Amphotericin b hydrazide derivative and use thereof

Abstract

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

Description

Amphotericin B hydrazide 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 hydrazide derivative and application thereof. BACKGROUND

[0002] In recent years, due to the rapid increase of immune compromised population, there are also malignant tumors, malignant hematological diseases, AIDS, SARS, diabetes, severe burns, etc. Occurrence, as well as the widespread 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 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 tissues. 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 with ergosterol in fungal cells, and has relatively small side effects on the kidney 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 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 reduce nephrotoxicity, red blood cell hemolysis toxicity and other properties while maintaining antibacterial activity, 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 hydrazine derivative.

[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 hydrazine derivative.

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

[0010] R1 is selected from -(CH2) n1 -OH, -CO-Y2-R2 or -(CH2) n5 -Y3-C(=X)-R3; optionally, the -CH2- is substituted with a substituent selected from D, F, Cl, Br, I, OH or C 1-6 alkyl;

[0011] R2 is selected from C 1-10 alkyl, C 1-10 alkoxy, NH2, OH, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, -(CH2) n1 -OH, -(CH2) n1-SH, -(CH2) n1 -NR 23 R 24 , -(CH2) n1 -N + R 23 R 24 R 25 Z-, -(CH2) n4 -3 to 10 membered cycloalkyl, -(CH2) n4 -3 to 10 membered heterocycloalkyl or -(CH2) n6 -O-(C=O)-O-(CH2CH2-O) n8 -R 41 ; optionally, said alkyl, alkoxy, heterocycloalkyl and cycloalkyl are substituted with a substituent selected from the group consisting of D, F, Cl, Br, I, C 1-6 NO2, CN, NH2, COOH or OH; said -CH2- is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I, OH or C 1-6 alkyl; said heterocycloalkyl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O or S;

[0012] R 23 , R 24 and R 25 are each independently selected from the group consisting of H or C 1-5 alkyl; optionally, said alkyl is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I or C 1-6 alkyl;

[0013] R 26 is hydroxyl or amino;

[0014] R3is selected from the group consisting of OH, NH2or C 1-10 alkyl; optionally, said alkyl is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I or C 1-6 alkyl;

[0015] R4and R5are each independently selected from the group consisting of H, -(C=O)-O-CH2-O-(C=O)-(CH2) n7 -O-(CH2CH2-O) n8 -R 41 , -(CH2) n42 -R 42 , -C(=O)-(CH2) n43 -Y4-R 43 ; said -CH2- is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I, OH or C 1-6 alkyl;

[0016] each R 41 and R 43 are each independently selected from C 1-5 alkyl; said alkyl is optionally substituted with a substituent selected from D, F, Cl, Br, I, C 1-6 alkyl, nitro, cyano, carboxyl or hydroxyl;

[0017] R 42 is hydroxyl or amino;

[0018] Y1is selected from -O-, -S- or -NH-;

[0019] Y2is selected from a bond, O, S, -NH-NH- or -NH-;

[0020] Y3and Y4are each independently selected from a bond, O, S or -NH-;

[0021] X is selected from O or NH;

[0022] Z is a negative ion; preferably a halogen negative ion; more preferably Cl - , Br - , I - ;

[0023] Ring A is a three- to ten-membered cycloalkyl or a three- to ten-membered heterocycloalkyl; said heterocycloalkyl contains 1, 2 or 3 heteroatoms selected from N, O or S; optionally, said cycloalkyl or heterocycloalkyl is substituted with a substituent selected from D, F, Cl, Br, I or C 1-5 alkyl;

[0024] each n1, n2, n3is independently a positive integer from 1 to 10;

[0025] each n4, n5, n6, n7, n42and n43is independently a positive integer from 1 to 5;

[0026] each n8is independently a positive integer from 1 to 20;

[0027] n11and n12are each independently a positive integer from 0 to 5.

[0028] According to some embodiments of the present application, wherein,

[0029] R1is selected from -(CH2) n1 -OH, -CO-Y2-R2or -(CH2) n5 -Y3-C(=X)-R3; optionally, said -CH2- is substituted with a substituent selected from F, Cl, Br, I, OH or C 1-6 alkyl;

[0030] R2is selected from C1-10 alkyl, NH2, OH, 3- to 10-membered cycloalkyl, -(CH2) n1 -OH, -(CH2) n4 -3- to 10-membered cycloalkyl; optionally, said alkyl and cycloalkyl are substituted with a substituent selected from the group consisting of F, Cl, Br, I, C 1-6 alkyl, nitro, cyano, carboxyl, or hydroxyl;

[0031] R3is selected from the group consisting of OH, NH2, or C 1-10 alkyl; optionally, said alkyl is substituted with a substituent selected from the group consisting of F, Cl, Br, I, or C 1-6 alkyl;

[0032] R5is selected from H;

[0033] Y1is selected from -O-, -S-, or -NH-;

[0034] Y2is selected from a bond, O, S, or -NH-;

[0035] Y3is selected from a bond, O, S, or -NH-;

[0036] X is selected from O or NH;

[0037] n1, n2, and n3 are each independently a positive integer from 1 to 10;

[0038] n4and n5are each independently a positive integer from 1 to 5.

[0039] According to some embodiments of the present application, wherein,

[0040] R1is selected from -(CH2) n1 -OH, -CO-Y2-R2or -(CH2) n5 -Y3-C(=X)-R3; optionally, said -CH2- is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I, OH, or C 1-3 alkyl;

[0041] R2is selected from C 1-5 alkyl, C 1-5 alkoxy, NH2, OH, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocycloalkyl, -(CH2) n1 -OH, -(CH2) n1 -SH, -(CH2) n1 -NR 23 R 24 , -(CH2) n1 -N + R 23 R 24 R25 Z-, -(CH2) n4 -3 to 8 membered cycloalkyl, -(CH2) n4 -3 to 8 membered heterocycloalkyl or -(CH2) n6 -O-(C=O)-O-(CH2CH2-O) n8 -R 41 ; optionally, said alkyl, alkoxy, heterocycloalkyl and cycloalkyl are substituted with a substituent selected from the group consisting of D, F, Cl, Br, I, C 1-3 R, nitro, cyano, amino, carboxyl or hydroxyl; said -CH2- is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I, OH or C 1-3 R, nitro, cyano, amino, carboxyl or hydroxyl; said -CH2- is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I, OH or C

[0042] R 23 , R 24 and R 25 are each independently selected from the group consisting of H or C 1-3 R, nitro, cyano, amino, carboxyl or hydroxyl; said -CH2- is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I, OH or C 1-3 R, nitro, cyano, amino, carboxyl or hydroxyl; said -CH2- is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I, OH or C

[0043] R 26 is hydroxyl or amino;

[0044] R3is selected from the group consisting of OH, NH2or C 1-5 R, nitro, cyano, amino, carboxyl or hydroxyl; said -CH2- is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I, OH or C 1-3 R, nitro, cyano, amino, carboxyl or hydroxyl; said -CH2- is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I, OH or C

[0045] R4and R5are each independently selected from the group consisting of H, -(C=O)-O-CH2-O-(C=O)-(CH2) n7 -O-(CH2CH2-O) n8 R, -(C=O)-(CH2) 41 , -(CH2) n42 R, -(C=O)-(CH2) 42 , -C(=O)-(CH2) n43 -Y4-R 43 ; said -CH2- is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I, OH or C 1-3 R, nitro, cyano, amino, carboxyl or hydroxyl; said -CH2- is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I, OH or C

[0046] each R 41 and R 43 are each independently selected from the group consisting of C 1-3 R, nitro, cyano, amino, carboxyl or hydroxyl; said -CH2- is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I, OH or C 1-3 R, nitro, cyano, amino, carboxyl or hydroxyl; said -CH2- is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I, OH or C

[0047] R 42 is hydroxyl or amino;

[0048] Y1is selected from -O-, -S-, or -NH-;

[0049] Y2is selected from a bond, O, S, -NH-NH-, or -NH-;

[0050] Y3and Y4are each independently selected from a bond, O, S, or -NH-;

[0051] X is selected from O or NH;

[0052] Z is a negative ion;

[0053] Ring A is a three- to eight-membered cycloalkyl or a three- to eight-membered heterocycloalkyl; the heterocycloalkyl contains one, two, or three heteroatoms selected from N, O, or S; optionally, the cycloalkyl or heterocycloalkyl is substituted with a substituent selected from D, F, Cl, Br, I, or a C 1-3 alkyl group;

[0054] n1, n2, and n3 are each independently a positive integer from 1 to 10;

[0055] n4, n5, n6, n7, n42, and n43 are each independently a positive integer from 1 to 5;

[0056] each n8 is independently a positive integer from 1 to 20;

[0057] n11and n12are each independently a positive integer from 0 to 5.

[0058] According to some embodiments of the present application, wherein,

[0059] R1is selected from -CO-Y2-R2or -(CH2) n5 -Y3-C(=X)-R3; optionally, the -CH2- is substituted with a substituent selected from D, F, Cl, Br, I, or a C 1-3 alkyl group;

[0060] Alternatively, R1is selected from -(CH2) n1 -OH; optionally, the -CH2- is substituted with a substituent selected from D, F, Cl, Br, I, OH, or a C 1-3 alkyl group;

[0061] R2is selected from C 1-5 alkyl, C 1-5 alkoxy, NH2, OH, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocycloalkyl, -(CH2) n1 -OH, -(CH2) n1 -SH, -(CH2)n1 -NR 23 R 24 -(CH2) n1 -N + R 23 R 24 R 25 Z-、 -(CH2) n4 -3- to 8-membered cycloalkyl groups, -(CH2) n4 -3 to 8-membered heterocyclic alkyl groups or -(CH2) n6 -O-(C=O)-O-(CH2CH2-O) n8 -R 41 Optionally, the alkyl, alkoxy, heterocyclic alkyl, and cycloalkyl groups are selected from D, F, Cl, Br, I, and C. 1-3 The heterocyclic alkyl group is substituted with alkyl, nitro, cyano, amino, carboxyl, or hydroxyl groups; the heterocyclic alkyl group contains one, two, or three heteroatoms selected from N, O, or S.

[0062] R3 is selected from OH, NH2, or C. 1-5 Alkyl; optionally, the alkyl group is selected from D, F, Cl, Br, I or C. 1-3 Substituents of alkyl groups;

[0063] R 23 R 24 and R 25 Each independently selected from H or C 1-3 Alkyl; optionally, the alkyl group is selected from D, F, Cl, Br, I or C. 1-3 Substituents of alkyl groups;

[0064] R 26 It is either hydroxyl or amino;

[0065] R4 and R5 are each independently selected from H, -(C=O)-O-CH2-O-(C=O)-(CH2). n7 -O-(CH2CH2-O) n8 -R 41 -(CH2) n42 -R 42 -C(=O)-(CH2) n43 -Y4-R 43 The -CH2- is selected from D, F, Cl, Br, I, OH, or C. 1-3 Substituents of alkyl groups;

[0066] Each R 41 and R 43 Each independently selected from C 1-3alkyl; said alkyl is optionally substituted with a substituent selected from the group consisting of D, F, Cl, Br, I, C 1-3 alkyl, nitro, cyano, carboxyl, or hydroxyl;

[0067] R 42 is hydroxyl or amino;

[0068] Y1is selected from the group consisting of -O-, -S-, or -NH-;

[0069] Y2is selected from the group consisting of a bond, O, S, -NH-NH-, or -NH-;

[0070] Y3and Y4are each independently selected from the group consisting of a bond, O, S, or -NH-;

[0071] X is selected from the group consisting of O or NH;

[0072] Z is a negative ion;

[0073] Ring A is a three- to eight-membered cycloalkyl or a three- to eight-membered heterocycloalkyl; said heterocycloalkyl contains one, two, or three heteroatoms selected from the group consisting of N, O, or S; optionally, said cycloalkyl or heterocycloalkyl is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I, or C 1-3 alkyl;

[0074] n1, n2, n3, n4, and n5 are each independently a positive integer from 1 to 10;

[0075] n4, n5, n6, n7, n42, and n43 are each independently a positive integer from 1 to 5;

[0076] each n8 is independently a positive integer from 1 to 20;

[0077] n11and n12are each independently a positive integer from 0 to 5.

[0078] According to some embodiments of the present application, wherein,

[0079] R1is selected from the group consisting of -CO-O-R 21 -CO-S-R 21 -CO-R 22 -CO-NH-R 21 or -(CH2) n5 -Y3-C(=X)-R3; optionally, said -CH2- is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I, or

[0080] R1is selected from the group consisting of -(CH2) n1 -OH; optionally, said -CH2- is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I, or OH;

[0081] R21 selected from C 1-5 alkyl, OH, NH2, C 1-5 alkyloxy, C 1-5 alkylamino, 3- to 6-membered cycloalkyl, -(CH2) n4 -3- to 6-membered cycloalkyl, -(CH2) n4 -3- to 6-membered heterocycloalkyl, -(CH2) n4 -NR 23 R 24 , -(CH2) n1 -N + R 23 R 24 R 25 Z - , -(CH2) n4 -O-C(=O)O(CH2CH2O) n8 -R 41 ; optionally, said alkyl, heterocycloalkyl and cycloalkyl are substituted with a substituent selected from D, F, Cl, Br, I, OH, NH2; said heterocycloalkyl contains 1 or 2 heteroatoms selected from N, O or S;

[0082] R 22 selected from C 1-5 alkyl, OH, NH2; optionally, said alkyl is substituted with a substituent selected from D, F, Cl, Br, I;

[0083] R3is selected from OH or NH2;

[0084] R4and R5are each independently selected from H, -(C=O)-O-CH2-O- (C=O)-(CH2) n7 -O-(CH2CH2-O) n8 -R 41 , -(CH2) n42 -R 42 , -C(=O)-(CH2) n43 -Y4-R 43 ; said -CH2- is substituted with a substituent selected from D, F, Cl, Br, I;

[0085] each R 41 and R 43 are each independently selected from C 1-3 alkyl; said alkyl is substituted with a substituent selected from D, F, Cl, Br, I;

[0086] R 42 is hydroxyl or amino;

[0087] R 23 , R24 and R 25 each independently selected from H or C 1-3 alkyl; optionally, said alkyl is substituted with a substituent selected from D, F, Cl, Br, I;

[0088] R 26 is hydroxyl or amino;

[0089] R 41 selected from C 1-3 alkyl; said alkyl is substituted with a substituent selected from D, F, Cl, Br, I;

[0090] ring A is a three- to six-membered cycloalkyl or a three- to six-membered heterocycloalkyl; said heterocycloalkyl contains one or two heteroatoms selected from N, O or S; optionally, said cycloalkyl or heterocycloalkyl is substituted with a substituent selected from D, F, Cl, Br, I;

[0091] Y1is selected from -O-, -S- or -NH-;

[0092] Y3is selected from a bond or -NH-;

[0093] X is selected from O or NH;

[0094] Z is Cl - , Br - , I - ;

[0095] n1, n2, n3, n4and n5are each independently 1, 2, 3, 4 or 5;

[0096] n8is 5, 6, 7, 8, 9, 10, 11 or 12;

[0097] n11and n12are each independently 0, 1, 2 or 3.

[0098] According to some embodiments of the present application, wherein,

[0099] R1is selected from -CO-O-R 21 , -CO-S-R 21 , -CO-R 22 , -CO-NH-R 21 or -(CH2) n5 -Y3-C(=X)-R3; optionally, said -CH2- is substituted with a substituent selected from D, F, Cl, Br or I; or

[0100] R1is selected from -(CH2) n1 -OH; optionally, said -CH2- is substituted with a substituent selected from D, F, Cl, Br, I or OH;

[0101] R 21 selected from C 1-5 alkyl, OH, NH2, C 1-5 alkyloxy, C 1-5 alkylamino, 3- to 6-membered cycloalkyl, -(CH2) n4 -NR 23 R 24 ; optionally, said alkyl and cycloalkyl are substituted with a substituent selected from D, F, Cl, Br, I, OH, NH2; or

[0102] R 21 selected from 3- to 6-membered heterocycloalkyl, -(CH2) n4 -3- to 6-membered cycloalkyl, -(CH2) n4 -O-C(=O)O(CH2CH2O) n8 -R 41 , -(CH2) n1 -N + R 23 R 24 R 25 Z - , said cycloalkyl, heterocycloalkyl are substituted with a substituent selected from D, F, Cl, Br, I; said heterocycloalkyl contains 1 or 2 heteroatoms selected from N, O or S;

[0103] R 22 selected from C 1-5 alkyl, OH or NH2; optionally, said alkyl is substituted with a substituent selected from D, F, Cl, Br, I;

[0104] R3is selected from OH or NH2;

[0105] R4and R5are each independently selected from H, -(C=O)-O-CH2-O-(C=O)-(CH2) n7 -O-(CH2CH2-O) n8 -R 41 , -(CH2) n42 -R 42 , -C(=O)-(CH2) n43 -Y4-R 43 ; said -CH2- is substituted with a substituent selected from D, F, Cl, Br, I;

[0106] each R 41 and R 43 are each independently selected from C 1-3 alkyl; said alkyl is substituted with a substituent selected from D, F, Cl, Br, I;

[0107] R 42 is hydroxyl or amino;

[0108] R 23 , R 24 and R 25 are each independently selected from H or C 1-3 alkyl; optionally, said alkyl is substituted with a substituent selected from D, F, Cl, Br, I;

[0109] R 26 is hydroxyl or amino;

[0110] R 41 is selected from C 1-3 alkyl; said alkyl is substituted with a substituent selected from D, F, Cl, Br, I;

[0111] ring A is a three- to six-membered cycloalkyl or a three- to six-membered heterocycloalkyl; said heterocycloalkyl contains 1 or 2 heteroatoms selected from N, O or S; optionally, said cycloalkyl or heterocycloalkyl is substituted with a substituent selected from D, F, Cl, Br, I;

[0112] Y1is selected from -O-, -S- or -NH-;

[0113] Y3is selected from a bond or -NH-;

[0114] X is selected from O or NH;

[0115] Z is Cl - , Br - , I - ;

[0116] n1, n2, n3and n5are each independently a positive integer of 1, 2, 3, 4 or 5;

[0117] n8is 5, 6, 7, 8, 9, 10, 11 or 12;

[0118] n11and n12are each independently 0, 1, 2 or 3.

[0119] According to some embodiments of the present application, wherein,

[0120] R1is selected from -CO-O-R 21 , -CO-S-R 21 , -CO-R 22 , -CO-NH-R 21 or -(CH2) n5 -Y3-C(=X)-R3; optionally, said -CH2- is substituted with a substituent selected from D, F, Cl, Br or I; or

[0121] R1is selected from -(CH2) n1 -OH; optionally, said -CH2- is substituted with a substituent selected from D, F, Cl, Br, I, or OH;

[0122] R 21 is selected from methyl, ethyl, propyl, butyl, pentyl, OH, NH2, methoxy, ethoxy, propoxy, butoxy, pentoxy, methylamino, ethylamino, propylamino, butylamino, pentoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH2) n4 -NR 23 R 24 ; optionally, said methyl, ethyl, propyl, butyl, pentyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, methylamino, ethylamino, propylamino, butylamino, pentoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl is substituted with a substituent selected from D, F, Cl, Br, I, hydroxyl, amino; or

[0123] R 21 is selected from oxiranyl, oxetanyl, oxolanyl, oxetanyl, thietanyl, thietanyl, thiolanyl, thiolanyl, aziridinyl, azetidinyl, azolidinyl, azolidinyl, -(CH2) n4 -cyclopropyl, -(CH2) n4 -cyclobutyl, -(CH2) n4 -cyclopentyl, -(CH2) n4 -cyclohexyl, -(CH2) n4 -O-C(=O)O(CH2CH2O) n8 -R 41 , -(CH2) n1 -N + R 23 R 24 R 25 Z - , wherein said cycloalkyl, heterocycloalkyl is substituted with a substituent selected from D, F, Cl, Br, I;

[0124] R 22 is selected from methyl, ethyl, propyl, butyl, pentyl, OH, or NH2; optionally, said methyl, ethyl, propyl, butyl, pentyl is substituted with a substituent selected from D, F, Cl, Br, I;

[0125] R3is selected from OH or NH2;

[0126] R4and R5are each independently selected from H, -(C=O)-O-CH2-O-(C=O)-(CH2)n7 -O-(CH2CH2-O) n8 -R 41 , -(CH2) n42 -R 42 , -C(=O)-(CH2) n43 -Y4-R 43 ; said -CH2- is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I;

[0127] each R 41 and R 43 are each independently selected from the group consisting of methyl, ethyl, propyl; said methyl, ethyl, propyl is optionally substituted with a substituent selected from the group consisting of D, F, Cl, Br, I;

[0128] R 42 is hydroxyl or amino;

[0129] R 23 , R 24 and R 25 are each independently selected from the group consisting of H or methyl, ethyl, propyl; said methyl, ethyl, propyl is optionally substituted with a substituent selected from the group consisting of D, F, Cl, Br, I;

[0130] R 26 is hydroxyl or amino;

[0131] Ring A oxiranyl, oxetanyl, oxolanyl, oxepanyl, thiiranyl, thietanyl, thiolanyl, thiepanyl, aziridinyl, azetidinyl, azolinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; optionally, wherein the cycloalkyl or heterocycloalkyl is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I;

[0132] Y1is selected from the group consisting of -O-, -S- or -NH-;

[0133] Y3is selected from the group consisting of a bond or -NH-;

[0134] X is selected from O or NH;

[0135] Z is Cl - , Br - , I - ;

[0136] n1, n2, n3and n5are each independently a positive integer of 1, 2, 3, 4 or 5;

[0137] n8is 5, 6, 7, 8, 9, 10, 11 or 12;

[0138] n11and n12are each independently 0, 1, 2 or 3.

[0139] According to some embodiments of the application, wherein,

[0140] R1is selected from -CO-O-R 21 -CO-S-R 21 -CO-R 22 -CO-NH-R 21 or -(CH2) n5 -Y3-C(=X)-R3; optionally, said -CH2- is substituted with a substituent selected from D, F, Cl, Br, or I; or

[0141] R1is selected from -(CH2) n1 -OH; said -CH2- is substituted with at least one OH; optionally, said -CH2- is further substituted with a substituent selected from D, F, Cl, Br, or I;

[0142] R 21 is selected from methyl, ethyl, propyl, butyl, pentyl, OH, NH2, methoxy, ethoxy, propoxy, butoxy, pentoxy, methylamino, ethylamino, propylamino, butylamino, pentoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH2) n4 -NR 23 R 24 ; optionally, said methyl, ethyl, propyl, butyl, pentyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, methylamino, ethylamino, propylamino, butylamino, pentoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are substituted with a substituent selected from D, F, Cl, Br, I, hydroxyl, amino; or

[0143] R 21 is selected from oxiranyl, oxetanyl, oxolanyl, oxetanyl, thietanyl, thietanyl, thiolanyl, thiolanyl, aziridinyl, azetidinyl, azolidinyl, azepanyl, -(CH2) n4 -cyclopropyl, -(CH2) n4 -cyclobutyl, -(CH2) n4 -cyclopentyl, -(CH2) n4 -cyclohexyl, -(CH2) n4 -O-C(=O)O(CH2CH2O) n8 -R 41 , -(CH2) n1 -N + R 23 R 24 R 25 Z-, wherein the cycloalkyl, heterocycloalkyl is selected from the group consisting of D, F, Cl, Br, I substituted substituents;

[0144] R 22 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, OH or NH2; optionally, the methyl, ethyl, propyl, butyl, pentyl is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I;

[0145] R3is selected from the group consisting of OH or NH2;

[0146] R4and R5are each independently selected from the group consisting of H, -(C=0)-0-CH2-0-(C=0)-(CH2) n7 -O-(CH2CH2-O) n8 -R 41 , -(CH2) n42 -R 42 , -C(=0)-(CH2) n43 -Y4-R 43 ; said -CH2- is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I;

[0147] each R 41 and R 43 is independently selected from the group consisting of methyl, ethyl, propyl; said methyl, ethyl, propyl is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I;

[0148] R 42 is hydroxyl or amino;

[0149] R 23 , R 24 and R 25 are each independently selected from the group consisting of H or methyl, ethyl, propyl; optionally, said methyl, ethyl, propyl is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I;

[0150] R 26 is hydroxyl or amino;

[0151] Ring A oxiranyl, oxetanyl, oxolanyl, oxanamyl, thiiranyl, thietanyl, thiolanyl, thianamyl, aziridinyl, azetidinyl, azolidinyl, azanamyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; optionally, wherein the cycloalkyl or heterocycloalkyl is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I;

[0152] Y1is selected from the group consisting of -0-, -S- or -NH-;

[0153] Y3is selected from the group consisting of a bond or -NH-;

[0154] X is selected from O or NH;

[0155] Z is Cl - , Br - , I - ;

[0156] n1, n2, n3 and n5 are each independently a positive integer of 1, 2, 3, 4 or 5;

[0157] n8 is 5, 6, 7, 8, 9, 10, 11 or 12;

[0158] n11 and n12 are each independently 0, 1, 2 or 3.

[0159] According to some embodiments of the present application, wherein,

[0160] R1 is selected from -CO-O-R 21 , -CO-S-R 21 , -CO-NH-R 21 , -(CH2) n1 -OH, -CO-R 22 or -(CH2) n5 -Y3-C(=X)-R3; optionally, said -CH2- is substituted with a substituent selected from D, F, Cl, Br, I or OH;

[0161] R 21 is selected from C 1-5 alkyl, -C 1-5 alkylene-OH, -C 1-5 alkylene-NH2, OH, NH2, C 1-5 alkyloxy, C 1-5 alkylimino, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, -(CH2) n4 -NR 23 R 24 , -(CH2) n4 -3- to 6-membered cycloalkyl, -(CH2) n4 -O-C(=O)O(CH2CH2O) n8 -R 41 , -(CH2) n1 -N + R 23 R 24 R 25 Z-, optionally, said alkyl, heterocycloalkyl and cycloalkyl are substituted with a substituent selected from the group consisting of D, F, Cl, Br, I; optionally, the alkyl of said alkyloxy and alkyl imino is substituted with a substituent selected from the group consisting of hydroxyl or amino; said heterocycloalkyl contains 1 or 2 heteroatoms selected from the group consisting of N, O or S;

[0162] R 22 selected from the group consisting of C 1-5 alkyl, OH or NH2; optionally, said alkyl is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I;

[0163] R3is selected from the group consisting of OH or NH2;

[0164] R4and R5are each independently selected from the group consisting of H, -(C=0)-0-(CH2) n6 -(C=0)-(CH2) n7 -(CH2CH2-0) n8 R 41 -(CH2) n42 R 42 -(C=0)-(CH2) n43 -Y4-R 43 ; said -CH2- is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I;

[0165] each R 41 and R 43 are each independently selected from the group consisting of C 1-5 alkyl; said alkyl is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I;

[0166] R 42 is hydroxyl or amino;

[0167] R 23 , R 24 and R 25 are each independently selected from the group consisting of H or C 1-5 alkyl; optionally, said alkyl is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I;

[0168] R 26 is hydroxyl or amino;

[0169] ring A is a three- to six-membered cycloalkyl or a three- to six-membered heterocycloalkyl; said heterocycloalkyl contains 1 or 2 heteroatoms selected from the group consisting of N, O or S; optionally, said cycloalkyl or heterocycloalkyl is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I;

[0170] Y1is selected from the group consisting of -0-, -S- or -NH-;

[0171] Y3is selected from the group consisting of a bond or -NH-;

[0172] X is selected from O or NH;

[0173] Z is Cl - , Br - , I - ;

[0174] n1, n2, n3, n5, n6 and n7 are each independently 1, 2, 3, 4 or 5;

[0175] n8 is 5, 6, 7, 8, 9 or 10;

[0176] n11 and n12 are each independently 0, 1, 2 or 3.

[0177] According to some embodiments of the present application, wherein,

[0178] R1is selected from -(CH2) n1 -OH, -CO-O-R 21 , -CO-S-R 21 , -CO-NH-R 21 , -CO-R 22 or -(CH2) n5 -Y3-C(=X)-R3; optionally, said -CH2- is substituted with a substituent selected from D, F, Cl, Br, I or OH;

[0179] R 21 is selected from methyl, ethyl, propyl, butyl, pentyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, OH, NH2, methoxy, ethoxy, propoxy, butoxy, pentoxy, methylamino, ethylamino, propylamino, butylamino, pentoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heterocyclopropyl, heterocyclobutyl, heterocyclopentyl, heterocyclohexyl or -(CH2) n4 -NR 23 R 24 , -(CH2) n4 -cyclopropyl, -(CH2) n4 -cyclobutyl, -(CH2) n4 -cyclopentyl, -(CH2) n4 -cyclohexyl, -(CH2) n4 -O-C(=O)O(CH2CH2O) n8 -R 41 , -(CH2) n1 -N + R 23 R 24 R25 Z - 、 optionally, said methyl, ethyl, propyl, butyl, pentyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, methylamino, ethylamino, propylamino, butylamino, pentylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heterocyclopropyl, heterocyclobutyl, heterocyclopentyl, heterocyclohexyl are substituted with a substituent selected from D, F, Cl, Br, I; optionally, said methoxy, ethoxy, propoxy, butoxy, pentoxy, methylamino, ethylamino, propylamino, butylamino, pentylamino are substituted with a substituent selected from hydroxyl or amino; said heterocyclopropyl, heterocyclobutyl, heterocyclopentyl, heterocyclohexyl contain 1 or 2 heteroatoms selected from N, O or S;

[0180] R 22 is selected from methyl, ethyl, propyl, butyl, pentyl, OH or NH2; optionally, said methyl, ethyl, propyl, butyl, pentyl are substituted with a substituent selected from D, F, Cl, Br, I;

[0181] R3is selected from OH or NH2;

[0182] R4and R5are each independently selected from H, -(C=0)-0-(CH2) n6 -O-(C=0)-(CH2) n7 -O-(CH2CH2-O) n8 -R 41 , -(CH2) n42 -R 42 , -C(=0)-(CH2) n43 -Y4-R 43 ; said -CH2- is substituted with a substituent selected from D, F, Cl, Br, I;

[0183] each R 41 and R 43 are each independently selected from methyl, ethyl, propyl, butyl, pentyl; said methyl, ethyl, propyl, butyl, pentyl are substituted with a substituent selected from D, F, Cl, Br, I;

[0184] R 42 is hydroxyl or amino;

[0185] R 23 , R 24 and R 25 are each independently selected from H or methyl, ethyl, propyl, butyl, pentyl; optionally, said methyl, ethyl, propyl, butyl, pentyl are substituted with a substituent selected from D, F, Cl, Br, I;

[0186] R 26hydroxyl or amino;

[0187] Ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heterocyclopropyl, heterocyclobutyl, heterocyclopentyl, or heterocyclohexyl; wherein the heterocycloalkyl contains 1 or 2 heteroatoms selected from N, O, or S; optionally, wherein the cycloalkyl or heterocycloalkyl is substituted with a substituent selected from D, F, Cl, Br, I;

[0188] Y1is selected from -O-, -S-, or -NH-;

[0189] Y3is selected from a bond or -NH-;

[0190] X is selected from O or NH;

[0191] Z is Cl - , Br - , I - ;

[0192] n1, n2, n3, n5, n6, n7 are each independently 1, 2, 3, 4, or 5;

[0193] n8 is 5, 6, 7, 8, 9, or 10;

[0194] n11and n12are each independently 0, 1, 2, or 3.

