Betulinic acid type saponin derivative as well as preparation method and application thereof

Abstract

The invention relates to betulinic acid type saponin derivatives as well as a preparation method and application thereof, and belongs to the technical field of biological medicines. The structural general formula of the betulinic acid type saponin derivative is # imgabs0, R1 is selected from hydroxyl or-O-G, and G is monosaccharide; r2 is selected from dopamine, 5-aminovaleric acid, 4-aminobutyric acid or 3-aminopropionic acid and the like and salts thereof. The betulinic acid type saponin derivative does not show obvious cytotoxicity to THP-1 macrophages, and can obviously reduce the release of IL-6 and IL-1beta in the THP-1 macrophages induced by LPS (lipopolysaccharide). Compared with betulinic acid and positive control medicine mesalazine, the pharmaceutical composition has better anti-inflammatory activity, has the treatment effect of improving diarrhea and hemafecia of mice with colitis remarkably superior to those of betulinic acid and positive control medicine mesalazine, has the treatment effect of dermatitis superior to that of positive control medicine dexamethasone, and does not have obvious toxic or side effects such as weight loss and immunosuppression. Therefore, the betulinic acid type saponin derivative has good in-vivo and in-vitro safety and druggability.

Description

Technical Field

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

[0002] Inflammation is a common clinical pathological process, which is a defensive reaction of the body to factors including infection, trauma and chemical stimuli, and has a dual role of defense and damage. However, excessive and uncontrollable inflammatory responses can kill tissue cells and damage human life. In addition, acute inflammation can progress to chronic and pathological inflammation, which will lead to continuous destruction of body tissues and systemic homeostasis disorders, thereby causing the occurrence of related diseases, including inflammatory bowel disease (IBD), atopic dermatitis (AD), pneumonia, hepatitis and cancer, etc.

[0003] Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a chronic and recurrent inflammation of the gastrointestinal tract, which is becoming increasingly common worldwide. The main symptoms of IBD include immune response disorders, abnormal cytokine production, intestinal flora imbalance and barrier damage. More seriously, long-term recurrent inflammatory damage often progresses to colitis-related colon cancer, posing a serious threat to patients and even endangering their lives. Currently, the classic therapeutic drugs used clinically to treat IBD are mainly aminosalicylates, corticosteroids, immunosuppressants and anti-TNF-α biological agents. However, these drugs can cause adverse reactions, including severe infections, cardiovascular toxicity and immunosuppression. Atopic dermatitis (AD) is a common, immune-mediated inflammatory skin disease, which is characterized by recurrent, itchy, local eczema, often accompanied by seasonal fluctuations; atopic dermatitis is also known as atopic eczema, neurodermatitis, atopic dermatitis, and is also the most common eczema. Currently, the therapeutic drugs for AD include various topical corticosteroids (TCS), topical calcineurin inhibitors tacrolimus, pimecrolimus, and phosphodiesterase 4 (PDE4) inhibitor crisaborole, etc. For more severe AD, in addition to using ultraviolet light, cyclosporine A, methotrexate, azathioprine or mycophenolate mofetil are also required, but these drugs have problems such as large side effects or high prices. It can be seen that developing new safe and effective anti-inflammatory drugs is a practical strategy.

[0004] Betulinic acid (BA) is a natural pentacyclic triterpenoid compound, which is mainly extracted from the bark of birch trees. BA has a wide range of pharmacological activities, including anti-tumor, anti-viral, anti-inflammatory, antioxidant stress and other effects. However, BA is significantly limited in its further development and application due to its poor water solubility, low bioavailability and cytotoxicity. Therefore, it is urgent to develop new drugs with high anti-inflammatory activity and low toxicity based on betulinic acid. Summary of the Invention

[0005] For this reason, the technical problem to be solved by the present invention is to overcome the obvious toxic and side effects of existing drugs, and some drugs have the problem of short half-life.

[0006] To solve the above technical problems, the present invention provides a betulinic acid-type saponin derivative, a preparation method and an application thereof. By chemically modifying and transforming betulinic acid, a series of saponin derivatives are obtained to solve the problem of poor druggability of BA and obtain compounds with significantly better anti-inflammatory activity than betulinic acid.

[0007] The first object of the present invention is to provide a betulinic acid-type saponin derivative, the general structural formula of which is as follows: , wherein, R 1 is selected from a hydroxyl group or -O-G, and G is a monosaccharide; R 2 is selected from benzyloxy, 1-O-benzotriazole, methyl 6-aminocaproate, 6-aminocaproic acid, 4-hydroxyphenethylamine, 28-O-β-D-glucopyranose, o-hydroxyphenethylamine, m-hydroxyphenethylamine, o-methoxyphenethylamine, m-methoxyphenethylamine, p-methoxyphenethylamine, p-bromophenethylamine, p-fluorophenethylamine, p-hydroxybenzylamine, 3,4-difluorophenethylamine, p-trifluoromethoxyphenethylamine, 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 methyl (1R,3S)-3-aminocyclopentanecarboxylate formate.

[0008] Further, R 2 is selected from dopamine, 5-aminovaleric acid, 4-aminobutyric acid or 3-aminopropionic acid and their salts.

[0009] In an 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.

[0010] Further, the monosaccharide is 3-O-α-L-arabinopyranose.

[0011] The second object of the present invention is to provide a preparation method of the betulinic acid-type saponin derivative, comprising the following steps: using betulinic acid as a raw material, and preparing the betulinic acid-type saponin derivative through a glycosidation reaction, an esterification reaction or an amidation reaction.

[0012] The third object of the present invention is to provide a pharmaceutically acceptable salt of the betulinic acid-type saponin derivative described above.

[0013] The fourth object of the present invention is to provide a pharmaceutical composition, and the active ingredient of the pharmaceutical composition is the betulinic acid-type saponin derivative and the pharmaceutically acceptable salt of the betulinic acid-type saponin derivative described above.

[0014] 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 gelling substances that can be used medicinally, have sufficient purity and low toxicity, and can be blended with each other among the components of the pharmaceutical composition and with the active ingredient of the present invention without reducing the efficacy of the active ingredient.

[0015] Furthermore, the pharmaceutically acceptable carrier is selected from one or more of cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, 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 dodecyl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, and pyrogen-free water.

[0016] The fifth object of the present invention is to provide the use of the betulinic acid-type saponin derivative, the pharmaceutically acceptable salt of the betulinic acid-type saponin derivative, and the pharmaceutical composition in the preparation of a drug for treating inflammation-related diseases.

[0017] In one embodiment of the present invention, the inflammation-related diseases are one or more of pneumonia, hepatitis, nephritis, gastritis, cholecystitis, pharyngitis, conjunctivitis, keratitis, otitis media, appendicitis, cervicitis, encephalitis, peritonitis, arthritis, stomatitis, enteritis, and skin inflammation.

[0018] 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.

[0019] The sixth object of the present invention is to provide the use of the betulinic acid-type saponin derivative, the pharmaceutically acceptable salt of the betulinic acid-type saponin derivative, and the pharmaceutical composition in the preparation of a drug for treating autoimmune diseases.

[0020] 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, Sjogren's syndrome, polymyositis / dermatomyositis, lupus erythematosus, and Hashimoto's thyroiditis.

[0021] In one embodiment of the present invention, the drug is for external use, oral administration, topical skin administration, systemic administration, rectal or gastrointestinal external use (such as intravenous, intramuscular or subcutaneous) drugs.

[0022] 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.

[0023] Further, the solution includes emulsion, solution, suspension, syrup or tincture.

