A betulinic acid saponin derivative and its preparation method and application

Abstract

The present invention relates to a betulinic acid saponin derivative, a preparation method and an application thereof, and belongs to the field of biomedicine technology. The betulinic acid saponin derivative of the present invention has the general structural formula: 1 Selected from hydroxyl or -O-G, G is a monosaccharide; R 2 Selected from dopamine, 5-aminovaleric acid, 4-aminobutyric acid or 3-aminopropionic acid and their salts. The betulic acid saponin derivative did not show obvious cytotoxicity to THP-1 macrophages, and could significantly reduce the release of IL-6 and IL-1β in LPS-induced THP-1 macrophages. It also has better anti-inflammatory activity, and its therapeutic effect on improving diarrhea and bloody stools in colitis mice is significantly better than that of betulic acid and the positive control drug mesalazine, while its therapeutic effect on dermatitis is better than that of the positive control drug dexamethasone, and there are no obvious toxic side effects such as weight loss and immunosuppression. This shows that the betulic acid saponin derivative has good in vitro and in vivo safety and drugability.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedicine, and in particular relates to a betulinic acid saponin derivative, a preparation method and an application thereof. Background Art

[0002] Inflammation is a common clinical pathological process, the body's defensive response to factors including infection, trauma, and chemical irritation, with both defensive and damaging effects. However, excessive and uncontrolled inflammatory responses can kill tissue cells and endanger human life. Furthermore, acute inflammation can progress to chronic and pathological inflammation, leading to persistent tissue destruction and systemic homeostasis disturbances, potentially contributing to the development of related diseases, including inflammatory bowel disease (IBD), atopic dermatitis (AD), pneumonia, hepatitis, and cancer.

[0003] Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a chronic, relapsing inflammatory condition of the gastrointestinal tract that is becoming increasingly prevalent worldwide. Key symptoms of IBD include dysregulated immune responses, abnormal cytokine production, imbalanced intestinal microbiota, and barrier damage. More seriously, long-term, recurrent inflammatory damage often progresses to colitis-associated colon cancer, posing a serious threat to patients and even life-threatening conditions. Currently, the main therapeutic agents used in clinical treatment of IBD are aminosalicylates, corticosteroids, immunosuppressants, and anti-TNF-α biologics. However, these drugs are associated with adverse effects, including serious infections, cardiovascular toxicity, and immunosuppression. Atopic dermatitis (AD) is a common, immune-mediated inflammatory skin disease characterized by recurrent, pruritic, localized eczema, often with seasonal fluctuations. Atopic dermatitis, also known as atopic eczema, neurodermatitis, or atopic dermatitis, is the most common form of eczema. Current treatments for AD include various topical corticosteroids (TCSs), the topical calcineurin inhibitors tacrolimus and pimecrolimus, and the phosphodiesterase 4 (PDE4) inhibitor crisaborole. For more severe AD, in addition to ultraviolet light, cyclosporine A, methotrexate, azathioprine, or mycophenolate mofetil are also used. However, these medications have significant side effects and are expensive. Therefore, developing new, safe, and effective anti-inflammatory drugs is a viable strategy.

[0004] Betulinic acid (BA) is a natural pentacyclic triterpenoid compound primarily extracted from birch bark. BA exhibits a wide range of pharmacological activities, including antitumor, antiviral, anti-inflammatory, and antioxidant effects. However, its poor water solubility, low bioavailability, and cytotoxicity significantly limit its further development and application. Therefore, the development of novel betulinic acid-based drugs with high anti-inflammatory activity and minimal toxicity is urgent. Summary of the Invention

[0005] Therefore, the technical problem to be solved by the present invention is to overcome the problem that existing drugs have obvious toxic side effects and some drugs have short half-lives.

[0006] In order to solve the above technical problems, the present invention provides a betulic acid-type saponin derivative, a preparation method and an application thereof. Betulic acid is structurally modified and transformed by chemical methods to obtain a series of saponin derivatives to solve the problem of poor drugability of the above-mentioned BA and obtain compounds with anti-inflammatory activity significantly better than betulic acid.

[0007] The first object of the present invention is to provide a betulinic acid saponin derivative, the general structural formula of which is shown below:

[0008] ,

[0009] Among them, R 1 Selected from hydroxyl or -OG, G is a monosaccharide;

[0010] R 2 Selected from benzyloxy, 1-O-benzotriazole, methyl 6-aminocaproate, 6-aminocaproic acid, p-hydroxyphenylethylamine, 28-O-β-D-pyranose, o-hydroxyphenylethylamine, m-hydroxyphenylethylamine, o-methoxyphenylethylamine, m-methoxyphenylethylamine, p-methoxyphenylethylamine, p-bromophenylethylamine, p-fluorophenylethylamine, p-hydroxybenzylamine, 3,4-difluorophenylethylamine, p-trifluoromethoxyphenylethylamine, dopamine, ethyl 6-aminocaproate, tert-butyl 6-aminocaproate, 6-aminocapronitrile, methyl 5-aminovalerate, 5-aminovaleric acid, methyl 4-aminobutyrate, 4-aminobutyric acid, methyl 3-aminopropionate, 3-aminopropionic acid, methyl (1R,3S)-3-aminocyclopentanecarboxylate or (1R,3S)-3-aminocyclopentanecarboxylic acid.

[0011] Furthermore, R 2 Selected from dopamine, 5-aminovaleric acid, 4-aminobutyric acid or 3-aminopropionic acid and salts thereof.

[0012] In one embodiment of the present invention, the monosaccharide is selected from 3-O-β-D-glucopyranose, 3-O-α-L-arabinopyranose, 3-O-α-D-mannopyranose, 3-O-β-D-galactopyranose or 3-O-β-D-xylopyranose.

[0013] Furthermore, the monosaccharide is 3-O-α-L-arabinopyranose.

[0014] The second object of the present invention is to provide a method for preparing the betulic acid-type saponin derivative, comprising the following steps: using betulic acid as a raw material, and preparing the betulic acid-type saponin derivative through a glycosylation reaction, an esterification reaction or an amidation reaction.

[0015] The third object of the present invention is to provide a pharmaceutically acceptable salt of the betulic acid saponin derivative.

[0016] The fourth object of the present invention is to provide a pharmaceutical composition, the active ingredient of which is the betulic acid saponin derivative or the pharmaceutically acceptable salt of the betulic acid saponin derivative.

[0017] In one embodiment of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier refers to one or more compatible solid or liquid fillers or gel substances that are pharmaceutically acceptable, have sufficient purity and low toxicity, and are compatible with each other and with the active ingredient of the present invention without reducing the efficacy of the active ingredient.

[0018] Furthermore, the pharmaceutically acceptable carrier is selected from one or more of cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), cyclodextrins (such as hydroxypropyl β-cyclodextrin), emulsifiers (such as Tween), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives and pyrogen-free water.

[0019] The fifth object of the present invention is to provide a use of the betulic acid saponin derivative, the pharmaceutically acceptable salt of the betulic acid saponin derivative, and the pharmaceutical composition in the preparation of drugs for treating inflammation-related diseases.

[0020] In one embodiment of the present invention, the inflammation-related disease is one or more of pneumonia, hepatitis, nephritis, gastritis, cholecystitis, pharyngitis, conjunctivitis, keratitis, otitis media, appendicitis, cervicitis, encephalitis, peritonitis, arthritis, stomatitis, enteritis and skin inflammation.

[0021] In one embodiment of the present invention, the skin inflammation is one or more of atopic dermatitis, contact dermatitis, eczema, acne, dermatomyositis, urticaria, lupus erythematosus, ichthyosis vulgaris, allergic dermatitis and psoriasis.

[0022] The sixth object of the present invention is to provide a use of the betulic acid saponin derivative, the pharmaceutically acceptable salt of the betulic acid saponin derivative, and the pharmaceutical composition in the preparation of drugs for treating autoimmune diseases.

[0023] In one embodiment of the present invention, the autoimmune disease includes one or more of rheumatoid arthritis, pemphigus, Graves' disease, systemic sclerosis, allergic rhinitis, allergic asthma, anaphylactic shock, familial Mediterranean fever, ankylosing spondylitis, urticaria, purpura, transplant rejection, secondary immunodeficiency, myasthenia gravis, autoimmune hemolytic anemia, Sjögren's syndrome, polymyositis / dermatomyositis, lupus erythematosus and Hashimoto's thyroiditis.

[0024] In one embodiment of the present invention, the drug is a topical, oral, skin-topical, or systemic, rectal, or parenteral (such as intravenous, intramuscular, or subcutaneous) drug.

[0025] In one embodiment of the present invention, the dosage form of the drug includes pills, tablets, powders, capsules, granules (powders), ointments, solutions, injections, gels or suppositories.

[0026] Furthermore, the solution includes an emulsion, a solution, a suspension, a syrup or a tincture.

[0027] The technical solution of the present invention has the following advantages over the prior art:

[0028] (1) The betulinic acid saponin derivatives described in the present invention have a suitable oil-water partition coefficient and solubility compared to BA, and are more conducive to intestinal absorption.

[0029] (2) Most of the betulinic acid saponin derivatives described in the present invention showed no significant cytotoxicity to THP-1 macrophages, but were able to significantly reduce the release of IL-6 and IL-1β in THP-1 macrophages induced by LPS. Some of the compounds had better anti-inflammatory activity, and were significantly better than betulinic acid and the positive control drug mesalazine in improving diarrhea and bloody stools in colitis mice, and better than the positive control drug dexamethasone in treating dermatitis, without significant side effects such as weight loss and immunosuppression. This indicates that the betulinic acid saponin derivatives have good in vitro and in vivo safety and drugability. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] In order to make the content of the present invention more clearly understood, the present invention is further described in detail below according to specific embodiments of the present invention in conjunction with the accompanying drawings, wherein:

[0031] Figure 1-Figure 2 The effect of the betulinic acid saponin derivatives on THP-1 macrophage cytotoxicity in Test Example 1 of the present invention;

[0032] Figure 3Effects of betulinic acid saponin derivatives in Test Example 3 of the present invention on weight change, stool characteristics, occult blood / hematochezia, and DAI scores in DSS-induced colitis mice;

[0033] Figure 4 The effect of the betulinic acid saponin derivatives in Test Example 3 of the present invention on the colon length of DSS-induced colitis mice;

[0034] Figure 5 The effect of betulinic acid saponin derivatives on the spleen index of DSS-induced colitis mice in Test Example 3 of the present invention;

[0035] Figure 6 The effects of multiple administrations of BA-52 on the body weight and organ indexes of mice in Test Example 4 of the present invention;

[0036] Figure 7 BA-52 in Test Example 5 of the present invention inhibits the release of inflammatory factors in a dose-dependent manner;

[0037] Figure 8 This is the effect of BA-52 on the back skin of mice with DNCB-induced dermatitis in Test Example 6 of the present invention;

[0038] Figure 9 The effect of BA-52 on the body weight and EASI score of DNCB-induced dermatitis mice in Test Example 6 of the present invention;

[0039] Figure 10 This is the effect of BA-52 on the ear skin of DNCB-induced dermatitis mice in Test Example 6 of the present invention;

[0040] Figure 11 This is the effect of BA-52 in Test Example 6 of the present invention on ear thickness difference, ear weight difference and spleen index in DNCB-induced dermatitis mice. DETAILED DESCRIPTION

[0041] The present invention will be further described below with reference to the accompanying drawings and specific embodiments so that those skilled in the art can better understand the present invention and implement it. However, the embodiments are not intended to limit the present invention.

[0042] In the present invention, unless otherwise specified, the reagents used in the examples of the present invention were mainly provided by Shanghai Aladdin Biochemical Technology Co., Ltd.; the TLC thin-layer chromatography silica gel plates were produced by Shandong Yantai Jiangyou Silica Gel Development Co., Ltd., model HSGF 254; the silica gel columns used for compound purification were produced by Beijing Inokai Technology Co., Ltd., 200-300 mesh; NMR was recorded using a Varian Mercury 400M nuclear magnetic resonance spectrometer, and chemical shifts are expressed in δ (ppm).

[0043] In the present invention, unless otherwise specified, the Chinese equivalents of the abbreviations used in the examples of the present invention are as follows: DMF is N,N-dimethylformamide, DCM is dichloromethane, TBTU is O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, DIEA is N,N-diisopropylethylamine, TMSOTf is trimethylsilyl trifluoromethanesulfonate, TEA is triethylamine, DSS is dextran sulfate sodium, and DNCB is dinitrochlorobenzene.

[0044] In the present invention, unless otherwise specified, the structural formula of betulinic acid used in the examples of the present invention is .

[0045] Example 1 Synthesis of BA-1

[0046]

[0047] Betulinic acid BA (2 g, 4.379 mmol) was dissolved in 25 mL of DMF, and benzyl chloride (0.65 mL, 5.649 mmol) and potassium carbonate (1.2 g, 8.696 mmol) were added sequentially. The mixture was heated and stirred at 35°C for 24 h. After the reaction was complete as detected by TLC, 200 mL of water was added to the reaction solution, and the filter cake was filtered to obtain a filter cake. The filter cake was washed with 1 mol / L hydrochloric acid (150 mL × 3), saturated sodium bicarbonate (150 mL × 3), and water (150 mL × 3) in sequence. After being drained, it was redissolved in DCM, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 1.9 g of a white solid was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 8:1) with a yield of 80%. 1H NMR (400MHz, CDCl3) δ 7.39 – 7.29 (5H, m, H–Ar), 5.12 (2H, m), 4.72 (1H, brs, H1-29), 4.59 (1H, brs, H2-29), 3.17 (1H, m, H-3), 3.02 (1H, m), 2.28 (1H, m), 2.18(1H, m), 1.88 (2H, m), 1.68 (3H, s), 1.64 (1H, m), 1.60 (2H, m), 1.55 (1H,m), 1.49 (1H, m), 1.45 (2H, s), 1.42 – 1.25 (9H, m), 1.22 (1H, m), 1.09 (1H,m), 0.96 (3H, s), 0.94 (3H, s), 0.87 (1H, m), 0.80 (3H, s), 0.76 (3H, s),0.75 (3H, s), 0.66 (1H, m). 13 C NMR (101 MHz, CDCl3) δ 176.0, 150.7, 136.6,128.6, 128.4, 128.2, 109.7, 79.1, 65.9, 56.7, 55.5, 50.7, 49.6, 47.1, 42.5,40.8, ESI-HRMS ( m / z ): C 37 H 54 O3Na [M+Na] + ,Calculated value, 569.3965; Measured value, 569.3978.

[0048] Example 2 Synthesis of BA-2

[0049]

[0050] BA (200 mg, 0.438 mmol), TBTU (210 mg, 0.657 mmol), and DIEA (229 μL, 1.314 mmol) were dissolved in 7 mL of DMF and reacted at room temperature for 5 h. 50 mL of water was added to the reaction solution to precipitate a white solid, which was filtered to obtain a crude product. After drying, the product was redissolved in DCM, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel column chromatography (petroleum ether:ethyl acetate = 9:1 to 8:1) gave 217 mg of a white solid with a yield of 86%. 1 H NMR (400 MHz, CDCl3) δ 8.08 (1H, dd, J =8.5, 1.0 Hz), 7.55 (1H, ddd, J = 8.1, 7.0, 0.9 Hz), 7.43 (1H, ddd, J = 8.1,7.0, 0.9 Hz), 7.36 (1H, m), 4.73 (1H, brs, H1-29), 4.64 (1H, brs, H2-29), 3.19(1H, m, H-3), 2.95 (1H, m), 2.64 (1H, m), 2.41 (1H, m), 2.21 (1H, m), 2.08(1H, m), 1.83 – 1.73 (4H, m), 1.71 (3H, s), 1.66 (2H, m), 1.60 (1H, m), 1.55(4H, m), 1.44 (5H, m), 1.27 (2H, m), 1.05 (3H, s), 0.99 (3H, s), 0.98 (3H, s), 0.89 (1H, m), 0.81 (3H, s), 0.76 (3H, s), 0.70 (1H, m). 13 C NMR (101 MHz, CDCl3) δ 172.0, 149.4, 143.8, 129.0, 128.8, 124.9, 120.8, 110.5, 108.1, 79.1,57.2, 55.5, 50.7, 50.1, 46.7, 42.6, 40.9, 39.0, 38.9, 38.6, 37.3, 36.9, 34.5,31.5, 30.4, 30.3, 28.1, 27.5, 25.5, 20.9, 19.5, 18.4, 16.3, 16.2, 15.5, 15.0.ESI-HRMS ( m / z ): C36 H 50 N3O3 [MH] - , Calculated value , 572.3858; Measured, 572.3860.

