Amphotericin b amide derivative and use thereof

Abstract

Provided are an amphotericin B amide derivative and a use thereof. The amphotericin B amide derivative is as shown in formula (I). The compound has good antifungal activity, is effective against various fungi, has good water solubility, is adapted to be developed into an injection dosage form, has excellent metabolic stability in animals (such as mice, rats, dogs, and monkeys), has a long half-life period, can effectively reduce the frequency of administration, has weak inhibition on CYP enzymes, and has a low risk of drug interaction.

Description

Amphotericin B amide derivative and application thereof TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular, the present application relates to an amphotericin B amide derivative and application thereof. BACKGROUND

[0002] In recent years, due to the rapid increase of immune compromised population, there are also malignant tumors, malignant hematopathy, AIDS, SARS, diabetes, severe burns, etc. Occurrence, as well as the wide use of broad-spectrum antibiotics and immunosuppressive agents, the development of new technologies such as catheter, cannula and organ transplantation, so that the incidence of opportunistic deep organ fungal infection is getting higher and higher, and it is getting more and more serious. The incidence of deep fungal infection in the above population is about 11%-40%, and the mortality rate is 40%. The incidence of deep fungal infection is much lower than that of superficial fungal infection, but deep fungal infection is more worrying because of its very high mortality rate, about 1.5 million people die from deep fungal infection every year. More than 90% of all fungal-related deaths are caused by one of the following four species: cryptococcus, candida, aspergillus and pneumocystis. Moreover, the epidemiological data of fungal infection is very poor, and fungal infection is often misdiagnosed because we greatly underestimate the risk of deep fungal infection.

[0003] Amphotericin B (AMB) is a polyene broad-spectrum antifungal drug, which is suitable for the treatment of the following fungal infection diseases: candidiasis, cryptococcosis, blastomycosis, coccidioidomycosis, mucormycosis caused by mucor, sporotrichosis caused by sporothrix, aspergillosis caused by most aspergillus, etc. Since amphotericin B was isolated from streptomyces metabolites in 1955, the compound has been highly valued. On the one hand, amphotericin B is the gold standard for the treatment of deep fungal infection and systemic infection in clinic, and it is the only effective treatment for some fatal systemic fungal infections; on the other hand, amphotericin B has relatively serious toxic and side effects at the treatment dose, such as hemolytic toxicity, nephrotoxicity, nervous system toxicity, etc., and amphotericin B has very poor water solubility, and after oral administration, it is poorly absorbed from the gastrointestinal tract and unstable, so the application of amphotericin B in clinic has been greatly limited.

[0004] Although studies have shown that liposomes as drug carriers can significantly reduce the toxic side effects of amphotericin B, amphotericin B liposomes are a new type of drug with targeted drug delivery function prepared by using phospholipid bilayer membrane to encapsulate drug molecules, which has better tolerance than ordinary preparations. On the one hand, it can be more distributed in the liver, spleen and lung, and has lower concentration in other organs, especially in kidney tissue. On the other hand, the cholesterol component in the liposome can reduce the binding of the drug with cholesterol in human cells and enhance the binding to the fungal cell ergosterol, and the side effects on the kidney are relatively small. However, amphotericin B liposome preparations also have the following disadvantages: 1. The antibacterial activity of liposome preparations is poorer than that of amphotericin B, and the treatment dose needs to be increased, 2. The cost of liposome preparations is high, and the price is relatively expensive, 3. The instability of liposomes, 4. The liposome preparations do not fundamentally eliminate the nephrotoxicity and other toxic side effects of amphotericin B.

[0005] Although there are currently many reports on the structural modification of amphotericin B, it is still necessary to develop new amphotericin B derivatives that can maintain antibacterial activity while reducing nephrotoxicity, hemolysis toxicity, and other side effects, and can also solve the problem of poor water solubility of amphotericin B. SUMMARY

[0006] One object of the present application is to provide an amphotericin B amide derivative, which has good antifungal activity, is effective against a variety of fungi, has good water solubility, is suitable for development into an injection dosage form, has excellent metabolic stability in animals (such as mice, rats, dogs, and monkeys), has a long half-life, can effectively reduce the frequency of administration, has weak inhibition of CYP enzymes, and has low risk of drug interaction.

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

[0008] Still another object of the present application is to provide the use of the amphotericin B amide derivative.

[0009] To achieve the above objects, on the one hand, the present application provides an amphotericin B amide derivative, wherein the amphotericin B amide derivative is shown as formula (I):

[0010] R1 is selected from -Cy-L-OH, NR 11 R 13 or N(R 11 )(CH2) n1 N(R 12 )R 13 ; optionally, the -CH2- is substituted with a substituent selected from F, Cl, Br, I or C 1-6 alkyl;

[0011] R2and R3are each independently selected from H or C 1-10 alkyl; or, R2and R3, together with the C atom to which they are attached, form a 3- to 10-membered cycloalkyl; optionally, said alkyl and cycloalkyl are substituted with a substituent selected from F, Cl, Br, I, or C 1-6 alkyl; or, R2and R3, together with the C atom to which they are attached, form a 3- to 10-membered cycloalkyl; optionally, said alkyl and cycloalkyl are substituted with a substituent selected from F, Cl, Br, I, or C

[0012] R4and R5are each independently selected from H or C 1-10 alkyl; or, R2and R3, together with the C atom to which they are attached, form a 3- to 10-membered cycloalkyl; optionally, said alkyl and cycloalkyl are substituted with a substituent selected from F, Cl, Br, I, or C 1-6 alkyl; or, R2and R3, together with the C atom to which they are attached, form a 3- to 10-membered cycloalkyl; optionally, said alkyl and cycloalkyl are substituted with a substituent selected from F, Cl, Br, I, or C

[0013] R 11 , R 12 , and R 13 are each independently selected from H or C 1-10 alkyl; or, R2and R3, together with the C atom to which they are attached, form a 3- to 10-membered cycloalkyl; optionally, said alkyl and cycloalkyl are substituted with a substituent selected from F, Cl, Br, I, or C 1-6 alkyl; or, R2and R3, together with the C atom to which they are attached, form a 3- to 10-membered cycloalkyl; optionally, said alkyl and cycloalkyl are substituted with a substituent selected from F, Cl, Br, I, or C

[0014] Cy is selected from 4- to 10-membered heteroarylene or 4- to 10-membered heterocycloalkylene; said heteroarylene or heterocycloalkylene contains 1, 2, or 3 heteroatoms selected from N, S, or O; optionally, said heteroarylene and heterocycloalkylene are substituted with a substituent selected from F, Cl, Br, I, or C 1-6 alkyl; or, R2and R3, together with the C atom to which they are attached, form a 3- to 10-membered cycloalkyl; optionally, said alkyl and cycloalkyl are substituted with a substituent selected from F, Cl, Br, I, or C

[0015] L is selected from straight- or branched-chain C 1-10 alkylene; optionally, said alkylene is substituted with a substituent selected from F, Cl, Br, I, or C 1-6 alkyl; or, R2and R3, together with the C atom to which they are attached, form a 3- to 10-membered cycloalkyl; optionally, said alkyl and cycloalkyl are substituted with a substituent selected from F, Cl, Br, I, or C

[0016] n1is a positive integer from 1 to 10.

[0017] According to some embodiments of the present application, wherein,

[0018] R1is selected from -Cy-L-OH, NR 11 R 13 , or N(R 11 )(CH2) n1 N(R 12 )R 13 ; optionally, said -CH2- is substituted with a substituent selected from F, Cl, Br, I, or C 1-3 alkyl; or, R2and R3, together with the C atom to which they are attached, form a 3- to 10-membered cycloalkyl; optionally, said alkyl and cycloalkyl are substituted with a substituent selected from F, Cl, Br, I, or C

[0019] R2and R3are each independently selected from H or C 1-5 alkyl; or, R2and R3, together with the C atom to which they are attached, form a 3- to 10-membered cycloalkyl; optionally, said alkyl and cycloalkyl are substituted with a substituent selected from F, Cl, Br, I, or C 1-3substituted by a substituent selected from F, Cl, Br, I, OH, or C

[0020] R4and R5are each independently selected from H, or C 1-5 alkyl; optionally, said alkyl is substituted by a substituent selected from D, F, Cl, Br, I, or C 1-3 substituted by a substituent selected from F, Cl, Br, I, OH, or C

[0021] R 11 , R 12 , and R 13 are each independently selected from H, or C 1-5 alkyl; optionally, said alkyl is substituted by a substituent selected from F, Cl, Br, I, OH, or C 1-3 substituted by a substituent selected from F, Cl, Br, I, OH, or C

[0022] Cy is selected from 4- to 10-membered heteroarylene or 4- to 10-membered heterocycloalkylene; said heteroarylene or heterocycloalkylene contains 1, 2, or 3 heteroatoms selected from N, S, or O; optionally, said heteroarylene and heterocycloalkylene is substituted by a substituent selected from F, Cl, Br, I, or C 1-3 alkyl; optionally, said alkyl is substituted by a substituent selected from F, Cl, Br, I, OH, or C

[0023] L is selected from straight-chained or branched C 1-5 alkylene; optionally, said alkylene is substituted by a substituent selected from F, Cl, Br, I, or C 1-3 alkyl; optionally, said alkyl is substituted by a substituent selected from F, Cl, Br, I, OH, or C

[0024] n1is a positive integer of 1, 2, 3, 4, or 5.