[0195] The present application also provides a hydrazide derivative of amphotericin B, wherein the hydrazide derivative of amphotericin B is represented by Formula (II):

[0196] R1is selected from -(CH2) n1 -OH, -CO-Y2-R2or -(CH2) n5 -Y3-C(=X)-R3; optionally, the -CH2- is substituted with a substituent selected from F, Cl, Br, I, OH, or C 1-6 alkyl;

[0197] R2is selected from C 1-10 alkyl, C 1-10 alkoxy, NH2, OH, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, -(CH2) n1 -OH, -(CH2) n1 -SH, -(CH2) n1 -NR 23 R 24 , -(CH2) n4 -3- to 10-membered cycloalkyl, -(CH2) n4 -3- to 10-membered heterocycloalkyl, or -(CH2) n6-O-(C=O)-O-(CH2CH2-O) n8 -R 41 ; optionally, said alkyl, alkoxy, heterocycloalkyl and cycloalkyl are substituted with a substituent selected from the group consisting of F, Cl, Br, I, C 1-6 alkyl, nitro, cyano, carboxyl or hydroxyl; said -CH2- is substituted with a substituent selected from the group consisting of F, Cl, Br, I, OH or C 1-6 alkyl; said heterocycloalkyl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O or S;

[0198] R 23 and R 24 are each independently selected from the group consisting of H or C 1-5 alkyl; optionally, said alkyl is substituted with a substituent selected from the group consisting of F, Cl, Br, I or C 1-6 alkyl;

[0199] R3is selected from the group consisting of OH, NH2or C 1-10 alkyl; optionally, said alkyl is substituted with a substituent selected from the group consisting of F, Cl, Br, I or C 1-6 alkyl;

[0200] R4is selected from the group consisting of H or -(C=O)-O-CH2-O-(C=O)-(CH2) n7 -O-(CH2CH2-O) n8 -R 41 ; said -CH2- is substituted with a substituent selected from the group consisting of F, Cl, Br, I, OH or C 1-6 alkyl;

[0201] each R 41 is independently selected from the group consisting of C 1-5 alkyl; said alkyl is substituted with a substituent selected from the group consisting of F, Cl, Br, I, C 1-6 alkyl, nitro, cyano, carboxyl or hydroxyl;

[0202] Y1is selected from the group consisting of -O-, -S- or -NH-;

[0203] Y2is selected from the group consisting of a bond, O, S or -NH-;

[0204] Y3is selected from the group consisting of a bond, O, S or -NH-;

[0205] X is selected from the group consisting of O or NH;

[0206] each n1, n2, n3is independently a positive integer from 1 to 10;

[0207] each n4, n5, n6and n7is independently a positive integer from 1 to 5;

[0208] each n8 is independently a positive integer from 1 to 20.

[0209] According to some embodiments of the application, wherein,

[0210] R1is selected from -(CH2) n1 -OH, -CO-Y2-R2or -(CH2) n5 -Y3-C(=X)-R3; optionally, said -CH2- is substituted with a substituent selected from F, Cl, Br, I, OH, or C 1-6 alkyl;

[0211] R2is selected from C 1-10 alkyl, OH, NH2, 3- to 10-membered cycloalkyl, -(CH2) n1 -OH, -(CH2) n4 -3- to 10-membered cycloalkyl; optionally, said alkyl and cycloalkyl are substituted with a substituent selected from F, Cl, Br, I, C 1-6 alkyl, nitro, cyano, carboxyl, or hydroxyl;

[0212] R3is selected from OH, NH2, or C 1-10 alkyl; optionally, said alkyl is substituted with a substituent selected from F, Cl, Br, I, or C 1-6 alkyl;

[0213] Y1is selected from -O-, -S-, or -NH-;

[0214] Y2is selected from a bond, O, S, or -NH-;

[0215] Y3is selected from a bond, O, S, or -NH-;

[0216] X is selected from O or NH;

[0217] n1, n2, and n3 are each independently a positive integer from 1 to 10;

[0218] n4and n5are each independently a positive integer from 1 to 5.

[0219] According to some embodiments of the application, wherein,

[0220] R1is selected from -(CH2) n1 -OH, -CO-Y2-R2or -(CH2) n5 -Y3-C(=X)-R3; optionally, said -CH2- is substituted with a substituent selected from F, Cl, Br, I, OH, or C 1-6 alkyl;

[0221] R2is selected from the group consisting of C1-10alkyl, OH, NH2, 3- to 10-membered cycloalkyl, -(CH2) n1 -OH, -(CH2) n4 -3- to 10-membered cycloalkyl; optionally, said alkyl and cycloalkyl are substituted with a substituent selected from the group consisting of F, Cl, Br, I, C 1-6 alkyl, nitro, cyano, carboxyl, or hydroxyl;

[0222] R3is selected from the group consisting of OH, NH2, or C 1-10 alkyl; optionally, said alkyl is substituted with a substituent selected from the group consisting of F, Cl, Br, I, or C 1-6 alkyl;

[0223] Y1is selected from the group consisting of -O-, -S-, or -NH-;

[0224] Y2is selected from the group consisting of a bond, O, or S;

[0225] Y3is selected from the group consisting of a bond, O, S, or -NH-;

[0226] X is selected from the group consisting of O or NH;

[0227] n1, n2, and n3 are each independently a positive integer from 1 to 10;

[0228] n4and n5are each independently a positive integer from 1 to 5.

[0229] According to some embodiments of the present application, wherein,

[0230] R1is selected from the group consisting of -(CH2) n1 -OH, -CO-Y2-R2, or -(CH2) n5 -Y3-C(=X)-R3; optionally, said -CH2- is substituted with a substituent selected from the group consisting of F, Cl, Br, I, OH, or C 1-3 alkyl;

[0231] R2is selected from the group consisting of C 1-5 alkyl, OH, NH2, 3- to 8-membered cycloalkyl, -(CH2) n1 -OH, -(CH2) n4 -3- to 8-membered cycloalkyl; optionally, said alkyl and cycloalkyl are substituted with a substituent selected from the group consisting of F, Cl, Br, I, C 1-3 alkyl, nitro, cyano, carboxyl, or hydroxyl;

[0232] R3is selected from the group consisting of OH, NH2, or C 1-5 alkyl; optionally, said alkyl is substituted with a substituent selected from the group consisting of F, Cl, Br, I, or C 1-3 alkyl;

[0233] Y1is selected from -O-, -S-, or -NH-;

[0234] Y2is selected from a bond, O, S, or -NH-;

[0235] Y3is selected from a bond, O, S, or -NH-;

[0236] X is selected from O or NH;

[0237] n1, n2, and n3 are each independently a positive integer from 1 to 10;

[0238] n4and n5are each independently a positive integer from 1 to 5.

[0239] According to some embodiments of the present application, wherein,

[0240] R1is selected from -CO-Y2-R2or -(CH2) n5 -Y3-C(=X)-R3; optionally, said -CH2- is substituted with a substituent selected from F, Cl, Br, I, or C 1-3 alkyl;

[0241] Alternatively, R1is selected from -(CH2) n1 -OH; optionally, said -CH2- is substituted with a substituent selected from F, Cl, Br, I, OH or C 1-3 alkyl;

[0242] R2is selected from C 1-5 alkyl, NH2, OH, 3- to 8-membered cycloalkyl, -(CH2) n1 -OH, -(CH2) n4 -3- to 8-membered cycloalkyl; optionally, said alkyl and cycloalkyl are substituted with a substituent selected from F, Cl, Br, I, C 1-3 alkyl, nitro, cyano, carboxy, or hydroxy;

[0243] R3is selected from OH, NH2, or C 1-5 alkyl; optionally, said alkyl is substituted with a substituent selected from F, Cl, Br, I, or C 1-3 alkyl;

[0244] Y1is selected from -O-, -S-, or -NH-;

[0245] Y2is selected from a bond, O, S, or -NH-;

[0246] Y3is selected from a bond, O, S, or -NH-;

[0247] X is selected from O or NH;

[0248] n1, n2, n3, n4, and n5 are each independently a positive integer from 1 to 10.

[0249] According to some embodiments of the application, wherein,

[0250] R1is selected from -CO-O-R 21 -CO-S-R 21 -CO-R 22 -CO-NH-R 21 or -(CH2) n5 -Y3-C(=X)-R3; optionally, said -CH2- is substituted with a substituent selected from F, Cl, Br, I; or

[0251] R1is selected from -(CH2) n1 -OH; optionally, said -CH2- is substituted with a substituent selected from F, Cl, Br, I, or OH;

[0252] R 21 is selected from C 1-5 alkyl, 3- to 6-membered cycloalkyl, -(CH2) n4 -3- to 6-membered cycloalkyl; optionally, said alkyl and cycloalkyl are substituted with a substituent selected from F, Cl, Br, I;

[0253] R 22 is selected from C 1-5 alkyl, OH, NH2; optionally, said alkyl is substituted with a substituent selected from F, Cl, Br, I;

[0254] R3is selected from OH or NH2;

[0255] Y1is selected from -O-, -S-, or -NH-;

[0256] Y3is selected from a bond or -NH-;

[0257] X is selected from O or NH;

[0258] n1, n2, n3, n4, and n5 are each independently 1, 2, 3, 4, or 5.

[0259] According to some embodiments of the application, wherein,

[0260] R1is selected from -CO-O-R 21 -CO-S-R 21 -CO-R 22 -CO-NH-R 21 or -(CH2) n5-Y3-C(=X)-R3; optionally, said -CH2- is substituted with a substituent selected from F, Cl, Br, or I; or

[0261] R1is selected from -(CH2) n1 -OH; optionally, said -CH2- is substituted with a substituent selected from F, Cl, Br, I, or OH;

[0262] R 21 is selected from C 1-5 alkyl, 3- to 6-membered cycloalkyl, optionally, said alkyl and cycloalkyl are substituted with a substituent selected from F, Cl, Br, I;

[0263] R 22 is selected from C 1-5 alkyl, OH, or NH2; optionally, said alkyl is substituted with a substituent selected from F, Cl, Br, I;

[0264] R3is selected from OH or NH2;

[0265] Y1is selected from -O-, -S-, or -NH-;

[0266] Y3is selected from a bond or -NH-;

[0267] X is selected from O or NH;

[0268] n1, n2, n3, and n5 are each independently a positive integer of 1, 2, 3, 4, or 5.

[0269] According to some embodiments of the present application, wherein,

[0270] R1is selected from -CO-O-R 21 -CO-S-R 21 -CO-R 22 -CO-NH-R 21 or -(CH2) n5 -Y3-C(=X)-R3; optionally, said -CH2- is substituted with a substituent selected from F, Cl, Br, or I; or

[0271] R1is selected from -(CH2) n1 -OH; optionally, said -CH2- is substituted with a substituent selected from F, Cl, Br, I, or OH; preferably, said -CH2- is substituted with at least one OH;

[0272] R 21 is selected from methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, optionally, said methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are substituted with a substituent selected from the group consisting of F, Cl, Br, I;

[0273] R 22 selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, OH or NH2; optionally, said methyl, ethyl, propyl, butyl, pentyl are substituted with a substituent selected from the group consisting of F, Cl, Br, I;

[0274] R3is selected from the group consisting of OH or NH2;

[0275] Y1is selected from the group consisting of -O-, -S- or -NH-;

[0276] Y3is selected from the group consisting of a bond or -NH-;

[0277] X is selected from the group consisting of O or NH;

[0278] n1, n2, n3and n5are each independently a positive integer of 1, 2, 3, 4 or 5.

[0279] According to some embodiments of the present application, wherein,

[0280] R1is selected from -CO-O-R 21 -CO-S-R 21 -CO-R 22 -CO-NH-R 21 or -(CH2) n5 -Y3-C(=X)-R3; optionally, said -CH2- is substituted with a substituent selected from the group consisting of F, Cl, Br or I; or

[0281] R1is selected from -(CH2) n1 -OH; said -CH2- is substituted with at least one OH; optionally, said -CH2- is further substituted with a substituent selected from the group consisting of F, Cl, Br or I;

[0282] R 21 selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, optionally, said methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are substituted with a substituent selected from the group consisting of F, Cl, Br, I;

[0283] R 22 selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, OH or NH2; optionally, said methyl, ethyl, propyl, butyl, pentyl are substituted with a substituent selected from the group consisting of F, Cl, Br, I;

[0284] R3is selected from the group consisting of OH or NH2;

[0285] Y1is selected from -O-, -S-, or -NH-;

[0286] Y3is selected from a bond or -NH-;

[0287] X is selected from O or NH;

[0288] n1, n2, n3, and n5 are each independently a positive integer of 1, 2, 3, 4, or 5.

[0289] According to some embodiments of the present application, wherein,

[0290] R1is selected from -CO-O-R 21 -CO-S-R 21 -CO-NH-R 21 -(CH2) n1 -OH, -CO-R 22 or -(CH2) n5 -Y3-C(=X)-R3; optionally, said -CH2- is substituted with a substituent selected from F, Cl, Br, I, or OH; or

[0291] R 21 is selected from C 1-5 alkyl, -C 1-5 alkylene-OH, -C 1-5 alkylene-NH2, OH, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, optionally, said alkyl, heterocycloalkyl, and cycloalkyl are substituted with a substituent selected from F, Cl, Br, I; said heterocycloalkyl contains 1 or 2 heteroatoms selected from N, O, or S;

[0292] R 22 is selected from C 1-5 alkyl, OH, or NH2; optionally, said alkyl is substituted with a substituent selected from F, Cl, Br, I;

[0293] R3is selected from OH or NH2;

[0294] R4is selected from H or -(C=O)-O-(CH2) n6 -O-(C=O)-(CH2) n7 -(CH2CH2-O) n8 -R 41 ;

[0295] R 41 is selected from C 1-5 alkyl; said alkyl is substituted with a substituent selected from F, Cl, Br, or I;

[0296] Y1 is selected from -O-, -S-, or -NH-;

[0297] Y3 is selected from either the bond or -NH-;

[0298] X is selected from O or NH;

[0299] n1, n2, n3, n5, n6, and n7 are each independently 1, 2, 3, 4, or 5;

[0300] n8 can be 5, 6, 7, 8, 9, or 10.

[0301] According to some specific embodiments of the present invention, wherein,

[0302] R1 is selected from -(CH2) n1 -OH, -CO-OR 21 -CO-SR 21 -CO-NH-R 21 -CO-R 22 Or -(CH2) n5 -Y3-C(=X)-R3; optionally, the -CH2- is replaced by a substituent selected from F, Cl, Br, I or OH; or

[0303] R 21 Selected from methyl, ethyl, propyl, butyl, pentyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heterocyclopropyl, heterocyclobutyl, heterocyclopentyl, heterocyclohexyl or Optionally, the methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heterocyclopropyl, heterocyclobutyl, heterocyclopentyl, and heterocyclohexyl groups are substituted with substituents selected from F, Cl, Br, and I; the heterocyclopropyl, heterocyclobutyl, heterocyclopentyl, and heterocyclohexyl groups contain one or two heteroatoms selected from N, O, or S.

[0304] R 22 The group is selected from methyl, ethyl, propyl, butyl, pentyl, OH, or NH2; optionally, the methyl, ethyl, propyl, butyl, or pentyl group is substituted with a substituent selected from F, Cl, Br, or I.

[0305] R3 is selected from OH or NH2;

[0306] R4 is selected from H or -(C=O)-O-(CH2). n6 -O-(C=O)-(CH2) n7 -(CH2CH2-O) n8 -R 41 ;

[0307] R 41 selected from the group consisting of methyl, ethyl, propyl, butyl or pentyl; optionally, said methyl, ethyl, propyl, butyl, pentyl is substituted with a substituent selected from the group consisting of F, Cl, Br, I;

[0308] Y1is selected from the group consisting of -O-, -S- or -NH-;

[0309] Y3is selected from the group consisting of a bond or -NH-;

[0310] X is selected from O or NH;

[0311] n1, n2, n3, n5, n6, n7 are each independently 1, 2, 3, 4 or 5;

[0312] n8 is 5, 6, 7, 8, 9 or 10.

[0313] According to some embodiments of the present application, wherein,

[0314] R1is selected from the group consisting of -(CH2) n1 -OH, -CO-O-R 21 , -CO-NH-R 21 , -CO-R 22 or -(CH2) n5 -Y3-C(=X)-R3; optionally, said -CH2- is substituted with a substituent selected from the group consisting of F, Cl, Br, I or OH; or

[0315] R 21 selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxy pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heterocyclopropyl, heterocyclobutyl, heterocyclopentyl, heterocyclohexyl or optionally, said methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heterocyclopropyl, heterocyclobutyl, heterocyclopentyl, heterocyclohexyl is substituted with a substituent selected from the group consisting of F, Cl, Br, I; said heterocyclopropyl, heterocyclobutyl, heterocyclopentyl, heterocyclohexyl contains 1 or 2 heteroatoms selected from the group consisting of N, O or S;

[0316] R 22 selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl or NH2; optionally, said methyl, ethyl, propyl, butyl, pentyl is substituted with a substituent selected from the group consisting of F, Cl, Br, I;

[0317] R3is selected from the group consisting of OH or NH2;

[0318] R4is selected from the group consisting of H or -(C=O)-O-(CH2) n6 -O-(C=O)-(CH2)n7 -(CH2CH2-O) n8 -R 41 ;

[0319] R 41 selected from the group consisting of F, Cl, Br, I;

[0320] Y1is selected from the group consisting of -O-, -S-, or -NH-;

[0321] Y3is selected from the group consisting of a bond or -NH-;

[0322] X is selected from the group consisting of O or NH;

[0323] n1, n2, n3, n5, n6, n7are each independently 1, 2, 3, 4, or 5;

[0324] n8is 5, 6, 7, 8, 9, or 10.

[0325] According to some embodiments of the application, wherein,

[0326] R1is selected from the group consisting of -CO-O-R 21 , -CO-S-R 21 , -CO-NH-R 21 , -(CH2) n1 -OH; optionally, said -CH2- is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I, or OH;

[0327] R 21 is selected from the group consisting of C 1-5 alkyl, -C 1-5 alkylene-OH, -C 1-5 alkylene-NH2, OH, 3- to 6-membered heterocycloalkyl; optionally, said alkyl, heterocycloalkyl is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I; said heterocycloalkyl contains 1 or 2 heteroatoms selected from the group consisting of N, O, or S;

[0328] R4and R5are selected from H;

[0329] Y1is selected from the group consisting of -O-, -S-, or -NH-;

[0330] n1is 1, 2, 3, 4, or 5.

[0331] According to some embodiments of the application, wherein,

[0332] R1is selected from the group consisting of -CO-O-R 21 , -CO-S-R 21 , -CO-NH-R 21’ , -(CH2)n1 -OH; optionally, the -CH2- is substituted with a substituent selected from D, F, Cl, Br, I, or OH;

[0333] R 21 selected from C 1-5 alkyl, -C 1-5 alkylene-OH; optionally, the alkyl is substituted with a substituent selected from D, F, Cl, Br, I;

[0334] R 21’ selected from C 1-5 alkyl, -C 1-5 alkylene-OH, OH, 3-, 4-, 5-, or 6-membered heterocycloalkyl; optionally, the alkyl, heterocycloalkyl is substituted with a substituent selected from D, F, Cl, Br, I; the heterocycloalkyl contains 1 or 2 heteroatoms selected from N, O, or S;

[0335] R4and R5are selected from H;

[0336] Y1is selected from -O-, -S-, or -NH-;

[0337] n1is 1, 2, 3, 4, or 5.

[0338] It is understood that the definitions of the substituents of the different embodiments described above can be arbitrarily combined with each other without contradiction.

[0339] According to some embodiments of the present application, the structure of the amphotericin B hydrazide derivative is selected from one of the following structures:

[0340] In another aspect, the present application also provides a pharmaceutical composition comprising a therapeutically effective amount of any of the amphotericin B hydrazide derivatives or stereoisomers, pharmaceutically acceptable salts, or deuterated forms thereof of the present application, and a pharmaceutically acceptable carrier.

[0341] In yet another aspect, the present application also provides the use of the amphotericin B hydrazide 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.

[0342] The compound of the present application has bacteriostatic activity and in-vivo stability comparable to existing drugs, but the cytotoxicity is significantly lower than that of existing drugs, and the risk of drug-drug interaction is also lower than that of existing drugs; at the same time, the compound of the present application also has a longer half-life compared with existing drugs. This shows that the antibacterial effect of the compound of the present application is comparable to that of existing drugs, but has more excellent drug safety and has the potential for longer drug administration intervals. DETAILED DESCRIPTION

[0343] The technical solutions of the present application are described in detail below in combination with the drawings and examples, but the protection scope of the present application includes but is not limited to this.

[0344] Synthesis of intermediate C2’epiAmB (ref. Nature, 2023, 623, 1079-1085)

[0345] Step 1: Synthesis of intermediate Int 1

[0346] Method: Amphotericin B (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, and the reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was added dropwise into methyl tert-butyl ether (8 L) stirred vigorously, 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).

[0347] MS (ESI, m / z) 1009 [M+H] + .

[0348] Step 2: Synthesis of intermediate Int 2

[0349] 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, and the reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, triethylamine (5 mL) was added to quench, the reaction solution was added dropwise into n-hexane / methyl tert-butyl ether (volume ratio 3:5, 8 L) stirred vigorously, 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).

[0350] MS (ESI, m / z) 1259 [M+H] + .

[0351] Step 3: Synthesis of intermediate Int 3

[0352] 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%).

[0353] MS (ESI, m / z) 1299 [M+H] + .

[0354] Step 4: Synthesis of intermediate Int 4

[0355] 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 with 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 the 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%).

[0356] MS (ESI, m / z) 1460 [M+H] + .

[0357] Step 5: Synthesis of intermediate Int 5

[0358] 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 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 addition was completed. The reaction was quenched by adding the reaction solution to 1 L of saturated sodium bicarbonate solution, and EA was used to extract twice. The organic phase was combined and washed with copper sulfate solution to remove 2,6-dimethylpyridine, and then concentrated brine was used for further washing. The solution was dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. Column chromatography (PE:EA = 15:1 to 10:1) was used to obtain yellow solid powder Int 5 (36 g, yield 66.6%).

[0359] MS (ESI, m / z) 1971 [M+H] + .

[0360] Step 6: Synthesis of intermediate Int 6

[0361] 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 the nitrogen, the solution was stirred at 40 °C for 24 h. The reaction solution was added to EA and saturated sodium bicarbonate solution, and the solution was separated and extracted. The aqueous phase was further extracted twice with EA, and the organic phase was combined and washed with concentrated brine. The solution was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography (PE:EA = 15:1 to PE:EA = 5:1) was used to obtain yellow solid powder Int 6 (8.5 g, yield 37.2%) and recover the raw material Int 5 (7 g).

[0362] MS (ESI, m / z) 1812 [M+H] + .

[0363] Step 7: Synthesis of intermediate Int 7

[0364] 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%).

[0365] MS (ESI, m / z) 1960 [M+H] + .

[0366] Step 8: Synthesis of intermediate Int 8

[0367] 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%).

[0368] MS (ESI, m / z) 1812 [M+H] + .

[0369] Step 9: Synthesis of intermediate Int 9

[0370] 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).

[0371] MS (ESI, m / z) 1299 [M+H] + .

[0372] Step 10: Synthesis of intermediate Int 10

[0373] 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 vacuum to obtain yellow solid powder Int 10 (3.75 g, 82% yield).

[0374] MS (ESI, m / z) 1175 [M+H] + .

[0375] Step 11: Synthesis of intermediate C2’epiAmB

[0376] 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.

[0377] MS (ESI, m / z) 924 [M+H] + .

[0378] 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).

[0379] Example 1: Synthesis of BX20-11-003

[0380] Step 1: Synthesis of Intermediate 3-3

[0381] Method: 3-1 (16.4 g, 51.1 mmol) was dissolved in THF (200 mL), 3-2 (10 g, 61.3 mmol) and PPh3 (16.1 g, 61.3 mmol) were added, and the ice water bath was cooled, and a solution of DIAD (12.4 g, 61.4 mmol) in THF (30 mL) was added dropwise. After addition, the reaction solution was stirred at room temperature for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure, the residue was added with MeOH (200 mL) and stirred at room temperature for half an hour, and the insoluble matter was filtered off, and the filtrate was collected and concentrated under reduced pressure, and then MeOH (100 mL) was added and stirred at room temperature for half an hour, and the insoluble matter was filtered off, and the filtrate was collected and concentrated under reduced pressure to obtain white solid 3-3 (15.4 g, 64.8%).

[0382] MS (ESI, m / z) 466 [M+H] + .

[0383] Step 2: Synthesis of intermediate 3-4

[0384] Method: Intermediate 3-3 (3.8 g, 8.2 mmol) was dissolved in MeOH (150 mL), hydrazine hydrate (80%, 2.5 g, 40 mmol) was added, and the reaction was stirred at 80°C for 3 hours. After the reaction, the filtrate was collected and concentrated under reduced pressure, and purified by column chromatography (PE:EA = 50:1~PE:EA = 10:1) to obtain colorless oil 3-4 (2.57 g, 93.5%).

[0385] MS (ESI, m / z) 336 [M+H] + .

[0386] Step 3: Synthesis of intermediate 3-5

[0387] Method: Compound 3-4 (1.3 g, 3.8 mmol) was dissolved in DCM (5 mL), HCl / 1,4-dioxane (4M, 5 mL, 20 mmol) was added, and the reaction was stirred at room temperature for 0.5 hours. After the reaction, it was concentrated under reduced pressure to obtain white solid 3-5 (0.56 g, hydrochloride).

[0388] MS (ESI, m / z) 108 [M+H] + .

[0389] Step 4: Synthesis of target compound BX20-11-003

[0390] Method: C2'epiAmB (100 mg, crude, HPLC purity about 50%, about 0.05 mmol) was dissolved in DMF (3 mL), 3-5 (70 mg, hydrochloride, about 0.4 mmol) was added, then TEA was added to adjust the pH of the reaction system to 9-10, after stirring for 10 minutes, PyBOP (62 mg, 0.12 mmol) was added, and the reaction was stirred at room temperature for 12 hours. 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 53:47, aq. NH4OAc (10 mM) / MeCN), and then freeze-dried to obtain a yellow solid powder BX20-11-003 (5 mg, yield 10%).

[0391] MS (ESI, m / z) 1014 [M+H] + .

[0392] 1 H 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), 1.35-1.38 (m, 6H), 1.42-1.45 (m, 1H), 1.47-1.56 (m, 2H), 1.57-1.63 (m, 1H), 1.64-1.74 (m, 2H), 1.75-1.87 (m, 2H), 1.96-2.05 (m, 3H), 2.11 (s, 3H), 2.28-2.41 (m, 4H), 2.42-2.60 (m, 3H), 3.11-3.12 (m, 2H), 3.31-3.37 (m, 2H), 3.55-3.63 (m, 2H), 3.86 (d, J = 11.2, 1H), 3.94-4.05 (m, 5H), 4.27-4.30 (m, 1H), 4.46 (t, J = 10.0 Hz, 1H), 4.60-4.67 (m, 3H), 4.73-4.78 (m, 1H), 5.02 (t, J = 9.2 Hz, 1H), 5.45-5.51 (m, 1H), 5.64-5.66 (m, 1H), 6.25-6.68 (m, 14H).

[0393] Example 2: Synthesis of BX20-11-007

[0394] Step 1: Synthesis of intermediate 7-2

[0395] Method: Compound 7-1 (5.0 g, 27.5 mmol) was dissolved in EtOH (250 mL), and tert-butyl hydrazinecarboxylate (7.35 g, 55 mmol) was added. The reaction was stirred at room temperature for 24 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from EA to obtain white solid 7-2 (9.8 g, yield 87%).

[0396] MS (ESI, m / z) 205 [M+H] + .

[0397] Step 2: Synthesis of intermediate 7-3

[0398] Method: NaBH4 (372 mg, 9.8 mmol) was added to THF (5 mL) and cooled to 0-5 °C. A solution of 7-2 (1.0 g, 4.9 mmol) in THF (8 mL) was added dropwise, and the mixture was stirred for 5 minutes. BF3·OEt2 (1.04 g, 7.35 mmol) was added dropwise, and the reaction was stirred at 0 °C for 1 hour. After the reaction was completed, EtOH (10 mL) was added dropwise to quench the reaction, and the mixture was heated to 80 °C and refluxed for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 30:1 to 10:1) to obtain colorless oil 7-3 (945 mg, yield 93.2%).

[0399] MS (ESI, m / z) 207 [M+H] + .

[0400] Step 3: Synthesis of intermediate 7-4

[0401] Method: Compound 7-3 (945 mg, 4.5 mmol) was dissolved in DCM (10 mL), and HCl / 1,4-dioxane (4 M, 4 mL, 16 mmol) was added dropwise. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain white solid 7-4 (650 mg, hydrochloride).

