Quaternary ammonium salt derivative of amphotericin b and use thereof

Abstract

The present invention provides a quaternary ammonium salt derivative of amphotericin B and a use thereof. The quaternary ammonium salt derivative of amphotericin B is as shown in formula (I), has good antifungal activity, is effective against various fungi, has good water solubility, is suitable for development into an injection dosage form, has excellent metabolic stability in animals and long half-life, can effectively reduce the frequency of administration, has weak inhibition on CYP enzymes, and has low risk of drug interaction.

Description

Amphotericin B quaternary ammonium salt 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 quaternary ammonium salt 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. The incidence of the disease, 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, make the incidence of opportunistic deep organ fungal infection higher and higher, and more and more serious. The incidence of deep fungal infection in the above population is about 11%-40%, and the mortality 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, 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 regarded. 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. Compared with ordinary preparations, amphotericin B liposomes have better tolerance. On the one hand, they can be more distributed in the liver, spleen and lungs, and have lower concentration in other organs, especially in kidney tissues. On the other hand, the cholesterol component in the liposomes can reduce the binding of drugs with cholesterol in human cells and enhance the binding with fungal cell ergosterol, and has relatively small side effects on the kidneys and other organs. 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 renal toxicity and other toxic side effects of amphotericin B have not been fundamentally eliminated.

[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 renal toxicity, red blood cell hemolysis toxicity and other toxic side effects, and 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 quaternary ammonium salt derivative. This type of compound 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, 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 quaternary ammonium salt derivative.

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

[0010] R1, R2, R3 are each independently selected from C 1-10 alkyl, or two of R1, R2, R3 and the N atom to which they are connected form a 3- to 10-membered heterocycloalkyl group containing at least one N atom and 0, 1 or 2 heteroatoms selected from N, O or S; optionally, the alkyl or heterocycloalkyl group is substituted with 1, 2 or 3 substituents selected from F, Cl, Br, I, C 1-6 alkyl, nitro, cyano, carboxyl or hydroxyl;

[0011] In some embodiments, the 3- to 10-membered heterocycloalkyl is selected from one of the following structures:

[0012] R4is selected from H or C 1-10 alkyl; optionally, the alkyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, I, C 1-6 alkyl, nitro, cyano, carboxyl, or hydroxyl;

[0013] R5is selected from H, C 1-10 alkyl, -CO-(CH2) n1 -(O) n2 -(CH2) n3 -NR 51 R 52 , -CO-(CH2) n1 -(O) n2 -(CH2) n3 -OH, -CO-O-(CH2CH2O) n4 -R 53 , -CO-O-(CH2) n5 -O-CO-(CH2) n6 -O-(CH2CH2O) n7 -R 53 , -CO-O-L2-N(R 54 )3 + Cl - or -CO-Cy;

[0014] R 51 , R 52 , and R 53 are each independently selected from H or C 1-10 alkyl; optionally, the alkyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, I, C 1-6 alkyl, nitro, cyano, carboxyl, or hydroxyl;

[0015] each R 54 is independently selected from C 1-10 alkyl; optionally, the alkyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, I, C 1-6 alkyl, nitro, cyano, carboxyl, or hydroxyl;

[0016] L1and L2are each independently a straight or branched alkylene chain of C 1-10 ; optionally, the alkylene is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, I, C 1-6 alkyl, nitro, cyano, carboxyl, or hydroxyl;

[0017] selected from N, O, or S; optionally, said heterocycloalkyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, I, C 1-6 substituted with 1, 2, or 3 substituents selected from F, Cl, Br, I, C

[0018] In some embodiments, the 3- to 10-membered heterocycloalkyl of Cy is selected from one of the following structures:

[0019] In some embodiments, the 3- to 10-membered heterocycloalkyl of Cy contains at least one N atom;

[0020] each n1and n3is independently selected from 0, 1, 2, 3, 4, or 5, and n1and n3are not simultaneously 0;

[0021] each n2is independently 0 or 1;

[0022] n4and n7are each independently a positive integer from 1 to 15;

[0023] n5and n6are each independently selected from 1, 2, 3, 4, or 5.

[0024] According to some embodiments of the application, each of the above-mentioned heterocycloalkyl groups is a monocyclic heterocycloalkyl group.

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

[0026] R1, R2, R3are each independently selected from C 1-5 or, two of R1, R2, R3and the N atom to which they are attached form a 3- to 8-membered heterocycloalkyl group, said heterocycloalkyl group containing at least one N atom, and 0, 1, or 2 heteroatoms selected from N, O, or S; optionally, said alkyl or heterocycloalkyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, I, C 1-3 substituted with 1, 2, or 3 substituents selected from F, Cl, Br, I, C

[0027] R4is selected from H or C 1-5 alkyl; optionally, said alkyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, I, C 1-3 substituted with 1, 2, or 3 substituents selected from F, Cl, Br, I, C

[0028] R5is selected from H, C 1-5 alkyl, -CO-(CH2) n1 -(O) n2 -(CH2) n3 -NR 51 R 52, -CO-(CH2) n1 -(O) n2 -(CH2) n3 -OH, -CO-O-(CH2CH2O) n4 -R 53 , -CO-O-(CH2) n5 -O-CO-(CH2) n6 -O-(CH2CH2O) n7 -R 53 , -CO-O-L2-N(R 54 )3 + Cl - or -CO-Cy;

[0029] R 51 , R 52 and R 53 are each independently selected from H or C 1-5 alkyl; optionally, said alkyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, I, C 1-3 alkyl, nitro, cyano, carboxy, or hydroxy;

[0030] each R 54 is independently selected from C 1-5 alkyl; optionally, said alkyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, I, C 1-3 alkyl, nitro, cyano, carboxy, or hydroxy;

[0031] L1and L2are each independently a straight or branched alkylene chain of C 1-6 ; optionally, said alkylene chain is substituted with substituents selected from F, Cl, Br, I, C 1-3 alkyl, nitro, cyano, carboxy, or hydroxy;

[0032] Cy is selected from a 3- to 8-membered heterocycloalkyl; said heterocycloalkyl contains 1, 2, or 3 heteroatoms selected from N, O, or S; optionally, said heterocycloalkyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, I, C 1-3 alkyl, nitro, cyano, carboxy, or hydroxy;

[0033] each n1and n3is independently selected from 0, 1, 2, 3, 4, or 5, and n1and n3are not simultaneously 0;

[0034] each n2is independently 0 or 1;

[0035] n4and n7are each independently selected from a positive integer from 1 to 15;

[0036] n5and n6are each independently selected from 1, 2, 3, 4, or 5.

[0037] According to some embodiments of the application, wherein,

[0038] R1, R2, R3are each independently selected from C 1-5 alkyl, or two of R1, R2, R3and the N atom to which they are attached form a 3- to 8-membered heterocycloalkyl group, said heterocycloalkyl group containing at least one N atom, and 0, 1 or 2 heteroatoms selected from N, O or S; optionally, said alkyl or heterocycloalkyl group is substituted with 1, 2 or 3 substituents selected from F, Cl, Br, I, C 1-3 alkyl, nitro, cyano, carboxyl or hydroxyl;

[0039] R4is selected from H;

[0040] R5is selected from H, C 1-5 alkyl, -CO-(CH2) n1 -NR 51 R 52 , -CO-(CH2) n1 -O-(CH2) n3 -NR 51 R 52 , -CO-(O) n2 -(CH2) n3 -OH, -CO-O-(CH2CH2O) n4 -R 53 , -CO-O-(CH2) n5 -O-CO-(CH2) n6 -O-(CH2CH2O) n7 -R 53 , -CO-O-L2-N(R 54 )3 + Cl - or -CO-Cy;

[0041] R 51 , R 52 and R 53 are each independently selected from H or C 1-5 alkyl; optionally, said alkyl is substituted with 1, 2 or 3 substituents selected from F, Cl, Br, I, C 1-3 alkyl, nitro, cyano, carboxyl or hydroxyl;

[0042] each R 54 is independently selected from C 1-5 alkyl; optionally, said alkyl is substituted with 1, 2 or 3 substituents selected from F, Cl, Br, I, C 1-3 alkyl, nitro, cyano, carboxyl or hydroxyl;

[0043] L1and L2are each independently a straight chain alkylene; optionally, said alkylene is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, I, C 1-5 alkyl, nitro, cyano, carboxyl, or hydroxyl; 1-3 alkyl, nitro, cyano, carboxyl, or hydroxyl;

[0044] Cy is selected from a 3- to 8-membered heterocycloalkyl; said heterocycloalkyl contains 1, 2, or 3 heteroatoms selected from N, O, or S; optionally, said heterocycloalkyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, I, C 1-3 alkyl, nitro, cyano, carboxyl, or hydroxyl;

[0045] each n1and n3is independently selected from 1, 2, 3, 4, or 5;

[0046] n2is 0 or 1;

[0047] n4is selected from a positive integer from 1 to 15;

[0048] n7is selected from a positive integer from 1 to 12;

[0049] n5and n6are each independently selected from 1, 2, 3, 4, or 5.