[0025] According to some embodiments of the present application, wherein,

[0026] R1is selected from -Cy-L-OH, NR 11 R 13 , or N(R 11 )(CH2) n1 N(R 12 )R 13 ; optionally, said -CH2- is substituted by a substituent selected from F, Cl, Br, I, or C 1-3 alkyl; optionally, said alkyl is substituted by a substituent selected from F, Cl, Br, I, OH, or C

[0027] R2and R3are each independently selected from H, or R2and R3form, together with the C atom to which they are attached, a 3- to 6-membered cycloalkyl; optionally, said alkyl and cycloalkyl is substituted by a substituent selected from F, Cl, Br, I, or C 1-3 alkyl; optionally, said alkyl is substituted by a substituent selected from F, Cl, Br, I, OH, or C

[0028] R4and R5are each independently selected from H, methyl, ethyl, propyl, or butyl; optionally, said methyl, ethyl, propyl, or butyl is substituted by a substituent selected from D, F, Cl, Br, or I;

[0029] R 11 , R 12 , and R 13 are each independently selected from H or C 1-5 alkyl; optionally, said alkyl is substituted with a substituent selected from F, Cl, Br, I, OH, or C 1-3 alkyl;

[0030] Cy is selected from 4- to 10-membered heterocycloalkylene; said heterocycloalkylene contains 1, 2, or 3 heteroatoms selected from N, S, or O; optionally, said heterocycloalkylene is substituted with a substituent selected from F, Cl, Br, I, or C 1-3 alkyl;

[0031] L is selected from straight-chain C 1-5 alkylene; optionally, said alkylene is substituted with a substituent selected from F, Cl, Br, I, or C 1-3 alkyl;

[0032] n1 is a positive integer of 1, 2, 3, 4, or 5.

[0033] According to some embodiments of the present application, wherein,

[0034] R1is selected from -Cy-L-OH, NHR 13 , or N(R 11 )(CH2) n1 N(R 12 )R 13 ; optionally, said -CH2- is substituted with a substituent selected from F, Cl, Br, I, or C 1-3 alkyl;

[0035] R2and R3are each independently selected from H, or R2and R3, together with the C atom to which they are attached, form a 3- to 6-membered cycloalkyl; optionally, said alkyl and cycloalkyl are substituted with a substituent selected from F, Cl, Br, I, or C 1-3 alkyl;

[0036] R4and R5are each independently selected from H, methyl, ethyl, propyl, or butyl; optionally, said methyl, ethyl, propyl, or butyl is substituted with a substituent selected from D, F, Cl, Br, or I;

[0037] R 11 , R 12 , and R 13 are each independently selected from H or C 1-5 alkyl; optionally, said alkyl is substituted with a substituent selected from F, Cl, Br, I, OH, or C 1-3 alkyl;

[0038] Cy is selected from 4- to 10-membered heterocyclic alkyl groups; the heterocyclic alkyl group contains 1, 2, or 3 heteroatoms selected from N, S, or O; optionally, the heterocyclic alkyl group is selected from F, Cl, Br, I, or C. 1-3 Substituents of alkyl groups;

[0039] L is selected from the straight chain C. 1-5 Alkylene; optionally, the alkylene is selected from F, Cl, Br, I or C. 1-3 Substituents of alkyl groups;

[0040] n1 is a positive integer of 1, 2, 3, 4 or 5.

[0041] According to some specific embodiments of the present invention, wherein,

[0042] R1 is selected from -Cy-L-OH or N(R) 11 (CH2) n1 N(R 12 )R 13 Optionally, the -CH2- is selected from F, Cl, Br, I or C. 1-6 Substituents of alkyl groups;

[0043] R2 and R3 are each independently selected from H or C. 1-10 Alkyl; or, R2 and R3 form a 3- to 10-membered cycloalkyl group with the C atom to which they are attached; optionally, the alkyl and cycloalkyl groups are selected from F, Cl, Br, I or C. 1-6 Substituents of alkyl groups;

[0044] R4 and R5 are each independently selected from H or C. 1-10 Alkyl; optionally, the alkyl group is selected from D, F, Cl, Br, I or C. 1-6 Substituents of alkyl groups;

[0045] R 11 R 12 and R 13 Each independently selected from H or C 1-10 Alkyl; optionally, the alkyl group is selected from F, Cl, Br, I or C. 1-6 Substituents of alkyl groups;

[0046] Cy is selected from 4- to 10-membered heteroaryl groups or 4- to 10-membered heterocyclic alkyl groups; the heteroaryl group or heterocyclic alkyl group contains 1, 2, or 3 heteroatoms selected from N, S, or O; optionally, the heteroaryl group and heterocyclic alkyl group are selected from F, Cl, Br, I, or C. 1-6 Substituents of alkyl groups;

[0047] L is selected from C, whether it is a straight chain or a branched chain. 1-10alkyl; optionally, said alkyl is substituted with a substituent selected from F, Cl, Br, I, or C 1-6 substituted with a substituent selected from F, Cl, Br, I, or C

[0048] n1 is a positive integer from 1 to 10.

[0049] According to some embodiments of the application, wherein,

[0050] R1 is selected from -Cy-L-OH or N(R 11 )(CH2) n1 N(R 12 )R 13 ; optionally, said -CH2- is substituted with a substituent selected from F, Cl, Br, I, or C 1-3 alkyl; optionally, said alkyl is substituted with a substituent selected from F, Cl, Br, I, or C

[0051] R2 and R3 are each independently selected from H or C 1-5 alkyl; or, R2 and R3 form, with the C atom to which they are attached, a 3- to 6-membered cycloalkyl; optionally, said alkyl and cycloalkyl are substituted with a substituent selected from F, Cl, Br, I, or C 1-3 alkyl; optionally, said alkyl is substituted with a substituent selected from F, Cl, Br, I, or C

[0052] R4 and R5 are each independently selected from H or C 1-5 alkyl; optionally, said alkyl is substituted with a substituent selected from D, F, Cl, Br, I, or C 1-3 alkyl; optionally, said alkyl is substituted with a substituent selected from F, Cl, Br, I, or C

[0053] R 11 , R 12 , and R 13 are each independently selected from H or C 1-5 alkyl; optionally, said alkyl is substituted with a substituent selected from F, Cl, Br, I, or C 1-3 alkyl; optionally, said alkyl is substituted with a substituent selected from F, Cl, Br, I, or C

[0054] Cy is selected from 4- to 10-membered heteroalkylene or 4- to 10-membered heterocycloalkylene; said heteroalkylene or heterocycloalkylene contains 1, 2, or 3 heteroatoms selected from N, S, or O; optionally, said heteroalkylene and heterocycloalkylene are substituted with a substituent selected from F, Cl, Br, I, or C 1-3 alkyl; optionally, said alkyl is substituted with a substituent selected from F, Cl, Br, I, or C

[0055] L is selected from straight or branched C 1-5 alkylene; optionally, said alkylene is substituted with a substituent selected from F, Cl, Br, I, or C 1-3 alkyl; optionally, said alkyl is substituted with a substituent selected from F, Cl, Br, I, or C

[0056] n1 is a positive integer from 1, 2, 3, 4, or 5.

[0057] According to some embodiments of the application, wherein,

[0058] said heteroarylene is selected from one of the following structures:

[0059] said heterocycloalkylene is selected from one of the following structures:

[0060] According to some embodiments of the application, wherein,

[0061] R1is selected from -Cy-L-OH or N(R 11 )(CH2) n1 N(R 12 )R 13 ; optionally, said -CH2- is substituted with a substituent selected from F, Cl, Br, I or C 1-3 alkyl;

[0062] R2and R3are each independently selected from H, or R2and R3, together with the C atom to which they are attached, form a 3- to 6-membered cycloalkyl; optionally, said alkyl and cycloalkyl are substituted with a substituent selected from F, Cl, Br, I or C 1-3 alkyl;

[0063] R4and R5are each independently selected from H, methyl, ethyl, propyl or butyl; optionally, said methyl, ethyl, propyl or butyl are substituted with a substituent selected from D, F, Cl, Br, or I;

[0064] R 11 , R 12 and R 13 are each independently selected from H or C 1-5 alkyl; optionally, said alkyl are substituted with a substituent selected from F, Cl, Br, I or C 1-3 alkyl;

[0065] Cy is selected from 4- to 10-membered heterocycloalkylene; said heterocycloalkylene contains 1, 2 or 3 heteroatoms selected from N, S or O; optionally, said heterocycloalkylene is substituted with a substituent selected from F, Cl, Br, I or C 1-3 alkyl;

[0066] L is selected from straight C 1-5 alkylene; optionally, said alkylene is substituted with a substituent selected from F, Cl, Br, I or C 1-3 alkyl;

[0067] n1is a positive integer of 1, 2, 3, 4 or 5.

[0068] According to some embodiments of the application, wherein,

[0069] R1is selected from -Cy-L-OH or N(R 11(CH2) n1 N(R 12 )R 13 ; optionally, said -CH2- is substituted with a substituent selected from F, Cl, Br, I, or C 1-3 alkyl;

[0070] R2and R3are each independently selected from H, or R2and R3, together with the C atom to which they are attached, form a 3- to 6-membered cycloalkyl; optionally, said alkyl and cycloalkyl are substituted with a substituent selected from F, Cl, Br, I, or C 1-3 alkyl;

[0071] R4and R5are each independently selected from H, methyl, ethyl, propyl, or butyl; optionally, said methyl, ethyl, propyl, or butyl is substituted with a substituent selected from D, F, Cl, Br, or I;

[0072] R 11 , R 12 , and R 13 are each independently selected from H or C 1-5 alkyl; optionally, said alkyl is substituted with a substituent selected from F, Cl, Br, I, or C 1-3 alkyl;

[0073] Cy is selected from 4- to 10-membered heterocycloalkylene; said heterocycloalkylene contains 1, 2, or 3 heteroatoms selected from N, S, or O; optionally, said heterocycloalkylene is substituted with a substituent selected from F, Cl, Br, I, or C 1-3 alkyl;

[0074] L is selected from straight-chain C 1-5 alkylene; optionally, said alkylene is substituted with a substituent selected from F, Cl, Br, I, or C 1-3 alkyl;

[0075] n1is a positive integer of 1, 2, 3, 4, or 5.