[0402] MS (ESI, m / z) 108 [M+H] + .

[0403] Step 4: Synthesis of target product BX20-11-007

[0404] Method: C2'epiAmB (100 mg, crude, HPLC purity about 50%, about 0.05 mmol) was dissolved in DMF (3 mL), 7-4 (35 mg, hydrochloride, about 0.24 mmol) was added, then TEA was added to adjust the pH of the reaction system to 9-10, after stirring for 10 minutes, PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate) (62 mg, 0.12 mmol) was added, and the reaction was stirred at room temperature for 30 minutes. 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 54:46, aq. NH4OAc (10 mM) / MeCN), and then freeze-dried to obtain a yellow solid powder BX20-11-007 (5 mg, yield 10%).

[0405] MS (ESI, m / z) 1013 [M+H] + .

[0406] 1 H NMR (400 MHz, CD3OD:Pyridine-d5 = 1:1) δ 1.14 (d, J = 7.2 Hz, 3H), 1.22 (d, J = 6.4 Hz, 3H), 1.32-1.36 (m, 6H), 1.39-1.43 (m, 1H), 1.44-1.53 (m, 2H), 1.57-1.61 (m, 1H), 1.61-1.69 (m, 2H), 1.76-1.83 (m, 2H), 1.92-1.98 (m, 3H), 2.11 (s, 3H), 2.26-2.38 (m, 4H), 2.43-2.57 (m, 3H), 3.11-3.17 (m, 2H), 3.27-3.35 (m, 2H), 3.52-3.58 (m, 2H), 3.81-3.95 (m, 7H), 4.42 (t, J = 10.0 Hz, 1H), 4.58-4.63 (m, 3H), 4.69 (ddd, J = 11.4, 10.2, 4.8 Hz, 1H), 4.96 (t, J = 9.2 Hz, 1H), 5.46 (dd, J = 14.4, 10.2 Hz, 1H), 5.60-5.63 (m, 1H), 6.24-6.65 (m, 14H).

[0407] Example 3: Synthesis of BX20-11-022

[0408] Step 1: Synthesis of BX20-11-022

[0409] Method: C2’epiAmB (120 mg, crude, HPLC purity about 50%, about 0.06 mmol) was dissolved in DMF (3 mL), methyl carbazate (32 mg, 0.36 mmol) was added, then NMM (N-methylmorpholine) was added to adjust the pH of the reaction system to 9-10, after stirring for 10 minutes, PyAOP (7-azabenzotriazol-1-oxyl) tripyrrolidinophosphonium hexafluorophosphate) (125 mg, 0.24 mmol) was added, and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was purified by preparative chromatography (95:5 to 55:45, aq. NH4OAc (10 mM) / MeCN), and then freeze-dried to obtain yellow powder BX20-11-022 (13 mg, yield 21%).

[0410] MS (ESI, m / z) 997 [M+H] + .

[0411] 1 H NMR (400 MHz, CD3OD:Pyridine-d5 = 1:1) δ 1.11 (d, J = 7.2 Hz, 3H), 1.19 (d, J = 6.4 Hz, 3H), 1.29 (d, J = 6.4 Hz, 3H), 1.35 (d, J = 6.4 Hz, 3H), 1.41-1.44 (m, 1H), 1.46-1.54 (m, 2H), 1.55-1.59 (m, 1H), 1.60-1.66 (m, 2H), 1.76-1.83 (m, 2H), 1.85-1.96 (m, 3H), 2.02 (s, 3H), 2.19-2.23 (m, 1H), 2.27-2.33 (m, 2H), 2.36-2.42 (m, 1H), 2.44-2.52 (m, 1H), 2.77-2.81 (m, 1H), 3.12 (t, J = 10.0 Hz, 1H), 3.26-3.34 (m, 2H), 3.46-3.51 (m, 1H), 3.62-3.78 (m, 6H), 3.86 (t, J = 9.6 Hz, 1H), 4.31-4.36 (m, 1H), 4.52-4.63 (m, 4H), 4.78 (d, J = 7.2 Hz, 1H), 4.87 (t, J = 9.6 Hz, 1H), 5.44 (dd, J = 14.4 Hz, 10.0 Hz, 1H), 5.55-5.57 (m, 1H), 6.20-6.63 (m, 14H).

[0412] Example 4: Synthesis of BX20-11-023

[0413] Step 1: Synthesis of intermediate 23-3

[0414] The synthetic route is shown in the following formula:

[0415] Method: CDI (1.5 g, 9.1 mmol) was dissolved in DCM (10 mL), cyclopropanol (0.5 g, 8.6 mmol) was added under stirring, after stirring at room temperature for 0.5 h, it was washed with water and concentrated brine successively, the organic phase was collected to obtain a DCM solution of 23-2. Cooling in ice water bath, hydrazine hydrate (0.6 g, 9.5 mmol, 80 wt% in H2O) was slowly added, after the addition was completed, it was stirred at room temperature for 0.5 h. After the reaction was completed, it was diluted with DCM, washed with water and concentrated brine successively, the organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 5:1 to 1:1) to obtain yellow oil 23-3 (0.22 g, 21.9%).

[0416] MS (ESI, m / z) 117 [M+H] + .

[0417] Step 2: Synthesis of BX20-11-023

[0418] The synthetic route is shown in the following formula:

[0419] Method: C2’epiAmB (90 mg, crude, HPLC purity about 50%, about 0.045 mmol) was dissolved in DMF (3 mL), 23-3 (32 mg, 0.27 mmol) was added, and NMM was added to adjust the pH of the reaction system to 9-10, after stirring for 10 min, PyAOP (125 mg, 0.24 mmol) was added, and the reaction was stirred at room temperature for 12 h. After the reaction was completed, the reaction solution was purified by preparative chromatography (95:5 to 53:47, aq. NH4OAc (10 mM) / MeCN), and after freeze-drying, yellow powder BX20-11-023 (6 mg, yield 13%) was obtained.

[0420] MS (ESI, m / z) 1023 [M+H] + .

[0421] 1H NMR (400 MHz, CD3OD:Pyridine-d5 = 1 : 1) δ 0.65-0.74 (m, 4H), 1.14 (d, J = 7.2 Hz, 3H), 1.22 (d, J = 6.0 Hz, 3H), 1.33 (d, J = 6.4 Hz, 3H), 1.39 (d, J = 6.4 Hz, 3H), 1.43-1.46 (m, 1H), 1.47-1.53 (m, 2H), 1.57-1.63 (m, 2H), 1.64-1.66 (m, 1H), 1.73-1.82 (m, 2H), 1.85-1.97 (m, 3H), 2.06-2.14 (m, 4H), 2.26-2.35 (m, 2H), 2.43-2.57 (m, 3H), 2.90-2.94 (m, 1H), 3.23 (t, J = 9.6 Hz, 1H), 3.31-3.38 (m, 2H), 3.53-3.58 (m, 1H), 3.73-3.84 (m, 2H), 3.92 (t, J = 10.0 Hz, 1H), 4.21-4.26 (m, 1H), 4.39-4.44 (m, 1H), 4.62 (t, J = 10.4 Hz, 1H), 4.66-4.75 (m, 2H), 4.93 (d, J = 7.6 Hz, 1H), 5.01 (t, J = 9.6 Hz, 1H), 5.46 (dd, J = 10.0 Hz, 14.4 Hz, 1H), 5.60-5.64 (m, 1H), 6.23-6.67 (m, 14H).

[0422] Example 5: Synthesis of BX20-11-027

[0423] Step 1: Synthesis of 27-3

[0424] The synthetic route is shown in the following formula:

[0425] Method: CDI (0.53 g, 3.30 mmol) was dissolved in DCM (10 mL), 27-1 (1.00 g, 3.10 mmol) was added under stirring, after stirring at room temperature for 0.5 h, water and saturated brine were added in turn to obtain a DCM solution of 27-2. Cooling in ice water bath, slowly drop hydrazine hydrate (0.21 g, 3.40 mmol, 80 wt% in H2O), after adding, stirring at room temperature for 0.5 h. After the reaction was completed, it was diluted with DCM, washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 5:1 to 1:1) to obtain colorless oil 27-3 (0.50 g, 42.7%).

[0426] MS (ESI, m / z) 379 [M+H] + .

[0427] Step 2: Synthesis of 27-4

[0428] The synthetic route is shown in the following formula:

[0429] Method: 27-3 (0.50 g, 1.32 mmol) was dissolved in DCM (20 mL), HCl / 1,4-dioxane (4 M, 6.6 mL, 26.4 mmol) was added slowly, and after the addition was completed, the mixture was stirred at room temperature for 0.5 h. After the reaction was completed, the reaction mixture was directly concentrated under reduced pressure to obtain white solid 27-4 (0.20 g, crude hydrochloride salt).

[0430] MS (ESI, m / z) 151 [M+H] + .

[0431] Step 3: Synthesis of BX20-11-027

[0432] The synthetic route is shown in the following formula:

[0433] Method: 27-4 (75 mg, crude hydrochloride salt, about 0.4 mmol) was dissolved in DMAc (N,N-dimethylacetamide) (5 mL), NMM was added to adjust the pH of the reaction system to 9-10, C2’epiAmB (120 mg, crude, about 0.06 mmol) was added after stirring for 5 min, and finally PyAOP (104 mg, 0.2 mmol) was added. The reaction was stirred at room temperature for 12 h. 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 BX20-11-027 (11 mg, yield 17%) was obtained.

[0434] MS (ESI, m / z) 1057 [M+H] + .

[0435] 1H NMR (400 MHz, CD3OD:Pyridine-d5 = 2: 1) δ 1.08 (d, J = 7.2 Hz, 3H), 1.17 (d, J = 6.4 Hz, 3H), 1.26 (d, J = 6.4 Hz, 3H), 1.33 (d, J = 6.0 Hz, 3H), 1.36-1.39 (m, 1H), 1.42-1.52 (m, 3H), 1.55-1.65 (m, 3H), 1.74-1.83 (m, 2H), 1.84-1.97 (m, 3H), 2.18 (dd, J = 12.4 Hz, 4.8 Hz, 1H), 2.24-2.29 (m, 2H), 2.35-2.41 (m, 1H), 2.43-2.50 (m, 1H), 2.74-2.78 (m, 1H), 3.18-3.31 (m, 4H), 3.46 (t, J = 8.8 Hz, 1H), 3.62-3.68 (m, 1H), 3.71-3.83 (m, 6H), 4.27-4.32 (m, 1H), 4.48-4.58 (m, 2H), 4.71 (d, J = 7.6 Hz, 1H), 4.78 (t, J = 10.0 Hz, 1H), 5.04-5.07 (m, 1H), 5.42 (dd, J = 14.4 Hz, 10.0 Hz, 1H), 5.51-5.53 (m, 1H), 6.21-6.60 (m, 14H).

[0436] Example 6: Synthesis of BX20-11-040

[0437] Step 1: Synthesis of intermediate 40-2

[0438] Method: 40-1 (4.5 g, 33.7 mmol) was dissolved in THF (120 mL), N-hydroxyphthalimide (6.6 g, 40.5 mmol) and PPh3 (10.6 g, 40.5 mmol) were added, the reaction was cooled in an ice water bath, DIAD (8.2 g, 40.5 mmol, diluted in 30 mL THF) was added dropwise, the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction was concentrated under reduced pressure, and purified by column chromatography (PE:EA = 10:1 ~ 5:1) to obtain white solid 40-2 (9.0 g, yield 96.4%).

[0439] MS (ESI, m / z) 278 [M+H] + .

[0440] Step 2: Synthesis of intermediate 40-3

[0441] Method: Compound 40-2 (4.2 g, 15.2 mmol) was dissolved in trifluoroacetic acid (22 mL), water (22 mL) was added, and the mixture was stirred at room temperature for 0.5 h. After the reaction was completed, the pH was adjusted to 7-8 with saturated aqueous sodium bicarbonate solution, and the mixture was extracted with EA. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give colorless oil 40-3 (2.3 g, yield 63.8%).

[0442] MS (ESI, m / z) 238 [M+H] + .

[0443] Step 3: Synthesis of intermediate 40-4

[0444] Method: Intermediate 40-3 (2.3 g, 9.7 mmol) was dissolved in MeOH (60 mL), hydrazine hydrate (80%, 3.0 g, 48.5 mmol) was added, and the mixture was stirred at 80 °C for 1 h. After the reaction was completed, the mixture was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (DCM:MeOH = 100:0 to 50:1) gave colorless oil 40-4 (0.35 g, 33.7%).

[0445] MS (ESI, m / z) 108 [M+H] + .

[0446] Step 4: Synthesis of target compound BX20-11-040

[0447] Method: C2’epiAmB (100 mg, crude, HPLC purity about 50%, about 0.05 mmol) was dissolved in DMF (3 mL), 40-4 (43 mg, 0.4 mmol) was added, and the pH of the reaction system was adjusted to 9-10 with NMM. Finally, PyAOP (104 mg, 0.2 mmol) was added, and the mixture was stirred at room temperature for 12 h. After the reaction was completed, the reaction mixture was purified by preparative chromatography (95:5 to 60:40, aq. HCOOH (1‰) / MeCN), and then lyophilized to give yellow solid powder BX20-11-040 (12 mg, yield 23%).

[0448] MS (ESI, m / z) 1014 [M+H] + .

[0449] 1H NMR (400 MHz, CD3OD:Pyridine-d5 = 1 : 1) δ 1.11 (d, J = 7.2 Hz, 3H), 1.19 (d, J = 6.4 Hz, 3H), 1.29 (d, J = 6.4 Hz, 3H), 1.32 (d, J = 6.0 Hz, 3H), 1.39-1.45 (m, 2H), 1.47-1.56 (m, 3H), 1.61-1.69 (m, 2H), 1.76-1.84 (m, 2H), 1.88-2.01 (m, 3H), 2.11 (t, J = 10.4 Hz, 1H), 2.20-2.31 (m, 3H), 2.38-2.44 (m, 1H), 2.46-2.52 (m, 1H), 3.14-3.20 (m, 1H), 3.27-3.35 (m, 3H), 3.46-3.58 (m, 2H), 3.75-3.78 (m, 3H), 3.86 (t, J = 10.0 Hz, 1H), 4.08-4.15 (m, 2H), 4.24-4.27 (m, 1H), 4.31-4.37 (m, 1H), 4.53-4.61 (m, 4H), 4.85 (t, J = 9.6 Hz, 1H), 5.44 (dd, J = 14.4 Hz, 10.0 Hz, 1H), 5.53-5.57 (m, 1H), 6.24-6.62 (m, 14H).

[0450] Example 7: Synthesis of BX20-11-041

[0451] Method: C2’epiAmB (100 mg, crude, HPLC purity about 50%, about 0.05 mmol) was dissolved in DMAc (3 mL), NMM was added to adjust the pH of the reaction system to 9-10, PyAOP (52 mg, 0.1 mmol) was added, after stirring for half an hour, carboxymethoxylamine hemi-hydrochloride (109 mg, 1 mmol) was added, and the reaction was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was purified by preparative chromatography (95:5 to 60:40, aq. NH4OAc (10 mM) / MeCN), and after lyophilization, yellow solid powder BX20-11-041 (3 mg, yield 6%) was obtained.

[0452] MS (ESI, m / z) 998 [M+H] + .

[0453] 1H NMR (400 MHz, CD3OD:Pyridine-d5 = 1 : 1) δ 1.09 (d, J = 7.2 Hz, 3H), 1.17 (d, J = 6.4 Hz, 3H), 1.27 (d, J = 6.4 Hz, 3H), 1.31 (d, J = 6.0 Hz, 3H), 1.33-1.36 (m, 1H), 1.39-1.48 (m, 3H), 1.51-1.59 (m, 2H), 1.63-1.73 (m, 3H), 1.85-1.95 (m, 3H), 2.13-2.18 (m, 2H), 2.23-2.28 (m, 2H), 2.35-2.50 (m, 2H), 3.25-3.31 (m, 2H), 3.48-3.54 (m, 1H), 3.56-3.61 (m, 1H), 3.69-3.72 (m, 1H), 3.79-3.85 (m, 1H), 4.28-4.34 (m, 1H), 4.44-4.55 (m, 4H), 4.68 (t, J = 9.6 Hz, 1H), 5.39-5.45 (m, 1H), 5.48-5.50 (m, 1H), 6.11-6.56 (m, 14H), 8.70 (s, 1H).

[0454] Example 8: Synthesis of BX20-11-042

[0455] Step 1: Synthesis of intermediate 42-2:

[0456] Method: NaH (60%, 2.0 g, 50 mmol) was added to THF (20 mL) and cooled to 0 °C. N-BOC-lH-pyrazole-l-carboxamide (10.0 g, 47.6 mmol) was dissolved in THF (150 mL) and slowly added to the NaH THF solution while maintaining 0 °C. After stirring for half an hour, (Boc)20 (11.4 g, 52.2 mmol) was added to the reaction solution and stirred at 70 °C for 3 hours. After the reaction was completed, AcOH (4.0 mL) was added to quench the reaction. The reaction solution was concentrated under reduced pressure, then NaHCO3 solution (5%) and EA were added for extraction. The organic phase was combined and washed with concentrated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 15:1 to 10:1) to obtain colorless oil 42-2 (14.0 g, yield 94.8%).

[0457] MS (ESI, m / z) 311 [M+H] + .

[0458] Step 2: Synthesis of intermediate 42-4

[0459] Method: 42-4 (4.7 g, 15.1 mmol) was dissolved in MeOH (40 mL), Pd / C (10%, 2.0 g) was added, the reaction system was replaced with hydrogen gas for 3 times, and the reaction solution was stirred at room temperature under hydrogen atmosphere (1 atm) for 2 hours. After the reaction was completed, the reaction solution was filtered through diatomite, the filter cake was washed with MeOH, and the filtrate was concentrated under reduced pressure to obtain 42-5 (2.5 g, a yield of 94.0%) as a colorless oil.

[0460] MS (ESI, m / z) 311 [M+H] + .

[0461] Step 3: Synthesis of intermediate 42-5

[0462] Method: 42-4 (4.7 g, 15.1 mmol) was dissolved in MeOH (40 mL), Pd / C (10%, 2.0 g) was added, the reaction system was replaced with hydrogen gas for 3 times, and the reaction solution was stirred at room temperature under hydrogen atmosphere (1 atm) for 2 hours. After the reaction was completed, the reaction solution was filtered through diatomite, the filter cake was washed with MeOH, and the filtrate was concentrated under reduced pressure to obtain 42-5 (2.5 g, a yield of 94.0%) as a colorless oil.

[0463] MS (ESI, m / z) 177 [M+H] + .

[0464] Step 4: Synthesis of intermediate 42-6

[0465] Method: 42-2 (6.2 g, 20 mmol) and 42-5 (2.5 g, 15 mmol) were dissolved in MeOH (50 mL), DIPEA (5.8 g, 45 mmol) was added, and the reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, MeOH was removed by concentration under reduced pressure, EA was added for dissolution, and the organic phase was washed with KHSO4 solution (1 N) and concentrated brine in sequence. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography (PE:EA = 10:1 to 5:1) to obtain 42-6 (5.0 g, a yield of 79.7%) as a white solid.

[0466] MS (ESI, m / z) 419 [M+H] + .

[0467] Step 5: Synthesis of intermediate 42-7

[0468] Method: 42-6 (5.0 g, 12.0 mmol) was dissolved in DCM (30 mL), HCl / 1,4-dioxane (4 M, 20 mL, 80 mmol) was added, and the reaction was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain white solid 42-7 (2.1 g, hydrochloride).

[0469] MS (ESI, m / z) 119 [M+H] + .

[0470] Step 6: Synthesis of the target product BX20-11-042

[0471] Method: C2’epiAmB (100 mg, crude, HPLC purity about 50%, about 0.05 mmol) was dissolved in DMAc (3 mL), 42-7 (57 mg, hydrochloride, about 0.3 mmol) was added, and NMM 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, and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was purified by preparative chromatography (95:5 to 67:33, aq. HCOOH (1 ‰) / MeCN), and BX20-11-042 (13 mg, a yield of 25%) was obtained as a yellow solid powder after freeze-drying.

[0472] MS (ESI, m / z) 1025 [M+H] + .

[0473] 1H NMR (400 MHz, CD3OD:Pyridine-d5 = 1 : 1) δ 1.11 (d, J = 7.2 Hz, 3H), 1.19 (d, J = 6.4 Hz, 3H), 1.29 (d, J = 6.4 Hz, 3H), 1.33 (d, J = 6.0 Hz, 3H), 1.39-1.44 (m, 1H), 1.47-1.55 (m, 2H), 1.61-1.72 (m, 4H), 1.77-1.89 (m, 4H), 1.94-2.00 (m, 2H), 2.12-2.27 (m, 4H), 2.29-2.40 (m, 2H), 2.46-2.52 (m, 1H), 2.78-2.85 (m, 1H), 2.92 (d, J = 14.4 Hz, 1H), 3.11-3.16 (m, 2H), 3.28-3.35 (m, 2H), 3.51-3.66 (m, 4H), 3.76 (d, J = 10.0 Hz, 1H), 3.86 (t, J = 10.0 Hz, 1H), 4.08-4.23 (m, 3H), 4.31-4.37 (m, 1H), 4.51-4.59 (m, 4H), 4.80 (t, J = 9.6 Hz, 1H), 5.41-5.47 (m, 1H), 5.52-5.56 (m, 1H), 6.21-6.62 (m, 14H).

[0474] Example 9: Synthesis of BX20-11-047

[0475] Method: C2’epiAmB (100 mg, crude, HPLC purity about 50%, about 0.05 mmol) was dissolved in DMAc (3 mL), amino oxazole (23 mg, 0.3 mmol) was added, then NMM 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, and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was purified by preparative chromatography (95:5 to 60:40, aq. HCOOH (1 ‰) / MeCN), and after lyophilization, yellow solid powder BX20-11-047 (3 mg, yield 6%) was obtained.

[0476] MS (ESI, m / z) 982 [M+H] + .

[0477] 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), 1.34 (d, J = 6.4 Hz, 3H), 1.39 (d, J = 6.0 Hz, 3H), 1.46-1.50 (m, 1H), 1.52-1.60 (m, 2H), 1.62-1.71 (m, 3H), 1.75-1.86 (m, 3H), 1.91-2.02 (m, 3H), 2.04-2.15 (m, 2H), 2.30-2.37 (m, 2H), 2.44-2.58 (m, 3H), 3.33-3.38 (m, 2H), 3.42-3.48 (m, 1H), 3.67-3.74 (m, 2H), 3.84 (d, J = 10.8 Hz, 1H), 3.94 (t, J = 10.0 Hz, 1H), 4.44-4.46 (m, 1H), 4.60-4.74 (m, 3H), 4.83-4.85 (m, 1H), 5.03 (t, J = 9.6 Hz, 1H), 5.45-5.51 (m, 1H), 5.62-5.65 (m, 1H), 6.25-6.67 (m, 14H).

[0478] Example 10 BX20-11-052

[0479] Step 1: Synthesis of intermediate 52-3

[0480] The synthetic route is shown in the following formula:

[0481] Method: CDI (1.9 g, 11.9 mmol) was dissolved in DCM (10 mL), 52-1 (2.0 g, 11.3 mmol) was added, stirred at room temperature for 0.5 h, then water, saturated brine was added, the organic phase was collected to give a DCM solution of 52-2. The reaction solution was cooled in an ice water bath, N2H4·H2O (2.1 g, 33.9 mmol, 80 wt% in H2O) was slowly added dropwise, and then the temperature was raised to room temperature and stirred for 0.5 h. After the reaction was completed, DCM was added for dilution, water, saturated brine was added for extraction, the organic phase was collected, anhydrous sodium sulfate was added for drying, and then concentrated under reduced pressure. Purification by column chromatography (PE:EA = 5:1 to 1:1) gave 52-3 as a colorless oil (2.0 g, yield 75.2%).

[0482] MS (ESI, m / z) 235 [M+H] + .

[0483] Step 2: Synthesis of intermediate 52-4

[0484] The synthetic route is shown in the following formula:

[0485] Method: 52-3 (2.0 g, 8.5 mmol) was dissolved in DCM (20 mL), HCl / 1,4-dioxane (4.0 M, 22 mL, 88 mmol) was added dropwise slowly, and the mixture was stirred at room temperature for 0.5 h after the addition was completed. After the reaction was completed, the reaction mixture was directly concentrated under reduced pressure to give white solid 52-4 (1.2 g, hydrochloride salt).

[0486] MS (ESI, m / z) 121 [M+H] + .

[0487] Step 3: Synthesis of BX20-11-052

[0488] The synthetic route is shown in the following formula:

[0489] Method: C2’epiAmB (95 mg, crude, HPLC purity about 50%, about 0.05 mmol) was dissolved in DMAc (5 mL), 52-4 (140 mg, 0.9 mmol) was added, and NMM was added to adjust the pH of the reaction system to 9-10. Finally, PyAOP (110 mg, 0.21 mmol) was added, and the reaction was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was filtered and purified by preparative chromatography (95:5 to 60:40, aq. HCOOH (1 ‰) / MeCN), and then freeze-dried to give yellow solid powder BX20-11-052 (18 mg, yield 35%).

[0490] MS (ESI, m / z) 1027 [M+H] + .

[0491] 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), 1.34 (d, J = 6.4 Hz, 3H), 1.42 (d, J = 6.0 Hz, 3H), 1.45-1.49 (m, 1H), 1.51-1.60 (m, 3H), 1.63-1.68 (m, 2H), 1.71-1.85 (m, 3H), 1.92-2.01 (m, 3H), 2.06-2.16 (m, 1H), 2.28-2.37 (m, 2H), 2.43-2.58 (m, 3H), 2.92-2.97 (m, 1H), 3.31-3.37 (m, 2H), 3.41-3.47 (m, 2H), 3.64-3.68 (m, 1H), 3.82-3.96 (m, 5H), 4.33-4.47 (m, 1H), 4.63 (t, J = 10.8 Hz, 1H), 4.70-4.76 (m, 2H), 4.96 (d, J = 7.6 Hz, 1H), 5.04 (t, J = 9.6 Hz, 1H), 5.44-5.50 (m, 1H), 5.62-5.66 (m, 1H), 6.24-6.68 (m, 14H).

[0492] Example 11 BX20-11-054

[0493] Step 1: Synthesis of intermediate 54-3

[0494] The synthetic route is shown in the following formula:

[0495] Method: CDI (4.9 g, 30.3 mmol) was dissolved in DMF (30 mL), cooled to -10 °C, and tert-butyl hydrazinecarboxylate (3.6 g, 27.2 mmol) was added slowly (10 min), and stirring was continued for 0.5 h to obtain a DMF solution of 54-2. 2-benzyloxyethylamine (5.0 g, 33 mol) was dissolved in DMF (30 mL) and added slowly to the above-mentioned DMF solution of 54-2, and the temperature was raised to room temperature after the addition was completed, and stirring was continued for 18 h. After the reaction was completed, water and EA were added and extracted 3 times, the organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 1:2) to obtain white solid 54-3 (8.4 g, yield 99%).

[0496] MS (ESI, m / z) 310 [M+H] + .

[0497] Step 2: Synthesis of intermediate 54-4

[0498] The synthetic route is shown in the following formula:

[0499] Method: 54-3 (4.0 g, 12.9 mmol) was dissolved in EA (30 mL), Pd / C (10%, 1.0 g) was added, the reaction system was replaced with hydrogen gas and stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was filtered through diatomite, and concentrated under reduced pressure to obtain yellow oil 54-4 (2.8 g, yield 99%).

[0500] MS (ESI, m / z) 220 [M+H] + .

[0501] Step 3: Synthesis of intermediate 54-5

[0502] Method: 54-4 (2.8 g, 12.7 mmol) was dissolved in DCM (20 mL), HCl / 1,4-dioxane (4.0 M, 30 mL, 120 mmol) was slowly added dropwise, and stirred at room temperature for 1 hour after the addition was completed. After the reaction was completed, it was directly concentrated under reduced pressure to obtain white solid 54-5 (2.0 g, hydrochloride).

[0503] MS (ESI, m / z) 120 [M+H] + .

[0504] Step 3: Synthesis of BX20-11-054

[0505] The synthetic route is shown in the following formula:

[0506] Method: C2’epiAmB (95 mg, crude, HPLC purity about 50%, about 0.05 mmol) was dissolved in DMAc (5 mL), 54-5 (140 mg, 0.9 mmol) was added, NMM was added to adjust the pH of the reaction system to 9-10, and finally PyAOP (110 mg, 0.21 mmol) was added, and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered and purified by preparative chromatography (95:5 to 60:40, aq. HCOOH (1 ‰) / MeCN), and then freeze-dried to obtain yellow solid powder BX20-11-054 (12 mg, yield 23.3%).

[0507] MS (ESI, m / z) 1026 [M+H] + .

[0508] 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), 1.30 (d, J = 6.4 Hz, 3H), 1.35 (d, J = 6.0 Hz, 3H), 1.38-1.42 (m, 1H), 1.46-1.57 (m, 4H), 1.60-1.72 (m, 3H), 1.76-1.85 (m, 2H), 1.87-1.96 (m, 3H), 1.98-2.06 (m, 1H), 2.22-2.43 (m, 4H), 2.47-2.53 (m, 1H), 2.59-2.68 (m, 1H), 3.25-3.35 (m, 3H), 3.42-3.45 (m, 2H), 3.55-3.64 (m, 2H), 3.71 (t, J = 5.6 Hz, 2H), 3.78 (d, J = 10.8 Hz, 1H), 3.87 (t, J = 10.0 Hz, 1H), 4.33-4.39 (m, 1H), 4.54-4.64 (m, 3H), 4.70-4.74 (m, 1H), 4.86-4.93 (m, 1H), 5.44 (dd, J = 14.4 Hz, 10.0 Hz, 1H), 5.55-5.60 (m, 1H), 6.21-6.63 (m, 14H).