[0024] The technical solution of the present invention has the following advantages compared with the prior art: (1) The betulinic acid-type saponin derivative described in the present invention has a suitable oil-water partition coefficient and solubility compared with BA, which is more conducive to intestinal absorption.

[0025] (2) Most of the compounds in the betulinic acid-type saponin derivative described in the present invention do not show obvious cytotoxicity to THP-1 macrophages, and can significantly reduce the release of IL-6 and IL-1β in LPS-induced THP-1 macrophages. Some compounds have better anti-inflammatory activity, and the therapeutic effect on improving diarrhea and bloody stools in colitis mice is significantly better than that of betulinic acid and the positive control drug mesalazine, and the 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. It shows that the betulinic acid-type saponin derivative has good in vitro and in vivo safety and drug-forming properties. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] In order to make the content of the present invention easier to be clearly understood, the following further details the present invention according to the specific embodiments of the present invention in combination with the drawings, wherein: Figures 1 - 2 Shows the effect of the betulinic acid-type saponin derivative on the cytotoxicity of THP-1 macrophages in Test Example 1 of the present invention; Figure 3 Shows the effect of the betulinic acid-type saponin derivative on the body weight change, fecal characteristics, occult blood / bloody stool conditions and DAI score of DSS-induced colitis mice in Test Example 3 of the present invention; Figure 4To study the effect of betulinic acid-type saponin derivatives on the colon length of DSS-induced colitis mice in Test Example 3 of the present invention; Figure 5 To study the effect of betulinic acid-type saponin derivatives on the spleen index of DSS-induced colitis mice in Test Example 3 of the present invention; Figure 6 To study the effect of multiple administrations of BA-52 in vivo on the body weight and organ indices of mice in Test Example 4 of the present invention; Figure 7 To study the dose-dependent inhibition of the release of inflammatory factors by BA-52 in Test Example 5 of the present invention; Figure 8 To study the effect of BA-52 on the dorsal skin of DNCB-induced dermatitis mice in Test Example 6 of the present invention; Figure 9 To study 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; Figure 10 To study the effect of BA-52 on the ear skin of DNCB-induced dermatitis mice in Test Example 6 of the present invention; Figure 11 To study the effect of BA-52 on the ear thickness difference, ear weight difference and spleen index of DNCB-induced dermatitis mice in Test Example 6 of the present invention. Detailed implementation manners

[0027] The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments, so that those skilled in the art can better understand the present invention and be able to implement it, but the examples given are not intended to limit the present invention.

[0028] In the present invention, unless otherwise specified, the reagents used in the embodiments of the present invention are mainly provided by Shanghai Aladdin Biochemical Technology Co., Ltd.; the TLC thin layer chromatography silica gel plate is produced by Jiangyou Silica Gel Development Company, Yantai, Shandong, model HSGF 254, and the silica gel column used for compound purification is produced by Beijing Innochem Science & Technology Co., Ltd., 200 mesh - 300 mesh; NMR is recorded with a Varian Mercury 400M nuclear magnetic resonance spectrometer, and the chemical shift is expressed in δ (ppm).

[0029] In the present invention, unless otherwise specified, the abbreviations used in the embodiments of the present invention correspond to the following Chinese: DMF is N,N-dimethylformamide, DCM is dichloromethane, TBTU is O-benzotriazol-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.

[0030] In the present invention, unless otherwise specified, the structural formula of betulinic acid used in the embodiments of the present invention is .

[0031] Example 1 Synthesis of BA-1

[0032] Dissolve betulinic acid BA (2 g, 4.379 mmol) in 25 mL of DMF, and successively add benzyl chloride (0.65 mL, 5.649 mmol) and potassium carbonate (1.2 g, 8.696 mmol) thereto, and heat and stir at 35 °C for 24 h; after detecting the completion of the reaction by TLC, add 200 mL of water to the reaction solution, filter to obtain a filter cake, and wash the filter cake successively with 1 mol / L hydrochloric acid (150 mL × 3), saturated sodium bicarbonate (150 mL × 3), and water (150 mL × 3). After suction drying, redissolve with DCM, add anhydrous sodium sulfate for drying, filter, concentrate under reduced pressure, and obtain 1.9 g of a white solid by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 8:1), with a yield of 80%. 1 H NMR (400 MHz, 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). 1313C 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, 39.0, 38.8, 38.3, 37.3, 37.1, 34.4, 32.2, 30.7, 29.7, 28.1, 27.5, 25.7, 21.0, 19.5, 18.4, 16.3, 16.0, 15.5, 14.8. ESI-HRMS ( m / z ): C 37 H 54 O3Na [M+Na] + , calculated, 569.3965; found, 569.3978. Example 2 Synthesis of BA-2

[0033] 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 the crude product. After drying, it was redissolved in DCM, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 9:1 to 8:1) to obtain 217 mg of a white solid with a yield of 86%. 1 1H NMR (400 MHz, CDCl3) δ 8.08 (1H, dd, J J =8.5, 1.0 Hz), 7.55 (1H, ddd, J 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 ): C 36 H 50 N3O3 [M-H] - , Calculated , 572.3858; found, 572.3860. Example 3 Synthesis of BA-3

[0034] BA (100 mg, 0.219 mmol) was dissolved in 4 mL of DMF. First, TBTU (105 mg, 0.328 mmol) and DIEA (115 μL, 0.657 mmol) were added, and the mixture was stirred at room temperature for 6 h. After the reaction was complete to form the intermediate, methyl 6-aminocaproate 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, 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 solution, 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 pale yellow solid with a yield of 73%. 1 HNMR (400 MHz, CDCl3) δ 5.62 (1H, t, J 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). 13 C 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 61NO4Cl [M+Cl] - , calculated value , 618.4284; measured value, 618.4254. Example 4 Synthesis of BA-4 Refer to BA-3, replace methyl 6-aminohexanoate with 4-hydroxyphenethylamine

[0035] 99 mg of off-white solid, yield 78%. 1 H NMR (400 MHz, CDCl3) δ 7.05 (2H, d, J J =8.0 Hz, H 2, 5 of benzene), 6.81 (2H, d, J 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). 13 C 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. Synthesis of Example 5 BA-5

[0036] Dissolve BA-1 (500 mg, 0.915 mmol), benzoyl-protected glucose trichloroacetimidate donor (881 mg, 1.190 mmol) and powdered 4 Å molecular sieve (500 mg) in anhydrous DCM (16 mL). Under nitrogen protection, stir at room temperature for 0.5 h, then cool to 0 °C and add TMSOTf (22 μL, 0.119 mmol); stir the mixture at room temperature for 2.5 h, then quench the reaction with TEA (50 μL); filter the mixture, concentrate under reduced pressure, and perform silica gel column chromatography (petroleum ether:ethyl acetate = 12:1) to obtain BA-3-O-β-D-benzoyl-protected pyranoglucoside-28-benzyl ester (649 mg, 63%); mix it (649 mg, 0.576 mmol) with 10% Pd / C (65 mg), stir at room temperature overnight under normal pressure hydrogen; filter the mixture through diatomaceous earth, concentrate under reduced pressure, and perform silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to obtain BA-3-O-β-D-benzoyl-protected pyranoglucoside (471 mg, 79%); dissolve it (450 mg, 0.435 mmol) in methanol / DCM (10 mL / 10 mL), add sodium methoxide (142 mg, 2.610 mmol), stir the mixture at room temperature for 5 h; neutralize the mixture with DOWEX50WX2-100 ion exchange resin (H+), then filter, concentrate under reduced pressure, and perform silica gel column chromatography (DCM:methanol = 15:1) to obtain 197 mg of white powder with a yield of 73%. 1 H 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. Example 6 Synthesis of BA-6