[0076] According to some embodiments of the application, R2and R3are each independently selected from H.

[0077] According to some embodiments of the application, Cy is selected from 4- to 10-membered heterocycloalkylene; said heterocycloalkylene contains 1, 2, or 3 heteroatoms selected from N; optionally, said heterocycloalkylene is substituted with a substituent selected from F, Cl, Br, I, or C 1-3 alkyl.

[0078] According to some embodiments of the application, said heterocycloalkylene is selected from one of the following structures:

[0079] According to some embodiments of the present application, wherein,

[0080] R1is selected from NHR 13 or NH(CH2) n1 NH2; optionally, said -CH2- is substituted with a substituent selected from F, Cl, Br, I or C 1-3 alkyl;

[0081] R2and R3are each independently selected from H;

[0082] R4is selected from H;

[0083] R5is selected from H, methyl, ethyl, propyl or butyl; optionally, said methyl, ethyl, propyl or butyl is substituted with a substituent selected from D, F, Cl, Br, or I;

[0084] R 13 is selected from C 1-3 alkyl (e.g., C1, C2, C3alkyl); optionally, said alkyl is substituted with a substituent selected from F, Cl, Br, I or OH;

[0085] L is selected from a straight chain C 1-3 alkylene (e.g., C1, C2, C3alkylene); optionally, said alkylene is substituted with 1 or 2 substituents selected from F, Cl, Br, I or C 1-3 alkyl;

[0086] n1is a positive integer of 1, 2, 3, 4 or 5.

[0087] According to some embodiments of the present application, wherein,

[0088] R1is selected from NH(CH2) n1 NH2; optionally, said -CH2- is substituted with a substituent selected from F, Cl, Br or I;

[0089] R2and R3are each independently selected from H;

[0090] R4is selected from H;

[0091] R5is selected from H, methyl, ethyl, propyl or butyl; optionally, said methyl, ethyl, propyl or butyl is substituted with a substituent selected from F, Cl, Br, or I;

[0092] n1is a positive integer of 1, 2, 3, 4 or 5.

[0093] According to some embodiments of the present application, wherein, the structure of the amphotericin B amide derivative is selected from one of the following structures:

[0094] In another aspect, the present application also provides a pharmaceutical composition comprising a therapeutically effective amount of any of the amphotericin B amide derivatives or stereoisomers, pharmaceutically acceptable salts or deuterated forms thereof, and a pharmaceutically acceptable carrier.

[0095] In still another aspect, the present application also provides use of any of the amphotericin B amide derivatives or stereoisomers, pharmaceutically acceptable salts or deuterated forms thereof, or the pharmaceutical composition of the present application in the preparation of an antifungal medicament. DETAILED DESCRIPTION

[0096] The following detailed description of the implementation process and the beneficial effects of the present application is intended to help the reader better understand the essence and characteristics of the present application, and is not intended to limit the scope of the present application.

[0097] Synthesis of intermediate C2’epiAmB (Ref: Nature, 2023, 623, 1079-1085)

[0098] Step 1: Synthesis of intermediate Int 1

[0099] Method: Amphotericin B (65 g, about 70.3 mmol) was added to DMF / MeOH (1:1, 500 mL) to form a yellow suspension, pyridine (45 mL) was added, and then allylsuccinimidyl carbonate (32 g, 161 mmol) was added. The reaction was stirred at room temperature for 16 hours. After the reaction was completed, the reaction was added dropwise to methyl tert-butyl ether (8 L) under vigorous stirring to precipitate a yellow solid, which was filtered, washed with methyl tert-butyl ether, and dried under reduced pressure to obtain a yellow solid powder Int 1 (70 g, crude).

[0100] MS (ESI, m / z) 1009 [M+H] + .

[0101] Step 2: Synthesis of intermediate Int 2

[0102] Method: Int 1 (72.5 g, crude, about 70 mmol) was added to MeOH (500 mL) to form a yellow suspension, 4-methoxybenzaldehyde dimethyl acetal (51 g, 280 mmol) was added, and then D(+)-10-camphorsulfonic acid (4.9 g, 21 mmol) was added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, triethylamine (5 mL) was added to quench the reaction, and the reaction was added dropwise to n-hexane / methyl tert-butyl ether (5:3, 8 L) under vigorous stirring to precipitate a yellow solid, which was filtered, washed with n-hexane, and dried under reduced pressure to obtain a yellow solid powder Int 2 (75 g, crude).

[0103] MS (ESI, m / z) 1259 [M+H] + .

[0104] Step 3: Synthesis of intermediate Int 3

[0105] Method: Int 2 (75 g, crude, about 70 mmol) was dissolved in DMF / MeOH (10:1, 385 mL), DIPEA (N,N-diisopropylethylamine) (45 mL) was added, then 3-bromopropene (60 mL, 84 g, 694 mmol) was added, the reaction was stirred at room temperature for 12 hours. After the reaction was completed, the reaction was quenched by adding to 1 L of saturated sodium bicarbonate solution, extracted with EA for 3 times, the organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure and purified by column chromatography (PE:EA = 1:1 to 1:2) to obtain yellow solid powder Int 3 (34 g, yield 38.4%).

[0106] MS (ESI, m / z) 1299 [M+H] + .

[0107] Step 4: Synthesis of intermediate Int 4

[0108] Method: DMAP (5.0 g, 40.6 mmol) was dissolved in THF (300 mL), 4-tert-butylbenzoyl chloride (7.0 g, 35.6 mmol) was added dropwise under stirring to obtain a uniform white suspension; Int 3 (33 g, 25.4 mmol) was dissolved in THF (500 mL), DIPEA (5.2 g, 40.6 mmol) was added, then the above white suspension was slowly added dropwise (45 minutes), and stirred for half an hour after dropwise addition was completed. After the reaction was completed, the reaction was quenched by adding to 1 L of saturated sodium bicarbonate solution, extracted with EA for 2 times, the organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure and purified by column chromatography (PE:EA = 2:1 to 1:1.5) to obtain yellow solid powder Int 4 (19 g, yield 51.1%).

[0109] MS (ESI, m / z) 1460 [M+H] + .

[0110] Step 5: Synthesis of intermediate Int 5

[0111] Method: Int 4 (40 g, 27.4 mmol) was dissolved in DCM / hexane (1:1, 800 mL), 2,6-lutidine (20.5 g, 192 mmol) was added, and the temperature was lowered to 0-5 °C. Diethylisopropylsilyl triflate (DEIPSOTf, 38 g, 136.6 mmol) was added dropwise, and the stirring was continued for 1 h in an ice water bath. After the reaction was completed, the reaction solution was added to 1 L of saturated sodium bicarbonate solution to quench, and EA was extracted twice. The organic phase was combined and washed with copper sulfate solution to remove 2,6-lutidine, and then concentrated brine was continuously washed, dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain yellow solid powder Int 5 (36 g, yield 66.6%).

[0112] MS (ESI, m / z) 1971 [M+H] + .

[0113] Step 6: Synthesis of intermediate Int 6

[0114] Method: Int 5 (25 g, 12.6 mmol) was dissolved in THF / MeOH (1:2, 450 mL), and KCN (1.24 g, 19 mmol) was added. After replacing nitrogen, it was stirred at 40 °C for 24 h. The reaction solution was added to EA and saturated sodium bicarbonate solution, and the extraction was separated. The aqueous phase was extracted with EA twice, and the organic phase was combined and washed with concentrated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then column chromatographed (PE:EA = 15:1 to PE:EA = 5:1) to obtain yellow solid powder Int 6 (8.5 g, yield 37.2%) and the raw material Int 5 (7 g) was recovered.

[0115] MS (ESI, m / z) 1812 [M+H] + .

[0116] Step 7: Synthesis of intermediate Int 7

[0117] 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, after replaced with nitrogen, dropwise added DIAD (diisopropyl azodicarboxylate) (13 mL, 66.2 mmol) in toluene (6 mL) under ice water bath, after the addition, continued to stir for 1 hour under ice water bath, then warmed to 70 °C for 2 hours. After the reaction, the reaction solution was cooled to room temperature, added to EA (100 mL) and saturated sodium bicarbonate solution (400 mL), extracted and separated, the organic phase was washed with water once, the water phase before and after was combined, extracted with EA twice, all the organic phase was combined, washed with concentrated brine, dried with anhydrous sodium sulfate, concentrated under reduced pressure, then purified by column chromatography (PE:EA = 15:1 to PE:EA = 10:1) to obtain yellow solid powder Int 7 (9.6 g, yield 45%).

[0118] MS (ESI, m / z) 1960 [M+H] + .

[0119] Step 8: Synthesis of intermediate Int 8

[0120] Method: Int 7 (12 g, 6.1 mmol) was dissolved in THF / MeOH (2:1, 110 mL), added KCN (0.6 g, 9.2 mmol), replaced with nitrogen, stirred at 40 °C for 24 hours. The reaction solution was added to EA and saturated sodium bicarbonate solution, extracted and separated, the water phase was extracted with EA twice, the organic phase was combined, washed with concentrated brine, dried with anhydrous sodium sulfate, concentrated under reduced pressure, then purified by column chromatography (PE:EA = 15:1 to PE:EA = 10:1) to obtain yellow solid powder Int 8 (7.9 g, yield 71.5%).

[0121] MS (ESI, m / z) 1812 [M+H] + .