[0509] Example 12 BX20-11-061

[0510] The synthetic route is shown in the following formula:

[0511] Method: C2’epiAmB (90 mg, crude, HPLC purity about 50%, about 0.045 mmol) was dissolved in DMAc (3 mL), 2-aminooxyethanol (14 mg, 0.18 mmol) was added, then NMM was added to adjust the pH of the reaction system to 9-10, finally PyAOP (125 mg, 0.24 mmol) was added, and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was purified by preparative chromatography (95:5 to 55:45, aq. HCOOH (1 ‰) / MeCN), and after freeze-drying, yellow powder BX20-11-061 (16 mg, yield 36%) was obtained.

[0512] MS (ESI, m / z) 984 [M+H] + .

[0513] 1H NMR (400 MHz, CD3OD:Pyridine-d5 = 1:1) δ 1.16 (d, J = 7.2 Hz, 3H), 1.24 (d, J = 6.0 Hz, 3H), 1.35 (d, J = 6.4 Hz, 3H), 1.38 (d, J = 6.4 Hz, 3H), 1.42-1.55 (m, 4H), 1.59-1.70 (m, 3H), 1.74-1.87 (m, 3H), 1.92-2.04 (m, 3H), 2.11-2.19 (m, 1H), 2.25-2.41 (m, 4H), 2.45-2.59 (m, 2H), 3.27-3.36 (m, 2H), 3.54-3.60 (m, 1H), 3.67-3.72 (m, 1H), 3.86 (d, J = 11.2 Hz, 1H), 3.91-4.00 (m, 3H), 4.22 (t, J = 4.8 Hz, 2H), 4.43-4.48 (m, 1H), 4.64-4.78 (m, 4H), 4.99-5.05 (m, 1H), 5.47-5.51 (m, 1H), 5.62-5.67 (m, 1H), 6.26-6.69 (m, 14H).

[0514] Example 13 BX20-11-063

[0515] Step 1: Synthesis of intermediate 63-2

[0516] Method: (R)-(-)-glycerol acetonide (3.4 g, 25.7 mmol) was dissolved in THF (100 mL), N-hydroxyphthalimide (5.0 g, 30.7 mmol) and PPh3(8.1 g, 30.7 mmol) were added, and the reaction solution was cooled in an ice water bath. DIAD (6.2 g, 30.7 mmol, diluted in 15 mL THF) was added dropwise, and the reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography (PE:EA = 10:1 ~ 5:1) to obtain white solid 63-2 (6.4 g, yield 89.9%).

[0517] MS (ESI, m / z) 278 [M+H] + .

[0518] Step 2: Synthesis of intermediate 63-3

[0519] Method: Compound 63-2 (6.4 g, 23.1 mmol) was dissolved in trifluoroacetic acid (34 mL), water (30 mL) was added, and the mixture was stirred at room temperature for 0.5 h. After the reaction was completed, the pH was adjusted to 7-8 with saturated aqueous sodium bicarbonate solution, and the mixture was extracted with EA. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give colorless oil 63-3 (3.0 g, yield 55.0%).

[0520] MS (ESI, m / z) 238 [M+H] + .

[0521] Step 3: Synthesis of intermediate 63-4

[0522] Method: Intermediate 63-3 (3.0 g, 12.7 mmol) was dissolved in MeOH (80 mL), hydrazine hydrate (80%, 4.0 g, 63.3 mmol) was added, and the mixture was stirred at 80 °C for 1 h. After the reaction was completed, the mixture was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (DCM:MeOH = 100:0 to 50:1) gave colorless oil 63-4 (0.5 g, yield 37.0%).

[0523] MS (ESI, m / z) 108 [M+H] + .

[0524] Step 4: Synthesis of target compound BX20-11-063

[0525] Method: C2’epiAmB (100 mg, crude, HPLC purity about 50%, about 0.05 mmol) was dissolved in DMAc (3 mL), 63-4 (43 mg, 0.4 mmol) was added, and the pH of the reaction system was adjusted to 9-10 by adding NMM. Finally, PyAOP (104 mg, 0.2 mmol) was added, and the mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was purified by preparative chromatography (95:5 to 62:38, aq. HCOOH (1‰) / MeCN), and then lyophilized to give yellow solid powder BX20-11-063 (14 mg, yield 27%).

[0526] MS (ESI, m / z) 1014 [M+H] + .

[0527] 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), 1.34 (d, J = 6.4 Hz, 3H), 1.37 (d, J = 6.0 Hz, 3H), 1.43-1.50 (m, 2H), 1.58-1.68 (m, 3H), 1.72-1.86 (m, 3H), 1.89-2.02 (m, 3H), 2.06-2.16 (m, 1H), 2.22-2.39 (m, 4H), 2.44-2.58 (m, 2H), 3.30-3.35 (m, 2H), 3.54-3.62 (m, 1H), 3.65-3.71 (m, 1H), 3.81-3.88 (m, 3H), 3.94 (t, J = 10.4 Hz, 1H), 4.19-4.27 (m, 2H), 4.37-4.46 (m, 2H), 4.62-4.76 (m, 4H), 4.99 (t, J = 9.6 Hz, 1H), 5.47 (dd, J = 14.4 Hz, 10.0 Hz, 1H), 5.61-5.66 (m, 1H), 6.25-6.69 (m, 14H).

[0528] Example 14 BX20-11-064

[0529] Step 1: Synthesis of intermediate 64-2

[0530] Method: (S)-(+)-glycerol acetonide (3.4 g, 25.7 mmol) was dissolved in THF (100 mL), N-hydroxyphthalimide (5.0 g, 30.7 mmol) and PPh3(8.1 g, 30.7 mmol) were added, the reaction was cooled in an ice water bath, DIAD (6.2 g, 30.7 mmol, diluted in 15 mL THF) was added dropwise, the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction was concentrated under reduced pressure, and then purified by column chromatography (PE:EA = 10:1 ~ 5:1) to obtain white solid 64-2 (6.9 g, yield 96.9%).

[0531] MS (ESI, m / z) 278 [M+H] + .

[0532] Step 2: Synthesis of intermediate 64-3

[0533] Method: Compound 64-2 (6.9 g, 24.9 mmol) was dissolved in trifluoroacetic acid (37 mL), water (30 mL) was added, and the mixture was stirred at room temperature for 0.5 h. After the reaction was completed, the pH was adjusted to 7-8 with saturated aqueous sodium bicarbonate solution, and the mixture was extracted with EA. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give colorless oil 64-3 (3.1 g, yield 52.6%).

[0534] MS (ESI, m / z) 238 [M+H] + .

[0535] Step 3: Synthesis of intermediate 64-4

[0536] Method: Intermediate 64-3 (3.1 g, 13.1 mmol) was dissolved in MeOH (100 mL), hydrazine hydrate (80%, 4.1 g, 65.5 mmol) was added, and the mixture was stirred at 80 °C for 1 h. After the reaction was completed, the mixture was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (DCM:MeOH = 100:0 to 50:1) gave colorless oil 64-4 (0.66 g, 47.1%).

[0537] MS (ESI, m / z) 108 [M+H] + .

[0538] Step 4: Synthesis of target compound BX20-11-064

[0539] Method: C2’epiAmB (100 mg, crude, HPLC purity about 50%, about 0.05 mmol) was dissolved in DMAc (3 mL), 64-4 (43 mg, 0.4 mmol) was added, and the pH of the reaction system was adjusted to 9-10 by adding NMM. Finally, PyAOP (104 mg, 0.2 mmol) was added, and the mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was purified by preparative chromatography (95:5 to 62:38, aq. HCOOH (1‰) / MeCN), and then lyophilized to give yellow solid powder BX20-11-064 (11 mg, yield 21%).

[0540] MS (ESI, m / z) 1014 [M+H] + .

[0541] 1H NMR(400MHz, CD3OD:Pyridine-d5=1:1)δ1.15(d,J=7.2Hz,3H),1.23(d,J=6.4Hz,3H),1.34(d,J=6.4Hz,3H),1.37(d,J=6.0Hz,3H) ,1.42-1.49(m,2H),1.52-1.64(m,3H),1.67-1.86(m,3H),1.90-2.01(m,3H),2.07-2.15(m,1H),2.22-2.40(m,4H),2.43-2.57(m, 2H),3.29-3.36(m,2H),3.54-3.61(m,1H),3.67(t,J=8.8Hz,1H),3.82-3.86(m,3H),3.93(t,J=10.4Hz,1H),4.22-4.26(m,2H),4. 33-4.46(m,2H),4.59-4.74(m,4H),4.99(t,J=9.6Hz,1H),5.47(dd,J=14.4Hz,10.0Hz,1H),5.60-5.65(m,1H),6.25-6.67(m,14H).

[0542] Example 15 BX20-11-066

[0543] Step 1: Synthesis of intermediate 33-2

[0544] 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 1 hour. After the reaction was complete, the filtrate was filtered, concentrated under reduced pressure, and extracted with EA and saturated NaHCO3 solution. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a brown oily liquid 33-2 (7.1 g, crude product).

[0545] MS(ESI,m / z)232[M+H] + .

[0546] Step 2: Synthesis of intermediate 33-3

[0547] 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 diatomite was filtered to obtain the filtrate which was concentrated under reduced pressure, the residue was dissolved with DCM, washed with saturated NaHCO3solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain brown oily liquid 33-3 (8.4 g, crude).

[0548] MS (ESI, m / z) 324 [M+H] + .

[0549] Step 3: Synthesis of intermediate 33-5

[0550] Method: 33-4 (5.0 g, 11.7 mmol) was dissolved in toluene (35 mL), and the reaction was cooled in an ice water bath. NaOH aqueous solution (50%, 24 g) was added dropwise, and then tert-butyl bromoacetate (9.1 g, 46.7 mmol) was added. The reaction was stirred at room temperature for 5 h. After reaction, the reaction was cooled in an ice water bath, and 50 mL of water was added to quench the reaction. After standing and separation, the aqueous phase was collected, and the pH was adjusted to 2-3 with concentrated hydrochloric acid. The aqueous phase was extracted with DCM (50 mL x 3), and the organic phase was combined, washed with concentrated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain colorless oily liquid 33-5 (5.0 g, crude).

[0551] MS (ESI, m / z) 487 [M+H] + .

[0552] Step 4: Synthesis of intermediate 33-6

[0553] Method: 33-5 (600 mg, crude, about 1.2 mmol) was dissolved in toluene (15 mL), and Ag2CO3 (331 mg, 1.2 mmol) was added and stirred for 5 min. Then 33-3 (387 mg, 1.2 mmol) was added, and the reaction was stirred at 80 °C for 15 min. After reaction, the diatomite was filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 100:0 to 90:10) to obtain yellow oily liquid 33-6 (380 mg, yield 46%).

[0554] MS (ESI, m / z) 682 [M+H] + .

[0555] Step 5: Synthesis of intermediate 33-7

[0556] 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 yellow solid powder 33-7 (100 mg, crude).

[0557] MS (ESI, m / z) 1467 [M+H] + .

[0558] Synthesis of BX20-11-066

[0559] Method: Methyl hydrazinecarboxylate (27 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) and PyAOP (104 mg, 0.2 mmol) were added. The reaction was stirred at 35°C for 1 hour. After the reaction was completed, the reaction solution was directly filtered and purified by preparative chromatography (95:5 to 45:55, aq. HCOOH (1 ‰) / MeCN), and then freeze-dried to obtain yellow solid powder BX20-11-066 (7 mg, yield 9%).

[0560] MS (ESI, m / z) 1561 [M+Na] + .

[0561] 1H NMR (400 MHz, CD3OD:Pyridine-d5 = 1 : 1) δ 1.14 (d, J = 7.2 Hz, 3H), 1.22 (d, J = 6.4 Hz, 3H), 1.33 (d, J = 6.4 Hz, 3H), 1.39 (d, J = 6.0 Hz, 3H), 1.44-1.55 (m, 3H), 1.58-1.69 (m, 3H), 1.73-1.85 (m, 2H), 1.91-1.99 (m, 3H), 2.03-2.13 (m, 1H), 2.25-2.35 (m, 2H), 2.42-2.57 (m, 3H), 2.82-2.90 (m, 1H), 3.33 (s, 3H), 3.52-3.54 (m, 2H), 3.62-3.67 (m, 35H), 3.69-3.75 (m, 4H), 3.80-3.94 (m, 6H), 4.17 (s, 2H), 4.38-4.45 (m, 1H), 4.58-4.72 (m, 3H), 4.81-4.84 (m, 1H), 4.97 (t, J = 9.6 Hz, 1H), 5.46 (dd, J = 14.4 Hz, 10.0 Hz, 1H), 5.58-5.63 (m, 1H), 5.86 (s, 2H), 6.22-6.65 (m, 14H).

[0562] Example 16 BX20-11-067

[0563] The synthetic route is shown in the following formula:

[0564] Method: C2’epiAmB (100 mg, crude, HPLC purity about 50%, about 0.05 mmol) was dissolved in DMAc (5 mL), N-methylhydrazinecarboxamide (27 mg, 0.3 mmol) was added, then 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 filtered and purified by preparative chromatography (95:5 to 60:40, aq. HCOOH (1 ‰) / MeCN), and then freeze-dried to obtain a yellow solid powder BX20-11-067 (13.5 mg, yield 27%).

[0565] MS (ESI, m / z) 996 [M+H] + .

[0566] 1H NMR (400 MHz, CD3OD:Pyridine-d5 = 1 : 1) δ 1.14 (d, J = 7.2 Hz, 3H), 1.22 (d, J = 6.4 Hz, 3H), 1.33 (d, J = 6.4 Hz, 3H), 1.38 (d, J = 6.0 Hz, 3H), 1.41-1.45 (m, 1H), 1.51-1.67 (m, 5H), 1.69-1.85 (m, 3H), 1.88-2.00 (m, 3H), 2.03-2.13 (m, 1H), 2.27-2.35 (m, 2H), 2.42-2.56 (m, 3H), 2.62-2.66 (m, 1H), 2.79 (s, 3H), 3.24-3.37 (m, 3H), 3.61-3.70 (m, 2H), 3.82 (d, J = 10.8 Hz, 1H), 3.92 (t, J = 10.0 Hz, 1H), 4.38-4.43 (m, 1H), 4.58-4.71 (m, 3H), 4.78 (d, J = 7.6 Hz, 1H), 4.98 (t, J = 9.6 Hz, 1H), 5.46 (dd, J = 14.4 Hz, 10.0 Hz, 1H), 5.59-5.64 (m, 1H), 6.24-6.67 (m, 14H).

[0567] Example 17 BX20-11-068

[0568] Step 1: Synthesis of intermediate 68-3

[0569] The synthetic route is shown in the following formula:

[0570] Method: CDI (4.5 g, 28 mmol) was dissolved in DMF (30 mL), replaced with nitrogen, and cooled to -10 °C. tert-Butyl carbazate (3.3 g, 25 mmol) in DMF (30 mL) was added dropwise slowly (20 min), and the mixture was stirred at -10 °C for 0.5 h after the addition was completed. 2-Fluoroethylamine hydrochloride (3.0 g, 30 mmol) was dissolved in DMF (30 mL), and TEA (6.1 g, 60 mmol) was added. The resulting turbid solution was added dropwise to the above-mentioned DMF solution of 68-2, and the mixture was stirred at room temperature for 3 h after the addition was completed. After the reaction was completed, water and EA were added and extracted 5 times, and the organic phase was combined, washed with water and concentrated brine once each, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 2:1 to 1:10) to obtain 68-3 (4.0 g, yield 72%) as a white solid.

[0571] MS (ESI, m / z) 222 [M+H] + .

[0572] Step 2: Synthesis of intermediate 68-4

[0573] Method: 68-3 (1.5 g, 6.8 mmol) was dissolved in DCM (10 mL), and HCl / 1,4-dioxane (4.0 M, 17 mL, 68 mmol) was added dropwise slowly. After the addition, the mixture was stirred at room temperature for 1 h. After the reaction was completed, the mixture was directly concentrated under reduced pressure to give 68-4 (1.0 g, hydrochloride) as a white solid.

[0574] MS (ESI, m / z) 122 [M+H] + .

[0575] Step 3: Synthesis of BX20-11-068

[0576] Method: C2’epiAmB (95 mg, crude, HPLC purity about 50%, about 0.05 mmol) was dissolved in DMAc (5 mL), and 68-4 (47 mg, hydrochloride, about 0.3 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 mixture 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 60:40, aq. HCOOH (1 ‰) / MeCN). After lyophilization, BX20-11-068 (8 mg, 15% yield) was obtained as a yellow solid powder.

[0577] MS (ESI, m / z) 1026 [M+H] + .

[0578] 1H NMR (400 MHz, CD3OD:Pyridine-d5 = 1 : 1) δ 1.09 (d, J = 7.2 Hz, 3H), 1.18 (d, J = 6.4 Hz, 3H), 1.27 (d, J = 6.4 Hz, 3H), 1.32 (d, J = 6.0 Hz, 3H), 1.37-1.40 (m, 1H), 1.42-1.51 (m, 3H), 1.56-1.68 (m, 3H), 1.75-1.83 (m, 2H), 1.86-1.98 (m, 3H), 2.19-2.31 (m, 3H), 2.35-2.42 (m, 1H), 2.44-2.54 (m, 2H), 3.08-3.14 (m, 1H), 3.26-3.32 (m, 3H), 3.41-3.65 (m, 5H), 3.74 (d, J = 10.4 Hz, 1H), 3.84 (t, J = 10.0 Hz, 1H), 4.29-4.35 (m, 1H), 4.42 (t, J = 5.2 Hz, 1H), 4.50-4.56 (m, 4H), 4.64 (d, J = 7.6 Hz, 1H), 4.83 (t, J = 10.0 Hz, 1H), 5.43 (dd, J = 14.4 Hz, 10.0 Hz, 1H), 5.51-5.56 (m, 1H), 6.22-6.60 (m, 14H).

[0579] Example 18 BX20-11-069

[0580] Step 1: Synthesis of intermediate 69-3

[0581] The synthetic route is shown in the following formula:

[0582] Method: CDI (4.07 g, 25.1 mmol) was dissolved in DMF (30 mL), replaced with nitrogen, and cooled to -10 °C. Benzyl carbazate (3.79 g, 22.83 mmol) in DMF (25 mL) was added dropwise slowly (20 min), and the mixture was stirred at -10 °C for 0.5 h after the addition was completed. 3-oxetanamine (2.0 g, 27.4 mmol) in DMF (25 mL) was added dropwise to the above DMF solution of 69-2, and the mixture was stirred at room temperature for 3 h after the addition was completed. After the reaction was completed, water (300 mL) was added, and the mixture was extracted with EA (50 mL x 10). The combined organic phase was washed with water and concentrated brine once each, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 2:1 to 0:1) to give 69-3 (4.4 g, 72% yield) as a yellow oil.

[0583] MS (ESI, m / z) 266 [M+H] + .

[0584] Step 2: Synthesis of intermediate 69-4

[0585] Method: 69-3 (4.4 g, 16.6 mmol) was dissolved in EtOH (80 mL), Pd / C (10%, 660 mg) was added, hydrogen was replaced, and the reaction was stirred at room temperature under a hydrogen atmosphere (1 atm) for 1 h. After the reaction was completed, the filtrate was filtered and concentrated under reduced pressure to obtain white solid 69-4 (2.17 g, yield 99%).

[0586] MS (ESI, m / z) 132 [M+H] + .

[0587] Step 3: Synthesis of BX20-11-069

[0588] The synthetic route is shown in the following formula:

[0589] Method: C2’epiAmB (110 mg, crude, HPLC purity about 50%, about 0.055 mmol) was dissolved in DMAc (5 mL), 69-4 (47 mg, 0.36 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 solution was filtered and purified by preparative chromatography (95:5 to 60:40, aq. HCOOH (1 ‰) / MeCN), and then freeze-dried to obtain yellow solid powder BX20-11-069 (9 mg, yield 14%).

[0590] MS (ESI, m / z) 1038 [M+H] + .

[0591] 1H 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), 1.32 (d, J = 6.4 Hz, 3H), 1.37 (d, J = 6.0 Hz, 3H), 1.41-1.44 (m, 1H), 1.47-1.59 (m, 4H), 1.62-1.74 (m, 3H), 1.76-1.87 (m, 2H), 1.90-1.99 (m, 3H), 2.04-2.11 (m, 1H), 2.28-2.34 (m, 2H), 2.41-2.65 (m, 4H), 3.14-3.19 (m, 1H), 3.30-3.37 (m, 3H), 3.55-3.66 (m, 2H), 3.80 (d, J = 11.2 Hz, 1H), 3.90 (t, J = 10.0 Hz, 1H), 4.36-4.42 (m, 1H), 4.57-4.69 (m, 5H), 4.74 (d, J = 7.2 Hz, 1H), 4.80-4.86 (m, 2H), 4.93-5.07 (m, 2H), 5.46 (dd, J = 14.4 Hz, 10.0 Hz, 1H), 5.58-5.62 (m, 1H), 6.23-6.65 (m, 14H).

[0592] Example 19 BX20-11-070

[0593] Step 1: Synthesis of intermediate 70-3

[0594] Method: CDI (3.6 g, 22 mmol) was dissolved in DMF (25 mL) and replaced with nitrogen, cooled to -10 °C, and a solution of tert-butyl carbazate (2.6 g, 20 mmol) in DMF (20 mL) was added dropwise slowly (20 min), and the mixture was stirred at -10 °C for 0.5 h to give a solution of 70-2 in DMF. (S)-3-aminotetrahydrofuran hydrochloride (3.0 g, 24 mmol) was dissolved in DMF (25 mL) and TEA (4.8 g, 48 mmol) was added, and the resulting turbid solution was added dropwise to the above solution of 70-2 in DMF. After the addition was completed, the mixture was allowed to warm to room temperature and stirred for 3 h. After the reaction was completed, water and EA were added and the mixture was extracted 10 times, and the organic phases were combined and washed with water and concentrated brine once each, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 1:1 to 0:1) to give 70-3 as a white solid (2.6 g, 53% yield).

[0595] MS (ESI, m / z) 246 [M+H] + .

[0596] Step 2: Synthesis of intermediate 70-4

[0597] Method: 70-3 (1.2 g, 4.9 mmol) was dissolved in DCM (8 mL), HCl / 1,4-dioxane (4.0 M, 12 mL, 48 mmol) was added dropwise slowly, and the mixture was stirred at room temperature for 1 h after the addition was completed. After the reaction was completed, the reaction mixture was directly concentrated under reduced pressure to give white solid 70-4 (0.6 g, hydrochloride salt).

[0598] MS (ESI, m / z) 146 [M+H] + .

[0599] Step 3: Synthesis of BX20-11-070

[0600] The synthetic route is shown in the following formula:

[0601] Method: C2’epiAmB (100 mg, crude, HPLC purity about 50%, about 0.05 mmol) was dissolved in DMAc (5 mL), 70-4 (55 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 h. After the reaction was completed, the reaction solution was filtered and purified by preparative chromatography (95:5 to 60:40, aq. HCOOH (1 ‰) / MeCN). After lyophilization, yellow solid powder BX20-11-070 (11 mg, yield 21%) was obtained.

[0602] MS (ESI, m / z) 1052 [M+H] + .

[0603] 1H NMR (400 MHz, CD3OD:Pyridine-d5 = 1 : 1) δ 1.12 (d, J = 7.2 Hz, 3H), 1.21 (d, J = 6.4 Hz, 3H), 1.31 (d, J = 6.4 Hz, 3H), 1.36 (d, J = 6.0 Hz, 3H), 1.39-1.43 (m, 1H), 1.44-1.54 (m, 3H), 1.58-1.70 (m, 3H), 1.74-1.86 (m, 3H), 1.88-1.97 (m, 2H), 1.99-2.19 (m, 3H), 2.25-2.33 (m, 2H), 2.37-2.44 (m, 2H), 2.46-2.58 (m, 2H), 3.18-3.23 (m, 1H), 3.29-3.35 (m, 2H), 3.57-3.64 (m, 2H), 3.67-3.80 (m, 4H), 3.83-3.91 (m, 3H), 4.35-4.45 (m, 2H), 4.55-4.64 (m, 3H), 4.72 (d, J = 7.6 Hz, 1H), 4.93 (t, J = 10.0 Hz, 1H), 5.45 (dd, J = 14.4 Hz, 10.0 Hz, 1H), 5.56-5.61 (m, 1H), 6.22-6.64 (m, 14H).

[0604] Example 20 BX20-11-071

[0605] Step 1: Synthesis of intermediate 71-3

[0606] The synthetic route is shown in the following formula:

[0607] Method: CDI (3.6 g, 22 mmol) was dissolved in DMF (25 mL) and replaced with nitrogen, cooled to -10 °C, and then tert-butyl hydrazinecarboxylate (2.6 g, 20 mmol) in DMF (20 mL) was added dropwise slowly (20 min), and the mixture was stirred at -10 °C for 0.5 h to obtain a DMF solution of 71-2. (R)-3-aminotetrahydrofuran hydrochloride (3.0 g, 24 mmol) was dissolved in DMF (25 mL), and TEA (4.8 g, 48 mmol) was added, and the resulting turbid solution was added dropwise to the above-mentioned DMF solution of 71-2, and the mixture was stirred at room temperature for 3 h. After the reaction was completed, water and EA were added and extracted 10 times, and the organic phases were combined, washed with water and concentrated brine once each, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography (PE:EA = 1:1 to 0:1) to obtain white solid 71-3 (2.5 g, yield 51%).

[0608] MS (ESI, m / z) 246 [M+H] + .

[0609] Step 2: Synthesis of intermediate 71-4

[0610] Method: 71-3 (2.5 g, 10.1 mmol) was dissolved in DCM (20 mL), HCl / 1,4-dioxane (4.0 M, 25 mL, 100 mmol) was added dropwise slowly, after the addition was completed, it was stirred at room temperature for 1 hour. After the reaction was completed, it was directly concentrated under reduced pressure to obtain white solid 71-4 (1.4 g, hydrochloride).

[0611] MS (ESI, m / z) 146 [M+H] + .

[0612] Step 3: Synthesis of BX20-11-071

[0613] The synthetic route is shown in the following formula:

[0614] Method: C2’epiAmB (100 mg, crude, HPLC purity about 50%, about 0.05 mmol) was dissolved in DMAc (5 mL), 71-4 (55 mg, 0.3 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 filtered and purified by preparative chromatography (95:5 to 60:40, aq. HCOOH (1 ‰) / MeCN), and then freeze-dried to obtain yellow solid powder BX20-11-071 (13 mg, yield 21%).

[0615] MS (ESI, m / z) 1052 [M+H] + .

[0616] 1H 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), 1.36 (d, J = 6.0 Hz, 3H), 1.40-1.44 (m, 1H), 1.46-1.56 (m, 3H), 1.61-1.73 (m, 3H), 1.78-1.97 (m, 6H), 2.01-2.07 (m, 1H), 2.11-2.19 (m, 1H), 2.26-2.34 (m, 2H), 2.37-2.45 (m, 2H), 2.47-2.57 (m, 2H), 3.24 (t, J = 10.0 Hz, 1H), 3.30-3.36 (m, 2H), 3.59-3.75 (m, 4H), 3.79 (d, J = 11.2 Hz, 1H), 3.85-3.92 (m, 3H), 4.36-4.44 (m, 2H), 4.56-4.65 (m, 3H), 4.74 (d, J = 7.6 Hz, 1H), 4.94 (t, J = 10.0 Hz, 1H), 5.45 (dd, J = 14.4 Hz, 10.0 Hz, 1H), 5.56-5.61 (m, 1H), 6.23-6.64 (m, 14H).

[0617] Example 21 BX20-11-072

[0618] The synthetic route is shown in the following formula:

[0619] Method: C2’epiAmB (100 mg, crude, HPLC purity about 50%, about 0.05 mmol) was dissolved in DMAc (5 mL), N-hydroxy-carbonylhydrazine (28 mg, 0.3 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 filtered and purified by preparative chromatography (95:5 to 64:36, aq. HCOOH (1 ‰) / MeCN), and then freeze-dried to obtain yellow solid powder BX20-11-072 (9 mg, yield 27%).

[0620] MS (ESI, m / z) 981 [M-16] + .

[0621] 1H NMR (400 MHz, CD3OD:Pyridine-d5 = 1:1) δ 1.14 (d, J = 7.2 Hz, 3H), 1.22 (d, J = 6.4 Hz, 3H), 1.32 (d, J = 6.4 Hz, 3H), 1.37 (d, J = 6.0 Hz, 3H), 1.41-1.45 (m, 1H), 1.47-1.56 (m, 3H), 1.57-1.66 (m, 2H), 1.68-1.84 (m, 3H), 1.87-1.99 (m, 3H), 2.04-2.11 (m, 1H), 2.26-2.35 (m, 2H), 2.42-2.59 (m, 4H), 3.25-3.37 (m, 3H), 3.57-3.70 (m, 2H), 3.81 (d, J = 10.8 Hz, 1H), 3.91 (t, J = 10.0 Hz, 1H), 4.37-4.43 (m, 1H), 4.58-4.71 (m, 3H), 4.78 (d, J = 7.6 Hz, 1H), 4.98 (t, J = 9.6 Hz, 1H), 5.46 (dd, J = 14.4 Hz, 10.0 Hz, 1H), 5.58-5.63 (m, 1H), 6.23-6.65 (m, 14H).

[0622] Example 22 BX20-11-073

[0623] Step 1: Synthesis of intermediate 73-3

[0624] The synthetic route is shown in the following formula:

[0625] Method: CDI (1.94 g, 12.0 mmol) was dissolved in DCM (20 mL), 73-1 (2.2 g, 11.5 mmol) was added, and a DCM solution of 73-2 was obtained after stirring at room temperature for 1 hour. The reaction solution was cooled in an ice water bath, N2H4·H2O (1.13 g, 18 mmol, 80 wt% in H2O) was slowly added dropwise, and after the addition was completed, the solution was stirred at room temperature for 1 hour. After the reaction was completed, DCM was removed by reduced pressure concentration, and water and EA were added for extraction, concentrated brine was washed, and the organic phase was collected and dried over anhydrous sodium sulfate. After being concentrated under reduced pressure, 73-3 (900 mg, yield 31%) was obtained as a colorless oil after column chromatography purification (PE:EA = 10:1~PE:EA = 4:1).

