S[M+2H] 2+ The theoretical value is m / z 795.9757, and the measured value is m / z 795.9759.

[0113] Example 7:

[0114]

[0115] The propionaldehyde in Example 1 was replaced with heptanal, and the remaining raw materials, reagents, and preparation method were the same as in Example 1 to obtain Bac007 (15 mg, yield 20%). RT = 16.087 min (analytical RP-HPLC). 1 H NMR (600MHz, DMSO-d6) δ8.95(s,1H),8.63(d,J=9.0Hz,1H),8.37(d,J=8.0Hz,2H),8.27(d,J=8.1Hz,1H),8.07(d,J= 8.9Hz,1H),7.85(d,J=8.6Hz,1H),7.83(d,J=8.3Hz,1H),7.51(d,J=8.1Hz,1H),7.30(s,1H),7.25–7.18(m,4H),7.14 (t,J=6.9Hz,1H),5.17(t,J=8.6Hz,1H),4.83(td,J=8.9,4.9Hz,1H),4.73(dd,J=8.6,5.1Hz,1H),4.71–4.64(m,1H), 4.51(dd,J=7.9,5.6Hz,1H),4.50–4.43(m,2H),4.42–4.36(m,1H),4.32–4.23(m,2H),4.23–4.17(m,1H),4.18–4.12( m,1H),3.70(t,J=10.6Hz,1H),3.56(dd,J=11.3,7.6Hz,1H),3.06–2.98(m,2H),2.98–2.90(m,1H),2.90–2.72(m,6H ),2.70–2.60(m,1H),2.49–2.41(m,3H),2.37(dd,J=15.2,8.1Hz,1H),2.20(td,J=7.5,6.2,3.3Hz,2H),1.96–1.85(m ,2H),1.82–1.71(m,3H),1.68–1.56(m,2H),1.57–1.40(m,12H),1.39–1.30(m,3H),1.31–1.15(m,13H),1.13–1.03(m,1H),0.97(d,J=7.0Hz,3H),0.91–0.83(m,13H),0.82–0.76(m,6H),0.75–0.65(m,1H),0.53–0.46(m,6H). High resolution mass spectrometry (ESI + )C 73 H117 N 17 O 16 S[M+2H] 2+ The theoretical value is m / z 760.9366, and the measured value is m / z 760.9389.

[0116] Example 8:

[0117]

[0118] The propionaldehyde in Example 1 was replaced with 6-heptynal, and the remaining raw materials, reagents, and preparation method were the same as in Example 1 to obtain Bac008 (15 mg, yield 20%). RT = 15.282 min (analytical RP-HPLC). 1H NMR (600MHz, DMSO-d6) δ8.96(s,1H),8.63(d,J=9.1Hz,1H),8.37(d,J=8.8Hz,1H),8.26(d,J=8.0Hz,1H),8.06(d,J=8.8Hz,1H),7 .89–7.77(m,1H),7.30(s,1H),7.26–7.18(m,4H),7.14(t,J=6.8Hz,1H),5.17(t,J=8.8Hz,1H),4.83(td,J=9.0,4.7Hz,1H),4.73 (dd,J=8.6,5.1Hz,1H),4.70–4.60(m,1H),4.51(dd,J=7.9,5.5Hz,1H),4.50–4.41(m,2H),4.38(dd,J=8.8,5.0Hz,1H),4.31–4.2 3(m,2H),4.23–4.17(m,1H),4.16(dd,J=9.5,5.1Hz,1H),3.70(t,J=10.7Hz,1H),3.60–3.55(m,1H),3.09–2.98(m,2H),2.98–2.9 1(m,1H),2.91–2.77(m,6H),2.74(t,J=2.7Hz,1H),2.65(dd,J=16.3,4.8Hz,1H),2.50–2.43(m,2H),2.38(dd,J=15.2,8.0Hz,1H) ,2.20(td,J=7.6,6.1,3.0Hz,2H),2.15(td,J=6.9,2.7Hz,2H),1.96–1.86(m,2H),1.83–1.70(m,2H),1.67–1.58(m,2H),1.58–1. 51(m,3H),1.46(dq,J=21.7,6.6Hz,10H),1.40–1.30(m,5H),1.27–1.15(m,3H),1.13–1.02(m,1H),0.97(d,J=6.8Hz,3H),0.91–0.85(m,6H),0.84(d,J=6.0Hz,3H),0.82–0.74(m,6H),0.74–0.64(m,1H),0.51(t,J=7.4Hz,3H),0.48(d,J=6.7Hz,3H). High resolution mass spectrometry (ESI + )C 73 H 113 N 17 O 16 S[M+2H] 2+ The theoretical value is m / z 758.9209, and the measured value is m / z 758.9223.

[0119] Example 9:

[0120]

[0121] The propionaldehyde in Example 1 was replaced with octanal, and the remaining raw materials, reagents, and preparation method were the same as in Example 1 to obtain Bac009 (16 mg, yield 21%). RT = 16.542 min (analytical RP-HPLC). 1 H NMR (600MHz, DMSO-d6) δ8.95(s,1H),8.63(d,J=9.0Hz,1H),8.37(d,J=8.0Hz,2H),8.27(d,J=8.1Hz,1H),8.07(d,J=8 .8Hz,1H),7.85(d,J=8.7Hz,1H),7.83(d,J=8.3Hz,1H),7.51(d,J=8.1Hz,1H),7.30(s,1H),7.25–7.19(m,4H),7.18–7 .10(m,1H),5.17(ddd,J=9.8,7.7,1.8Hz,1H),4.83(td,J=8.9,5.0Hz,1H),4.73(dd,J=8.6,5.1Hz,1H),4.71–4.65(m ,1H),4.51(dd,J=7.9,5.5Hz,1H),4.49–4.43(m,2H),4.38(dd,J=8.2,5.4Hz,1H),4.32–4.25(m,2H),4.20(t,J=7.8Hz ,1H),4.17–4.12(m,1H),3.73–3.65(m,1H),3.56(dd,J=11.3,7.7Hz,1H),3.07–2.98(m,2H),2.97–2.91(m,1H),2.90 –2.73(m,7H),2.69–2.57(m,1H),2.49–2.42(m,2H),2.41–2.33(m,1H),2.20(td,J=13.3,11.2,6.8Hz,2H),1.96–1.85 (m, 2H), 1.82–1.69 (m, 3H), 1.66–1.57 (m, 2H), 1.56–1.40 (m, 13H), 1.40–1.31 (m, 3H), 1.30–1.15 (m, 16H), 1.14–1.02 (m, 1H), 0.97 (d, J=6.9 Hz, 3H), 0.91–0.83 (m, 13H), 0.82–0.76 (m, 6H), 0.75–0.66 (m, 1H), 0.53–0.47 (m, 6H). High resolution mass spectrometry (ESI) + )C 73 H113 N 17 O 16 S[M+2H] 2+ The theoretical value is m / z 767.9444, and the measured value is m / z 767.9457.

[0122] Example 10:

[0123]

[0124] Dissolve 15 mg of Bac004 in 1.5 mL of glacial acetic acid, add butylene oxide (8.7 μL, 0.1 mmol), heat the reaction to 40°C, and stir overnight. Add an appropriate amount of water, separate and purify using preparative reverse-phase HPLC, and lyophilize the collected fractions to yield Bac010 (6 mg, 35% yield) as a white, fluffy solid. RT = 13.182 min (analytical RP-HPLC). 1HNMR (600MHz, DMSO-d6) δ8.95(s,1H),8.63(d,J=9.1Hz,1H),8.37(d,J=8.2Hz,1H),8.28(d,J=8.1Hz,1H),8.07(d,J=8. 9Hz,1H),7.91–7.77(m,1H),7.29(s,1H),7.26–7.19(m,4H),7.17–7.10(m,1H),5.17(ddd,J=9.8,7.8,1.8Hz,1H),4.87– 4.80(m,1H),4.73(dd,J=8.7,5.0Hz,1H),4.70–4.62(m,1H),4.52(dd,J=7.9,5.5Hz,1H),4.50–4.43(m,2H),4.38(dd,J= 8.7,5.0Hz,1H),4.32–4.23(m,2H),4.23–4.10(m,2H),3.89–3.80(m,1H),3.70(t,J=10.7Hz,1H),3.56(dd,J=11.3,7.7H z,1H),3.38–3.28(m,2H),3.07–2.95(m,4H),2.94(s,1H),2.91(s,2H),2.88–2.79(m,2H),2.77(d,J=12.0Hz,1H),2.68 –2.60(m,1H),2.49–2.43(m,2H),2.41–2.34(m,1H),2.26–2.13(m,2H),2.13–1.99(m,2H),1.96–1.84(m,2H),1.83–1.71 (m, 2H), 1.68–1.58 (m, 2H), 1.56–1.39 (m, 11H), 1.40–1.30 (m, 3H), 1.27–1.15 (m, 3H), 1.13–1.03 (m, 1H), 0.97 (d, J = 6.9 Hz, 3H), 0.94–0.85 (m, 9H), 0.84 (d, J = 6.1 Hz, 3H), 0.79 (q, J = 7.3 Hz, 6H), 0.77–0.64 (m, 1H), 0.53–0.42 (m, 6H). High resolution mass spectrometry (ESI) + )C 74 H 120 N 17 O 17 S2 + [M+2H] 2+ The theoretical value is m / z 791.9279, and the measured value is m / z 791.9286.

[0125] Example 11:

[0126]

[0127] The propionaldehyde in Example 1 was replaced by nonanal, and the remaining raw materials, reagents, and preparation method were the same as in Example 1 to obtain Bac011 (17 mg, yield 22%). RT = 17.080 min (analytical RP-HPLC). 1 H NMR (600MHz, DMSO-d6) δ8.95(s,1H),8.63(d,J=9.0Hz,1H),8.37(d,J=8.1Hz,1H),8.26(d,J=8.0Hz,1H),8.07(d,J= 8.8Hz,1H),7.85(d,J=8.4Hz,2H),7.83(d,J=8.3Hz,1H),7.52(d,J=8.1Hz,1H),7.30(s,1H),7.26–7.19(m,4H),7.14 (t,J=6.8Hz,1H),5.17(ddd,J=9.7,7.7,1.7Hz,1H),4.83(td,J=8.8,4.7Hz,1H),4.73(dd,J=8.6,5.1Hz,1H),4.71– 4.63(m,1H),4.51(dd,J=7.9,5.6Hz,1H),4.49–4.43(m,2H),4.38(dd,J=8.3,5.5Hz,1H),4.19(t,J=7.8Hz,1H),4.17 –4.10(m,1H),3.70(t,J=10.6Hz,1H),3.56(dd,J=11.3,7.7Hz,1H),3.08–2.98(m,2H),2.98–2.90(m,1H),2.92–2.7 2(m,6H),2.69–2.57(m,1H),2.49–2.41(m,2H),2.40–2.32(m,1H),2.20(td,J=12.9,11.0,6.5Hz,2H),1.97–1.85(m, 2H),1.84–1.69(m,1H),1.67–1.57(m,2H),1.57–1.40(m,11H),1.39–1.30(m,3H),1.30–1.17(m,16H),1.15–1.02(m,1H),0.97(d,J=6.9Hz,3H),0.91–0.83(m,12H),0.82–0.76(m,6H),0.75–0.63(m,1H),0.53–0.43(m,6H). High resolution mass spectrometry (ESI + )C 75 H 121 N 17 O 16 S[M+2H] 2+The theoretical value is m / z 774.9522, and the measured value is m / z 774.9529.

