Amphotericin b saturated heterocyclic derivative and use thereof

Abstract

Provided in the present invention are an amphotericin B saturated heterocyclic derivative and the use thereof. The amphotericin derivative is as represented by formula (I). The compound of the present invention exhibits a good inhibitory effect on the growth of Candida albicans, Aspergillus fumigatus, and Aspergillus flavus.

Description

A saturated heterocyclic derivative of amphotericin B and its applications Technical Field

[0001] This invention relates to the pharmaceutical field, and more specifically, to an amphotericin B saturated heterocyclic derivative and its applications. Background Technology

[0002] In recent years, the incidence and severity of opportunistic deep organ fungal infections have increased due to the rapid increase in the immunocompromised population, the prevalence of malignant tumors, hematological malignancies, AIDS, SARS, diabetes, severe burns, the widespread use of broad-spectrum antibiotics and immunosuppressants, and the development of new technologies such as catheterization, intubation, and organ transplantation. The incidence of deep fungal infections in the aforementioned populations is approximately 11%-40%, with a mortality rate of 40%. While the incidence of deep fungal infections is much lower than that of superficial fungal infections, they are more concerning because of their extremely high mortality rate, with approximately 1.5 million deaths annually. Over 90% of all reported fungal-related deaths are caused by species belonging to one of the following four groups: Cryptococcus, Candida, Aspergillus, and Pneumocystis. Furthermore, the epidemiological data for fungal infections are very poor, and they are frequently misdiagnosed because the danger of deep fungal infections is significantly underestimated.

[0003] Amphotericin B is an organic compound with the chemical formula C. 47 H 73 NO 17 Amphotericin B is a polyene antifungal drug. Fungi sensitive to this drug include Cryptococcus neoformans, Blastomyces dermatitidis, Histoplasma capsulatum, Coccidioides spp., Sporothrix spp., and Candida spp. Some Aspergillus species are resistant to this drug, and most dermatophytes and Trichophyton mentagrophytes are also resistant. It has no antimicrobial activity against bacteria, rickettsiae, or viruses. The commonly used therapeutic doses only achieve bacteriostatic effects against fungi. Amphotericin B is highly toxic and may cause reactions such as fever, chills, headache, loss of appetite, nausea, and vomiting. Intravenous administration can cause thrombophlebitis, and intrathecal injection can cause back and lower limb pain.

[0004] Although studies have shown that liposomes, as drug carriers, can significantly reduce the toxic side effects of amphotericin B, a novel drug with targeted drug delivery capabilities is made by encapsulating drug molecules in vesicles formed by a phospholipid bilayer membrane. Compared to conventional formulations, it exhibits better tolerability. On one hand, it can be more widely distributed in the liver, spleen, and lungs, while its concentration in other organs, especially the kidneys, is lower. On the other hand, the cholesterol component in liposomes can reduce the binding of the drug to cholesterol in human cells and enhance its binding to ergosterol in fungal cells, resulting in relatively fewer side effects on the kidneys. However, liposomal formulations of amphotericin B also have the following drawbacks: 1. The antibacterial activity of liposomal formulations is weaker than that of amphotericin B, requiring higher therapeutic doses; 2. Liposome formulations are more expensive; 3. Liposomes themselves are unstable; 4. Liposome formulations do not fundamentally eliminate the nephrotoxicity and other toxic side effects of amphotericin B.

[0005] Although various structural modifications of amphotericin B have been reported in the literature, it is still necessary to develop new amphotericin B derivatives that can maintain antibacterial activity while reducing its nephrotoxicity, erythrocyte hemolytic toxicity, etc., and also solve the problem of poor water solubility of amphotericin B. Summary of the Invention

[0006] One object of the present invention is to provide a saturated heterocyclic derivative of amphotericin B.

[0007] Another object of the present invention is to provide a pharmaceutical composition.

[0008] Another object of the present invention is to provide the application of the aforementioned amphotericin B saturated heterocyclic derivative.

[0009] To achieve the above objectives, in one respect, the present invention provides an amphotericin B saturated heterocyclic derivative, wherein the amphotericin B saturated heterocyclic derivative is as shown in formula (I):

[0010] L1 and L2 are each independently selected from the key or C. 1-10 Alkylene; optionally, the alkylene group is selected from F, Cl, Br, I, hydroxyl, nitro, cyano, carboxyl, C 1-5 Substituents of alkyl groups;

[0011] X is selected from O, S, or -N(R2)-;

[0012] R1 and R2 are each independently selected from H or C. 1-10 Alkyl group; optionally, the alkyl group is selected from F, Cl, Br, I, hydroxyl, nitro, cyano, carboxyl, C 1-5 Substituents of alkyl groups;

[0013] Ring A is selected from 3- to 10-membered heterocyclic alkyl groups; the heterocyclic alkyl group contains 1, 2, or 3 heteroatoms selected from N, O, or S; optionally, the heterocyclic alkyl group is selected from F, Cl, Br, I, hydroxyl, nitro, cyano, carboxyl, C. 1-6 Alkyl, C 1-6 Alkoxy group, -C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -C(O)OC 1-6 Alkyl-OC 1-6 Alkyl groups are substituted.

[0014] According to some specific embodiments of the present invention, wherein,

[0015] L1 and L2 are each independently selected from the key or C. 1-5 Alkylene; optionally, the alkylene group is selected from F, Cl, Br, I, hydroxyl, nitro, cyano, carboxyl, C 1-3 Substituents of alkyl groups;

[0016] X is selected from O, S, or -N(R2)-;

[0017] R1 and R2 are each independently selected from H or C. 1-5 Alkyl group; optionally, the alkyl group is selected from F, Cl, Br, I, hydroxyl, nitro, cyano, carboxyl, C 1-3 Substituents of alkyl groups;

[0018] Ring A is selected from 3- to 8-membered heterocyclic alkyl groups; the heterocyclic alkyl group contains 1, 2, or 3 heteroatoms selected from N, O, or S; optionally, the heterocyclic alkyl group is selected from F, Cl, Br, I, hydroxyl, nitro, cyano, carboxyl, C. 1-5 Alkyl, C 1-6 Alkoxy group, -C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -C(O)OC 1-6 Alkyl-OC 1-6 Alkyl groups are substituted.

[0019] According to some specific embodiments of the present invention, wherein,

[0020] L1 is selected from key or C 1-5 Alkylene; optionally, the alkylene group is selected from F, Cl, Br, I, hydroxyl, nitro, cyano, carboxyl, C 1-3 Substituents of alkyl groups;

[0021] L2 is C 1-5 Alkylene; optionally, the alkylene group is selected from F, Cl, Br, I, hydroxyl, nitro, cyano, carboxyl, C1-3 Substituents of alkyl groups;

[0022] X is selected from O, S, or -N(R2)-;

[0023] R1 and R2 are each independently selected from H or C. 1-5 Alkyl group; optionally, the alkyl group is selected from F, Cl, Br, I, hydroxyl, nitro, cyano, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy group, -C(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, -C(O)OC 1-3 Alkyl-OC 1-3 Alkyl groups are substituted.