[0051] Example 3 Synthesis of BA-3

[0052]

[0053] BA (100 mg, 0.219 mmol) was dissolved in 4 mL of DMF, and TBTU (105 mg, 0.328 mmol) and DIEA (115 μL, 0.657 mmol) were added first, and the mixture was stirred at room temperature for 6 h. After the reaction was completed to form the intermediate, methyl 6-aminohexanoate hydrochloride (185 μL, 0.328 mmol) and DIEA (142 mg, 1.095 mmol) were added, and the mixture was stirred at room temperature overnight. After the reaction was completed, 30 mL of ethyl acetate was added to the reaction solution. The organic layer was washed three times with an appropriate amount of distilled water and once with an appropriate amount of saturated NaCl water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 6:1) to obtain 94 mg of a light yellow solid with a yield of 73%. 1 HNMR (400 MHz, CDCl3) δ 5.62 (1H, t, J = 5.9 Hz, -CONH), 4.73 (1H, brs, H1-29), 4.58 (1H, brs, H2-29), 3.66 (3H, s, -OCH3), 3.29 (1H, m, H-3), 3.16 (1H, m), 2.45 (1H, m), 2.31 (2H, t, J = 7.4 Hz), 1.92 (2H, m), 1.74 – 1.69 (3H, m), 1.67 (3H, s), 1.63 (2H, m), 1.58 (2H, m), 1.55 –1.45 (8H, m), 1.43 – 1.31(10H, m), 1.25 (2H, m), 1.14 (1H, m), 0.96 (6H, s), 0.92 (3H, s), 0.81 (3H,s), 0.75 (3H, s), 0.67 (1H, m). 13C NMR (101 MHz, CDCl3) δ 176.2, 174.2, 151.2,109.4, 79.1, 55.7, 55.5, 51.7, 50.8, 50.3, 46.9, 42.6, 40.9, 39.0, 39.0,38.8, 38.6, 37.9, 37.3, 34.5, 34.0, 34.0, 31.0, 29.7, 29.6, 28.1, 27.6, 26.6,25.8, 24.6, 21.1, 19.6, 18.4, 16.3, 15.5, 14.8. ESI-HRMS ( m / z ): C 37 H 61 NO4Cl [M+Cl] - , calculated value , 618.4284; Measured value, 618.4254.

[0054] Example 4 Synthesis of BA-4: Referring to BA-3, 6-aminocaproic acid methyl ester was replaced by p-hydroxyphenylethylamine

[0055]

[0056] 99 mg of off-white solid, yield 78%. 1 H NMR (400 MHz, CDCl3) δ 7.05 (2H, d, J =8.0 Hz, H 2, 5 of benzene), 6.81 (2H, d, J = 8.0 Hz, H 3, 4 of benzene), 5.60 (1H,s, -CONH), 4.70 (1H, brs, H1-29), 4.58 (1H, brs, H2-29), 3.47 (2H, m), 3.19(1H, m), 3.03 (1H, m), 2.74 (2H, m), 2.48 (1H, m), 1.95 – 1.80 (2H, m), 1.65– 1.17 (19H, m), 1.66, 0.96, 0.94, 0.89, 0.81, 0.75 (each 3H, s, 6×CH3), 0.67 (1H, m). 13C NMR (101 MHz, CDCl3) δ 175.3, 153.7, 149.8, 129.6, 128.8,114.6, 108.4, 78.1, 54.7, 54.4, 49.6, 49.0, 45.8, 41.5, 39.7, 39.5, 37.8,37.7, 37.4, 36.8, 36.2, 33.9, 33.4, 32.8, 29.8, 28.7, 28.4, 27.0, 26.4, 24.6,19.9, 18.4, 17.3, 15.1, 14.4, 13.6. ESI-HRMS ( m / z ): C 38 H 58 NO3 [M+H] + , calculated value , 576.4411; Measured value, 576.4395.

[0057] Example 5 Synthesis of BA-5

[0058]

[0059] BA-1 (500 mg, 0.915 mmol), benzoyl-protected glucose trichloroacetimidate donor (881 mg, 1.190 mmol) and powdered 4Å molecular sieves (500 mg) were dissolved in anhydrous DCM (16 mL) and stirred at room temperature for 0.5 h under nitrogen protection, then cooled to 0°C and TMSOTf (22 μL, 0.119 mmol) was added; the mixture was stirred at room temperature for 2.5 h, and then quenched with TEA (50 μL); the mixture was filtered, concentrated under reduced pressure, and subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 12:1) to obtain BA-3-O-β-D-benzoyl-protected pyranoglucopyranoside-28-benzyl ester (649 mg, 63%); it (649 mg, 0.576 mmol) and 10% Pd / C (65 mg) were mixed and stirred at room temperature under normal pressure of hydrogen overnight; the mixture was filtered through celite, concentrated under reduced pressure, and chromatographed on a silica gel column (petroleum ether:ethyl acetate = 8:1) to obtain BA-3-O-β-D-benzoyl-protected pyranoglucoside (471 mg, 79%); this (450 mg, 0.435 mmol) was dissolved in methanol / DCM (10 mL / 10 mL), sodium methoxide (142 mg, 2.610 mmol) was added, and the mixture was stirred at room temperature for 5 h; the mixture was neutralized with DOWEX50WX2-100 ion exchange resin (H+), then filtered, concentrated under reduced pressure, and chromatographed on a silica gel column (DCM:methanol = 15:1) to obtain 197 mg of a white powder with a yield of 73%. 1H NMR (400 MHz, CD3OD) δ 4.72 (1H, brs, H1-29), 4.61 (1H, brs, H2-29), 4.33(1H, d, J = 7.7 Hz, H-1 of Glc), 3.85 (1H, dd, J = 11.8, 2.2 Hz), 3.67 (1H,dd, J = 11.8, 5.2 Hz), 3.31–3.14 (4H, m), 3.04 (1H, m), 2.36–2.22 (2H, m), 2.00 (1H, s), 1.98–1.88 (3H, m), 1.75 (1H, d, J = 6.5 Hz), 1.71 (3H, s),1.69–1.16 (17H, m), 1.05 (3H, s), 1.02 (3H, s), 0.98 (3H, s), 0.93 (1H, m),0.88 (3H, s), 0.84 (3H, s), 0.76 (1H, d, J = 9.7 Hz). 13 C NMR (101 MHz, CD3OD)δ 150.7, 109.6, 105.4, 87.9, 76.9, 76.6, 74.0, 70.2, 61.2, 55.5, 55.1, 49.9,48.6, 46.7, 42.0, 40.3, 38.8, 38.3, 37.5, 36.5, 33.9, 30.2, 29.3, 27.5, 25.7,25.1, 20.5, 19.0, 17.8, 16.3, 16.0, 15.9, 14.3. ESI-HRMS ( m / z ): C 36 H 59 O8 [M+H] + , calculated value , 619.4205; Measured value, 619.4175.

[0060] Example 6 Synthesis of BA-6

[0061]

[0062] The synthesis method of BA-3-O-β-D-benzoyl protected glucopyranoside-28-benzyl ester was the same as that in Example 5; BA-3-O-β-D-benzoyl protected glucopyranoside-28-benzyl ester (649 mg, 0.576 mmol) was dissolved in methanol / DCM (10 mL / 10 mL), sodium methoxide (157 mg, 2.882 mmol) was added, and the mixture was stirred at room temperature for 5 h; the mixture was washed with DOWEX50WX2-100 ion exchange resin (H + ) was neutralized, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM:methanol=18:1) to obtain 351 mg of white powder with a yield of 86%. 1 H NMR (400 MHz, DMSO-d6) δ 7.38–7.30 (5H, m, benzene), 5.09 (2H, m, benzyl), 4.87–4.82 (3H,m), 4.67 (1H, brs, H1-29), 4.56 (1H, brs, H2-29), 4.34 (1H, t, J = 5.7 Hz),4.12 (1H, d, J = 7.7 Hz), 3.63 (1H, m), 3.41 (1H, m), 3.10 (1H, m), 3.03 (1H,d, J 0.94 (3H, s), 0.90 (3H,s), 0.84 (1H, m), 0.74 (3H, s), 0.72 (3H, s), 0.68 (3H, s). 13C NMR (101 MHz, DMSO-d6) δ 174.9, 150.1, 136.5, 128.4, 128.1, 128.0, 109.8, 105.4, 87.9,76.9, 76.6, 74.0, 70.1, 65.1, 61.2, 55.9, 55.1, 49.8, 48.7, 46.6, 41.9, 38.8,38.3, 37.6, 36.4, 36.2, 33.8, 31.4, 30.4, 30.0, 29.0, 27.5, 25.7, 25.0, 20.4,18.9, 17.7, 16.3, 16.0, 15.5, 14.3, 14.0. ESI-HRMS ( m / z ): C 43 H 65 O8 [M+H] + , calculated value, 731.4493; measured value, 731.4490.

[0063] Example 7 Synthesis of BA-7

[0064]

[0065] BA-5 (100 mg, 0.162 mmol), TBTU (77 mg, 0.242 mmol), and DIEA (85 μL, 0.486 mmol) were dissolved in 4 mL of DMF and reacted at room temperature for 5 h. 25 mL of water was added to the reaction solution to precipitate a white solid, which was filtered to obtain a crude product. After drying, the product was redissolved in DCM, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by silica gel column chromatography (DCM: methanol = 20:1) to obtain 108 mg of a white solid with a yield of 91%. 1 H NMR (400 MHz, DMSO-d6) δ 8.19 (1H, d, J = 8.4 Hz, H1ofbenzene), 7.72 (1H, m, H2ofbenzene), 7.64 (1H, d, J = 8.3 Hz, H3ofbenzene), 7.56 (1H, m, H4of benzene), 4.85 (3H, m), 4.74 (1H, brs, H1-29), 4.63 (1H, brs, H2-29), 4.35 (1H, t, J = 5.7 Hz), 4.16 (1H, d, J= 7.7 Hz),3.66 (1H, m), 3.43 (1H, m), 3.12 (1H, dd, J = 8.9, 3.2 Hz), 3.08–3.01 (3H,m), 2.97 (1H, m), 2.84 (1H, m), 2.36 (1H, d, J = 5.1 Hz), 2.10 (1H, m), 1.98 (2H, m), 1.90–1.80 (3H, m), 1.71 (3H, s), 1.64 (2H, m), 1.59–1.47 (5H, m), 1.46–1.23 (10H, m), 1.15 (1H, m), 1.04 (3H, s), 0.99 (3H, s), 0.91 (3H, s), 0.86 (2H, m), 0.78 (3H, s), 0.75 (3H, s). 13 C NMR (101 MHz, DMSO-d6) δ 172.0,149.1, 142.8, 129.5, 128.3, 125.3, 120.1, 110.4, 108.4, 105.3, 87.9, 76.9,76.6, 74.0, 70.2, 61.2, 56.6, 55.0, 49.7, 49.1, 46.4, 42.1, 38.8, 38.3, 38.1,36.4, 35.7, 33.8, 30.4, 29.8, 29.5, 27.5, 25.7, 24.9, 20.3, 18.9, 17.7, 16.3,15.9, 15.6, 14.4. ESI-HRMS ( m / z ): C 42 H 60 N3O8 [MH] - , calculated value, 734.4386; measured value, 734.4382.

[0066] Example 8 Synthesis of BA-8

[0067]

[0068] BA-5 (50 mg, 0.081 mmol) was dissolved in 2 mL of DMF. TBTU (39 mg, 0.122 mmol) and DIEA (43 μL, 0.243 mmol) were added first and stirred at room temperature for 6 h. After the reaction was complete to form an intermediate, p-hydroxyphenylethylamine (17 mg, 0.122 mmol) and DIEA (72 μL, 0.405 mmol) were added and stirred at room temperature overnight. After the reaction was completed, 25 mL of water was added to the reaction solution to precipitate a white solid, which was filtered to obtain a crude product. After drying, the product was re-dissolved in DCM, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM:methanol = 16:1) to obtain 53 mg of a white solid with a yield of 89%. 1 H NMR (400 MHz, CD3OD) δ7.44 (1H, t, J = 5.4 Hz, -CONH), 7.06 (2H, m, H 2,5 of benzene), 6.71 (2H, m,H 3,4 of benzene), 4.70 (1H, brs, H1-29), 4.58 (1H, brs, H2-29), 4.32 (1H, d, J = 7.7 Hz, H-1 of Glc), 3.85 (1H, m), 3.67 (1H, m), 3.46 (1H, m), 3.22–3.13(2H, m), 3.05 (1H, m), 2.72 (2H, d, J = 7.2 Hz), 2.55 (1H, m), 2.05 (1H, d, J = 12.4 Hz), 1.94 (1H, d, J = 11.8 Hz), 1.88–1.73 (3H, m), 1.69 (3H, s), 1.60–1.24 (21H, m), 1.04 (3H, s), 0.98 (3H, s), 0.91 (3H, s), 0.88 (3H, s), 0.84 (3H, s), 0.73 (1H, m). 13C NMR (101 MHz, CD3OD) δ 179.0, 156.8, 152.4, 131.4,130.8, 116.2, 109.9, 106.7, 90.9, 78.3, 77.6, 75.6, 71.6, 66.7, 62.8, 57.2,56.9, 52.1, 51.4, 48.1, 43.5, 42.0, 41.9, 40.3, 40.0, 39.3, 38.8, 38.1, 35.8,35.5, 34.2, 31.9, 30.5, 28.4, 27.2, 27.0, 23.7, 22.1, 20.2, 19.6, 19.3, 16.8,16.8, 15.0, 14.0. ESI-HRMS ( m / z ): C 44 H 67 NO8Na [M+Na] + , calculated value, 760.4759; measured value, 760.4748.

[0069] Example 9 Synthesis of BA-9 Referring to BA-5, the β-D-pyranose group was replaced by α-L-pyranose group.

[0070]

[0071] Off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.07 (1H, s, -COOH), 4.68 (1H,brs, H1-29), 4.55 (1H, brs, H2-29), 4.10 (1H, d, J = 5.8 Hz, H-1 of Ara), 3.64(1H, dd, J = 12.0, 3.2 Hz), 3.58 (1H, m), 2.95 (2H, m), 2.21 (1H, m), 2.11(1H, d, J = 9.1 Hz), 1.79 (2H, m), 1.70 (1H, m), 1.64 (3H, s), 1.60–1.21(15H, m), 1.17–1.06 (2H, m), 0.94 (3H, s), 0.92 (3H, s), 0.86 (3H, s), 0.77(3H, s), 0.72 (3H, s), 0.67 (1H, m). 13C NMR (101 MHz, DMSO-d6) δ 177.3,150.3, 109.7, 105.9, 87.7, 72.7, 71.0, 67.6, 65.1, 55.4, 55.0, 49.9, 48.6,46.6, 42.0, 40.3, 38.2, 37.6, 36.5, 36.3, 33.9, 31.7, 30.1, 29.2, 27.5, 25.9,25.1, 20.4, 19.0, 17.8, 16.2, 16.0, 15.7, 14.4. ESI-HRMS ( m / z ): C 35 H 56 O7Na [M+Na] + , calculated value, 611.3918; measured value, 611.3895.

[0072] Example 10 Synthesis of BA-10: Referring to BA-6, β-D-pyranose glucopyranosyl was replaced by α-L-pyranose arabinosyl.

[0073]

[0074] Off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.40–7.32 (5H, m, benzene), 5.11 (2H, m, benzyl), 4.69 (1H, brs, H1-29), 4.57 (1H, brs, H2-29), 4.46 (2H,m), 4.12 (1H, d, J = 5.9 Hz, H-1 of Ara), 3.65 (1H, dd, J = 11.9, 3.2 Hz),3.60 (1H, d, J = 5.6 Hz), 2.95 (2H, m), 2.20–2.07 (2H, m), 1.76 (3H, m), 1.65(3H, s), 1.58 (4H, m), 1.51–1.41 (3H, m), 1.29 (10H, m), 1.08 (3H, m), 0.94(3H, s), 0.92 (3H, s), 0.85 (1H, m), 0.76 (3H, s), 0.73 (3H, s), 0.69 (3H,s), 0.66 (1H, m). 13C NMR (101 MHz, DMSO-d6) δ 174.9, 150.1, 136.5, 128.6,128.4, 128.1, 128.0, 109.8, 105.8, 87.7, 72.7, 71.0, 67.6, 65.1, 65.0, 55.9,55.0, 49.8, 48.7, 46.6, 41.9, 38.9, 38.2, 37.6, 36.4, 36.2, 33.8, 31.4, 30.0,29.0, 27.5, 25.8, 25.1, 20.4, 18.9, 17.7, 16.2, 15.9, 15.5, 14.3.ESI-HRMS( m / z ): C 42 H 62 O7Cl [M+Cl] - , calculated value, 713.4179; measured value, 713.4177.

[0075] Example 11 Synthesis of BA-11 Referring to BA-7, the β-D-pyranose glucopyranosyl group was replaced by α-L-pyranose arabinosyl group.

[0076]

[0077] Off-white solid, yield 92%. 1 H NMR (400 MHz, DMSO-d6) δ 8.18 (1H, d, J = 8.4Hz, H1of benzene), 7.71 (1H, t, J = 7.6 Hz, H2of benzene), 7.63 (1H, d, J =8.3 Hz, H3of benzene), 7.55 (1H, t, J = 7.7 Hz, H4of benzene), 4.79 (1H, d, J = 4.2 Hz, H-1 of Ara), 4.73 (1H, brs, H1-29), 4.62 (1H, brs, H2-29), 4.50–4.43 (2H, m), 4.13 (1H, d, J = 5.8 Hz), 3.66 (1H, dd, J= 12.0, 3.2 Hz), 3.61(1H, s), 3.00 (1H, m), 2.83 (1H, m), 2.33 (1H, m), 2.08 (1H, m), 2.00–1.90(2H, m), 1.83 (2H, t, J = 11.6 Hz), 1.70 (3H, s), 1.67–1.45 (7H, m), 1.45–1.22 (8H, m), 1.14 (1H, m), 1.03 (3H, s), 0.97 (3H, s), 0.90 (3H, s), 0.85(1H, m), 0.77 (3H, s), 0.74 (3H, s), 0.69 (1H, m). 13 C NMR (101 MHz, DMSO-d6)δ 172.0, 149.1, 142.9, 129.5, 128.3, 125.3, 120.1, 110.4, 108.4, 105.8, 87.7,72.7, 71.0, 67.6, 65.1, 56.5, 55.0, 49.7, 49.1, 46.4, 42.1, 40.3, 38.2, 38.1,36.4, 35.7, 33.8, 30.5, 29.8, 29.5, 27.5, 25.8, 24.9, 20.3, 18.9, 17.7, 16.2,15.9, 15.6, 14.4. ESI-HRMS ( m / z ): C 41 H 60 N3O7 [M+H] + ,Calculated value, 706.4426; Measured value, 706.4395.