[0626] MS (ESI, m / z) 251 [M+H] + .

[0627] Step 2: Synthesis of intermediate 73-4

[0628] The synthetic route is shown in the following formula:

[0629] Method: 73-3 (900 mg, 3.6 mmol) was dissolved in DCM (20 mL), HCl / 1,4-dioxane (4.0 M, 9 mL, 36 mmol) was added dropwise slowly, after the addition was completed, it was stirred at room temperature for 0.5 hours. After the reaction was completed, it was directly concentrated under reduced pressure to obtain white solid 73-4 (600 mg, hydrochloride).

[0630] MS (ESI, m / z) 137 [M+H] + .

[0631] Step 3: Synthesis of BX20-11-073

[0632] The synthetic route is shown in the following formula:

[0633] Method: C2’epiAmB (100 mg, crude, HPLC purity about 50%, about 0.05 mmol) was dissolved in DMAc (5 mL), 73-4 (104 mg, 0.6 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 35°C for 5 hours. After the reaction was completed, the reaction solution was filtered and purified by preparative chromatography (95:5 to 60:40, aq. HCOOH (1 ‰) / MeCN), and then freeze-dried to obtain yellow solid powder BX20-11-073 (17.5 mg, yield 33.5%).

[0634] MS (ESI, m / z) 1043 [M+H] + .

[0635] 1H 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), 1.38 (d, J = 6.0 Hz, 3H), 1.44-1.51 (m, 2H), 1.54-1.68 (m, 4H), 1.70-1.84 (m, 2H), 1.89-1.98 (m, 3H), 2.01-2.09 (m, 1H), 2.24-2.34 (m, 2H), 2.40-2.47 (m, 2H), 2.49-2.57 (m, 1H), 2.83-2.88 (m, 1H), 3.25-3.36 (m, 6H), 3.56-3.60 (m, 1H), 3.75-3.92 (m, 5H), 4.36-4.41 (m, 1H), 4.57-4.68 (m, 3H), 4.85-4.87 (m, 1H), 4.96 (t, J = 9.6 Hz, 1H), 5.45 (dd, J = 14.8 Hz, 10.0 Hz, 1H), 5.57-5.62 (m, 1H), 6.22-6.65 (m, 14H).

[0636] Example 23 BX20-11-074

[0637] Step 1: Synthesis of intermediate 74-3

[0638] Method: Dissolve CDI (3.6 g, 22.0 mmol) in THF (50 mL), add 2-benzyloxyethanol (3.0 g, 20 mmol), stir at room temperature for 1 hour to get THF solution of 74-2. Add tert-butyl carbazate (6.3 g, 47.7 mmol) to the reaction solution, after adding, increase to 40 °C and stir for 16 hours. After the reaction, the reaction solution is extracted with water and EA for 3 times, washed with dilute hydrochloric acid (0.5 N) and concentrated brine in turn, dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography (PE:EA = 10:1 to 1:1) to obtain white solid 74-3 (5.28 g, yield 85%).

[0639] MS (ESI, m / z) 311 [M+H] + .

[0640] Step 2: Synthesis of intermediate 74-4

[0641] Method: 74-3 (5.28 g, 17.0 mmol) was dissolved in EA (50 mL), Pd / C (1.32 g, 10%) was added, and hydrogen was replaced. The reaction solution was stirred at room temperature for 5 hours under the atmosphere of hydrogen (1 atm). After the reaction was completed, diatomite was filtered, and the filtrate was concentrated under reduced pressure to obtain colorless oil 74-4 (3.6 g, yield 96%).

[0642] MS (ESI, m / z) 221 [M+H] + .

[0643] Step 3: Synthesis of intermediate 74-5

[0644] Method: Octaethylene glycol monomethyl ether (768 mg, 2 mmol) was dissolved in THF (10 mL), and triphosgene (297 mg, 1 mmol) was added with stirring. After cooling to 0°C, pyridine (240 mg, 3 mmol) dissolved in 3 mL of THF was slowly added dropwise, and the solution was warmed to room temperature and stirred for 1 hour. After the reaction was completed, the reaction solution was filtered, and the filtrate was added dropwise to a THF solution (10 mL) of 74-4 (374 mg, 1.7 mmol) and pyridine (240 mg, 3 mmol). The solution was stirred at room temperature for 1 hour. THF was removed by concentration under reduced pressure, and water and DCM were added for extraction. After washing with concentrated brine and drying over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH=1:0 to 15:1) to obtain colorless oily liquid 74-5 (950 mg, yield 88%).

[0645] MS (ESI, m / z) 631 [M+H] + .

[0646] Step 4: Synthesis of intermediate 74-6

[0647] Method: 74-5 (950 mg, 1.5 mmol) was dissolved in DCM (10 mL), and HCl / 1,4-dioxane (4 M, 3.75 mL, 15 mmol) was added dropwise. 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 colorless oil 74-6 (860 mg, hydrochloride).

[0648] MS (ESI, m / z) 531 [M+H] +

[0649] Step 5: Synthesis of BX20-11-074

[0650] The synthetic route is shown in the following formula:

[0651] Method: C2’epiAmB (100 mg, crude, HPLC purity about 50%, about 0.05 mmol) was dissolved in DMAc (5 mL), 74-6 (189 mg, hydrochloride salt, about 0.3 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 35 °C for 6 hours. After the reaction was completed, the reaction solution was filtered and purified by preparative chromatography (95:5 to 50:50, aq. NH4OAc (10 mM) / MeCN), and then freeze-dried to obtain a yellow solid powder BX20-11-074 (8.5 mg, yield 12%).

[0652] MS (ESI, m / z) 1437 [M+H] + .

[0653] 1 H NMR (400 MHz, CD3OD:Pyridine-d5 = 1:1) δ 1.14 (d, J = 7.2 Hz, 3H), 1.22 (d, J = 6.4 Hz, 3H), 1.33 (d, J = 6.4 Hz, 3H), 1.40 (d, J = 6.0 Hz, 3H), 1.44-1.46 (m, 1H), 1.48-1.57 (m, 3H), 1.61-1.66 (m, 2H), 1.73-1.88 (m, 3H), 1.91-1.96 (m, 2H), 2.06-2.10 (m, 4H), 2.25-2.35 (m, 2H), 2.42-2.48 (m, 2H), 2.50-2.56 (m, 1H), 2.85-2.90 (m, 1H), 3.16-3.21 (m, 1H), 3.31-3.31 (m, 5H), 3.52-3.54 (m, 3H), 3.62-3.64 (m, 28H), 3.71-3.76 (m, 3H), 3.82 (d, J = 10.4 Hz, 1H), 3.89-3.94 (m, 1H), 4.32-4.49 (m, 7H), 4.52-4.71 (m, 4H), 4.88 (d, J = 7.6 Hz, 1H), 5.00 (t, J = 9.6 Hz, 1H), 5.46 (dd, J = 14.8 Hz, 10.0 Hz, 1H), 5.59-5.64 (m, 1H), 6.23-6.67 (m, 14H).

[0654] Example 24 BX20-11-075

[0655] Step 1: Synthesis of intermediate 75-1

[0656] Method: Dissolve octaethylene glycol monomethyl ether (768 mg, 2 mmol) in THF (10 mL), add triphosgene (297 mg, 1 mmol), cool to 0 °C, slowly drop pyridine (240 mg, 3 mmol, dissolved in 3 mL of THF), and then raise the temperature to room temperature and stir for 1 hour. After the reaction is completed, filter out the white insoluble material, and then drop the filtrate into a THF solution (10 mL) of 54-4 (374 mg, 1.7 mmol) and pyridine (240 mg, 3 mmol), and then stir at room temperature for 1 hour. Concentrate under reduced pressure to remove THF, extract with water and DCM, wash with concentrated brine, dry over anhydrous sodium sulfate, and then concentrate under reduced pressure and purify by column chromatography (DCM:MeOH = 1:0 to 15:1) to obtain colorless oily liquid 75-1 (900 mg, with a yield of 84%).

[0657] MS (ESI, m / z) 630 [M+H] +

[0658] Step 2: Synthesis of intermediate 75-2

[0659] Method: Dissolve 75-1 (900 mg, 1.42 mmol) in DCM (10 mL), drop HCl / 1,4-dioxane (4 M, 3.5 mL, 14 mmol), and then stir the reaction at room temperature for 1 hour. After the reaction is completed, directly concentrate the reaction solution under reduced pressure to obtain colorless oily substance 75-2 (800 mg, hydrochloride).

[0660] MS (ESI, m / z) 530 [M+H] + .

[0661] Step 3: Synthesis of BX20-11-075

[0662] The synthetic route is shown in the following formula:

[0663] Method: Dissolve C2’epiAmB (100 mg, crude product, HPLC purity about 50%, about 0.05 mmol) in DMAc (5 mL), add 75-2 (190 mg, hydrochloride, about 0.3 mmol), then add NMM to adjust the pH of the reaction system to 9-10, and finally add PyAOP (104 mg, 0.2 mmol), and then stir the reaction at 35 °C for 6 hours. After the reaction is completed, filter the reaction solution and purify by preparative chromatography (95:5 to 50:50, aq. NH4OAc (10 mM) / MeCN), and then freeze-dry to obtain yellow solid powder BX20-11-075 (5 mg, with a yield of 7%).

[0664] MS (ESI, m / z) 1436 [M+H] + .

[0665] 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), 1.40 (d, J = 6.0 Hz, 3H), 1.46-1.50 (m, 1H), 1.54-1.59 (m, 2H), 1.61-1.72 (m, 3H), 1.74-1.87 (m, 3H), 1.92-2.03 (m, 3H), 2.06-2.10 (m, 1H), 2.24-2.37 (m, 3H), 2.45-2.59 (m, 3H), 3.25-3.30 (m, 1H), 3.33-3.36 (m, 4H), 3.52-3.54 (m, 3H), 3.62-3.64 (m, 30H), 3.72-3.74 (m, 3H), 3.85 (d, J = 10.4 Hz, 1H), 3.95 (t, J = 10.0 Hz, 1H), 4.23-4.34 (m, 5H), 4.42-4.47 (m, 1H), 4.62-4.76 (m, 3H), 4.83 (d, J = 7.6 Hz, 1H), 5.03 (t, J = 9.6 Hz, 1H), 5.44-5.50 (m, 1H), 5.62-5.66 (m, 1H), 6.25-6.68 (m, 14H).

[0666] Example 25 BX20-11-076

[0667] Step 1: Synthesis of intermediate 76-3

[0668] The synthetic route is shown in the following formula:

[0669] Method: CDI (1.53 g, 9.41 mmol) was dissolved in DMF (15 mL), cooled to -10 °C, and tert-butyl hydrazinecarboxylate (1.13 g, 8.55 mmol) in DMF (10 mL) was added slowly (10 min), and the reaction was stirred for 0.5 h. NMM (1.9 g, 18.8 mmol) and (9H-fluoren-9-yl)methyl (2-aminoethyl)carbamate hydrochloride (3.0 g, 9.41 mol) were added to the reaction solution at -10 °C, and the reaction was stirred for 1 h at room temperature. After the reaction, water and EA were added and the mixture was extracted three times with EA. The organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 2:1 to 0:1) to obtain 76-3 as a white solid (3.0 g, yield 72%).

[0670] MS (ESI, m / z) 441 [M+H] + .

[0671] Step 2: Synthesis of intermediate 76-4

[0672] The synthetic route is shown in the following formula:

[0673] Method: 76-3 (1.0 g, 2.27 mmol) was dissolved in DCM (10 mL), HCl / 1,4-dioxane (4 M, 5.7 mL, 22.8 mmol) was added, and the reaction was stirred at room temperature for 1 h. After the reaction was completed, the reaction was concentrated under reduced pressure to obtain white solid 76-4 (850 mg, hydrochloride salt).

[0674] MS (ESI, m / z) 341 [M+H] + .

[0675] Step 3: Synthesis of BX20-11-076

[0676] The synthetic route is shown in the following formula:

[0677] Method: C2’epiAmB (100 mg, crude, HPLC purity about 50%, about 0.05 mmol) was dissolved in DMAc (5 mL), 76-4 (112 mg, 0.3 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 h. Piperidine (200 mg, 2.35 mmol) was added to the reaction solution, and the stirring was continued for 1 h. After the reaction was completed, the reaction solution was filtered and purified by preparative chromatography (95:5 to 65:35, aq. HCOOH (1 ‰) / MeCN), and then freeze-dried to obtain yellow solid powder BX20-11-076 (15 mg, yield 29%).

[0678] MS (ESI, m / z) 1025 [M+H] + .

[0679] 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), 1.36 (d, J = 6.0 Hz, 3H), 1.40-1.44 (m, 1H), 1.47-1.55 (m, 3H), 1.59-1.68 (m, 2H), 1.71-1.85 (m, 4H), 1.92-1.99 (m, 4H), 2.03-2.10 (m, 1H), 2.26-2.34 (m, 2H), 2.41-2.55 (m, 3H), 3.17-3.26 (m, 3H), 3.30-3.36 (m, 2H), 3.51-3.70 (m, 5H), 3.81 (d, J = 10.8 Hz, 1H), 3.90 (t, J = 10.0 Hz, 1H), 4.36-4.43 (m, 1H), 4.56-4.71 (m, 4H), 4.91 (d, J = 10.4 Hz, 1H), 5.46 (dd, J = 14.4 Hz, 10.0 Hz, 1H), 5.57-5.62 (m, 1H), 6.24-6.65 (m, 14H).

[0680] Example 26 BX20-11-077

[0681] Step 1: Synthesis of intermediate 77-3

[0682] The synthetic route is shown in the following formula:

[0683] Method: CDI (2.24 g, 13.8 mmol) was dissolved in DCM (30 mL), 3-(tert- butyldimethylsiloxy)propanol (2.5 g, 13.1 mmol) was added, stirred at room temperature for 1 hour, then water, saturated brine was added for extraction, the organic phase was collected to get DCM solution of 77-2. The reaction solution was cooled in ice water bath, N2H4·H2O (1.64 g, 26.2 mmol, 80 wt% in H2O) was slowly added dropwise, then the temperature was raised to room temperature and stirred for 1 hour. After the reaction was completed, DCM was removed under reduced pressure, water and EA were added for extraction, concentrated brine was washed, anhydrous sodium sulfate was dried, concentrated under reduced pressure, then purified by column chromatography (PE:EA = 9:1 ~ PE:EA = 1:2) to obtain colorless oil 77-3 (2.75 g, yield 84.2%).

[0684] MS (ESI, m / z) 249 [M+H] + .

[0685] Step 2: Synthesis of intermediate 77-4

[0686] The synthetic route is shown in the following formula:

[0687] Method: 77-3 (2.75 g, 11 mmol) was dissolved in DCM (30 mL), HCl / 1,4-dioxane (4.0 M, 27.5 mL, 110 mmol) was added dropwise slowly, and after the addition was completed, the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was directly concentrated under reduced pressure to obtain white solid 77-4 (1.8 g, hydrochloride).

[0688] MS (ESI, m / z) 135 [M+H] + .

[0689] Step 3: Synthesis of BX20-11-077

[0690] The synthetic route is shown in the following formula:

[0691] Method: C2’epiAmB (95 mg, crude, HPLC purity about 50%, about 0.05 mmol) was dissolved in DMAc (5 mL), 77-4 (51 mg, 0.3 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 35°C for 1 hour. After the reaction was completed, the reaction solution was filtered and purified by preparative chromatography (95:5 to 60:40, aq. HCOOH (1 ‰) / MeCN), and then freeze-dried to obtain yellow solid powder BX20-11-077 (14.5 mg, yield 27.8%).

[0692] MS (ESI, m / z) 1041 [M+H] + .

[0693] 1H 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), 1.32 (d, J = 6.4 Hz, 3H), 1.38 (d, J = 6.0 Hz, 3H), 1.43-1.46 (m, 1H), 1.48-1.65 (m, 5H), 1.68-1.84 (m, 3H), 1.87-1.98 (m, 5H), 2.02-2.10 (m, 1H), 2.24-2.34 (m, 2H), 2.38-2.47 (m, 2H), 2.49-2.57 (m, 1H), 2.86-2.90 (m, 1H), 3.22-3.36 (m, 3H), 3.55-3.61 (m, 1H), 3.73-3.81 (m, 4H), 3.87-3.92 (m, 1H), 4.33-4.44 (m, 3H), 4.57-4.68 (m, 3H), 4.86-4.99 (m, 2H), 5.42-5.48 (m, 1H), 5.58-5.62 (m, 1H), 6.22-6.66 (m, 14H).

[0694] Example 27 BX20-11-078

[0695] Step 1: Synthesis of intermediate 78-3

[0696] The synthetic route is shown below:

[0697] Method: CDI (2.14 g, 13.2 mmol) was dissolved in DMF (30 mL), cooled to -10 °C, and tert-butyl carbazate (1.58 g, 12.0 mmol) in DMF (10 mL) was added slowly (10 min), and the mixture was stirred for another 0.5 h. Then 3-(tert-butyldimethylsilyloxy)propan-1-amine (2.5 g, 13.2 mol) in DMF (30 mL) was added slowly to the above solution of 78-2, and the mixture was stirred at room temperature for 1 h. After the reaction, the mixture was extracted with water and EA for 3 times, and the organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1 to 3:1) to give 78-3 (4.0 g, 95% yield) as a white solid.

[0698] MS (ESI, m / z) 348 [M+H] + .

[0699] Step 2: Synthesis of intermediate 78-4

[0700] Method: 78-3 (2.0 g, 5.76 mmol) was dissolved in DCM (20 mL), HCl / 1,4-dioxane (4.0 M, 15 mL, 60 mmol) was added dropwise slowly, after the addition was completed, it was stirred at room temperature for 1 hour. After the reaction was completed, it was directly concentrated under reduced pressure to obtain white solid 78-4 (1.0 g, hydrochloride).

[0701] MS (ESI, m / z) 134 [M+H] + .

[0702] Step 3: Synthesis of BX20-11-078

[0703] The synthetic route is shown in the following formula:

[0704] Method: C2’epiAmB (100 mg, crude, HPLC purity about 50%, about 0.05 mmol) was dissolved in DMAc (5 mL), 78-4 (51 mg, 0.3 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 35°C for 1 hour. After the reaction was completed, the reaction solution was filtered and purified by preparative chromatography (95:5 to 60:40, aq. HCOOH (1 ‰) / MeCN), and then freeze-dried to obtain yellow solid powder BX20-11-078 (5 mg, yield 10%).

[0705] MS (ESI, m / z) 1040 [M+H] + .

[0706] 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), 1.30 (d, J = 6.4 Hz, 3H), 1.35 (d, J = 6.0 Hz, 3H), 1.38-1.42 (m, 1H), 1.46-1.57 (m, 4H), 1.60-1.72 (m, 3H), 1.76-1.85 (m, 2H), 1.87-1.96 (m, 3H), 1.98-2.06 (m, 1H), 2.22-2.43 (m, 4H), 2.47-2.53 (m, 1H), 2.59-2.68 (m, 1H), 3.25-3.35 (m, 3H), 3.42-3.45 (m, 2H), 3.55-3.64 (m, 2H), 3.71 (t, J = 5.6 Hz, 2H), 3.78 (d, J = 10.8 Hz, 1H), 3.87 (t, J = 10.0 Hz, 1H), 4.33-4.39 (m, 1H), 4.54-4.64 (m, 3H), 4.70-4.74 (m, 1H), 4.86-4.93 (m, 1H), 5.44 (dd, J = 14.4 Hz, 10.0 Hz, 1H), 5.55-5.60 (m, 1H), 6.21-6.63 (m, 14H).

[0707] Example 28 BX20-11-079

[0708] Method: C2’epiAmB (100 mg, crude, HPLC purity about 50%, about 0.05 mmol) was dissolved in DMAc (5 mL), hydrazine (28 mg, 0.3 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 filtered and purified by preparative chromatography (95:5 to 63:37, aq. HCOOH (1 ‰) / MeCN), and then freeze-dried to obtain yellow solid powder BX20-11-079 (6 mg, yield 12%).

[0709] MS (ESI, m / z) 997 [M+H] + .

[0710] 1H NMR (400 MHz, CD3OD:Pyridine-d5 = 1 : 1) δ 1.16 (d, J = 7.2 Hz, 3H), 1.23 (d, J = 6.4 Hz, 3H), 1.35 (d, J = 6.4 Hz, 3H), 1.40 (d, J = 6.0 Hz, 3H), 1.45-1.50 (m, 1H), 1.53-1.68 (m, 5H), 1.72-1.86 (m, 3H), 1.90-2.03 (m, 3H), 2.09-2.18 (m, 1H), 2.30-2.37 (m, 2H), 2.45-2.59 (m, 3H), 3.24-3.39 (m, 3H), 3.59-3.65 (m, 2H), 3.81-3.86 (m, 2H), 3.95 (t, J = 10.0 Hz, 1H), 4.42-4.47 (m, 1H), 4.62-4.68 (m, 1H), 4.71-4.79 (m, 2H), 4.92 (d, J = 7.6 Hz, 1H), 5.02-5.09 (m, 1H), 5.48-5.52 (m, 1H), 5.63-5.66 (m, 1H), 6.24-6.69 (m, 14H).

[0711] Example 29 BX20-11-080

[0712] Step 1: Synthesis of intermediate 80-3

[0713] The synthetic route is shown in the following formula:

[0714] Method: CDI (2.7 g, 16.66 mmol) was dissolved in DMF (30 mL), cooled to -10 °C, and tert-butyl hydrazinecarboxylate (2.0 g, 15.15 mmol) in DMF (10 mL) was added slowly (10 min), and the mixture was stirred for another 0.5 h. 2-Dimethylaminoethylamine (2.5 g, 13.2 mol) was dissolved in DMF (30 mL) and added slowly to the above solution of 80-2. The mixture was stirred at room temperature for 1 h. After the reaction, water and EA were added and the mixture was extracted three times. The organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 5:1) to give 80-3 (800 mg, yield 21%) as a colorless oil.

[0715] MS (ESI, m / z) 247 [M+H] + .

[0716] Step 2: Synthesis of intermediate 80-4

[0717] Method: 80-3 (800 mg, 3.25 mmol) was dissolved in DCM (20 mL), HCl / 1,4-dioxane (4.0 M, 8 mL, 32 mmol) was added dropwise slowly, after the addition, the reaction was stirred at room temperature for 1 hour. After the reaction was completed, it was directly concentrated under reduced pressure to obtain white solid 80-4 (770 mg, hydrochloride).

[0718] MS (ESI, m / z) 147 [M+H] + .

[0719] Step 3: Synthesis of BX20-11-080

[0720] The synthetic route is shown in the following formula:

[0721] Method: C2’epiAmB (100 mg, crude, HPLC purity about 50%, about 0.05 mmol) was dissolved in DMAc (5 mL), 80-4 (71 mg, hydrochloride, about 0.3 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 35°C for 1 hour. After the reaction was completed, the reaction solution was filtered and purified by preparative chromatography (95:5 to 67:33, aq. HCOOH (1 ‰) / MeCN), and then freeze-dried to obtain yellow solid powder BX20-11-080 (12 mg, yield 22%).

[0722] MS (ESI, m / z) 1053 [M+H] + .

[0723] 1H NMR (400 MHz, CD3OD:Pyridine-d5 = 1 : 1) δ 1.16 (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), 1.43-1.46 (m, 1H), 1.50-1.60 (m, 3H), 1.63-1.69 (m, 2H), 1.73-1.80 (m, 5H), 1.92-2.00 (m, 4H), 2.10-2.16 (m, 1H), 2.28-2.37 (m, 3H), 2.44-2.58 (m, 9H), 3.33-3.40 (m, 2H), 3.46-3.56 (m, 3H), 3.69-3.75 (m, 2H), 3.85 (d, J = 10.8 Hz, 1H), 3.94 (t, J = 10.0 Hz, 1H), 4.41-4.46 (m, 1H), 4.61-4.70 (m, 3H), 4.83-4.85 (m, 1H), 4.98-5.03 (m, 1H), 5.47-5.51 (m, 1H), 5.62-5.66 (m, 1H), 6.26-6.68 (m, 14H).

[0724] Example 30 BX20-11-081

[0725] Step 1: Synthesis of intermediate 81-3

[0726] The synthetic route is shown below:

[0727] Method: CDI (1.78 g, 11.0 mmol) was dissolved in ACN (40 mL), cooled to 0 °C, and tert-butyl hydrazinecarboxylate (1.32 g, 10.0 mmol) in ACN (10 mL) was added slowly (10 min), and the mixture was stirred for 1 h. Imidazole (2.72 g, 40 mmol) and methoxyamine hydrochloride (4.18 g, 50 mmol) were added, and the mixture was stirred at room temperature for 4 h. The reaction was quenched with water and extracted with EA three times. The combined organic phase was washed with dilute hydrochloric acid (0.5 N) and concentrated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 10:1 to 1:1) to give 81-3 as a white solid (550 mg, 27% yield).

[0728] MS (ESI, m / z) 206 [M+H] + .

[0729] Step 2: Synthesis of intermediate 81-4

[0730] Method: 81-3 (550 mg, 2.68 mmol) was dissolved in DCM (20 mL), HCl / 1,4-dioxane (4.0 M, 7 mL, 28 mmol) was added dropwise slowly, after the addition was completed, it was stirred at room temperature for 1 hour. After the reaction was completed, it was directly concentrated under reduced pressure to obtain white solid 81-4 (320 mg, hydrochloride).

[0731] MS (ESI, m / z) 106 [M+H] + .

[0732] Step 3: Synthesis of BX20-11-081

[0733] The synthetic route is shown in the following formula:

[0734] Method: C2’epiAmB (100 mg, crude, HPLC purity about 50%, about 0.05 mmol) was dissolved in DMAc (5 mL), 81-4 (47 mg, 0.3 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 35°C for 1 hour. After the reaction was completed, the reaction solution was filtered and purified by preparative chromatography (95:5 to 60:40, aq. HCOOH (1 ‰) / MeCN), and then freeze-dried to obtain yellow solid powder BX20-11-081 (13 mg, yield 25%).

[0735] MS (ESI, m / z) 1012 [M+H] + .

[0736] 1H NMR (400 MHz, CD3OD:Pyridine-d5 = 1:1) δ 1.14 (d, J = 7.2 Hz, 3H), 1.22 (d, J = 6.4 Hz, 3H), 1.32 (d, J = 6.4 Hz, 3H), 1.37 (d, J = 6.0 Hz, 3H), 1.43-1.47 (m, 1H), 1.49-1.58 (m, 3H), 1.60-1.66 (m, 2H), 1.72-1.87 (m, 3H), 1.91-1.99 (m, 2H), 2.04-2.12 (m, 1H), 2.26-2.31 (m, 2H), 2.42-2.56 (m, 3H), 2.89-2.94 (m, 1H), 3.27-3.36 (m, 3H), 3.57-3.61 (m, 1H), 3.73-3.82 (m, 5H), 3.91 (t, J = 10.0 Hz, 1H), 4.37-4.43 (m, 1H), 4.61 (t, J = 10.8 Hz, 1H), 4.66-4.72 (m, 2H), 4.94 (d, J = 7.6 Hz, 1H), 4.98 (t, J = 9.6 Hz, 1H), 5.45 (dd, J = 14.4 Hz, 10.0 Hz, 1H), 5.59-5.64 (m, 1H), 6.22-6.66 (m, 14H).

[0737] Example 31 BX20-11-082

[0738] Step 1: Synthesis of intermediate 82-3

[0739] The synthetic route is shown in the following formula:

[0740] Method: CDI (2.49 g, 15.39 mmol) was dissolved in ACN (35 mL), cooled to 0 °C, and a solution of tert-butyl carbazate (1.35 g, 10.26 mmol) in ACN (10 mL) was added slowly (10 min), and the mixture was stirred for 1 h. Imidazole (2.79 g, 41.04 mmol) and ethylenediamine hydrochloride (5.0 g, 51.3 mmol) were added, and the mixture was stirred at room temperature for 1.5 h. The reaction was quenched with water and extracted with EA three times. The combined organic phase was washed with dilute hydrochloric acid (0.5 N) and concentrated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 10:1 to 1:1) to give 82-3 (1.85 g, 82% yield) as a colorless oily liquid.

[0741] MS (ESI, m / z) 220 [M+H] + .

[0742] Step 2: Synthesis of intermediate 82-4

[0743] Method: 82-3 (1.85 g, 8.4 mmol) was dissolved in DCM (20 mL), HCl / 1,4-dioxane (4.0 M, 21 mL, 84 mmol) was added dropwise slowly, and the mixture was stirred at room temperature for 1 h after the addition was completed. After the reaction was completed, the reaction mixture was directly concentrated under reduced pressure to give white solid 82-4 (1.27 g, hydrochloride salt).

[0744] MS (ESI, m / z) 120 [M+H] + .

[0745] Step 3: Synthesis of BX20-11-082

[0746] The synthetic route is shown in the following formula:

[0747] Method: C2’epiAmB (100 mg, crude, HPLC purity about 50%, about 0.05 mmol) was dissolved in DMAc (5 mL), 82-4 (47 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 35 °C for 1 h. After the reaction was completed, the reaction solution was filtered and purified by preparative chromatography (95:5 to 60:40, aq. HCOOH (1 ‰) / MeCN). After lyophilization, yellow solid powder BX20-11-082 (15 mg, yield 29%) was obtained.

[0748] MS (ESI, m / z) 1026 [M+H] + .