[0024] According to some specific embodiments of the present invention, wherein,

[0025] L1 is selected from key or C 1-3 Alkylene; optionally, the alkylene group is selected from F, Cl, Br, I, hydroxyl, nitro, cyano, carboxyl, C 1-3 Substituents of alkyl groups;

[0026] L2 is C 1-5 Alkylene; optionally, the alkylene group is selected from F, Cl, Br, I, hydroxyl, nitro, cyano, carboxyl, C 1-3 Substituents of alkyl groups;

[0027] X is selected from O, S, or -N(R2)-;

[0028] R1 and R2 are each independently selected from H or C. 1-3 Alkyl group; optionally, the alkyl group is selected from F, Cl, Br, I, hydroxyl, nitro, cyano, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy group, -C(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, -C(O)OC 1-3 Alkyl-OC 1-3 Substituents of alkyl groups;

[0029] Ring A is selected from 3- to 6-membered heterocyclic alkyl groups; the heterocyclic alkyl group contains 1, 2, or 3 heteroatoms selected from N, O, or S; optionally, the heterocyclic alkyl group is selected from F, Cl, Br, I, hydroxyl, nitro, cyano, carboxyl, C 1-5 Alkyl groups are substituted.

[0030] According to some specific embodiments of the present invention, wherein,

[0031] L1 is selected from key or C1-3 Alkylene; optionally, the alkylene group is selected from F, Cl, Br, I, hydroxyl, nitro, cyano, carboxyl, C 1-3 Substituents of alkyl groups;

[0032] L2 is C 1-5 Alkylene; optionally, the alkylene group is selected from F, Cl, Br, I, hydroxyl, nitro, cyano, carboxyl, C 1-3 Substituents of alkyl groups;

[0033] X is selected from O or S;

[0034] R1 is selected from H or C. 1-3 Alkyl group; optionally, the alkyl group is selected from F, Cl, Br, I, hydroxyl, nitro, cyano, carboxyl, C 1-3 Substituents of alkyl groups;

[0035] Ring A is selected from 3- to 6-membered heterocyclic alkyl groups; the heterocyclic alkyl group contains 1, 2, or 3 heteroatoms selected from N, O, or S; optionally, the heterocyclic alkyl group is selected from F, Cl, Br, I, hydroxyl, nitro, cyano, carboxyl, C 1-5 Alkyl groups are substituted.

[0036] According to some specific embodiments of the present invention, wherein,

[0037] L1 is selected from key or C 1-3 Alkylene; optionally, the alkylene is substituted with a substituent selected from F, Cl, Br or I;

[0038] L2 is C 1-5 Alkylene; optionally, the alkylene is substituted with a substituent selected from F, Cl, Br or I;

[0039] X is selected from O or S;

[0040] R1 is selected from H or methyl, ethyl or propyl; optionally, the methyl, ethyl or propyl group is substituted with a substituent selected from F, Cl, Br or I;

[0041] Ring A is selected from 3- to 6-membered heterocyclic alkyl groups; the heterocyclic alkyl group contains 1, 2 or 3 heteroatoms selected from N, O or S; optionally, the heterocyclic alkyl group is substituted with a substituent selected from F, Cl, Br or I.

[0042] According to some specific embodiments of the present invention, wherein,

[0043] L1 is selected from the group consisting of a bond, methylene, ethylene, or propylene; optionally, the methylene, ethylene, or propylene group is substituted with a substituent selected from F, Cl, Br, or I.

[0044] L2 is methylene, ethylene, propylene, or butylene; optionally, the methylene, ethylene, propylene, or butylene is substituted with a substituent selected from F, Cl, Br, or I.

[0045] X is selected from O or S;

[0046] R1 is selected from H;

[0047] Ring A is selected from 3-, 4-, 5-, or 6-membered heterocyclic alkyl groups; the heterocyclic alkyl group contains one or two heteroatoms selected from N, O, or S; optionally, the heterocyclic alkyl group is substituted with a substituent selected from F, Cl, Br, or I.

[0048] According to some specific embodiments of the present invention, ring A is X1 is selected from heteroatoms of N, O, or S.

[0049] According to some specific embodiments of the present invention, the structure of the amphotericin B saturated heterocyclic derivative is selected from one of the following structures:

[0050] On the other hand, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of any of the amphotericin B saturated heterocyclic derivatives or stereoisomers thereof described in the present invention, a pharmaceutically acceptable salt or deuterated derivative, and a pharmaceutically acceptable carrier.

[0051] Furthermore, the present invention also provides the use of the aforementioned amphotericin B saturated heterocyclic derivatives or stereoisomers thereof, pharmaceutically acceptable salts or deuterated derivatives, or the pharmaceutical compositions of the present invention in the preparation of antifungal drugs. Detailed Implementation

[0052] The following detailed embodiments illustrate the implementation process and beneficial effects of the present invention, aiming to help readers better understand the essence and characteristics of the present invention, and are not intended to limit the scope of implementation of this case.

[0053] Synthesis of intermediate C2'epiAmB (see Nature, 2023, 623, 1079-1085).

[0054] Step 1: Synthesis of intermediate Int 1

[0055] Method: Amphotericin B (750 mg / g, 65 g, approximately 70.3 mmol) was added to DMF / MeOH (1:1, 500 mL), resulting in a yellow suspension. Pyridine (45 mL) was then added, followed by allyl succinimide carbonate (32 g, 161 mmol). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was added dropwise to methyl tert-butyl ether (8 L) under vigorous stirring, precipitating a yellow solid. After filtration, the solid was washed with methyl tert-butyl ether and dried under reduced pressure to obtain a yellow solid powder, Int 1 (70 g, crude product).

[0056] MS(ESI,m / z)1009[M+H] + .

[0057] Step 2: Synthesis of intermediate Int 2

[0058] Method: Int 1 (72.5 g, crude product, approximately 70 mmol) was added to MeOH (500 mL), forming a yellow suspension. 4-Methoxybenzaldehyde dimethyl acetal (51 g, 280 mmol) was then added, followed by D(+)-10-camphorsulfonic acid (4.9 g, 21 mmol). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, triethylamine (5 mL) was added to quench the reaction. The reaction mixture was then added dropwise to a vigorously stirred n-hexane / methyl tert-butyl ether (3:5, 8 L), precipitating a yellow solid. After filtration, the solid was washed with n-hexane and dried under reduced pressure to obtain a yellow solid powder, Int 2 (75 g, crude product).