[0078] Example 12 Synthesis of BA-12: Referring to BA-8, the β-D-pyranose group was replaced by α-L-arabinopyranose group.

[0079]

[0080] Off-white solid, yield 88%. 1 H NMR (400 MHz, DMSO-d6) δ 9.12 (1H, s, phenol),7.54 (1H, t, J = 5.6 Hz, -CONH), 6.97 (2H, d, J = 8.4 Hz, H 2,5of benzene),6.65 (2H, d, J = 8.4 Hz, H 3,4 of benzene), 4.78 (1H, d, J = 4.2 Hz), 4.65 (1H,brs, H1-29), 4.53 (1H, brs, H2-29), 4.46 (2H, dd, J = 7.4, 4.8 Hz), 4.12 (1H,d, J = 5.8 Hz), 3.65 (1H, dd, J = 12.0, 3.2 Hz), 3.59 (1H, d, J = 6.0 Hz),3.15 (2H, dd, J = 16.2, 5.8 Hz), 3.00 (2H, m), 2.59 (2H, m), 2.08 (1H, d, J =12.7 Hz), 1.71 (3H, m), 1.62 (3H, s), 1.56 (3H, m), 1.32 (13H, m), 1.13 (1H,m), 0.94 (3H, s), 0.89 (3H, s), 0.81 (3H, s), 0.78 (3H, s), 0.73 (3H, s), 0.66 (1H, m). 13 C NMR (101 MHz, DMSO-d6) δ 175.3, 155.5, 150.9, 129.7, 129.4,115.0, 109.2, 105.8, 87.8, 72.7, 71.0, 67.6, 65.0, 55.1, 54.8, 50.0, 49.7,48.6, 46.2, 41.9, 40.3, 40.3, 38.2, 37.6, 36.6, 36.5, 34.5, 33.9, 32.4, 30.3,28.8, 27.5, 25.9, 25.2, 20.5, 19.0, 17.8, 16.2, 16.0, 15.8, 14.3.ESI-HRMS( m / z ): C 43 H 66 NO7 [M+H] + , calculated value, 708.4834; measured value, 708.4811.

[0081] Example 13 Synthesis of BA-13: Refer to BA-12, except that p-hydroxyphenylethylamine was replaced with methyl 6-aminocaproate.

[0082]

[0083] Off-white solid, yield 76%. 1 H NMR (400 MHz, CDCl3) δ 5.62 (1H, t, J = 5.9Hz, -CONH), 4.73 (1H, brs, H1-29), 4.58 (1H, brs, H2-29), 4.38 (1H, d, J = 5.6Hz, H-1 of Ara), 3.95–3.86 (2H, m), 3.79–3.70 (3H, m), 3.66 (3H, s, -OCH3), 3.55 (1H, d, J = 10.4 Hz), 3.28 (1H, m), 3.22–3.08 (4H, m), 2.44 (1H, m), 2.31 (2H, t, J = 7.4 Hz), 1.92 (3H, m), 1.87–1.78 (3H, m), 1.77–1.69 (5H, m), 1.67 (3H, s), 1.63 (2H, m), 1.50 (6H, m), 1.42 – 1.30 (8H, m), 1.27 – 1.20(3H, m), 1.15–1.09 (1H, m), 0.95 (3H, s), 0.94 (3H, s), 0.92 (3H, s), 0.81(3H, s), 0.78 (3H, s), 0.68 (1H, m). 13C NMR (101 MHz, CDCl3) δ 176.2, 174.3,151.2, 109.5, 104.5, 90.1, 72.5, 71.7, 68.1, 67.0, 64.1, 55.7, 51.7, 50.8,50.3, 46.9, 42.6, 40.9, 39.2, 39.0, 38.8, 38.6, 37.8, 37.1, 34.5, 34.0, 34.0,31.0, 29.6, 29.5, 29.4, 28.3, 26.6, 26.1, 25.7, 24.6, 21.1, 19.6, 18.3, 16.5,16.3, 16.3, 14.7. ESI-HRMS ( m / z ): C 42 H 68 NO8 [MH] - , calculated value, 714.4950; measured value, 714.4916.

[0084] Example 14 Synthesis of BA-14: Referring to BA-5, the β-D-pyranose glucopyranosyl group was replaced by α-D-pyranose mannosyl group.

[0085]

[0086] Off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.04 (1H, s, -COOH), 4.75 (1H,s), 4.70 (1H, m), 4.68 (1H, s), 4.65 (1H, m), 4.55 (1H, s), 4.37 (1H, t, J =5.7 Hz), 3.60 (1H, m), 3.51 (1H, s), 3.46 (1H, d, J = 9.1 Hz), 3.15 (2H, m), 2.94 (1H, m), 2.22 (1H, t, J = 11.0 Hz), 2.10 (1H, d, J = 10.8 Hz), 1.78 (2H,q, J= 6.7, 5.5 Hz), 1.74–1.67 (2H, m), 1.64 (3H, s), 1.60 (1H, s), 1.55–1.22(16H, m), 1.15 (1H, m), 1.11–1.07 (1H, m), 0.92 (6H, m), 0.86 (3H, s), 0.83–0.79 (2H, m), 0.78 (3H, s), 0.70 (3H, s). 13 C NMR (101 MHz, DMSO-d6) δ 177.3,150.3, 109.7, 95.8, 80.2, 74.5, 71.2, 71.0, 66.8, 61.3, 55.9, 55.4, 55.0,49.9, 48.5, 46.6, 42.0, 40.3, 38.0, 37.7, 37.6, 36.7, 33.9, 31.7, 30.1, 29.2,28.4, 25.1, 21.3, 20.5, 18.9, 17.8, 16.4, 15.9, 15.7, 14.4. ESI-HRMS ( m / z ):C 36 H 59 O8 [M+H] + , calculated value, 619.4205; measured value, 619.4210.

[0087] Example 15 Synthesis of BA-15 Referring to BA-6, the β-D-pyranose glucopyranosyl group was replaced by α-D-pyranose mannosyl group.

[0088]

[0089] Off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.40–7.33 (5H, m, benzene), 5.10 (2H, m, benzyl), 4.77 (1H, s), 4.70 (2H, t, J = 4.2 Hz), 4.65 (1H, d, J = 4.2 Hz), 4.58 (1H, brs), 4.52 (1H, d, J = 5.7 Hz), 4.36 (1H, t, J= 5.7Hz), 3.62 (1H, m), 3.53 (1H, m), 3.50–3.40 (4H, m), 3.16 (1H, dd, J = 11.6,4.2 Hz), 2.94 (1H, m), 2.19–2.10 (2H, m), 1.85–1.75 (2H, m), 1.65 (3H, s), 1.59 (2H, m), 1.48–1.42 (2H, m), 1.40–1.22 (12H, m), 1.09–0.98 (2H, m), 0.93(6H, s), 0.89–0.81 (2H, m), 0.77 (3H, s), 0.71 (6H, s). 13 C NMR (101 MHz, DMSO-d6) δ 174.9, 150.1, 136.5, 128.4, 128.1, 128.0, 109.8, 95.8, 80.2, 74.4,71.2, 71.0, 66.8, 65.1, 61.3, 55.9, 55.0, 49.8, 48.7, 46.6, 42.0, 38.0, 37.7,37.6, 36.6, 36.1, 33.8, 31.4, 30.0, 29.0, 28.3, 25.0, 22.1, 21.3, 20.4, 18.9,17.8, 16.3, 15.9, 15.5, 14.3. ESI-HRMS ( m / z ): C 43 H 64 O8Na [M+Na] + , calculated value, 731.4493; measured value, 731.4500.

[0090] Example 16 Synthesis of BA-16: Referring to BA-7, the β-D-pyranose glucopyranosyl group was replaced by α-D-pyranose mannosyl group.

[0091]

[0092] Off-white solid, yield 88%. 1 H NMR (400 MHz, DMSO-d6) δ 8.18 (1H, d, J = 8.5Hz, H1 of benzene), 7.72 (1H, t, J = 7.7 Hz, H2 of benzene), 7.64 (1H, d,J =9.3 Hz, H3 of benzene), 7.55 (1H, t, J = 7.9 Hz, H4 of benzene), 4.78 (1H, s), 4.75–4.69 (2H, m), 4.68–4.60 (2H, m), 4.53 (1H, s), 4.37 (1H, t, J = 5.8 Hz),3.68–3.61 (1H, m), 3.56–3.40 (6H, m), 3.21–3.15 (1H, m), 2.88–2.80 (1H, m),2.34 (1H, m), 2.10 (1H, m), 1.94 (2H, m), 1.84 (2H, t, J = 11.8 Hz), 1.70(3H, s), 1.63 (3H, m), 1.52 (2H, m), 1.41 (5H, m), 1.31 (2H, m), 1.24 (1H,m), 1.04 (3H, s), 1.02 (1H, m), 0.96 (3H, s), 0.91 (3H, s), 0.84 (2H, m), 0.78 (3H, s), 0.72 (3H, s). 13 C NMR (101 MHz, DMSO-d6) δ 172.0, 149.1, 142.9,129.5, 128.3, 125.3, 120.1, 110.4, 108.4, 95.8, 80.1, 74.5, 71.2, 71.0, 66.9,61.3, 56.5, 55.0, 49.7, 49.1, 46.4, 42.1, 40.3, 38.1, 38.0, 37.7, 36.7, 35.7,33.8, 30.4, 29.8, 29.5, 28.3, 24.8, 22.8, 21.2, 20.3, 18.9, 17.7, 16.3, 15.8,15.6, 14.4. ESI-HRMS ( m / z ): C 43 H 62 N3O 10 [M+HCOO] - , calculated value, 780.4430; measured value, 780.4447.

[0093] Example 17 Synthesis of BA-17: Referring to BA-8, the β-D-pyranose glucopyranosyl group was replaced by α-D-pyranose mannosyl group.

[0094]

[0095] Off-white solid, yield 82%. 1 H NMR (400 MHz, DMSO-d6) δ 9.14 (1H, s, phenol),7.56 (1H, t, J = 5.6 Hz, -CONH), 6.96 (2H, d, J = 8.2 Hz, H 2,5 of benzene),6.65 (2H, d, J = 8.2 Hz, H 3,4 of benzene), 4.74 (2H, m), 4.68–4.63 (2H, m), 4.52 (1H, s), 4.38 (1H, s), 3.60 (1H, d, J = 10.7 Hz), 3.14 (3H, m), 2.99(1H, m), 2.68–2.60 (2H, m), 2.07 (1H, d, J = 12.7 Hz), 1.69 (3H, s), 1.61(3H, m), 1.58–1.55 (1H, m), 1.48–1.17 (15H, m), 1.01 (2H, t, J = 7.2 Hz), 0.96 (1H, m), 0.92 (3H, s), 0.89 (3H, s), 0.80 (3H, s), 0.78 (3H, s), 0.70 (3H, s), 0.67 (1H, m). 13C NMR (101 MHz, DMSO-d6) δ 175.4, 155.6, 151.0,129.7, 129.4, 115.0, 109.2, 95.8, 80.2, 74.5, 71.2, 71.0, 66.9, 61.3, 55.1,54.8, 50.0, 49.7, 46.2, 45.6, 41.9, 40.3, 38.0, 37.7, 36.7, 36.6, 34.5, 33.9,32.4, 30.3, 28.8, 28.4, 25.2, 21.3, 20.6, 19.0, 17.8, 16.4, 15.9, 15.8, 14.3,13.5, 10.6. ESI-HRMS ( m / z ): C 44 H 67 NO8Br [M+Br] - , calculated value, 816.4045; measured value, 816.4017.

[0096] Example 18 Synthesis of BA-18 Referring to BA-5, β-D-pyranose glucopyranosyl was replaced by β-D-xylopyranosyl

[0097]

[0098] Off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 4.68 (1H, brs, H1-29), 4.55(1H, brs, H2-29), 4.10 (1H, d, J = 7.5 Hz, 1-H of Xyl), 3.63 (1H, dd, J =11.2, 5.3 Hz), 3.24 (2H, m), 3.06 (1H, m), 3.03–2.91 (4H, m), 2.25 (1H, s), 2.11 (1H, m), 1.81 (2H, m), 1.68 (1H, m), 1.64 (3H, s), 1.59 (1H, m), 1.55–1.49 (2H, m), 1.48–1.21 (12H, m), 1.17–1.04 (2H, m), 0.94 (3H, s), 0.92 (3H,s), 0.87 (3H, s), 0.77 (3H, s), 0.72 (3H, s), 0.67 (1H, m). 13C NMR (101 MHz, DMSO-d6) δ 150.4, 109.6, 106.2, 87.7, 76.8, 73.8, 69.6, 65.6, 55.4, 55.1, 49.9, 48.6, 46.6, 42.0, 40.3, 38.2, 37.6, 36.5, 33.9, 31.8, 30.2, 29.2, 27.4,25.9, 25.2, 20.5, 19.0, 17.8, 16.2, 16.0, 15.8, 14.3. ESI-HRMS ( m / z ): C 36 H 57 O9[M+HCOO] - , calculated value, 633.3997; measured value, 633.4006.

[0099] Example 19 Synthesis of BA-19: Referring to BA-6, β-D-pyranose glucopyranosyl was replaced by β-D-xylopyranosyl.

[0100]

[0101] Off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.36 (5H, d, J = 4.4 Hz,benzene), 5.09 (2H, d, J = 7.2 Hz, benzyl ), 4.94–4.85 (3H, m), 4.68 (1H,brs, H1-29), 4.56 (1H, brs, H2-29), 4.09 (1H, d, J = 7.5 Hz, 1-H of Xyl), 3.63(1H, dd, J = 11.4, 5.3 Hz), 3.28–3.21 (1H, m), 2.98 (5H, m), 2.12 (2H, m), 1.79 (2H, m), 1.64 (3H, s), 1.60–1.39 (7H, m), 1.26 (8H, m), 1.08 (2H, m),0.93 (3H, s), 0.90 (3H, s), 0.85 (1H, s), 0.74 (3H, s), 0.71 (3H, s), 0.68(3H, s), 0.64 (1H, m). 13C NMR (101 MHz, DMSO-d6) δ 174.9, 150.1, 136.5,128.4, 128.1, 128.0, 109.8, 106.2, 87.7, 76.7, 73.8, 69.6, 65.6, 65.1, 55.9,55.0, 49.8, 48.7, 46.6, 41.9, 38.2, 37.6, 36.4, 36.2, 33.8, 31.4, 30.0, 29.0,27.4, 25.9, 25.1, 20.4, 18.9, 17.7, 16.2, 15.9, 15.5, 14.3. ESI-HRMS ( m / z ):C 42 H 62 O7Cl [M+Cl] - , calculated value, 713.4179; measured value, 713.4169.

[0102] Example 20 Synthesis of BA-20 Referring to BA-7, the β-D-pyranose glucopyranosyl group was replaced with β-D-pyranose xylosyl group.

[0103]

[0104] Off-white solid, yield 90%. 1 H NMR (400 MHz, DMSO-d6) δ 8.17 (1H, d, J = 8.5Hz, H1 of benzene), 7.70 (1H, t, J = 7.6 Hz, H2 of benzene), 7.62 (1H, d, J =8.3 Hz, H3 of benzene), 7.54 (1H, t, J = 7.7 Hz, H4 of benzene), 4.89 (3H, m), 4.72 (1H, s, 1H, brs, H1-29), 4.60 (1H, brs, H2-29), 4.11 (1H, d, J = 7.5 Hz,1-H of Xyl), 3.64 (1H, dd, J= 11.2, 5.3 Hz), 3.24 (1H, m), 3.10–2.92 (4H,m), 2.82 (1H, m), 2.33 (1H, m), 2.07 (1H, m), 1.93 (2H, m), 1.82 (2H, m),1.69 (3H, s), 0.88 (3H, s),0.75 (3H, s), 0.73 (3H, s). 13 C NMR (101 MHz, DMSO-d6) δ 172.0, 149.2, 142.9,129.5, 128.3, 125.4, 120.1, 110.4, 108.4, 106.2, 87.7, 76.7, 73.8, 69.6,65.6, 56.6, 55.0, 49.8, 49.1, 46.4, 42.1, 40.3, 38.2, 38.1, 36.4, 35.7, 33.8,30.5, 29.8, 29.5, 27.4, 25.9, 24.9, 20.3, 18.9, 17.7, 16.2, 15.9, 15.6, 14.4.ESI-HRMS ( m / z ): C 41 H 59 N3O7Na [M+Na] + , calculated value, 728.4245; measured value, 728.4210.

[0105] Example 21 Synthesis of BA-21 Referring to BA-8, the β-D-pyranose glucopyranosyl group was replaced with β-D-pyranose xylosyl group.