[0037] The synthesis method of BA-3-O-β-D-benzoyl-protected glucopyranoside-28-benzyl ester was the same as that in Example 5; (649 mg, 0.576 mmol) of it 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 neutralized with DOWEX50WX2-100 ion exchange resin (H + ), then filtered, concentrated under reduced pressure, and silica gel column chromatography (DCM:methanol = 18:1) gave 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 = 4.2 Hz), 2.95 (2H, m), 2.18–2.07 (2H, m), 1.80 (2H, m), 1.63 (3H, s), 1.59–1.39 (7H, m), 1.36–1.18 (12H, m), 1.02 (2H, m), 0.94 (3H, s), 0.90 (3H, s), 0.84 (1H, m), 0.74 (3H, s), 0.72 (3H, s), 0.68 (3H, s). 13 C 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. Example 7 Synthesis of BA-7

[0038] 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 the crude product; after drying, it was redissolved in DCM, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM:methanol = 20:1) to obtain 108 mg of a white solid with a yield of 91%. 11H NMR (400 MHz, DMSO-d6) δ 8.19 (1H, d, J J = 8.4 Hz, H1 of benzene), 7.72 (1H, m, H2 of benzene), 7.64 (1H, d, J J = 8.3 Hz, H3 of benzene), 7.56 (1H, m, H4 of benzene), 4.85 (3H, m), 4.74 (1H, brs, H1-29), 4.63 (1H, brs, H2-29), 4.35 (1H, t, J J = 5.7 Hz), 4.16 (1H, d, J J = 7.7 Hz), 3.66 (1H, m), 3.43 (1H, m), 3.12 (1H, dd, J 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 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 13C 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 ): C42 H 60 N3O8 [M-H] - , Calculated value, 734.4386; Measured value, 734.4382. Synthesis of Example 8 BA-8

[0039] Dissolve BA-5 (50 mg, 0.081 mmol) in 2 mL of DMF. First, add TBTU (39 mg, 0.122 mmol) and DIEA (43 μL, 0.243 mmol), and stir at room temperature for 6 h. After the reaction is complete to form the intermediate, then add 4-hydroxyphenethylamine (17 mg, 0.122 mmol) and DIEA (72 μL, 0.405 mmol), and stir at room temperature overnight. After the reaction is completed, add 25 mL of water to the reaction solution to precipitate a white solid, and filter to obtain the crude product; after drying by suction, redissolve it in DCM, add anhydrous sodium sulfate for drying, filter, concentrate under reduced pressure, and perform silica gel column chromatography (DCM:methanol = 16:1) to obtain 53 mg of white solid, with a yield of 89%. 1 H NMR (400 MHz, CD3OD) δ7.44 (1H, t, J 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 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 J = 7.2 Hz), 2.55 (1H, m), 2.05 (1H, d, J J = 12.4 Hz), 1.94 (1H, d, J 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). 1313C 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, 760.4759; found, 760.4748. Example 9 Synthesis of BA-9 Refer to BA-5, replace β-D-glucopyranosyl with α-L-arabinopyranosyl

[0040] Off-white solid. 1 1H 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 J = 5.8 Hz, H-1 of Ara), 3.64(1H, dd, J J = 12.0, 3.2 Hz), 3.58 (1H, m), 2.95 (2H, m), 2.21 (1H, m), 2.11(1H, d, J 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). 1313C 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, 611.3918; found, 611.3895. Example 10 Synthesis of BA-10 Referring to BA-6, replace β-D-glucopyranosyl with α-L-arabinopyranosyl

[0041] Off-white solid. 1 1H 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 J = 5.9 Hz, H-1 of Ara), 3.65 (1H, dd, J J = 11.9, 3.2 Hz), 3.60 (1H, d, J 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). 1313C 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, 713.4179; found, 713.4177. Example 11 Synthesis of BA-11 Referring to BA-7, replace β-D-glucopyranosyl with α-L-arabinopyranosyl

[0042] Off-white solid, yield 92%. 1 1H NMR (400 MHz, DMSO-d6) δ 8.18 (1H, d, J J = 8.4 Hz, H1 of benzene), 7.71 (1H, t, J J = 7.6 Hz, H2 of benzene), 7.63 (1H, d, J J = 8.3 Hz, H3 of benzene), 7.55 (1H, t, J J = 7.7 Hz, H4 of benzene), 4.79 (1H, d, J 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 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. Example 12 Synthesis of BA-12 Referring to BA-8, replace β-D-glucopyranosyl with α-L-arabinopyranosyl

[0043] 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 2,5 of 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, 708.4834; found, 708.4811. Example 13 Synthesis of BA-13 Referring to BA-12, replace 4-hydroxyphenethylamine with methyl 6-aminocaproate

[0044] Off-white solid, yield 76%. 1 H NMR (400 MHz, CDCl3) δ 5.62 (1H, t, J J = 5.9Hz, -CONH), 4.73 (1H, brs, H1-29), 4.58 (1H, brs, H2-29), 4.38 (1H, d, J 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 J = 10.4 Hz), 3.28 (1H, m), 3.22–3.08 (4H, m), 2.44 (1H, m),2.31 (2H, t, J 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). 13 C 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 [M-H] - , Calculated value, 714.4950; Measured value, 714.4916. Example 14 Synthesis of BA-14 Refer to BA-5, replace β-D-glucopyranosyl with α-D-mannopyranosyl

[0045] 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 J =5.7 Hz), 3.60 (1H, m), 3.51 (1H, s), 3.46 (1H, d, J J = 9.1 Hz), 3.15 (2H, m),2.94 (1H, m), 2.22 (1H, t, J J = 11.0 Hz), 2.10 (1H, d, J J = 10.8 Hz), 1.78 (2H,q, J 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). 13C 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, 619.4205; found, 619.4210. Example 15 Synthesis of BA-15 Refer to BA-6, replace β-D-glucopyranosyl with α-D-mannopyranosyl

[0046] 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 J = 4.2 Hz), 4.65 (1H, d, J J = 4.2 Hz), 4.58 (1H, brs), 4.52 (1H, d, J J = 5.7 Hz), 4.36 (1H, t, J J = 5.7 Hz), 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. Example 16 Synthesis of BA-16 Referring to BA-7, replace β-D-glucopyranosyl with α-D-mannopyranosyl

[0047] 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. Example 17 The synthesis of BA-17 refers to BA-8, replacing β-D-glucopyranosyl with α-D-mannopyranosyl

[0048] A white solid, with a yield of 82%. 1 1H NMR (400 MHz, DMSO-d6) δ 9.14 (1H, s, phenol), 7.56 (1H, t, J J = 5.6 Hz, -CONH), 6.96 (2H, d, J J = 8.2 Hz, H 2,5 of benzene), 6.65 (2H, d, J 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 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 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). 13 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. Example 18 Synthesis of BA-18 Referring to BA-5, replace β-D-glucopyranosyl with β-D-xylopyranosyl

[0049] 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 J = 7.5 Hz, 1-H of Xyl), 3.63 (1H, dd, J 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). 13 C 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. Example 19 Synthesis of BA-19 Referring to BA-6, replace β-D-glucopyranosyl with β-D-xylopyranosyl

[0050] Off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.36 (5H, d, J J = 4.4 Hz, benzene), 5.09 (2H, d, J 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 J = 7.5 Hz, 1-H of Xyl), 3.63(1H, dd, J 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). 13 C 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, 713.4179; found, 713.4169. Example 20 Synthesis of BA-20 Refer to BA-7, replace β-D-glucopyranosyl with β-D-xylopyranosyl