[0059] MS(ESI,m / z)1259[M+H] + .

[0060] Step 3: Synthesis of intermediate Int 3

[0061] Method: Int 2 (75 g, crude product, approximately 70 mmol) was dissolved in DMF / MeOH (10:1, 385 mL), DIPEA (N,N-diisopropylethylamine) (45 mL) was added, followed by 3-bromopropene (60 mL, 84 g, 694 mmol). The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the reaction mixture was quenched in 1 L of saturated sodium bicarbonate solution, extracted three times with EA, and the organic phases were combined. After washing with brine and drying with anhydrous sodium sulfate, the solution was concentrated under reduced pressure and purified by column chromatography (PE:EA = 1:1 to 1:2) to obtain a yellow solid powder Int 3 (34 g, yield 38.4%).

[0062] MS(ESI,m / z)1299[M+H] + .

[0063] Step 4: Synthesis of intermediate Int 4

[0064] Methods: DMAP (5.0 g, 40.6 mmol) was dissolved in THF (300 mL), and 4-tert-butylbenzoyl chloride (7.0 g, 35.6 mmol) was added dropwise with stirring to obtain a homogeneous white suspension. Int 3 (33 g, 25.4 mmol) was dissolved in THF (500 mL), and DIPEA (5.2 g, 40.6 mmol) was added. Then, the above white suspension was slowly added dropwise (45 minutes), and the mixture was stirred for half an hour after the addition was completed. After the reaction was complete, the reaction solution was quenched in 1 L of saturated sodium bicarbonate solution, extracted twice with EA, and the organic phases were combined. After washing with brine and drying with anhydrous sodium sulfate, the solution was concentrated under reduced pressure and then subjected to column chromatography (PE:EA = 2:1 to 1:1.5) to obtain a yellow solid powder Int 4 (19 g, yield 51.1%).

[0065] MS(ESI, m / z) 1460 [M+H] + .

[0066] Step 5: Synthesis of intermediate Int 5

[0067] Method: Int 4 (40 g, 27.4 mmol) was dissolved in DCM / hexane (1:1, 800 mL), and 2,6-dimethylpyridine (20.5 g, 192 mmol) was added. The mixture was cooled to 0–5 °C, and diethylisopropylsilyltrifluoromethanesulfonate (DEIPSOTf, 38 g, 136.6 mmol) was added dropwise. After the addition was complete, the mixture was stirred for 1 hour in an ice-water bath. After the reaction was complete, the reaction solution was quenched in 1 L of saturated sodium bicarbonate solution, extracted twice with EA, and the organic phases were combined. The organic phases were washed with copper sulfate solution to remove 2,6-dimethylpyridine, followed by washing with concentrated brine, drying with anhydrous sodium sulfate, and finally concentrated under reduced pressure and subjected to column chromatography (PE:EA = 15:1 to 10:1) to obtain a yellow solid powder Int 5 (36 g, yield 66.6%).

[0068] MS(ESI, m / z)1971[M+H] + .

[0069] Step 6: Synthesis of intermediate Int 6

[0070] Method: Int 5 (25 g, 12.6 mmol) was dissolved in THF / MeOH (1:2, 450 mL), KCN (1.24 g, 19 mmol) was added, and the mixture was stirred at 40 °C for 24 hours after purging with nitrogen. The reaction solution was added to EA and saturated sodium bicarbonate solution, and the mixture was extracted and separated. The aqueous phase was extracted twice more with EA. The combined organic phases were washed with concentrated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography (PE:EA = 15:1 to PE:EA = 5:1) to obtain a yellow solid powder Int 6 (8.5 g, yield 37.2%) and the starting material Int 5 (7 g) was recovered.

[0071] MS(ESI,m / z)1812[M+H] + .

[0072] Step 7: Synthesis of intermediate Int 7

[0073] Method: Int 6 (20 g, 11.0 mmol) was dissolved in toluene (350 mL), p-nitrobenzoic acid (11.0 g, 66.2 mmol) and triphenylphosphine (17.3 g, 66.2 mmol) were added, and the mixture was cooled in an ice-water bath after purging with nitrogen. A toluene solution (6 mL) of DIAD (diisopropyl azodicarboxylate) (13 mL, 66.2 mmol) was added dropwise. After the addition was complete, the mixture was stirred in an ice-water bath for 1 hour, and then the temperature was raised to 70 °C and stirred for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature and added to EA (100 mL) and saturated sodium bicarbonate solution (400 mL). The mixture was extracted and separated. The organic phase was washed once with water. The aqueous phases were combined and extracted twice more with EA. All organic phases were combined, washed with concentrated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 15:1 to PE:EA = 10:1) to obtain a yellow solid powder Int 7 (9.6 g, yield 45%).

[0074] MS(ESI, m / z)1960[M+H] + .

[0075] Step 8: Synthesis of intermediate Int 8

[0076] Method: Int 7 (12 g, 6.1 mmol) was dissolved in THF / MeOH (2:1, 110 mL), KCN (0.6 g, 9.2 mmol) was added, and the mixture was stirred at 40 °C for 24 hours after purging with nitrogen. The reaction solution was added to EA and saturated sodium bicarbonate solution, and the mixture was extracted and separated. The aqueous phase was extracted twice more with EA. The combined organic phases were washed with concentrated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 15:1 to PE:EA = 10:1) to obtain a yellow solid powder Int 8 (7.9 g, yield 71.5%).

[0077] MS(ESI,m / z)1812[M+H] + .

[0078] Step 9: Synthesis of intermediate Int 9

[0079] Method: Int 8 (10 g, 5.5 mmol) was dissolved in THF (60 mL) and cooled in an ice-water bath to obtain reaction solution A. Separately, MeOH (122 mL) and pyridine (23 mL) were mixed and cooled in an ice-water bath. Hydrogen fluoride-pyridine (17.3 mL, purity 65%–85%) was slowly added dropwise to obtain reaction solution B. Reaction solution B was slowly added dropwise to reaction solution A, and after the addition was complete, the mixture was brought to room temperature and stirred for 2.5 hours. After the reaction was complete, the mixture was cooled in an ice-water bath. A saturated sodium bicarbonate solution (200 mL) was added to quench the reaction mixture, and the mixture was stirred for 20 minutes. Another saturated sodium bicarbonate solution (200 mL) and EA (200 mL) were added, and the mixture was extracted and separated. The mixture was extracted again with EA, and the organic phases were combined. The mixture was washed once with saturated sodium bicarbonate solution, water, and brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the mixture was purified by column chromatography (DCM:MeOH = 100:0 to DCM:MeOH = 97:3) to obtain a yellow solid powder Int 9 (5.1 g, yield 71%).