[0122] Step 9: Synthesis of intermediate Int 9

[0123] Method: Int 8 (10 g, 5.5 mmol) was dissolved in THF (60 mL) and cooled in an ice water bath to form reaction solution A. MeOH (122 mL) and pyridine (23 mL) were mixed and cooled in an ice water bath. Hydrogen fluoride-pyridine (17.3 mL, 65-85% content) was slowly added to the mixture to form reaction solution B. Reaction solution B was slowly added to reaction solution A. After the addition was completed, the reaction solution was allowed to warm to room temperature and stirred for 2.5 hours. After the reaction was completed, the reaction solution was cooled in an ice water bath. Saturated sodium bicarbonate solution (200 mL) was added to quench the reaction. After stirring for 20 minutes, saturated sodium bicarbonate solution (200 mL) and EA (200 mL) were added. The organic phase was extracted once more with EA. The combined organic phases were washed with saturated sodium bicarbonate solution, water, and brine, successively. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 100:0 to DCM:MeOH = 97:3) to obtain yellow solid powder Int 9 (5.1 g, 71% yield).

[0124] MS (ESI, m / z) 1299 [M+H] + .

[0125] Step 10: Synthesis of intermediate Int 10

[0126] 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-neck flask. A solution of thiosalicylic acid (3.03 g, 19.6 mmol) in DMF (120 mL) was added dropwise. After the addition was completed, the reaction was replaced with nitrogen and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was added dropwise to vigorously stirred ether (2 L). The solution was allowed to stand to separate into layers. The supernatant was poured out, and the turbid lower layer was filtered to obtain a yellow solid. The yellow solid was added to MeOH (40 mL) to form a suspension. The suspension was added dropwise to vigorously stirred ether (500 mL). After filtration, the residue was dried under reduced pressure to obtain yellow solid powder Int 10 (3.75 g, 82% yield).

[0127] MS (ESI, m / z) 1175 [M+H] + .

[0128] Step 11: Synthesis of intermediate C2’epiAmB

[0129] Method: Int 10 (200 mg, 0.17 mmol) was dissolved in ACN / H2O (2:1, 84 mL) and cooled in an ice water bath. D(+)-10-camphorsulfonic acid (3.0 g, 12.93 mmol) was added slowly. The reaction was stirred at room temperature for 2 hours. The reaction was quenched by the addition of TEA (2.8 mL). The reaction was concentrated under reduced pressure. The residue was added to Et2O / ACN (10:1, 220 mL) and stirred for 10 minutes. The yellow solid was collected by centrifugation. The solid was dissolved in ACN (120 mL) and the yellow solid was collected by centrifugation. The crude C2’epiAmB (140 mg, crude, HPLC purity 50%) was used directly in the next reaction.

[0130] MS (ESI, m / z) 924 [M+H] + .

[0131] 1 H NMR (600 MHz, CD3OD:Pyridine-d5 = 1:1) δ 1.18 (d, J = 7.0 Hz, 3H), 1.25 (d, J = 6.4 Hz, 4H), 1.37 (d, J = 6.4 Hz, 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 = 9.4 Hz, 1H), 3.44-3.46 (m, 2H), 3.52-3.57 (m, 2H), 3.68-3.82 (m, 2H), 3.88 (d, J = 10.3 Hz, 1H), 3.98 (t, J = 9.7 Hz, 1H), 4.49 (t, J = 9.8, 1H), 4.69 (t, J = 10.8 Hz, 1H), 4.77 (s, 2H), 4.89 (d, J = 7.6 Hz, 1H), 4.99 (t, J = 9.6 Hz, 1H), 5.66 (d, J = 7.2 Hz, 1H), 6.30-6.67 (m, 14H).

[0132] Example 1: Synthesis of BX20-11-015

[0133] Step 1: Synthesis of Intermediate 15-2

[0134] Method: Compound 15-1 (5.0 g, 16.0 mmol) was dissolved in DMF (60 mL), and then NHS (N-hydroxysuccinimide) (2.0 g, 17.6 mmol) and DCC (dicyclohexyl carbodiimide) (3.6 g, 17.6 mmol) were added. The reaction was stirred at room temperature for 12 hours. After the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in EA, and the insoluble matter was filtered off. The filtrate was washed with saturated NaHCO3solution and concentrated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a light yellow solid 15-2 (3.5 g, crude).

[0135] MS (ESI, m / z) 409 [M+H] + .

[0136] Step 2: Synthesis of intermediate 15-3

[0137] Method: Compound C2'epiAmB (150 mg, about 0.075 mmol) and 15-2 (185 mg, 0.45 mmol) were dissolved in DMAc (N,N-dimethylacetamide) (5 mL), and then pyridine (103 mg, 1.3 mmol) was added dropwise. The reaction was stirred at room temperature for 16 hours. After the reaction, the reaction mixture was added dropwise to methyl tert-butyl ether (200 mL), and centrifuged (3000 rpm, 5 min) to obtain a yellow solid powder 15-3 (120 mg, crude).

[0138] MS (ESI, m / z) 1218 [M+H] + .

[0139] Step 3: Synthesis of intermediate N2

[0140] Method: Compound 4-(1-hydroxy-2-methylpropan-2-yl)piperazine-1-carboxylic acid tert-butyl ester (1 g, 3.8 mmol) was dissolved in DCM (10 mL), and then HCl / 1,4-dioxane (4 M, 9 mL, 36 mmol) was added. The reaction was stirred at room temperature for 1 hour. After the reaction, the reaction mixture was directly concentrated under reduced pressure to obtain a white solid N2 (900 mg, hydrochloride).

[0141] MS (ESI, m / z) 159 [M+H] + .

[0142] Step 4: Synthesis of intermediate 15-4

[0143] Method: 15-3 (120 mg, crude, ca. 0.07 mmol) was dissolved in DMF (5 mL), intermediate N2 (100 mg, hydrochloride salt, ca. 0.4 mmol) was added, followed by TEA to adjust the pH of the reaction system to 9-10, PyAOP (hexafluorophosphoric acid (7-azabenzotriazol-1- oxy)tripyrrolidinophosphonium) (146 mg, 0.28 mmol) was added, and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was added dropwise to methyl tert-butyl ether (200 mL) under vigorous stirring, centrifuged (3000 rpm, 5 min) to obtain yellow solid 15-4 (110 mg, crude).

[0144] MS (ESI, m / z) 1358 [M+H] + .

[0145] Step 5: Synthesis of the target product BX20-11-015

[0146] Method: 15-4 (110 mg, crude) was dissolved in DMF (3 mL), piperidine (170 mg, 2 mmol) was added, and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly purified by preparative chromatography (95:5 to 67:33, aq. HCOOH (1 ‰) / MeCN), and after lyophilization, yellow solid powder BX20-11-015 (12 mg, yield 14%) was obtained.

[0147] MS (ESI, m / z) 1136 [M+H] + .

[0148] 1H NMR (400 MHz, CD3OD:Pyridine-d5 = 1 : 1) δ 1.09 (s, 6 H), 1.16 (d, J = 7.2 Hz, 3 H), 1.24 (d, J = 6.4 Hz, 3 H), 1.35 (d, J = 6.4 Hz, 3 H), 1.41 (d, J = 6.0 Hz, 3 H), 1.44-1.49 (m, 1 H), 1.54-1.62 (m, 3 H), 1.68-1.81 (m, 3 H), 1.82-1.90 (m, 2 H), 1.94-2.08 (m, 3 H), 2.11-2.22 (m, 2 H), 2.28-2.37 (m, 2 H), 2.45-2.66 (m, 4 H), 2.71-2.73 (m, 1 H), 2.83 (s, 2 H), 2.84-2.88 (m, 2 H), 2.92-2.99 (m, 1 H), 3.33-3.37 (m, 2 H), 3.40-3.45 (m, 1 H), 3.52-3.68 (m, 5 H), 3.85-3.97 (m, 6 H), 4.25 (t, J = 10.0 Hz, 1 H), 4.42-4.48 (m, 1 H), 4.61-4.72 (m, 4 H), 5.08 (t, J = 9.6 Hz, 1 H), 5.45-5.50 (m, 1 H), 5.63-5.65 (m, 1 H), 6.30-6.69 (m, 14 H).

[0149] Example 2: Synthesis of BX20-11-018

[0150] Step 1: Synthesis of intermediate 16-2

[0151] Method: Compound Fmoc-glycine 16-1 (5 g, 16.8 mmol) was dissolved in DCM (60 mL), then NHS (2.03 g, 17.7 mmol) and DCC (3.64 g, 17.7 mmol) were added, and the reaction was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with DCM, and the combined filtrate was concentrated under reduced pressure. The residue was dissolved in EA (part of the solid was not dissolved), and the solution was filtered to obtain a filtrate, which was washed with saturated aqueous sodium bicarbonate solution, water, and saturated aqueous sodium chloride solution, respectively, and dried over anhydrous sodium sulfate. After being concentrated under reduced pressure, a light yellow solid 16-2 (3.5 g, crude) was obtained.

[0152] MS (ESI, m / z) 395 [M+H] + .

[0153] Step 2: Synthesis of intermediate 16-3

[0154] Method: C2'epiAmB (100 mg, crude, HPLC purity about 50%, about 0.05 mmol) was dissolved in DMAc (5 mL), 16-2 (120 mg, 0.3 mmol) was added, then pyridine (47 mg, 0.6 mmol) was added, the reaction was stirred at room temperature for 16 hours. After the reaction, the reaction solution was added dropwise to methyl tert-butyl ether (200 mL) under vigorous stirring, centrifugation (3000 rpm, 5 min) to obtain yellow solid powder 16-3 (110 mg, crude).

[0155] MS (ESI, m / z) 1024 [M+H] + .

[0156] Step 3: Synthesis of intermediate 18-1

[0157] Method: 16-3 (150 mg, crude, about 0.08 mmol) was dissolved in DMAc (3 mL), N-hydroxyethylpiperazine (39 mg, 0.3 mmol) was added, then NMM (N-methylmorpholine) was added to adjust the pH of the reaction system to 9-10, after stirring for 5 minutes, PyAOP (104 mg, 0.2 mmol) was added, the reaction was stirred at room temperature for 12 hours. After the reaction, the reaction solution was added dropwise to methyl tert-butyl ether (200 mL) under vigorous stirring, centrifugation (3000 rpm, 5 min) to obtain yellow solid 18-1 (160 mg, crude).