[0106]

[0107] Off-white solid, yield 86%. 1 H NMR (400 MHz, DMSO-d6) δ 9.11 (1H, s, phenol), 7.53 (1H, t, J = 5.6 Hz, -CONH), 6.95 (2H, d, J = 8.0 Hz, H 2,5of benzene),6.64 (2H, d, J = 8.0 Hz, H 3,4 of benzene), 4.88 (3H, m), 4.63 (1H, brs, H1-29), 4.52 (1H, brs, H2-29), 4.09 (1H, d, J = 7.6 Hz, 1-H of Xyl), 3.63 (1H,dd, J = 11.3, 5.2 Hz), 3.23 (2H, m), 3.12 (1H, t, J = 6.6 Hz), 3.05 (1H, m), 3.03–2.91 (5H, m), 2.58 (2H, m), 2.06 (1H, d, J = 12.6 Hz), 1.75–1.63 (3H,m), 1.61 (3H, s), 1.59–1.50 (4H, m), 1.45–1.15 (15H, m), 1.11 (1H, m), 0.93(3H, s), 0.89 (1H, s), 0.87 (3H, s), 0.79 (3H, s), 0.75 (3H, s), 0.71 (3H, s), 0.64 (1H, m). 13 C NMR (101 MHz, DMSO-d6) δ 175.4, 155.6, 151.0, 129.7,129.4, 115.0, 109.2, 106.2, 87.7, 76.8, 73.8, 69.6, 65.6, 55.1, 54.8, 50.0,49.7, 46.2, 41.9, 40.3, 38.2, 37.7, 36.6, 36.5, 34.5, 33.9, 32.4, 30.3, 28.9,27.4, 25.9, 25.3, 20.6, 19.0, 17.8, 16.2, 16.0, 15.8, 14.3, 13.6. ESI-HRMS( m / z ): C 43 H 69 N2O7 [M+NH4] + , calculated value, 725.5099; measured value, 725.5106.

[0108] Example 22 Synthesis of BA-22 Referring to BA-5, the β-D-pyranose glucopyranose group was replaced with β-D-pyranose galactose group.

[0109]

[0110] Off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 4.68 (1H, brs, H1-29), 4.56 1H, brs, H2-29), 4.09 (1H, d, J = 6.8 Hz, H-1 of Gal), 3.61 (1H, d, J = 2.8 Hz),3.52 (2H, dd, J = 10.6, 6.5 Hz), 3.40 (2H, dd, J = 10.7, 5.9 Hz), 3.30–3.24(3H, m), 2.97 (2H, m), 2.25 (1H, t, J = 11.6 Hz), 2.15–2.08 (1H, m), 1.83–1.74 (3H, m), 1.64 (3H, s), 1.61–1.22 (14H, m), 1.17–1.04 (2H, m), 0.96 (3H,s), 0.92 (3H, s), 0.87 (3H, s), 0.85–0.79 (1H, m), 0.77 (3H, s), 0.73 (3H,s), 0.67 (1H, m). 13 C NMR (101 MHz, DMSO-d6) δ 150.5, 109.6, 106.0, 88.0,74.9, 73.6, 71.1, 68.1, 60.4, 55.5, 55.1, 49.9, 48.6, 46.6, 42.0, 40.3, 38.8,38.3, 37.6, 36.5, 33.9, 31.8, 30.2, 29.2, 27.6, 25.9, 25.1, 21.4, 20.5, 19.0,17.8, 16.3, 16.0, 15.8, 14.3. ESI-HRMS ( m / z ): C 36 H 58 O8Na [M+Na] + , calculated value, 641.4024; measured value, 641.3997.

[0111] Example 23 Synthesis of BA-23 Referring to BA-6, the β-D-pyranose glucopyranose group was replaced with β-D-pyranose galactose group.

[0112]

[0113] Off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.37–7.30 (5H, m, benzene), 5.09 (2H, m, benzyl), 4.69 (1H, d, J = 4.6 Hz), 4.67 (1H, brs, H1-29), 4.58(1H, d, J = 5.1 Hz), 4.56 (1H, brs, H2-29), 4.48 (1H, t, J = 5.5 Hz), 4.27(1H, d, J = 4.7 Hz, 1-H of Gal), 4.08 (1H, d, J = 6.9 Hz), 3.61 (1H, t, J =3.9 Hz), 3.52 (1H, m), 3.40 (1H, m), 3.26 (3H, m), 2.94 (2H, m), 2.17–2.06(2H, m), 1.77 (3H, m), 1.63 (3H, s), 1.59–1.17 (13H, m), 1.17–0.98 (3H, m),0.94 (3H, s), 0.90 (3H, s), 0.86–0.77 (2H, m), 0.74 (3H, s), 0.71 (3H, s),0.68 (3H, s), 0.63 (1H, m). 13C NMR (101 MHz, DMSO-d6) δ 174.9, 150.0, 136.5,128.4, 128.1, 128.0, 109.8, 106.0, 87.9, 74.8, 73.6, 71.1, 68.0, 65.1, 60.3,55.9, 55.1, 49.8, 48.7, 46.6, 41.9, 38.8, 38.3, 37.6, 36.4, 36.2, 33.8, 31.4,30.0, 29.0, 27.5, 25.8, 25.1, 20.4, 18.9, 17.7, 16.3, 15.9, 15.5, 14.3. ESI-HRMS ( m / z ): C 43 H 63 O8 [MH] - , calculated value, 707.4528; measured value, 707.4510.

[0114] Example 24 Synthesis of BA-24: Referring to BA-7, the β-D-pyranose glucopyranose group was replaced with β-D-pyranose galactose group.

[0115]

[0116] Off-white solid, yield 93%. 1 H NMR (400 MHz, CD3OD) δ 8.08 (1H, d, J = 8.5Hz, H1 of benzene), 7.68 (1H, t, J = 7.6 Hz, H2 of benzene), 7.54 (2H, m, H 3,4 benzene), 4.75 (1H, brs, H1-29), 4.66 (1H, brs, H2-29), 4.29 (1H, d, J = 7.5Hz, 1-H of Gal), 3.84 (1H, d, J = 3.4 Hz), 3.72 (2H, dd, J = 6.4, 2.5 Hz),3.56–3.42 (3H, m), 3.17 (1H, dd, J = 11.7, 4.5 Hz), 2.94 (1H, m), 2.64 (1H,d, J= 11.5 Hz), 2.42 (1H, dd, J = 13.2, 7.8 Hz), 2.24 (1H, t, J = 12.0 Hz),2.07 (1H, dd, J = 13.1, 8.9 Hz), 1.96–1.79 (5H, m), 1.75 (3H, s), 1.73–1.13(17H, m), 1.11 (3H, s), 1.06 (3H, s), 1.00 (3H, s), 0.93 (2H, d, J = 14.5Hz), 0.86 (3H, s), 0.84 (3H, s), 0.78 (1H, m). 13 C NMR (101 MHz, CD3OD) δ173.4, 150.8, 144.7, 130.4, 130.2, 126.5, 121.0, 111.0, 109.3, 107.4, 90.7,75.9, 75.2, 73.1, 70.2, 62.4, 58.4, 57.2, 51.9, 51.1, 43.6, 42.0, 40.3, 40.0,38.1, 37.5, 35.6, 32.3, 31.4, 31.3, 28.4, 27.2, 26.7, 22.0, 19.5, 19.3, 16.8,16.7, 15.2. ESI-HRMS ( m / z ): C 43 H 62 N3O 10 [M+HCOO] - , calculated value, 780.4430; measured value, 780.4445.

[0117] Example 25 Synthesis of BA-25 Referring to BA-8, the β-D-pyranose glucopyranose group was replaced with β-D-pyranose galactose group.

[0118]

[0119] Off-white solid, yield 89%. 1 H NMR (400 MHz, DMSO-d6) 7.54 (1H, s, -CONH), 6.96 (2H, d, J = 7.9 Hz, H 2,5 of benzene), 6.64 (2H, d,J = 7.9 Hz, H 3,4 ofbenzene), 4.64 (1H, brs, H1-29), 4.53 (1H, brs, H2-29), 4.09 (1H, d, J = 6.8Hz, 1-H of Gal), 3.61 (1H, s), 2.98 (2H, d, J = 10.9 Hz), 2.07 (1H, d, J =12.7 Hz), 1.85 (1H, s), 1.81–1.65 (4H, m), 1.61 (3H, s), 1.58–1.09 (22H, m), 0.95 (3H, s), 0.88 (3H, s), 0.80 (3H, s), 0.77 (3H, s), 0.72 (3H, s). 13 C NMR(101 MHz, DMSO-d6) δ 175.4, 155.6, 151.0, 129.6, 129.4, 115.0, 109.2, 106.0,88.0, 74.9, 73.6, 71.1, 68.1, 63.9, 60.4, 55.2, 54.8, 50.0, 49.7, 46.2, 41.9,40.3, 38.8, 37.7, 36.6, 36.5, 34.5, 33.9, 32.4, 30.3, 28.9, 27.6, 25.9, 25.2,24.1, 20.6, 19.4, 19.2, 19.0, 17.8, 16.3, 16.0, 15.8, 14.3, 13.7, 13.5. ESI-HRMS ( m / z ): C 44 H 68 NO8 [M+H] + , calculated value, 738.4940; measured value, 738.4932.

[0120] Example 26 Synthesis of BA-26

[0121]

[0122] To a solution of BA (200 mg, 0.324 mmol) and acetyl-protected 1-bromoglucose donor (234 mg, 0.570 mmol) in DCM / water (4 mL / 4 mL) were added potassium carbonate (152 mg, 1.094 mmol) and tetrabutylammonium bromide (56 mg, 0.176 mmol). The reaction solution was stirred at room temperature under nitrogen atmosphere for 6 h. After the reaction was completed, the mixture was diluted with DCM (50 mL) and then washed with water (30 mL). ×2) The organic phase was washed and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain BA-28-O-β-D-acetyl-protected pyranose glucopyranose ester (224 mg, 88%); BA-28-O-β-D-acetyl-protected pyranose glucopyranose ester (200 mg, 0.257 mmol), benzoyl-protected L-pyranose arabinose trichloroacetimidate donor (203 mg, 0.334 mmol) and powdered 4Å molecular sieves (300 mg) were dissolved in anhydrous DCM (8 m L), stirred at room temperature for 0.5 h under a nitrogen atmosphere, then cooled to 0°C and TMSOTf (5 μL, 0.026 mmol) was added; the mixture was stirred at room temperature for 2.5 h, and then the reaction was quenched with TEA (10 μL); the mixture was filtered, concentrated under reduced pressure, and subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 5:2) to obtain 3-α-L-benzoyl-protected arabinopyranose-BA-28-O-β-D-acetyl-protected glucopyranose ester (193 mg, 61%); it (180 mg, 0.146 mmol) was dissolved in a mixed solution of methanol:tetrahydrofuran:water = 1:2:1, sodium hydroxide (61 mg, 1.535 mmol) was added thereto, and the reaction solution was stirred at room temperature until the protecting group was completely removed; after the reaction, the pH was adjusted to 4-5 with 1 mol / L hydrochloric acid solution, filtered and dried, and silica gel column chromatography (DCM:methanol = 14:1) was used to obtain BA-26 as a white solid powder 76 mg with a yield of 63%. 1 H NMR (400 MHz, CD3OD) δ 5.50 (1H, d, J = 8.1 Hz, H-1 ofGlc), 4.72 (1H, brs, H1-29), 4.60 (1H, brs, H2-29), 4.27 (1H, d, J = 6.6 Hz,H-1 of Ara), 3.82 (3H, m), 3.70 (1H, dd, J = 12.3, 3.4 Hz), 3.57 (1H, t, J =7.7 Hz), 3.54–3.47 (2H, m), 3.37 (3H, m), 3.11 (1H, dd,J = 11.7, 4.5 Hz),3.00 (1H, m), 2.33 (2H, t, J = 12.9 Hz), 2.03–1.89 (2H, m), 1.88–1.80 (1H,m), 1.70 (3H, s), 1.68–1.23 (20H, m), 1.19–1.14 (1H, m), 1.02 (3H, s), 1.00(3H, s), 0.96 (3H, s), 0.91 (1H, m), 0.87 (3H, s), 0.82 (3H, s), 0.74 (1H,m). 13 C NMR (101 MHz, CD3OD) δ 176.1, 151.8, 110.3, 107.2, 95.2, 90.7, 78.8,78.4, 74.3, 74.1, 72.8, 71.1, 69.5, 66.4, 62.4, 57.9, 57.1, 52.0, 50.6, 43.5,42.0, 40.3, 40.0, 39.4, 38.1, 37.5, 35.5, 33.1, 32.8, 31.4, 30.9, 30.8, 30.5,28.4, 27.2, 26.9, 23.7, 22.1, 19.5, 19.3, 16.8, 16.6, 15.1, 14.4. ESI-HRMS( m / z ): C 41 H 65 O 12 [MH] - , calculated value, 749.4482; measured value, 749.4479.

[0123] Example 27 Synthesis of BA-27

[0124]

[0125] BA-13 (50 mg, 0.070 mmol) was dissolved in a mixture of methanol:tetrahydrofuran:water = 1:2:1, and sodium hydroxide (25 mg, 0.630 mmol) was added thereto. The reaction solution was stirred at room temperature for 12 h. After the reaction, the pH was adjusted to 4-5 with 1 mol / L hydrochloric acid solution. The mixture was filtered and dried, and then redissolved in methanol and purified by medium pressure (methanol:water = 85:15) to obtain 43 mg of an off-white solid with a yield of 88%. 1H NMR (400 MHz, DMSO-d6) δ 7.54 (1H, t, J = 5.8 Hz, -CONH),4.79 (1H, brs, H1-29), 4.65 (1H, brs, H2-29), 4.53 (1H, s), 4.46 (1H, s), 4.11(1H, d, J = 5.9 Hz, H-1 of Ara), 3.64 (1H, dd, J = 12.0, 3.3 Hz), 3.59 (1H,t, J = 3.0 Hz), 3.14–3.06 (1H, m), 2.99 (2H, m), 2.90 (1H, m), 2.57 (1H, m),2.16 (2H, t, J = 7.4 Hz), 2.12 (1H, d, J = 10.0 Hz), 1.72 (3H, m), 1.62 (3H,s), 1.60–1.19 (20H, m), 1.12 (1H, dd, J = 12.5, 4.3 Hz), 1.02 (1H, d, J =11.1 Hz), 0.94 (3H, s), 0.90 (3H, s), 0.83 (3H, s), 0.77 (3H, s), 0.73 (3H,s), 0.66 (1H, m). 13 C NMR (101 MHz, DMSO-d6) δ 175.3, 174.5, 151.0, 109.2,105.9, 87.8, 72.7, 71.0, 67.6, 65.1, 55.1, 54.8, 50.0, 49.7, 46.2, 41.9,40.3, 38.2, 38.0, 37.8, 36.6, 36.5, 34.0, 33.7, 32.5, 30.4, 29.0, 28.9, 27.5,26.0, 25.9, 25.3, 24.3, 20.6, 19.1, 17.8, 16.2, 16.0, 15.8, 14.3. ESI-HRMS( m / z ): C 41 H 68 NO8 [M+H] +, calculated value, 702.4940; measured value, 702.4920.

[0126] Example 28 Synthesis of BA-28 Referring to BA-6, the β-D-pyranose glucopyranosyl group was replaced with α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranosyl

[0127]

[0128] 2.55 g of white solid powder, yield 91%. 1 H NMR (400 MHz, DMSO-d6) δ 7.40–7.31 (5H,m, H-Ar), 5.09 (2H, m, benzyl), 4.89 (1H, d, J = 1.5 Hz, H-1 of Rha), 4.67(2H, d, J = 3.5 Hz), 4.60–4.54 (3H, m), 4.46 (1H, d, J = 6.0 Hz), 4.41 (1H,d, J = 5.8 Hz), 4.20 (1H, d, J = 6.5 Hz, 1-H of Ara), 3.93–3.85 (1H, m), 3.64(1H, dd, J = 12.2, 2.3 Hz), 3.59 (2H, m), 3.44 (1H, m), 3.39–3.36 (2H, m), 3.16 (1H, m), 3.09 (1H, m), 2.92 (1H, m), 2.18–2.05 (2H, m), 1.79 (2H, m),1.63 (3H, s), 1.59–1.17 (18H, m), 1.07 (3H, m), 1.00 (1H, s), 0.89 (6H, s),0.85–0.79 (1H, m), 0.76 (3H, s), 0.68 (3H, s), 0.67 (3H, s). 13C NMR (101 MHz, DMSO-d6) δ 174.9, 150.1, 136.5, 128.4, 128.1, 128.0, 109.8, 100.5, 99.9,83.2, 75.1, 72.1, 71.5, 70.5, 68.5, 68.0, 65.8, 65.2, 55.9, 55.3, 49.7, 48.7,46.7, 42.0, 40.2, 37.8, 37.7, 36.6, 36.2, 33.8, 31.4, 30.0, 29.0, 27.9, 25.1,22.3, 20.5, 18.9, 17.9, 16.3, 15.8, 15.5, 14.3. ESI-HRMS ( m / z ): C 48 H 73 O 11 [M+H] + , calculated value, 825.5147; measured value, 825.5138.