[0080] MS(ESI,m / z)1299[M+H] + .

[0081] Step 10: Synthesis of intermediate Int 10

[0082] Method: Int 9 (5.1 g, 3.9 mmol) and Pd(PPh3)4 (1.36 g, 1.18 mol) were added to a 250 mL single-necked flask. A DMF solution of thiosalicylic acid (3.03 g, 19.6 mmol) in 120 mL was added dropwise. After the addition was complete, nitrogen gas was introduced, and the reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was added dropwise to 2 L of vigorously stirred diethyl ether. The mixture was allowed to stand and separate into layers. The supernatant was poured off, and the lower turbid liquid was filtered to obtain a yellow solid. The yellow solid was added to MeOH (40 mL) and stirred to form a suspension. The suspension was then added dropwise to 500 mL of vigorously stirred diethyl ether. After filtration, the mixture was dried under reduced pressure to obtain a yellow solid powder, Int 10 (3.75 g, yield 82%).

[0083] MS(ESI,m / z)1175[M+H] + .

[0084] Step 11: Synthesis of intermediate C2'epiAmB

[0085] Method: Int 10 (200 mg, 0.17 mmol) was dissolved in ACN / H2O (2:1, 84 mL), cooled in an ice-water bath, and D(+)-10-camphorsulfonic acid (3.0 g, 12.93 mmol) was slowly added. The mixture was then heated to room temperature and stirred for 2 hours. After the reaction was complete, TEA (2.8 mL) was added to quench the reaction. The reaction solution was concentrated under reduced pressure to remove the solvent. The residue was then added dropwise to Et2O / ACN (10:1, 220 mL), stirred for 10 minutes, and allowed to stand. The lower turbid layer was collected, and acetonitrile (120 mL) was added, resulting in the precipitation of a yellow solid. Centrifugation yielded crude C2'epiAmB (140 mg, crude product, HPLC purity 50%), which was directly used in subsequent reactions.

[0086] MS(ESI,m / z)924[M+H] + .

[0087] 1H NMR(600MHz, CD3OD:Pyridine-d5=1:1)δ1.18(d,J=7.0Hz,3H),1.25(d,J=6.4Hz,4H),1.37(d,J=6.4Hz,3H),1.42-1.49(m,4H),1.52-1.57(m,1H),1.57 -1.65(m,1H),1.67-1.74(m,2H),1.80-1.90(m,1H),1.99-2.08(m,3H),2.15 -2.25(m,1H),2.32-2.41(m,2H),2.47-2.53(m,1H),2.53-2.55(m,1H),2.55 -2.65(m,1H),2.65-2.68(m,1H),3.38(d,J=9.4Hz,1H),3.44-3.46(m,2H),3 .52-3.57(m,2H),3.68-3.82(m,2H),3.88(d,J=10.3Hz,1H),3.98(t,J=9.7H z,1H),4.49(t,J=9.8,1H),4.69(t,J=10.8Hz,1H),4.77(s,2H),4.89(d,J=7 .6Hz,1H),4.99(t,J=9.6Hz,1H),5.66(d,J=7.2Hz,1H),6.30-6.67(m,14H).

[0088] Example 1: Synthesis of BX20-11-045

[0089] Method: C2'epiAmB (100 mg, crude product, HPLC purity approximately 50%, approximately 0.05 mmol) was dissolved in DMAc (N,N-dimethylacetamide) (3 mL), and (3-(aminomethyl)oxetane-3-yl)methanol (35 mg, 0.3 mmol) was added. Then, NMM (N-methylmorpholine) was added to adjust the pH of the reaction system to 9–10. Finally, PyAOP (104 mg, 0.2 mmol) was added, and the reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was purified by preparative chromatography (95:5 to 55:45, aq. HCOOH (1‰) / MeCN), and lyophilized to obtain a yellow solid powder BX20-11-045 (16 mg, yield 31%).

[0090] MS(ESI, m / z) 1024 [M+H] + .

[0091] 1H NMR(400MHz, CD3OD:Pyridine-d5=1:1)δ=1.16(d,J=7.2Hz,3H),1.24(d,J=6.4Hz,3H),1.35(d,J=6.4Hz,3H),1.39(d,J=6.0Hz,3H),1.44- 1.47(m,1H),1.49-1.55(m,2H),1.59-1.70(m,3H),1.76-1.87(m,2H) ,1.93-2.04(m,3H),2.09-2.18(m,1H),2.29-2.39(m,2H),2.41-2.49( m,2H),2.52-2.59(m,1H),3.29-3.36(m,2H),3.44-3.48(m,2H),3.55-3.62(m,1H),3.70-3.74(m,1H),3.79(s,2H),3.85(d,J=10.8Hz,1H) ,3.93-4.01(m,3H),4.42-4.47(m,1H),4.59-4.75(m,8H),5.01(t,J= 9.6Hz,1H),5.44-5.51(m,1H),5.60-5.66(m,1H),6.27-6.69(m,14H).

[0092] Example 2: Synthesis of BX20-11-062

[0093] Method: C2'epiAmB (75 mg, crude product, HPLC purity approximately 50%, approximately 0.035 mmol) was dissolved in DMAc (3 mL), and (3-aminooxetane-3-yl)methanol (25 mg, 0.24 mmol) was added. NMM was then added to adjust the pH of the reaction system to 9–10. Finally, PyAOP (hexafluorophosphate (7-azabenzotriazol-1-oxy)tripyrrolidinephosphide) (83 mg, 0.16 mmol) was added, and the reaction was stirred at 40 °C for 1 hour. After the reaction was complete, the reaction solution was purified by preparative chromatography (95:5 to 60:40, aq. HCOOH (1‰) / MeCN), and lyophilized to obtain a yellow powder BX20-11-062 (12 mg, yield 34%).

[0094] MS(ESI,m / z)1010[M+H) + .

[0095] 1H NMR(400MHz, CD3OD:Pyridine-d5=1:1)δ=1.15(d,J=7.2Hz,3H),1.23(d,J=6.0Hz,3H),1.34(d,J=6.4Hz,3H),1.39(d,J=6.4Hz,3H),1.42-1.60(m,5H), 1.63-1.69(m,2H),1.75-1.86(m,2H),1.94-2.02(m,3H),2.09-2.16(m,1H) ,2.28-2.36(m,2H),2.44-2.59(m,4H),3.25-3.30(m,1H),3.34(d,J=8.8Hz, 1H),3.42-3.45(m,1H),3.57-3.63(m,1H),3.65-3.70(m,1H),3.84(d,J=10 .8Hz,1H),3.94(t,J=10.0Hz,1H),4.16-4.26(m,2H),4.42-4.46(m,1H),4.6 0-4.72(m,4H),4.75-4.80(m,2H),4.93(t,J=9.6Hz,1H),5.00(d,J=6.4Hz,2 H),5.48(dd,J=14.4Hz,10.4Hz,1H),5.61-5.65(m,1H),6.25-6.67(m,14H).