[0158] MS (ESI, m / z) 1316 [M+H] + .

[0159] Step 4: Synthesis of target product BX20-11-018

[0160] Method: Crude 18-1 (160 mg) was dissolved in DMF (3 mL), piperidine (170 mg, 2 mmol) was added, the reaction was stirred at room temperature for 1 hour. After the reaction, the reaction solution was directly purified by preparative chromatography (95:5 to 64:36, aq. HCOOH (1 ‰) / MeCN), and after freeze-drying, yellow solid powder BX20-11-018 (10 mg, yield 11%) was obtained.

[0161] MS (ESI, m / z) 1094 [M+H] + .

[0162] 1H NMR (400 MHz, CD3OD:Pyridine-d5 = 1 : 1) δ 1.15 (d, J = 7.2 Hz, 3H), 1.23 (d, J = 6.4 Hz, 3H), 1.35 (d, J = 6.4 Hz, 3H), 1.39-1.42 (m, 3H), 1.48-1.50 (m, 1H), 1.53-1.59 (m, 2H), 1.63-1.71 (m, 3H), 1.73-1.80 (m, 2H), 1.86-1.90 (m, 1H), 1.92-2.02 (m, 3H), 2.11-2.18 (m, 2H), 2.27-2.38 (m, 2H), 2.44-2.63 (m, 9H), 2.66-2.72 (m, 2H), 2.93 (t, J = 10.0 Hz, 1H), 3.32-3.37 (m, 2H), 3.45-3.53 (m, 1H), 3.58-3.64 (m, 2H), 3.72-3.85 (m, 6H), 3.92-3.97 (m, 2H), 4.22-4.28 (m, 1H), 4.41-4.46 (m, 1H), 4.60-4.68 (m, 4H), 5.07 (t, J = 9.6 Hz, 1H), 5.45-5.50 (m, 1H), 5.62-5.65 (m, 1H), 6.28-6.68 (m, 14H).

[0163] Example 3: Synthesis of BX20-11-019

[0164] Step 1: Synthesis of intermediate 19-1

[0165] Method: Dissolve 15-3 (150 mg, crude, about 0.08 mmol) in DMAc (3 mL), add N-hydroxyethylpiperazine (39 mg, 0.3 mmol), then adjust the pH of the reaction system to 9-10 by adding NMM, and then add PyAOP (104 mg, 0.2 mmol). Stir the reaction at room temperature for 12 hours. After the reaction is complete, add the reaction solution dropwise to vigorously stirred methyl tert-butyl ether (200 mL), and centrifuge (3000 rpm, 5 min) to obtain yellow solid 19-1 (150 mg, crude).

[0166] MS (ESI, m / z) 1330 [M+H] + .

[0167] Step 2: Synthesis of target product BX20-11-019

[0168] Method: The crude 19-1 (150 mg) was dissolved in DMF (5 mL), piperidine (170 mg, 2 mmol) was added, and the reaction was stirred at room temperature for 30 min. After the reaction was completed, the reaction solution was directly purified by preparative chromatography (95:5 to 64:36, aq. HCOOH (1 ‰) / MeCN), and BX20-11-019 (15 mg, 16% yield) was obtained as a yellow solid powder after lyophilization.

[0169] MS (ESI, m / z) 1108 [M+H] + .

[0170] 1 H NMR (400 MHz, CD3OD:Pyridine-d5 = 1:1) δ 1.15 (d, J = 7.2 Hz, 3H), 1.23 (d, J = 6.4 Hz, 3H), 1.34 (d, J = 6.4 Hz, 3H), 1.40 (d, J = 6.0 Hz, 3H), 1.44-1.47 (m, 1H), 1.53-1.62 (m, 2H), 1.63-1.67 (m, 1H), 1.72-1.79 (m, 3H), 1.82-1.89 (m, 2H), 1.93-2.02 (m, 3H), 2.07-2.18 (m, 2H), 2.28-2.38 (m, 2H), 2.42-2.48 (m, 2H), 2.50-2.62 (m, 5H), 2.69 (br s, 2H), 2.81 (s, 2H), 2.88-3.00 (m, 2H), 3.31-3.36 (m, 2H), 3.56-3.65 (m, 2H), 3.65-3.85 (m, 5H), 3.87-3.93 (m, 4H), 4.21 (t, J = 10.4 Hz, 1H), 4.41-4.46 (m, 1H), 4.58-4.67 (m, 4H), 5.05 (t, J = 9.6 Hz, 1H), 5.44-5.50 (m, 1H), 5.62-5.65 (m, 1H), 6.29-6.68 (m, 14H).

[0171] Example 4: Synthesis of BX20-11-020

[0172] Step 1: Synthesis of intermediate 20-1

[0173] Method: 16-3 (110 mg, crude, about 0.05 mmol) was dissolved in DMAc (3 mL), 2-amino-N,N,N-trimethylethanaminium chloride hydrochloride (42 mg, 0.24 mmol) was added, then NMM 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 completed, the reaction solution was added dropwise into methyl tert-butyl ether (200 mL), and centrifugation (3000 rpm, 5 min) was performed to obtain yellow solid powder 20-1 (120 mg, crude).

[0174] MS (ESI, m / z) 1468 [M+H] + .

[0175] Step 2: Synthesis of target product BX20-11-020

[0176] Method: Intermediate 20-1 (120 mg, crude) was dissolved in DMF (3 mL), and piperidine (85 mg, 1 mmol) was added dropwise, and the reaction was stirred at room temperature for half an hour. After the reaction was completed, the reaction solution was directly filtered and purified by preparative chromatography (95:5 to 66:34, aq. HCOOH (1 ‰) / MeCN), and after freeze-drying, yellow solid powder BX20-11-020 (8 mg, yield 12%) was obtained.

[0177] MS (ESI, m / z) 1024 [M+H] + .

[0178] 1H NMR (400 MHz, CD3OD:Pyridine-d5 = 1 : 1) δ 1.13 (d, J = 7.2 Hz, 3H), 1.22 (d, J = 6.4 Hz, 3H), 1.32 (d, J = 6.4 Hz, 3H), 1.39 (d, J = 6.0 Hz, 3H), 1.45-1.56 (m, 3H), 1.61-1.70 (m, 3H), 1.73-1.84 (m, 2H), 1.86-1.97 (m, 2H), 2.02-2.08 (m, 1H), 2.24-2.37 (m, 4H), 2.39-2.48 (m, 2H), 2.49-2.54 (m, 1H), 3.19-3.23 (m, 1H), 3.27-3.38 (m, 4H), 3.50-3.60 (m, 3H), 3.64-3.73 (m, 2H), 3.75-3.81 (m, 2H), 3.90 (t, J = 10.0 Hz, 1H), 4.15 (t, J = 10.0 Hz, 1H), 4.39 (t, J = 10.4 Hz, 1H), 4.57-4.66 (m, 4H), 4.86 (t, J = 9.6 Hz, 1H), 5.46 (dd, J = 14.4 Hz, 10.0 Hz, 1H), 5.58-5.60 (m, 1H), 6.28-6.63 (m, 14H).

[0179] Example 5: Synthesis of BX20-11-021

[0180] Step 1: Synthesis of intermediate 21-1

[0181] Method: Compound 15-3 (100 mg, crude, about 0.05 mmol) was dissolved in DMAc (6 mL), (9H-fluoren-9-yl)methyl (2-aminoethyl)carbamate hydrochloride (95 mg, 0.3 mmol) was added, and then NMM 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 completed, the reaction solution was added dropwise into methyl tert-butyl ether (200 mL), and centrifugation (3000 rpm, 5 min) was performed to obtain yellow solid powder 21-1 (110 mg, crude).

[0182] MS (ESI, m / z) 1482 [M+H] + .

[0183] Step 2: Synthesis of target product BX20-11-021

[0184] Method: Intermediate 21-1 (110 mg, crude) was dissolved in DMF (3 mL), piperidine (85 mg, 1 mmol) was added dropwise, and the reaction was stirred at room temperature for half an hour. After the reaction was completed, the reaction solution was directly filtered and purified by preparative chromatography (95:5 to 67:33, aq. HCOOH (1 ‰) / MeCN), and then freeze-dried to obtain a yellow solid powder BX20-11-021 (3.5 mg, yield 14%).

[0185] MS (ESI, m / z) 1038 [M+H] + .

[0186] 1 H NMR (400 MHz, CD3OD:Pyridine-d5 = 1:1) δ 1.16 (d, J = 7.2 Hz, 3H), 1.24 (d, J = 6.4 Hz, 3H), 1.34 (d, J = 6.4 Hz, 3H), 1.41 (d, J = 6.0 Hz, 3H), 1.46-1.51 (m, 1H), 1.54-1.59 (m, 2H), 1.61-1.70 (m, 3H), 1.74-1.82 (m, 2H), 1.83-1.88 (m, 1H), 1.93-2.04 (m, 3H), 2.05-2.12 (m, 1H), 2.28-2.38 (m, 4H), 2.44-2.58 (m, 3H), 2.65 (s, 2H), 3.34-3.42 (m, 4H), 3.56-3.64 (m, 2H), 3.72-3.76 (m, 4H), 3.85 (d, J = 10.4 Hz, 1H), 3.94 (t, J = 10.0 Hz, 1H), 4.31 (t, J = 10.0 Hz, 1H), 4.44 (t, J = 10.0 Hz, 1H), 4.58-4.73 (m, 4H), 4.91 (t, J = 9.6 Hz, 1H), 5.45-5.51 (m, 1H), 5.62 (d, J = 6.8 Hz, 1H), 6.30-6.65 (m, 14H).