[0051] A white solid, with a yield of 90%. 1 H NMR (400 MHz, DMSO-d6) δ 8.17 (1H, d, J J = 8.5Hz, H1 of benzene), 7.70 (1H, t, J J = 7.6 Hz, H2 of benzene), 7.62 (1H, d, J J =8.3 Hz, H3 of benzene), 7.54 (1H, t, J 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 J = 7.5 Hz,1-H of Xyl), 3.64 (1H, dd, J 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), 1.66–1.59 (2H, m), 1.57–1.45 (4H, m), 1.42-1.32 (5H, m), 1.31–1.21 (3H, m), 1.16–1.09 (1H, m), 1.02 (3H, s), 0.96 (3H, s), 0.88 (3H, s),0.75 (3H, s), 0.73 (3H, s). 1313C 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, 728.4245; found, 728.4210. Example 21 Synthesis of BA-21 Referring to BA-8, replace β-D-glucopyranosyl with β-D-xylopyranosyl

[0052] Off-white solid, yield 86%. 1 1H NMR (400 MHz, DMSO-d6) δ 9.11 (1H, s, phenol), 7.53 (1H, t, J J = 5.6 Hz, -CONH), 6.95 (2H, d, J J = 8.0 Hz, H 2,5 of benzene), 6.64 (2H, d, J 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 J = 7.6 Hz, 1-H of Xyl), 3.63 (1H, dd, J J = 11.3, 5.2 Hz), 3.23 (2H, m), 3.12 (1H, t, J 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. Example 22 Synthesis of BA-22 Referring to BA-5, replace β-D-glucopyranosyl with β-D-galactopyranosyl

[0053] 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. Example 23 Synthesis of BA-23 Refer to BA-6, replace β-D-glucopyranosyl with β-D-galactopyranosyl

[0054] 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). 13 C 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 [M-H] - , calculated value, 707.4528; measured value, 707.4510. Example 24 Synthesis of BA-24 Refer to BA-7, replace β-D-glucopyranosyl with β-D-galactopyranosyl

[0055] 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. Example 25 Synthesis of BA-25 Refer to BA-8, replace β-D-glucopyranosyl with β-D-galactopyranosyl

[0056] Off-white solid, yield 89%. 1 H NMR (400 MHz, DMSO-d6) 7.54 (1H, s, -CONH), 6.96 (2H, d, J J = 7.9 Hz, H 2,5 of benzene), 6.64 (2H, d, J J = 7.9 Hz, H 3,4 of benzene), 4.64 (1H, brs, H1-29), 4.53 (1H, brs, H2-29), 4.09 (1H, d, J J = 6.8Hz, 1-H of Gal), 3.61 (1H, s), 2.98 (2H, d, J J = 10.9 Hz), 2.07 (1H, d, J 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). 1313C 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] + , calcd, 738.4940; found, 738.4932. Example 26 Synthesis of BA-26

[0057] To a solution of BA (200 mg, 0.324 mmol) and the acetyl-protected -1-bromoglucose donor (234 mg, 0.570 mmol) in DCM / water (4 mL / 4 mL) was added potassium carbonate (152 mg, 1.094 mmol) and tetrabutylammonium bromide (56 mg, 0.176 mmol). The reaction mixture was stirred at room temperature for 6 h under a nitrogen atmosphere. After completion of the reaction, the mixture was diluted with DCM (50 mL), and then the organic phase was washed with water (30 mL×2) and dried over anhydrous sodium sulfate. It was concentrated under reduced pressure, and silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) gave BA-28-O-β-D-acetyl-protected glucopyranoside (224 mg, 88%); (200 mg, 0.257 mmol) of it, the benzoyl-protected L-arabinopyranose trichloroacetimidate donor (203 mg, 0.334 mmol) and powdered 4Å molecular sieve (300 mg) were dissolved in anhydrous DCM (8 mL). Under a nitrogen atmosphere, it was stirred at room temperature for 0.5 h, 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 silica gel column chromatography (petroleum ether:ethyl acetate = 5:2) gave 3-α-L-benzoyl-protected arabinopyranose-BA-28-O-β-D-acetyl-protected glucopyranoside (193 mg, 61%); (180 mg, 0.146 mmol) of it was dissolved in a mixed solution of methanol:tetrahydrofuran:water = 1:2:1, and sodium hydroxide (61 mg, 1.535 mmol) was added thereto. The reaction mixture was stirred at room temperature until the protecting groups were completely removed; after completion of 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) gave 76 mg of BA-26 as a white solid powder, 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 [M-H] - , calculated value, 749.4482; measured value, 749.4479. Synthesis of Example 27 BA-27

[0058] BA-13 (50 mg, 0.070 mmol) was dissolved in a mixed solution of methanol:tetrahydrofuran:water = 1:2:1. Sodium hydroxide (25 mg, 0.630 mmol) was added thereto, and the reaction solution was stirred at room temperature for 12 h; after the reaction was completed, the pH was adjusted to 4-5 with 1 mol / L hydrochloric acid solution, filtered and dried, redissolved in methanol, and purified by medium-pressure preparation (methanol:water = 85:15) to obtain 43 mg of an off-white solid with a yield of 88%. 1 H 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, 702.4940; found, 702.4920. Example 28 Synthesis of BA-28 Referring to BA-6, replace β-D-glucopyranosyl with α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranosyl

[0059] 2.55 g of white solid powder, with a yield of 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 J = 1.5 Hz, H-1 of Rha), 4.67(2H, d, J J = 3.5 Hz), 4.60–4.54 (3H, m), 4.46 (1H, d, J J = 6.0 Hz), 4.41 (1H,d, J J = 5.8 Hz), 4.20 (1H, d, J J = 6.5 Hz, 1-H of Ara), 3.93–3.85 (1H, m), 3.64(1H, dd, J 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). 1313C 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] + , calcd, 825.5147; found, 825.5138. Example 29 Synthesis of BA-29 Referring to BA-5, replace β-D-glucopyranosyl with α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranosyl

[0060] 1.45 g of white powder, yield 65%. 1 1H NMR (Pyridine-d5, 400 MHz) δ 5.96 (1H, d, J 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 J = 9.2, 7.4 Hz), 4.36–4.25 (3H, m), 4.13 (1H, dd, J J = 9.1, 3.6 Hz), 3.91–3.85 (1H, m), 3.75 (1H, d, J J = 12.0 Hz), 3.40 (1H, dd, J 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, 757.4497; found, 757.4491. Example 30 Synthesis of BA-30 Referring to BA-7, replace β-D-glucopyranosyl with α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranosyl

[0061] 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. Synthesis of Example 31 BA-31

[0062] Dissolve BA-29 (100 mg, 0.136 mmol), TBTU (65 mg, 0.204 mmol), and DIEA (71 μL, 0.408 mmol) in 4 mL of DMF, stir the reaction at room temperature for 5 h. After the reaction is complete to form the intermediate, add 4-(4-Aminophenethyl)phenol (28 mg, 0.204 mmol) and DIEA (119 μL, 0.680 mmol), stir overnight at room temperature. After the reaction is complete, add 40 mL of water to the reaction solution to precipitate a solid, and filter to obtain the crude product; the residue is subjected to silica gel column chromatography (DCM / methanol 12:1) to obtain 99 mg of a pale yellow solid, and the yield is 85%. 1 H NMR (400 MHz, DMSO-d6) δ 9.12 (1H, s, phenol), 7.47 (1H, t, J J =5.6 Hz, -CONH), 6.95 (2H, d, J J = 8.5 Hz, H 2,5 of benzene), 6.64 (2H, d, J J =8.5 Hz, H 3,4 of benzene), 4.90 (1H, brs, H-1 of Rha), 4.67 (1H, d, J J = 3.7Hz), 4.61–4.56 (2H, m), 4.46 (1H, d, J J = 5.8 Hz), 4.41 (1H, d, J J = 5.8 Hz),4.21 (1H, d, J 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 J = 5.1 Hz), 3.13–3.06 (2H, m), 2.16(1H, s), 2.07 (1H, d, J 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. Example 32 Synthesis of BA-32 Referring to BA-31, replace 4-hydroxyphenethylamine with methyl 6-aminohexanoate