[0096] Example 3: Synthesis of BX20-11-083

[0097] Step 1: Synthesis of intermediate 83-2

[0098] Method: tert-butyl carbamate hydrochloride (CAS: 2173991-96-1, 500 mg, 1.9 mmol) was dissolved in 1,4-dioxane (4 mL). The solution was cooled to 0 °C and NaHCO3 solution (2.5 g, 10%) was added. Finally, Fmoc-Cl (620 mg, 2.4 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was extracted with EA and saturated NaHCO3 solution, washed with brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain a white solid 83-2 (850 mg, crude product).

[0099] MS(ESI,m / z)439[M+H] + .

[0100] Step 2: Synthesis of intermediate 83-3

[0101] Method: 83-2 (850 mg, crude product, approximately 1.9 mmol) was dissolved in DCM (10 mL), and HCl / 1,4-dioxane (4 M, 5 mL, 20 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, saturated NaHCO3 solution was added dropwise to adjust the pH to 9–10. The mixture was extracted with EA, washed with concentrated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 20:1 to 4:1) to obtain a white solid 83-3 (160 mg, yield 25%).

[0102] MS(ESI,m / z)339[M+H] + .

[0103] Step 3: Synthesis of BX20-11-083

[0104] Method: C2'epiAmB (100 mg, crude product, HPLC purity approximately 50%, approximately 0.05 mmol) was dissolved in DMAc (5 mL), 83-3 (101 mg, 0.3 mmol) was added, and NMM was added to adjust the pH of the reaction system to 9–10. Then, PyAOP (104 mg, 0.2 mmol) was added, and the reaction was stirred at 35 °C for 1 hour. Finally, piperidine (250 mg, 2.9 mmol) was added, and the reaction was continued to be stirred at 25 °C for 0.5 hours. After the reaction was complete, the reaction solution was directly purified by preparative chromatography (95:5 to 67:33, aq. HCOOH (1‰) / MeCN), and lyophilized to obtain a yellow solid powder BX20-11-083 (7 mg, yield 14%).

[0105] MS(ESI, m / z) 1023 [M+H] + .

[0106] 1H NMR(600MHz, CD3OD:Pyridine-d5=1:1)δ1.16(d,J=7.2Hz,3H),1.23(d,J=6.4Hz,3H),1.34(d,J=6.4Hz,3H),1.38(d,J=6.0Hz,3H),1.43-1.4 6(m,1H),1.50-1.62(m,4H),1.65-1.70(m,2H),1.75-1.80(m,3H),1.9 5-2.01(m,3H),2.10-2.16(m,1H),2.29-2.35(m,2H),2.45-2.57(m,3H ),2.90-2.95(m,1H),3.28-3.37(m,3H),3.49-3.58(m,2H),3.70(t,J=9.0Hz,1H),3.83-3.87(m,3H),3.92-3.99(m,2H),4.21(t,J=11.4Hz,2 H),4.30-4.36(m,2H),4.42-4.46(m,1H),4.63-4.69(m,4H),4.98(t,J =9.6Hz,1H),5.46-5.50(m,1H),5.61-5.64(m,1H),6.29-6.66(m,14H).

[0107] Example 4: Synthesis of BX20-11-084

[0108] Step 1: Synthesis of intermediate 84-2

[0109] Method: (3-(hydroxymethyl)azacyclobutane-3-yl)carbamate tert-butyl hydrochloride (CAS: 2173991-87-0, 500 mg, 2.1 mmol) was dissolved in 1,4-dioxane (4 mL), cooled to 0 °C, and then NaHCO3 solution (2.5 g, 10%) was added. Finally, Fmoc-Cl (620 mg, 2.4 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was extracted with EA and saturated NaHCO3 solution, washed with brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain a white solid 84-2 (900 mg, crude product).

[0110] MS(ESI,m / z)425[M+H] + .

[0111] Step 2: Synthesis of intermediate 84-3

[0112] Method: 84-2 (900 mg, crude product, approximately 2.1 mmol) was dissolved in DCM (10 mL), and HCl / 1,4-dioxane (4 M, 5 mL, 20 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the mixture was extracted with EA and saturated NaHCO3 solution, washed with brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 20:1 to 4:1) to give a white solid 84-3 (390 mg, yield 57%).

[0113] MS(ESI,m / z)325[M+H] + .

[0114] Step 3: Synthesis of BX20-11-084

[0115] Method: C2'epiAmB (100 mg, crude product, HPLC purity approximately 50%, approximately 0.05 mmol) was dissolved in DMAc (5 mL), 84-3 (97 mg, 0.3 mmol) was added, and DIPEA was added to adjust the pH of the reaction system to 9–10. Then, PyAOP (104 mg, 0.2 mmol) was added, and the reaction was stirred at 35 °C for 1 hour. Finally, piperidine (250 mg, 2.9 mmol) was added, and the reaction was continued to be stirred at 25 °C for 0.5 hours. After the reaction was complete, the reaction solution was directly purified by preparative chromatography (90:10 to 66:34, aq. HCOOH (1‰) / MeCN), and lyophilized to obtain a yellow solid powder BX20-11-084 (9 mg, yield 17%).

[0116] MS(ESI,m / z)1009[M+H] + .

[0117] 1H NMR(600MHz, CD3OD:Pyridine-d5=1:1)δ1.15(d,J=7.2Hz,3H),1.23(d,J=6.4Hz,3H),1.33(d,J=6.4Hz,3H),1.37(d,J=6.0Hz,3H),1.41-1 .45(m,1H),1.50-1.60(m,3H),1.62-1.68(m,2H),1.73-1.82(m,3H), 1.93-2.00(m,3H),2.07-2.13(m,1H),2.29-2.39(m,3H),2.44-2.49( m,2H),2.52-2.56(m,1H),3.18-3.30(m,2H),3.28-3.34(m,1H),3.55-3.60(m,1H),3.64-3.67(m,1H),3.83(d,J=10.8Hz,1H),3.90-3.94( m,1H),4.06(s,2H),4.36-4.44(m,3H),4.56-4.70(m,6H),4.89(t,J=9.6Hz,1H),5.45-5.49(m,1H),5.60-5.63(m,1H),6.28-6.65(m,14H).

[0118] Comparative Example 1:

[0119] Referring to the synthesis method of compound 1 in patent CN116323632A, Comparative Example 1 was synthesized.