[0050] According to some embodiments of the present application, wherein,

[0051] R1, R2, R3are each independently selected from C 1-5 alkyl, or, two of R1, R2, R3and the N atom to which they are attached form a 5- to 6-membered heterocycloalkyl, said heterocycloalkyl contains at least one N atom, and 0 or 1 heteroatom selected from N, O, or S; optionally, said alkyl or heterocycloalkyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, I, or C 1-3 alkyl;

[0052] R4is selected from H;

[0053] R5is selected from H, -CO-(CH2) n11 -NR 51 R 52 , -CO-(CH2) n12 -O-(CH2) n3 -NR 51 R 52 , -CO-O-(CH2) n3 -OH, -CO-O-(CH2CH2O) n4 -R 53 , -CO-O-(CH2) n5 -O-CO-(CH2) n6 -O-(CH2CH2O) n7 -R53 -CO-O-L2-N(R 54 )3 + Cl - or -CO-Cy;

[0054] R 51 is H;

[0055] R 52 and R 53 are each independently selected from H or C 1-5 alkyl; optionally, said alkyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, I, or C 1-3 alkyl;

[0056] each R 54 is independently selected from C 1-5 alkyl; optionally, said alkyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, I, or C 1-3 alkyl;

[0057] L1is a straight chain alkylene of C 1-5 ; optionally, said alkylene is substituted with a substituent selected from F, Cl, Br, I, or C 1-3 alkyl;

[0058] L2is a straight chain alkylene of C 1-3 ; optionally, said alkylene is substituted with a substituent selected from F, Cl, Br, I, or C 1-3 alkyl;

[0059] Cy is selected from a 5- to 6-membered heterocycloalkyl; said heterocycloalkyl contains 1 or 2 heteroatoms selected from N, O, or S; optionally, said heterocycloalkyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, I, or C 1-3 alkyl;

[0060] each n11, n12, and n3is independently selected from 1, 2, or 3;

[0061] n4is selected from a positive integer from 1 to 15;

[0062] n7is selected from a positive integer from 2 to 10;

[0063] n5and n6are each independently selected from 1, 2, or 3.

[0064] According to some embodiments of the application, wherein,

[0065] R1, R2, R3are each independently selected from the group consisting of methyl, ethyl, propyl or butyl, or, two of R1, R2, R3form, together with the N atom to which they are attached, a 5- to 6-membered heterocycloalkyl group, said heterocycloalkyl group containing at least one N atom, and 0 or 1 heteroatom selected from N, O or S; optionally, said methyl, ethyl, propyl, butyl or heterocycloalkyl group is substituted with 1, 2 or 3 substituents selected from F, Cl, Br or I;

[0066] R4is selected from H;

[0067] R5is selected from H, -CO-(CH2) n11 -NR 51 R 52 , -CO-(CH2) n12 -O-(CH2) n3 -NR 51 R 52 , -CO-O-(CH2) n3 -OH, -CO-O-(CH2CH2O) n4 -R 53 , -CO-O-(CH2) n5 -O-CO-(CH2) n6 -O-(CH2CH2O) n7 -R 53 , -CO-O-L2-N(R 54 )3 + Cl - or -CO-Cy;

[0068] R 51 is H;

[0069] R 52 is selected from H, methyl, ethyl, propyl or butyl; optionally, said methyl, ethyl, propyl or butyl is substituted with 1, 2 or 3 substituents selected from F, Cl, Br or I;

[0070] R 53 is selected from methyl, ethyl, propyl or butyl; optionally, said methyl, ethyl, propyl or butyl is substituted with 1, 2 or 3 substituents selected from F, Cl, Br or I;

[0071] each R 54 is independently selected from C 1-5 alkyl; optionally, said alkyl is substituted with 1, 2 or 3 substituents selected from F, Cl, Br or I;

[0072] L1is a straight chain alkylene group of C 1-5 ; optionally, said alkylene group is substituted with a substituent selected from F, Cl, Br, I or C 1-3 alkyl;

[0073] L2is C 1-3 a straight chain alkylene; optionally, said alkylene is substituted with a substituent selected from F, Cl, Br, I, or C 1-3 alkyl;

[0074] Cy is selected from a 5- to 6-membered heterocycloalkyl; said heterocycloalkyl contains 1 or 2 heteroatoms selected from N, O, or S; optionally, said heterocycloalkyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, or I;

[0075] each n11, n12, and n3 is independently selected from 1, 2, or 3;

[0076] n4 is selected from a positive integer from 1 to 15;

[0077] n7 is selected from a positive integer from 2 to 10;

[0078] n5 and n6 are each independently selected from 1, 2, or 3.

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

[0080] R1, R2, R3 are each independently selected from methyl, ethyl, propyl, or butyl, or, two of R1, R2, R3 form, together with the N atom to which they are attached, a 5- to 6-membered heterocycloalkyl, said heterocycloalkyl containing at least one N atom, and 0 or 1 heteroatoms selected from N, O, or S; optionally, said methyl, ethyl, propyl, butyl, or heterocycloalkyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, or I;

[0081] R4 is selected from H;

[0082] R5 is selected from H, -CO-(CH2) n11 -NR 51 R 52 , -CO-CH2-O-(CH2) n3 -NR 51 R 52 , -CO-O-(CH2) n3 -OH, -CO-O-(CH2CH2O) n4 -R 53 , -CO-O-CH2-O-CO-CH2-O-(CH2CH2O) n7 -R 53 , -CO-O-L2-N(R 54 )3 + Cl - or -CO-Cy;

[0083] R 51 is H;

[0084] R 52 selected from H, methyl, ethyl, propyl, or butyl; optionally, said methyl, ethyl, propyl, or butyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, or I;

[0085] R 53 selected from methyl, ethyl, propyl, or butyl; optionally, said methyl, ethyl, propyl, or butyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, or I;

[0086] each R 54 is independently selected from methyl, ethyl, propyl, or butyl; optionally, said methyl, ethyl, propyl, or butyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, or I;

[0087] L1is a straight chain alkylene of the formula 1-5 ; optionally, said alkylene is substituted with a substituent selected from F, Cl, Br, I, or C 1-3 alkyl;

[0088] L2is a straight chain alkylene of the formula 1-3 ; optionally, said alkylene is substituted with a substituent selected from F, Cl, Br, I, or C 1-3 alkyl;

[0089] Cy is selected from a 5- to 6-membered heterocycloalkyl; said heterocycloalkyl contains 1 or 2 heteroatoms selected from N, O, or S; optionally, said heterocycloalkyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, or I;

[0090] each n11and n3is independently selected from 1, 2, or 3;

[0091] n4is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15;

[0092] n7is selected from 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0093] According to some embodiments of the application, wherein,

[0094] R1, R2, R3are each independently selected from methyl, ethyl, propyl, or butyl; optionally, said methyl, ethyl, propyl, or butyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, or I;

[0095] R4is selected from H;

[0096] R5is selected from H, -CO-(CH2) n11 -NR 51 R52 or -CO-O-CH2-O-CO-CH2-O-(CH2CH2O) n7 -R 53 ;

[0097] R 51 is H;

[0098] R 52 is selected from H, methyl, ethyl, propyl or butyl; optionally, said methyl, ethyl, propyl or butyl is substituted with 1, 2 or 3 substituents selected from F, Cl, Br, or I;

[0099] R 53 is selected from methyl, ethyl, propyl or butyl; optionally, said methyl, ethyl, propyl or butyl is substituted with 1, 2 or 3 substituents selected from F, Cl, Br, or I;

[0100] L1is a linear alkylene group of C 1-5 ; optionally, said alkylene group is substituted with a substituent selected from F, Cl, Br, I or C 1-3 alkyl;

[0101] n11is selected from 1, 2 or 3;

[0102] n7is selected from 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0103] According to some embodiments of the application, wherein,

[0104] R1, R2, R3are each independently selected from methyl, ethyl, propyl or butyl; optionally, said methyl, ethyl, propyl or butyl is substituted with 1, 2 or 3 substituents selected from F, Cl, Br or I;

[0105] R4is selected from H;

[0106] R5is selected from H or -CO-O-CH2-O-CO-CH2-O-(CH2CH2O) n7 -R 53 ;

[0107] R 53 is selected from methyl, ethyl, propyl or butyl; optionally, said methyl, ethyl, propyl or butyl is substituted with 1, 2 or 3 substituents selected from F, Cl, Br, or I;

[0108] L1is a linear alkylene group of C 1-3 ; optionally, said alkylene group is substituted with a substituent selected from F, Cl, Br or I;

[0109] n7is selected from 6, 7, 8, 9 or 10.