[0063] 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 = 7.4 Hz), 2.14 (2H, m), 1.80–1.56 (4H, m), 1.52–1.44 (6H, m), 1.39–1.28 (9H, m), 1.28–1.11 (8H, m), 1.08 (3H, m), 1.01 (2H, m), 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 (101 MHz, 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, 879.5941; found, 879.5963. Example 33 Synthesis of BA-33 Referring to BA-12, replace 4-hydroxy phenethylamine with 2-hydroxy phenethylamine

[0064] 52 mg of pale 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). 13 C 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. Example 34 Synthesis of BA-34 Refer to BA-12 and replace 4-hydroxy phenethylamine with 3-hydroxy phenethylamine

[0065] Light brown solid, yield 92%. 1 H NMR (400 MHz, DMSO-d6) δ 9.22 (1H, s, phenol), 7.58 (1H, t, J 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 J = 12.2 Hz), 4.10(1H, d, J 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 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). 13CNMR (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] + , calcd, 730.4653; found, 730.4644. Example 35 Synthesis of BA-35 Referring to BA-12, p-Hydroxyphenethylamine was replaced with o-Methoxyphenethylamine

[0066] Off-white solid, yield 86%. 1 H NMR (400 MHz, DMSO-d6) δ 7.54 (1H, t, J J = 5.6Hz, -CONH), 7.17–6.83 (4H, m, benzene), 4.79 (1H, d, J J = 4.2 Hz), 4.64 (1H,brs, H1-29), 4.52 (1H, brs, H2-29), 4.48 (1H, d, J J = 5.0 Hz), 4.45 (1H, d, J J =4.3 Hz), 4.10 (1H, dd, J J = 5.7, 3.0 Hz, H-1 of Ara), 3.77 (3H, s, -OCH3),3.64 (1H, dd, J J = 12.0, 3.2 Hz), 3.58 (1H, m), 3.17 (2H, d, J J = 5.2 Hz), 2.98(2H, m), 2.69 (2H, m), 2.54 (1H, m), 2.07 (1H, d,J = 12.7 Hz), 1.76–1.64(3H, m), 1.61 (3H, s), 1.59–1.50 (3H, m), 1.40 (2H, m), 1.37–1.15 (11H, m),1.11 (1H, m), 0.93 (3H, s), 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. Example 36 Synthesis of BA-36 Refer to BA-12, replace 4-hydroxyphenethylamine with 3-methoxyphenethylamine

[0067] 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 of Ara), 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] + , calcd, 722.4990; found, 722.4964. Example 37 Synthesis of BA-37 Refer to BA-12, replace 4-hydroxyphenethylamine with 4-methoxyphenethylamine

[0068] 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). 13 C 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. Example 38 Synthesis of BA-38 Referring to BA-12, replace 4-Hydroxyphenethylamine with 4-Fluorophenethylamine

[0069] Light red-brown solid, yield 78%. 1 H NMR (400 MHz, DMSO-d6) δ 7.57 (1H, t, J 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 J = 10.6 Hz), 4.10 (1H, d, J J = 5.8 Hz, H-1 of Ara), 3.64 (1H, dd, J 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 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). 1313C 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, 744.4401; found, 744.4411. Example 39 Synthesis of BA-39 Refer to BA-12, replace 4-Hydroxyphenethylamine with 4-Bromophenethylamine

[0070] Light brown solid, yield 72%. 1 1H NMR (400 MHz, DMSO-d6) δ 7.53 (1H, t, J = 5.6 Hz, -CONH), 7.41 (2H, d, J = 7.9 Hz, H 2,5 of benzene), 7.14 (2H, d, J = 7.9 Hz, 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 [M-H] - , calculated value, 770.3834; found value, 770.3811. Example 40 Synthesis of BA-40 Refer to BA-12, replace 4-hydroxyphenethylamine with 4-(trifluoromethoxy)phenethylamine

[0071] Light brown solid, yield 65%. 1 H NMR (400 MHz, DMSO-d6) δ 7.59 (1H, t, J= 5.6 Hz, -CONH), 7.32 (2H, d, J = 8.3 Hz, H 2,5 of benzene), 7.24 (2H, d, J = 8.3 Hz, 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. Example 41 Synthesis of BA-41 Refer to BA-12, replace p-hydroxyphenethylamine with p-hydroxybenzylamine

[0072] Off-white solid, yield 95%. 1 H NMR (400 MHz, DMSO-d6) δ 8.00 (1H, t, J J = 6.0Hz, -CONH), 7.02 (2H, d, J J = 8.0 Hz, H 2,5 of benzene), 6.65 (2H, d, J J = 8.0Hz, H 3,4 of benzene), 4.53 (1H, s), 4.19 (1H, dd, J J = 14.7, 5.9 Hz), 4.11 (1H,d, J J = 5.9 Hz, H- 1 of Ara), 4.02 (1H, dd, J J = 14.7, 5.8 Hz), 3.64 (1H, dd, J 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 J = 12.3 Hz), 1.79 (1H, dd, J J = 11.5, 7.6 Hz), 1.70 (2H, t, J 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 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). 1313C 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, 716.4497; found, 716.4473. Example 42 Synthesis of BA-42 Refer to BA-12, replace 4-hydroxyphenethylamine with 3,4-dihydroxyphenethylamine

[0073] Light red-brown solid, yield 84%. 1 1H NMR (400 MHz, DMSO-d6) δ 8.68, 8.59 (each 1H, s, phenol), 7.52 (1H, t, J J = 5.7 Hz, -CONH), 6.58–6.39 (3H, m, benzene), 4.77(1H, d, J 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 J = 6.0 Hz, H-1 of Ara), 3.62 (1H, dd, J 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, J= 12.5 Hz), 1.72–1.64 (3H, m), 1.60 (3H, s), 1.59–1.50 (4H, m), 1.45–1.15 (15H, m), 1.10 (1H, m), 0.97 (3H, s), 0.91 (3H, s), 0.87 (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 [M-H] - , calculated value, 722.4637; measured value, 722.4627. Example 43 Synthesis of BA-43 Referring to BA-12, replace 4-hydroxyphenethylamine with 3,4-difluorophenethylamine

[0074] 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, 728.4702; found, 728.4703. Example 44 Synthesis of BA-44 Refer to BA-13, replace methyl 6-aminohexanoate with ethyl 6-aminohexanoate

[0075] 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] + , Calcd, 752.5072; Found, 752.5055. Example 45 Synthesis of BA-45 Referring to BA-13, methyl 6-aminocaproate was replaced with tert-butyl 6-aminocaproate

[0076] Off-white solid, yield 90%. 1 H NMR (400 MHz, DMSO-d6) δ 7.53 (1H, t, J J = 5.8Hz, -CONH), 4.79 (1H, d, J J = 4.2 Hz), 4.64 (1H, brs, H1-29), 4.52 (1H, brs,H2-29), 4.48 (1H, d, J J = 5.1 Hz), 4.45 (1H, d, J J = 4.3 Hz), 4.10 (1H, d, J J =5.9 Hz, H-1 of Ara), 3.64 (1H, dd, J 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 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). 1313C 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] + , calcd, 758.5566; found, 758.5537. Example 46 Synthesis of BA-46 Referring to BA-13, methyl 6-aminocaproate was replaced with 6-aminocapronitrile