[0128] Example 12:

[0129]

[0130] The propanal in Example 1 was replaced with decanal, and the remaining raw materials, reagents, and preparation method were the same as in Example 1 to obtain Bac012 (18 mg, yield 23%). RT = 17.515 min (analytical RP-HPLC). 1 H NMR (600MHz, DMSO-d6) δ8.94(s,1H),8.63(d,J=9.0Hz,1H),8.37(d,J=8.2Hz,1H),8.26(d,J=8.0Hz,1H),8.07(d, J=8.8Hz,1H),7.85(d,J=9.0Hz,1H),7.83(d,J=8.6Hz,1H),7.52(d,J=8.0Hz,1H),7.29(s,1H),7.28–7.18(m,4H) ,7.14(t,J=7.0Hz,1H),5.17(t,J=9.6Hz,1H),4.89–4.78(m,1H),4.73(dd,J=8.6,5.1Hz,1H),4.70–4.62(m,1H), 4.51(dd,J=7.9,5.6Hz,1H),4.49–4.42(m,2H),4.41–4.32(m,1H),4.19(t,J=7.9Hz,1H),4.17–4.11(m,1H),3.70( t,J=10.6Hz,1H),3.56(dd,J=11.3,7.6Hz,1H),3.08–2.97(m,2H),2.97–2.91(m,1H),2.90–2.72(m,7H),2.71–2. 58(m,1H),2.50–2.41(m,3H),2.37(dd,J=15.2,8.0Hz,1H),2.20(td,J=13.5,11.3,6.8Hz,2H),1.97–1.86(m,2H), 1.83–1.70 (m, 2H), 1.66–1.57 (m, 2H), 1.57–1.39 (m, 13H), 1.39–1.30 (m, 3H), 1.30–1.15 (m, 20H), 1.14–1.02 (m, 1H), 0.97 (d, J=6.9 Hz, 3H), 0.91–0.82 (m, 12H), 0.82–0.76 (m, 6H), 0.76–0.65 (m, 1H), 0.54–0.46 (m, 6H). High resolution mass spectrometry (ESI +)C 76 H 123 N 17 O 16 S[M+2H] 2+ The theoretical value is m / z 781.9600, and the measured value is m / z 781.9600.

[0131] Example 13:

[0132]

[0133] The butylene oxide in Example 10 was replaced with octyl oxide, and the remaining raw materials, reagents, and preparation method were the same as in Example 10 to obtain Bac013 (5 mg, yield 29%). RT = 14.703 min (analytical RP-HPLC). 1H NMR (600MHz, DMSO-d6) δ8.93(s,1H),8.62(d,J=9.1Hz,1H),8.37(dd,J=10.5,4.0Hz,1H),8.26(d,J=7.9Hz,1H),8.07(d,J=8.8 Hz,1H),7.88–7.79(m,2H),7.28(s,1H),7.26–7.18(m,4H),7.16–7.09(m,1H),5.17(ddd,J=9.8,7.7,1.8Hz,1H),4.83(q,J=7. 6,6.2Hz,1H),4.73(dd,J=8.6,5.1Hz,1H),4.70–4.62(m,1H),4.52(dd,J=7.9,5.5Hz,1H),4.47(td,J=8.9,5.5Hz,2H),4.42–4 .31(m,1H),4.32–4.25(m,2H),4.22–4.13(m,2H),3.90(ddt,J=9.6,6.5,3.4Hz,1H),3.73–3.66(m,1H),3.56(dd,J=11.3,7.7H z,1H),3.45–3.38(m,2H),3.38–3.27(m,2H),3.06–2.95(m,4H),2.93(s,1H),2.91(s,2H),2.87–2.74(m,2H),2.68–2.60(m,1H) ),2.49–2.42(m,3H),2.42–2.32(m,1H),2.24–2.15(m,2H),2.11–2.01(m,2H),1.96–1.85(m,2H),1.82–1.70(m,2H),1.68–1.5 7(m,2H),1.57–1.41(m,10H),1.40–1.32(m,3H),1.32–1.14(m,11H),1.08(p,J=7.6Hz,1H),0.97(d,J=6.9Hz,3H),0.92–0.84(m,9H),0.84(d,J=5.9Hz,3H),0.79(q,J=7.2Hz,6H),0.76–0.64(m,2H),0.50(t,J=7.5Hz,3H),0.48(d,J=6.7Hz,3H). High resolution mass spectrometry (ESI + )C 78 H 128 N 17 O 17 S2 + [M+2H] 2+ The theoretical value is m / z 819.9592, and the measured value is m / z 819.9571.

[0134] Example 14:

[0135]

[0136] The propionaldehyde in Example 1 was replaced with N-(9-fluorenyl-9-methoxycarbonyl)decylaminoacetaldehyde. The remaining raw materials, reagents, and preparation method were the same as in Example 1 to obtain Bac014 (15 mg, 17% yield). RT = 20.802 min (analytical RP-HPLC). 1H NMR (600MHz, DMSO-d6) δ8.96(d,J=1.4Hz,1H),8.63(d,J=9.0Hz,1H),8.37(d,J=8.5Hz,1H),8.26(d,J=8.4Hz,1H),8.06(d,J=8. 9Hz,1H),7.87(d,J=7.6Hz,2H),7.83(d,J=8.6Hz,1H),7.61(d,J=7.5Hz,2H),7.40(t,J=7.5Hz,2H),7.37–7.28(m,3H),7.21(dd ,J=13.0,5.7Hz,4H),7.14(t,J=6.8Hz,1H),5.16(ddd,J=9.8,7.7,1.8Hz,1H),4.84(q,J=7.9,7.5Hz,1H),4.73(dd,J=8.5,5.1H z,1H),4.71–4.65(m,0H),4.54–4.49(m,2H),4.49–4.42(m,3H),4.38(dd,J=8.6,5.2Hz,1H),4.32–4.24(m,3H),4.22–4.12(m,2 H),3.69(t,J=10.6Hz,1H),3.56(dd,J=11.3,7.7Hz,1H),3.35–3.26(m,1H),3.05–2.97(m,2H),2.97–2.91(m,1H),2.90–2.80(m ,3H),2.80–2.72(m,2H),2.68–2.57(m,2H),2.49–2.42(m,3H),2.41–2.33(m,1H),2.20(td,J=13.4,11.3,6.9Hz,2H),1.97–1.8 5(m,2H),1.83–1.69(m,2H),1.65–1.53(m,2H),1.53–1.38(m,9H),1.39–1.30(m,3H),1.29–1.14(m,14H),1.14–1.05(m,3H),1.05–0.99(m,2H),0.96(d,J=6.9Hz,3H),0.91–0.82(m,12H),0.82–0.73(m,6H),0.74–0.60(m,1H),0.53–0.42(m,6H). High resolution mass spectrometry (ESI + )C 93 H 138 N 18 O 18 S[M+2H] 2+ The theoretical value is m / z 914.5152, and the measured value is m / z 914.5157.

[0137] Example 15:

[0138]

[0139] 10 mg of Bac014 was dissolved in 500 μL of DMF, and 100 μL of piperidine was slowly added dropwise. The reaction was stirred at room temperature for 15 minutes. After adjusting the pH with TFA, the product was directly purified by preparative reverse-phase HPLC. The collected fractions were lyophilized to yield Bac015 (8 mg, 88% yield) as a white, fluffy solid. RT = 16.218 min (analytical RP-HPLC). 1H NMR (600MHz, DMSO-d6) δ8.96(s,1H),8.37(t,J=7.2Hz,1H),8.27(d,J=8.1Hz,1H),8.07(d,J=8.9Hz,1H),7.84(t,J=9 .5Hz,1H),7.30(s,1H),7.26–7.19(m,4H),7.17–7.10(m,1H),5.17(ddd,J=9.8,7.8,1.8Hz,1H),4.83(dd,J=9.0,5.2 Hz,1H),4.74(dd,J=8.7,5.0Hz,1H),4.68(dt,J=10.9,5.5Hz,1H),4.52(dd,J=8.0,5.5Hz,1H),4.50–4.43(m,2H),4. 38(dd,J=8.7,5.0Hz,1H),4.31–4.25(m,2H),4.23–4.12(m,2H),3.73–3.65(m,1H),3.56(dd,J=11.3,7.7Hz,1H),3.24 –3.13(m,4H),3.03(dd,J=14.9,5.4Hz,2H),2.98–2.87(m,4H),2.84(dd,J=15.3,9.3Hz,1H),2.80–2.71(m,2H),2.69 –2.61(m,1H),2.49–2.42(m,2H),2.40–2.34(m,1H),2.20(td,J=13.6,11.5,7.1Hz,2H),1.91(qd,J=12.6,11.3,5.4H z, 2H), 1.83–1.69 (m, 2H), 1.65–1.58 (m, 2H), 1.59–1.40 (m, 12H), 1.39–1.32 (m, 3H), 1.32–1.14 (m, 21H), 1.12–1.01 (m, 1H), 0.97 (d, J=6.8 Hz, 3H), 0.91–0.82 (m, 12H), 0.83–0.75 (m, 6H), 0.75–0.62 (m, 1H), 0.53–0.39 (m, 6H). High resolution mass spectrometry (ESI + )C 78 H 128 N 18 O 16 S[M+2H] 2+ The theoretical value is m / z 803.4811, and the measured value is m / z 803.4832.

[0140] Example 16:

[0141]

[0142] The propionaldehyde in Example 1 was replaced with D-glucose, and the remaining raw materials, reagents, and preparation method were the same as in Example 1 to obtain Bac016 (11 mg, yield 14%). RT = 13.727 min (analytical RP-HPLC). 1 H NMR (600MHz, DMSO-d6) δ8.95(s,1H),8.63(d,J=9.1Hz,1H),8.37(dd,J=8.5,4.6Hz,1H),8.27(d,J=7.5Hz,1H),8.06–7.98(m,1H ),7.85(d,J=8.8Hz,1H),7.82(d,J=8.4Hz,1H),7.30(s,1H),7.28–7.19(m,4H),7.14(t,J=6.8Hz,1H),5.17(ddd,J=9.7,7.7,1. 8Hz,1H),4.86–4.80(m,1H),4.73(dd,J=8.5,5.1Hz,1H),4.69–4.62(m,1H),4.54–4.50(m,1H),4.49–4.41(m,2H),4.38(dd,J=8 .8,5.1Hz,1H),4.31–4.24(m,2H),4.23–4.19(m,1H),4.19–4.13(m,1H),3.95–3.88(m,1H),3.79(d,J=11.6Hz,1H),3.74–3.71(m ,1H),3.71–3.67(m,1H),3.67–3.62(m,1H),3.60–3.52(m,2H),3.08–2.98(m,3H),2.98–2.92(m,2H),2.92–2.81(m,3H),2.77(d ,J=12.5Hz,1H),2.69–2.61(m,1H),2.49–2.41(m,2H),2.42–2.34(m,1H),2.25–2.15(m,2H),1.96–1.84(m,2H),1.84–1.69(m,2H) ),1.67–1.56(m,2H),1.55–1.40(m,9H),1.40–1.28(m,3H),1.27–1.15(m,3H),1.11–1.01(m,1H),0.97(d,J=6.9Hz,3H),0.91–0.85(m,6H),0.84(d,J=6.0Hz,3H),0.82–0.77(m,6H),0.75–0.64(m,1H),0.51(t,J=7.1Hz,3H),0.48(d,J=6.4Hz,3H). High resolution mass spectrometry (ESI + )C 72 H115 N 17 O 21 S[M+2H] 2+ The theoretical value is m / z 793.9160, and the measured value is m / z 793.9100.

[0143] Example 17:

[0144]

[0145] The propionaldehyde in Example 1 was replaced with benzaldehyde, and the remaining raw materials, reagents, and preparation method were the same as in Example 1 to obtain Bac017 (20 mg, yield 26%). RT = 15.152 min (analytical RP-HPLC). 1H NMR (600MHz, DMSO-d6) δ8.96(d,J=1.4Hz,1H),8.63(d,J=9.1Hz,1H),8.37(d,J=8.4Hz,1H),8.26(d,J=8.0Hz,1H),8.05(d, J=8.8Hz,1H),7.85(d,J=8.6Hz,1H),7.82(d,J=8.3Hz,1H),7.49–7.40(m,4H),7.30(s,1H),7.27–7.18(m,4H),7.17–7.09( m,1H),5.17(ddd,J=9.7,7.7,1.8Hz,1H),4.84(td,J=8.9,4.8Hz,1H),4.73(dd,J=8.6,5.0Hz,1H),4.71–4.64(m,1H),4.52 (dd,J=7.9,5.5Hz,1H),4.50–4.42(m,2H),4.38(dd,J=8.7,5.2Hz,1H),4.32–4.25(m,2H),4.23–4.13(m,2H),4.09(s,2H), 3.74–3.66(m,1H),3.56(dd,J=11.3,7.7Hz,1H),3.08–2.98(m,2H),2.98–2.80(m,4H),2.81–2.74(m,1H),2.70–2.60(m,1H ),2.50–2.42(m,3H),2.41–2.32(m,1H),2.20(td,J=13.1,11.0,6.7Hz,2H),1.97–1.85(m,2H),1.84–1.69(m,2H),1.68–1. 58(m,2H),1.57–1.40(m,9H),1.40–1.28(m,3H),1.28–1.15(m,3H),1.13–1.02(m,1H),0.97(d,J=6.9Hz,3H),0.91–0.85(m,6H),0.84(d,J=6.0Hz,3H),0.81–0.75(m,6H),0.75–0.65(m,1H),0.51(t,J=7.3Hz,2H),0.48(d,J=7.4Hz,3H). High resolution mass spectrometry (ESI + )C 73 H 109 N 17 O 16 S[M+2H] 2+ The theoretical value is m / z 756.9053, and the measured value is m / z 756.9050.