[0110] According to some embodiments of the present application, wherein,

[0111] two of R1, R2, R3and the N atom to which they are attached form a 5- to 6- membered heterocycloalkyl selected from one of the following structures:

[0112] Cy is selected from one of the following structures:

[0113] Optionally, the above heterocycloalkyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, or I.

[0114] According to some embodiments of the present application, wherein, the structure of the amphotericin B quaternary ammonium salt derivative is selected from one of the following structures:

[0115] In another aspect, the present application also provides a pharmaceutical composition comprising a therapeutically effective amount of any of the amphotericin B quaternary ammonium salt derivatives of the present application, or a stereoisomer, a pharmaceutically acceptable salt, or a deuterated form thereof, and a pharmaceutically acceptable carrier.

[0116] In yet another aspect, the present application also provides the use of the amphotericin B quaternary ammonium salt derivative, or a stereoisomer, a pharmaceutically acceptable salt, or a deuterated form thereof, or the pharmaceutical composition of the present application in the preparation of an antifungal medicament. DETAILED DESCRIPTION

[0117] The following detailed description of the implementation process and the beneficial effects produced by the present application through specific examples 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.

[0118] Synthesis of intermediate C2’epiAmB (ref. Nature, 2023, 623, 1079-1085)

[0119] Step 1: Synthesis of intermediate Int 1

[0120] Method: Amphotericin B (AmB, 65 g, about 70.3 mmol) was added to DMF / MeOH (1:1, 500 mL), a yellow suspension was presented, pyridine (45 mL) was added, then allyl succinimidyl carbonate (32 g, 161 mmol) was added, the reaction was stirred at room temperature for 16 hours. After the reaction was completed, triethylamine (5 mL) was added to quench, the reaction was added dropwise to methyl tert-butyl ether (8 L) under vigorous stirring, a yellow solid was precipitated, 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).

[0121] MS (ESI, m / z) 1009 [M+H] + .

[0122] Step 2: Synthesis of intermediate Int 2

[0123] Method: Int 1 (72.5 g, crude, about 70 mmol) was added to MeOH (500 mL), a yellow suspension was presented, 4-methoxybenzaldehyde dimethyl acetal (51 g, 280 mmol) was added, 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, the reaction was added dropwise to n-hexane / methyl tert-butyl ether (3:5, 8 L) under vigorous stirring, a yellow solid was precipitated, which was filtered, washed with n-hexane, and dried under reduced pressure to obtain a yellow solid powder Int 2 (75 g, crude).

[0124] MS (ESI, m / z) 1259 [M+H] + .

[0125] Step 3: Synthesis of intermediate Int 3

[0126] 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 added to 1 L of saturated sodium bicarbonate solution to quench, 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 to purify by column chromatography (PE:EA=1:1 to 1:2) to obtain a yellow solid powder Int 3 (34 g, yield 38.4%).

[0127] MS (ESI, m / z) 1299 [M+H] + .

[0128] Step 4: Synthesis of intermediate Int 4

[0129] 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 give 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, and the above white suspension was added slowly dropwise (45 min), and stirred for half an hour after dropwise addition was completed. After the reaction was completed, the reaction solution was added to 1 L of saturated sodium bicarbonate solution to quench, extracted with EA twice, the organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure to give yellow solid powder Int 4 (19 g, yield 51.1%).

[0130] MS (ESI, m / z) 1460 [M+H] + .

[0131] Step 5: Synthesis of intermediate Int 5

[0132] Method: Int 4 (40 g, 27.4 mmol) was dissolved in DCM / hexane (1:1, 800 mL), 2,6- dimethylpyridine (20.5 g, 192 mmol) was added, and the temperature was lowered to 0-5 °C, diethylisopropylsilyl trifluoromethanesulfonate (DEIPSOTf, 38 g, 136.6 mmol) was added dropwise, and stirring was continued for 1 hour under ice water bath after dropwise addition was completed. After the reaction was completed, the reaction solution was added to 1 L of saturated sodium bicarbonate solution to quench, extracted with EA twice, the organic phase was combined, washed with copper sulfate solution to remove 2,6-dimethylpyridine, and then washed with concentrated brine, dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure to give yellow solid powder Int 5 (36 g, yield 66.6%).

[0133] MS (ESI, m / z) 1971 [M+H] + .

[0134] Step 6: Synthesis of intermediate Int 6

[0135] 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 reaction was stirred at 40 °C for 24 h under nitrogen. The reaction was added to EA and saturated sodium bicarbonate solution, and the mixture was extracted with EA twice. The aqueous phase was extracted with EA twice more, and the combined organic phases were washed with concentrated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 15:1 to PE:EA = 5:1) to give yellow solid powder Int 6 (8.5 g, 37.2% yield) and the starting material Int 5 (7 g) was recovered.

[0136] MS (ESI, m / z) 1812 [M+H] + .

[0137] Step 7: Synthesis of intermediate Int 7

[0138] 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 reaction was stirred at 70 °C for 2 h after being cooled in an ice water bath and dropwise addition of DIAD (diisopropyl azodicarboxylate) (13 mL, 66.2 mmol) in toluene (6 mL) under nitrogen. After the reaction was completed, the reaction was cooled to room temperature, added to EA (100 mL) and saturated sodium bicarbonate solution (400 mL), and the mixture was extracted with EA once. The aqueous phase was extracted with EA twice more, and the combined organic phases were washed with concentrated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 15:1 to PE:EA = 10:1) to give yellow solid powder Int 7 (9.6 g, 45% yield).

[0139] MS (ESI, m / z) 1960 [M+H] + .

[0140] Step 8: Synthesis of intermediate Int 8

[0141] 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 reaction was stirred at 40 °C for 24 h under nitrogen. The reaction was added to EA and saturated sodium bicarbonate solution, and the aqueous phase was extracted twice with EA. The combined organic phase was 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 give yellow solid powder Int 8 (7.9 g, yield 71.5%).

[0142] MS (ESI, m / z) 1812 [M+H] + .

[0143] Step 9: Synthesis of intermediate Int 9

[0144] Method: Int 8 (10 g, 5.5 mmol) was dissolved in THF (60 mL) and cooled in an ice water bath to give reaction solution A; MeOH (122 mL) and pyridine (23 mL) were mixed and cooled in an ice water bath, and hydrogen fluoride-pyridine (17.3 mL, content 65%-85%) was slowly added dropwise to give reaction solution B. Reaction solution B was slowly added dropwise to reaction solution A, and the reaction was stirred at room temperature for 2.5 h. After the reaction, the reaction was cooled in an ice water bath, saturated sodium bicarbonate solution (200 mL) was added to quench the reaction, and the mixture was stirred for 20 min. Saturated sodium bicarbonate solution (200 mL) and EA (200 mL) were added, and the mixture was extracted once with EA. The combined organic phase was washed successively with saturated sodium bicarbonate solution, water, and brine once, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 100:0 to DCM:MeOH = 97:3) to give yellow solid powder Int 9 (5.1 g, yield 71%).

[0145] MS (ESI, m / z) 1299 [M+H] + .

[0146] Step 10: Synthesis of intermediate Int 10

[0147] 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, to which a solution of thiosalicylic acid (3.03 g, 19.6 mmol) in DMF (120 mL) was added dropwise. After the addition was complete, the reaction was replaced with nitrogen and stirred at room temperature for 1 hour. Upon completion of the reaction, the reaction solution was added dropwise to vigorously stirred diethyl ether (2 L), and the layers were allowed to separate. The supernatant was decanted and the turbid lower layer was filtered to give a yellow solid. The yellow solid was added to MeOH (40 mL) and stirred to give a suspension. The suspension was further added dropwise to vigorously stirred diethyl ether (500 mL), and after filtration, the yellow solid powder was dried under reduced pressure to give Int 10 (3.75 g, 82% yield).

[0148] MS (ESI, m / z) 1175 [M+H] + .