[0187] Example 6: Synthesis of BX20-11-031

[0188] Step 1: Synthesis of intermediate 31-2

[0189] Method: 31-1 (1.0 g, 5.7 mmol) was dissolved in THF (15 mL), cooled in an ice water bath, and NaH (60%, 800 mg, 20 mmol) was added slowly. After the reaction was stirred until no gas was generated, CD3I (1.7 g, 11.7 mmol) was added, and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, water was added to quench the reaction, and THF was removed by concentration under reduced pressure. MTBE was added to extract the reaction, the aqueous phase was adjusted to pH 2-3 with hydrochloric acid (1 N), and EA was added to extract the reaction three times. The combined organic phase was washed with concentrated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain yellow oil intermediate 31-2 (730 mg, crude).

[0190] MS (ESI, m / z) 137 [M- t Bu+H] + .

[0191] Step 2: Synthesis of intermediate 31-3

[0192] Method: 31-2 (730 mg, crude) was dissolved in DCM (10 mL), and HCl / 1,4-dioxane (4 M, 9 mL, 36 mmol) was added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain yellow solid 31-3 (500 mg, crude hydrochloride salt).

[0193] Step 3: Synthesis of intermediate 31-4

[0194] Method: 31-3 (500 mg, hydrochloride salt) was dissolved in saturated NaHCO3 (10 mL), and a solution of FmocOSu (fluorenylmethoxycarbonylsuccinimide) (1.5 g, 4.5 mmol) in 1,4-dioxane (10 mL) was added dropwise. The reaction was stirred at room temperature for 5 hours. After the reaction was completed, saturated NH4Cl was added to quench the reaction, and EA was added to extract the reaction three times. The combined organic phase was washed with concentrated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography was performed to purify the reaction to obtain white solid 31-4 (180 mg, 15% yield).

[0195] MS (ESI, m / z) 315 [M+H] + .

[0196] Step 4: Synthesis of intermediate 31-5

[0197] Method: Compound 31-4 (180 mg, 0.57 mmol) was dissolved in DCM (6 mL), and then NHS (69 mg, 0.6 mmol) and DCC (124 mg, 0.6 mmol) were added. The reaction was stirred at room temperature for 3 hours. After the reaction was completed, the insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in EA, and the insoluble matter was further removed by filtration. The filtrate was washed with saturated NaHCO3solution, concentrated brine, and anhydrous sodium sulfate successively, and finally concentrated under reduced pressure to obtain white solid 31-5 (220 mg, crude).

[0198] MS (ESI, m / z) 412 [M+H] + .

[0199] Step 5: Synthesis of intermediate 31-6

[0200] Method: Compound C2'epiAmB (100 mg, crude, about 0.05 mmol) and 31-5 (85 mg, crude, about 0.2 mmol) were dissolved in DMF (5 mL), and then pyridine (79 mg, 1.0 mmol) was added. The reaction was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was added dropwise into methyl tert-butyl ether (200 mL), and centrifugation (3000 rpm, 5 min) was performed to obtain yellow solid powder 31-6 (100 mg, crude).

[0201] MS (ESI, m / z) 1221 [M+H] + .

[0202] Step 6: Synthesis of intermediate 31-7

[0203] Method: Compound 31-6 (100 mg, crude, about 0.05 mmol) was dissolved in DMAc (6 mL), and then (9H-fluoren-9-yl)methyl (2-aminoethyl)carbamate hydrochloride (38 mg, 0.12 mmol) was added. NMM was added to adjust the pH of the reaction system to 9-10, and finally PyAOP (104 mg, 0.2 mmol) was added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was added dropwise into methyl tert-butyl ether (200 mL), and centrifugation (3000 rpm, 5 min) was performed to obtain yellow solid powder 31-7 (110 mg, crude).

[0204] MS (ESI, m / z) 1485 [M+H] + .

[0205] Step 7: Synthesis of target product BX20-11-031

[0206] Method: Intermediate 31-7 (100 mg, crude) was dissolved in DMF (3 mL), piperidine (85 mg, 1 mmol) was added dropwise, and the reaction was stirred at room temperature for half an hour. After the reaction was completed, the reaction solution was directly filtered and purified by preparative chromatography (95:5 to 65:35, aq. HCOOH (1 ‰) / MeCN), and then freeze-dried to obtain yellow solid powder BX20-11-031 (3.5 mg, with a yield of 6%).

[0207] MS (ESI, m / z) 1041 [M+H] + .

[0208] 1 H NMR (400 MHz, CD3OD:Pyridine-d5 = 1 : 1) δ 1.13 (d, J = 7.2 Hz, 3H), 1.21 (d, J = 6.4 Hz, 3H), 1.31 (d, J = 6.4 Hz, 3H), 1.39 (d, J = 6.0 Hz, 3H), 1.45-1.47 (m, 1H), 1.51-1.56 (m, 3H), 1.62-1.68 (m, 3H), 1.76-1.84 (m, 3H), 1.93-2.04 (m, 4H), 2.25-2.36 (m, 4H), 2.41-2.55 (m, 2H), 3.31-3.36 (m, 3H), 3.49-3.57 (m, 3H), 3.59-3.67 (m, 3H), 3.79-3.82 (m, 2H), 3.90 (t, J = 10.4 Hz, 1H), 4.13 (t, J = 10.0 Hz, 1H), 4.40 (t, J = 9.6 Hz, 1H), 4.56-4.65 (m, 4H), 4.86 (t, J = 9.6 Hz, 1H), 5.43-5.49 (m, 1H), 5.58-5.60 (m, 1H), 6.27-6.63 (m, 14H).

[0209] Example 7: BX20-11-053

[0210] Step 1: Synthesis of intermediate 53-1

[0211] Method: 15-3 (100 mg, crude, about 0.06 mmol) was dissolved in DMAc (5 mL), 2-fluoroethylamine hydrochloride (30 mg, 0.3 mmol) was added, NMM was added to adjust the pH of the reaction system to 9-10, and finally PyAOP (146 mg, 0.28 mmol) was added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was added dropwise to vigorously stirred methyl tert-butyl ether (200 mL), centrifuged (3000 rpm, 5 min), and yellow solid 53-1 (110 mg, crude) was obtained.

[0212] MS (ESI, m / z) 1263 [M+H] + .

[0213] Step 2: Synthesis of the target product BX20-11-053

[0214] Method: 53-1 (110 mg, crude) was dissolved in DMF (3 mL), piperidine (170 mg, 2 mmol) was added, and the reaction was stirred at room temperature for 0.5 h. After the reaction was completed, the reaction solution was directly purified by preparative chromatography (95:5 to 60:40, aq. HCOOH (1 ‰) / MeCN), and after lyophilization, yellow solid powder BX20-11-053 (12 mg, yield 16%) was obtained.

[0215] MS (ESI, m / z) 1041 [M+H] + .

[0216] 1 H NMR (400 MHz, CD3OD:Pyridine-d5 = 1:1) δ 1.10 (d, J = 7.2 Hz, 3H), 1.19 (d, J = 6.4 Hz, 3H), 1.28 (d, J = 6.4 Hz, 3H), 1.34 (d, J = 6.0 Hz, 3H), 1.37-1.39 (m, 1H), 1.44-1.54 (m, 3H), 1.57-1.70 (m, 3H), 1.76-2.03 (m, 6H), 2.18-2.30 (m, 3H), 2.33-2.43 (m, 2H), 2.45-2.52 (m, 1H), 2.63 (s, 2H), 3.20-3.34 (m, 3H), 3.45-3.56 (m, 3H), 3.63-3.78 (m, 3H), 3.83-3.88 (m, 1H), 4.07 (t, J = 10.0 Hz, 1H), 4.31-4.37 (m, 1H), 4.46-4.66 (m, 6H), 4.81 (t, J = 9.2 Hz, 1H), 5.43 (dd, J = 14.0 Hz, 10.0 Hz, 1H), 5.52-5.56 (m, 1H), 6.22-6.60 (m, 14H).

[0217] Example 8: BX20-11-055

[0218] Step 1: Synthesis of intermediate 55-1

[0219] Method: 15-3 (100 mg, crude, ca. 0.06 mmol) was dissolved in DMAc (5 mL), ethanolamine (18 mg, 0.3 mmol) was added, the pH of the reaction system was adjusted to 9-10 by adding NMM, and finally PyAOP (130 mg, 0.25 mmol) was added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was added dropwise to methyl tert-butyl ether (200 mL) stirred vigorously, centrifuged (3000 rpm, 5 min) to obtain yellow solid 55-1 (110 mg, crude).

[0220] MS (ESI, m / z) 1261 [M+H] + .

[0221] Step 2: Synthesis of the target product BX20-11-055

[0222] Method: 55-1 (110 mg, crude) was dissolved in DMF (3 mL), piperidine (170 mg, 2 mmol) was added, and the reaction was stirred at room temperature for 0.5 hours. After the reaction was completed, the reaction solution was directly purified by preparative chromatography (95:5 to 60:40, aq. HCOOH (1 ‰) / MeCN), and after freeze-drying, yellow solid powder BX20-11-055 (13 mg, yield 21%) was obtained.

[0223] MS (ESI, m / z) 1039 [M+H] + .

[0224] 1H NMR (400 MHz, CD3OD:Pyridine-d5 = 1:1) δ 1.12 (d, J = 7.2 Hz, 3H), 1.20 (d, J = 6.4 Hz, 3H), 1.31 (d, J = 6.4 Hz, 3H), 1.35 (d, J = 6.0 Hz, 3H), 1.39-1.52 (m, 4H), 1.57-1.65 (m, 2H), 1.68-1.73 (m, 1H), 1.78-1.97 (m, 5H), 1.99-2.07 (m, 1H), 2.22-2.26 (m, 1H), 2.29-2.44 (m, 4H), 2.48-2.55 (m, 1H), 2.71 (s, 2H), 3.20-3.35 (m, 3H), 3.40-3.46 (m, 3H), 3.50-3.65 (m, 3H), 3.75-3.81 (m, 4H), 3.88 (t, J = 9.6 Hz, 1H), 4.13 (t, J = 10.0 Hz, 1H), 4.35-4.40 (m, 1H), 4.55-4.65 (m, 4H), 4.83-4.90 (m, 1H), 5.45 (dd, J = 14.0 Hz, 10.0 Hz, 1H), 5.54-5.59 (m, 1H), 6.22-6.64 (m, 14H).