[0146] Example 18:

[0147]

[0148] The propionaldehyde in Example 1 was replaced with pyridine-2-carboxaldehyde, and the remaining raw materials, reagents, and preparation method were the same as in Example 1 to obtain Bac018 (32 mg, yield 42%). RT = 14.622 min (analytical RP-HPLC). 1H NMR (600MHz, DMSO-d6) δ8.94(d,J=1.4Hz,1H),8.62(dt,J=5.1,1.3Hz,1H),8.37(d,J=8.4Hz,1H),8.25(d,J=7.9Hz,1H),8.04(d ,J=8.8Hz,1H),7.88(td,J=7.7,1.8Hz,1H),7.85(d,J=8.4Hz,1H),7.82(d,J=8.3Hz,1H),7.46(d,J=7.8Hz,1H),7.45–7.42(m,1H ),7.30–7.27(m,1H),7.25–7.19(m,4H),7.16–7.11(m,1H),5.16(ddd,J=9.8,7.7,1.8Hz,1H),4.82(td,J=9.1,4.8Hz,1H),4.72 (dd,J=8.5,5.1Hz,1H),4.70–4.60(m,1H),4.51(dd,J=8.0,5.4Hz,1H),4.49–4.40(m,2H),4.37(dd,J=8.8,5.1Hz,1H),4.29–4.2 2(m,4H),4.22–4.10(m,2H),3.73–3.65(m,1H),3.07–2.99(m,2H),2.99–2.89(m,3H),2.83(dd,J=15.3,9.3Hz,1H),2.78(dd,J= 13.7,3.6Hz,1H),2.68–2.62(m,1H),2.49–2.43(m,2H),2.41–2.35(m,1H),2.20(td,J=12.9,10.9,6.6Hz,2H),1.96–1.85(m,2H) ,1.82–1.69(m,2H),1.68–1.40(m,11H),1.39–1.28(m,3H),1.27–1.15(m,3H),1.12–1.00(m,1H),0.96(d,J=6.9Hz,3H),0.90–0.85(m,6H),0.83(d,J=6.0Hz,3H),0.81–0.74(m,6H),0.75–0.65(m,1H),0.51(t,J=7.3Hz,3H),0.47(d,J=6.7Hz,3H). High resolution mass spectrometry (ESI + )C 72 H 108 N 18 O 16 S[M+2H] 2+ The theoretical value is m / z 757.4029, and the measured value is m / z 757.4039.

[0149] Example 19:

[0150]

[0151] The propionaldehyde in Example 1 was replaced with pyridine-4-carboxaldehyde, and the remaining raw materials, reagents, and preparation method were the same as in Example 1 to obtain Bac019 (34 mg, yield 45%). RT = 13.760 min (analytical RP-HPLC). 1 H NMR (600MHz, DMSO-d6) δ8.68(d,J=6.1Hz,2H),8.63(d,J=9.1Hz,1H),8.37(d,J=8.6Hz,1H),8.26(d,J=8.0Hz,1H),8.05 (d,J=8.9Hz,1H),7.84(dd,J=12.7,8.4Hz,1H),7.54(d,J=5.7Hz,2H),7.30(s,1H),7.26–7.18(m,4H),7.14(t,J=6.9Hz, 1H),5.16(ddd,J=9.7,7.7,1.8Hz,1H),4.83(td,J=8.9,5.0Hz,1H),4.73(dd,J=8.6,5.0Hz,1H),4.70–4.63(m,1H),4.52 (dd,J=8.0,5.5Hz,1H),4.49–4.41(m,2H),4.38(dd,J=8.8,5.0Hz,1H),4.33–4.24(m,2H),4.23–4.10(m,4H),3.69(t,J= 10.7Hz,1H),3.08–2.99(m,2H),2.98–2.88(m,3H),2.84(dd,J=15.3,9.3Hz,1H),2.80–2.71(m,1H),2.68–2.60(m,1H), 2.49–2.42(m,3H),2.38(dd,J=15.1,8.0Hz,1H),2.27–2.12(m,2H),1.98–1.84(m,2H),1.84–1.70(m,2H),1.68–1.58(m, 2H),1.58–1.40(m,10H),1.39–1.29(m,5H),1.27–1.14(m,3H),1.13–1.01(m,1H),0.97(d,J=6.9Hz,3H),0.91–0.85(m,6H),0.83(d,J=5.9Hz,3H),0.81–0.75(m,6H),0.74–0.65(m,1H),0.50(t,J=7.4Hz,3H),0.47(d,J=6.8Hz,3H). High resolution mass spectrometry (ESI +)C 72 H 108 N 18 O 16 S[M+2H] 2+ The theoretical value is m / z 757.4029, and the measured value is m / z 757.4039.

[0152] Example 20:

[0153]

[0154] The propionaldehyde in Example 1 was replaced with p-bromobenzaldehyde, and the remaining raw materials, reagents, and preparation method were the same as in Example 1 to obtain Bac020 (21 mg, yield 26%). RT = 15.720 min (analytical RP-HPLC). 1H NMR (600MHz, DMSO-d6) δ8.95(s,1H),8.63(d,J=9.1Hz,1H),8.37(d,J=8.5Hz,1H),8.27(d,J=8.1Hz,1H),8.05(d,J=8.9Hz,1H),7. 85(d,J=8.5Hz,1H),7.82(d,J=8.3Hz,1H),7.64(d,J=8.4Hz,2H),7.41(d,J=8.5Hz,2H),7.30(s,1H),7.26–7.19(m,4H),7.14(t,J= 6.7Hz,1H),5.17(ddd,J=9.8,7.7,1.8Hz,1H),4.83(dd,J=9.0,5.0Hz,1H),4.73(dd,J=8.6,5.0Hz,1H),4.68(dd,J=11.3,3.9Hz,1 H),4.52(dd,J=7.9,5.5Hz,1H),4.49–4.42(m,2H),4.38(dd,J=8.8,4.9Hz,1H),4.31–4.24(m,2H),4.20(t,J=6.8Hz,1H),4.18–4.1 3(m,1H),4.07(s,2H),3.69(t,J=10.6Hz,1H),3.56(dd,J=11.3,7.7Hz,1H),3.07–2.98(m,2H),2.97–2.81(m,4H),2.77(d,J=12.7 Hz,1H),2.69–2.59(m,1H),2.50–2.42(m,2H),2.41–2.32(m,1H),2.21(td,J=11.4,9.9,6.1Hz,2H),1.97–1.86(m,2H),1.82–1.69( m, 2H), 1.68–1.56 (m, 2H), 1.56–1.39 (m, 9H), 1.39–1.26 (m, 3H), 1.27–1.14 (m, 3H), 1.14–1.01 (m, 1H), 0.97 (d, J = 6.8 Hz, 3H), 0.91–0.86 (m, 6H), 0.84 (d, J = 6.0 Hz, 3H), 0.81–0.74 (m, 6H), 0.74–0.65 (m, 1H), 0.50 (t, J = 7.5 Hz, 3H), 0.47 (d, J = 6.9 Hz, 3H). High resolution mass spectrometry (ESI) + )C 73 H 109 N 17 O 16 S[M+2H] 2+ The theoretical value is m / z 795.8605, and the measured value is m / z 795.8614.

[0155] Example 21:

[0156]

[0157] The propionaldehyde in Example 1 was replaced with 4-alkynylbenzaldehyde, and the remaining raw materials, reagents, and preparation method were the same as in Example 1 to obtain Bac021 (17 mg, yield 22%). RT = 17.080 min (analytical RP-HPLC). 1H NMR (600MHz, DMSO-d6) δ8.96(d,J=1.4Hz,1H),8.63(d,J=9.1Hz,1H),8.37(d,J=8.4Hz,1H),8.26(d,J=8.0Hz,1H),8.06(d,J=8. 8Hz,1H),7.85(d,J=8.9Hz,1H),7.83(d,J=8.5Hz,1H),7.54(d,J=8.0Hz,2H),7.47(d,J=8.0Hz,2H),7.30(s,1H),7.27–7.18(m, 4H),7.14(t,J=6.8Hz,1H),5.17(ddd,J=9.7,7.7,1.8Hz,1H),4.88–4.80(m,1H),4.73(dd,J=8.6,5.0Hz,1H),4.70–4.64(m,1H) ,4.52(dd,J=7.9,5.5Hz,1H),4.49–4.42(m,2H),4.38(dd,J=8.8,5.2Hz,1H),4.29–4.26(m,2H),4.25(s,1H),4.23–4.12(m,2H) ,4.11(s,2H),3.69(t,J=10.6Hz,1H),3.56(dd,J=11.3,7.7Hz,1H),3.08–2.97(m,2H),2.98–2.81(m,4H),2.80–2.71(m,1H),2. 69–2.59(m,1H),2.49–2.42(m,2H),2.42–2.33(m,1H),2.20(td,J=13.3,11.2,6.8Hz,2H),1.99–1.85(m,2H),1.84–1.67(m,2H) ,1.67–1.57(m,2H),1.57–1.41(m,9H),1.40–1.28(m,3H),1.28–1.12(m,3H),1.12–1.00(m,1H),0.97(d,J=6.9Hz,3H),0.91–0.85(m,6H),0.83(d,J=5.9Hz,3H),0.81–0.74(m,6H),0.75–0.62(m,1H),0.50(t,J=7.4Hz,3H),0.47(d,J=6.7Hz,3H). High resolution mass spectrometry (ESI + )C 75 H 109 N 17 O 16 S[M+2H] 2+ The theoretical value is m / z 768.9053, and the measured value is m / z 768.9051.

[0158] Example 22:

[0159]

[0160] The propionaldehyde in Example 1 was replaced with 2-naphthaldehyde, and the remaining raw materials, reagents, and preparation method were the same as in Example 1 to obtain Bac022 (22 mg, yield 28%). RT = 15.902 min (analytical RP-HPLC). 1H NMR (600MHz, DMSO-d6) δ8.96(s,1H),8.63(d,J=9.1Hz,1H),8.37(d,J=8.4Hz,1H),8.26(d,J=8.1Hz,1H),8.06(d,J=8.8Hz,1H) ,7.99(s,1H),7.96(dd,J=6.2,3.3Hz,1H),7.92(dd,J=6.3,3.3Hz,1H),7.85(d,J=8.7Hz,1H),7.82(d,J=8.3Hz,1H),7.60–7.55 (m,3H),7.30(s,1H),7.26–7.19(m,4H),7.14(t,J=7.1Hz,1H),5.16(t,J=8.9Hz,1H),4.90–4.80(m,1H),4.73(dd,J=8.6,5.0H z,1H),4.71–4.63(m,1H),4.52(dd,J=7.9,5.5Hz,1H),4.49–4.41(m,2H),4.38(dd,J=8.7,5.2Hz,1H),4.32–4.23(m,4H),4.22– 4.12(m,2H),3.69(t,J=10.7Hz,1H),3.56(dd,J=11.3,7.6Hz,1H),3.08–2.99(m,2H),2.98–2.89(m,2H),2.84(dd,J=15.3,9.2 Hz,1H),2.77(d,J=12.7Hz,1H),2.68–2.56(m,1H),2.50–2.42(m,2H),2.37(dd,J=15.1,8.0Hz,1H),2.19(td,J=13.0,11.2,6.7 Hz, 2H), 1.99–1.85(m, 2H), 1.82–1.69(m, 2H), 1.69–1.39(m, 9H), 1.39–1.28(m, 3H), 1.27–1.14(m, 3H), 1.11–1.00(m, 1H), 0.96(d, J=6.9Hz, 3H), 0.91–0.85(m, 6H), 0.83(d, J=5.9Hz, 3H), 0.81–0.74(m, 6H), 0.73–0.63(m, 1H), 0.53–0.40(m, 6H). High resolution mass spectrometry (ESI + )C 77 H 111 N 17 O 16 S[M+2H] 2+ The theoretical value is m / z 781.9131, and the measured value is m / z 781.9139.