[0120] 1H NMR(600MHz, CD3OD:Pyridine-d5=1:1)δ1.17(d,J=7.2Hz,3H),1.25(d,J=6.6Hz,3H),1.36(d,J=6.6Hz,3H),1.39(d,J=6.0Hz,3H),1.44-1.47(m,1H),1.5 1-1.56(m,2H),1.56-1.63(m,1H),1.63-1.72(m,2H),1.75-1.87(m,2H),1.9 3-2.02(m,3H),2.11(s,3H),2.13-2.23(m,1H),2.31-2.39(m,2H),2.47-2.61 (m,4H),3.17(t,J=10.2Hz,1H),3.30-3.37(m,2H),3.58-3.63(m,2H),3.88( d,J=10.8,1H),3.93-3.98(m,3H),4.01-4.08(m,2H),4.45-4.50(m,2H),4.63 -4.68(m,2H),4.71(d,J=7.8Hz,1H),4.77(ddd,J=11.4,10.2,4.8Hz,1H),5.0 3(t,J=9.6Hz,1H),5.45-5.51(m,1H),5.64-5.68(m,1H),6.25-6.67(m,14H).

[0121] Biological testing evaluation

[0122] Test Example 1: In vitro antifungal activity of the compound of the present invention

[0123] 1. Experimental Objective

[0124] The in vitro antifungal concentration of the compound of this invention was tested.

[0125] 2. Experimental Materials

[0126] 2.1. The embodiments and reference compounds of this invention are self-made.

[0127] 2.2. The strains to be tested were provided by WuXi AppTec.

[0128] 3. Test methods

[0129] The determination method for minimum inhibitory concentration (MIC) is the same as that for CLSI M27, CLSIM38 and CLSIM60.

[0130] 3.1. Compound Preparation

[0131] Prepare a high-concentration stock solution by dissolving the test compound in a suitable solvent. Use the solution on the same day or store it at -20°C or lower. On the day of testing, serially dilute the stock solution by 2-fold to prepare a working solution of the compound at a final test concentration of 100x. Transfer 2 μL of the working solution to a 96-well plate to obtain the compound test plate.

[0132] 3.2. Preparation of inoculum

[0133] 3.2.1. Preparation of yeast-like fungal inoculum

[0134] Cryopreserved bacteria at -80℃ glycerol were inoculated onto SDA plates and incubated overnight at 35±2℃. On the day of testing, single colonies were picked and dissolved in sterile physiological saline to prepare a 0.5×McFarland bacterial suspension. The suspension was then diluted 2000-fold in RPMI 1640 (pH 7.0) medium to obtain an inoculum solution (0.5×10⁻⁶). 3 ~2.5×10 3 CFU / mL). Add 198 μL of inoculum to the compound test plate prepared in 3.1.

[0135] 3.2.2. Preparation of inoculum for filamentous fungi (non-dermatophytes and molds)

[0136] Cryopreserved bacteria at -80℃ glycerol were inoculated onto PDA or SDA plates and incubated at 35±2℃ for 2–7 days. On the day of testing, spores from the plates were collected and dissolved in sterile physiological saline (or with 0.1% Tween 20 added), and the number of spores was counted using a cell counter. The spore suspension was then diluted to 0.2–2.5 × 10⁻⁶ in RPMI 1640 (pH 7.0) medium. 4 CFU / mL was used to obtain the inoculation spore solution. 198 μL of the inoculation spore solution was added to the compound test plate prepared in 3.1.

[0137] 3.3. MIC readings

[0138] Yeast-like fungi: After incubating the test plate at 35°±2℃ for 24h, the minimum concentration (MIC) of the compound that inhibits 100% or ≥50% is read visually.

[0139] Filamentous fungi (non-dermatophyte molds): After incubating the test plate at 35±2℃ for 48h, the minimum concentration (MIC) of the compound that inhibits 100%, ≥80%, or ≥50% is read visually.

[0140] 4. Test Results

[0141] The results are shown in Table 1 below.

[0142] Table 1. Minimum inhibitory concentrations (MIC, μg / mL) of the compounds of this invention.

[0143] Conclusion: The compounds of this invention have a good inhibitory effect on the growth of Candida albicans, Aspergillus fumigatus, and Aspergillus flavus.

[0144] Test Example 2: In vitro human liver microsomal stability determination

[0145] 1. Testing method:

[0146] The final incubation reaction solution contained phosphate buffer (pH 7.4, 100 mM, 216.25 μL, final concentration 100 mM), a positive control compound (verapamil) or a test compound (100 μM, 2.5 μL, final concentration 1 μM), and human liver microsomes (20 mg / mL, 6.25 μL, final concentration 0.5 mg / mL). After pre-incubation at 37°C for 10 minutes, NADPH (10 mM, 25 μL) was added to initiate the reaction. At fixed time points (0.5, 5, 15, 30, 60 min), a fixed volume (30 μL) of the reaction mixture was sampled and added to 5 times the volume of cold acetonitrile (containing 200 nM labetalol, 100 nM ketoprofen, and 100 nM toluenebutyramide) to terminate the reaction. After centrifugation (3220g, 40min), the supernatant (100μL) was mixed with ultrapure water (100μL) and then analyzed by LC-MS / MS.

[0147] 2. Data Analysis

[0148] Peak areas were determined from the extracted ion chromatograms. The slope value k was determined by linear regression of the natural logarithm of the curve showing the remaining percentage of parent drug versus incubation time.

[0149] The in vitro half-life (in vitro t1 / 2) is determined by the slope value: T 1 / 2 =0.693 / k.

[0150] 3. Test Results

[0151] The results are shown in Table 2 below:

[0152] Table 2. Stability of the compounds of the present invention in human liver microsomes

[0153] 4. Conclusion: The compounds of this invention exhibit good metabolic stability in human liver microsomes.

[0154] Test Example 3: Testing the in vitro cell tolerance of the compounds of the present invention

[0155] 1. Experimental Objective

[0156] The tolerance of the compounds of this invention to different cell lines was investigated.

[0157] 2. Test Methods

[0158] Hemolysis test: Take sterile blood (heparin sodium anticoagulation, Guoying Kangsheng) into a 1.5 mL tube, gently mix by inverting, and centrifuge at 1000 rpm for 5 minutes at 4°C. Discard the supernatant, add PBS for washing, and centrifuge at 1000 rpm for 5 minutes at 4°C. Repeat step 2 twice. Take an appropriate amount of washed red blood cells and dilute with PBS. Seed the red blood cells into a 96-well culture plate. Serially dilute the compound to twice the final concentration (final compound concentrations: 500, 166.67, 55.56, 18.52, 6.17, 2.06, 0.69, 0 μM). Use PBS and 0.1% Tritone X-100 as 0% and 100% controls, respectively. Add 100 μL of the compound to a 96-well culture plate. Mix 100 μL of 8% red blood cells with 100 μL of the compound, add to the 96-well culture plate, and incubate at 37°C for 1 hour. Centrifuge the mixture at 1500 rpm for 5 minutes at 4°C, and transfer the supernatant to a new culture plate. Measure the absorbance using an OD540 microplate reader (BMG).