[0149] Step 11: Synthesis of Intermediate C2’epiAmB

[0150] 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 and the reaction was stirred at room temperature for 2 hours. Upon completion of the reaction, TEA (2.8 mL) was added to quench the reaction. The reaction solution was concentrated under reduced pressure, and after removal of the solvent, the residue was added dropwise to Et2O / ACN (10:1, 220 mL) and stirred for 10 minutes. The turbid lower layer was decanted and the yellow solid was precipitated by adding acetonitrile (120 mL). The crude C2’epiAmB (140 mg, crude, HPLC purity 50%) was obtained by centrifugation and used directly in the subsequent reaction.

[0151] MS (ESI, m / z) 924 [M+H] + .

[0152] 1H 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).

[0153] Example 1: Synthesis of BX20-11-002

[0154] Step 1:

[0155] Method: C2’epiAmB (80 mg, crude, HPLC purity about 50%, about 0.04 mmol) was dissolved in DMF (3 mL), 2-amino-N,N,N-trimethylethanaminium chloride hydrochloride (42 mg, 0.24 mmol) was added, and TEA was added to adjust the pH of the reaction system to 9-10. After stirring for 10 min, PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate) (62 mg, 0.12 mmol) was added, and the reaction was stirred at room temperature for 3 h. After the reaction was completed, the reaction solution was added dropwise into methyl tert-butyl ether (200 mL), centrifuged (3000 rpm, 5 min) to obtain the crude product, which was purified by preparative chromatography (95:5 to 65:35, aq. HCOOH (1 ‰) / MeCN), and then lyophilized to obtain a yellow solid powder BX20-11-002 (5 mg, yield 11%).

[0156] MS (ESI, m / z) 1009 [M] + .

[0157] 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), 1.33 (d, J = 6.4 Hz, 3H), 1.37 (d, J = 6.0 Hz, 3H), 1.43-1.53 (m, 1H), 1.55-1.65 (m, 2H), 1.65-1.71 (m, 1H), 1.72-1.80 (m, 2H), 1.81-1.88 (m, 2H), 1.92-2.02 (m, 3H), 2.11 (s, 3H), 2.20-2.25 (m, 1H), 2.31-2.39 (m, 2H), 2.40-2.61 (m, 4H), 3.13 (br s, 1H), 3.36 (s, 11H), 3.50-3.63 (m, 2H), 3.65-3.78 (m, 2H), 3.83 (d, J = 10.8, 1H), 3.88-4.01 (m, 3H), 4.43 (t, J = 10.4 Hz, 1H), 4.56-4.69 (m, 4H), 4.91 (t, J = 9.6 Hz, 1H), 5.45-5.51 (m, 1H), 5.61 (d, J = 6.8 Hz, 1H), 6.30-6.65 (m, 14H).

[0158] Example 2: Synthesis of BX20-11-016

[0159] Step 1: Synthesis of intermediate 16-2

[0160] Method: Compound Fmoc-glycine 16-1 (5 g, 16.8 mmol) was dissolved in DCM (60 mL), then added with NHS (N-hydroxysuccinimide) (2.03 g, 17.7 mmol) and DCC (dicyclohexyl carbodiimide) (3.64 g, 17.7 mmol), the reaction was stirred at room temperature for 16 hours. After the reaction, the reaction solution was filtered, the filter cake was washed with DCM, the combined filtrate was concentrated under reduced pressure, the residue was dissolved in EA (part of the solid was not dissolved), and then filtered to obtain the filtrate, which was washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution once, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a light yellow solid 16-2 (3.5 g, crude).

[0161] MS (ESI, m / z) 395 [M+H] + .

[0162] Step 2: Synthesis of intermediate 16-3

[0163] Method: C2'epiAmB (100 mg, crude, HPLC purity about 50%, about 0.05 mmol) was dissolved in DMAc (N,N-dimethylacetamide) (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) stirred vigorously, centrifuged (3000 rpm, 5 min) to obtain yellow solid powder 16-3 (110 mg, crude).

[0164] MS (ESI, m / z) 1024 [M+H] + .

[0165] Step 3: Synthesis of intermediate 16-4

[0166] Method: 16-3 (110 mg, crude, about 0.05 mmol) was dissolved in DMAc (3 mL), 2-amino-N,N,N-trimethylammonium chloride hydrochloride (42 mg, 0.24 mmol) was added, then NMM (N-methylmorpholine) was added to adjust the pH of the reaction system to 9-10, finally PyAOP (7-azabenzotriazol-1-yl)oxypyrrrolidinophosphonium hexafluorophosphate) (104 mg, 0.2 mmol) was added, the reaction was stirred at room temperature for 1 hour. After the reaction, the reaction solution was added dropwise to methyl tert-butyl ether (200 mL), centrifuged (3000 rpm, 5 min) to obtain yellow solid powder 16-4 (100 mg, crude).

[0167] MS (ESI, m / z) 1288 [M] + .

[0168] Step 4: Synthesis of target product BX20-11-016

[0169] Method: Intermediate 16-4 (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, the reaction solution was directly filtered and purified by preparative chromatography (95:5 to 67:33, aq. HCOOH (1 ‰) / MeCN), and after freeze-drying, yellow solid powder BX20-11-016 (7 mg, yield 12%) was obtained.

[0170] MS (ESI, m / z) 1066 [M] + .

[0171] 1H NMR (400 MHz, CD3OD:Pyridine-d5 = 1:1) δ 1.17 (d, J = 7.2 Hz, 3H), 1.24 (d, J = 6.4 Hz, 3H), 1.35 (d, J = 6.4 Hz, 3H), 1.41 (d, J = 6.0 Hz, 3H), 1.47-1.52 (m, 1H), 1.55-1.63 (m, 2H), 1.65-1.70 (m, 2H), 1.76-1.82 (m, 3H), 1.83-1.88 (m, 2H), 1.93-2.01 (m, 4H), 2.10-2.15 (m, 1H), 2.30-2.38 (m, 2H), 2.43-2.58 (m, 3H), 3.11-3.15 (m, 1H), 3.42-3.38 (m, 13H), 3.59-3.73 (m, 4H), 3.83-3.85 (m, 2H), 3.93-3.97 (m, 1H), 4.45 (t, J = 10.4 Hz, 1H), 4.61-4.68 (m, 4H), 4.96 (t, J = 9.6 Hz, 1H), 5.46-5.51 (m, 1H), 5.62-5.64 (m, 1H), 6.30-6.66 (m, 14H).

[0172] Example 3: Synthesis of BX20-11-017

[0173] Step 1: Synthesis of intermediate 15-2

[0174] Method: 15-1 (5.0 g, 16.0 mmol) was dissolved in DMF (60 mL), and NHS (2.0 g, 17.6 mmol) and DCC (3.6 g, 17.6 mmol) were added. The reaction was stirred at room temperature for 12 hours. After the reaction was completed, it was filtered, the filtrate was concentrated under reduced pressure, 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).

[0175] MS (ESI, m / z) 409 [M+H] + .

[0176] Step 2: Synthesis of intermediate 15-3

[0177] Method: Compound C2'epiAmB (150 mg, about 0.075 mmol) was dissolved in DMAc (5 mL) with 15-2 (185 mg, 0.45 mmol), then pyridine (103 mg, 1.3 mmol) was added dropwise, and the reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was added dropwise to methyl tert-butyl ether (200 mL), and centrifugation (3000 rpm, 5 min) was performed to obtain yellow solid powder 15-3 (120 mg, crude).

[0178] MS (ESI, m / z) 1218 [M+H] + .

[0179] Step 3: Synthesis of intermediate 17-1

[0180] Method: Compound 15-3 (100 mg, crude, about 0.05 mmol) was dissolved in DMAc (6 mL), 2-amino-N,N,N-trimethylethanaminium chloride hydrochloride (42 mg, 0.24 mmol) was added, and 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 to methyl tert-butyl ether (200 mL), and centrifugation (3000 rpm, 5 min) was performed to obtain yellow solid powder 17-1 (100 mg, crude).

[0181] MS (ESI, m / z) 1302 [M] + .

[0182] Step 4: Synthesis of target product BX20-11-017

[0183] Method: Intermediate 17-1 (100 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 67:33, aq. HCOOH (1 ‰) / MeCN), and after freeze-drying, yellow solid powder BX20-11-017 (10 mg, yield 17%) was obtained.

[0184] MS (ESI, m / z) 1080 [M] + .

[0185] 1H NMR(400MHz, 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),1.40(d,J=6.0Hz,3H),1.46 -1.52(m,1H),1.53-1.58(m,2H),1.63-1.70(m,2H),1.75-1.84(m,3H),1.92-2.02(m,4H),2.06-2.13(m,1H),2.28-2.39(m,3H),2.41-2. 49(m,2H),2.52-2.59(m,3H),3.34-3.41(m,13H),3.54-3.63(m,3H),3.70-3.74(m,1H),3.83-3.85(m,2H),3.92-4.01(m,2H),4.22(t,J= 10.0Hz,1H),4.45(t,J=10.0Hz,1H),4.59-4.72(m,4H),4.96(t,J=9.6Hz,1H),5.45-5.51(m,1H),5.62-5.65(m,1H),6.32-6.66(m,14H).