[0161] Example 23:

[0162]

[0163] The propionaldehyde in Example 1 was replaced with 4-butoxybenzaldehyde, and the remaining raw materials, reagents, and preparation method were the same as in Example 1 to obtain Bac023 (25 mg, yield 32%). RT = 16.527 min (analytical RP-HPLC). 11H NMR (600 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.63 (d, J = 9.0 Hz, 1H), 8.37 (d, J = 8.5 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 8.6 Hz, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.35 (d, J = 8.5 Hz, 2H), 7.30 (s, 1H), 7.25–7.17 (m, 4H), 7.14 (t, J = 6.8 Hz, 1H), 7.01–6.92 (m, 2H), 5.16 (ddd, J = 9.7, 7.7, 1.8 Hz, 1H), 4.87–4.80 (m, 1H), 4.73 (dd, J = 8.6, 5.1 Hz, 1H), 4.67 (dd, J = 11.2, 3.9 Hz, 1H), 4.51 (dd, J = 7.9, 5.5 Hz, 1H), 4.49–4.40 (m, 2H), 4.38 (dd, J = 8.8, 5.0 Hz, 1H), 4.31–4.23 (m, 2H), 4.23–4.09 (m, 2H), 4.00 (s, 2H), 3.97 (t, J = 6.5 Hz, 2H), 3.69 (t, J = 10.6 Hz, 1H), 3.56 (dd, J = 11.3, 7.7 Hz, 1H), 3.09–2.98 (m, 2H), 2.98–2.91 (m, 1H), 2.90–2.80 (m, 3H), 2.79–2.72 (m, 1H), 2.69–2.60 (m, 1H), 2.49–2.42 (m, 2H), 2.41–2.33 (m, 1H), 2.20 (td, J = 12.9, 10.9, 6.7 Hz, 2H), 1.98–1.84 (m, 2H), 1.82–1.71 (m, 2H), 1.68 (p, J = 6.7 Hz, 2H), 1.64–1.57 (m, 2H), 1.57–1.38 (m, 11H), 1.38–1.29 (m, 3H), 1.28–1.15 (m, 3H), 1.12–1.02 (m, 1H), 0.97 (d, J = 6.9 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H), 0.90–0.85 (m, 6H), 0.83 (d, J = 6.0 Hz, 3H), 0.81–0.74 (m, 6H), 0.75–0.67 (m, 1H), 0.50 (t, J = 7.7 Hz, ...... + ) C 77 H 117 N 17 O 17 S [M + 2H]2+ The theoretical value is m / z 792.9340, and the measured value is m / z 792.9350.

[0164] Example 24:

[0165]

[0166] The propionaldehyde in Example 1 was replaced with 4-butoxybenzaldehyde, and the remaining raw materials, reagents, and preparation method were the same as in Example 1 to obtain Bac024 (11 mg, yield 14%). RT = 17.267 min (analytical RP-HPLC). 1H NMR (600MHz, DMSO-d6) δ8.95(d,J=1.4Hz,1H),8.63(d,J=9.0Hz,1H),8.37(d,J=8.4Hz,1H),8.26(d,J=8.0Hz,1H),8.06(d,J=8.8H z,1H),7.85(d,J=8.6Hz,1H),7.83(d,J=8.3Hz,1H),7.35(d,J=7.8Hz,2H),7.30(s,1H),7.26–7.18(m,6H),7.14(t,J=6.7Hz,1H),5 .17(ddd,J=9.7,7.8,1.8Hz,1H),4.83(td,J=8.8,4.7Hz,1H),4.73(dd,J=8.6,5.0Hz,1H),4.71–4.61(m,1H),4.51(dd,J=7.9,5.5 Hz,1H),4.49–4.43(m,2H),4.37(dd,J=8.5,5.3Hz,1H),4.31–4.24(m,2H),4.19(t,J=8.0Hz,1H),4.17–4.11(m,1H),4.03(s,2H),3 .69(t,J=10.6Hz,1H),3.56(dd,J=11.3,7.6Hz,1H),3.05–2.97(m,2H),2.98–2.91(m,1H),2.92–2.80(m,3H),2.77(d,J=12.3Hz,1 H),2.69–2.61(m,1H),2.57(t,J=7.7Hz,2H),2.49–2.41(m,2H),2.41–2.33(m,1H),2.26–2.14(m,2H),1.96–1.84(m,2H),1.81–1.7 0(m,2H),1.68–1.58(m,2H),1.58–1.51(m,4H),1.50–1.39(m,6H),1.39–1.32(m,2H),1.32–1.25(m,2H),1.26–1.16(m,4H),1.13–1.00(m,1H),0.97(d,J=6.9Hz,3H),0.91–0.82(m,12H),0.81–0.74(m,6H),0.50(t,J=7.5Hz,3H),0.47(d,J=6.7Hz,3H). High resolution mass spectrometry (ESI + )C 78 H 119 N 17 O 16 S[M+2H] 2+ The theoretical value is m / z 791.9444, and the measured value is m / z 791.9464.

[0167] Example 25:

[0168]

[0169] The propionaldehyde in Example 1 was replaced with 4'-chlorobiphenyl-4-carboxaldehyde, and the remaining raw materials, reagents, and preparation method were the same as in Example 1 to obtain Bac025 (25 mg, yield 31%). RT = 16.970 min (analytical RP-HPLC). 1 H NMR (600MHz, DMSO-d6) δ8.95(d,J=1.3Hz,1H),8.63(d,J=9.2Hz,1H),8.37(d,J=8.3Hz,1H),8.26(d,J=7.6Hz,1H),8.05(d,J= 8.8Hz,1H),7.85(d,J=8.7Hz,1H),7.82(d,J=8.3Hz,1H),7.74(d,J=8.2Hz,2H),7.72(d,J=8.6Hz,2H),7.54(t,J=8.3Hz,4H), 7.30(s,1H),7.25–7.18(m,4H),7.17–7.09(m,1H),5.16(t,J=9.8Hz,0H),4.83(td,J=8.9,5.1Hz,1H),4.73(dd,J=8.6,5.1Hz ,1H),4.70–4.63(m,1H),4.52(dd,J=7.9,5.5Hz,1H),4.49–4.42(m,2H),4.38(dd,J=8.7,5.2Hz,1H),4.31–4.24(m,2H),4.22–

[0170] 4.15(m,2H),4.13(s,2H),3.69(t,J=10.6Hz,1H),3.56(dd,J=11.3,7.7H z,1H),3.06–2.98(m,2H),2.98–2.87(m,3H),2.84(dd,J=15.3,9.2Hz,1H ),2.77(d,J=12.6Hz,1H),2.65(dd,J=16.1,4.8Hz,1H),2.49–2.42(m,2H ),2.37(dd,J=15.4,8.2Hz,1H),2.20(td,J=13.1,11.2,6.9Hz,2H),1.96– 1.85 (m, 2H), 1.82–1.70 (m, 2H), 1.68–1.58 (m, 2H), 1.57–1.39 (m, 8H), 1.39–1.28 (m, 3H), 1.21 (ddd, J = 13.2, 9.3, 6.7 Hz, 3H), 1.07 (dq, J = 14.4, 7.3, 6.9 Hz, 1H), 0.96 (d, J = 6.9 Hz, 3H), 0.90–0.85 (m, 6H), 0.83 (d, J = 6.0 Hz, 3H), 0.82–0.73 (m, 6H), 0.75–0.63 (m, 1H), 0.56–0.42 (m, 6H). High resolution mass spectrometry (ESI) + )C 79 H 112 C1N 17 O 16 S[M+2H] 2+ The theoretical value is m / z 811.9014, and the measured value is m / z 811.9033.

[0171] Example 26:

[0172]

[0173] The propionaldehyde in Example 1 was replaced with 4'-(trifluoromethyl)biphenyl-4-carboxaldehyde, and the remaining raw materials, reagents, and preparation method were the same as in Example 1 to obtain Bac026 (25 mg, yield 31%). RT = 17.122 min (analytical RP-HPLC). 11H NMR (600 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.63 (d, J = 9.0 Hz, 1H), 8.37 (d, J = 8.7 Hz, 1H), 8.27 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 8.9 Hz, 1H), 7.92 (d, J = 8.1 Hz, 2H), 7.84 (d, J = 8.3 Hz, 2H), 7.82 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 7.9 Hz, 2H), 7.30 (s, 1H), 7.27–7.18 (m, 4H), 7.14 (t, J = 7.1 Hz, 1H), 5.16 (t, J = 8.9 Hz, 1H), 4.83 (dd, J = 9.0, 5.1 Hz, 1H), 4.73 (dd, J = 8.6, 5.1 Hz, 1H), 4.68 (dd, J = 11.1, 4.0 Hz, 1H), 4.52 (dd, J = 7.9, 5.6 Hz, 1H), 4.49–4.41 (m, 2H), 4.38 (dd, J = 8.8, 5.0 Hz, 1H), 4.32–4.25 (m, 2H), 4.22–4.17 (m, 2H), 4.16 (s, 2H), 3.69 (t, J = 10.6 Hz, 1H), 3.56 (dd, J = 11.3, 7.7 Hz, 1H), 3.06–2.99 (m, 2H), 2.98–2.88 (m, 3H), 2.84 (dd, J = 15.3, 9.2 Hz, 1H), 2.77 (d, J = 11.9 Hz, 1H), 2.68–2.58 (m, 1H), 2.50–2.42 (m, 2H), 2.38 (dd, J = 15.0, 7.9 Hz, 1H), 2.29–

[0174] 2.14 (m, 2H), 1.99–1.85 (m, 2H), 1.83–1.69 (m, 2H), 1.68–1.59 (m, 2H), 1.59–1.39 (m, 9H), 1.40–1.28 (m, 3H), 1.27–1.12 (m, 3H), 1.14–1.00 (m, 1H), 0.96 (d, J = 6.9 Hz, 3H), 0.90–0.85 (m, 6H), 0.83 (d, J = 5.8 Hz, 3H), 0.80 (d, J = 6.7 Hz, 3H), 0.77 (t, J = 7.4 Hz, 3H), 0.74–0.65 (m, 1H), 0.52–0.46 (m, 6H). High resolution mass spectrometry (ESI + ) C 80 H 112 F3N 17 O 16 S [M+2H] 2+The theoretical value is m / z828.9146, and the measured value is m / z828.9154.

[0175] Example 27:

[0176]

[0177] Intermediate Bac027-i was obtained by replacing the propanal in Example 1 with 4'-(tert-butyloxycarbonylaminomethyl)biphenyl-4-carboxaldehyde. The remaining raw materials, reagents, and preparation method were the same as in Example 1. The crude product was dissolved in 50% TFA in dichloromethane and stirred at room temperature for 10 minutes. The solvent was removed by concentration and the product was redissolved in appropriate amounts of water and acetonitrile. The product was then directly purified by preparative reverse-phase HPLC. The collected fraction was lyophilized to yield Bac027 (5 mg, 12% yield over two steps) as a white, fluffy solid. RT = 14.112 min (analytical RP-HPLC). 1H NMR (600MHz, DMSO-d6) δ8.89(s,1H),7.74(dd,J=8.2,5.1Hz,4H),7.55(dd,J=8.0,5.5Hz,4H),7.26(s,1H),7. 24–7.17(m,4H),7.14(td,J=6.0,2.8Hz,1H),5.15(t,J=8.9Hz,1H),4.79(dd,J=9.1,5.1Hz,1H),4.70(dd,J=8. 4,5.1Hz,1H),4.63(dd,J=11.0,4.4Hz,1H),4.50(dd,J=8.0,5.4Hz,1H),4.48–4.40(m,2H),4.35(dd,J=8.8,4. 9Hz,1H),4.28–4.19(m,2H),4.16(d,J=6.9Hz,2H),4.13(s,2H),4.07(s,2H),3.11–2.97(m,2H),2.98–2.88(m, 3H),2.82(dt,J=30.2,11.1Hz,2H),2.65(td,J=15.0,13.4,4.1Hz,1H),2.43–2.32(m,1H),2.26–2.10(m,2H),1 .96–1.84(m,2H),1.76(qd,J=10.1,6.6,5.6Hz,2H),1.68–1.57(m,2H),1.48(dtt,J=28.4,10.4,6.4Hz,9H),1. 34(p,J=8.5,7.8Hz,3H),1.26–1.11(m,3H),1.12–1.00(m,1H),0.96(d,J=6.9Hz,3H),0.90–0.84(m,6H),0.82(d,J=5.8Hz,3H),0.80–0.72(m,6H),0.73–0.62(m,1H),0.51(t,J=7.4Hz,3H),0.47(d,J=6.6Hz,3H). High resolution mass spectrometry (ESI + )C 80 H 116 N 18 O 16 S[M+2H] 2+ The theoretical value is m / z 809.4342, and the measured value is m / z 809.4344.