[0225] Comparative Example 1:

[0226] Comparative Example 1 was synthesized according to the synthetic method of compound 1 in patent CN116323632A.

[0227] 1H NMR (600 MHz, CD3OD:Pyridine-d5 = 1 : 1) δ 1.17 (d, J = 7.2 Hz, 3H), 1.25 (d, J = 6.6 Hz, 3H), 1.36 (d, J = 6.6 Hz, 3H), 1.39 (d, J = 6.0 Hz, 3H), 1.44-1.47 (m, 1H), 1.51-1.56 (m, 2H), 1.56-1.63 (m, 1H), 1.63-1.72 (m, 2H), 1.75-1.87 (m, 2H), 1.93-2.02 (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 = 10.2 Hz, 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 = 7.8 Hz, 1H), 4.77 (ddd, J = 11.4, 10.2, 4.8 Hz, 1H), 5.03 (t, J = 9.6 Hz, 1H), 5.45-5.51 (m, 1H), 5.64-5.68 (m, 1H), 6.25-6.67 (m, 14H).

[0228] Biological test evaluation

[0229] The present application is further described below in connection with test examples

[0230] Test Example 1 In vitro antifungal activity of compounds of the present application

[0231] 1. Purpose of the experiment

[0232] The in vitro fungistatic concentration of the compounds of the present application was tested.

[0233] 2. Experimental materials

[0234] 2.1. The compounds of the present application and the reference compounds were self-made.

[0235] 2.2. The strains to be tested were provided by Shanghai Pharmaron.

[0236] 3. Test method

[0237] The detection method of the minimum inhibitory concentration (MIC) was performed according to CLSI M27, CLSI M38 and CLSI M60.

[0238] 3.1. Preparation of test compounds

[0239] The test compounds were dissolved in appropriate solvents to prepare high concentration stock solutions, which were used on the day of testing or stored at -20°C or lower. On the day of testing, the stock solutions of compounds were diluted in 2-fold gradient, to prepare working solutions of compounds at 100x the final concentration of the test, and 2 μL was transferred to 96-well plates to obtain the compound test plates.

[0240] 3.2. Preparation of inoculum

[0241] 3.2.1. Preparation of inoculum for yeast-like fungi

[0242] The -80°C glycerol stock was inoculated into SDA plates and incubated at 35±2°C overnight. On the day of testing, a single colony was picked and suspended in sterile physiological saline to prepare a 0.5 McFarland bacterial suspension. The bacterial suspension was then diluted 2000-fold in RPMI 1640 (pH 7.0) medium to obtain the inoculum (0.5 x 10 3 ~ 2.5 x 10 3 CFU / mL). 198 μL of the inoculum was added to the compound test plates prepared in 3.1.

[0243] 3.2.2. Preparation of inoculum for filamentous fungi (non-dermatophytic molds)

[0244] The -80°C glycerol stock was inoculated into PDA or SDA plates and incubated at 35±2°C for 2-7 days. On the day of testing, the spores were collected from the plates and suspended in sterile physiological saline (or with 0.1% Tween 20) and the spore number was counted using a cell counter. The spore suspension was then diluted to 0.2-2.5 x 10 4 CFU / mL in RPMI 1640 (pH 7.0) medium to obtain the inoculum of spores. 198 μL of the inoculum of spores was added to the compound test plates prepared in 3.1.

[0245] 3.3. MIC reading

[0246] Yeast-like fungi: The minimum compound concentration (MIC) that gave 100% or >50% inhibition was read by naked eye after incubation of the test plates at 35o±2°C for 24 h.

[0247] Filamentous fungi (non-dermatophytic molds): The minimum compound concentration (MIC) that gave 100%, >80% or >50% inhibition was read by naked eye after incubation of the test plates at 35±2°C for 48 h.

[0248] 4. Test results

[0249] Table 1. Minimum inhibitory concentration (MIC, ug / mL) of the compounds of the present application Table 1. Minimum inhibitory concentration (MIC, ug / mL) of the compounds of the present application

[0250] Conclusion: As shown in Table 1, the compounds of the present application have good inhibitory effect on the growth of Candida albicans, Aspergillus fumigatus and Aspergillus flavus.

[0251] Test Example 2 In vitro human liver microsomal stability assay

[0252] 1. Test method:

[0253] The final incubation reaction solution contained phosphate buffer (pH 7.4, 100 mM, 216.25 μL, final concentration 100 mM), positive control compound (verapamil) or 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 min, NADPH (10 mM, 25 μL) was added to start the reaction. At fixed time points (0.5, 5, 15, 30, 60 min), a fixed volume of reaction mixture (30 μL) was sampled to 5-fold volume of cold acetonitrile (containing 200 nM labetalol, 100 nM ketoprofen, 100 nM tolmetin) to terminate the reaction. After centrifugation (3220 g, 40 min), the supernatant (100 μL) was mixed with ultrapure water (100 μL) and then subjected to LC-MS / MS analysis.

[0254] 2. Data analysis

[0255] The peak area was determined from the extracted ion chromatogram. The slope value k was determined from the linear regression of the natural logarithm plot of the percentage of parent drug remaining versus incubation time.

[0256] The in vitro half-life (in vitro t1 / 2) was determined from the slope value: T1 / 2 = 0.693 / k.

[0257] 3. Test results

[0258] The results are shown in Table 2 below:

[0259] Table 2, Human liver microsomal stability of the compounds of the present application

[0260] 4. Conclusion: The compounds of the present application have good metabolic stability in human liver microsomes.

[0261] Test Example 3 SD rat pharmacokinetic assay

[0262] 1. Purpose of the test

[0263] SD rats were used as test animals to test the pharmacokinetic behavior of the compounds of the present application in rat plasma after intravenous injection at a dose of 1 mg / kg.

[0264] 2. Test method

[0265] 2.1. Test drug

[0266] The test drug was prepared by the inventor.

[0267] 2.2. Test animals

[0268] Male SPF SD rats, weighing (200±20) g, 3 rats per compound.

[0269] 2.3. Preparation of test drug

[0270] Drug preparation: The drug concentration was prepared to be 0.2 mg / mL, and the prepared solution was 5% glucose solution for injection.

[0271] 2.4. Drug administration:

[0272] Male SPF SD rats were adaptively fed for 3-4 days, and then tail intravenous injection was performed, with a dose of 1 mg / kg and a volume of 5 mL / kg.

[0273] Blood samples were collected before drug administration (0 h) and after drug administration at 0.0833 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h. The blood was collected from the jugular vein, with a volume of about 0.2 mL, and placed in an EDTA-K2 anticoagulant test tube with a label. After blood collection, the blood collection tube was completely inverted 3 times to mix with the anticoagulant, and then immediately centrifuged at 4000 g at 4°C in an ice water bath for 5 min. After the centrifugation was completed, the plasma was promptly aliquoted into EP tubes with corresponding labels, and stored in a -80°C refrigerator.

[0274] 2.6. Sample detection

[0275] In this experiment, a brief verification LC-MS / MS method was used to determine the concentration of the compound in the plasma after drug administration.

[0276] 2.6.1. Sample processing:

[0277] The analyte stock solution was diluted with acetonitrile solution to obtain the required working solution series concentration. In 50 μL of blank plasma, 5 μL of working solution (10, 20, 50, 100, 200, 500, 1000, 2000, 5000 ng / mL) was added to achieve a calibration standard of 1-500 ng / mL (1, 2, 5, 10, 20, 50, 100, 200, 500 ng / mL) with a total volume of 55 μL. The plasma quality control samples were 2 ng / mL, 5 ng / mL, 50 ng / mL, and 400 ng / mL, which were prepared independently from the samples used for calibration curve. These QC samples were prepared on the same day as the calibration standards.

[0278] Plasma samples from the same point were pooled equally from 3 animals.

[0279] 55 μL of standard, 55 μL of QC sample and 55 μL of unknown sample (50 μL of unknown plasma plus 5 μL of blank solution) were added to 200 μL of IS containing acetonitrile mixture to precipitate the proteins. The samples were then vortexed for 30 s. After centrifugation at 4 °C, 4000 rpm for 15 min, 2 μL of the diluted supernatant was injected into the LC / MS / MS system for quantitative analysis.

[0280] 2.6.2. Liquid chromatography-mass spectrometry analysis:

[0281] 1) Liquid chromatography conditions

[0282] HPLC: Shimadzu Nexera Series System Controller CBM-40, Serial NO. IT23075017; CTO-40A, Serial NO: IT23075008; Prominence Degasser DGU-405, Serial NO: L22176051216US; Shimadzu Nexera Series Pump LC-40D XS, Serial NO. L22426002279AE, L22426002345AE; Shimadzu Nexera Series Autosampler SIL-40C XS, Serial NO. L22456001370; Shimadzu Nexera Series Rack changer Serial NO. L22226000814CZ, L22226000884CZ.

[0283] Chromatographic column: HALO 90A AQ-C18, 2 pm 3.0 x 30 mm

[0284] Mass spectrometry: AB Sciex Triple Quad 6500+ LC / MS / MS instrument (Serial NO. DZ248562305)

[0285] Injection volume: 2 pL

[0286] Mobile phase A: 5% acetonitrile water (0.1% formic acid)

[0287] Mobile phase B: 95% acetonitrile water (0.1% formic acid)

[0288] Flow rate: 0.6 mL / min

[0289] Elution procedure and mobile phase partition ratio: Gradient elution was as shown in Table 3 below.