[0186] Example 4: Synthesis of BX20-11-033

[0187] Step 1: Synthesis of intermediate 33-2

[0188] Method: 33-1 (4.8 g, 34.5 mmol) was dissolved in THF (120 mL), methyl chloroformate (5.0 g, 38.0 mmol) was added, and then TEA (3.8 g, 38.0 mmol) was slowly added dropwise. The reaction mixture was stirred at room temperature for one hour. After the reaction was complete, the filtrate was filtered, concentrated under reduced pressure, and extracted with EA and saturated NaHCO3 solution. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a brown oily liquid 33-2 (7.1 g, crude product).

[0189] MS(ESI,m / z)232[M+H] + .

[0190] Step 2: Synthesis of intermediate 33-3

[0191] Method: Dissolve 33-2 (7.1 g, crude product, approximately 30 mmol) in acetone (120 mL), add... Molecular sieve (7.1 g) and NaI (13.8 g, 92 mmol), the reaction was stirred at 40 °C for 16 h. After reaction, the filtrate was concentrated under reduced pressure, the residue was dissolved in DCM, washed with saturated NaHCO3solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give brown oil 33-3 (8.4 g, crude).

[0192] MS (ESI, m / z) 324 [M+H] + .

[0193] Step 3: Synthesis of intermediate 33-5

[0194] Method: 33-5 (600 mg, crude, about 1.2 mmol) was dissolved in toluene (15 mL), Ag2CO3(331 mg, 1.2 mmol) was added and stirred for 5 min, then 33-3 (387 mg, 1.2 mmol) was added, the reaction was heated to 80 °C and stirred for 15 min. After reaction, the filtrate was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 100:0 to 90:10) to give yellow oil 33-6 (380 mg, yield 46%).

[0195] MS (ESI, m / z) 487 [M+H] + .

[0196] Step 4: Synthesis of intermediate 33-6

[0197] Method: 33-5 (600 mg, crude, about 1.2 mmol) was dissolved in toluene (15 mL), Ag2CO3(331 mg, 1.2 mmol) was added and stirred for 5 min, then 33-3 (387 mg, 1.2 mmol) was added, the reaction was heated to 80 °C and stirred for 15 min. After reaction, the filtrate was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 100:0 to 90:10) to give yellow oil 33-6 (380 mg, yield 46%).

[0198] MS (ESI, m / z) 682 [M+H] + .

[0199] Step 5: Synthesis of intermediate 33-7

[0200] Method: 33-6 (102 mg, 0.15 mmol) was dissolved in DMAc (3 mL), pyridine (79 mg, 1 mmol) was added, and finally C2'epiAmB (100 mg, crude, about 0.05 mmol) was added. The reaction was stirred at room temperature for 6 hours. After the reaction was completed, the reaction solution was added dropwise to methyl tert-butyl ether (200 mL) stirred vigorously, and centrifuged (3000 rpm, 5 min) to obtain a yellow solid powder 33-7 (100 mg, crude).

[0201] MS (ESI, m / z) 1467 [M+H] + .

[0202] Step 6: Synthesis of the target product BX20-11-033

[0203] Method: 2-amino-N,N,N-trimethylethanaminium chloride hydrochloride (52 mg, 0.3 mmol) was dissolved in DMAc (3 mL), NMM was added to adjust the pH of the reaction system to 9-10, and finally 33-7 (100 mg, crude, about 0.05 mmol) was added. The reaction was stirred at room temperature for 1 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 BX20-11-033 (7 mg, yield 12%).

[0204] MS (ESI, m / z) 1551 [M] + .

[0205] 1H NMR (400 MHz, CD3OD:Pyridine-d5 = 1:1) δ 1.11 (d, J = 7.2 Hz, 3H), 1.20 (d, J = 6.4 Hz, 3H), 1.29 (d, J = 6.4 Hz, 3H), 1.36 (d, J = 6.0 Hz, 3H), 1.40-1.45 (m, 1H), 1.47-1.56 (m, 3H), 1.61-1.70 (m, 3H), 1.85-1.93 (m, 3H), 1.96-2.07 (m, 2H), 2.13-2.24 (m, 2H), 2.25-2.35 (m, 2H), 2.38-2.53 (m, 2H), 3.26-3.32 (m, 4H), 3.35 (s, 9H), 3.45-3.50 (m, 1H), 3.52-3.55 (m, 3H), 3.62-3.68 (m, 40H), 3.72-3.77 (m, 4H), 3.81-3.99 (m, 2H), 4.21 (s, 2H), 4.32-4.35 (m, 1H), 4.50-4.57 (m, 4H), 4.82 (t, J = 9.2 Hz, 1H), 5.41-5.47 (m, 1H), 5.54-5.56 (m, 1H), 5.82-5.85 (m, 1H), 5.93 (d, J = 10.0 Hz, 1H), 6.23-6.61 (m, 14H).

[0206] Synthesis of Example 5B X20-11-050

[0207] Step 1: Synthesis of intermediate 50-2

[0208] Method: Dissolve N-tert-butoxycarbonyl-1,3-propanediamine (2.0 g, 11.5 mmol) in acetonitrile (30 mL), add K2CO3(6.3 g, 45.6 mmol) and Mel (8.2 g, 57.7 mmol), the reaction is raised to 70 °C and continue to stir for 6 hours. After the reaction is completed, the reaction solution is lowered to room temperature, 30 mL of water is added, stirred and then separated, the upper organic phase is collected and concentrated under reduced pressure. Finally, add DCM (50 mL) to the residue, filter the filtrate and concentrate under reduced pressure to obtain white solid 50-2 (3.65 g, crude).

[0209] MS (ESI, m / z) 217 [M] + .

[0210] Step 2: Synthesis of intermediate 50-3

[0211] Method: 50-2 (3.65 g, ca. 10 mmol, crude) was dissolved in DCM (20 mL), HCl / 1,4-dioxane (4 M, 26 mL, 104 mmol) was added dropwise, and the reaction was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give yellow solid 50-3 (2.7 g, crude).

[0212] MS (ESI, m / z) 117 [M] + .

[0213] Step 3: Synthesis of the target product BX20-11-050

[0214] Method: C2’epiAmB (110 mg, crude, HPLC purity ca. 50%, ca. 0.06 mmol) was dissolved in DMAc (5 mL), 50-3 (120 mg, crude, ca. 0.6 mmol) was added, NMM was added to adjust the pH of the reaction system to 9-10, and finally PyAOP (125 mg, 0.24 mmol) was added. The reaction was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was filtered and purified by preparative chromatography (95:5 to 65:35, aq. HCOOH (1 ‰) / MeCN). After lyophilization, yellow solid powder BX20-11-050 (10 mg, yield 15.7%) was obtained.

[0215] MS (ESI, m / z) 1023 [M] + .

[0216] 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), 1.30 (d, J = 6.4 Hz, 3H), 1.34 (d, J = 6.0 Hz, 3H), 1.37-1.40 (m, 1H), 1.44-1.53 (m, 3H), 1.57-1.67 (m, 2H), 1.69-1.73 (m, 1H), 1.78-1.82 (m, 2H), 1.89-1.95 (m, 3H), 2.00-2.08 (m, 2H), 2.18-2.35 (m, 4H), 2.39-2.45 (m, 1H), 2.47-2.55 (m, 1H), 3.11-3.15 (m, 2H), 3.22 (s, 9H), 3.29-3.37 (m, 3H), 3.45-3.61 (m, 4H), 3.67-3.74 (m, 1H), 3.79 (d, J = 10.8 Hz, 1H), 3.85-3.90 (m, 1H), 4.34-4.40 (m, 1H), 4.52-4.60 (m, 4H), 4.84 (t, J = 9.6 Hz, 1H), 5.45 (dd, J = 14.0 Hz, 10.0 Hz, 1H), 5.54-5.59 (m, 1H), 6.23-6.63 (m, 14H).

[0217] Synthesis of Example 6B X20-11-051

[0218] Step 1: Synthesis of intermediate 51-2

[0219] Method: Dissolve N-tert-butoxycarbonyl-1,4-butanediamine (1.3 g, 6.9 mmol) in acetonitrile (15 mL), add K2CO3 (3.8 g, 27.6 mmol) and Mel (4.9 g, 34.5 mmol), the reaction is raised to 70 °C and continue to stir for 6 hours. After the reaction is completed, the reaction solution is lowered to room temperature, 15 mL of water is added, stirred and then separated, the upper organic phase is collected and concentrated under reduced pressure. Finally, add DCM (50 mL) to the residue, filter the filtrate and concentrate under reduced pressure to obtain white solid 51-2 (2.4 g, crude).