[0178] Example 28:

[0179]

[0180] Commercially available bacitracin (71 mg, 0.05 mmol) was dissolved in 1.5 mL of pure water, 250 μL of acetonitrile, and 50 μL of glacial acetic acid in a single-necked reaction vial and stirred. Valeraldehyde (6.4 μL, 0.06 mmol) was pipetted into the reaction mixture and stirred at room temperature for 2 minutes. Sodium cyanoborohydride (6.3 mg, 0.1 mmol) was then weighed and added to the reaction mixture. Stirring was continued while monitoring the reaction progress using analytical reversed-phase high-performance liquid chromatography (RP-HPLC). The reaction was stopped when the reaction stopped. The target fraction was directly separated and purified using preparative reversed-phase HPLC, and lyophilized to yield Bac028 as a white, fluffy solid (40 mg, 54% yield). RT = 14.727 min (analytical RP-HPLC). 11H NMR (600 MHz, DMSO-d6) δ 8.95 (d, J = 1.4 Hz, 1H), 8.62 (d, J = 9.0 Hz, 1H), 8.38 (t, J = 8.6 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 8.3 Hz, 1H), 7.84 (d, J = 8.6 Hz, 1H), 7.29 (d, J = 1.4 Hz, 1H), 7.25–7.18 (m, 4H), 7.17–7.12 (m, 1H), 5.26–5.20 (m, 1H), 4.86–4.79 (m, 1H), 4.72 (dd, J = 8.5, 5.1 Hz, 1H), 4.70–4.62 (m, 1H), 4.51 (dd, J = 8.0, 5.5 Hz, 1H), 4.48–4.42 (m, 2H), 4.36 (dd, J = 8.8, 5.1 Hz, 1H), 4.28 (d, J = 4.1 Hz, 1H), 4.27–4.23 (m, 1H), 4.22–4.19 (m, 1H), 4.18–4.13 (m, 1H), 3.73–3.67 (m, 1H), 3.03 (dq, J = 13.3, 7.7, 6.1 Hz, 2H), 2.92 (tq, J = 16.6, 6.1 Hz, 3H), 2.83 (dd, J = 15.3, 9.3 Hz, 1H), 2.79 (s, 3H), 2.70–2.61 (m, 1H), 2.50–2.43 (m, 3H), 2.41–2.32 (m, 1H), 2.20 (td, J = 7.6, 6.2, 2.9 Hz, 2H), 2.08–1.97 (m, 1H), 1.91 (tt, J = 13.6, 6.0 Hz, 1H), 1.81–1.70 (m, 2H), 1.63 (dq, J = 19.1, 11.1, 8.5 Hz, 4H), 1.56–1.49 (m, 3H), 1.49–1.41 (m, 6H), 1.39–1.31 (m, 3H), 1.30–1.25 (m, 4H), 1.24–1.16 (m, 2H), 1.10–1.03 (m, 1H), 0.94 (d, J = 6.8 Hz, 3H), 0.91 (t, J = 7.4 Hz, 3H), 0.88–0.85 (m, 6H), 0.84 (d, J = 6.1 Hz, 3H), 0.82–0.75 (m, 6H), 0.75–0.66 (m, 1H), 0.51 (t, J = 7.3 Hz, 3H), 0.47 (d, J = 6.7 Hz, 3H). High resolution mass spectrometry (ESI + ) C 71 H 113 N 17 O 16S[M+2H] 2+ The theoretical value is m / z 746.9209, and the measured value is m / z 746.9210.

[0181] Example 29:

[0182]

[0183] The valeraldehyde in Example 28 was replaced with hexanal, and the remaining raw materials, reagents, and preparation method were the same as in Example 28 to obtain Bac029 (28 mg, yield 37%). RT = 15.100 min (analytical RP-HPLC). 11H NMR (600 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.62 (d, J = 9.0 Hz, 1H), 8.38 (t, J = 9.0 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.84 (d, J = 8.6 Hz, 1H), 7.29 (s, 1H), 7.27–7.18 (m, 4H), 7.14 (t, J = 6.8 Hz, 1H), 5.23 (t, J = 9.0 Hz, 1H), 4.83 (dt, J = 9.0, 6.0 Hz, 1H), 4.72 (dd, J = 8.6, 5.1 Hz, 1H), 4.70–4.61 (m, 1H), 4.51 (dd, J = 8.0, 5.4 Hz, 1H), 4.48–4.40 (m, 2H), 4.37 (dd, J = 8.9, 5.0 Hz, 1H), 4.31–4.24 (m, 2H), 4.23–4.18 (m, 1H), 4.18–4.13 (m, 1H), 3.70 (t, J = 10.6 Hz, 1H), 3.53 (dd, J = 11.3, 8.2 Hz, 2H), 3.03 (dd, J = 15.4, 5.1 Hz, 2H), 2.98–2.88 (m, 3H), 2.83 (dd, J = 15.3, 9.3 Hz, 1H), 2.81–2.69 (m, 3H), 2.65 (dd, J = 16.3, 4.8 Hz, 1H), 2.50–2.41 (m, 3H), 2.37 (dd, J = 15.2, 8.1 Hz, 1H), 2.20 (td, J = 13.2, 11.2, 6.7 Hz, 2H), 2.01 (dq, J = 13.0, 5.1 Hz, 1H), 1.91 (dp, J = 13.7, 6.3, 5.6 Hz, 1H), 1.76 (tdd, J = 17.8, 15.0, 12.6, 7.7 Hz, 2H), 1.62 (ddp, J = 16.4, 11.2, 6.3, 5.9 Hz, 4H), 1.56–1.48 (m, 3H), 1.48–1.39 (m, 6H), 1.39–1.31 (m, 3H), 1.31–1.14 (m, 10H), 1.11–1.03 (m, 1H), 0.96–0.89 (m, 6H), 0.89–0.82 (m, 11H), 0.81–0.76 (m, 6H), 0.72 (dq, J = 9.4, 6.9 Hz, 1H), 0.51 (t, J = 7.3 Hz, 3H), 0.47 (d, J = 6.7 Hz, 3H). High resolution mass spectrometry (ESI + ) C 72 H 115 N 17 O16 S[M+2H] 2+ The theoretical value is m / z 753.9287, and the measured value is m / z 753.9293.

[0184] Example 30:

[0185]

[0186] The valeraldehyde in Example 28 was replaced with heptanal, and the remaining raw materials, reagents, and preparation method were the same as in Example 28 to obtain Bac030 (28 mg, yield 37%). RT = 15.570 min (analytical RP-HPLC). 1H NMR(600MHz, DMSO-d6)δ8.96(d,J=1.4Hz,1H),7.30(d,J=1.3Hz,1H),7.26–7.19(m,4H),7.17–7.10(m,1H),5.23(ddd,J=9.7,8.0, 1.2Hz,1H),4.85–4.80(m,1H),4.73(dd,J=8.6,5.1Hz,1H),4.66(dd,J=11.3,3.9Hz,1H),4.51(dd,J=8.1,5.4Hz,1H),4.45(dt,J= 8.5,5.8Hz,2H),4.37(dd,J=8.9,5.0Hz,1H),4.30–4.27(m,1H),4.26(d,J=5.8Hz,1H),4.20(d,J=7.0Hz,1H),4.16(dd,J=9.3,4.9 Hz,1H),3.74–3.67(m,1H),3.03(dq,J=13.7,7.9,6.1Hz,2H),2.99–2.88(m,3H),2.84(dd,J=15.3,9.3Hz,1H),2.76(tq,J=12.6,1 0.4,5.8,4.8Hz,3H),2.65(dd,J=16.3,4.8Hz,1H),2.50–2.43(m,2H),2.38(dd,J=15.5,8.4Hz,1H),2.25–2.14(m,2H),2.01(ddt, J=12.9,9.2,5.1Hz,1H),1.95–1.86(m,1H),1.77(qt,J=15.6,5.9Hz,2H),1.62(q,J=11.1,8.3Hz,4H),1.52(tdd,J=14.6,7.9,3.6 Hz, 3H), 1.49–1.40 (m, 6H), 1.38–1.32 (m, 3H), 1.30–1.16 (m, 11H), 1.13–1.03 (m, 1H), 0.94 (d, J = 6.8 Hz, 3H), 0.91 (t, J = 7.4 Hz, 3H), 0.88–0.83 (m, 9H), 0.81–0.77 (m, 6H), 0.71 (ddd, J = 13.1, 8.0, 4.7 Hz, 1H), 0.51 (t, J = 7.3 Hz, 3H), 0.47 (d, J = 6.7 Hz, 3H). High resolution mass spectrometry (ESI + )C 73 H 117 N 17 O 16 S[M+2H] 2+ The theoretical value is m / z 760.9366, and the measured value is m / z 760.9389.

[0187] Example 31:

[0188]

[0189] Commercially available bacitracin (71 mg, 0.05 mmol) was dissolved in 1 mL of DMF in a single-necked reaction vial. DIPEA (17 μL, 0.1 mmol) was added with stirring at room temperature, followed by the dropwise addition of hexanoyl chloride (10.5 μL, 0.075 mmol) pre-dissolved in 200 μL of DMF. Stirring was continued, and the reaction progress was monitored by analytical reversed-phase high-performance liquid chromatography (RP-HPLC). The reaction was stopped when it ceased to progress. The target fraction was directly separated and purified by preparative reversed-phase HPLC, and lyophilized to yield Bac031 as a white, fluffy solid (8 mg, 11% yield). RT = 16.797 min (analytical RP-HPLC). 11H NMR (600 MHz, DMSO-d6) δ 8.98–8.89 (m, 1H), 8.62 (d, J = 8.9 Hz, 1H), 8.38 (dd, J = 16.0, 8.7 Hz, 1H), 8.31 (t, J = 9.8 Hz, 0H), 8.19 (t, J = 8.0 Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.30 (s, 1H), 7.22 (q, J = 7.8 Hz, 4H), 7.14 (t, J = 6.8 Hz, 1H), 5.14 (t, J = 8.9 Hz, 0H), 5.05 (dd, J = 9.7, 6.9 Hz, 0H), 4.83 (td, J = 9.0, 5.0 Hz, 1H), 4.72 (ddd, J = 8.1, 5.1, 2.3 Hz, 1H), 4.69–4.63 (m, 2H), 4.53–4.49 (m, 1H), 4.48–4.37 (m, 2H), 4.34 (td, J = 9.3, 5.0 Hz, 1H), 4.29–4.21 (m, 1H), 4.21–4.12 (m, 2H), 3.45–3.42 (m, 2H), 3.42–3.36 (m, 1H), 3.07–2.99 (m, 2H), 2.94 (p, J = 6.7 Hz, 1H), 2.86–2.77 (m, 2H), 2.77–2.69 (m, 2H), 2.69–2.59 (m, 1H), 2.49–2.42 (m, 2H), 2.41–2.33 (m, 1H), 2.24–2.18 (m, 2H), 2.18–2.07 (m, 2H), 1.95–1.86 (m, 2H), 1.83–1.70 (m, 2H), 1.66–1.57 (m, 2H), 1.48 (ddt, J = 30.8, 11.2, 6.7 Hz, 10H), 1.35 (dq, J = 13.8, 6.4 Hz, 3H), 1.30–1.18 (m, 6H), 1.19–1.11 (m, 1H), 1.11–1.01 (m, 1H), 0.91–0.82 (m, 13H), 0.79 (qd, J = 7.2, 2.3 Hz, 6H), 0.75–0.66 (m, 1H), 0.52 (t, J = 7.2 Hz, 3H), 0.47 (d, J = 6.7 Hz, 3H). High resolution mass spectrometry (ESI + ) C 72 H 113 N 17 O 17 S [M+2H] 2+The theoretical value is m / z 760.9184, and the measured value is m / z 760.9179.