[0129] Example 29 Synthesis of BA-29: Referring to BA-5, β-D-pyranose glucopyranosyl was replaced with α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranosyl

[0130]

[0131] 1.45 g of white powder, yield 65%. 1 H NMR (Pyridine-d5, 400 MHz) δ 5.96 (1H, d, J = 1.5 Hz, H-1 of Rha), 5.13–4.89 (5H, m), 4.76–4.72 (1H, m), 4.71–4.65 (2H,m), 4.51 (1H, dd, J = 9.2, 7.4 Hz), 4.36–4.25 (3H, m), 4.13 (1H, dd, J = 9.1,3.6 Hz), 3.91–3.85 (1H, m), 3.75 (1H, d, J = 12.0 Hz), 3.40 (1H, dd, J =11.7, 4.4 Hz), 2.77–2.62 (3H, m), 2.20 (1H, dd, J= 12.0, 7.5 Hz), 1.98–1.79(6H, m), 1.79–1.68 (3H, m), 1.65–1.59 (5H, m), 1.55 (1H, m), 1.51 (1H, m),1.50 – 1.21 (19H, m), 1.16 (3H, s), 1.07 (3H, s), 1.00 (3H, s), 0.96 (3H, m), 0.87 (6H, s, 2×CH3), 0.86 (2H, s), 0.68 (3H, s). 13 C NMR (101 MHz, Pyridine-d5) δ 179.4, 109.8, 102.6, 102.3, 85.0, 77.7, 74.8, 73.8, 73.4, 72.9, 70.6,70.2, 67.8, 67.7, 57.5, 56.6, 50.9, 49.7, 45.3, 43.4, 41.5, 39.0, 38.9, 38.8,38.4, 37.6, 35.2, 33.3, 30.7, 30.6, 30.4, 30.2, 28.8, 27.9, 24.8, 23.8, 23.8,21.7, 19.1, 19.0, 17.2, 16.8, 16.6, 15.4, 15.1. ESI-HRMS ( m / z ): C 41 H 66 O 11 Na [M+Na] + , calculated value, 757.4497; measured value, 757.4491.

[0132] Example 30 Synthesis of BA-30: Referring to BA-7, the β-D-pyranose glucopyranosyl group was replaced with α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranosyl group.

[0133]

[0134] 96 mg of white solid, yield 83%. 1 H NMR (400 MHz, DMSO-d6) δ 8.16 (1H, d, J =8.5 Hz, H1 of benzene), 7.70 (1H, m, H2 of benzene), 7.59 (1H, d, J= 8.3 Hz,H3 of benzene), 7.53 (1H, m, H4 of benzene), 4.92 (1H, brs, H-1 of Rha), 4.68(1H, d, J = 3.7 Hz), 4.59 (2H, dd, J = 7.7, 4.8 Hz), 4.47 (1H, d, J = 5.9Hz), 4.42 (1H, d, J = 5.8 Hz), 4.22 (1H, d, J = 6.5 Hz, H-1 of Ara), 3.89(1H, m), 3.66 (1H, dd, J = 12.0, 2.2 Hz), 3.60 (3H, m), 3.44 (1H, m), 3.15(2H, m), 2.27 (1H, dd, J = 11.3, 7.3 Hz), 2.08 (2H, d, J = 12.2 Hz), 1.83–1.72 (4H, m), 1.70–1.34 (17H, m), 1.24–1.16 (2H, m), 1.08 (3H, m), 0.99 (3H,s), 0.93 (3H, s), 0.90 (3H, s), 0.86–0.76 (10H, m), 0.69 (3H, s). 13 C NMR (101MHz, DMSO-d6) δ 172.1, 142.9, 129.5, 128.3, 125.4, 120.1, 108.3, 100.4, 99.9,83.1, 75.1, 72.1, 71.5, 70.6, 70.5, 68.5, 68.0, 67.0, 65.8, 57.1, 55.3, 49.4,48.7, 43.6, 42.2, 40.3, 37.9, 37.7, 36.6, 33.9, 29.6, 29.3, 27.9, 26.3, 25.1,22.8, 22.3, 17.9, 16.3, 15.8, 15.7, 14.5, 14.3. ESI-HRMS ( m / z ): C 48 H 70 N3O 13 [M+HCOO]- , calculated value, 896.4903; measured value, 896.4895.

[0135] Example 31 Synthesis of BA-31

[0136]

[0137] BA-29 (100 mg, 0.136 mmol), TBTU (65 mg, 0.204 mmol), and DIEA (71 μL, 0.408 mmol) were dissolved in 4 mL of DMF and stirred at room temperature for 5 h. After the reaction was complete to form an intermediate, p-hydroxyphenylethylamine (28 mg, 0.204 mmol) and DIEA (119 μL, 0.680 mmol) were added and stirred at room temperature overnight. After the reaction was complete, 40 mL of water was added to the reaction solution to precipitate a solid, which was filtered to obtain a crude product. The residue was purified by silica gel column chromatography (DCM / methanol 12:1) to obtain 99 mg of a light yellow solid with a yield of 85%. 1 H NMR (400 MHz, DMSO-d6) δ 9.12 (1H, s, phenol), 7.47 (1H, t, J =5.6 Hz, -CONH), 6.95 (2H, d, J = 8.5 Hz, H 2,5 of benzene), 6.64 (2H, d, J =8.5 Hz, H 3,4 of benzene), 4.90 (1H, brs, H-1 of Rha), 4.67 (1H, d, J = 3.7Hz), 4.61–4.56 (2H, m), 4.46 (1H, d, J = 5.8 Hz), 4.41 (1H, d, J = 5.8 Hz),4.21 (1H, d, J = 6.6 Hz, H-1 of Ara), 4.12–4.08 (1H, m), 3.88 (1H, m), 3.69–3.57 (3H, m), 3.45 (1H, m), 3.16 (2H, d, J = 5.1 Hz), 3.13–3.06 (2H, m), 2.16(1H, s), 2.07 (1H, d, J= 11.2 Hz), 1.65 (5H, m), 1.56–1.20 (16H, m), 1.14(2H, d, J = 10.6 Hz), 1.07 (3H, m), 1.04 (1H, s), 0.90 (3H, s), 0.86 (3H, s), 0.79 (10H, m), 0.69 (6H, m). 13 C NMR (101 MHz, DMSO-d6) δ 175.4, 155.6, 129.7,129.4, 115.0, 100.4, 99.9, 83.2, 75.1, 72.1, 71.5, 70.6, 70.5, 68.5, 68.0,55.4, 55.2, 49.7, 49.2, 48.6, 43.4, 42.0, 40.4, 40.3, 38.0, 37.9, 37.7, 36.6,36.4, 34.5, 32.3, 29.5, 28.9, 28.0, 26.8, 23.1, 22.6, 17.9, 16.3, 15.8, 14.5,14.1. ESI-HRMS ( m / z ): C 49 H 76 NO 11 [M+H] + , calculated value, 854.5413; measured value, 854.5431.

[0138] Example 32 Synthesis of BA-32: Refer to BA-31, except that p-hydroxyphenylethylamine was replaced with 6-aminocaproic acid methyl ester.

[0139]

[0140] Pale yellow solid, yield 81%. 1 H NMR (400 MHz, DMSO-d6) δ 7.47 (1H, t, J = 5.7Hz, -CONH), 4.90 (1H, brs, H-1 of Rha), 4.67 (1H, d, J = 3.7 Hz), 4.58 (2H,dd, J = 6.4, 4.8 Hz), 4.46 (1H, d, J = 5.8 Hz), 4.42 (1H, d, J = 5.8 Hz),4.22 (1H, d,J = 6.6 Hz, H-1 of Ara), 3.90 (1H, m), 3.66 (1H, dd, J = 12.1,2.3 Hz), 3.62–3.58 (2H, m), 3.57 (3H, s, -OCH3), 3.45 (1H, m), 3.41–3.36 (2H,m), 3.19–3.12 (2H, m), 3.11–3.03 (2H, m), 2.89 (1H, m), 2.57 (1H, m), 2.27(2H, t, J 0.91 (3H, s), 0.88 (3H, s), 0.84 (3H, s), 0.80 (7H, m), 0.72–0.67 (7H, m). 13 C NMR (101MHz, DMSO-d6) δ 175.4, 173.3, 100.4, 99.9, 83.2, 75.1, 72.1, 71.5, 70.6,70.5, 68.5, 68.0, 65.8, 55.4, 55.2, 51.2, 49.7, 49.2, 43.4, 42.0, 40.3, 38.0,37.7, 36.6, 36.4, 33.3, 29.5, 29.0, 28.0, 25.8, 24.2, 23.1, 22.6, 22.2, 17.9,16.3, 15.8, 14.5, 14.2. ESI-HRMS ( m / z ): C 48 H 83 N2O 12 [M+NH4] + , calculated value, 879.5941; measured value, 879.5963.

[0141] Example 33 Synthesis of BA-33: Refer to BA-12, except that p-hydroxyphenylethylamine is replaced by o-hydroxyphenylethylamine.

[0142]

[0143] 52 mg of light yellow solid, yield 86%.1 H NMR (400 MHz, DMSO-d6) δ 9.31 (1H, s,phenol), 7.55 (1H, t, J = 5.6 Hz, -CONH), 6.99-6.67 (4H, m, benzene), 4.79(1H, d, J = 4.3 Hz), 4.64 (1H, brs, H1-29), 4.52 (1H, brs, H2-29), 4.48 (1H,d, J = 5.2 Hz), 4.45 (1H, d, J = 4.4 Hz), 4.10 (1H, d, J = 6.0 Hz, H-1 ofAra), 3.63 (1H, dd, J = 12.1, 3.3 Hz), 3.58 (1H, d, J = 4.1 Hz), 3.16 (1H,m), 2.99 (2H, m), 2.65 (2H, m), 2.54 (1H, m), 2.09 (1H, d, J = 12.6 Hz),1.81-1.63 (4H, m), 1.61 (3H, s), 1.56 (3H, m), 1.41 (2H, m), 1.38–1.16 (11H,m), 1.12 (1H, m), 0.98 (1H, s), 0.93 (3H, s), 0.88 (3H, s), 0.79 (3H, s),0.76 (3H, s), 0.72 (3H, s), 0.65 (1H, m). 13C NMR (101 MHz, DMSO-d6) δ 175.5,155.3, 151.0, 130.2, 127.1, 125.7, 118.8, 114.8, 107.0, 105.9, 87.8, 72.7,71.0, 67.7, 66.6, 65.7, 65.1, 55.1, 54.8, 50.0, 49.7, 46.2, 41.9, 40.3, 38.7,36.6, 36.5, 33.9, 32.4, 30.3, 30.0, 28.9, 27.5, 25.9, 25.3, 23.6, 20.6, 19.0,17.8, 16.3, 16.0, 15.8, 14.3. ESI-HRMS ( m / z ): C 43 H 65 NO7Na [M+Na] + , calculated value, 730.4653; measured value, 730.4644.

[0144] Example 34 Synthesis of BA-34: Refer to BA-12, except that p-hydroxyphenylethylamine was replaced with m-hydroxyphenylethylamine.

[0145]

[0146] Light brown solid, yield 92%. 1 H NMR (400 MHz, DMSO-d6) δ 9.22 (1H, s, phenol),7.58 (1H, t, J = 5.6 Hz, -CONH), 7.04–6.59 (4H, m, benzene), 4.79 (1H, s), 4.64 (1H, brs, H1-29), 4.52 (1H, brs, H2-29), 4.47 (2H, d, J = 12.2 Hz), 4.10(1H, d, J = 5.9 Hz, H-1 of Ara), 3.67–3.57 (2H, m), 3.16 (2H, m), 3.04–2.94(2H, m), 2.62–2.50 (3H, m), 2.07 (1H, d, J= 12.6 Hz), 1.80–1.63 (3H, m), 1.61 (3H, s), 1.61–1.51 (3H, m), 1.43–1.18 (13H, m), 1.12 (1H, m), 0.93 (3H, s), 0.88 (3H, s), 0.80 (3H, s), 0.77 (3H, s), 0.72 (3H, s), 0.65 (1H, m). 13 CNMR (101 MHz, DMSO-d6) δ 175.4, 157.3, 151.0, 141.0, 129.1, 119.2, 115.5,113.0, 109.2, 105.9, 87.8, 72.7, 71.0, 67.6, 65.1, 55.1, 54.8, 50.0, 49.7,48.6, 46.2, 41.9, 40.3, 38.2, 37.6, 36.6, 36.5, 35.4, 33.9, 32.4, 30.3, 28.8,27.5, 25.9, 25.3, 20.6, 19.0, 17.8, 16.2, 16.0, 15.8, 14.3. ESI-HRMS ( m / z ):C 43 H 65 NO7Na [M+Na] + , calculated value, 730.4653; measured value, 730.4644.

[0147] Example 35 Synthesis of BA-35: Refer to BA-12, replacing p-hydroxyphenylethylamine with o-methoxyphenylethylamine

[0148]

[0149] Off-white solid, yield 86%. 1 H NMR (400 MHz, DMSO-d6) δ 7.54 (1H, t, J = 5.6Hz, -CONH), 7.17–6.83 (4H, m, benzene), 4.79 (1H, d, J = 4.2 Hz), 4.64 (1H,brs, H1-29), 4.52 (1H, brs, H2-29), 4.48 (1H, d, J = 5.0 Hz), 4.45 (1H, d, J=4.3 Hz), 4.10 (1H, dd, J = 5.7, 3.0 Hz, H-1 of Ara), 3.77 (3H, s, -OCH3), 3.64 (1H, dd, J = 12.0, 3.2 Hz), 3.58 (1H, m), 3.17 (2H, d, J = 5.2 Hz), 2.98(2H, m), 2.69 (2H, m), 2.54 (1H, m), 2.07 (1H, d, J 0.91 (1H, m), 0.88 (3H, s), 0.78 (3H, s), 0.77(3H, s), 0.72 (3H, s), 0.64 (1H, m). 13 C NMR (101 MHz, DMSO-d6) δ 175.3,157.2, 151.0, 130.0, 127.4, 120.2, 110.6, 109.2, 105.9, 87.8, 72.7, 71.0,67.6, 65.1, 55.2, 55.1, 54.8, 50.0, 49.7, 48.6, 46.2, 41.9, 40.3, 38.4, 38.2,37.6, 36.6, 36.5, 33.9, 32.4, 30.3, 29.9, 28.8, 27.5, 25.9, 25.2, 20.5, 19.0,17.8, 16.2, 16.0, 15.8, 14.3. ESI-HRMS ( m / z ): C 44 H 68 NO7 [M+H] + , calculated value,722.4990' Measured value, 722.4979.

[0150] Example 36 Synthesis of BA-36: Refer to BA-12, except that p-hydroxyphenylethylamine was replaced with m-methoxyphenylethylamine.

[0151]

[0152] Off-white solid, yield 82%. 1 H NMR (400 MHz, DMSO-d6) δ 7.58 (1H, t, J = 5.6Hz, -CONH), 7.20–6.71 (4H, m, benzene), 4.79 (1H, s), 4.64 (1H, brs, H1-29), 4.52 (1H, brs, H2-29), 4.51–4.44 (2H, m), 4.10 (1H, d, J = 5.9 Hz, H-1 ofAra), 3.72 (3H, s, -OCH3), 3.64 (1H, dd, J = 12.1, 3.2 Hz), 3.59 (1H, d, J =4.1 Hz), 3.25–3.14 (2H, m), 2.98 (2H, m), 2.75–2.61 (2H, m), 2.57–2.52 (1H,m), 2.06 (1H, d, J = 12.9 Hz), 1.77– 1.65 (3H, m), 1.61 (3H, s), 1.58–1.50(3H, m), 1.35–1.10 (14H, m), 0.93 (3H, s), 0.91 (3H, s), 0.88 (3H, s), 0.82(1H, m), 0.77 (6H, s), 0.72 (3H, s), 0.65 (1H, m). 13 C NMR (101 MHz, DMSO-d6)δ 175.4, 159.2, 150.9, 141.3, 129.2, 120.9, 114.2, 111.4, 109.2, 105.9, 87.8,72.7, 71.0, 67.6, 65.1, 55.1, 54.8, 50.0, 49.7, 48.6, 46.2, 41.9, 40.3, 38.2,37.6, 36.6, 36.5, 35.2, 33.9, 32.4, 30.2, 28.8, 27.5, 25.9, 25.2, 20.5, 19.0,17.8, 16.2, 16.0, 15.8, 14.3. ESI-HRMS ( m / z ): C 44 H 68 NO7 [M+H] +, calculated value, 722.4990; measured value, 722.4964.

[0153] Example 37 The synthesis of BA-37 was carried out with reference to BA-12, except that p-hydroxyphenylethylamine was replaced with p-methoxyphenylethylamine.

[0154]

[0155] Off-white solid, yield 90%. 1 H NMR (400 MHz, DMSO-d6) δ 7.54 (1H, t, J = 5.7Hz, -CONH), 7.09 (2H, d, J = 8.0 Hz, H 2,5 of benzene), 6.81 (2H, d, J = 8.0Hz, H 3,4 of benzene), 4.79 (1H, d, J = 4.2 Hz), 4.63 (1H, brs, H1-29), 4.52(1H, brs, H2-29), 4.47 (2H, dd, J = 12.5, 4.6 Hz), 4.10 (1H, d, J = 5.9 Hz,H-1 of Ara), 3.70 (3H, s, -OCH3), 3.64 (1H, dd, J = 12.0, 3.2 Hz), 3.59 (1H,m), 3.14 (2H, m), 3.02–2.93 (2H, m), 2.62 (2H, m), 2.05 (1H, d, J = 12.9 Hz),1.80–1.63 (3H, m), 1.61 (3H, s), 1.59–1.48 (3H, m), 1.46–1.05 (16H, m), 0.93(3H, s), 0.87 (3H, s), 0.82 (1H, m), 0.75 (6H, s), 0.72 (3H, s), 0.64 (1H,m). 13C NMR (101 MHz, DMSO-d6) δ 175.3, 157.6, 151.0, 131.5, 129.6, 113.6,109.3, 105.9, 87.8, 72.7, 71.0, 67.7, 65.1, 55.1, 54.9, 54.8, 50.0, 49.7,46.2, 41.9, 40.2, 40.2, 38.2, 37.7, 36.5, 36.5, 34.4, 33.8, 32.4, 30.3, 28.8,27.5, 25.9, 25.2, 20.5, 19.0, 17.7, 16.3, 16.0, 15.8, 14.3. ESI-HRMS ( m / z ):C 44 H 67 NO7Na [M+Na] + , calculated value, 744.4810; measured value, 744.4800.