[0077] Off-white solid, yield 91%. 1 1H NMR (400 MHz, DMSO-d6) δ 7.56 (1H, t, J J = 5.8Hz, -CONH), 4.64 (1H, brs, H1-29), 4.52 (1H, brs, H2-29), 4.10 (1H, d, J J = 6.0Hz, H-1 of Ara), 3.63 (1H, dd, J J = 12.0, 3.2 Hz), 3.58 (1H, q, J 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, 705.4813; found, 705.4793. Example 47 Synthesis of BA-47 Refer to BA-13, replace methyl 6-aminocaproate with methyl 5-aminovalerate

[0078] 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. Example 48 Synthesis of BA-48

[0079] Dissolve BA-47 (50 mg, 0.071 mmol) in a mixed solution of methanol:tetrahydrofuran:water = 1:2:1. Add sodium hydroxide (26 mg, 0.639 mmol) to it, and stir the reaction solution at room temperature for 6 h. After the reaction is completed, adjust the pH to 4 - 5 with 1 mol / L hydrochloric acid solution, filter and dry. Redissolve it in methanol and purify it by medium-pressure preparation (methanol:water = 85:15) to obtain 44 mg of 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. Example 49 Synthesis of BA-49 Refer to BA-13, replace methyl 6 - aminocaproate with methyl 4 - aminobutyrate

[0080] White solid, yield 91%. 1 H NMR (400 MHz, DMSO - d6) δ 7.60 (1H, t, J 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 J = 5.9 Hz, H - 1 of Ara), 3.64 (1H, dd, J 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 J =12.7, 3.4 Hz), 2.27 (2H, t, J J = 7.5 Hz), 2.11 (1H, d, J 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). 1313C 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, 710.4602; found, 710.4568. Example 50 Synthesis of BA-50 Refer to BA-48, replacing aminovaleric acid with aminobutyric acid

[0081] White solid, yield 88%. 1 1H NMR (400 MHz, DMSO-d6) δ 7.60 (1H, t, J J = 5.8Hz, -CONH), 4.65 (1H, brs, H1-29), 4.53 (1H, brs, H2-29), 4.11 (1H, d, J J = 5.9Hz, H-1 of Ara), 3.64 (1H, dd, J J = 12.0, 3.2 Hz), 3.59 (1H, d, J J = 3.5 Hz), 3.09 (1H, dd, J 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, 712.4185; found, 712.4161. Example 51 Synthesis of BA-51 Referring to BA-13, methyl 6-aminocaproate was replaced with methyl 3-aminopropionate

[0082] White solid, yield 94%. 1 H NMR (400 MHz, DMSO-d6) δ 7.68 (1H, t, J J = 5.7 Hz, -CONH), 4.79 (1H, d, J J = 4.3 Hz), 4.67 (1H, brs, H1-29), 4.55 (1H, brs, H2-29), 4.48 (1H, d, J J = 5.3 Hz), 4.46 (1H, d, J J = 4.4 Hz), 4.13 (1H, d, J J = 6.0 Hz, H-1 of Ara), 3.66 (1H, dd, J J = 12.0, 3.3 Hz), 3.62 (1H, d, J J = 5.7 Hz), 3.59 (3H, s, -OCH3), 3.25–3.17 (1H, m), 3.00 (2H, m), 2.57 (1H, d, J J = 14.5 Hz), 2.46 (2H, t, J J = 6.7 Hz), 2.09 (1H, d,J = 12.2 Hz), 1.77–1.70 (3H, m), 1.64 (3H, s), 1.60–1.54 (3H, m), 1.49–1.21 (13H, m), 1.15 (1H, m), 1.02(1H, m), 0.96 (3H, s), 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. Example 52 Synthesis of BA-52 Refer to BA-48, replacing aminovaleric acid with aminopropionic acid

[0083] White solid, yield 91%. 1 H 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, 660.4475; found, 660.4479. Example 53 Synthesis of BA-53 Refer to BA-13, replace methyl 6-aminohexanoate with methyl (1R,3S)-3-aminocyclopentanecarboxylate

[0084] White solid, yield 78%. 1 H 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. Example 54 Synthesis of BA-54 Refer to BA-48, replace aminovaleric acid with (1R,3S)-3-aminocyclopentanecarboxylic acid

[0085] 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. Example 55 Synthesis of BA-55

[0086] Dissolve BA-47 (50 mg, 0.071 mmol) in a mixed solution of methanol:tetrahydrofuran:water = 1:2:1, add sodium hydroxide (26 mg, 0.639 mmol) thereto, and stir the reaction solution at room temperature for 6 h; after the reaction is completed, adjust the pH to 8 - 9 with 1 mol / L hydrochloric acid solution, filter and dry, redissolve with methanol, and perform medium-pressure preparation (methanol:water = 75:25) to obtain 43 mg of white solid, with a yield of 85%. 11H 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 of Ara), 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). 13 13C NMR (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. Test Example 1

[0087] THP-1 macrophages at 1×10 4Cells were seeded at 5 cells / well in a 96-well plate at a volume of 100 μL / well and cultured routinely. After the cells reached 80% confluence, they were induced with 100 ng / mL phorbol 12-myristate 13-acetate (PMA) for 12 h, and then the original medium was discarded and 100 μL of fresh complete medium was added. A medium-only well was set as the zero control, and a normal group without any drugs was also set. 1 μL of betulinic acid-type 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. The plate was incubated in an incubator for 24 h. After incubation, 10 μL of CCK-8 was added to each well and incubated in the dark for 4 h. The absorbance of each well was measured at a wavelength of 450 nm using a microplate reader, and the cell viability of each well was calculated. Cell viability (%) = [A (drug-treated) - A (blank)] / [A (drug-free) - A (blank)] × 100, where A (drug-treated) is the absorbance of the well with cells, CCK-8, and drug solution; A (blank) is the absorbance of the well with medium and CCK-8 but without cells; A (drug-free) is the absorbance of the well with cells and CCK-8 but without drugs. The results are shown as Figures 1 - 2 follows. As Figures 1 - 2 shown, 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, BA-55) did not show significant cytotoxicity to THP-1 macrophages at 50 μM, and 3 compounds (BA-29, BA-31, BA-32) did not show significant cytotoxicity to THP-1 macrophages at 10 μM.

[0088] Test Example 2

[0089] THP-1 cells were seeded at 2×10 5 cells / well in a 6-well plate and cultured routinely. After the cells reached 80% confluence, they were induced with 100 ng / mL PMA for 12 h, and then the original medium was discarded and fresh complete 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 betulinic acid-type saponin derivatives (10 μM) for 1 h. After 1 h, 1 μg / mL lipopolysaccharide (LPS) was added to all groups except the blank group and incubated for 24 h. The culture supernatant was collected, and the levels of IL-6, IL-1β, and TNF-α were measured and calculated using ELISA. The results are shown in Table 1: Table 1

[0090] aData are presented as "mean ± standard error" based on at least 3 independent experiments, with 3 replicates in each experiment. NA indicates that no significant effect was observed.

[0091] As can be seen from Table 1, most betulinic acid-type saponin derivatives significantly inhibited the secretion of pro-inflammatory factors IL-6, IL-1β, and TNF-α in LPS-induced THP-1 macrophages, and their activities were superior to BA. Among them, the inhibitory activities of BA-42, BA-48, BA-52, and BA-55 on IL-6 secretion were the most significant, and the inhibition rates were all above 60%.