[0749] 1H NMR (400 MHz, CD3OD:Pyridine-d5 = 1:1) δ 1.14 (d, J = 7.2 Hz, 3H), 1.21-1.25 (m, 6H), 1.33 (d, J = 6.4 Hz, 3H), 1.37 (d, J = 6.0 Hz, 3H), 1.43-1.47 (m, 1H), 1.50-1.58 (m, 3H), 1.60-1.67 (m, 2H), 1.69-1.85 (m, 3H), 1.88-2.00 (m, 3H), 2.03-2.14 (m, 1H), 2.26-2.35 (m, 2H), 2.42-2.57 (m, 3H), 2.89-2.94 (m, 1H), 3.25-3.38 (m, 3H), 3.58 (dd, J = 10.4 Hz, 8.0 Hz, 1H), 3.74-3.83 (m, 2H), 3.89-4.00 (m, 3H), 4.38-4.44 (m, 1H), 4.61 (t, J = 10.4 Hz, 1H), 4.66-4.73 (m, 2H), 4.94 (d, J = 7.6 Hz, 1H), 4.94 (t, J = 10.0 Hz, 1H), 5.46 (dd, J = 14.4 Hz, 10.0 Hz, 1H), 5.59-5.64 (m, 1H), 6.22-6.66 (m, 14H).

[0750] Example 32 BX20-11-085

[0751] Step 1: Synthesis of intermediate 85-2

[0752] Method: 2-tert-butyldimethylsilanyloxyethanol (5.0 g, 28.4 mmol) was dissolved in THF (120 mL), N-hydroxyphthalimide (5.56 g, 34.09 mmol) and PPh3 (8.93 g, 34.09 mmol) were added, and the ice water bath was cooled, DIAD (6.89 g, 34.09 mmol, diluted in 15 mL THF) was slowly added dropwise, and the temperature was raised to room temperature and stirred for 1 hour. After the reaction was completed, it was filtered, washed with EA, and the filtrate was concentrated under reduced pressure, and then purified by column chromatography (PE:EA = 10:1 to 5:1) to obtain white solid 85-2 (8.86 g, yield 97.1%).

[0753] MS (ESI, m / z) 322 [M+H] + .

[0754] Step 2: Synthesis of intermediate 85-3

[0755] Method: 85-2 (8.86 g, 27.6 mmol) was dissolved in MeOH (150 mL), hydrazine hydrate (8.6 g, 138 mmol, 80% wt) was added, the reaction was raised to 80 °C and stirred for 1 hour. After the reaction was completed, it was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE:EA = 3:2) to obtain yellow oily liquid 85-3 (4.3 g, yield 91.5%).

[0756] MS (ESI, m / z) 192 [M+H] + .

[0757] Step 3: Synthesis of intermediate 85-4

[0758] Method: CDI (2.5 g, 16.0 mmol) was dissolved in ACN (40 mL), cooled to 0 °C, and tert-butyl hydrazinecarboxylate (1.91 g, 14.5 mmol) in ACN (10 mL) was slowly added (10 minutes), and stirring was continued at 0 °C for 1 hour. At 0 °C, imidazole (2.0 g, 29.0 mmol) and 85-3 (4.3 g, 22.5 mmol) were added to the reaction solution. After the addition was complete, it was raised to 35 °C and stirred for 4 hours. After the reaction was completed, it was extracted with water and EA three times, the organic phases were combined, washed successively with dilute hydrochloric acid (0.5 N) and concentrated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 5:1 to 1.5:1) to obtain white solid 85-4 (3.0 g, yield 59%).

[0759] MS (ESI, m / z) 350 [M+H] + .

[0760] Step 4: Synthesis of intermediate 85-5

[0761] Method: 85-4 (1.28 g, 3.66 mmol) was dissolved in DCM (8 mL), and HCl / 1,4-dioxane (4.0 M, 13 mL, 42 mmol) was slowly added dropwise, and stirring was continued at room temperature for 1 hour. After the reaction was completed, it was directly concentrated under reduced pressure to obtain white solid 85-5 (600 mg, hydrochloride).

[0762] MS (ESI, m / z) 136 [M+H] + .

[0763] Step 5: Synthesis of BX20-11-085

[0764] The synthetic route is shown in the following formula:

[0765] Method: C2’epiAmB (100 mg, crude, HPLC purity about 50%, about 0.05 mmol) was dissolved in DMAc (5 mL), 85-5 (75 mg, 0.44 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 35 °C for 1 hour. After the reaction was completed, the reaction solution was filtered and purified by preparative chromatography (95:5 to 60:40, aq. HCOOH (1 ‰) / MeCN), and then freeze-dried to obtain a yellow solid powder BX20-11-085 (12 mg, yield 23%).

[0766] MS (ESI, m / z) 1042 [M+H] + .

[0767] 1 H NMR (400 MHz, CD3OD:Pyridine-d5 = 1:1) δ 1.12 (d, J = 7.2 Hz, 3H), 1.21 (d, J = 6.4 Hz, 3H), 1.31 (d, J = 6.4 Hz, 3H), 1.35 (d, J = 6.0 Hz, 3H), 1.38-1.43 (m, 1H), 1.45-1.55 (m, 3H), 1.58-1.65 (m, 2H), 1.69-1.86 (m, 3H), 1.88-1.97 (m, 2H), 2.00-2.08 (m, 1H), 2.23-2.33 (m, 2H), 2.40-2.54 (m, 3H), 2.83-2.87 (m, 1H), 3.22-3.36 (m, 4H), 3.53 (dd, J = 10.4 Hz, 7.6 Hz, 1H), 3.73 (dd, J = 8.8 Hz, 6.0 Hz, 1H), 3.84-3.96 (m, 3H), 4.05 (t, J = 4.8 Hz, 2H), 4.34-4.41 (m, 1H), 4.55-4.68 (m, 3H), 4.88 (d, J = 7.6 Hz, 1H), 4.94 (t, J = 9.6 Hz, 1H), 5.44 (dd, J = 14.4 Hz, 10.0 Hz, 1H), 5.57-5.61 (m, 1H), 6.20-6.64 (m, 14H).

[0768] Example 33 BX20-11-086

[0769] Step 1: Synthesis of intermediate 86-3

[0770] The synthetic route is shown in the following formula:

[0771] Method: CDI (1.1 g, 6.82 mmol) was dissolved in DCM (10 mL), and cyclopropylmethanethiol (500 mg, 5.68 mmol) was added. After stirring at room temperature for 1 h, a DCM solution of 86-2 was obtained. The reaction was cooled in an ice water bath, and N2H4·H2O (710 mg, 11.36 mmol, 80 wt% in H2O) was added dropwise. After the addition was completed, the reaction was stirred at room temperature for 1 h. After the reaction was completed, the DCM was removed by reduced pressure concentration. The reaction was extracted with water and EA, washed with brine, dried over anhydrous sodium sulfate, and concentrated by reduced pressure. The residue was purified by column chromatography (PE:EA = 5:1 to 3:1) to obtain white solid 86-3 (247 mg, yield 30%).

[0772] MS (ESI, m / z) 147 [M+H] + .

[0773] Step 2: Synthesis of BX20-11-086

[0774] The synthetic route is shown in the following formula:

[0775] Method: C2’epiAmB (100 mg, crude, HPLC purity about 50%, about 0.05 mmol) was dissolved in DMAc (5 mL), and 86-3 (44 mg, 0.3 mmol) was added. 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 35°C for 5 h. After the reaction was completed, the reaction solution was filtered and purified by preparative chromatography (95:5 to 45:55, aq. NH4OAc (10 mM) / MeCN). After lyophilization, yellow solid powder BX20-11-086 (10 mg, yield 19%) was obtained.

[0776] MS (ESI, m / z) 1053 [M+H] + .

[0777] 1H NMR (400 MHz, CD3OD:Pyridine-d5 = 1:1) δ 0.25-0.32 (m, 2H), 0.49-0.53 (m, 2H), 1.16 (d, J = 7.2 Hz, 3H), 1.24 (d, J = 6.4 Hz, 3H), 1.35 (d, J = 6.4 Hz, 3H), 1.42-1.45 (m, 4H), 1.50-1.57 (m, 2H), 1.61-1.70 (m, 3H), 1.74-1.86 (m, 3H), 1.91-2.00 (m, 3H), 2.11-2.18 (m, 1H), 2.30-2.37 (m, 2H), 2.45-2.59 (m, 3H), 2.86-3.02 (m, 3H), 3.12-3.24 (m, 2H), 3.33-3.38 (m, 2H), 3.58-3.62 (m, 1H), 3.85 (d, J = 10.8 Hz, 1H), 3.95 (t, J = 10.0 Hz, 1H), 4.42-4.48 (m, 1H), 4.64 (t, J = 10.4 Hz, 1H), 4.72-4.78 (m, 2H), 4.94-4.95 (m, 1H), 5.08 (t, J = 9.6 Hz, 1H), 5.46-5.50 (m, 1H), 5.62-5.67 (m, 1H), 6.24-6.69 (m, 14H).

[0778] Example 34 BX20-11-090

[0779] Step 1: Synthesis of intermediate 90-3

[0780] Method: CDI (1.8 g, 11.12 mmol) was dissolved in DCM (30 mL), 2-(N- fluorenylmethoxycarbonylamino)ethanol (3.0 g, 10.59 mmol) was added, stirred at room temperature for 1 hour. The reaction solution was cooled in an ice water bath, N2H4·H2O (1.32 g, 21.18 mmol, 80 wt% in H2O) was added slowly dropwise, and after the addition was completed, it was stirred at room temperature for 1 hour. After the reaction was completed, DCM was removed under reduced pressure, extracted with water and EA, washed with concentrated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 10:1) to obtain white solid 90-3 (1.8 g, yield 50%).

[0781] MS (ESI, m / z) 342 [M+H] + .

[0782] Step 2: Synthesis of BX20-11-090

[0783] Method: C2’epiAmB (100 mg, crude, HPLC purity about 50%, about 0.05 mmol) was dissolved in DMAc (5 mL), 90-3 (102 mg, 0.3 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 35 °C for 6 hours. After the completion of the condensation reaction, piperidine (220 mg, 2.59 mmol) was added dropwise to the reaction solution, and stirring was continued for 0.5 hours. 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, a yellow solid powder BX20-11-090 (7 mg, yield 13%) was obtained.

[0784] MS (ESI, m / z) 1026 [M+H] + .

[0785] 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), 1.37 (d, J = 6.0 Hz, 3H), 1.44-1.55 (m, 4H), 1.61-1.67 (m, 2H), 1.70-1.78 (m, 3H), 1.91-1.97 (m, 3H), 2.02-2.09 (m, 1H), 2.24-2.34 (m, 3H), 2.38-2.54 (m, 3H), 2.78-2.88 (m, 1H), 3.11-3.25 (m, 1H), 3.29-3.35 (m, 3H), 3.56-3.61 (m, 1H), 3.65-3.71 (m, 1H), 3.80 (d, J = 10.8 Hz, 1H), 3.89 (t, J = 10.0 Hz, 1H), 4.35-4.40 (m, 2H), 4.56-4.67 (m, 4H), 4.80 (d, J = 7.6 Hz, 1H), 4.92 (t, J = 10.0 Hz, 1H), 5.45 (dd, J = 14.8 Hz, 10.4 Hz, 1H), 5.58-5.62 (m, 1H), 6.22-6.66 (m, 14H).

[0786] Example 35 BX20-11-091

[0787] Step 1: Synthesis of intermediate 91-2

[0788] Method: 2-(N-Fluorenylmethoxycarbonylamino)ethanol (5.66 g, 20 mmol) was dissolved in THF (100 mL), N-hydroxyphthalimide (3.92 g, 24 mmol) and PPh3(6.29 g, 24 mmol) were added, the reaction was cooled in an ice water bath, DIAD (4.85 g, 24 mmol, diluted in 5 mL THF) was added slowly dropwise, the reaction was allowed to warm to room temperature and stirred for 1 hour. After the reaction was completed, it was filtered, washed with EA, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE:EA = 10:1 to 5:1) to obtain white solid 91-2 (8.0 g, yield 93%).

[0789] MS (ESI, m / z) 429 [M+H] + .

[0790] Step 2: Synthesis of intermediate 91-3

[0791] Method: 91-2 (8.0 g, 18.6 mmol) was dissolved in MeOH (200 mL), hydrazine hydrate (6.25 g, 100 mmol, 80% wt) was added, and the reaction was stirred in an 80 °C oil bath for 1 hour. After the reaction was completed, it was filtered, the filter cake was washed with ethyl acetate, the filtrate was collected and concentrated under reduced pressure, and purified by column chromatography (PE:EA = 10:1 to 1:1) to obtain yellow solid 91-3 (5.0 g, yield 90%).

[0792] MS (ESI, m / z) 299 [M+H] + .

[0793] Step 3: Synthesis of intermediate 91-4

[0794] Method: CDI (2.5 g, 16.0 mmol) was dissolved in ACN (40 mL), cooled to 0 °C, and a solution of tert-butyl carbazate (1.91 g, 14.5 mmol) in ACN (10 mL) was slowly added (10 minutes), and the reaction was stirred at 0 °C for 1 hour. While maintaining the temperature at 0 °C, imidazole (2.0 g, 29.0 mmol) and 91-3 (5.0 g, 16.7 mmol) were added to the reaction. After the addition was complete, the temperature was raised to 35 °C and the reaction was stirred for 16 hours. After the reaction was completed, it was extracted with water and EA three times, the organic phases were combined, washed successively with dilute hydrochloric acid (0.5 N) and concentrated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 5:1 to 1:2) to obtain white solid 91-4 (2.2 g, yield 33%).

[0795] MS (ESI, m / z) 457 [M+H] + .

[0796] Step 4: Synthesis of intermediate 91-5

[0797] Method: 91-4 (770 mg, 1.69 mmol) was dissolved in DCM (5 mL), HCl / 1,4-dioxane (4.0 M, 4 mL, 16 mmol) was added dropwise slowly, and the mixture was stirred at room temperature for 1 h after the addition was completed. After the reaction was completed, the reaction mixture was directly concentrated under reduced pressure to give white solid 91-5 (660 mg, hydrochloride salt).

[0798] MS (ESI, m / z) 357 [M+H] + .

[0799] Step 5: Synthesis of BX20-11-091

[0800] The synthetic route is shown in the following formula:

[0801] Method: C2’epiAmB (100 mg, crude, HPLC purity about 50%, about 0.05 mmol) was dissolved in DMAc (5 mL), 91-5 (160 mg, hydrochloride salt, about 0.4 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 35 °C for 1 h. After the reaction was completed, the reaction solution was filtered and purified by preparative chromatography (95:5 to 67:33, aq. HCOOH (1 ‰) / MeCN). After lyophilization, yellow solid powder BX20-11-091 (16 mg, yield 30%) was obtained.

[0802] MS (ESI, m / z) 1041 [M+H] + .

[0803] 1H NMR (600 MHz, CD3OD:Pyridine-d5 = 1 : 1) δ 1.16 (d, J = 7.2 Hz, 3H), 1.23 (d, J = 6.4 Hz, 3H), 1.34 (d, J = 6.4 Hz, 3H), 1.39 (d, J = 6.0 Hz, 3H), 1.43-1.45 (m, 1H), 1.50-1.60 (m, 3H), 1.64-1.70 (m, 2H), 1.75-1.81 (m, 3H), 1.92-2.00 (m, 3H), 2.10-2.16 (m, 1H), 2.29-2.36 (m, 3H), 2.45-2.57 (m, 3H), 2.86-2.91 (m, 1H), 3.33-3.35 (m, 1H), 3.46-3.52 (m, 4H), 3.71-3.79 (m, 2H), 3.84 (d, J = 10.8 Hz, 1H), 3.94 (t, J = 10.2 Hz, 1H), 4.26-4.33 (m, 2H), 4.42-4.45 (m, 1H), 4.62-4.66 (m, 1H), 4.71-4.76 (m, 2H), 4.96 (d, J = 7.2 Hz, 1H), 5.01 (t, J = 9.6 Hz, 1H), 5.46-5.50 (m, 1H), 5.62-5.65 (m, 1H), 6.25-6.67 (m, 14H).

[0804] Example 36 BX20-11-092

[0805] Step 1: Synthesis of intermediate 92-2

[0806] Method: N-Fluorenylmethoxycarbonylglycinaldehyde (5.0 g, 17.8 mmol) and tert- butylhydrazinecarboxylate (2.59 g, 19.6 mmol) were dissolved in MeOH (60 mL) and THF (40 mL), NaBH3CN (1.34 g, 21.3 mmol) was added, AcOH (2 mL) was added dropwise slowly, the reaction was stirred at room temperature for 16 hours. After the reaction was completed, EA and saturated NaHCO3 solution were added for extraction, washed with brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure, then purified by column chromatography (PE:EA = 3:1 to 1:1) to obtain white solid 92-2 (6.8 g, yield 96%).

[0807] MS (ESI, m / z) 398 [M+H] + .

[0808] Step 2: Synthesis of intermediate 92-3

[0809] Method: Dissolve 92-2 (6.8 g, 17.1 mmol) in DCM (50 mL), add HC1 / 1,4-dioxane (4 M, 43 mL, 172 mmol), stir the reaction mixture at room temperature for 12 hours. Upon completion, directly concentrate under reduced pressure to give white solid 92-3 (6.0 g, HC1 salt).

[0810] MS (ESI, m / z) 298 [M+H] + .

[0811] Step 3: Synthesis of intermediate 92-4

[0812] Method: Dissolve CDI (2.5 g, 16.0 mmol) in ACN (40 mL), cool to 0 °C, slowly add tert-butyl carbazate (1.91 g, 14.5 mmol) in ACN (10 mL) (10 minutes), after addition, continue to stir at 0 °C for 1 hour. At 0 °C, add NMM (2.9 g, 29.0 mmol) and 92-3 (6.0 g, HC1 salt, about 17 mmol) to the reaction mixture. After addition, warm to 35 °C and stir for 12 hours. Upon completion, concentrate under reduced pressure, then purify by column chromatography (PE:EA = 1:1 to 0:1) to give yellow solid 92-4 (1.5 g, yield 23%).

[0813] MS (ESI, m / z) 456 [M+H] + .

[0814] Step 4: Synthesis of intermediate 92-5

[0815] Method: Dissolve 92-4 (1.5 g, 3.3 mmol) in DCM (15 mL), slowly add HC1 / 1,4-dioxane (4.0 M, 8 mL, 32 mmol), after addition, stir at room temperature for 1 hour. Upon completion, directly concentrate under reduced pressure to give yellow solid 92-5 (1.3 g, HC1 salt).

[0816] MS (ESI, m / z) 356 [M+H] + .

[0817] Step 5: Synthesis of BX20-11-092

[0818] The synthetic route is shown in the following formula:

[0819] Method: C2’epiAmB (100 mg, crude, HPLC purity about 50%, about 0.05 mmol) was dissolved in DMAc (5 mL), 92-5 (117 mg, hydrochloride salt, about 0.3 mmol) was added, then NMM was added to adjust the pH of the reaction system to 9-10, PyAOP (104 mg, 0.2 mmol) was added, the reaction was stirred at 35 °C for 1 hour, finally piperidine (250 mg, 2.9 mmol) was added, and stirred at room temperature for 0.5 hour. After the reaction was completed, the reaction solution was 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 BX20-11-092 (10 mg, yield 19%).

[0820] MS (ESI, m / z) 1040 [M+H] + .

[0821] 1 H NMR (600 MHz, CD3OD:Pyridine-d5 = 1:1) δ 1.14 (d, J = 7.2 Hz, 3H), 1.22 (d, J = 6.4 Hz, 3H), 1.32-1.36 (m, 6H), 1.39-1.44 (m, 2H), 1.48-1.58 (m, 4H), 1.62-1.67 (m, 2H), 1.73-1.86 (m, 4H), 1.94-1.98 (m, 2H), 2.05-2.10 (m, 1H), 2.27-2.34 (m, 2H), 2.43-2.55 (m, 3H), 2.82-2.87 (m, 1H), 3.20-3.23 (m, 1H), 3.28-3.36 (m, 2H), 3.56-3.66 (m, 2H), 3.81 (d, J = 10.8 Hz, 1H), 3.91 (t, J = 10.2 Hz, 1H), 4.15-4.24 (m, 1H), 4.39-4.42 (m, 1H), 4.61-4.76 (m, 3H), 4.90-5.00 (m, 1H), 5.45 (dd, J = 14.4 Hz, 10.0 Hz, 1H), 5.60-5.64 (m, 1H), 6.23-6.65 (m, 14H).

[0822] Example 37 BX20-11-093

[0823] Step 1: Synthesis of intermediate 93-2

[0824] Method: CDI (5.36 g, 33.1 mmol) was dissolved in ACN (50 mL) and replaced with nitrogen, and then hydrazinecarboxylic acid benzyl ester (5.0 g, 30.1 mmol) in DMF (25 mL) was slowly added at -10 °C. After the addition was completed, the reaction was continued to stir at -10 °C for 0.5 h, and then hydrazine hydrate (6 mL, 80 wt%) was added dropwise. After the addition was completed, the reaction was stirred at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and then purified by column chromatography (DCM:MeOH = 15:1 to 10:1) to obtain white solid 93-2 (3.8 g, yield 56%).

[0825] MS (ESI, m / z) 225 [M+H] + .

[0826] Step 2: Synthesis of intermediate 93-3

[0827] Method: Benzyl oxyacetaldehyde (2.33 g, 15.42 mmol) and 93-2 (3.8 g, 16.96 mmol) were dissolved in MeOH (50 mL) and THF (30 mL), and then NaBH3CN (2.32 g, 37.0 mmol) was added. AcOH (10 mL) was slowly added dropwise, and the reaction was stirred at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and then extracted with EA and water three times. The combined organic phase was washed with saturated sodium bicarbonate solution and concentrated brine successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (EA:MeOH = 100:1 to 50:1) gave yellow oily liquid 93-3 (3.45 g, yield 62%).

[0828] MS (ESI, m / z) 359 [M+H] + .

[0829] Step 3: Synthesis of intermediate 93-4

[0830] Method: 93-3 (3.45 g, 9.6 mmol) was dissolved in MeOH (40 mL), and then Pd / C (1.0 g, 10 wt%) was added. After the reaction system was replaced with hydrogen, the reaction was stirred at room temperature for 6 h. After the reaction was completed, the reaction was filtered through diatomite, and the filtrate was concentrated under reduced pressure to obtain colorless oily liquid 93-4 (1.9 g, yield 88%).

[0831] MS (ESI, m / z) 225 [M+H] + .

[0832] Step 4: Synthesis of intermediate 93-5

[0833] Method: Dissolve 93-4 (1.9 g, 8.48 mmol) in DCM (30 mL), cool to 0 °C, add BCI3(1 M in hexanes, 25.5 mL, 25.5 mmol) dropwise, continue stirring at 0 °C for 1 h. Upon completion, slowly add MeOH (5 mL) to the reaction mixture, warm to room temperature, and stir for 1 h to give a white suspension. Filter, wash with methyl tert-butyl ether, and dry under vacuum to give 93-5 (1.0 g, hydrochloride salt) as a white solid.

[0834] MS (ESI, m / z) 135 [M+H] + .

[0835] Step 6: Synthesis of BX20-11-093

[0836] Method: Dissolve C2’epiAmB (100 mg, crude, HPLC purity ~50%, ~0.05 mmol) in DMAc (5 mL), add 93-5 (51 mg, hydrochloride salt, ~0.3 mmol), adjust the pH of the reaction system to 9-10 with NMM, add PyAOP (104 mg, 0.2 mmol), and stir the reaction at 35 °C for 1 h. Upon completion, filter the reaction mixture and purify by preparative chromatography (90:10 to 60:40, aq. HCOOH (1‰) / MeCN). Lyophilize to give BX20-11-093 (12 mg, 23% yield) as a yellow solid powder.

[0837] MS (ESI, m / z) 1041 [M+H] + .

[0838] 1H NMR (600 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 = 6.0 Hz, 3H), 1.34 (d, J = 6.0 Hz, 3H), 1.38-1.52 (m, 5H), 1.56-1.68 (m, 3H), 1.76-1.91 (m, 4H), 1.95-2.01 (m, 1H), 2.21 (dd, J = 12.6 Hz, 4.8 Hz, 1H), 2.27-2.30 (m, 1H), 2.34-2.42 (m, 2H), 2.45-2.54 (m, 1H), 3.02 (t, J = 5.4 Hz, 2H), 3.18 (t, J = 10.2 Hz, 1H), 3.27-3.32 (m, 3H), 3.47-3.50 (m, 1H), 3.65-3.68 (m, 1H), 3.74-3.86 (m, 4H), 4.31-4.35 (m, 1H), 4.52-4.57 (m, 2H), 4.62 (br. s, 1H), 4.78 (d, J = 7.2 Hz, 1H), 4.85 (t, J = 9.6 Hz, 1H), 5.43 (dd, J = 14.4 Hz, 10.2 Hz, 1H), 5.54-5.56 (m, 1H), 6.20-6.60 (m, 14H).

[0839] Example 38 BX20-11-094

[0840] Step 1: Synthesis of intermediate 94-3

[0841] The synthetic route is shown in the following formula:

[0842] Method: CDI (1.44 g, 8.9 mmol) was dissolved in DMF (15 mL), replaced with nitrogen, and cooled to -10 °C. Benzyl carbazate (1.34 g, 8.1 mmol) in DMF (10 mL) was added dropwise slowly. After the addition was completed, the mixture was stirred at -10 °C for 0.5 h to obtain a DMF solution of 94-2. (3-Aminooxetan-3-yl)methanol (1.0 g, 9.7 mmol) was dissolved in DMF (10 mL) and added dropwise to the above DMF solution of 94-2. After the addition was completed, the mixture was stirred at 35 °C for 16 h. After the reaction was completed, water and EA were added and extracted 3 times. The organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 5:1) to obtain yellow oil 94-3 (1.26 g, yield 52%).

[0843] MS (ESI, m / z) 296 [M+H] + .

[0844] Step 2: Synthesis of intermediate 94-4

[0845] Method: 94-3 (1.26 g, 4.27 mmol) was dissolved in MeOH (20 mL), Pd / C (10%, 315 mg) was added, the reaction system was replaced by hydrogen and stirred at room temperature for 1 hour. After the reaction was completed, it was filtered and concentrated under reduced pressure to obtain light yellow oily liquid 94-4 (460 mg, yield 67%).

[0846] MS (ESI, m / z) 162 [M+H] + .

[0847] Step 3: Synthesis of BX20-11-094

[0848] The synthetic route is shown in the following formula:

[0849] Method: C2’epiAmB (100 mg, crude, HPLC purity about 50%, about 0.05 mmol) was dissolved in DMAc (5 mL), 94-4 (48 mg, 0.3 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 filtered and purified by preparative chromatography (90:10 to 60:40, aq. HCOOH (1 ‰) / MeCN), and then freeze-dried to obtain yellow solid powder BX20-11-094 (6 mg, yield 11%).

[0850] MS (ESI, m / z) 1068 [M+H] + .

[0851] 1H NMR (600 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), 1.39-1.54 (m, 5H), 1.60-1.71 (m, 3H), 1.77-1.61 (m, 1H), 1.88-1.94 (m, 3H), 1.98-2.04 (m, 1H), 2.23-2.31 (m, 2H), 2.35-2.44 (m, 2H), 2.48-2.52 (m, 1H), 3.21 (t, J = 10.2 Hz, 1H), 3.29-3.35 (m, 3H), 3.51-3.59 (m, 2H), 3.78 (d, J = 10.8 Hz, 1H), 3.85-3.89 (m, 1H), 4.01 (s, 2H), 4.33-4.37 (m, 1H), 4.53-4.61 (m, 3H), 4.64-4.71 (m, 3H), 4.83-4.89 (m, 3H), 5.44 (dd, J = 14.4 Hz, 10.2 Hz, 1H), 5.55-5.58 (m, 1H), 6.22-6.62 (m, 14H).

[0852] Example 39 BX20-11-095

[0853] Step 1: Synthesis of intermediate 95-2:

[0854] Method: Methyl 1-hydroxycyclopropanecarboxylate (6.23 g, 53.66 mmol) was dissolved in DMF (60 mL), and imidazole (9.49 g, 139.52 mmol) and TBSCl (11.0 g, 72.98 mmol) were added. The reaction was stirred at 35 °C for 16 h. After the reaction was completed, EA and water were added and extracted 3 times, and the organic phase was combined and washed with concentrated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 100:1 to 30:1) to obtain colorless oily liquid 95-2 (12.0 g, yield 97%).

[0855] MS (ESI, m / z) 231 [M+H] + .

[0856] Step 2: Synthesis of intermediate 95-3:

[0857] Method: Dissolve 95-2 (12 g, 52.1 mmol) in toluene (120 mL), cool to -78 °C, add DIBAL-H (1 M in toluene, 115 mL, 115 mmol) dropwise, stir the reaction at -78 °C for 2 h. Upon completion, quench the reaction by slow dropwise addition of MeOH (45 mL), warm to room temperature and stir overnight. Filter off the white solid and concentrate the filtrate directly under reduced pressure to give 95-3 as a colorless oil (7.0 g, 66% yield).

[0858] MS (ESI, m / z) 203 [M+H] + .

[0859] Step 3: Synthesis of intermediate 95-5:

[0860] Method: Dissolve CDI (2.53 g, 15.6 mmol) in DCM (40 mL), add 95-3 (3.0 g, 14.8 mmol), stir at room temperature for 1 h to give a DCM solution of 95-4. Cool the reaction in an ice water bath, add N2H4-H2O (1.86 g, 29.7 mmol, 80 wt% in H2O) slowly dropwise. Warm to room temperature and stir for 1 h. Upon completion, concentrate under reduced pressure and purify by column chromatography (PE:EA = 3:1 to 1:2) to give 95-5 as a colorless oil (3.4 g, 88% yield).

[0861] MS (ESI, m / z) 261 [M+H] + .

[0862] Step 4: Synthesis of intermediate 95-6:

[0863] Method: Dissolve 95-5 (3.4 g, 13 mmol) in DCM (30 mL), add HCl / 1,4-dioxane (4 M, 32 mL, 128 mmol) dropwise, stir the reaction at room temperature for 1 h. Upon completion, concentrate under reduced pressure to give 95-6 as a white solid (2.3 g, hydrochloride salt).

[0864] MS (ESI, m / z) 147 [M+H] + .