[0159] Nephrotoxicity assay: Primary human proximal tubular epithelial cells (RPTEC, PCS-400-010, ATCC). Cells were cultured in a renal epithelial cell growth kit (PCS-400-040, ATCC) and renal epithelial cell basal medium (PCS-400-030, ATCC), and cytotoxicity was tested in duplicate in 384-well plates. DMSO and culture medium were used as negative and positive controls, respectively. During the experiment, the seeding density was maintained at 6000 cells / well / 40 μL. All test compound stock solutions were prepared in DMSO, and the DMSO concentration in the final culture was maintained at 0.5%. After adding the compounds to the culture, it was incubated at 5% CO2 and 37°C for 24 hours. 20 μL of Cell Titer Glo solution was added to each well, and the cells were centrifuged at 1000 rpm for 1 minute. Then, incubation was continued for 10 minutes, and the luminescence intensity was measured using EnSight (PerkinElmer).

[0160] Hepatotoxicity: Hep-G2 (HB-8065, ATCC; human hepatocytes). Cells were grown in complete MEM medium (containing 1% penicillin antibody, 10% FBS) and cytotoxicity was tested in duplicate in 384-well plates. DMSO and medium were used as negative and positive controls, respectively. The seeding density was maintained at 6000 cells / well / 30 μL throughout the experiment. All test compound stock solutions were prepared in DMSO, and the DMSO concentration in the final culture was maintained at 0.5%. After adding the compounds to the culture, it was incubated at 5% CO2 and 37°C for 24 h. 30 μL of Cell Titer Glo solution (Vazyme, DD1101-03) was added to each well, the cells were shaken rapidly for 2 min, and incubated at room temperature in the dark for 10 min. The luminescence intensity was measured using EnSight (PerkinElmer).

[0161] Except for the hemolysis test, the final concentrations of the compounds in the above tests were: 50.00, 16.67, 5.56, 1.85, 0.62, 0.21, 0.07, 0.02, 0.008, and 0 μM.

[0162] Data processing: The data were analyzed using the four-parameter regression method in the nonlinear curve fitting mode to calculate the IC50 of the compounds.

[0163] 3. Test Results

[0164] Table 3. Results of Cell Tolerance Assessment

[0165] Conclusion: Table 3 shows that, compared with amphotericin B, the compounds of this invention exhibit significantly reduced in vitro hemolytic activity, IC50... 50 The value is greater than 500 μM. This indicates that the compound of the present invention has lower hemolytic toxicity than amphotericin B, and its safety is significantly improved. The compound of the present invention has low inhibitory activity against normal hepatocytes and kidney cells, and good tolerability, which is significantly better than amphotericin B, suggesting that the compound of the present invention has better safety.

[0166] Test Example 4: Testing the rat PK characteristics of the compound of the present invention.

[0167] 1. Experimental Objective

[0168] Using SD rats as test animals, the pharmacokinetic behavior of the compound of this invention after tail vein injection in rats was studied.

[0169] 2. Test Methods

[0170] 2.1 Test Drugs

[0171] The embodiments and reference compounds of this invention are self-made.

[0172] 2.2 Test animals

[0173] Male SPF-grade SD rats (weighing 200 - 300 g), 3 rats per compound, sourced from Vital River Laboratories, production license number SCXK(Zhe)2024 - 0001.

[0174] 2.3 Preparation of test drugs

[0175] Prepare a drug concentration of 0.2 mg / mL with 5% glucose solution.

[0176] 2.4 Drug administration

[0177] After 3 - 4 days of adaptive feeding of the rats, inject 1 mg / kg via the tail vein, and the administration volume is 5 mL / kg.

[0178] Blood samples are collected from the rats before drug administration (0 h) and at 5 min, 15 min, 30 min, 1, 2, 4, 6, 8, 2 and 4 h after drug administration. Blood is collected via the jugular vein, with a blood collection volume of approximately 0.2 mL, and placed in an EDTA-K2 anticoagulant test tube with a label attached. After blood collection, immediately invert the blood collection tube gently and completely 3 times to mix with the anticoagulant, and immediately place it in an ice-water bath. Centrifuge at 4000 g for 5 min at 4°C. After the centrifugation operation is completed, the plasma samples from the same sampling point are equally combined among 3 animals and promptly aliquoted into EP tubes with corresponding labels attached, and stored at -80°C in a refrigerator until measurement.

[0179] 2.5 Sample detection

[0180] In this experiment, the LC-MS / MS method is used to measure the compound concentration in the pooled plasma. WinNonlin(Phoenix TM , version 8.3) software is used to calculate the pharmacokinetic parameters.

[0181] 3. Test results and analysis

[0182] The results of the rat pharmacokinetic experiment are shown in the following table.

[0183] Table 4. Results of the rat pharmacokinetic experiment

[0184] Conclusion: As can be seen from the data in Table 4, at the same administration dose, the compound of the present invention increases the drug exposure.

Claims

1. A saturated heterocyclic derivative of amphotericin B or its stereoisomer, a pharmaceutically acceptable salt, or a deuterated derivative, wherein, The amphotericin B derivative is shown in formula (I): L1 and L2 are each independently selected from the key or C. 1-10 Alkylene; optionally, the alkylene group is selected from F, Cl, Br, I, hydroxyl, nitro, cyano, carboxyl, C 1-5 Substituents of alkyl groups; X is selected from O, S, or -N(R2)-; R1 and R2 are each independently selected from H or C. 1-10 Alkyl group; optionally, the alkyl group is selected from F, Cl, Br, I, hydroxyl, nitro, cyano, carboxyl, C 1-5 Substituents of alkyl groups; Ring A is selected from 3- to 10-membered heterocyclic alkyl groups; the heterocyclic alkyl group contains 1, 2, or 3 heteroatoms selected from N, O, or S; optionally, the heterocyclic alkyl group is selected from F, Cl, Br, I, hydroxyl, nitro, cyano, carboxyl, C. 1-6 Alkyl, C 1-6 Alkoxy group, -C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -C(O)OC 1-6 Alkyl-OC 1-6 Alkyl groups are substituted.