[0092] Test Example 3

[0093] After weighing, 63 male C57BL / 6 mice aged 6 - 8 weeks were randomly divided into 9 groups (n = 7 in each group): normal group, model group, mesalazine group, betulin group, betulinic acid group, BA-42 group, BA-48 group, BA-52 group, BA-55 group; due to the poor water solubility of betulin, betulinic acid, BA-42, BA-48, BA-52, and BA-55, they were respectively prepared into hydroxypropyl-β-cyclodextrin inclusion complexes for this test; the mice were weighed one day before modeling, and mesalazine, betulin, betulinic acid, BA-42, BA-48, BA-52, and BA-55 were given; then DSS was dissolved in the drinking water of the mice, and the mice in the model group and the drug administration groups were continuously given 3% DSS for 8 days; after modeling, the mice were weighed every day, and administered drugs by gavage once a day according to their body weights; the mice in the normal group were gavaged with normal saline once a day, and the mice in the model group were gavaged with the solvent once a day; the body weights were measured every day, the fecal traits of the mice were observed, and the occult blood / hematochezia conditions of the mice were checked, and the DAI scores were calculated. The results are as Figure 3 shown. From Figure 3It can be seen that the body weight of the mice in the DSS group began to decline from the 4th day until the end of the experiment. Compared with the DSS group, after treatment with mesalazine, betulin, betulinic acid, BA-42, BA-48, BA-52, and BA-55, the symptoms were significantly improved. The mesalazine group was only statistically significant on the 6th day (P<0.001); the betulin group was only statistically significant on the 5th day (P<0.001) and the 6th day (P<0.01); the betulinic acid group was only statistically significant 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-49 group was only statistically significant on the 4th day (P<0.001) and the 6th day (P<0.01); the BA-52 group showed a significant improvement trend on the 6th day (P<0.01), the 7th day (P<0.001), and the 8th day (P<0.001); the BA-55 group was statistically significant on the 4th day (P<0.001), the 5th day (P<0.01), and the 6th day (P<0.01), but not statistically significant on the 7th and 8th days. After administration of DSS, from the fourth day, symptoms of rectal bleeding and diarrhea were observed in all DSS-treated mice, and the DAI score of the DSS group also increased significantly. However, treatment with mesalazine, betulin, betulinic acid, BA-42, BA-48, BA-52, and BA-55 could significantly reduce the DAI score and relieve the symptoms of diarrhea and bloody stools. Compared with the DAI score results of the mice in the DSS group, the mesalazine group was statistically significant on the 6th day (P<0.05) and the 8th day (P<0.001); the betulin group was only statistically significant on the 6th day (P<0.05) and the 8th day (P<0.05); the betulinic acid group was only statistically significant on the 6th day (P<0.01) and the 8th day (P<0.001); the BA-42 group was statistically significant 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 was statistically significant on the 4th day (P<0.01), the 5th day (P<0.001), the 6th day (P<0.001), the 7th day (P<0.001), and the 8th day (P<0.001); the BA-52 group was statistically significant on the 4th day (P<0.05), the 5th day (P<0.001), the 6th day (P<0.001), the 7th day (P<0.001), and the 8th day (P<0.001); the BA-55 group was statistically significant on the 4th day (P<0.05), the 5th day (P<0.001), the 6th day (P<0.001), the 7th day (P<0.05), and the 8th day (P<0.001), and the symptoms of loose stools and bloody stools on the 7th and 8th days were significantly aggravated.Among them, the activities of the BA-42 group and the BA-52 group were the most significant, and they had better curative effects than mesalazine in improving weight loss and alleviating diarrhea and bloody stool symptoms.

[0094] The mice were sacrificed after administration on the 9th day, and the colon was taken to measure the colon length. The results are as Figure 4 shown. It can be seen from Figure 4 that the colon length of the mice in the DSS-induced model group was significantly shorter than that in the normal group (P<0.001). After treatment with mesalazine, betulin, BA-42, BA-48, BA-52, and BA-55, the colon length of the mice was increased to varying degrees. There were significant differences between the BA derivatives BA-42, BA-48, BA-52, and BA-55 and the DSS group (P<0.001), and their curative effects on alleviating the shortening of the colon length were not weaker than those of mesalazine.

[0095] The mice were sacrificed after administration on the 9th day, and the spleen was taken to weigh the spleen weight. The results are as Figure 5 shown. It can be seen from Figure 5 that compared with the normal group, the spleen index of the mice in the model group was significantly increased, and there was a statistical significance in its value compared with the normal group (P<0.001). Compared with the model group, the mesalazine group did not relieve splenomegaly in mice; the spleen index of the betulinic acid group was lower than that of the mice treated with DSS (P<0.05); the spleen index of the BA-55 group was significantly decreased and there was a statistical significance compared with the spleen index of the model group (P<0.01, P<0.05). It shows that betulinic acid-type saponin derivatives play a role in protecting the colon from inflammatory damage, and among them, the activity of BA-52 is the most significant.

[0096] In summary, the inhibitory effects of betulinic acid-type saponin derivatives on IBD are better than those of their parent nuclei B and BA themselves, indicating that the inhibitory activity of BA series saponin derivatives on DSS-induced IBD is possessed by their original molecular structure forms, rather than because they are degraded into BA parent nuclei in vivo to exert curative effects. Among them, the activity of BA-52 is the most significant, and it has a better curative effect than mesalazine in improving weight loss and alleviating diarrhea and bloody stool symptoms.

[0097] Test Example 4

[0098] To evaluate the safety of BA-52, a 7-day repeated-dose toxicity test was conducted on ICR mice. BA-52 was administered by oral gavage at a dose of 200 mg / kg once a day for 7 consecutive days. The results of the toxicity test are as Figure 6 shown. It can be seen from Figure 6It can be seen that within 8 days after drug administration, compared with the control group (excipient), no obvious weight loss or adverse reactions were observed in the BA-52 group, such as abnormal behavior, food and water intake, and digestive system disorders. Subsequently, on the 8th day, the mice were sacrificed and organ samples were collected for analysis, and no significant changes were found in the organ indices of the mice. This indicates that BA-52 has good in vivo safety.

[0099] Test Example 5

[0100] THP-1 cells were pretreated with different concentrations of BA-52 for 1 h, and then stimulated with LPS (1 μg / mL) for 24 h. The supernatant was collected, and the contents of inflammatory cytokines IL-6, IL-1β, and TNF-α were detected by an ELISA kit. The results are as Figure 7 shown. It can be Figure 7 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.

[0101] Test Example 6

[0102] Forty-two 6-8-week-old male C57BL / 6 mice were randomly divided into 6 groups (n = 7 per 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 depilatory cream, and an area of about 3 cm × 3 cm was selected for each mouse for later use. On the 1st and 2nd days, except for the normal group, the other groups were sensitized by applying 50 μL of 5% DNCB to the back of the mice. On the 3rd, 4th, and 5th days, 50 μL of 1% DNCB was applied to the inner and outer surfaces of the right auricle of the mice with a pipette for elicitation, and an equal amount of acetone matrix was applied to the inner surface of the left auricle. On the 1st - 2nd days, the dexamethasone group applied 0.05 g of dexamethasone to the back of the mice at 4 pm. From the 3rd - 7th days, a total of 0.08 g of dexamethasone cream was applied to the back, inner and outer surfaces of the right ear of the mice. On the 1st - 2nd days, the BA-52 (2.5 mg / kg), BA-52 (5 mg / kg), and BA-52 (10 mg / kg) treatment groups applied 200 μL of the drug-containing solution to the back of the mice at 10 am and applied it again at 4 pm. From the 3rd - 7th days, the BA-52 (2.5 mg / kg), BA-52 (5 mg / kg), and BA-52 (10 mg / kg) treatment groups applied 200 μL of the drug-containing solution to the back of the mice at 10 am, and 50 μL of the drug-containing solution was applied to the inner and outer surfaces of the right ear respectively, and the back and right ear were applied again at 4 pm. The model group applied an equal amount of a mixed solvent of ethanol: water: glycerol (70:28:2) to the back, inner and outer surfaces of the right ear of the mice at the same time as above to keep the overall behavior consistent with the treatment groups. On the 8th day, the mice were sacrificed, and the spleen and auricles of the mice were taken to calculate the spleen index and ear weight difference (ear discs were obtained by punching the same part with a 6 mm diameter punch and weighed).