[0156] Example 38 Synthesis of BA-38: Refer to BA-12, except that p-hydroxyphenylethylamine was replaced with p-fluorophenylethylamine.

[0157]

[0158] Light reddish brown solid, yield 78%. 1 H NMR (400 MHz, DMSO-d6) δ 7.57 (1H, t, J =5.5 Hz, -CONH), 7.21 (2H, m, H 2,5 of benzene), 7.07 (2H, m, m, H 3,4 ofbenzene), 4.79 (1H, s), 4.63 (1H, brs, H1-29), 4.52 (1H, brs, H2-29), 4.47(2H, d, J = 10.6 Hz), 4.10 (1H, d, J = 5.8 Hz, H-1 of Ara), 3.64 (1H, dd, J =12.2, 3.2 Hz), 3.59 (1H, s), 3.19 (2H, m), 2.97 (2H, m), 2.69 (2H, m), 2.04(1H, d, J= 13.0 Hz), 1.75–1.67 (2H, m), 1.61 (3H, s), 1.59–1.51 (3H, m), 1.46–1.05 (16H, m), 0.93 (3H, s), 0.87 (3H, s), 0.82 (1H, s), 0.78–0.71 (9H, s), 0.64 (1H, m). 13 C NMR (101 MHz, DMSO-d6) δ 175.4, 162.0, 159.6, 150.9,135.8, 135.8, 130.4, 130.3, 115.0, 114.7, 109.2, 105.8, 87.7, 72.7, 71.0,67.6, 65.0, 55.1, 54.8, 50.0, 49.6, 46.1, 41.8, 40.2, 38.2, 37.6, 36.5, 36.5,34.3, 33.8, 32.4, 30.2, 29.8, 28.8, 27.5, 25.8, 25.2, 20.5, 19.0, 17.7, 16.2,15.9, 15.8, 14.2. ESI-HRMS ( m / z ): C 43 H 64 FNO6Cl [M+Cl] - , calculated value, 744.4401; measured value, 744.4411.

[0159] Example 39 Synthesis of BA-39: Refer to BA-12, except that p-hydroxyphenylethylamine was replaced with p-bromophenylethylamine.

[0160]

[0161] Light brown solid, yield 72%. 1 H NMR (400 MHz, DMSO-d6) δ 7.53 (1H, t, J = 5.6Hz, -CONH), 7.41 (2H, d, J = 7.9 Hz, H 2,5 of benzene), 7.14 (2H, d, J = 7.9Hz, H 3,4of benzene), 4.76 (1H, s), 4.62 (1H, brs, H1-29), 4.51 (1H, brs, H2-29), 4.44 (2H, t, J = 5.6 Hz), 4.10 (1H, d, J = 5.8 Hz, H-1 of Ara), 3.68–3.55 (2H, m), 3.17 (1H, dd, J = 10.0, 5.3 Hz), 2.95 (2H, m), 2.68 (2H, m), 2.01 (1H, d, J = 12.9 Hz), 1.74–1.66 (2H, m), 1.59 (3H, s), 1.58–1.52 (3H,m), 1.45–1.21 (12H, m), 1.11–0.97 (3H, m), 0.93 (3H, s), 0.85 (3H, s), 0.75(3H, s), 0.72 (3H, s), 0.70 (3H, s), 0.63 (1H, m). 13 C NMR (101 MHz, DMSO) δ175.3, 150.9, 139.2, 131.0, 131.0, 119.1, 109.2, 105.8, 87.8, 72.7, 71.0,67.6, 65.0, 55.1, 54.8, 50.0, 49.6, 48.6, 46.1, 41.8, 40.2, 38.2, 37.6, 36.5,34.4, 33.8, 32.4, 30.2, 28.8, 27.5, 25.9, 25.2, 20.5, 19.0, 17.8, 16.2, 16.0,15.7, 14.2. ESI-HRMS ( m / z ): C 43 H 63 BrNO6 [MH] - , calculated value, 770.3834; measured value, 770.3811.

[0162] Example 40 Synthesis of BA-40: Refer to BA-12, except that p-hydroxyphenylethylamine was replaced with p-trifluoromethoxyphenylethylamine.

[0163]

[0164] Light brown solid, yield 65%. 1 H NMR (400 MHz, DMSO-d6) δ 7.59 (1H, t,J = 5.6Hz, -CONH), 7.32 (2H, d, J = 8.3 Hz, H 2,5 of benzene), 7.24 (2H, d, J = 8.3Hz, H 3,4 of benzene), 4.78 (1H, d, J = 4.3 Hz), 4.63 (1H, brs, H1-29), 4.52(1H, brs, H2-29), 4.46 (2H, dd, J = 9.9, 4.7 Hz), 4.11 (1H, d, J = 5.9 Hz, H-1 of Ara), 3.65 (1H, dd, J = 12.0, 3.3 Hz), 3.60 (1H, s), 2.96 (2H, m), 2.76(2H, m), 2.05 (1H, d, J = 13.1 Hz), 1.78–1.63 (3H, m), 1.61 (3H, s), 1.59–1.51 (3H, m), 1.46–1.08 (16H, m), 0.94 (3H, s), 0.88 (3H, s), 0.84 (2H, m),0.77 (3H, s), 0.75 (3H, s), 0.73 (3H, s), 0.65 (1H, m). 13 C NMR (101 MHz,DMSO-d6) δ 175.4, 150.9, 146.7, 139.2, 130.4, 120.7, 109.2, 105.8, 87.7,72.7, 71.0, 67.6, 65.0, 55.1, 54.8, 50.0, 49.6, 46.1, 41.8, 40.2, 38.9, 38.2,37.6, 36.5, 36.5, 34.3, 33.8, 32.4, 30.2, 28.8, 27.5, 25.8, 25.2, 20.5, 19.0,17.7, 16.2, 15.9, 15.7, 14.2. ESI-HRMS ( m / z ): C 44 H 65 F3NO7 [M+H] +, calculated value, 776.4713; measured value, 776.4712.

[0165] Example 41 Synthesis of BA-41: Refer to BA-12, except that p-hydroxyphenylethylamine was replaced with p-hydroxybenzylamine.

[0166]

[0167] Off-white solid, yield 95%. 1 H NMR (400 MHz, DMSO-d6) δ 8.00 (1H, t, J = 6.0Hz, -CONH), 7.02 (2H, d, J = 8.0 Hz, H 2,5 of benzene), 6.65 (2H, d, J = 8.0Hz, H 3,4 of benzene), 4.53 (1H, s), 4.19 (1H, dd, J = 14.7, 5.9 Hz), 4.11 (1H,d, J = 5.9 Hz, H- 1 of Ara), 4.02 (1H, dd, J = 14.7, 5.8 Hz), 3.64 (1H, dd, J = 12.0, 3.3 Hz), 3.59 (1H, m), 3.06–2.95 (2H, m), 2.57 (1H, m), 2.15 (1H, d, J = 12.3 Hz), 1.79 (1H, dd, J = 11.5, 7.6 Hz), 1.70 (2H, t, J = 9.1 Hz), 1.62(3H, s), 1.60–1.52 (3H, m), 1.49– 1.41 (3H, m), 1.39–1.19 (10H, m), 1.13 (1H,m), 0.99 (1H, d, J = 12.4 Hz), 0.94 (3H, s), 0.90 (3H, s), 0.84 (1H, m), 0.80(3H, s), 0.78 (3H, s), 0.73 (3H, s), 0.66 (1H, m). 13C NMR (101 MHz, DMSO-d6)δ 175.3, 156.2, 150.9, 130.7, 128.3, 114.8, 109.2, 105.8, 87.7, 72.7, 71.0,67.6, 65.0, 55.1, 54.8, 50.0, 49.7, 46.1, 41.9, 41.4, 40.3, 38.2, 37.7, 36.7,36.5, 34.0, 32.3, 30.3, 28.8, 27.5, 25.9, 25.3, 20.6, 19.1, 17.8, 16.2, 16.0,15.8, 14.3. ESI-HRMS ( m / z ): C 42 H 63 NO7Na [M+Na] + , calculated value, 716.4497; measured value, 716.4473.

[0168] Example 42 Synthesis of BA-42: Refer to BA-12, replacing p-hydroxyphenylethylamine with 3, 4-dihydroxyphenylethylamine

[0169]

[0170] Light reddish brown solid, yield 84%. 1 H NMR (400 MHz, DMSO-d6) δ 8.68, 8.59 (each 1H,s, phenol), 7.52 (1H, t, J = 5.7 Hz, -CONH), 6.58–6.39 (3H, m, benzene), 4.77(1H, d, J = 4.2 Hz), 4.63 (1H, brs, H1-29), 4.51 (1H, brs, H2-29), 4.48–4.41(2H, m), 4.09 (1H, d, J = 6.0 Hz, H-1 of Ara), 3.62 (1H, dd, J = 12.0, 3.3Hz), 3.57 (1H, m), 3.20 (1H, m), 3.07 (1H, m), 2.95 (2H, m), 2.06 (1H, d, J0.87 (3H, s), 0.79 (3H, s), 0.75 (3H, s), 0.70 (3H, s), 0.63 (1H, m). 13 C NMR (101 MHz, DMSO-d6) δ 175.3,151.0, 145.0, 143.4, 130.4, 119.1, 115.9, 115.4, 109.2, 105.9, 87.8, 72.7,71.0, 67.6, 65.1, 55.1, 54.8, 50.0, 49.7, 46.2, 41.9, 40.3, 38.2, 37.7, 36.6,36.5, 34.9, 33.9, 32.4, 30.3, 28.8, 27.5, 25.9, 25.3, 20.6, 19.0, 17.8, 16.3,16.0, 15.8, 14.3. ESI-HRMS ( m / z ): C 43 H 64 NO8 [MH] - , calculated value, 722.4637; measured value, 722.4627.

[0171] Example 43 Synthesis of BA-43: Refer to BA-12, replacing p-hydroxyphenylethylamine with 3, 4-difluorophenylethylamine

[0172]

[0173] Light brown solid, yield 60%. 1 H NMR (400 MHz, DMSO-d6) δ 7.89 (1H, d, J = 7.5Hz, -CONH), 7.39–7.13 (3H, m, benzene), 4.88 (1H, m), 4.78 (1H, m), 4.64 (1H,brs, H1-29), 4.53 (1H, brs, H2-29), 4.46 (2H, s), 4.11 (1H, d, J = 5.8 Hz),3.65 (1H, dd, J= 12.0, 3.2 Hz), 3.60 (1H, s), 2.99 (2H, m), 2.41 (1H, td, J = 12.2, 3.5 Hz), 2.29 (1H, d, J = 12.2 Hz), 1.85 (1H, dd, J = 11.7, 7.6 Hz),1.76–1.67 (2H, m), 1.62 (3H, s), 1.58–1.51 (3H, m), 1.46–1.00 (18H, m), 0.93(3H, s), 0.88 (3H, s), 0.84 (3H, s), 0.80 (1H, d, J = 10.0 Hz), 0.72 (6H, s), 0.63 (1H, m), 0.52 (3H, s). 13 C NMR (101 MHz, DMSO-d6) δ 175.0, 150.9, 143.5,122.8, 116.9, 116.8, 115.0, 114.9, 109.2, 105.8, 87.7, 72.7, 71.0, 67.6,65.0, 55.1, 54.6, 49.9, 49.7, 47.0, 46.1, 41.8, 38.2, 37.6, 36.5, 36.4, 33.9,32.1, 30.3, 29.0, 28.7, 27.5, 25.8, 25.2, 21.4, 20.5, 19.0, 17.7, 16.2, 15.9,15.3, 14.2. ESI-HRMS ( m / z ): C 43 H 64 F2NO6 [M+H] + , calculated value, 728.4702; measured value, 728.4703.

[0174] Example 44 Synthesis of BA-44: Refer to BA-13, except that 6-aminocaproic acid methyl ester was replaced by 6-aminocaproic acid ethyl ester.

[0175]

[0176] Off-white solid, yield 92%. 1 H NMR (400 MHz, DMSO-d6) δ 7.53 (1H, t, J= 5.8Hz, -CONH), 4.79 (1H, d, J = 4.2 Hz), 4.64 (1H, brs, H1-29), 4.52 (1H, brs,H2-29), 4.48 (1H, d, J = 5.1 Hz), 4.45 (1H, d, J = 4.3 Hz), 4.10 (1H, d, J =5.9 Hz, H-1 of Ara), 4.03 (2H, m), 3.64 (1H, dd, J = 12.0, 3.2 Hz), 3.59 (1H,s), 3.10 (1H, m), 2.98 (2H, m), 2.90 (1H, m), 2.56 (1H, m), 2.24 (2H, t, J =7.4 Hz), 2.11 (1H, d, J = 11.4 Hz), 1.77–1.65 (3H, m), 1.62 (3H, s), 1.52–1.21 (22H, m), 1.17 (3H, t, J = 7.1 Hz, -CH3), 1.02 (1H, m), 0.93 (3H, s),0.90 (3H, s), 0.83 (3H, s), 0.77 (3H, s), 0.72 (3H, s), 0.66 (1H, m). 13 C NMR(101 MHz, DMSO-d6) δ 175.3, 172.8, 151.0, 109.2, 105.9, 87.8, 72.7, 71.0,67.6, 65.1, 59.6, 55.1, 54.8, 50.0, 49.7, 46.2, 41.9, 40.3, 38.2, 38.0, 37.7,36.6, 36.5, 33.9, 33.5, 32.4, 30.3, 28.9, 28.9, 27.5, 25.9, 25.8, 25.3, 24.2,20.6, 19.0, 17.8, 16.2, 16.0, 15.8, 14.3, 14.1. ESI-HRMS ( m / z ): C 43 H 71 NO8Na [M+Na] +, calculated value, 752.5072; measured value, 752.5055.

[0177] Example 45 Synthesis of BA-45: Refer to BA-13, except that 6-aminocaproic acid methyl ester was replaced with 6-aminocaproic acid tert-butyl ester.

[0178]

[0179] Off-white solid, yield 90%. 1 H NMR (400 MHz, DMSO-d6) δ 7.53 (1H, t, J = 5.8Hz, -CONH), 4.79 (1H, d, J = 4.2 Hz), 4.64 (1H, brs, H1-29), 4.52 (1H, brs,H2-29), 4.48 (1H, d, J = 5.1 Hz), 4.45 (1H, d, J = 4.3 Hz), 4.10 (1H, d, J =5.9 Hz, H-1 of Ara), 3.64 (1H, dd, J = 12.1, 3.2 Hz), 3.59 (1H, s), 3.10 (1H,m), 2.98 (2H, m), 2.90 (1H, m), 2.57 (1H, d, J = 13.2 Hz), 2.17–2.08 (3H, m), 1.73 (3H, m), 1.62 (3H, s), 1.56 (2H, m), 1.49–1.41 (4H, m), 1.39 (9H, s, -Bu), 1.37–1.10 (16H, m), 1.02 (1H, m), 0.93 (3H, s), 0.90 (3H, s), 0.83 (3H,s), 0.77 (3H, s), 0.72 (3H, s), 0.66 (1H, m). 13C NMR (101 MHz, DMSO-d6) δ175.3, 172.2, 151.0, 109.2, 105.9, 87.7, 79.3, 72.7, 71.0, 67.6, 65.1, 55.1,54.8, 50.0, 49.7, 48.6, 46.2, 41.9, 40.3, 38.2, 38.0, 37.7, 36.6, 36.5, 34.7,33.9, 32.4, 30.4, 29.0, 28.9, 27.8, 27.5, 25.9, 25.8, 25.3, 24.3, 20.6, 19.1,17.8, 16.2, 16.0, 15.8, 14.3. ESI-HRMS ( m / z ): C 45 H 76 NO8 [M+H] + , calculated value, 758.5566; measured value, 758.5537.

[0180] Example 46 Synthesis of BA-46: Refer to BA-13, except that 6-aminocaproic acid methyl ester was replaced by 6-aminocapronitrile.

[0181]

[0182] Off-white solid, yield 91%. 1 H NMR (400 MHz, DMSO-d6) δ 7.56 (1H, t, J = 5.8Hz, -CONH), 4.64 (1H, brs, H1-29), 4.52 (1H, brs, H2-29), 4.10 (1H, d, J = 6.0Hz, H-1 of Ara), 3.63 (1H, dd, J = 12.0, 3.2 Hz), 3.58 (1H, q, J = 2.6 Hz),3.09 (1H, m), 2.98 (3H, m), 2.60–2.52 (1H, m), 2.45 (2H, t, J= 7.0 Hz),2.15–2.08 (1H, m), 1.79–1.66 (3H, m), 1.61 (3H, s), 1.55–1.18 (20H, m), 1.12(1H, m), 1.02 (1H, m), 0.93 (3H, s), 0.90 (3H, s), 0.83 (3H, s), 0.77 (3H,s), 0.72 (3H, s), 0.65 (1H, m). 13 C NMR (101 MHz, DMSO-d6) δ 175.4, 151.0,120.6, 109.2, 105.9, 87.8, 72.7, 71.0, 67.6, 65.1, 55.1, 54.8, 50.0, 49.7,46.2, 41.9, 40.3, 38.2, 37.8, 37.8, 36.6, 36.5, 33.9, 32.4, 30.4, 28.9, 28.4,27.5, 25.9, 25.5, 25.3, 24.5, 20.6, 19.1, 17.8, 16.2, 16.2, 16.0, 15.8, 14.3.ESI-HRMS ( m / z ): C 41 H 66 N2O6Na [M+Na] + , calculated value, 705.4813; measured value, 705.4793.