2. The amphotericin B saturated heterocyclic derivative or its stereoisomer, pharmaceutically acceptable salt, or deuterated derivative according to claim 1, wherein, L1 and L2 are each independently selected from the key or C. 1-5 Alkylene; optionally, the alkylene group is selected from F, Cl, Br, I, hydroxyl, nitro, cyano, carboxyl, C 1-3 Substituents of alkyl groups; X is selected from O, S, or -N(R2)-; R1 and R2 are each independently selected from H or C. 1-5 Alkyl group; optionally, the alkyl group is selected from F, Cl, Br, I, hydroxyl, nitro, cyano, carboxyl, C 1-3 Substituents of alkyl groups; Ring A is selected from 3- to 8-membered heterocyclic alkyl groups; the heterocyclic alkyl group contains 1, 2, or 3 heteroatoms selected from N, O, or S; optionally, the heterocyclic alkyl group is selected from F, Cl, Br, I, hydroxyl, nitro, cyano, carboxyl, C. 1-5 Alkyl, C 1-6 Alkoxy group, -C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -C(O)OC 1-6 Alkyl-OC 1-6 Alkyl groups are substituted.

3. The amphotericin B saturated heterocyclic derivative or its stereoisomer, pharmaceutically acceptable salt, or deuterated derivative according to claim 2, wherein, L1 is selected from key or C 1-5 Alkylene; optionally, the alkylene group is selected from F, Cl, Br, I, hydroxyl, nitro, cyano, carboxyl, C 1-3 Substituents of alkyl groups; L2 is C 1-5 Alkylene; optionally, the alkylene group is selected from F, Cl, Br, I, hydroxyl, nitro, cyano, carboxyl, C 1-3 Substituents of alkyl groups; X is selected from O, S, or -N(R2)-; R1 and R2 are each independently selected from H or C. 1-5 Alkyl group; optionally, the alkyl group is selected from F, Cl, Br, I, hydroxyl, nitro, cyano, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy group, -C(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, -C(O)OC 1-3 Alkyl-OC 1-3 Alkyl groups are substituted.

4. The amphotericin B saturated heterocyclic derivative or its stereoisomer, pharmaceutically acceptable salt, or deuterated derivative according to claim 1, wherein, L1 is selected from key or C 1-3 Alkylene; optionally, the alkylene group is selected from F, Cl, Br, I, hydroxyl, nitro, cyano, carboxyl, C 1-3 Substituents of alkyl groups; L2 is C 1-5 Alkylene; optionally, the alkylene group is selected from F, Cl, Br, I, hydroxyl, nitro, cyano, carboxyl, C 1-3 Substituents of alkyl groups; X is selected from O, S, or -N(R2)-; R1 and R2 are each independently selected from H or C. 1-3 Alkyl group; optionally, the alkyl group is selected from F, Cl, Br, I, hydroxyl, nitro, cyano, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy group, -C(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, -C(O)OC 1-3 Alkyl-OC 1-3 Substituents of alkyl groups; Ring A is selected from 3- to 6-membered heterocyclic alkyl groups; the heterocyclic alkyl group contains 1, 2, or 3 heteroatoms selected from N, O, or S; optionally, the heterocyclic alkyl group is selected from F, Cl, Br, I, hydroxyl, nitro, cyano, carboxyl, C 1-5 Alkyl groups are substituted.

5. The amphotericin B saturated heterocyclic derivative or its stereoisomer, pharmaceutically acceptable salt, or deuterated derivative according to claim 1, wherein, L1 is selected from key or C 1-3 Alkylene; optionally, the alkylene group is selected from F, Cl, Br, I, hydroxyl, nitro, cyano, carboxyl, C 1-3 Substituents of alkyl groups; L2 is C 1-5 Alkylene; optionally, the alkylene group is selected from F, Cl, Br, I, hydroxyl, nitro, cyano, carboxyl, C 1-3 Substituents of alkyl groups; X is selected from O or S; R1 is selected from H or C. 1-3 Alkyl group; optionally, the alkyl group is selected from F, Cl, Br, I, hydroxyl, nitro, cyano, carboxyl, C 1-3 Substituents of alkyl groups; Ring A is selected from 3- to 6-membered heterocyclic alkyl groups; the heterocyclic alkyl group contains 1, 2, or 3 heteroatoms selected from N, O, or S; optionally, the heterocyclic alkyl group is selected from F, Cl, Br, I, hydroxyl, nitro, cyano, carboxyl, C 1-5 Alkyl groups are substituted.

6. The amphotericin B saturated heterocyclic derivative or its stereoisomer, pharmaceutically acceptable salt or deuterated derivative according to claim 1, wherein, L1 is selected from key or C 1-3 Alkylene; optionally, the alkylene is substituted with a substituent selected from F, Cl, Br or I; L2 is C 1-5 Alkylene; optionally, the alkylene is substituted with a substituent selected from F, Cl, Br or I; X is selected from O or S; R1 is selected from H or methyl, ethyl or propyl; optionally, the methyl, ethyl or propyl group is substituted with a substituent selected from F, Cl, Br or I; Ring A is selected from 3- to 6-membered heterocyclic alkyl groups; the heterocyclic alkyl group contains 1, 2 or 3 heteroatoms selected from N, O or S; optionally, the heterocyclic alkyl group is substituted with a substituent selected from F, Cl, Br or I.

7. The amphotericin B saturated heterocyclic derivative or its stereoisomer, pharmaceutically acceptable salt or deuterated derivative according to any one of claims 1 to 6, wherein, L1 is selected from the group consisting of a bond, methylene, ethylene, or propylene; optionally, the methylene, ethylene, or propylene group is substituted with a substituent selected from F, Cl, Br, or I. L2 is methylene, ethylene, propylene, or butylene; optionally, the methylene, ethylene, propylene, or butylene is substituted with a substituent selected from F, Cl, Br, or I. X is selected from O or S; R1 is selected from H; Ring A is selected from 3-, 4-, 5-, or 6-membered heterocyclic alkyl groups; the heterocyclic alkyl group contains one or two heteroatoms selected from N, O, or S; optionally, the heterocyclic alkyl group is substituted with a substituent selected from F, Cl, Br, or I.

8. The amphotericin B saturated heterocyclic derivative or its stereoisomer, pharmaceutically acceptable salt or deuterated derivative according to claim 1, wherein, The structure of the amphotericin B saturated heterocyclic derivative is selected from one of the following structures:

9. A pharmaceutical composition comprising a therapeutically effective amount of any one of claims 1 to 8 a saturated heterocyclic derivative of amphotericin B or a stereoisomer thereof, a pharmaceutically acceptable salt or deuterated derivative, and a pharmaceutically acceptable carrier.

10. The use of the amphotericin B saturated heterocyclic derivative or its stereoisomer, pharmaceutically acceptable salt or deuterated derivative, or the pharmaceutical composition of claim 9 in the preparation of a therapeutic antifungal drug.

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