[0865] Step 5: Synthesis of BX20-11-095:

[0866] Method: C2’epiAmB (100 mg, crude, HPLC purity about 50%, about 0.05 mmol) was dissolved in DMAc (5 mL), 95-6 (104 mg, 0.6 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 35 °C for 1 hour. After the reaction was completed, the reaction solution was filtered and purified by preparative chromatography (90:10 to 58:42, aq. HCOOH (1 ‰) / MeCN), and then freeze-dried to obtain a yellow solid powder BX20-11-095 (10 mg, yield 19%).

[0867] MS (ESI, m / z) 1053 [M+H] + .

[0868] 1 H NMR (600 MHz, CD3OD:Pyridine-d5 = 1:1) δ 0.69-0.75 (m, 2H), 0.80-0.82 (m, 2H), 1.11 (d, J = 7.2 Hz, 3H), 1.19 (d, J = 6.4 Hz, 3H), 1.29 (d, J = 6.4 Hz, 3H), 1.35 (d, J = 6.0 Hz, 3H), 1.38-1.41 (m, 1H), 1.45-1.53 (m, 3H), 1.57-1.69 (m, 4H), 1.77-1.84 (m, 2H), 1.88-1.92 (m, 2H), 1.98-2.03 (m, 1H), 2.22 (dd, J = 11.4 Hz, 4.8 Hz, 1H), 2.28-2.36 (m, 2H), 2.38-2.43 (m, 1H), 2.47-2.51 (m, 1H), 2.77-2.84 (m, 1H), 3.17 (t, J = 10.2 Hz, 1H), 3.26-3.33 (m, 3H), 3.50 (t, J = 9.6 Hz, 1H), 3.71-3.77 (m, 2H), 3.86 (t, J = 10.2 Hz, 1H), 4.23 (d, J = 12.0 Hz, 1H), 4.32-4.36 (m, 1H), 4.45 (d, J = 12.0 Hz, 1H), 4.53-4.61 (m, 2H), 4.64-4.66 (m, 1H), 4.80 (d, J = 7.8 Hz, 1H), 4.88 (t, J = 9.6 Hz, 1H), 5.43 (dd, J = 15.0 Hz, 10.2 Hz, 1H), 5.55-5.57 (m, 1H), 6.22-6.65 (m, 14H).

[0869] Example 40 BX20-11-096

[0870] Step 1 : Synthesis of intermediate 96-3

[0871] Method: CDI (2.68 g, 16.5 mmol) was dissolved in DCM (20 mL), ethane-d4-1,2-diol (CAS: 2219-51-4, 1.0 g, 15.15 mmol) was added, and the mixture was stirred at room temperature for 1 h to give a DCM solution of 96-2. Hydrazine hydrate (1.12 g, 18 mmol, 80 wt%) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 1 h. After the reaction was completed, the mixture was directly concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 20:1 to 8:1) to give white solid 96-3 (630 mg, yield 33%).

[0872] MS (ESI, m / z) 125 [M+H] + .

[0873] Step 2: Synthesis of BX20-11-096

[0874] Method: C2’epiAmB (100 mg, crude, HPLC purity about 50%, about 0.05 mmol) was dissolved in DMAc (5 mL), 96-3 (50 mg, 0.4 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 mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was filtered and purified by preparative chromatography (90:10 to 58:42, aq. HCOOH (1‰) / MeCN). After lyophilization, yellow solid powder BX20-11-096 (6 mg, yield 11%) was obtained.

[0875] MS (ESI, m / z) 1031 [M+H] + .

[0876] 1H NMR (600 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), 1.37 (d, J = 6.0 Hz, 3H), 1.41-1.52 (m, 4H), 1.59-1.71 (m, 3H), 1.77-1.86 (m, 2H), 1.89-1.94 (m, 2H), 2.00-2.05 (m, 1H), 2.22-2.24 (m, 1H), 2.29-2.31 (m, 1H), 2.34-2.44 (m, 2H), 2.48-2.52 (m, 1H), 2.82-2.85 (m, 1H), 3.21-3.35 (m, 3H), 3.52-3.55 (m, 1H), 3.70-3.73 (m, 1H), 3.78 (d, J = 10.8 Hz, 1H), 3.87 (t, J = 10.2 Hz, 1H), 4.33-4.37 (m, 1H), 4.55-4.66 (m, 3H), 4.82 (d, J = 7.8 Hz, 1H), 4.90 (t, J = 10.2 Hz, 1H), 5.44 (dd, J = 14.4 Hz, 10.2 Hz, 1H), 5.56-5.59 (m, 1H), 6.22-6.63 (m, 14H).

[0877] Example 41 BX20-11-097

[0878] Step 1: Synthesis of intermediate 97-2:

[0879] Method: Dissolve 1-amino-3,3-diethoxypropane (4.4 g, 30 mmol) in 1,4-dioxane (100 mL), add water (100 mL), K2CO3(5.0 g, 41 mmol) and Fmoc-Cl (9.3 g, 41 mmol), stir the reaction at room temperature for 1 hour. After the reaction is completed, remove 1,4-dioxane under reduced pressure, extract with EA for 3 times, wash with water and concentrated brine successively, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and then purify by column chromatography (PE:EA = 20:1 to 5:1) to obtain white solid 97-2 (9.5 g, yield 85%).

[0880] MS (ESI, m / z) 370 [M+H] + .

[0881] Step 2: Synthesis of intermediate 97-3:

[0882] Method: Dissolve 97-2 (9.5 g, 25.7 mmol) in THF (100 mL), add hydrochloric acid (10%, 45 mL) under ice water bath, stir the reaction solution under ice water bath for 1 hour. After the reaction is completed, quench the reaction with saturated NaHCO3solution, extract with EA, wash with brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography (PE:EA = 1:1) to obtain white solid 97-3 (4.1 g, yield 54%).

[0883] MS (ESI, m / z) 296 [M+H] + .

[0884] Step 3: Synthesis of intermediate 97-4:

[0885] Method: Dissolve BX20-11-052 (120 mg, crude) in DMF (5 mL), add 97-3 (177 mg, 0.6 mmol), NaBH3CN (38 mg, 0.6 mmol) and concentrated hydrochloric acid (2 drops), stir the reaction solution at room temperature for 48 hours. LCMS shows about 30% product formation (385 nm), add the reaction solution dropwise to vigorously stirred ether (200 mL), centrifuge (3000 rpm, 5 min) to obtain yellow solid 97-4 (110 mg, crude).

[0886] MS (ESI, m / z) 1585 [M+H] + .

[0887] Step 4: Synthesis of BX20-11-097

[0888] Method: Dissolve 97-4 (110 mg, crude) in DMF (3 mL), add piperidine (200 mg, 2.35 mmol), stir the reaction solution at room temperature for 30 minutes. After the reaction is completed, filter the reaction solution and purify by preparative chromatography (90:10 to 65:35, aq. HCOOH (1‰) / MeCN), and freeze-dry to obtain yellow solid powder BX20-11-097 (3 mg).

[0889] MS (ESI, m / z) 1141 [M+H] + .

[0890] Example 42 BX20-11-100

[0891] Step 1: Synthesis of intermediate 100-3

[0892] Method: Dissolve CDI (5.35 g, 33 mmol) in ACN (40 mL), cool to 0 °C, slowly drop in tert-butyl hydrazinecarboxylate (3.96 g, 30 mmol) in ACN (10 mL), continue stirring at 0 °C for 1 h to get 100-2 in ACN. Keep at 0 °C, add 2-dimethylaminoethylamine (3.17 g, 36 mmol), stir at room temperature for 16 h. After reaction, concentrate under reduced pressure, then purify by column chromatography (EA:MeOH = 10:1 to 5:1) to get yellow oily liquid 100-3 (3.4 g, yield 46%).

[0893] MS (ESI, m / z) 247 [M+H] + .

[0894] Step 2: Synthesis of intermediate 100-4

[0895] Method: Dissolve 100-3 (1.7 g, 6.91 mmol) in ACN (20 mL), add Mel (2.94 g, 20.73 mmol), after adding, stir at 70 °C for 6 h. After reaction, directly concentrate under reduced pressure to get yellow solid 100-4 (1.8 g, crude).

[0896] MS (ESI, m / z) 261 [M] + .

[0897] Step 3: Synthesis of intermediate 100-5

[0898] Method: Dissolve 100-4 (1.8 g, crude, about 6.9 mmol) in DCM / MeOH (1:1, 30 mL), add HCl / 1,4-dioxane (4 M, 18 mL, 72 mmol), stir at room temperature for 1 h. After reaction, directly concentrate under reduced pressure, then wash with methyl tert-butyl ether to get brown solid 100-5 (1.2 g, hydrochloride).

[0899] MS (ESI, m / z) 161 [M] + .

[0900] Step 4: Synthesis of BX20-11-100

[0901] Method: C2’epiAmB (100 mg, crude, HPLC purity about 50%, about 0.05 mmol) was dissolved in DMAc (5 mL), 100-5 (47 mg, 0.3 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 35 °C for 1 hour. After the reaction was completed, the reaction solution was filtered and purified by preparative chromatography (90:10 to 68:32, aq. HCOOH (1 ‰) / MeCN), and then freeze-dried to obtain a yellow solid powder BX20-11-100 (12 mg, yield 22%).

[0902] MS (ESI, m / z) 1067 [M] + .

[0903] 1 H NMR (600 MHz, CD3OD:Pyridine-d5 = 1:1) δ 1.10 (d, J = 7.2 Hz, 3H), 1.18 (d, J = 6.4 Hz, 3H), 1.28 (d, J = 6.4 Hz, 3H), 1.33 (d, J = 6.0 Hz, 3H), 1.37-1.51 (m, 5H), 1.57-1.72 (m, 4H), 1.77-1.82 (m, 1H), 1.86-1.92 (m, 2H), 1.95-2.00 (m, 2H), 2.18-2.31 (m, 3H), 2.34-2.42 (m, 2H), 2.45-2.50 (m, 1H), 2.78-2.83 (m, 1H), 3.12-3.16 (m, 1H), 3.25-3.32 (m, 12H), 3.51-3.60 (m, 3H), 3.73-3.78 (m, 2H), 3.84 (t, J = 10.2 Hz, 1H), 4.31-4.34 (m, 1H), 4.47-4.57 (m, 4H), 4.80 (t, J = 9.6 Hz, 1H), 5.43 (dd, J = 14.4 Hz, 10.0 Hz, 1H), 5.51-5.55 (m, 1H), 6.22-6.59 (m, 14H).

[0904] Example 43 BX20-11-101

[0905] Synthesis of BX20-11-101:

[0906] Step 1: Synthesis of intermediate 15-2

[0907] Method: 15-1 (5.0 g, 16.0 mmol) was dissolved in DMF (60 mL), and then 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 h. After the reaction, the 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 give 15-2 (3.5 g, crude) as a light yellow solid.

[0908] MS (ESI, m / z) 409 [M+H] + .

[0909] Step 2: Synthesis of intermediate 15-3

[0910] Method: Compound C2'epiAmB (150 mg, about 0.075 mmol) and 15-2 (185 mg, 0.45 mmol) were dissolved in DMAc (5 mL), and then pyridine (103 mg, 1.3 mmol) was added dropwise. The reaction was stirred at room temperature for 16 h. After the reaction, the reaction solution was added dropwise to methyl tert-butyl ether (200 mL), and centrifuged (3000 rpm, 5 min) to give 15-3 (110 mg, crude) as a yellow solid powder.

[0911] MS (ESI, m / z) 1218 [M+H] +

[0912] Step 3: Synthesis of BX20-11-101

[0913] Method: 15-3 (110 mg, crude) was dissolved in DMAc (5 mL), and then intermediate 52-4 (63 mg, hydrochloride, about 0.4 mmol) was added. NMM was added to adjust the pH of the reaction system to 9-10, and then PyAOP (104 mg, 0.2 mmol) was added. The reaction was stirred at 35 °C for 1 h. After the reaction, piperidine (170 mg, 2 mmol) was added, and the mixture was stirred at room temperature for 0.5 h. The reaction solution was directly purified by preparative chromatography (90:10 to 60:40, aq. HCOOH (1 ‰) / MeCN), and then lyophilized to give BX20-11-101 (15 mg, 27% yield) as a yellow solid powder.

[0914] MS (ESI, m / z) 1098 [M+H] + .

[0915] 1H NMR (600 MHz, CD3OD:Pyridine-d5 = 2:1) δ 1.06 (d, J = 7.2 Hz, 3H), 1.16 (d, J = 6.4 Hz, 3H), 1.24 (d, J = 6.4 Hz, 3H), 1.30 (d, J = 6.0 Hz, 3H), 1.34-1.38 (m, 2H), 1.41-1.47 (m, 3H), 1.52-1.62 (m, 3H), 1.74-1.90 (m, 5H), 2.12-2.15 (m, 1H), 2.20-2.26 (m, 2H), 2.33-2.37 (m, 1H), 2.42-2.47 (m, 1H), 2.63-2.70 (m, 3H), 3.12-3.16 (m, 1H), 3.23-3.27 (m, 2H), 3.53-3.59 (m, 1H), 3.69-3.80 (m, 6H), 3.97-4.01 (m, 1H), 4.21-4.35 (m, 3H), 4.45-4.54 (m, 3H), 4.64-4.73 (m, 2H), 5.38-5.42 (m, 1H), 5.48-5.50 (m, 1H), 6.18-6.56 (m, 14H).

[0916] Comparative Example 1:

[0917] Comparative Example 1 was synthesized according to the synthetic method of compound 1 in patent CN116323632A.

[0918] 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).

[0919] Biological test evaluation

[0920] The present application is further described below in connection with test examples

[0921] Test Example 1 In vitro antifungal activity of compounds of the present application

[0922] 1. Purpose of the experiment

[0923] The compounds of the present application were tested for their in vitro fungistatic concentration.

[0924] 2. Materials of the experiment

[0925] 2.1. The compounds of the present application and the reference compounds were self-made.

[0926] 2.2. The strains to be tested were provided by Shanghai Pharmaron.

[0927] 3. Test method

[0928] The method for detecting the minimum inhibitory concentration (MIC) was performed according to CLSI M27, CLSI M38 and CLSI M60.

[0929] 3.1. Preparation of test compounds

[0930] 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.

[0931] 3.2. Preparation of inoculum

[0932] 3.2.1. Preparation of inoculum for yeast-like fungi

[0933] 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 up 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.

[0934] 3.2.2. Preparation of inoculum for filamentous fungi (non-dermatophytic molds)

[0935] 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.

[0936] 3.3. MIC reading

[0937] Yeast-like fungi: The minimum compound concentration (MIC) for 100% or ≥50% inhibition was read by naked eye after the test plate was incubated at 35o±2°C for 24h.

[0938] Filamentous fungi (non-dermatophytic molds): The minimum compound concentration (MIC) for 100%, ≥80% or ≥50% inhibition was read by naked eye after the test plate was incubated at 35±2°C for 48h.

[0939] 4. Test results

[0940] The results are shown in Table 1 below:

[0941] Table 1. Minimum inhibitory concentration (MIC, ug / mL) of the compounds of the present application

[0942] Conclusion: The results in Table 1 show that the compounds of the present application have broad-spectrum antifungal activity as amphotericin B and the same as the comparative example 1, and have obvious inhibitory effect on the 7 fungi (C. albicans, A. fumigatus, A. flavus, C. krusei, C. glabrata, C. parapsilosis, C. gattii) in the above table. The antifungal activity of the compounds of the present application on most fungi is not much different from amphotericin B or comparative example 1, and is at the same level; among them, examples 10, 11, 21 and 22 have better and more balanced antifungal activity on each fungus, and the antifungal activity is equivalent or stronger than that of comparative example 1.

[0943] Test Example 2 Test the in vitro cell tolerance of the compounds of the present application

[0944] 1. Purpose of the test

[0945] The tolerance of the compounds of the present application to different cell lines was studied.

[0946] 2. Test method

[0947] Hemolysis test: Take sterile blood (anticoagulated with sodium heparin, Guoying Kangsheng) into a 1.5 mL tube, mix gently upside down, centrifuge at 4°C, 1000 rpm for 5 minutes. Discard the supernatant, add PBS for washing, centrifuge at 4°C, 1000 rpm for 5 minutes. Repeat step 2 twice. Take an appropriate amount of washed red blood cells and dilute with PBS. Dilute the compounds to twice the final concentration (the final concentration of the compounds is 500, 166.67, 55.56, 18.52, 6.17, 2.06, 0.69, 0 μM, respectively). PBS and 0.1% Tritone X-100 were used as 0% and 100% controls, respectively. Add 100 μL of compound to the 96-well culture plate. Mix 100 μL of 8% red blood cells with 100 μL of compound, add to the 96-well culture plate and incubate at 37°C for 1 hour. Centrifuge the mixture at 4°C, 1500 rpm for 5 minutes, and take the supernatant to a new culture plate. Measure the absorbance by OD540 (enzyme marker, BMG).

[0948] Nephrotoxicity Test: Primary human renal proximal tubular epithelial cells (RPTEC, PCS-400-010, ATCC). Cells were cultured in Renal Epithelial Cell Growth Medium-2 (PCS-400-040, ATCC) and Renal Epithelial Cell Basal Medium-2 (PCS-400-030, ATCC) and tested for cytotoxicity in 384-well plates in duplicate. DMSO and media were used as negative and positive controls. Inoculum density was maintained at 6000 cells / well / 40 pL during the experiment. All test compound stock solutions were prepared in DMSO and the DMSO concentration in the final culture was maintained at 0.5%. After addition of compounds to the culture, they were incubated at 5% CO2 and 37 °C for 24 hours, 20 pL of Cell Titer Glo solution was added per well, centrifuged at 1000 rpm / min for 1 min. Then, incubation was continued for 10 min and luminescence intensity was measured using EnSight (PerkinElmer).

[0949] Neurotoxicity: SH-SY5Y (CRL-2266, ATCC; human neuroblastoma). Cells were grown in DMEM medium (with 10% inactivated fetal bovine serum (FBS, A5669701, Gibco), IX GLUTAMAX I (35050061, Invitrogen) and 1% penicillin-streptomycin) and tested for cytotoxicity in 384-well plates in duplicate. DMSO and media were used as negative and positive controls. Inoculum density was maintained at 104 cells / well / 40 pL during the experiment. All test compound stock solutions were prepared in DMSO and the DMSO concentration in the final culture was maintained at 0.1%. After addition of compounds to the culture, they were incubated at 5% CO2 and 37 °C for 24 hours, 20 pL of Cell Titer Glo solution (G7573, Promega) was added per well, centrifuged at 1000 rpm / min for 1 min. Then, incubation was continued for 10 min. Luminescence intensity was measured using EnSight (PerkinElmer).

[0950] Hepatotoxicity: Hep-G2 (HB-8065, ATCC; human hepatocytes). Cells were grown in complete MEM medium (containing 1% double antibiotics, 10% FBS) and tested for cytotoxicity in 384-well plates in duplicate. DMSO and medium were used as negative and positive controls. The seeding density was maintained at 6000 cells / well / 30 μL during the experiment. All test compound stock solutions were prepared in DMSO, and the DMSO concentration in the final culture was maintained at 0.5%. After the compound was added to the culture, it was incubated at 5% CO2 and 37 °C for 24 hours, 30 μL Cell Titer Glo solution (Vazyme, DD1101-03) was added per well, placed on a rapid shaker for 2 minutes, incubated at room temperature in the dark for 10 minutes, and the luminescence intensity was determined using EnSight (PerkinElmer).

[0951] Cardiotoxicity: H9C2 (CRL-1446, ATCC; rat cardiomyocytes). Cells were grown in complete DMEM medium and tested for cytotoxicity in 384-well plates in duplicate. DMSO and medium were used as negative and positive controls. The seeding density was maintained at 3000 cells / well / 40 μL during the experiment. All test compound stock solutions were prepared in DMSO, and the DMSO concentration in the final culture was maintained at 0.5%. After the compound was added to the culture, it was incubated at 5% CO2 and 37 °C for 24 hours, 20 μL Cell Titer Glo solution was added per well, placed on a rapid shaker for 2 minutes, incubated at room temperature in the dark for 10 minutes, and the luminescence intensity was determined using EnSight (PerkinElmer).

[0952] Hematotoxicity: K562 (CCL-243, ATCC; human lymphoblastoid cells). Cells were grown in complete IMDM medium and tested for cytotoxicity in 384-well plates in duplicate. DMSO and medium were used as negative and positive controls. The seeding density was maintained at 2500 cells / well / 40 μL during the experiment. All test compound stock solutions were prepared in DMSO, and the DMSO concentration in the final culture was maintained at 0.5%. After the compound was added to the culture, it was incubated at 5% CO2 and 37 °C for 24 hours, 20 μL Cell Titer Glo solution was added per well, placed on a rapid shaker for 2 minutes, incubated at room temperature in the dark for 10 minutes, and the luminescence intensity was determined using EnSight (PerkinElmer).

[0953] The final concentration of the compound in the above tests, except for the hemolysis test, was: 50.00, 16.67, 5.56, 1.85, 0.62, 0.21, 0.07, 0.02, 0.008, 0 μM.

[0954] Data processing: Data were analyzed using a four-parameter regression calculation method in a non-linear curve fitting mode to calculate the IC50 of the compounds.

[0955] 3. Test results

[0956] Table 2, results of cell tolerance investigation

[0957] Conclusion: Compared with amphotericin B, the in vitro hemolytic activity of the compound of the present application is greatly reduced, the IC50 value is greater than 500 μM. It shows that the compound of the present application has lower hemolytic toxicity than amphotericin B, and the safety is greatly improved. The inhibitory activity of the compound of the present application on other cells is low, and the tolerance is good, which is significantly better than amphotericin B, indicating that the compound of the present application has better safety. 50

[0958] Test Example 3: Test the in vitro stability of the compound of the present application

[0959] Liver microsomal stability test:

[0960] 1) Two independent experiments were performed, and the specific operation was as follows: a) Add cofactor (NADPH): add 25 μL of 10 mM NADPH to the reaction system. The final concentrations of microsomes and NADPH are 0.5 mg / mL and 1 mM, respectively. b) Without cofactor (NADPH): add 25 μL of 100 mM phosphate buffer to the reaction system. The final concentration of microsomes is 0.5 mg / mL. The mixture is preheated at 37°C for 10 minutes.

[0961] 2) The reaction is started by adding 2.5 μL of 100 μM control compound or test compound solution. Verapamil is used as a positive control in this study. The final concentration of the test compound or control compound is 1 μM. The incubation solution is incubated in a 37°C water bath.

[0962] 3) At 0.5, 5, 15, 30 and 60 minutes, 30 μL aliquots are taken from the reaction solution. The reaction is terminated by adding 5 volumes of cold acetonitrile containing internal standards (200 nM labetalol, 100 nM ketoprofen and 100 nM tolbutamide). The samples are centrifuged at 3220 g for 40 minutes. 100 μL of supernatant is mixed with 100 μL of ultrapure water, and then used for LC-MS / MS analysis.

[0963] Plasma stability test:

[0964] ​1) Preparation of standard solutions: Prepare 1 mM test compound working solution in DMSO. Prepare 1 mM prilocaine working solution in acetonitrile. Prepare 1 mM moricizine working solution in DMSO. In this assay, prilocaine is used as the positive control for human plasma, while moricizine is used as the positive control for rat plasma.

[0965] 2) Plasma stability procedure:

[0966] a. Add 398 μL of plasma to the plate and pre-warm the plate to 37°C for 15 minutes.

[0967] b. After the pre-incubation is complete, add 2 μL of 1 mM test compound and 2 μL of 1 mM control compound to the 398 μL of plasma to achieve a final concentration of 5 μM, and adjust the concentration of the control compound to 5 μM. The final concentration of organic solvent is 0.5%. The experiment will be run in duplicate.

[0968] c. Incubate the reaction samples at 37°C.

[0969] d. At 0, 15, 30, 60, and 120 minutes, remove 50 μL of the reaction sample. Terminate the reaction by adding 450 μL of cold acetonitrile containing 0.1% formic acid containing an internal standard.

[0970] e. All samples are vortexed for 10 minutes and then centrifuged at 3220 g for 30 minutes to pellet the proteins. 200 μL of supernatant is transferred to a new plate. The supernatant is diluted with acetonitrile containing 0.1% formic acid according to the LC-MS / MS signal response and peak shape.

[0971] 3) Sample analysis: The samples are analyzed by LC-MS / MS to determine the concentration of the compound.

[0972] CYP inhibition test:

[0973] 1) Preparation of stock solutions:

[0974] Prepare stock solutions according to the following table:

[0975] 2) Incubations are performed in 96-well deep well plates. The following volumes are added to each well: 169 μL of stock solution and 1 μL of compound working solution or solvent (DMSO). Place the incubation plate in a water bath and pre-warm at 37°C for 5 minutes. Add 10 μL of substrate to the incubation plate, mix the incubation mixture using a vortex mixer for 15 seconds, and then add 20 μL of 10 mM NADPH solution to achieve a final concentration of 1 mM to start the reaction. The experiment is run in duplicate.

[0976] 3) The reaction was terminated by adding 1.5 volumes (300 μL) of cold acetonitrile (containing 3% formic acid and 200 nM of tolbutamide, 200 nM of alprazolam and 200 nM of labetalol). The plate was centrifuged at 3,220 g for 40 minutes. Then, 150 μL of supernatant was transferred to a new plate. The supernatant can be diluted with 150 μL of pure water. After mixing well, the sample was analyzed using LC-MS / MS.

[0977] Table 3 Plasma stability of compounds

[0978] Conclusion: The compounds of the present application have good stability in rat and human plasma.

[0979] Table 4 In vitro liver microsomal stability of compounds

[0980] Conclusion: The compounds of the present application have good stability in human liver microsomes.

[0981] Table 5 Inhibition rate of compounds on CYP enzymes at 10 μM

[0982] Conclusion: The compounds of the present application have low inhibition activity on each subtype of CYP enzymes, and the risk of drug interaction is low.

[0983] Test Example 4 Test the rat PK characteristics of the compounds of the present application

[0984] 1. Purpose of the test

[0985] The pharmacokinetic behavior of the compounds of the present application in rats after tail vein injection was studied using SD rats as test animals.

[0986] 2. Test method

[0987] 2.1 Test drug

[0988] The compounds of the present application and the reference compounds were self-made.

[0989] 2.2 Test animals

[0990] Male SPF SD rats (weighing 200-300 g), 3 per compound, were obtained from Vantian Li Hua, production license number SCXK (Zhejiang) 2024-0001.

[0991] 2.3 Preparation of the test drug

[0992] 5% glucose solution was used to prepare the drug at a concentration of 0.2 mg / mL.

[0993] 2.4 Dosing

[0994] Rats were adapted for 3-4 days, and then injected with 1 mg / kg via the tail vein, with a dose volume of 5 mL / kg.

[0995] Blood samples were collected from the rats before administration (0 h) and at 5 min, 15 min, 30 min, 1, 2, 4, 6, 8, and 24 h after administration, via the carotid vein, with a blood volume of about 0.2 mL, and placed in labeled EDTA-K2 anticoagulant test tubes. After blood collection, the blood collection tube was gently inverted completely 3 times to mix with the anticoagulant, and immediately placed in an ice water bath at 4°C, centrifuged at 4000g for 5 min. After the centrifugation operation was completed, the plasma samples from the same sampling point were equally combined among 3 animals and promptly divided into labeled EP tubes, and stored in a -80°C refrigerator until determination.

[0996] 2.5 Sample detection

[0997] In this experiment, the LC-MS / MS method was used to determine the compound concentration in the combined plasma. The WinNonlin (Phoenix TM , version 8.3) software was used to calculate the pharmacokinetic parameters.

[0998] 3. Test results and analysis

[0999] The results of the rat pharmacokinetic experiment are shown in the following table.

[1000] Table 6 Rat pharmacokinetic experiment results

[1001] Conclusion: From the above data, it can be seen that, under the same dose, the compound of the present application prolongs the half-life and prolongs the drug action time.

[1002] Test Example 5: Test the efficacy of the compound of the present application on the fungal infection model of immunocompromised mice

[1003] 1. Purpose of the test

[1004] The effectiveness of multiple doses of the compound of the present application on the Candida albicans infection model of immunocompromised BALB / c mice was studied.

[1005] 2. Test method

[1006] 2.1 Test drug

[1007] The compounds of the present application and the reference compounds: self-made.

[1008] 2.2 Test animals

[1009] BALB / c mice, SPF level, 6 in each test group, half male and half female, body weight 10-12 g, purchased from Hunan Slike Jingda Experimental Animal Co., Ltd., Experimental Animal Production License No.: SCXK(Xiang)2021-0002. Raising in the barrier environment animal laboratory C area (BSL-II, laboratory record number: SYS430181440001), experimental animal use license number: SYXK(Xiang)2020-0015.

[1010] 2.3 Strains

[1011] C. albicans, No. 17015177. Cultured and amplified in the pathogenic microorganism laboratory of the center (BSL-II, laboratory record number: SYS430181430003).

[1012] 2.4 Modeling, grouping, administration and detection

[1013] SPF level BALB / c mice that passed quarantine were selected, half male and half female, intraperitoneally injected with cyclophosphamide, once every other day, for 3 injections, and the next day after the last injection, intraperitoneally injected with C. albicans suspension (1x10 8 CFU / mL) 0.1 mL per mouse, to induce a low immune candidiasis model. 24 hours after modeling, the animals in each administration group were given the corresponding concentration of compound by tail vein injection at 20 mL / kg, once a day, for 7 consecutive days. The normal control group, the cyclophosphamide control group, and the model control group were given the same volume of 5% glucose injection by tail vein injection. The next day after the last administration, the brain, spleen, lung, liver, and kidney (left) tissues of the animals in each group were collected, ground into homogenate, cultured for fungi, and counted.

[1014] 3. Test results and analysis

[1015] Table 7. Effect of the compound of the present application on the low immune mouse Candida albicans infection model Note: compared with the cyclophosphamide control group + P≤0.05, ++ P≤0.01; compared with the model control group * P≤0.05, ** P≤0.01.

[1016] Table 8. Organ bacterial detection rate Note: The detection rate is the number of animals with detected colonies / the total number of animals tested.