[0190] Example 32:

[0191]

[0192] The valeraldehyde in Example 28 was replaced with 1-chlorobenzaldehyde, and the remaining raw materials, reagents, and preparation method were the same as in Example 28 to obtain Bac032 (46 mg, yield 59%). RT = 15.130 min (analytical RP-HPLC). 1H NMR(600MHz, DMSO-d6)δ8.95(d,J=1.4Hz,1H),7.57–7.43(m,4H),7.29(d,J=1.3Hz,1H),7.24–7.19(m,4H),7.16–7. 10(m,1H),5.23(ddd,J=9.7,8.0,1.3Hz,1H),4.85–4.78(m,1H),4.72(dd,J=8.5,5.1Hz,1H),4.65(dd,J=11.2,3.9H z,1H),4.51(dd,J=8.0,5.4Hz,1H),4.47–4.42(m,2H),4.37(dd,J=8.9,4.9Hz,1H),4.25(d,J=5.6Hz,1H),4.22–4.1 8(m,3H),4.18–4.09(m,2H),3.72–3.62(m,1H),3.08–2.99(m,2H),2.94(dt,J=13.3,6.8Hz,1H),2.83(dd,J=15.3,9 .3Hz,1H),2.80–2.70(m,3H),2.65(dd,J=16.3,4.8Hz,1H),2.49–2.42(m,2H),2.41–2.35(m,1H),2.26–2.12(m,2H) ,2.04(ddt,J=13.0,9.7,4.1Hz,1H),1.94–1.86(m,1H),1.82–1.70(m,2H),1.67–1.57(m,2H),1.55–1.39(m,9H),1. 38–1.30(m,3H),1.30–1.24(m,1H),1.24–1.15(m,2H),1.13–1.00(m,1H),0.92(d,J=6.8Hz,3H),0.90–0.85(m,6H),0.83(d,J=6.1Hz,3H),0.81–0.75(m,6H),0.76–0.65(m,1H),0.51(t,J=7.3Hz,3H),0.47(d,J=6.7Hz,3H). High resolution mass spectrometry (ESI + )C 73 H 108 C1N 17 O 17 S[M+2H] 2+ The theoretical value is m / z 773.8858, and the measured value is m / z 773.8839.

[0193] Example 33:

[0194]

[0195] The valeraldehyde in Example 28 was replaced with biphenylaldehyde, and the remaining raw materials, reagents, and preparation method were the same as in Example 28 to obtain Bac033 (15 mg, yield 19%). RT = 15.943 min (analytical RP-HPLC). 11H NMR (600 MHz, DMSO-d6) δ 8.95 (d, J = 1.4 Hz, 1H), 7.78–7.73 (m, 2H), 7.70–7.67 (m, 2H), 7.60 (d, J = 8.2 Hz, 2H), 7.51–7.46 (m, 2H), 7.43–7.36 (m, 1H), 7.29 (d, J = 1.3 Hz, 1H), 7.25–7.19 (m, 4H), 7.17–7.11 (m, 1H), 5.26 (ddd, J = 9.6, 8.0, 1.3 Hz, 1H), 4.86–4.80 (m, 1H), 4.73 (dd, J = 8.5, 5.1 Hz, 1H), 4.66 (dt, J = 11.3, 5.4 Hz, 1H), 4.52 (dd, J = 8.0, 5.5 Hz, 1H), 4.46 (dd, J = 8.7, 6.0 Hz, 2H), 4.38 (dd, J = 8.8, 5.0 Hz, 1H), 4.28–4.23 (m, 3H), 4.21 (t, J = 6.6 Hz, 2H), 4.18–4.12 (m, 1H), 3.72–3.65 (m, 1H), 3.56 (dd, J = 11.1, 7.8 Hz, 2H), 3.06–2.98 (m, 2H), 2.93 (dt, J = 13.2, 6.8 Hz, 1H), 2.83 (dd, J = 15.2, 9.2 Hz, 1H), 2.76 (dq, J = 19.0, 7.3, 5.5 Hz, 3H), 2.65 (dd, J = 16.2, 4.8 Hz, 1H), 2.49–2.43 (m, 2H), 2.43–2.32 (m, 1H), 2.27–2.14 (m, 2H), 2.14–1.97 (m, 1H), 1.97–1.84 (m, 1H), 1.77 (ttd, J = 15.0, 8.8, 8.0, 4.6 Hz, 2H), 1.66–1.57 (m, 2H), 1.57–1.49 (m, 3H), 1.49–1.39 (m, 6H), 1.39–1.27 (m, 4H), 1.21 (p, J = 7.6, 6.7 Hz, 2H), 1.12–1.03 (m, 1H), 0.94 (d, J = 6.7 Hz, 3H), 0.89 (t, J = 7.3 Hz, 3H), 0.86 (d, J = 6.3 Hz, 3H), 0.84 (d, J = 6.2 Hz, 3H), 0.79 (q, J = 7.3 Hz, 6H), 0.76–0.66 (m, 1H), 0.52 (d, J = 7.3 Hz, 3H), 0.47 (d, J = 6.7 Hz, 3H). High resolution mass spectrometry (ESI + ) C 79 H 113 N 17 O 16S[M+2H] 2+ The theoretical value is m / z 794.9209, and the measured value is m / z 794.9211.

[0196] Example 34:

[0197]

[0198] The valeraldehyde in Example 28 was replaced with 4'-chlorobiphenyl-4-carboxaldehyde, and the remaining raw materials, reagents, and preparation method were the same as in Example 28 to obtain Bac034 (10 mg, yield 12%). RT = 16.835 min (analytical RP-HPLC). 11H NMR (600 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.63 (d, J = 9.0 Hz, 1H), 8.39 (d, J = 8.3 Hz, 1H), 8.27 (d, J = 8.0 Hz, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 8.3 Hz, 2H), 7.73 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H), 7.30 (s, 1H), 7.25–7.18 (m, 4H), 7.16–7.10 (m, 1H), 5.25 (t, J = 9.0 Hz, 1H), 4.83 (td, J = 9.0, 4.4 Hz, 1H), 4.73 (dd, J = 8.6, 5.1 Hz, 1H), 4.69–4.61 (m, 1H), 4.52 (dd, J = 8.0, 5.5 Hz, 1H), 4.49–4.42 (m, 2H), 4.38 (dd, J = 8.9, 5.1 Hz, 1H), 4.29–4.23 (m, 3H), 4.23–4.19 (m, 2H), 4.19–4.14 (m, 1H), 3.68 (t, J = 10.6 Hz, 1H), 3.55 (dd, J = 11.1, 7.9 Hz, 1H), 3.08–2.97 (m, 2H), 2.93 (dd, J = 13.2, 6.8 Hz, 1H), 2.83 (dd, J = 15.3, 9.2 Hz, 1H), 2.80–2.70 (m, 3H), 2.65 (dd, J = 16.2, 4.8 Hz, 1H), 2.50–2.42 (m, 3H), 2.42–2.34 (m, 1H), 2.27–2.15 (m, 2H), 2.13–2.00 (m, 1H), 1.96–1.86 (m, 0H), 1.82–1.69 (m, 2H), 1.66–1.57 (m, 2H), 1.56–1.49 (m, 2H), 1.48–1.39 (m, 6H), 1.38–I.26 (m, 3H), 1.25–1.16 (m, 2H), 1.07 (dt, J = 14.4, 7.7 Hz, 1H), 0.94 (d, J = 6.8 Hz, 3H), 0.89 (t, J = 7.4 Hz, 3H), 0.86 (d, J = 6.2 Hz, 3H), 0.84 (d, J = 6.2 Hz, 3H), 0.81–0.76 (m, 6H), 0.75–0.65 (m, 0H), 0.51 (t, J = 7.3 Hz, 3H), 0.47 (d, J = 6.7 Hz, 3H). High resolution mass spectrometry (ESI + ) C 79 H112 C1N 17 O 16 S[M+2H] 2+ The theoretical value is m / z 811.9014, and the measured value is m / z 811.9033.

[0199] Example 35:

[0200]

[0201] The valeraldehyde in Example 28 was replaced with 4'-(trifluoromethyl)biphenyl-4-carboxaldehyde. The remaining raw materials, reagents, and preparation method were the same as in Example 28 to obtain Bac035 (10 mg, 12% yield). RT = 16.400 min (analytical RP-HPLC). 1 HNMR (600MHz, DMSO-d6) δ8.91(d,J=1.6Hz,1H),8.59(d,J=9.0Hz,1H),8.37(d,J=8.3Hz,1H),8.22(d,J=7 .9Hz,1H),8.05(d,J=8.5Hz,1H),7.91(d,J=8.2Hz,2H),7.83(d,J=8.3Hz,2H),7.82–7.76(m,2H),7.63(d ,J=8.1Hz,2H),7.27(s,1H),7.23–7.17(m,4H),7.13(tt,J=5.5,2.8Hz,1H),5.24(t,J=9.0Hz,1H),4.85– 4.75(m,1H),4.69(dd,J=8.5,5.2Hz,1H),4.62(dt,J=10.9,5.6Hz,1H),4.50(dd,J=8.1,5.3Hz,1H),4.47–

[0202] 4.38(m,2H),4.35(dt,J=8.9,5.6Hz,1H),4.26(s,2H),4.23–4.19(m,2H),4. 19–4.08(m,2H),3.10–2.98(m,2H),2.93(dt,J=13.3,6.6Hz,1H),2.87–2.77 (m,2H),2.77–2.70(m,2H),2.70–2.59(m,1H),2.49–2.42(m,2H),2.42–2.34 (m,1H),2.20(tt,J=13.3,7.1Hz,2H),2.11–2.03(m,1H),1.96–1.87(m,1H),1 .82–1.69(m,2H),1.69–1.56(m,2H),1.57–1.39(m,9H),1.38–1.25(m,4H),1.21(h,J=7.4,5.8Hz,2H),1.10–0.97(m,1H),0.93(d,J=6.7Hz,3H),0.88(t,J=7.4Hz,3H),0.85(d,J=6.1Hz,3H),0.82(d,J=6.1Hz,3H),0.80–0.72(m,6H),0.74–0.64(m,1H),0.52(t,J=7.3Hz,3H),0.45(d,J=6.7Hz,3H). High resolution mass spectrometry (ESI + )C 80 H 112 F3N 17 O 16 S[M+2H] 2+ Theoretical value m / z 828.9146, measured value m / z

[0203] 828.9154.

[0204] Example 36:

[0205]

[0206] The propionaldehyde in Example 28 was replaced with 4'-(tert-butyloxycarbonylaminomethyl)biphenyl-4-carboxaldehyde. The remaining raw materials, reagents, and preparation method were the same as in Example 28 to obtain intermediate Bac036-i. The crude product was dissolved in 50% TFA in dichloromethane and stirred at room temperature for 10 minutes. The solvent was removed by concentration, and the product was redissolved in appropriate amounts of water and acetonitrile. The product was then directly purified by preparative reverse-phase high-performance liquid chromatography (RP-HPLC). The collected fraction was lyophilized to yield Bac036 as a white, fluffy solid (5 mg, 12% yield over two steps). RT = 13.770 min (analytical RP-HPLC). 1H NMR (600MHz, DMSO-d6) δ8.90(s,1H),7.79–7.71(m,4H),7.58(d,J=7.9Hz,2H),7.56–7.50(m,2H),7.27(d,J=1 .3Hz,1H),7.24–7.18(m,4H),7.14(tt,J=5.6,2.8Hz,1H),5.24(t,J=8.9Hz,1H),4.80(dd,J=9.1,5.0Hz,1H),4 .70(dd,J=8.4,5.1Hz,1H),4.62(dd,J=11.1,4.1Hz,1H),4.50(dd,J=8.0,5.4Hz,1H),4.46–4.40(m,2H),4.35( dd,J=8.9,5.0Hz,1H),4.26–4.09(m,4H),4.07(s,2H),3.10–2.99(m,2H),2.93(dd,J=13.2,6.8Hz,1H),2.88–2 .77(m,2H),2.74(q,J=6.4,5.9Hz,2H),2.70–2.61(m,1H),2.49–2.43(m,2H),2.43–2.35(m,1H),2.20(td,J=13 .1,11.1,6.8Hz,2H),2.08–1.97(m,0H),1.97–1.86(m,1H),1.82–1.70(m,2H),1.69–1.59(m,2H),1.58–1.40(m ,9H),1.38–1.24(m,3H),1.24–1.15(m,2H),1.14–0.98(m,1H),0.92(d,J=6.7Hz,3H),0.88–0.84(m,6H),0.83(d,J=6.3Hz,3H),0.80–0.75(m,5H),0.74–0.68(m,1H),0.52(t,J=7.3Hz,3H),0.46(d,J=6.7Hz,3H). High resolution mass spectrometry (ESI + )C 80 H 116 N 18 O 16 S[M+2H] 2+ The theoretical value is m / z809.4342, and the measured value is m / z809.4344.