[0103] During the experiment, the eczema conditions (obvious redness, maculopapules, erosion, and exudation on the skin) of the back skin of each group of mice were observed and photographed every day. Referring to the clinical symptoms of the skin of each group of mice, the eczema area and severity index (EASI) scoring standard was used to evaluate from 4 indicators: erythema, papules / pustules, scales, and crusts, and the scores were recorded from 0 - 3 points: 0 points = no symptoms; 1 point = mild; 2 points = moderate; 3 points = severe. The integral of each indicator was added to obtain the total integral. Two observers scored blindly on the 1st, 3rd, 5th, and 7th days of the intervention respectively, and digital photography was used for recording. Twenty-four hours after the last administration, the thickness of both ears was measured with a vernier caliper (the average value was taken after measuring 3 points), 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 were as Figures 8 - 11 shown. It can be seen from Figures 8 - 9 that after the first application of DNCB on the 3rd day, compared with the blank group, after applying DNCB to the back skin of the model group, exudation, erosion, and crusting occurred on the skin, and eczema-like skin lesions were produced (Figure 8 ). During the model establishment process, when weighing the body weight of the mice, it was found that no significant weight loss was observed in the BA-52 group, while obvious weight loss was observed in the dexamethasone group, indicating that BA-52 has good safety characteristics in vivo ( Figure 9 ). After DNCB was applied to the back skin of the mice, compared with the blank group, the skin of the model group showed exudation, erosion and crusting, and produced eczema-like skin lesions. With the continuous action of the drug, the skin lesions in the model group became increasingly severe from the 2nd to 3rd day, with obvious erythema, obvious skin infiltration and crusting. The comprehensive EASI scores of the control group and the model group on the 3rd, 5th and 7th days (P<0.001) were all statistically significant, indicating that the eczema mouse model was successfully established; compared with the model group, the skin lesions of the low, medium and high-dose BA-52 administration groups were significantly reduced at the same stage, the skin was smoother, the exudation was less, and the crusting was mild or fell off earliest; the skin of the dexamethasone group had more severe crusting, and almost no crust fell off, with obvious scales and papules; among them, the differences in the comprehensive EASI scores between the model group and the normal group were statistically significant on the 3rd day (P<0.001), 5th day (P<0.001), and 7th day (P<0.001); there were no statistical differences in the comprehensive EASI scores between the dexamethasone group and the model group on the 3rd day, 5th day, and 7th day. Compared with the model group, the back scores of the BA-52 (2.5mg / kg), BA-52 (5mg / kg) and BA-52 (10mg / kg) groups were all statistically significant. DNCB caused slight redness of the auricular skin. The redness and swelling in the model group became increasingly severe from the 4th day, with desquamation, and exudation, ulceration and crusting began on the 5th day ( Figure 9 ). From Figures 10 - 11 it can be seen that the difference in the thickness of the left and right ears between the control group and the model group on the 7th day (P<0.001) was statistically significant, indicating that the eczema mouse model was successfully established. Compared with the model group, the ear swelling symptoms of the low, medium and high-dose BA-52 groups were significantly reduced at the same stage, and there was almost no ulceration of the ears; the effect of the dexamethasone positive drug group was slightly worse, with some exudation and crusting; among them, the differences in the thickness of the left and right ears between the dexamethasone group, BA-52 (2.5mg / kg), BA-52 (5mg / kg) and BA-52 (10mg / kg) groups and the model group on the 7th day (P<0.001) were all statistically significant; after 7 days of administration, the spleen index of the mice in the model group increased significantly. Compared with the model group, the spleen index of the dexamethasone group was significantly lower than that of the normal group, indicating that dexamethasone produced immunosuppression in the mice. The spleen index of the mice in the BA-52 (10mg / kg) group decreased significantly, while the low-dose BA-52 group did not show a statistical difference from the model group, indicating that BA-52 can improve the immunity of the mice ( Figure 11). It can be seen that BA-52 has a protective effect on the eczema skin lesions caused by DNCB, and it is superior to glucocorticoids in improving erythema, scaling, edema, and epidermal exfoliation of the back skin of mice, and has higher safety.

[0104] Obviously, the above embodiments are only examples for clear illustration and are not limitations on the implementation manners. For those of ordinary skill in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to enumerate all implementation manners here. And the obvious changes or modifications derived therefrom are still within the protection scope of the present invention.

Claims

1. A betulinic acid-type saponin derivative, characterized in that, The structural general formula is as follows: ， wherein, R 1 is selected from hydroxy or -O-G, and G is a monosaccharide; R 2 Selected from benzyloxy, 1-O-benzotriazole, methyl 6-aminocaproate, 6-aminocaproic acid, 4-hydroxyphenethylamine, 28-O-β-D-glucopyranose, o-hydroxyphenethylamine, m-hydroxyphenethylamine, o-methoxyphenethylamine, m-methoxyphenethylamine, p-methoxyphenethylamine, p-bromophenethylamine, p-fluorophenethylamine, p-hydroxybenzylamine, 3,4-difluorophenethylamine, p-trifluoromethoxyphenethylamine, 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 formate.

2. The betulinic acid type saponin derivative according to claim 1, wherein, 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.

3. A method for preparing a betulinic acid-type saponin derivative as described in any one of claims 1-2, characterized in that, It includes the following steps: Using betulinic acid as a raw material, the betulinic acid-type saponin derivative is prepared through glycosylation reaction, esterification reaction or amidation reaction.

4. A pharmaceutically acceptable salt of the betulinic acid-type saponin derivative according to any one of claims 1-2.

5. A pharmaceutical composition, characterized in that, The active ingredient of the pharmaceutical composition is the betulinic acid-type saponin derivative according to any one of claims 1-2, and the pharmaceutically acceptable salt of the betulinic acid-type saponin derivative according to claim 4.

6. Use of the betulinic acid-type saponin derivative according to any one of claims 1-2, the pharmaceutically acceptable salt of the betulinic acid-type saponin derivative according to claim 4, and the pharmaceutical composition according to claim 5 in the preparation of a drug for treating inflammation-related diseases.

7. The application according to claim 6, wherein The inflammation-related diseases are one or more of pneumonia, hepatitis, nephritis, gastritis, cholecystitis, pharyngitis, conjunctivitis, keratitis, otitis media, appendicitis, cervicitis, encephalitis, peritonitis, arthritis, stomatitis, enteritis and skin inflammation.

8. The application according to claim 7, 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.

9. Use of the betulinic acid-type saponin derivative according to any one of claims 1-2, the pharmaceutically acceptable salt of the betulinic acid-type saponin derivative according to claim 4, and the pharmaceutical composition according to claim 5 in the preparation of a drug for treating autoimmune diseases.

10. The application according to claim 9, characterized in that, The autoimmune diseases include 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, Sjogren's syndrome, polymyositis / dermatomyositis, lupus erythematosus and Hashimoto's thyroiditis.

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