[0220] MS (ESI, m / z) 231 [M] + .

[0221] Step 2: Synthesis of intermediate 51-3

[0222] Method: Dissolve 51-2 (2.4 g, ca. 6 mmol, crude) in DCM (20 mL), add HC1 / 1,4-dioxane (4 M, 15 mL, 60 mmol) dropwise, stir the reaction at room temperature for 1 hour. Upon completion, concentrate the reaction under reduced pressure to give yellow solid 51-3 (1.7 g, crude).

[0223] MS (ESI, m / z) 131 [M] + .

[0224] Step 3: Synthesis of the target product BX20-11-051

[0225] Method: Dissolve C2’epiAmB (110 mg, crude, HPLC purity ca. 50%, ca. 0.06 mmol) in DMAc (5 mL), add 51-3 (130 mg, crude, ca. 0.6 mmol), adjust the pH of the reaction to 9-10 by adding NMM, finally add PyAOP (125 mg, 0.24 mmol), stir the reaction at room temperature for 1 hour. Upon completion, filter the reaction and purify by preparative chromatography (95:5 to 65:35, aq. HC00H (1 ‰) / MeCN), lyophilize to give yellow solid powder BX20-11-051 (15 mg, yield 23%).

[0226] MS (ESI, m / z) 1037 [M] + .

[0227] 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), 1.33 (d, J = 6.4 Hz, 3H), 1.38 (d, J = 6.0 Hz, 3H), 1.45-1.50 (m, 1H), 1.52-1.58 (m, 3H), 1.61-1.72 (m, 4H), 1.74-1.80 (m, 3H), 1.92-2.01 (m, 5H), 2.07-2.14 (m, 1H), 2.27-2.35 (m, 3H), 2.39-2.57 (m, 3H), 3.11-3.15 (m, 1H), 3.22-3.35 (m, 13H), 3.44-3.56 (m, 4H), 3.64-3.72 (m, 2H), 3.83 (d, J = 10.8, 1H), 3.93 (t, J = 10.0 Hz, 1H), 4.39-4.66 (m, 1H), 4.57-4.63 (m, 4H), 4.91 (t, J = 9.6 Hz, 1H), 5.43-5.51 (m, 1H), 5.58-5.63 (m, 1H), 6.27-6.66 (m, 14H).

[0228] Comparative Example 1:

[0229] Comparative Example 1 was synthesized according to the synthetic method of compound 1 in patent CN116323632A.

[0230] 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).

[0231] Biological test evaluation

[0232] The present application is further described below in connection with test examples

[0233] Test Example 1 In vitro antifungal activity of compounds of the present application

[0234] 1. Purpose of the experiment

[0235] The compounds of the present application were tested for their in vitro fungistatic concentration.

[0236] 2. Experimental materials

[0237] 2.1. The compounds of the present application and the reference compounds were self-made.

[0238] 2.2. The strains to be tested were provided by Shanghai Pharmaron.

[0239] 3. Test method

[0240] The method for detecting the minimum inhibitory concentration (MIC) was performed according to CLSI M27, CLSI M38 and CLSI M60.

[0241] 3.1. Preparation of test compounds

[0242] The test compounds were dissolved in a suitable solvent to prepare a high concentration stock solution, which was used on the same day or stored at -20°C or lower. On the test day, the stock solution of the test compound was diluted in 2-fold gradient, to prepare the working solution of the test compound at 100x the final concentration of the test, and 2 μL was transferred to a 96-well plate to obtain the test plate of the compound.

[0243] 3.2. Preparation of inoculum

[0244] 3.2.1. Preparation of inoculum for yeast-like fungi

[0245] The -80°C glycerol stock was inoculated to SDA plate and incubated at 35±2°C overnight. On the test day, a single colony was picked and dissolved in sterile physiological saline to prepare a 0.5 McFarland bacterial suspension. Then the bacterial suspension was diluted 2000-fold in RPMI 1640 (pH 7.0) medium to obtain the inoculum (0.5x10 3 ~2.5x10 3 CFU / mL). 198 μL of the inoculum was added to the compound test plate prepared in 3.1.

[0246] 3.2.2. Preparation of inoculum for filamentous fungi (non-dermatophytic molds)

[0247] The -80°C glycerol stock was inoculated to PDA or SDA plate and incubated at 35±2°C for 2-7 days. On the test day, the spores on the plate were collected and dissolved in sterile physiological saline (or with 0.1% Tween 20) and the spore number was counted using a cell counter. Then the spore suspension was diluted to 0.2-2.5x10 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 plate prepared in 3.1.

[0248] 3.3. MIC reading

[0249] Yeast-like fungi: The minimum compound concentration (MIC) for 100% or ≥50% inhibition was read by naked eye after incubation of the test plate at 35±2°C for 24 h.

[0250] Filamentous fungi (non-dermatophytic molds): The minimum compound concentration (MIC) for 100%, ≥80% or ≥50% inhibition was read by naked eye after incubation of the test plate at 35±2°C for 48 h.

[0251] 4. Test results

[0252] The results are shown in Table 1 below

[0253] Table 1. Minimum inhibitory concentration (MIC, ug / mL) of the compounds of the present application

[0254] N / A: Not tested

[0255] The compound of the present application has a good inhibitory effect on the growth of Candida albicans, Aspergillus fumigatus and Aspergillus flavus.

[0256] Test Example 2: In vitro human liver microsomal stability assay

[0257] 1. Test method:

[0258] The final incubation reaction solution contains 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 minutes, 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.

[0259] 2. Data analysis

[0260] The peak area was determined from the extracted ion chromatogram. The slope value k was determined by linear regression of the natural logarithm of the percentage of parent drug remaining versus incubation time.

[0261] The in vitro half-life (in vitro t1 / 2) was determined from the slope value: T1 / 2 = 0.693 / k.

[0262] 3. Test results

[0263] The results are shown in Table 2 below:

[0264] Table 2: Human liver microsomal stability of the compound of the present application

[0265] 4. Conclusion: The compound of the present application has good metabolic stability in human liver microsomes.

[0266] Test Example 3: SD rat pharmacokinetic assay

[0267] 1. Purpose of the test

[0268] The SD rats are used as the test animals to test the pharmacokinetic behavior of the compound of the present application in the plasma of the rats at a dose of 1 mg / kg by intravenous injection.

[0269] 2. Test method

[0270] 2.1. Test drug

[0271] The compounds of the present application and the reference compounds are self-made.

[0272] 2.2. Test animals

[0273] Male SPF SD rats, weighing (200±20) g, 3 rats per compound.

[0274] 2.3. Preparation of test drugs

[0275] Drug preparation: The drug concentration is prepared to be 0.2 mg / mL, and the prepared solution is a 5% glucose aqueous solution for injection.

[0276] 2.4. Drug administration

[0277] Male SPF SD rats, after adaptive feeding for 3-4 days, are respectively injected with drugs through the tail vein, and the dose is 1 mg / kg, and the volume is 5 mL / kg.

[0278] Blood is collected before administration (0 h) and after administration at 0.0833 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h, and the blood is collected through the jugular vein, the amount of blood is about 0.2 mL, and the blood is placed in an EDTA-K2 anticoagulant test tube with a label. After blood collection, the blood collection tube is completely inverted 3 times with the anticoagulant immediately, and then centrifuged at 4000g at 4°C in an ice water bath for 5 min. After the centrifugation is completed, the plasma is promptly divided into EP tubes with corresponding labels, and stored in a-80°C refrigerator.

[0279] 2.6. Sample detection

[0280] In this experiment, the concentration of the compound in the plasma after administration is determined by a simple verification LC-MS / MS method.

[0281] 2.6.1. Sample processing

[0282] The analyte stock solution was diluted with acetonitrile solution to obtain the required working solution series concentration. 5 μL of working solution (10, 20, 50, 100, 200, 500, 1000, 2000, 5000 ng / mL) was added to 50 μL of blank plasma to achieve the calibration standards 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, respectively, which were prepared independently of the samples used for the calibration curve. These QC samples were prepared on the day of analysis in the same way as the calibration standards.

[0283] The same point of plasma samples was equally pooled from 3 animals.

[0284] 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 protein. Then the samples were 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.

[0285] 2.6.2. Liquid chromatography analysis:

[0286] 1) Liquid chromatography conditions

[0287] 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.