[0290] Table 3

[0291] 2) Mass spectrometry conditions

[0292] Ion detection mode: Multiple reaction ion monitoring (MRM)

[0293] Ionization mode: Pneumatic assisted electrospray ionization (ESI)

[0294] Ion polarity: Positive ion

[0295] CAD: 9

[0296] CUR: 35 psi

[0297] GS1: 50 psi

[0298] GS2: 50 psi

[0299] TEM: 400℃

[0300] IS: 5500 v

[0301] 3. Test results and analysis

[0302] The main pharmacokinetic parameters were calculated by WinNonlin 8.3, and the results of the rat pharmacokinetic experiment are shown in Table 4 below.

[0303] Table 4, results of rat pharmacokinetic experiment

[0304] 4. Experimental conclusion

[0305] From the results of the rat pharmacokinetic experiment in the table, it can be seen that the compound of the embodiment of the application exhibits good absorption characteristics, the exposure amount is significantly better than that of the comparative example 1 under the same dose, and the half-life is significantly longer, which can maintain the drug efficacy for a longer time.

Claims

1. An amphotericin B amide derivative or its stereoisomer, pharmaceutically acceptable salt, or deuterated derivative, wherein, The amphotericin B amide derivative is represented by formula (I): R1is selected from -Cy-L-OH, NR 11 R 13 or N(R 11 )(CH2) n1 N(R 12 )R 13 ; optionally, said -CH2- is substituted with a substituent selected from F, Cl, Br, I or C 1-6 alkyl; R2and R3are each independently selected from H or C 1-10 alkyl; or, R2and R3, together with the C atom to which they are attached, form a 3- to 10-membered cycloalkyl; optionally, said alkyl and cycloalkyl are substituted with a substituent selected from F, Cl, Br, I, or C 1-6 alkyl; or, R2and R3, together with the C atom to which they are attached, form a 3- to 10-membered cycloalkyl; optionally, said alkyl and cycloalkyl are substituted with a substituent selected from F, Cl, Br, I, or C R4and R5are each independently selected from H or C 1-10 alkyl; optionally, said alkyl is substituted with a substituent selected from D, F, Cl, Br, I, or C 1-6 alkyl; optionally, said alkyl is substituted with a substituent selected from D, F, Cl, Br, I, or C R 11 , R 12 , and R 13 are each independently selected from H or C 1-10 alkyl; optionally, said alkyl is substituted with a substituent selected from F, Cl, Br, I, OH, or C 1-6 alkyl; Cy is selected from a 4- to 10-membered heteroaryl or a 4- to 10-membered heterocycloalkyl; said heteroaryl or heterocycloalkyl contains 1, 2, or 3 heteroatoms selected from N, S, or O; optionally, said heteroaryl and heterocycloalkyl are substituted with 1, 2, or 3 substituents selected from F, Cl, Br, I, or C 1-6 substituted with 1, 2, or 3 substituents selected from F, Cl, Br, I, or C L is selected from a straight-chained or branched C 1-10 alkylene; optionally, the alkylene is substituted with a substituent selected from F, Cl, Br, I, or C 1-6 alkyl; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. n1 is a positive integer of 1 to 10.

2. The amphotericin B amide derivative or a stereoisomer, a pharmaceutically acceptable salt, or a deuterated form thereof according to claim 1, wherein, R1is selected from -Cy-L-OH, NR 11 R 13 or N(R 11 )(CH2) n1 N(R 12 )R 13 ; optionally, said -CH2- is substituted with a substituent selected from F, Cl, Br, I or C 1-3 alkyl; R2and R3are each independently selected from H or C 1-5 alkyl; or, R2and R3, together with the C atom to which they are attached, form a 3- to 6-membered cycloalkyl; optionally, said alkyl and cycloalkyl are substituted with a substituent selected from F, Cl, Br, I, or C 1-3 alkyl; or, R2and R3, together with the C atom to which they are attached, form a 3- to 6-membered cycloalkyl; optionally, said alkyl and cycloalkyl are substituted with a substituent selected from F, Cl, Br, I, or C R4and R5are each independently selected from H or C 1-5 alkyl; optionally, said alkyl is substituted with a substituent selected from D, F, Cl, Br, I, or C 1-3 alkyl; optionally, said alkyl is substituted with a substituent selected from D, F, Cl, Br, I, or C R 11 , R 12 , and R 13 are each independently selected from H or C 1-5 alkyl; optionally, said alkyl is substituted with a substituent selected from F, Cl, Br, I, OH, or C 1-3 alkyl; Cy is selected from a 4- to 10-membered heteroaryl or a 4- to 10-membered heterocycloalkyl; said heteroaryl or heterocycloalkyl contains 1, 2, or 3 heteroatoms selected from N, S, or O; optionally, said heteroaryl and heterocycloalkyl are substituted with 1, 2, or 3 substituents selected from F, Cl, Br, I, or C 1-3 substituted with 1, 2, or 3 substituents selected from F, Cl, Br, I, or C L is selected from a straight-chained or branched C 1-5 alkylene; optionally, the alkylene is substituted with a substituent selected from F, Cl, Br, I, or C 1-3 alkyl; n1 is a positive integer of 1, 2, 3, 4, or 5.

3. The amphotericin B amide derivative or a stereoisomer, a pharmaceutically acceptable salt, or a deuterated form thereof according to claim 1 or 2, wherein, R1is selected from -Cy-L-OH, NR 11 R 13 or N(R 11 )(CH2) n1 N(R 12 )R 13 ; optionally, said -CH2- is substituted with a substituent selected from F, Cl, Br, I or C 1-3 alkyl; R2and R3are each independently selected from H, or R2and R3, together with the C atom to which they are attached, form a 3- to 6-membered cycloalkyl; optionally, the alkyl and cycloalkyl are substituted with a substituent selected from F, Cl, Br, I, or C 1-3 substituted with a substituent selected from F, Cl, Br, I, or C R4 and R5 are each independently selected from the group consisting of H, methyl, ethyl, propyl, or butyl; optionally, the methyl, ethyl, propyl, or butyl is substituted with a substituent selected from the group consisting of D, F, Cl, Br, or I; R 11 , R 12 , and R 13 are each independently selected from H or C 1-5 alkyl; optionally, said alkyl is substituted with a substituent selected from F, Cl, Br, I, OH, or C 1-3 alkyl; Cy is selected from a 4- to 10-membered heterocycloalkylene; said heterocycloalkylene contains 1, 2, or 3 heteroatoms selected from N, S, or O; optionally, said heterocycloalkylene is substituted with a substituent selected from F, Cl, Br, I, or C 1-3 substituted with a substituent selected from F, Cl, Br, I, or C substituted with a substituent selected from F, Cl, Br, I, or C L is selected from the group consisting of a straight chain C 1-5 alkylene; optionally, said alkylene is substituted with a substituent selected from the group consisting of F, Cl, Br, I or C 1-3 alkyl; n1 is a positive integer of 1, 2, 3, 4, or 5.

4. The amphotericin B amide derivative or a stereoisomer, a pharmaceutically acceptable salt, or a deuterated form thereof according to any one of claims 1 to 3, wherein, R1is selected from -Cy-L-OH, NHR 13 or N(R 11 )(CH2) n1 N(R 12 )R 13 ; optionally, said -CH2- is substituted with a substituent selected from F, Cl, Br, I or C 1-3 alkyl; R2and R3are each independently selected from H, or R2and R3, together with the C atom to which they are attached, form a 3- to 6-membered cycloalkyl; optionally, the alkyl and cycloalkyl are substituted with a substituent selected from F, Cl, Br, I, or C 1-3 substituted with a substituent selected from F, Cl, Br, I, or C R4 and R5 are each independently selected from the group consisting of H, methyl, ethyl, propyl, or butyl; optionally, the methyl, ethyl, propyl, or butyl is substituted with a substituent selected from the group consisting of D, F, Cl, Br, or I; R 11 , R 12 , and R 13 are each independently selected from H or C 1-5 alkyl; optionally, said alkyl is substituted with a substituent selected from F, Cl, Br, I, OH, or C 1-3 alkyl; Cy is selected from a 4- to 10-membered heterocycloalkylene; said heterocycloalkylene contains 1, 2, or 3 heteroatoms selected from N, S, or O; optionally, said heterocycloalkylene is substituted with a substituent selected from F, Cl, Br, I, or C 1-3 substituted with a substituent selected from F, Cl, Br, I, or C substituted with a substituent selected from F, Cl, Br, I, or C L is selected from the group consisting of a straight chain C 1-5 alkylene; optionally, said alkylene is substituted with a substituent selected from the group consisting of F, Cl, Br, I or C 1-3 alkyl; n1 is a positive integer of 1, 2, 3, 4, or 5.

5. The amphotericin B amide derivative or a stereoisomer, a pharmaceutically acceptable salt, or a deuterated form thereof according to any one of claims 1 to 4, wherein, R2 and R3 are each independently selected from H.

6. The amide derivative of amphotericin B or a stereoisomer, a pharmaceutically acceptable salt, or a deuterated form thereof according to any one of claims 1 to 5, wherein, Cy is selected from a 4- to 10-membered heterocycloalkylene; said heterocycloalkylene contains 1, 2, or 3 heteroatoms selected from N; optionally, said heterocycloalkylene is substituted with a substituent selected from F, Cl, Br, I, or C 1-3 substituted with a substituent selected from F, Cl, Br, I, or C substituted with a substituent selected from F, Cl, Br, I, or C 7. The amide derivative of amphotericin B or a stereoisomer, a pharmaceutically acceptable salt, or a deuterated form thereof according to claim 6, wherein, Cy is selected from one of the following structures:

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

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

10. Use of the amphotericin B amide derivative or a stereoisomer, a pharmaceutically acceptable salt, or a deuterated form thereof according to any one of claims 1 to 8, or the pharmaceutical composition according to claim 9, for the manufacture of an antifungal agent.

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