[0183] Example 47 Synthesis of BA-47: Refer to BA-13, except that 6-aminocaproic acid methyl ester was replaced by 5-aminovaleric acid methyl ester.

[0184]

[0185] Off-white solid, yield 93%. 1 H NMR (400 MHz, DMSO-d6) δ 7.55 (1H, t, J = 5.8Hz, -CONH), 4.78 (1H, d, J = 4.6 Hz), 4.64 (1H, brs, H1-29), 4.52 (1H, brs,H2-29), 4.47 (1H, d, J = 5.3 Hz), 4.45 (1H, d, J = 4.4 Hz), 4.10 (1H, d, J=6.0 Hz, H-1 of Ara), 3.64 (1H, dd, J = 12.0, 3.2 Hz), 3.59 (1H, m), 3.56 (3H,s, -OCH3), 3.09 (1H, m), 2.98 (3H, m), 2.59–2.51 (1H, m), 2.29 (2H, t, J =7.3 Hz), 2.11 (1H, d, J = 11.8 Hz), 1.72 (3H, m), 1.61 (3H, s), 1.56 (2H, m), 1.53–1.18 (18H, m), 1.11 (1H, m), 1.01 (1H, m), 0.93 (3H, s), 0.90 (3H, s),0.82 (3H, s), 0.77 (3H, s), 0.72 (3H, s), 0.65 (1H, m). 13 C NMR (101 MHz, DMSO-d6) δ 175.4, 173.3, 151.0, 109.2, 105.9, 87.8, 72.7, 71.0, 67.6, 65.1,55.1, 54.8, 51.2, 50.0, 49.7, 46.2, 41.9, 40.3, 38.2, 37.7, 37.6, 36.6, 36.5,34.0, 32.9, 32.4, 30.3, 28.9, 28.7, 27.5, 25.9, 25.3, 21.8, 20.6, 19.1, 17.8,16.2, 16.0, 15.8, 14.3. ESI-HRMS ( m / z ): C 41 H 67 NO8Na [M+Na] + , calculated value, 724.4759; measured value, 724.4736.

[0186] Example 48 Synthesis of BA-48

[0187]

[0188] BA-47 (50 mg, 0.071 mmol) was dissolved in a mixture of methanol:tetrahydrofuran:water = 1:2:1, and sodium hydroxide (26 mg, 0.639 mmol) was added. The reaction solution was stirred at room temperature for 6 h. After the reaction, the pH was adjusted to 4-5 with 1 mol / L hydrochloric acid solution. The mixture was filtered and dried, and then redissolved in methanol and purified by medium pressure (methanol:water = 85:15) to obtain 44 mg of a white solid with a yield of 90%. 1 H NMR (400 MHz, DMSO-d6) δ 7.55 (1H, t, J = 5.8 Hz, -CONH),4.64 (1H, brs, H1-29), 4.52 (1H, brs, H2-29), 4.10 (1H, d, J = 5.9 Hz, H-1 ofAra), 3.06 (2H, dd, J = 13.0, 7.0 Hz), 3.02–2.91 (3H, m), 2.56 (1H, dd, J =12.4, 3.4 Hz), 2.18 (2H, t, J = 7.1 Hz), 2.11 (1H, d, J = 10.6 Hz), 1.79–1.66(3H, m), 1.62 (3H, s), 1.59–1.54 (2H, m), 1.50–1.18 (15H, m), 1.13 (1H, m),1.01 (1H, m), 0.93 (3H, s), 0.90 (3H, s), 0.83 (3H, s), 0.77 (3H, s), 0.72(3H, s), 0.65 (1H, m). 13 C NMR (101 MHz, DMSO-d6) δ 175.3, 151.0, 109.2,105.9, 87.8, 72.7, 71.0, 67.6, 65.1, 55.1, 54.8, 50.0, 49.7, 46.2, 41.9,40.3, 38.2, 37.8, 36.6, 36.5, 33.9, 33.4, 32.4, 30.3, 28.9, 28.8, 27.5, 25.9,25.3, 21.9, 20.6, 19.1, 17.8, 16.2, 16.0, 15.8, 14.3. ESI-HRMS ( m / z ):C 40 H65 NO8K [M+K] + , calculated value, 726.4342; measured value, 726.4311.

[0189] Example 49 Synthesis of BA-49: Refer to BA-13, except that 6-aminohexanoic acid methyl ester was replaced by 4-aminobutyric acid methyl ester.

[0190]

[0191] White solid, yield 91%. 1 H NMR (400 MHz, DMSO-d6) δ 7.60 (1H, t, J = 5.7Hz, -CONH), 4.79 (1H, m), 4.64 (1H, brs, H1-29), 4.53 (1H, brs, H2-29), 4.47(2H, m), 4.10 (1H, d, J = 5.9 Hz, H-1 of Ara), 3.64 (1H, dd, J = 12.0, 3.2Hz), 3.57 (3H, s, -OCH3), 3.10 (1H, m), 3.06–2.92 (3H, m), 2.56 (1H, dd, J =12.7, 3.4 Hz), 2.27 (2H, t, J = 7.5 Hz), 2.11 (1H, d, J = 12.2 Hz), 1.78–1.64(5H, m), 1.62 (3H, s), 1.60–1.51 (3H, m), 1.43 (2H, m), 1.39–1.02 (12H, m), 0.93 (3H, s), 0.90 (3H, s), 0.82 (3H, s), 0.77 (3H, s), 0.72 (3H, s), 0.66(1H, m). 13C NMR (101 MHz, DMSO-d6) δ 175.6, 173.2, 150.9, 109.3, 105.9, 87.8,72.7, 71.0, 67.6, 65.1, 55.1, 54.9, 51.3, 50.0, 49.7, 46.2, 41.9, 40.3, 38.2,37.7, 37.6, 36.6, 36.5, 34.0, 32.4, 30.7, 30.3, 28.9, 27.5, 25.9, 25.3, 24.6,20.6, 19.1, 17.8, 16.2, 16.0, 15.8, 14.3. ESI-HRMS ( m / z ): C 40 H 65 NO8Na [M+Na] + ,Calculated value, 710.4602; Measured value, 710.4568.

[0192] Example 50 Synthesis of BA-50: Refer to BA-48, replacing aminovaleric acid with aminobutyric acid

[0193]

[0194] White solid, yield 88%. 1 H NMR (400 MHz, DMSO-d6) δ 7.60 (1H, t, J = 5.8Hz, -CONH), 4.65 (1H, brs, H1-29), 4.53 (1H, brs, H2-29), 4.11 (1H, d, J = 5.9Hz, H-1 of Ara), 3.64 (1H, dd, J = 12.0, 3.2 Hz), 3.59 (1H, d, J = 3.5 Hz),3.09 (1H, dd, J= 13.0, 6.4 Hz), 3.05–2.96 (3H, m), 2.15 (3H, m), 1.79–1.67(3H, m), 1.62 (3H, s), 1.61–1.51 (4H, m), 1.46–1.20 (12H, m), 1.12 (1H, m),1.03 (1H, m), 0.94 (3H, s), 0.90 (3H, s), 0.83 (3H, s), 0.77 (3H, s), 0.73(3H, s), 0.66 (1H, m). 13 C NMR (101 MHz, DMSO-d6) δ 175.5, 174.4, 150.9,109.2, 105.8, 87.7, 72.7, 71.0, 67.6, 65.0, 55.1, 54.8, 50.0, 49.7, 46.1,41.9, 40.3, 38.2, 37.8, 36.6, 36.5, 33.9, 32.4, 31.2, 30.3, 28.9, 27.5, 25.8,25.3, 24.7, 20.6, 19.0, 17.8, 16.2, 16.0, 15.8, 14.3. ESI-HRMS ( m / z ):C 39 H 63 NO8K [M+K] + , calculated value, 712.4185; measured value, 712.4161.

[0195] Example 51 Synthesis of BA-51: Refer to BA-13, except that 6-aminocaproic acid methyl ester was replaced by 3-aminopropionic acid methyl ester.

[0196]

[0197] White solid, yield 94%. 1 H NMR (400 MHz, DMSO-d6) δ 7.68 (1H, t, J = 5.7Hz, -CONH), 4.79 (1H, d, J = 4.3 Hz), 4.67 (1H, brs, H1-29), 4.55 (1H, brs,H2-29), 4.48 (1H, d, J = 5.3 Hz), 4.46 (1H, d, J = 4.4 Hz), 4.13 (1H, d,J =6.0 Hz, H-1 of Ara), 3.66 (1H, dd, J = 12.0, 3.3 Hz), 3.62 (1H, d, J = 5.7Hz), 3.59 (3H, s, -OCH3), 3.25–3.17 (1H, m), 3.00 (2H, m), 2.57 (1H, d, J =14.5 Hz), 2.46 (2H, t, J = 6.7 Hz), 2.09 (1H, d, J 0.92 (3H, s), 0.86 (3H, s), 0.80 (3H, s), 0.75 (3H, s), 0.68 (1H, m). 13 C NMR (101 MHz, DMSO) δ 175.7, 171.9, 150.9, 109.2, 105.8,87.7, 72.7, 71.0, 67.6, 65.0, 55.1, 54.8, 51.2, 50.0, 49.6, 46.1, 41.9, 40.3,38.2, 37.5, 36.6, 36.5, 34.9, 33.9, 33.7, 32.3, 30.2, 28.7, 27.5, 25.8, 25.2,20.5, 19.0, 17.7, 16.2, 16.0, 15.7, 14.3. ESI-HRMS ( m / z ): C 39 H 64 NO8 [M+H] + ,Calculated value, 674.4632; Measured value, 674.4635.

[0198] Example 52 Synthesis of BA-52: Refer to BA-48, replacing aminovaleric acid with aminopropionic acid

[0199]

[0200] White solid, yield 91%. 1H NMR (400 MHz, DMSO-d6) δ 7.60 (1H, t, J = 5.6Hz, -CONH), 4.65 (1H, brs, H1-29), 4.53 (1H, brs, H2-29), 4.11 (1H, d, J = 6.0Hz, H-1 of Ara), 3.69–3.57 (2H, m), 3.00 (2H, m), 2.35 (2H, t, J = 7.2 Hz),2.08 (1H, d, J = 10.2 Hz), 1.79–1.66 (3H, m), 1.62 (3H, s), 1.60–1.51 (3H,m), 1.40–1.22 (12H, m), 1.13 (1H, m), 1.00 (1H, m), 0.94 (3H, s), 0.90 (3H, s), 0.85 (3H, s), 0.78 (3H, s), 0.73 (3H, s), 0.66 (1H, m). 13 C NMR (101 MHz, DMSO-d6) δ 175.6, 173.1, 150.9, 109.2, 105.8, 87.7, 72.7, 71.0, 67.6, 65.0,55.1, 54.8, 50.0, 49.6, 46.2, 41.9, 40.3, 38.2, 37.6, 36.7, 36.5, 34.9, 33.9,32.3, 30.3, 28.8, 27.5, 25.8, 25.3, 20.5, 19.0, 17.7, 16.2, 16.0, 15.8, 14.3.ESI-HRMS ( m / z ): C 38 H 62 NO8 [M+H] + , calculated value, 660.4475; measured value, 660.4479.

[0201] Example 53 Synthesis of BA-53: Refer to BA-13, except that 6-aminohexanoic acid methyl ester was replaced with (1R,3S)-3-aminocyclopentylcarboxylic acid methyl ester.

[0202]

[0203] White solid, yield 78%. 1H NMR (400 MHz, DMSO-d6) δ 7.38 (1H, d, J = 7.0Hz, -CONH), 4.80 (1H, s), 4.67 (1H, brs, H1-29), 4.55 (1H, brs, H2-29), 4.48(2H, s), 4.13 (1H, d, J = 5.9 Hz, H-1 of Ara), 4.04 (1H, q, J = 7.0 Hz), 3.66(1H, dd, J = 12.0, 3.2 Hz), 3.61 (3H, s, -OCH3), 3.01 (2H, m), 2.81 (1H, m),2.58 (1H, m), 2.16 (1H, d, J = 11.9 Hz), 2.08 (1H, m), 1.89–1.66 (8H, m), 1.64 (3H, s), 1.62–1.21 (17H, m), 1.14 (1H, m), 1.04 (1H, m), 0.96 (3H, s), 0.92 (3H, s), 0.85 (3H, s), 0.79 (3H, s), 0.75 (3H, s), 0.68 (1H, m). 13 C NMR(101 MHz, DMSO-d6) δ 176.0, 175.2, 150.9, 109.2, 105.8, 87.7, 72.7, 71.0,67.6, 65.0, 55.1, 54.7, 51.5, 50.0, 49.7, 46.2, 41.8, 41.2, 40.3, 38.2, 37.5,36.6, 36.5, 35.0, 33.9, 32.3, 31.6, 30.3, 28.8, 27.5, 27.0, 25.8, 25.3, 20.5,19.0, 17.7, 16.2, 16.0, 15.8, 14.3. ESI-HRMS ( m / z ): C 42 H 68 NO8 [M+H] + ,Calculated value,714.4945; Measured value, 714.4949.

[0204] Example 54 Synthesis of BA-54: Refer to BA-48, except that aminovaleric acid is replaced by (1R,3S)-3-aminocyclopentylcarboxylic acid.

[0205]

[0206] White solid, yield 88%. 1 H NMR (400 MHz, DMSO-d6) δ 7.39 (1H, d, J = 7.0Hz, -CONH), 4.65 (1H, brs, H1-29), 4.53 (1H, brs, H2-29), 4.11 (1H, d, J = 5.9Hz, H-1 of Ara), 3.64 (1H, dd, J = 12.1, 3.2 Hz), 3.59 (1H, m), 3.00 (2H, m), 2.70 (1H, m), 2.13 (1H, d, J = 10.1 Hz), 2.02 (1H, m), 1.80–1.70 (8H, m), 1.62 (3H, s), 1.60–1.55 (3H, m), 1.45–1.29 (14H, m), 1.13 (1H, m), 1.02 (1H,d, J = 10.9 Hz), 0.94 (3H, s), 0.90 (3H, s), 0.84 (3H, s), 0.77 (3H, s), 0.73(3H, s), 0.66 (1H, m). 13 C NMR (101 MHz, DMSO-d6) δ 177.9, 175.6, 151.4,109.7, 106.3, 88.2, 73.2, 71.5, 68.1, 65.5, 55.6, 55.2, 50.7, 50.5, 50.2,46.7, 42.3, 42.0, 40.8, 38.7, 38.1, 37.2, 37.0, 35.5, 34.4, 32.8, 32.3, 30.9,29.3, 28.0, 27.6, 26.3, 25.7, 21.0, 19.5, 18.2, 16.7, 16.4, 16.2, 14.8. ESI-HRMS ( m / z ): C 41 H 66 NO8 [M+H] +, calculated value, 700.4788; measured value, 700.4787.

[0207] Example 55 Synthesis of BA-55

[0208]

[0209] BA-47 (50 mg, 0.071 mmol) was dissolved in a mixture of methanol:tetrahydrofuran:water = 1:2:1, and sodium hydroxide (26 mg, 0.639 mmol) was added. The reaction solution was stirred at room temperature for 6 h. After the reaction, the pH was adjusted to 8-9 with 1 mol / L hydrochloric acid solution. The product was filtered and dried, and then redissolved in methanol and purified by medium pressure (methanol:water = 75:25) to obtain 43 mg of a white solid with a yield of 85%. 1 H NMR (400 MHz, DMSO-d6) δ 7.72 (1H, t, J = 5.5 Hz, -CONH), 4.64 (1H, brs, H1-29), 4.52 (1H, brs, H2-29), 4.09 (1H, d, J = 5.3 Hz, H-1 ofAra), 3.64 (1H, dd, J = 12.1, 3.1 Hz), 3.58 (1H, m), 3.06–2.92 (4H, m), 2.16(1H, d, J = 9.6 Hz), 1.89 (2H, d, J = 8.1 Hz), 1.81 – 1.67 (3H, m), 1.62 (3H,s), 1.56 (2H, m), 1.46 – 1.20 (15H, m), 1.13 (1H, m), 1.01 (1H, m), 0.94 (3H, s), 0.90 (3H, s), 0.83 (3H, s), 0.77 (3H, s), 0.72 (3H, s), 0.66 (1H, m). 13CNMR (101 MHz, DMSO-d6) δ 176.9, 175.2, 151.0, 109.2, 106.0, 87.7, 72.8, 71.1,67.7, 65.2, 55.2, 54.8, 50.1, 49.7, 48.6, 46.2, 41.9, 40.3, 38.3, 37.8, 37.4,36.6, 36.5, 34.0, 32.4, 30.4, 29.3, 28.9, 27.5, 25.9, 25.3, 23.4, 20.6, 19.1,17.8, 16.2, 16.0, 15.8, 14.3. ESI-HRMS ( m / z ): C 40 H 64 NO8 [M-Na] - , calculated value, 686.4632; measured value, 686.4636.