[0288] Chromatographic column: HALO 90A AQ-C18, 2 μm 3.0 x 30 mm

[0289] Mass Spectrometry: AB Sciex Triple Quad 6500+ LC / MS / MS instrument (Serial NO. DZ248562305)

[0290] Injection volume: 2 μL

[0291] Mobile phase A: 5% acetonitrile water (0.1% formic acid)

[0292] Mobile phase B: 95% acetonitrile water (0.1% formic acid)

[0293] Flow rate: 0.6 mL / min

[0294] Elution program and mobile phase distribution ratio: Gradient elution is shown in Table 3 below.

[0295] Table 3

[0296] 2) Mass Spectrometry Conditions

[0297] Ion detection mode: Multiple reaction ion monitoring (MRM)

[0298] Ionization mode: Pneumatic assisted electrospray ionization (ESI)

[0299] Ion polarity: Positive ion

[0300] CAD: 9

[0301] CUR: 35 psi

[0302] GS1: 50 psi

[0303] GS2: 50 psi

[0304] TEM: 400 °C

[0305] IS: 5500 v

[0306] 3. Test Results and Analysis

[0307] The main pharmacokinetic parameters were calculated by WinNonlin 8.3, and the results of rat pharmacokinetic experiments are shown in Table 4 below.

[0308] Table 4, Results of rat pharmacokinetic experiments

[0309] Note: Example 4 is a prodrug of compound BX20-11-002, and after intravenous injection, BX20-11-002 is detected.

[0310] 4. Experimental Conclusion

[0311] From the rat pharmacokinetic test results in the table, it can be seen that the compound of the embodiment of the application has good absorption characteristics, the exposure amount is obviously better than that of the comparative example 1 under the same dose, and the half-life is obviously longer, and the drug efficacy can be maintained for a longer time.

Claims

1. An amphipathic amphotericin B quaternary ammonium salt derivative or a stereoisomer, a pharmaceutically acceptable salt, or a deuterated form thereof, wherein, The amphotericin B quaternary ammonium salt derivative is shown as formula (I): R1, R2, R3are each independently selected from C 1-10 alkyl, or two of R1, R2, R3and the N atom to which they are attached form a 3- to 10-membered heterocycloalkyl group, said heterocycloalkyl group containing at least one N atom, and 0, 1 or 2 heteroatoms selected from N, O or S; optionally, said alkyl or heterocycloalkyl group is substituted with 1, 2 or 3 substituents selected from F, Cl, Br, I, C 1-6 alkyl, nitro, cyano, carboxyl or hydroxyl; R4is selected from H or C 1-10 alkyl; optionally, the alkyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, I, C 1-6 alkyl, nitro, cyano, carboxyl, or hydroxyl; R5is selected from H, C 1-10 alkyl, -CO-(CH2) n1 -(O) n2 -(CH2) n3 -NR 51 R 52 , -CO-(CH2) n1 -(O) n2 -(CH2) n3 -OH, -CO-O-(CH2CH2O) n4 -R 53 , -CO-O-(CH2) n5 -O-CO-(CH2) n6 -O-(CH2CH2O) n7 -R 53 , -CO-O-L2-N(R 54 )3 + Cl - or -CO-Cy; R 51 , R 52 , and R 53 are each independently selected from H or C 1-10 alkyl; optionally, said alkyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, I, C 1-6 alkyl, nitro, cyano, carboxy, or hydroxy; Each R 54 Each independently selected from C 1-10 Alkyl group; optionally, the alkyl group is composed of 1, 2, or 3 atoms selected from F, Cl, Br, I, C. 1-6 Substituted by alkyl, nitro, cyano, carboxyl, or hydroxyl groups; L1and L2are each independently C 1-10 straight or branched alkylene; optionally, said alkylene is substituted with a substituent selected from F, Cl, Br, I, C 1-6 alkyl, nitro, cyano, carboxyl, or hydroxyl; Cy is selected from a 3- to 10-membered heterocycloalkyl; said heterocycloalkyl contains 1, 2, or 3 heteroatoms selected from N, O, or S; optionally, said heterocycloalkyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, I, C 1-6 alkyl, nitro, cyano, carboxyl, or hydroxyl; each n1 and n3 is independently selected from 0, 1, 2, 3, 4, or 5, and n1 and n3 are not simultaneously 0; each n2 is independently 0 or 1; n4 and n7 are each independently a positive integer from 1-15; n5 and n6 are each independently selected from 1, 2, 3, 4, or 5.

2. The amphotericin B quaternary ammonium salt derivative of claim 1, or a stereoisomer, a pharmaceutically acceptable salt, or a deuterated form thereof, wherein, R1, R2, R3are each independently selected from C 1-5 alkyl, or two of R1, R2, R3and the N atom to which they are attached form a 3- to 8-membered heterocycloalkyl group, said heterocycloalkyl group containing at least one N atom, and 0, 1 or 2 heteroatoms selected from N, O or S; optionally, said alkyl or heterocycloalkyl group is substituted with 1, 2 or 3 substituents selected from F, Cl, Br, I, C 1-3 alkyl, nitro, cyano, carboxyl or hydroxyl; R4is selected from H or C 1-5 alkyl; optionally, the alkyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, I, C 1-3 alkyl, nitro, cyano, carboxyl, or hydroxyl; R5is selected from H, C 1-5 alkyl, -CO-(CH2) n1 -(O) n2 -(CH2) n3 -NR 51 R 52 , -CO-(CH2) n1 -(O) n2 -(CH2) n3 -OH, -CO-O-(CH2CH2O) n4 -R 53 , -CO-O-(CH2) n5 -O-CO-(CH2) n6 -O-(CH2CH2O) n7 -R 53 , -CO-O-L2-N(R 54 )3 + Cl - or -CO-Cy; R 51 , R 52 , and R 53 are each independently selected from H or C 1-5 alkyl; optionally, said alkyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, I, C 1-3 alkyl, nitro, cyano, carboxy, or hydroxy; Each R 54 Each independently selected from C 1-5 Alkyl group; optionally, the alkyl group is composed of 1, 2, or 3 atoms selected from F, Cl, Br, I, C. 1-3 Substituted by alkyl, nitro, cyano, carboxyl, or hydroxyl groups; L1and L2are each independently C 1-6 straight or branched alkylene; optionally, said alkylene is substituted with a substituent selected from F, Cl, Br, I, C 1-3 alkyl, nitro, cyano, carboxyl, or hydroxyl; Cy is selected from a 3- to 8-membered heterocycloalkyl; said heterocycloalkyl contains 1, 2, or 3 heteroatoms selected from N, O, or S; optionally, said heterocycloalkyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, I, C 1-3 substituted with 1, 2, or 3 substituents selected from F, Cl, Br, I, C alkyl, nitro, cyano, carboxyl, or hydroxyl; each n1 and n3 is independently selected from 0, 1, 2, 3, 4, or 5, and n1 and n3 are not simultaneously 0; each n2 is independently 0 or 1; n4 and n7 are each independently a positive integer from 1-15; n5 and n6 are each independently selected from 1, 2, 3, 4, or 5.

3. The amphotericin B quaternary ammonium salt derivative of claim 2, or a stereoisomer, a pharmaceutically acceptable salt, or a deuterated form thereof, wherein, R1, R2, R3are each independently selected from C 1-5 alkyl, or two of R1, R2, R3and the N atom to which they are attached form a 3- to 8-membered heterocycloalkyl group, said heterocycloalkyl group containing at least one N atom, and 0, 1 or 2 heteroatoms selected from N, O or S; optionally, said alkyl or heterocycloalkyl group is substituted with 1, 2 or 3 substituents selected from F, Cl, Br, I, C 1-3 alkyl, nitro, cyano, carboxyl or hydroxyl; R4 is selected from H; R5is selected from H, C 1-5 alkyl, -CO-(CH2) n1 -NR 51 R 52 , -CO-(CH2) n1 -O-(CH2) n3 -NR 51 R 52 , -CO-(O) n2 -(CH2) n3 -OH, -CO-O-(CH2CH2O) n4 -R 53 , -CO-O-(CH2) n5 -O-CO-(CH2) n6 -O-(CH2CH2O) n7 -R 53 , -CO-O-L2-N(R 54 )3 + Cl - or -CO-Cy; R 51 , R 52 , and R 53 are each independently selected from H or C 1-5 alkyl; optionally, said alkyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, I, C 1-3 alkyl, nitro, cyano, carboxy, or hydroxy; Each R 54 Each independently selected from C 1-5 Alkyl group; optionally, the alkyl group is composed of 1, 2, or 3 atoms selected from F, Cl, Br, I, C. 1-3 Substituted by alkyl, nitro, cyano, carboxyl, or hydroxyl groups; L1and L2are each independently C 1-5 a straight chain alkylene; optionally, said alkylene is substituted with a substituent selected from F, Cl, Br, I, C 1-3 alkyl, nitro, cyano, carboxyl, or hydroxyl; Cy is selected from a 3- to 8-membered heterocycloalkyl; said heterocycloalkyl contains 1, 2, or 3 heteroatoms selected from N, O, or S; optionally, said heterocycloalkyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, I, C 1-3 substituted with 1, 2, or 3 substituents selected from F, Cl, Br, I, C substituted with 1, 2, or 3 substituents selected from F, Cl, Br, I, C each n1 and n3 is independently selected from 1, 2, 3, 4, or 5; n2 is 0 or 1; n4 is a positive integer from 1-15; n7 is a positive integer from 1-12; n5 and n6 are each independently selected from 1, 2, 3, 4, or 5.