[0207] Example 37:

[0208]

[0209] Commercially available bacitracin (71 mg, 0.05 mmol) was dissolved in 2 mL of DMF in a single-necked reaction vial. DIPEA (17 μL, 0.1 mmol) was added with stirring at room temperature. 1H-pyrazole-1-carboximidamide hydrochloride (8.8 mg, 0.06 mmol) was then added to the reaction solution. The reaction was heated to 50°C and stirred continuously. The reaction progress was monitored by analytical reversed-phase high-performance liquid chromatography (RP-HPLC). The reaction was stopped when it stopped. The target fraction was directly separated and purified by preparative reversed-phase HPLC. The collected fraction was lyophilized to yield Bac037 (15 mg, 10% yield) as a white, fluffy solid. RT = 13.875 min (analytical RP-HPLC). 1 H NMR (600MHz, DMSO-d6) δ8.28(d,J=7.9Hz,1H),7.87(d,J=8.4Hz,1H),7.82(d,J=8.4Hz,1H),7.27–7.17( m,4H),7.17–7.09(m,1H),5.22–5.12(m,1H),4.79(s,1H),4.70(d,J=6.9Hz,1H),4.67–4.62(m,1H),4.5 1(dd,J=7.8,5.6Hz,1H),4.50–4.43(m,2H),4.38(dd,J=8.9,5.0Hz,1H),4.31–4.23(m,2H),4.22–4.18( m,1H),4.18–4.10(m,1H),3.70(t,J=10.6Hz,1H),3.56(dd,J=11.3,7.7Hz,1H),3.13–2.98(m,3H),2.98– 2.90(m,1H),2.86–2.73(m,2H),2.69–2.59(m,1H),2.49–2.41(m,2H),2.43–2.32(m,1H),2.21(td,J=11 .5,10.1,6.2Hz,2H),1.96–1.84(m,2H),1.85–1.70(m,2H),1.67–1.55(m,2H),1.55–1.40(m,6H),1.40–1 .28(m,4H),1.28–1.14(m,3H),1.15–1.00(m,1H),0.97(d,J=6.9Hz,3H),0.91–0.85(m,6H),0.84(d,J=5.8Hz,3H),0.82–0.76(m,6H),0.76–0.67(m,1H),0.52(t,J=7.3Hz,3H),0.47(d,J=6.7Hz,3H). High resolution mass spectrometry (ESI + )C 67 H 105 N19 O 16 S[M+2H] 2+ The theoretical value is m / z 732.8927, and the measured value is m / z 732.8928.

[0210] Example 38:

[0211]

[0212] The valeraldehyde in Example 28 was replaced with hexanal, and the remaining raw materials, reagents, and preparation method were the same as in Example 28 to obtain Bac038 (16 mg, yield 21%). RT = 16.447 min (analytical RP-HPLC). 1H NMR (600MHz, DMSO-d6) δ8.95(s,1H),8.63(d,J=9.1Hz,1H),8.38(d,J=8.6Hz,1H),8.26(d,J=8.0Hz,1H),8.07(d,J=9 .0Hz,1H),7.91(d,J=8.2Hz,1H),7.85(d,J=8.5Hz,1H),7.30(s,1H),7.26–7.19(m,4H),7.17–7.10(m,1H),5.23(t,J= 9.0Hz,1H),4.84(dt,J=8.9,6.1Hz,1H),4.73(dd,J=8.6,5.0Hz,1H),4.68(dt,J=11.7,5.4Hz,1H),4.52(dd,J=8.0,5 .5Hz,1H),4.49–4.41(m,2H),4.37(dd,J=8.9,5.0Hz,1H),4.31–4.25(m,2H),4.24–4.10(m,2H),3.70(t,J=10.6Hz,1H ),3.53(dd,J=11.3,8.1Hz,1H),3.07–2.98(m,2H),2.98–2.90(m,2H),2.89–2.72(m,6H),2.68–2.62(m,1H),2.41–2. 33(m,1H),2.26–2.14(m,2H),2.05–1.96(m,1H),1.95–1.87(m,1H),1.83–1.71(m,2H),1.62(qd,J=12.4,11.8,6.3Hz, 4H),1.57–1.49(m,6H),1.49–1.39(m,6H),1.39–1.32(m,3H),1.31–1.14(m,18H),1.12–1.03(m,1H),0.95–0.90(m,6H),0.89–0.82(m,14H),0.82–0.75(m,6H),0.75–0.65(m,1H),0.50(t,J=7.5Hz,4H),0.48(d,J=6.8Hz,3H). High resolution mass spectrometry (ESI + )C 78 H 127 N 17 O 16 S[M+2H] 2+ The theoretical value is m / z 795.9757, and the measured value is m / z 795.9756.

[0213] Example 39:

[0214]

[0215] The valeraldehyde in Example 28 was replaced with biphenylaldehyde, and the remaining raw materials, reagents, and preparation method were the same as in Example 28 to obtain Bac039 (15 mg, yield 17%). RT = 17.580 min (analytical RP-HPLC). 11H NMR (600 MHz, DMSO-d6) δ 8.96 (d, J = 1.4 Hz, 1H), 7.76–7.71 (m, 4H), 7.68 (ddd, J = 8.2, 5.7, 1.3 Hz, 4H), 7.60 (d, J = 8.3 Hz, 2H), 7.57–7.53 (m, 2H), 7.48 (td, J = 7.8, 2.7 Hz, 4H), 7.42–7.36 (m, 2H), 7.30 (d, J = 1.3 Hz, 1H), 7.26–7.18 (m, 4H), 7.16–7.10 (m, 1H), 5.26 (ddd, J = 9.6, 7.9, 1.3 Hz, 1H), 4.86–4.81 (m, 1H), 4.73 (dd, J = 8.6, 5.0 Hz, 1H), 4.67 (dd, J = 11.2, 3.9 Hz, 1H), 4.52 (dd, J = 8.0, 5.5 Hz, 1H), 4.47 (td, J = 8.4, 5.7 Hz, 2H), 4.37 (dd, J = 8.9, 5.0 Hz, 1H), 4.28 (d, J = 5.5 Hz, 1H), 4.27–4.14 (m, 5H), 4.13 (s, 2H), 3.71–3.64 (m, 1H), 3.58–3.53 (m, 2H), 3.02 (tt, J = 13.1, 5.9 Hz, 2H), 2.93 (dp, J = 20.6, 6.8 Hz, 3H), 2.84 (dd, J = 15.3, 9.2 Hz, 1H), 2.80–2.75 (m, 1H), 2.68–2.62 (m, 1H), 2.51–2.43 (m, 3H), 2.41–2.34 (m, 1H), 2.24–2.15 (m, 2H), 2.12–2.03 (m, 1H), 1.92 (tt, J = 13.6, 6.3 Hz, 1H), 1.77 (tdd, J = 15.4, 11.4, 7.5 Hz, 2H), 1.64 (s, one hydrogen atom), 1.58–1.49 (m, 4H), 1.49–1.40 (m, 4H), 1.39–1.26 (m, 4H), 1.25–1.17 (m, 2H), 1.12–1.03 (m, 1H), 0.93 (d, J = 6.8 Hz, 3H), 0.88 (t, J = 7.4 Hz, 3H), 0.86 (d, J = 6.2 Hz, 3H), 0.83 (d, J = 6.2 Hz, 3H), 0.80 (d, J = 6.7 Hz, 3H), 0.77 (t, J = 7.4 Hz, 3H), z 0.74–0.66 (m, 1H), and a signal at 0.53–0.44 (m, 6H). High-resolution mass spectrometry (ESI + ) C 92 H 123 N<000??327>O[[ID=??]] 16 It should be noted that there seems to be an unclear "z" in the NMR data description part, and the "??" in the tag <000??327> needs to be corrected if it is an incorrect input.S[M+2H] 2+ The theoretical value is m / z 877.9600, and the measured value is m / z 877.9609.

[0216] Example 40:

[0217]

[0218] The valeraldehyde in Example 28 was replaced with 4'-chlorobiphenyl-4-carboxaldehyde, and the remaining raw materials, reagents, and preparation method were the same as in Example 28 to obtain Bac040 (7 mg, yield 8%). RT = 18.843 min (analytical RP-HPLC). 11H NMR (600 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.63 (d, J = 9.1 Hz, 1H), 8.37 (d, J = 8.7 Hz, 1H), 8.26 (d, J = 8.1 Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 8.6 Hz, 1H), 7.76–7.69 (m, 8H), 7.60 (d, J = 8.1 Hz, 2H), 7.57–7.50 (m, 6H), 7.30 (s, 1H), 7.25–7.18 (m, 4H), 7.14 (t, J = 7.1 Hz, 1H), 5.25 (t, J = 9.0 Hz, 1H), 4.87–4.79 (m, 1H), 4.73 (dd, J = 8.6, 5.1 Hz, 1H), 4.70–4.63 (m, 0H), 4.52 (dd, J = 8.0, 5.5 Hz, 1H), 4.49–4.43 (m, 2H), 4.37 (dd, J = 8.8, 5.1 Hz, 1H), 4.31–4.26 (m, 0H), 4.24 (s, 2H), 4.23–4.18 (m, 1H), 4.18–4.15 (m, 1H), 4.13 (s, 2H), 3.67 (t, J = 10.6 Hz, 1H), 3.54 (dd, J = 11.2, 7.8 Hz, 1H), 3.05–2.98 (m, 2H), 2.96–2.86 (m, 3H), 2.84 (dd, J = 15.2, 9.1 Hz, 1H), 2.77 (d, J = 11.6 Hz, 1H), 2.68–2.62 (m, 1H), 2.49–2.43 (m, 3H), 2.41–2.33 (m, 1H), 2.28–2.13 (m, 2H), 2.12–1.99 (m, 1H), 1.96–1.87 (m, 1H), 1.83–1.69 (m, 2H), 1.67–1.57 (m, 2H), 1.57–1.48 (m, 5H), 1.48–1.39 (m, 4H), 1.39–1.26 (m, 4H), 1.24–1.13 (m, 2H), 1.12–1.02 (m, 1H), 0.93 (d, J = 6.7 Hz, 3H), 0.88 (t, J = 7.5 Hz, 3H), 0.86 (d, J = 6.2 Hz, 3H), 0.83 (d, J = 6.1 Hz, 3H), 0.79 (d, J = 6.8 Hz, 3H), 0.77 (t, J = 7.4 Hz, 3H), 0.73–0.65 (m, 1H), 0.52–0.44 (m, 6H). High-resolution mass spectrometry (ESI + ) C 92 H 121 Cl2N 17 O16 S[M+2H] 2+ The theoretical value is m / z911.9211, and the measured value is m / z911.9220.