[0210] Test Example 1

[0211] THP-1 macrophages were cultured at 1×10 4 Cells were seeded into 96-well plates at 100 μL / well and cultured conventionally. After the cells reached 80%, they were induced with 100 ng / mL phorbol myristate monophosphate (PMA) for 12 h, the original culture medium was discarded, and 100 μL of new complete culture medium was added. A zero-well culture medium without cells and a normal group without drugs were set up. 1 μL of betulinic acid saponin derivatives (1 mM, 5 mM) was added to each well to make the final concentrations of drugs BA-1 to BA-27, BA-33 to BA-55 50 μM, and the final concentrations of drugs BA-28 to BA-32 10 μM and 50 μM, respectively. The cells were then placed in an incubator for co-incubation. Incubate for 24 hours; after the incubation, add 10 μL of CCK-8 to each well and incubate in the dark for 4 hours; use a microplate reader to measure the absorbance of each well at a wavelength of 450 nm, and calculate the cell viability of each well; cell viability (%) = [A(drug added) - A(blank)] / [A(0 drug added) - A(blank)] × 100; where A(drug added) is the absorbance of the well with cells, CCK-8 and drug solution; A(blank) is the absorbance of the well with culture medium and CCK-8 but no cells; A(0 drug added) is the absorbance of the well with cells and CCK-8 but no drug. The results are shown in Figure 2. Figure 1-Figure 2 As shown. Figure 1-Figure 2It can be seen that 15 compounds (BA-1, BA-2, BA-12, BA-22, BA-26, BA-27, BA-42, BA-47, BA-48, BA-49, BA-50, BA-52, BA-54, and BA-55) showed no obvious cytotoxicity against THP-1 macrophages at 50 µM, and 3 compounds (BA-29, BA-31, and BA-32) showed no obvious cytotoxicity against THP-1 macrophages at 10 µM.

[0212] Test Example 2

[0213] THP-1 cells were collected at 2×10 5 Cells were seeded at 100 ng / mL per well in a 6-well plate and cultured conventionally. After the cells reached 80% confluence, they were induced with 100 ng / mL PMA for 12 h, after which the original culture medium was discarded and fresh complete culture medium was added. Dimethyl sulfoxide (DMSO) was used as a vehicle control. The positive control group was pretreated with betulinic acid (10 µM) for 1 h, and the experimental group was pretreated with a betulinic acid-type saponin derivative (10 µM) for 1 h. After 1 h, the blank group was removed and the other groups were incubated with 1 μg / mL LPS for 24 h. The culture supernatants were collected and the levels of IL-6, IL-1β, and TNF-α were determined and calculated using ELISA. The results are shown in Table 1.

[0214] Table 1

[0215]

[0216] aThe data are expressed as “mean ± standard error” and are based on at least three independent experiments with three replicates each.

[0217] NA indicates no significant effect was observed.

[0218] As can be seen from Table 1, most betulinic acid saponin derivatives significantly inhibited the secretion of proinflammatory factors IL-6, IL-1β, and TNF-α in THP-1 macrophages induced by LPS, and their activity was better than that of BA. Among them, BA-42, BA-48, BA-52, and BA-55 had the most significant inhibitory activity on IL-6 secretion, with inhibition rates of more than 60%.

[0219] Test Example 3

[0220] After weighing, 63 6-8 week old C57BL / 6 male mice were randomly divided into 9 groups (n=7 in each group): normal group, model group, mesalazine group, betulin group, betulic acid group, BA-42 group, BA-48 group, BA-52 group, and BA-55 group. Because betulin, betulic acid, BA-42, BA-48, BA-52, and BA-55 have poor water solubility, they were prepared into hydroxypropyl-β-cyclodextrin inclusion complexes in this test. The mice were weighed one day before modeling and given mesalazine, betulin, betulic acid, BA-42, BA-48, BA-52, and BA-55. DSS was then dissolved in the drinking water of the mice, and the mice in the model group and the treatment group were continuously given 3% DSS. 8 days; after modeling, mice were weighed every day and administered orally according to body weight once a day; mice in the normal group were orally administered with normal saline once a day, and mice in the model group were orally administered with solvent once a day; body weight was weighed every day, fecal characteristics of mice were observed, occult blood / hematochezia of mice were checked, and DAI score was calculated. The results are as follows Figure 3 As shown. Figure 3It can be seen that the weight of mice in the DSS group began to decrease from the 4th day until the end of the experiment. Compared with the DSS group, the symptoms were significantly improved after treatment with mesalazine, betulin, betulic acid, BA-42, BA-48, BA-52, and BA-55. The mesalazine group was statistically significant only on the 6th day (P<0.001); the betulin group was statistically significant only on the 5th day (P<0.001) and the 6th day (P<0.01); the betulic acid group was statistically significant only on the 5th day (P<0.001); the BA-42 group was statistically significant on the 4th day (P<0.05), the 6th day (P<0.01), the 7th day (P<0.01), and the 8th day (P<0.001); the BA-48 group was statistically significant on the 5 ...). Statistically significant differences were observed in all nine groups only on days 4 (P < 0.001) and 6 (P < 0.01). The BA-52 group showed a significant trend toward improvement on days 6 (P < 0.01), 7 (P < 0.001), and 8 (P < 0.001). The BA-55 group showed statistically significant improvements on days 4 (P < 0.001), 5 (P < 0.01), and 6 (P < 0.01), but not on days 7 and 8. Following DSS administration, rectal bleeding and diarrhea were observed in all DSS-treated mice starting on day 4, and the DAI scores in the DSS group also increased significantly. However, treatment with mesalazine, betulin, betulic acid, BA-42, BA-48, BA-52, and BA-55 significantly reduced the DAI scores and alleviated the symptoms of diarrhea and bloody stools. Compared with the DAI scores of mice in the DSS group, the mesalazine group had statistical significance on the 6th day (P<0.05) and the 8th day (P<0.001); the betulin group had statistical significance only on the 6th day (P<0.05) and the 8th day (P<0.05); the betulic acid group had statistical significance only on the 6th day (P<0.01) and the 8th day (P<0.001); the BA-42 group had statistical significance on the 4th day (P<0.001), the 5th day (P<0.01), the 6th day (P<0.001), the 7th day (P<0.001), and the 8th day (P<0.001); the BA-48 group had statistical significance on the 4th day (P<0.01) and the 5th day (P<0.01). There were statistically significant differences in the BA-52 group on the 4th day (P<0.05), 5th day (P<0.001), 6th day (P<0.001), 7th day (P<0.001), and 8th day (P<0.001); there were statistically significant differences in the BA-55 group on the 4th day (P<0.05), 5th day (P<0.001), 6th day (P<0.001), 7th day (P<0.05), and 8th day (P<0.001), and the symptoms of loose stools and bloody stools were significantly aggravated on the 7th and 8th day.Among them, the BA-42 group and the BA-52 group had the most significant activity, and were superior to mesalazine in improving weight loss and relieving diarrhea and bloody stool symptoms.

[0221] On the 9th day after administration, the mice were killed, the colon was removed, and the length of the colon was measured. Figure 4 As shown. Figure 4 As can be seen, the colon length of mice in the DSS model group was significantly shortened compared to the normal group (P < 0.001). Treatment with mesalazine, betulin, BA-42, BA-48, BA-52, and BA-55 all increased the colon length of mice to varying degrees. The BA derivatives BA-42, BA-48, BA-52, and BA-55 all showed significant differences compared to the DSS group (P < 0.001), demonstrating that their efficacy in alleviating colon length shortening was comparable to that of mesalazine.

[0222] On the 9th day after administration, the mice were killed, the spleens were removed, and the spleen weight was measured. Figure 5 As shown. Figure 5 As can be seen, the spleen index of mice in the model group was significantly increased compared with the normal group, with statistically significant differences (P < 0.001). Mesalazine treatment did not alleviate splenomegaly compared with the model group. The spleen index of mice in the betulic acid group was lower than that of mice treated with DSS (P < 0.05). The spleen index of mice in the BA-55 group was significantly decreased, with statistically significant differences compared with the spleen index of the model group (P < 0.01, P < 0.05, respectively). This suggests that betulic acid saponin derivatives play a role in protecting the colon from inflammatory damage, with BA-52 showing the most significant activity.

[0223] In summary, the inhibitory effects of betulinic acid-type saponin derivatives on IBD are better than those of the parent nucleus B and BA itself, indicating that the inhibitory activity of BA series saponin derivatives on DSS-induced IBD is due to the original form of their molecular structure, and is not due to their degradation into the BA parent nucleus in the body. Among them, BA-52 has the most significant activity, and is superior to mesalazine in improving weight loss, relieving diarrhea and bloody stool symptoms.

[0224] Test Example 4

[0225] To evaluate the safety of BA-52, a 7-day multiple-dose toxicity test was conducted on ICR mice. BA-52 was administered orally by gavage at a dose of 200 mg / kg once a day for 7 consecutive days. The toxicity test results are shown in Figure 2. Figure 6 As shown. Figure 6As can be seen, compared to the control group (vehicle) within 8 days of administration, the BA-52 group showed no significant weight loss or adverse reactions, such as abnormal behavior, food and water intake, or digestive system disturbances. Subsequently, on day 8, the mice were sacrificed and organ samples were collected for analysis, revealing no significant changes in organ indices. This demonstrates the favorable in vivo safety profile of BA-52.

[0226] Test Example 5

[0227] THP-1 cells were pretreated with BA-52 at different concentrations for 1 h and then stimulated with LPS (1 μg / mL) for 24 h. The supernatant was collected and the levels of inflammatory cytokines IL-6, IL-1β, and TNF-α were detected by ELISA kits. The results are shown in Figure 3. Figure 7 As shown. Figure 7 It can be seen that BA-52 inhibits the release of IL-6, IL-1β, and TNF-α in LPS-induced human macrophages THP-1 in a dose-dependent manner.

[0228] Test Example 6

[0229] Forty-two 6-8 week old C57BL / 6 male mice were randomly divided into 6 groups (n=7 in each group): normal group, model group, dexamethasone group (3 mg / kg), BA-52 group (2.5 mg / kg), BA-52 group (5 mg / kg), and BA-52 group (10 mg / kg). One day before the experiment, the back skin of the mice was depilated with a depilatory cream, and an area of ​​approximately 3 cm × 3 cm was selected for use. On the first and second days, except for the normal group, the backs of the mice in other groups were sensitized by applying 50 µL of 5% DNCB externally. On the third, fourth, and fifth days, 50 µL of 1% DNCB was applied externally to the inside and outside of the right auricle of the mice using a pipette for stimulation, and an equal amount of acetone matrix was applied to the left auricle. On days 1-2, 0.05 g of dexamethasone was applied to the back of mice in the dexamethasone group at 4 p.m., and 0.08 g of dexamethasone cream was applied to the back and the inner and outer sides of the right ears of mice on days 3-7. On days 1-2, 200 μL of drug-containing solution was applied to the back of mice in the BA-52 (2.5 mg / kg), BA-52 (5 mg / kg), and BA-52 (10 mg / kg) treatment groups at 10 a.m. and again at 4 p.m.; on days 3-7, 200 μL of drug-containing solution was applied to the back of mice in the BA-52 (2.5 mg / kg), BA-52 (5 mg / kg), and BA-52 (10 mg / kg) treatment groups at 10 a.m., and 50 μL of drug-containing solution was applied to the inner and outer sides of the right ears of mice, and again at 4 p.m. For the same period of time, the model group applied equal amounts of a mixture of ethanol:water:glycerol (70:28:2) to the back and inside and outside of the right ear of the mice, respectively, to maintain overall behavior consistent with that of the drug-treated group. On day 8, the mice were sacrificed, and the spleen and auricles were removed to calculate the spleen index and ear weight difference (ear discs were obtained by punching the same area with a 6 mm diameter punch and weighing them).

[0230] During the experiment, the eczema condition of the back skin of each group of mice was observed every day (obvious redness, swelling, macules, erosion and exudation on the skin) and photographed. The eczema area and severity index (EASI) scoring standard was used with reference to the clinical symptoms of the skin of each group of mice. The four indicators of erythema, papules / pustules, scales and scabs were evaluated, and scored from 0 to 3 points: 0 points = no symptoms; 1 point = mild; 2 points = moderate; 3 points = severe. The points of each indicator were added together to obtain the total score. Two observers used a blind method to score on the 1st, 3rd, 5th and 7th days of intervention, and recorded them by digital photography. 24 hours after the last administration, the thickness of both ears was measured with a vernier caliper (the average of 3 points was measured), and the thickness difference was calculated: thickness difference = right ear thickness - left ear thickness; the body weight was weighed and recorded every day, and the results are as follows. Figures 8-11 As shown. Figure 8-Figure 9 It can be seen that after the first application of DNCB on the third day, compared with the blank group, the model group had exudation, erosion and scab on the back skin after DNCB was applied, producing eczema-like skin lesions ( Figure 8 During the modeling process, the mice were weighed and it was found that no significant weight loss was observed in the BA-52 group, while significant weight loss was observed in the dexamethasone group, indicating that BA-52 has a good safety profile in vivo ( Figure 9 After DNCB was applied to the back skin of mice, the model group showed exudation, erosion and scab compared with the blank group, resulting in eczema-like skin lesions. With the continued effect of the drug, the skin lesions in the model group became increasingly severe from the 2nd to 3rd day, with obvious erythema, skin infiltration and scabs. The EASI comprehensive scores of the control group and the model group were statistically significant on the 3rd, 5th and 7th days (P<0.001), indicating that the eczema mouse model was successfully established. The skin lesions in the low, medium and high dose BA-52 groups were significantly alleviated compared with the model group during the same period, with smoother skin, less exudation, mild scabs or the earliest detachment. The skin scabs in the dexamethasone group were more severe, with almost no detachment of scabs and obvious scales and papules. The difference in EASI comprehensive scores between the model group and the normal group was statistically significant on the 3rd day (P<0.001), 5th day (P<0.001) and 7th day (P<0.001). There was no statistical difference in EASI comprehensive scores between the dexamethasone group and the model group on the 3rd, 5th and 7th days. The back scores of the BA-52 (2.5 mg / kg), BA-52 (5 mg / kg) and BA-52 (10 mg / kg) groups were statistically significant compared with the model group. DNCB caused slight redness of the auricle skin. The redness and swelling in the model group became increasingly severe from the fourth day, and desquamation occurred. On the fifth day, exudation, ulceration and scabs began to form ( Figure 9 ).from Figure 10-11 It can be seen that the difference in thickness between the left and right ears of the control group and the model group was statistically significant on the 7th day (P<0.001), indicating that the eczema mouse model was successfully established. The ear swelling symptoms of the low, medium and high dose groups of BA-52 were significantly reduced compared with the model group during the same period, and there was almost no ear ulceration; the effect of the dexamethasone positive drug group was slightly worse, with some exudation and scabs; among them, the difference in thickness between the dexamethasone group, BA-52 (2.5 mg / kg), BA-52 (5 mg / kg) and BA-52 (10 mg / kg) groups and the model group was statistically significant on the 7th day (P<0.001); after 7 days of administration, the spleen index of the model group mice was significantly increased, and the spleen index of the dexamethasone group was significantly lower than that of the normal group, indicating that dexamethasone produced immunosuppression in mice. The spleen index of the mice in the BA-52 (10 mg / kg) group was significantly reduced, while the low dose group of BA-52 did not show statistical differences from the model group, indicating that BA-52 can improve the immunity of mice ( Figure 11). It can be seen that BA-52 has a protective effect on DNCB-induced eczema skin lesions, and is more effective and safer than glucocorticoids in improving erythema, scaling, edema, and exfoliation on the back skin of mice.

[0231] Obviously, the above embodiments are merely examples for clarity of explanation and are not intended to limit the implementation methods. Those skilled in the art will appreciate that other variations or modifications can be made based on the above description. It is not necessary and impossible to enumerate all implementation methods here. Obvious variations or modifications arising therefrom remain within the scope of protection of the present invention.

Claims

1. A betulinic acid saponin derivative, characterized in that The betulinic acid saponin derivatives are selected from the following compounds:

2. A method for preparing the betulic acid saponin derivative according to claim 1, characterized in that: The following steps are involved: Betulic acid is used as a raw material, and the betulic acid saponin derivative is prepared through glycosylation reaction and amidation reaction.

3. A pharmaceutically acceptable salt of the betulic acid-type saponin derivative according to claim 1.

4. A pharmaceutical composition, characterized in that The active ingredient of the pharmaceutical composition is the betulic acid saponin derivative according to claim 1 and the pharmaceutically acceptable salt of the betulic acid saponin derivative according to claim 3.

5. Use of the betulic acid saponin derivative according to claim 1, the pharmaceutically acceptable salt of the betulic acid saponin derivative according to claim 3, and the pharmaceutical composition according to claim 4 in the preparation of a drug for treating inflammation-related diseases.

6. The use according to claim 5, characterized in that The inflammation-related disease is one or more of pneumonia, hepatitis, nephritis, gastritis, cholecystitis, pharyngitis, conjunctivitis, keratitis, otitis media, appendicitis, cervicitis, encephalitis, peritonitis, arthritis, stomatitis, enteritis and skin inflammation.

7. The use according to claim 6, characterized in that The skin inflammation is one or more of atopic dermatitis, contact dermatitis, eczema, acne, dermatomyositis, urticaria, lupus erythematosus, ichthyosis vulgaris, allergic dermatitis and psoriasis.

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