4. The amphotericin B quaternary ammonium salt derivative of claim 1, or a stereoisomer, a pharmaceutically acceptable salt, or a deuterated form thereof, wherein, R1, R2, R3are each independently selected from C 1-5 alkyl, or, two of R1, R2, R3and the N atom to which they are attached form a 5- to 6-membered heterocycloalkyl group, said heterocycloalkyl group containing at least one N atom, and 0 or 1 heteroatom selected from N, O or S; optionally, said alkyl or heterocycloalkyl group is substituted with 1, 2 or 3 substituents selected from F, Cl, Br, I or C 1-3 alkyl; R4 is selected from H; R5is selected from H, -CO-(CH2) n11 -NR 51 R 52 , -CO-(CH2) n12 -O-(CH2) n3 -NR 51 R 52 , -CO-O-(CH2) n3 -OH, -CO-O-(CH2CH2O) n4 -R 53 , -CO-O-(CH2) n5 -O-CO-(CH2) n6 -O-(CH2CH2O) n7 -R 53 , -CO-O-L2-N(R 54 )3 + Cl - or -CO-Cy; R 51 is H; R 52 and R 53 each independently is selected from H or C 1-5 alkyl; optionally, said alkyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, I, or C 1-3 alkyl; Each R 54 Each independently selected from C 1-5 Alkyl group; optionally, the alkyl group is composed of 1, 2, or 3 atoms selected from F, Cl, Br, I, or C. 1-3 Substituents of alkyl groups; L1is C 1-5 a straight chain alkylene; optionally, said alkylene is substituted with a substituent selected from F, Cl, Br, I or C 1-3 alkyl; L2is C 1-3 a straight chain alkylene; optionally, said alkylene is substituted with a substituent selected from F, Cl, Br, I or C 1-3 alkyl; Cy is selected from a 5- to 6-membered heterocycloalkyl; said heterocycloalkyl contains 1 or 2 heteroatoms selected from N, O or S; optionally, said heterocycloalkyl is 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 each n11, n12, and n3 is independently selected from 1, 2, or 3; n4 is a positive integer from 1-15; n7 is a positive integer from 2-10; n5 and n6 are each independently selected from 1, 2, or 3.

5. The amphotericin B quaternary ammonium salt derivative of claim 1, or a stereoisomer, a pharmaceutically acceptable salt, or a deuterated form thereof, wherein, R1, R2, R3 are each independently selected from methyl, ethyl, propyl, or butyl, or, two of R1, R2, R3 and the N atom to which they are attached form a 5- to 6-membered heterocycloalkyl, which contains at least one N atom, and 0 or 1 heteroatom selected from N, O, or S; optionally, the methyl, ethyl, propyl, butyl, or heterocycloalkyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, or I; R4 is selected from H; R5is selected from H, -CO-(CH2) n11 -NR 51 R 52 , -CO-(CH2) n12 -O-(CH2) n3 -NR 51 R 52 , -CO-O-(CH2) n3 -OH, -CO-O-(CH2CH2O) n4 -R 53 , -CO-O-(CH2) n5 -O-CO-(CH2) n6 -O-(CH2CH2O) n7 -R 53 , -CO-O-L2-N(R 54 )3 + Cl - or -CO-Cy; R 51 is H; R 52 is selected from H, methyl, ethyl, propyl, or butyl; optionally, the methyl, ethyl, propyl, or butyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, or I; R 53 is selected from methyl, ethyl, propyl or butyl; optionally, said methyl, ethyl, propyl or butyl is substituted with 1, 2 or 3 substituents selected from F, Cl, Br, or I; Each R 54 Each independently selected from C 1-5 Alkyl group; optionally, the alkyl group is substituted with one, two or three substituents selected from F, Cl, Br or I; L1is C 1-5 a straight chain alkylene; optionally, said alkylene is substituted with a substituent selected from F, Cl, Br, I or C 1-3 alkyl; L2is C 1-3 a straight chain alkylene; optionally, said alkylene is substituted with a substituent selected from F, Cl, Br, I or C 1-3 alkyl; Cy is selected from a 5- to 6-membered heterocycloalkyl; the heterocycloalkyl contains 1 or 2 heteroatoms selected from N, O, or S; optionally, the heterocycloalkyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, or I; each n11, n12, and n3 is independently selected from 1, 2, or 3; n4 is a positive integer from 1-15; n7 is a positive integer from 2-10; n5 and n6 are each independently selected from 1, 2, or 3.

6. The amphotericin B quaternary ammonium salt derivative of claim 1, or a stereoisomer, a pharmaceutically acceptable salt, or a deuterated form thereof, wherein, each of R1, R2, R3is independently selected from the group consisting of methyl, ethyl, propyl, or butyl, or, two of R1, R2, R3and the N atom to which they are attached form a 5- to 6-membered heterocycloalkyl, said heterocycloalkyl containing at least one N atom, and 0 or 1 heteroatom selected from N, O, or S; optionally, said methyl, ethyl, propyl, butyl, or heterocycloalkyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, or I; R4is selected from H; R5is selected from H, -CO-(CH2) n11 -NR 51 R 52 , -CO-CH2-O-(CH2) n3 -NR 51 R 52 , -CO-O-(CH2) n3 -OH, -CO-O-(CH2CH2O) n4 -R 53 , -CO-O-CH2-O-CO-CH2-O-(CH2CH2O) n7 -R 53 , -CO-O-L2-N(R 54 )3 + Cl - or -CO-Cy; R 51 is H; R 52 is selected from H, methyl, ethyl, propyl, or butyl; optionally, the methyl, ethyl, propyl, or butyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, or I; R 53 is selected from methyl, ethyl, propyl or butyl; optionally, said methyl, ethyl, propyl or butyl is substituted with 1, 2 or 3 substituents selected from F, Cl, Br, or I; each R is independently selected from the group consisting of methyl, ethyl, propyl, or butyl; optionally, the methyl, ethyl, propyl, or butyl is substituted with 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, or I; 54 each R is independently selected from the group consisting of methyl, ethyl, propyl, or butyl; optionally, the methyl, ethyl, propyl, or butyl is substituted with 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, or I; L1is C 1-5 a straight chain alkylene; optionally, said alkylene is substituted with a substituent selected from F, Cl, Br, I or C 1-3 alkyl; L2is C 1-3 a straight chain alkylene; optionally, said alkylene is substituted with a substituent selected from F, Cl, Br, I or C 1-3 alkyl; Cy is selected from a 5- to 6-membered heterocycloalkyl; said heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O, or S; optionally, said heterocycloalkyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, or I; each of n11and n3is independently selected from 1, 2, or 3; n4is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; n7is selected from 2, 3, 4, 5, 6, 7, 8, 9, or 10.

7. The AmB QAC derivative of any one of claims 1-6, or a stereoisomer, a pharmaceutically acceptable salt, or a deuterated form thereof, wherein, two of R1, R2, R3form, together with the N atom to which they are attached, a 5- to 6- membered heterocycloalkyl selected from one of the following structures: Cy is selected from one of the following structures: optionally, said heterocycloalkyl is substituted with 1, 2, or 3 substituents selected from F, Cl, Br, or I.

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

9. A pharmaceutical composition comprising a therapeutically effective amount of the AmB QAC derivative of any one of claims 1-8, or a stereoisomer, a pharmaceutically acceptable salt, or a deuterated form thereof, and a pharmaceutically acceptable carrier.

10. Use of the AmB QAC derivative of any one of claims 1-8, or a stereoisomer, a pharmaceutically acceptable salt, or a deuterated form thereof, or the pharmaceutical composition of claim 9, in the manufacture of an antifungal medicament.

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