[0219] Example 41:

[0220]

[0221] The valeraldehyde in Example 28 was replaced with 4'-(trifluoromethyl)biphenyl-4-carboxaldehyde. The remaining raw materials, reagents, and preparation method were the same as in Example 28 to obtain Bac041 (15 mg, 16% yield). RT = 18.830 min (analytical RP-HPLC). 11H NMR (600 MHz, DMSO-d6) δ 8.97 (d, J = 1.4 Hz, 1H), 8.64 (d, J = 9.0 Hz, 1H), 8.38 (d, J = 8.6 Hz, 1H), 8.27 (d, J = 8.2 Hz, 1H), 8.06 (d, J = 8.7 Hz, 1H), 7.96–7.88 (m, 4H), 7.86–7.79 (m, 8H), 7.66–7.63 (m, 2H), 7.62–7.54 (m, 2H), 7.30 (d, J = 1.3 Hz, 1H), 7.26–7.18 (m, 4H), 7.16–7.08 (m, 1H), 5.26 (ddd, J = 9.6, 7.9, 1.3 Hz, 1H), 4.84 (td, J = 9.0, 4.5 Hz, 1H), 4.74 (dd, J = 8.6, 5.0 Hz, 1H), 4.71–4.62 (m, 1H), 4.53 (dd, J = 8.0, 5.5 Hz, 1H), 4.50–4.43 (m, 2H), 4.38 (dd, J = 8.8, 5.0 Hz, 1H), 4.31–4.25 (m, 3H), 4.25–4.18 (m, 2H), 4.17–4.12 (m, 3H), 3.75–3.64 (m, 1H), 3.55 (dd, J = 11.1, 7.8 Hz, 1H), 3.08–2.98 (m, 2H), 2.97–2.88 (m, 3H), 2.84 (dd, J = 15.3, 9.2 Hz, 1H), 2.79–2.74 (m, 1H), 2.68–2.59 (m, 1H), 2.49–2.41 (m, 3H), 2.42–2.34 (m, 1H), 2.27–2.14 (m, 2H), 2.07 (dt, J = 12.4, 4.7 Hz, 1H), 1.93 (dt, J = 15.4, 7.2 Hz, 1H), 1.82–1.70 (m, 2H), 1.68–1.58 (m, 2H), 1.57–1.48 (m, 4H), 1.48–1.40 (m, 3H), 1.39–1.26 (m, 4H), 1.25–1.18 (m, 2H), 1.14–1.03 (m, 1H), 0.94 (d, J = 6.8 Hz, 3H), 0.89 (t, J = 7.4 Hz, 3H), 0.86 (d, J = 6.2 Hz, 3H), 0.84 (d, J = 6.2 Hz, 3H), 0.80 (d, J = 6.8 Hz, 3H), 0.77 (t, J = 7.4 Hz, 3H), 0.70 (dq, J = 10.2, 7.0 Hz, 1H), 0.53–0.44 (m, 6H). High resolution mass spectrometry (ESI + ) C 94 H 121 F6N 17 O16 S[M+2H] 2+ The theoretical value is m / z 945.9474, and the measured value is m / z 945.9465.

[0222] Activity test:

[0223] Biological test example 1 in vitro antibacterial activity test

[0224] Bacitracin and the 41 compounds of the present invention were tested for in vitro antibacterial activity. The minimum inhibitory concentration (MIC) of the compounds was determined according to the WS / T639-2018 Technical Requirements for Antimicrobial Susceptibility Testing and the 32nd edition of the CLSIM-100 Antimicrobial Susceptibility Testing Implementation Standards, referring to the CLSI drug susceptibility testing standards of the United States.

[0225] The test strains were vancomycin-susceptible Staphylococcus aureus (MSSA, Newman strain), vancomycin-intermediate Staphylococcus aureus (VISA, Mu50 strain), methicillin-resistant Staphylococcus aureus (MRSA, SA-COL strain, 2011-137 strain and 2012-3 strain), vancomycin-resistant Enterococcus faecium (VRE, VanA phenotype Efm-HS0649 strain, VanM phenotype Efm-HS08257 strain and VanB phenotype VanBR strain) and vancomycin-resistant Enterococcus faecalis (VRE, VanA phenotype Efm-HS0649 strain, VanM phenotype Efm-HS08257 strain and VanB phenotype VanBR strain) and vancomycin-resistant Enterococcus faecalis (VRE, VanA phenotype Efm-HS0649 strain, VanM phenotype Efm-HS08257 strain and VanB phenotype VanBR strain). faecalis, VRE, VanB phenotype). Some of the compounds in the present invention were also tested for their antibacterial activity against 5 strains of Clostridium difficile, and the test strains were Clostridium difficile-2, Clostridium difficile-4, Clostridium difficile-9, Clostridium difficile-11, and Clostridium difficile-23. Some of the compounds in the present invention were also tested for their antibacterial activity against 2 strains of negative bacteria, and the test strains were Escherichia coli (AB1157 strain) and Acinetobacter baumannii (clinical isolate). Bacitracin was purchased from Titan Technology Co., Ltd. with batch number 01022008 and a potency of 65 Units / mg. Vancomycin was purchased from Titan Technology Co., Ltd. with batch number 011073672.

[0226] In the experiment, 100 μL of the test sample solution of different concentrations (256, 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125 mg / L) was respectively added to the 1st to 12th wells of a sterilized 96-well polystyrene plate, and then 100 μL of the test bacterial solution was added to each well (the capacity of each well was 200 μL). The final concentration of the bacterial solution was about 10 5CFU / mL, with final drug concentrations of 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, and 0.0625 mg / L, respectively. Each test was performed with one replicate well. After sealing, the wells were incubated in a 35-37°C incubator for 15-24 hours, and the results were determined. The lowest drug concentration that completely inhibited bacterial growth in the wells was defined as the minimum inhibitory concentration (MIC). The results are shown in Tables 1, 2, 3, 4, and 5.

[0227] Table 1 Test results of the antibacterial activity of the compounds of the present invention against Staphylococcus aureus in vitro

[0228]

[0229]

[0230]

[0231] Table 2 Test results of the in vitro antibacterial activity of the compounds of the present invention against Enterococci

[0232]

[0233]

[0234] Table 3 Antibacterial activity test of some compounds of the present invention against Clostridium difficile

[0235]

[0236] Table 4 Test results of in vitro antibacterial activity of some compounds of the present invention against negative bacteria

[0237]

[0238]

[0239] Table 5 Effect of adding additional zinc ions (0.3 mM) on the antibacterial activity of some compounds of the present invention

[0240]

[0241] The above-mentioned in vitro antibacterial activity studies show that the antibacterial activity of the bacitracin derivatives of the present invention represented by the examples against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) is mostly higher than that of bacitracin, and some are higher than vancomycin. Among them, the antibacterial activity of the preferred compounds is 4-128 times that of bacitracin and 2-128 times that of vancomycin. The preferred compounds Bac012 and Bac026 are 4-32 times more active than bacitracin in combating Clostridium difficile. The preferred compound Bac015 also exhibits certain anti-negative bacteria activity. Bacitracin has obvious zinc ion dependence characteristics in terms of antibacterial activity, while some compounds of the present invention exhibit zinc ion-independent characteristics. Therefore, the above antibacterial experiments show that the structural modification strategy of the novel bacitracin analogues involved in the present invention can significantly enhance its antibacterial activity and change its antibacterial properties.

[0242] Biological Test Example 2 Kidney Cytotoxicity Experiment

[0243] Renal cell toxicity experiments were conducted on Bac011, Bac012, Bac024, Bac025, Bac026, and bacitracin. Renal cell viability was determined using the Cell Counting Kit-8 method.

[0244] HEK-293 cells (human embryonic kidney cells) in logarithmic growth phase were seeded at an appropriate density (approximately 6,000 cells) into 96-well culture plates, with 100 μL per well. After overnight culture, the culture medium was discarded. Bac011, Bac012, Bac024, Bac025, Bac026, and bacitracin were diluted with culture medium to final concentrations of 200 mg / L, 100 mg / L, 50 mg / L, and 25 mg / L, respectively, and added to the 96-well plate (100 μL / well) for 72 hours. Three replicates were set for each concentration, and a 0.5% DMSO control group and a blank control group were set up. After the incubation period, 10 μL of CCK8 assay solution was added to each well. The cells were incubated at 37°C for 120 minutes, and the optical density (OD) at 450 nm was measured using a Multiskan FC microplate reader. The cell viability was calculated based on the OD value: Cell viability = [(OD of experimental well - OD of blank well) / (OD of control well - OD of blank well)] * 100%. Figure 1 shown.

[0245] The results showed that the toxicity of Bac011 and Bac026 in the present invention in kidney cells was comparable to that of bacitracin, and they had better safety.

[0246] Biological Test Example 3 Antiviral Experiment

[0247] The antiviral efficacy of Bac012, Bac026 and the isolated and purified bacitracin A fraction was studied. Hep-2 cells in the logarithmic growth phase were cultured at 0.3*10 6 Cells were plated at a concentration of 100 μL / well in a 96-well plate. Cultures were incubated overnight (confluence >80%). Bacitracin A, Bac012, and Bac026 (target working concentration 10 μM) were mixed with 50 μL of RSV-ON1-GFP virus (MOI = 0.1). Four replicate wells were set up for each drug group, with DMSO and 1:100 and 1:1000 heparin control wells at the corresponding drug concentrations. 100 μL of the drug-virus mixture was added to the washed cells and incubated at 37°C for 36 h. Following incubation, cells were fixed with 4% paraformaldehyde for 30 min at room temperature. The paraformaldehyde was discarded, and 100 μL of 1x PBS solution was added to each well. Plates were scanned using a PE high-content imaging system, and the results were analyzed statistically.

[0248] Add 10 μM of bacitracin A, Bac012 and Bac026 to the plate containing 3×10 4 Hep-2 cells were treated for 36 hours, and a DMSO control group and a culture medium control group were set up, with four replicate wells in each group. Following co-culture, 10 μL of CCK8 reagent was added to each well using the CCK-8 assay kit (Solebol CA1210). After incubation at 37°C for 1.5 hours, the absorbance was measured at OD = 450 nm using a microplate reader. OD values ​​were converted to cell viability using the formula: Cell viability = [A(drug added) - A(blank)] / [A(0 drug added) - A(blank)], where A(0 drug added) = DMSO control group and A(blank) = culture medium control group.

[0249] The results are as follows Figure 2 shown.

[0250] Conclusion: Bac026 of the present invention has a good inhibitory effect on the proliferation of RSV-ON1 virus in Hep-2 cells, and the drug is non-toxic in Hep-2 cells at a concentration of 10 μM.

[0251] Although some specific embodiments of the present invention have been described in detail by way of examples, it should be understood by those skilled in the art that the above examples are for illustration only and are not intended to limit the scope of the present invention. It should be understood by those skilled in the art that modifications may be made to the above embodiments without departing from the scope and spirit of the present invention. The scope of the present invention is defined by the appended claims.

Claims

1. A bacitracin derivative and a pharmaceutically acceptable salt thereof, characterized in that: The general structural formula of the Bacitracin derivative is as follows: wherein R1 and R2 are each independently selected from substituted or unsubstituted C1-C 20 Straight chain or branched alkyl, substituted or unsubstituted C4-C 20 Straight chain or branched chain alkanoyl, substituted or unsubstituted C4-C 20 Straight chain or branched alkenyl, substituted or unsubstituted C4-C 20 Straight chain or branched alkynyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 20 Aryl, 3-10 membered non-aromatic heterocyclic group containing one or more heteroatoms selected from N, O and S in the substituted or unsubstituted ring, 5-10 membered heteroaryl group containing one or more heteroatoms selected from N, O and S in the substituted or unsubstituted ring; the substitution refers to substitution by one or more substituents selected from the following: halogen, -OH, -NH2, cyano, C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Alkylamino, C1-C 10 Alkanoyl, C3-C 10 Cycloalkyl, halogenated C1-C 10 Alkyl, C2-C6 straight-chain or branched alkynyl, phenylethynyl, trimethylsilylethynyl, pyridyl, phenyl, cyanophenyl, C1-C6 alkylphenyl, trifluoromethylphenyl, chlorophenyl, biphenyl, methylbiphenyl, trifluoromethylbiphenyl, halogen-substituted biphenyl.

2. The bacitracin derivative and pharmaceutically acceptable salt thereof according to claim 1, characterized in that: Including compounds with the following structural formula:

3. A method for preparing the bacitracin derivative and the pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: include: The bacitracin derivative is obtained by subjecting bacitracin to one or more of reductive amination reaction, acylation reaction, substitution reaction and epoxy ring-opening reaction.

4. Use of the bacitracin derivative and pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: Used for preparing medicines for treating and / or preventing diseases related to bacterial infection, wherein the bacteria are Gram-negative bacteria and / or Gram-positive bacteria.

5. The use according to claim 4, characterized in that The disease comprises one or more of bacteremia, sepsis, pneumonia, meningitis, urinary tract infection, impetigo, erysipelas, cellulitis, skin infection, and Clostridium difficile infection.

6. A pharmaceutical composition, characterized in that The invention comprises the bacitracin derivative according to claim 1 or 2 and a pharmaceutically acceptable salt thereof.

7. Use of the pharmaceutical composition according to claim 6, characterized in that: Used for preparing medicines for treating and / or preventing diseases related to bacterial infection, wherein the bacteria are Gram-negative bacteria and / or Gram-positive bacteria.

8. The use according to claim 7, characterized in that The disease comprises one or more of bacteremia, sepsis, pneumonia, meningitis, urinary tract infection, impetigo, erysipelas, cellulitis, skin infection, and Clostridium difficile infection.

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