[1017] As shown in Table 7, compared with the cyclophosphamide control group, the colony load in the brain, liver, spleen, lung and kidney tissues of the model control group of mice was significantly increased (P≤0.01); compared with the model control group, the colony load in the liver, spleen, lung and kidney tissues of the mice in the compound of the application and amphotericin B groups was significantly reduced (P≤0.05 or P≤0.01).

[1018] Conclusion: From the data in Table 7, it can be seen that the in vivo antifungal activity of Examples 10, 11, 21 and 22 in the compound of the application on Candida albicans infected mice is equivalent to that of amphotericin B.

[1019] Test Example 6: Test the inhibition effect of the compound of the application on the cardiotoxic hERG channel

[1020] 1. Purpose of the test

[1021] The hand patch clamp technique is used to evaluate whether the test compound has potential inhibition effect on the voltage-gated potassium ion channel hERG.

[1022] 2. Cell lines and cell culture

[1023] The HEK 293 cell line stably expressing hERG ion channel (Invitrogen, catalog number K1236). The cell strain is cultured in a culture medium containing 85% DMEM, 10% dialyzed fetal bovine serum, 0.1 mM non-essential amino acid solution, 100 U / mL penicillin-streptomycin solution, 25 mM HEPES, 5 μg / mL blasticidin and 400 μg / mL geneticin. When the cell density grows to 40%-80% of the bottom area of the culture dish, digestion is performed by trypsin, and the cells are passaged three times a week. Before the experiment, the cells are cultured in 3.5 cm culture dishes at a density of 5x105, 1 μg / mL doxycycline is added for induction for 48 hours, then the cells are digested and inoculated on glass slides for subsequent hand patch clamp experiments.

[1024] 3. Experimental procedure

[1025] 1) Place the small glass slide loaded with HEK293 cells in the culture dish in the perfusion tank of the micro-operation stage.

[1026] 2) Under the Olympus IX71 or IX73 inverted microscope, place the appropriate cells in the center of the field of view, use a x10 objective lens to find the tip of the glass electrode and place it in the center of the field of view. Then lower the electrode using the micro-manipulator, while adjusting the coarse focus screw, so that the electrode slowly approaches the cell.

[1027] 3) When close to the cell, switch to a x40 objective lens for observation, and use the micro-manipulator fine adjustment to gradually approach the surface of the cell.

[1028] 4) Apply a negative voltage to form a seal between the electrode tip and the cell membrane with a resistance higher than 1 GΩ.

[1029] 5) Compensate for the transient capacitance current C fast . Then repeat the short negative voltage pulse to break the membrane and finally form a whole cell recording mode.

[1030] 6) Compensate for the slow capacitance current Cslow, cell membrane capacitance (Cm) and input membrane resistance (Ra) respectively, with the membrane potential clamped at -60 mV.

[1031] 7) After the cell is stable, change the clamping voltage to -90 mV, set the sampling frequency to 20 kHz, and the filter frequency to 10 kHz. The leakage current detection condition is to change the clamping voltage to -80 mV and the time course is 500 ms.

[1032] 8) The hERG current test method is as follows: apply a 4.8-second depolarization command voltage to depolarize the membrane potential from -80 mV to +30 mV, and then instantaneously apply a 5.2-second repolarization voltage to reduce the membrane potential to -50 mV to remove channel inactivation, so that the hERG tail current can be observed. The peak value of the tail current is the size of the hERG current.

[1033] 9) The hERG current of the test compound is continuously recorded for 120 seconds before administration to evaluate the stability of the hERG current generated by the test cell. Only stable cells within the evaluation standard acceptance range can proceed to subsequent compound testing.

[1034] 10) Test of the inhibitory effect of the test compound on hERG current: First, the hERG current measured in the extracellular fluid containing 0.1% DMSO is taken as the detection baseline. After the hERG current remains stable for at least 5 minutes, a solution containing the test compound is perfused around the cells from low concentration to high concentration (the final concentrations are 30, 10, 3.33, 1.11 and 0.37 μM, respectively). After each perfusion, wait for about 5 minutes to allow the compound to fully act on the cell and record the hERG current synchronously. After the recorded current tends to be stable, record the last 5 hERG current values, and take their average as the final current value at a specific concentration. After testing the compound, 450 nM dofetilide is added to the same cell to completely inhibit its current as a positive control. At the same time, the positive compound dofetilide is tested synchronously before and after the test drug experiment using the same patch clamp system to ensure the reliability and sensitivity of the entire test system. The above test steps will be repeated on two separate test cells (n = 2)

[1035] 4. Data analysis

[1036] 1) After perfusion of blank solvent or compound gradient solution, the average of 5 consecutive current values was obtained as "tail current size 空白 " and "tail current size 化合物 ", respectively. The percentage of current inhibition was calculated by the following formula. Note: the peak current was extracted from the raw data using PatchMaster software.

[1037] 2) The dose-response curve was fitted by Graphpad Prism 8.0 software and the IC50 value was calculated.

[1038] 3) The standard deviation range of three groups of data is less than 15 (SD < 15)

[1039] 4) A widely accepted assessment standard for the inhibition effect of compounds on hERG channel is as follows:

[1040] 1) Low inhibition effect: IC50 > 10 μM

[1041] 2) Moderate inhibition effect: 1 μM < IC50 < 10 μM

[1042] 3) High inhibition effect: IC50 < 1 μM

[1043] 5. Test results and analysis

[1044] Table 9 Test results of compounds of the present application on cardiotoxic hERG inhibition

[1045] Conclusion: From the data in Table 9, it can be seen that the inhibition activity of compounds Example 11 and 21 on hERG is greater than 30 μM, indicating that the compounds have low cardiotoxicity.

Claims

1. An amphotericin B hydrazide derivative of the formula: ###0001### or a stereoisomer, a pharmaceutically acceptable salt, or a deuterated form thereof, wherein, The amphotericin B hydrazide derivative is represented by formula (I): R1is selected from -(CH2) n1 -OH, -CO-Y2-R2or -(CH2) n5 -Y3-C(=X)-R3; optionally, said -CH2- is replaced by a substituent selected from the group consisting of D, F, Cl, Br, I, OH or C 1-6 substituted by a substituent selected from the group consisting of D, F, Cl, Br, I, OH or C R2is selected from C 1-10 alkyl, C 1-10 alkoxy, NH2, OH, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, -(CH2) n1 -OH, -(CH2) n1 -SH, -(CH2) n1 -NR 23 R 24 , -(CH2) n1 -N + R 23 R 24 R 25 Z - , -(CH2) n4 -3 to 10 membered cycloalkyl, -(CH2) n4 -3 to 10 membered heterocycloalkyl or -(CH2) n6 -O-(C=O)-O-(CH2CH2-O) n8 -R 41 ; optionally, said alkyl, alkoxy, heterocycloalkyl and cycloalkyl are substituted with a substituent selected from the group consisting of D, F, Cl, Br, I, OH or C 1-6 alkyl; said -CH2- is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I, OH or C 1-6 alkyl; said heterocycloalkyl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O or S; R 23 , R 24 , and R 25 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 1-6 alkyl; R 26 is hydroxyl or amino; R3is selected from OH, NH2or C 1-10 alkyl; optionally, the alkyl is substituted with a substituent selected from D, F, Cl, Br, I or C 1-6 alkyl; optionally, the alkyl is substituted with a substituent selected from D, F, Cl, Br, I or C R4and R5are each independently selected from the group consisting of H, -(C=0)-0-(CH2) n6 -(CH2) n7 -O-(CH2CH2-O) n8 -R 41 -(CH2) n42 -R 42 -(CH2) n43 -Y4-R 43 ; said -CH2- is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I, OH or C 1-6 alkyl; each R 41 and R 43 are each independently selected from C 1-5 alkyl; optionally, said alkyl is substituted with a substituent selected from D, F, Cl, Br, I, C 1-6 alkyl, nitro, cyano, carboxyl, or hydroxyl; R 42 is hydroxyl or amino; Y1is selected from -O-, -S-, or -NH-; Y2is selected from a bond, O, S, -NH-NH-, or -NH-; Y3and Y4are each independently selected from a bond, O, S, or -NH-; X is selected from O or NH; Z is an anion; Ring A is a three- to ten-membered cycloalkyl or a three- to ten-membered heterocycloalkyl; the heterocycloalkyl contains one, two, or three heteroatoms selected from N, O, or S; optionally, the cycloalkyl or heterocycloalkyl is substituted with a substituent selected from D, F, Cl, Br, I, or C 1-5 substituted with a substituent selected from D, F, Cl, Br, I, or C each n1, n2, n3is independently a positive integer from 1 to 10; each n4, n5, n6, n7, n42, and n43is independently a positive integer from 1 to 5; each n8is independently a positive integer from 1 to 20; n11and n12are each independently a positive integer from 0 to 5.

2. The amphotericin B hydrazide derivative or stereoisomer, pharmaceutically acceptable salt, or deuterated form thereof of claim 1, wherein, The amphotericin B hydrazide derivative is represented by Formula (I): R1is selected from -(CH2) n1 -OH, -CO-Y2-R2or -(CH2) n5 -Y3-C(=X)-R3; optionally, said -CH2- is substituted with a substituent selected from the group consisting of F, Cl, Br, I, OH or C 1-6 substituted with a substituent selected from the group consisting of F, Cl, Br, I, OH or C R2is selected from C 1-10 alkyl, NH2, OH, 3- to 10-membered cycloalkyl, -(CH2) n1 -OH, -(CH2) n4 -3 to 10 membered cycloalkyl; optionally, the alkyl and cycloalkyl groups are substituted with a substituent selected from the group consisting of F, Cl, Br, I, C 1-6 alkyl, nitro, cyano, carboxyl, or hydroxyl; R3is selected from OH, NH2or C 1-10 alkyl; optionally, the alkyl is substituted with a substituent selected from F, Cl, Br, I or C 1-6 alkyl; optionally, the alkyl is substituted with a substituent selected from F, Cl, Br, I or C R4and R5are selected from H; Y1is selected from -O-, -S-, or -NH-; Y2is selected from a bond, O, S, or -NH-; Y3is selected from a bond, O, S, or -NH-; X is selected from O or NH; n1, n2, and n3are each independently a positive integer from 1 to 10; n4and n5are each independently a positive integer from 1 to 5.

3. The amphotericin B hydrazide derivative of claim 1, or a stereoisomer, a pharmaceutically acceptable salt, or a deuterated form thereof, wherein, R1is selected from -(CH2) n1 -OH, -CO-Y2-R2or -(CH2) n5 -Y3-C(=X)-R3; optionally, said -CH2- is replaced by a substituent selected from the group consisting of D, F, Cl, Br, I, OH, or C 1-3 substituted by a substituent selected from the group consisting of D, F, Cl, Br, I, OH, or C R2is selected from C 1-5 alkyl, C 1-5 alkoxy, NH2, OH, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocycloalkyl, -(CH2) n1 -OH, -(CH2) n1 -SH, -(CH2) n1 -NR 23 R 24 , -(CH2) n1 -N + R 23 R 24 R 25 Z - , -(CH2) n4 -3 to 8 membered cycloalkyl, -(CH2) n4 -3 to 8 membered heterocycloalkyl or -(CH2) n6 -O-(C=O)-O-(CH2CH2-O) n8 -R 41 ; optionally, said alkyl, alkoxy, heterocycloalkyl and cycloalkyl are substituted with a substituent selected from the group consisting of D, F, Cl, Br, I, OH or C 1-3 alkyl; said -CH2- is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I, OH or C 1-3 alkyl; said heterocycloalkyl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O or S; R 23 , R 24 , and R 25 are each independently selected from H or C 1-3 alkyl; optionally, said alkyl is substituted with a substituent selected from D, F, Cl, Br, I, or C 1-3 alkyl; R 26 is hydroxyl or amino; R3is selected from OH, NH2or C 1-5 alkyl; optionally, the alkyl is substituted with a substituent selected from D, F, Cl, Br, I or C 1-3 alkyl; optionally, the alkyl is substituted with a substituent selected from D, F, Cl, Br, I or C R4and R5are each independently selected from the group consisting of H, -(C=0)-0-(CH2) n6 -(CH2) n7 -(CH2) n8 -R 41 -(CH2) n42 -R 42 -(CH2) n43 -Y4-R 43 ; said -CH2- is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I, OH or C 1-3 alkyl; each R 41 and R 43 are each independently selected from C 1-3 alkyl; optionally, said alkyl is substituted with a substituent selected from D, F, Cl, Br, I, C 1-3 alkyl, nitro, cyano, carboxyl, or hydroxyl; R 42 is hydroxyl or amino; Y1is selected from -O-, -S-, or -NH-; Y2is selected from a bond, O, S, -NH-NH-, or -NH-; Y3and Y4are each independently selected from a bond, O, S, or -NH-; X is selected from O or NH; Z is an anion; Ring A is a three- to eight-membered cycloalkyl or a three- to eight-membered heterocycloalkyl; the heterocycloalkyl contains one, two, or three heteroatoms selected from N, O, or S; optionally, the cycloalkyl or heterocycloalkyl is substituted with a substituent selected from D, F, Cl, Br, I, or C 1-3 substituted with a substituent selected from D, F, Cl, Br, I, or C n1, n2, and n3are each independently a positive integer from 1 to 10; n4, n5, n6, n7, n42, and n43are each independently a positive integer from 1 to 5; each n8is independently a positive integer from 1 to 20; n11and n12are each independently a positive integer from 0 to 5.

4. The amphotericin B hydrazide derivative of any one of claims 1 to 3, or a stereoisomer, a pharmaceutically acceptable salt, or a deuterated form thereof, wherein, R1is selected from -CO-Y2-R2or -(CH2) n5 -Y3-C(=X)-R3; optionally, said -CH2- is replaced by a member selected from the group consisting of D, F, Cl, Br, I, or C 1-3 substituted by a member selected from the group consisting of D, F, Cl, Br, I, or C R1is selected from -CH2 n1 -OH; optionally, said -CH2- is substituted with a substituent selected from D, F, Cl, Br, I, OH or C 1-3 alkyl; and R2is selected from -H, -OH, -NH2, R2is selected from C 1-5 alkyl, C 1-5 alkoxy, NH2, OH, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocycloalkyl, -(CH2) n1 -OH, -(CH2) n1 -SH, -(CH2) n1 -NR 23 R 24 , -(CH2) n1 -N + R 23 R 24 R 25 Z - , -(CH2) n4 -3 to 8 membered cycloalkyl, -(CH2) n4 -3 to 8 membered heterocycloalkyl or -(CH2) n6 -O-(C=O)-O-(CH2CH2-O) n8 -R 41 ; optionally, said alkyl, alkoxy, heterocycloalkyl and cycloalkyl are substituted with a substituent selected from the group consisting of D, F, Cl, Br, I, C 1-3 alkyl, nitro, cyano, amino, carboxyl or hydroxyl; said heterocycloalkyl contains 1, 2 or 3 heteroatoms selected from N, O or S; R3is selected from OH, NH2or C 1-5 alkyl; optionally, the alkyl is substituted with a substituent selected from D, F, Cl, Br, I or C 1-3 alkyl; optionally, the alkyl is substituted with a substituent selected from D, F, Cl, Br, I or C R 23 , R 24 , and R 25 are each independently selected from H or C 1-3 alkyl; optionally, said alkyl is substituted with a substituent selected from D, F, Cl, Br, I, or C 1-3 alkyl; R 26 is hydroxyl or amino; R4and R5are each independently selected from the group consisting of H, -(C=0)-0-(CH2) n6 -(CH2) n7 -(CH2) n8 -R 41 -(CH2) n42 -R 42 -(CH2) n43 -Y4-R 43 ; said -CH2- is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I, OH or C 1-3 alkyl; each R 41 and R 43 are each independently selected from C 1-3 alkyl; optionally, said alkyl is substituted with a substituent selected from D, F, Cl, Br, I, C 1-3 alkyl, nitro, cyano, carboxyl, or hydroxyl; R 42 is hydroxyl or amino; Y1is selected from -O-, -S-, or -NH-; Y2is selected from a bond, O, S, -NH-NH-, or -NH-; Y3and Y4are each independently selected from a bond, O, S, or -NH-; X is selected from O or NH; Z is an anion; Ring A is a three- to eight-membered cycloalkyl or a three- to eight-membered heterocycloalkyl; the heterocycloalkyl contains one, two, or three heteroatoms selected from N, O, or S; optionally, the cycloalkyl or heterocycloalkyl is substituted with a substituent selected from D, F, Cl, Br, I, or C 1-3 substituted with a substituent selected from D, F, Cl, Br, I, or C n1, n2, n3, n4, and n5are each independently a positive integer from 1 to 10; n4, n5, n6, n7, n42, and n43are each independently a positive integer from 1 to 5; each n8is independently a positive integer from 1 to 20; n11and n12are each independently a positive integer from 0 to 5.

5. The amphotericin B hydrazide derivative of any one of claims 1 to 4, or a stereoisomer, a pharmaceutically acceptable salt, or a deuterated form thereof, wherein, R1is selected from -CO-O-R 21 , -CO-S-R 21 , -CO-R 22 , -CO-NH-R 21 or -(CH2) n5 -Y3-C(=X)-R3; optionally, said -CH2- is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I; or R1is selected from -(CH2) n1 -OH; optionally, said -CH2- is substituted with a substituent selected from D, F, Cl, Br, I, or OH; R 21 selected from C 1-5 alkyl, OH, NH2, C 1-5 alkyloxy, C 1-5 alkylimino, 3- to 6-membered cycloalkyl, -(CH2) n4 -3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, -(CH2) n4 -NR 23 R 24 , -(CH2) n1 -N + R 23 R 24 R 25 Z - , -(CH2) n4 -O-C(=O)O(CH2CH2O) n8 -R 41 ; optionally, said alkyl, heterocycloalkyl and cycloalkyl are substituted with a substituent selected from the group consisting of D, F, Cl, Br, I, OH, NH2; said heterocycloalkyl contains 1 or 2 heteroatoms selected from N, O or S; R 22 selected from C 1-5 alkyl, OH, NH2; optionally, said alkyl is substituted with a substituent selected from D, F, Cl, Br, I; R3is selected from OH or NH2; R4and R5are each independently selected from the group consisting of H, -(C=0)-0-(CH2) n6 -(CH2)2-6-N(R7)2 n7 -(CH2)2-6-N(R7)2 n8 -R 41 -(CH2)2-6-N(R7)2 n42 -R 42 -(CH2)2-6-N(R7)2 n43 -Y4-R 43 ; said -CH2- is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I; each R 41 and R 43 are each independently selected from C 1-3 alkyl; optionally, said alkyl is substituted with a substituent selected from D, F, Cl, Br, I; R 42 is hydroxyl or amino; R 23 , R 24 , and R 25 are each independently selected from H or C 1-3 alkyl; optionally, said alkyl is substituted with a substituent selected from D, F, Cl, Br, I; R 26 is hydroxyl or amino; Ring A is a three- to six-membered cycloalkyl or a three- to six-membered heterocycloalkyl; the heterocycloalkyl contains 1 or 2 heteroatoms selected from N, O, or S; optionally, the cycloalkyl or heterocycloalkyl is substituted with a substituent selected from D, F, Cl, Br, I; Y1is selected from -O-, -S-, or -NH-; Y3is selected from a bond or -NH-; X is selected from O or NH; Z is Cl - , Br - , I - ; n1, n2, n3, n4, and n5are each independently 1, 2, 3, 4, or 5; n8is 5, 6, 7, 8, 9, 10, 11, or 12; n11 and n12 are each independently 0, 1, 2, or 3.

6. The amphotericin B hydrazide derivative or a stereoisomer, a pharmaceutically acceptable salt, or a deuterated form thereof of claim 5, wherein, R1is selected from -CO-O-R 21 , -CO-S-R 21 , -CO-R 22 , -CO-NH-R 21 or -(CH2) n5 -Y3-C(=X)-R3; optionally, said -CH2- is substituted with a substituent selected from the group consisting of D, F, Cl, Br, or I; or R1is selected from -(CH2) n1 -OH; optionally, said -CH2- is substituted with a substituent selected from D, F, Cl, Br, I, or OH; R 21 selected from C 1-5 alkyl, OH, NH2, C 1-5 alkyloxy, C 1-5 alkylimino, 3- to 6-membered cycloalkyl, -(CH2) n4 -NR 23 R 24 ; optionally, said alkyl and cycloalkyl groups are substituted with substituents selected from the group consisting of D, F, CI, Br, I, OH, NH2; or R 21 selected from 3- to 6-membered heterocycloalkyl, -(CH2) n4 -3- to 6-membered cycloalkyl, -(CH2) n4 -O-C(=O)O(CH2CH2O) n8 R 41 -(CH2) n1 -N + R 23 R 24 R 25 Z - 、 the cycloalkyl, heterocycloalkyl is substituted with a substituent selected from D, F, Cl, Br, I; R 22 selected from C 1-5 alkyl, OH or NH2; optionally, said alkyl is substituted with a substituent selected from D, F, Cl, Br, I; R3 is selected from OH or NH2; R4and R5are each independently selected from the group consisting of H, -(C=0)-0-(CH2) n6 -(CH2) n7 -(CH2) n8 -R 41 -(CH2) n42 -R 42 -(CH2) n43 -Y4-R 43 ; said -CH2- is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I; each R 41 and R 43 each independently selected from C 1-3 alkyl; optionally, said alkyl is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I; R 42 is hydroxyl or amino; R 23 , R 24 , and R 25 are each independently selected from H or C 1-3 alkyl; optionally, said alkyl is substituted with a substituent selected from D, F, Cl, Br, I; R 26 is hydroxyl or amino; Ring A is a three- to six-membered cycloalkyl or a three- to six-membered heterocycloalkyl; the heterocycloalkyl contains 1 or 2 heteroatoms selected from N, O, or S; optionally, the cycloalkyl or heterocycloalkyl is substituted with a substituent selected from D, F, Cl, Br, I; Y1 is selected from -O-, -S-, or -NH-; Y3 is selected from a bond or -NH-; X is selected from O or NH; Z is Cl - , Br - , I - ; n1, n2, n3, and n5 are each independently a positive integer of 1, 2, 3, 4, or 5; n8 is 5, 6, 7, 8, 9, 10, 11, or 12; n11 and n12 are each independently 0, 1, 2, or 3.

7. The amphotericin B hydrazide derivative or a stereoisomer, a pharmaceutically acceptable salt, or a deuterated form thereof of claim 6, wherein, R1is selected from -CO-O-R 21 , -CO-S-R 21 , -CO-R 22 , -CO-NH-R 21 or -(CH2) n5 -Y3-C(=X)-R3; optionally, said -CH2- is substituted with a substituent selected from the group consisting of D, F, Cl, Br, or I; or R1is selected from -(CH2) n1 -OH; optionally, said -CH2- is substituted with a substituent selected from D, F, Cl, Br, I, or OH; R 21 selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, OH, NH2, methoxy, ethoxy, propoxy, butoxy, pentoxy, methylamino, ethylamino, propylamino, butylamino, pentylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH2) n4 -NR 23 R 24 ; optionally, the methyl, ethyl, propyl, butyl, pentyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, methylamino, ethylamino, propylamino, butylamino, pentylamino, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are substituted with a substituent selected from the group consisting of D, F, Cl, Br, I, hydroxyl, amino; or R 21 selected from oxiranyl, oxetanyl, oxolanyl, oxanyl, thiiranyl, thietanyl, thiolanyl, thianyl, aziridinyl, azetidinyl, azolinyl, azolinidinyl, -(CH2) n4 - cyclopropyl, -(CH2) n4 - cyclobutyl, -(CH2) n4 - cyclopentyl, -(CH2) n4 - cyclohexyl, -(CH2) n4 - -O-C(=O)O(CH2CH2O) n8 R 41 , -(CH2) n1 -N + R 23 R 24 R 25 Z - , the cycloalkyl, heterocycloalkyl is substituted with a substituent selected from D, F, Cl, Br, I; R 22 selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, OH, or NH2; optionally, said methyl, ethyl, propyl, butyl, pentyl is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I; R3 is selected from OH or NH2; R4and R5are each independently selected from the group consisting of H, -(C=0)-0-(CH2) n6 -(CH2) n7 -O-(CH2CH2-O) n8 -R 41 -(CH2) n42 -R 42 -C(=0)-(CH2) n43 -Y4-R 43 ; said -CH2- is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I; each R is independently selected from the group consisting of H, F, Cl, Br, I, and C1-C3 alkyl; 41 each R is independently selected from the group consisting of H, F, Cl, Br, I, and C1-C3 alkyl; 43 each R is independently selected from the group consisting of H, F, Cl, Br, I, and C1-C3 alkyl; R 42 is hydroxyl or amino; R 23 , R 24 , and R 25 are each independently selected from H or methyl, ethyl, propyl; optionally, said methyl, ethyl, propyl is substituted with a substituent selected from D, F, Cl, Br, I; R 26 is hydroxyl; Ring A is a three- to six-membered cycloalkyl or a three- to six-membered heterocycloalkyl; the heterocycloalkyl contains 1 or 2 heteroatoms selected from N, O, or S; optionally, the cycloalkyl or heterocycloalkyl is substituted with a substituent selected from D, F, Cl, Br, I; Y1 is selected from -O-, -S-, or -NH-; Y3 is selected from a bond or -NH-; X is selected from O or NH; Z is Cl - , Br - , I - ; n1, n2, n3, and n5 are each independently a positive integer of 1, 2, 3, 4, or 5; n8 is 5, 6, 7, 8, 9, 10, 11, or 12; n11 and n12 are each independently 0, 1, 2, or 3.

8. The amphotericin B hydrazide derivative or a stereoisomer, a pharmaceutically acceptable salt, or a deuterated form thereof of claim 7, wherein, R1is selected from -CO-O-R 21 , -CO-S-R 21 , -CO-R 22 , -CO-NH-R 21 or -(CH2) n5 -Y3-C(=X)-R3; optionally, said -CH2- is substituted with a substituent selected from the group consisting of D, F, Cl, Br, or I; or R1is selected from -(CH2) n1 -OH; said -CH2- is substituted with at least one OH; optionally, said -CH2- is further substituted with a substituent selected from D, F, Cl, Br, or I; R 21 selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, OH, NH2, methoxy, ethoxy, propoxy, butoxy, pentoxy, methylamino, ethylamino, propylamino, butylamino, pentylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH2) n4 -NR 23 R 24 ; optionally, said methyl, ethyl, propyl, butyl, pentyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, methylamino, ethylamino, propylamino, butylamino, pentylamino, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are substituted with a substituent selected from the group consisting of D, F, Cl, Br, I, hydroxyl, amino; or R 21 selected from oxiranyl, oxetanyl, oxolanyl, oxanyl, thiiranyl, thietanyl, thiolanyl, thianyl, aziridinyl, azetidinyl, azolinyl, azolinidinyl, -(CH2) n4 - cyclopropyl, -(CH2) n4 - cyclobutyl, -(CH2) n4 - cyclopentyl, -(CH2) n4 - cyclohexyl, -(CH2) n4 - O-C(=O)O(CH2CH2O) n8 - R 41 , -(CH2) n1 - N + R 23 R 24 R 25 Z - , the cycloalkyl, heterocycloalkyl is substituted with a substituent selected from D, F, Cl, Br, I; R 22 selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, OH, or NH2; optionally, said methyl, ethyl, propyl, butyl, pentyl is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I; R3 is selected from OH or NH2; R4and R5are each independently selected from the group consisting of H, -(C=0)-0-(CH2) n6 -(CH2) n7 -(CH2) n8 -R 41 -(CH2) n42 -R 42 -(CH2) n43 -Y4-R 43 ; said -CH2- is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I; each R is independently selected from the group consisting of H, F, Cl, Br, I, and C1-C3 alkyl; 41 each R is independently selected from the group consisting of H, F, Cl, Br, I, and C1-C3 alkyl; 43 each R is independently selected from the group consisting of H, F, Cl, Br, I, and C1-C3 alkyl; R 42 is hydroxyl or amino; R 23 , R 24 , and R 25 are each independently selected from H or methyl, ethyl, propyl; optionally, said methyl, ethyl, propyl is substituted with a substituent selected from D, F, Cl, Br, I; R 26 is hydroxyl; Ring A is a three- to six-membered cycloalkyl or a three- to six-membered heterocycloalkyl; the heterocycloalkyl contains 1 or 2 heteroatoms selected from N, O, or S; optionally, the cycloalkyl or heterocycloalkyl is substituted with a substituent selected from D, F, Cl, Br, I; Y1 is selected from -O-, -S-, or -NH-; Y3 is selected from a bond or -NH-; X is selected from O or NH; Z is Cl - , Br - , I - ; n1, n2, n3, and n5 are each independently a positive integer of 1, 2, 3, 4, or 5; n8 is 5, 6, 7, 8, 9, 10, 11, or 12; each of n11 and n12 is independently 0, 1, 2, or 3.

9. The amphotericin B hydrazide derivative of claim 1, or a stereoisomer, a pharmaceutically acceptable salt, or a deuterated form thereof, wherein, R1is selected from -CO-O-R 21 , -CO-S-R 21 , -CO-NH-R 21 , -(CH2) n1 -OH, -CO-R 22 or -(CH2) n5 -Y3-C(=X)-R3; optionally, said -CH2- is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I or OH; R 21 selected from C 1-5 alkyl, -C 1-5 alkylene-OH, -C 1-5 alkylene-NH2, OH, NH2, C 1-5 alkyloxy, C 1-5 alkylimino, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, -(CH2) n4 -NR 23 R 24 -(CH2) n4 -3 to 6-membered cycloalkyl, -(CH2) n4 -O-C(=O)O(CH2CH2O) n8 -R 41 -(CH2) n1 -N + R 23 R 24 R 25 Z-, optionally, the alkyl, heterocycloalkyl, and cycloalkyl are substituted with a substituent selected from the group consisting of D, F, Cl, Br, and I; optionally, the alkyl of the alkyloxy and alkylamido is substituted with a substituent selected from the group consisting of hydroxyl and amino; the heterocycloalkyl contains 1 or 2 heteroatoms selected from the group consisting of N, O, and S; R 22 selected from C 1-5 alkyl, OH or NH2; optionally, said alkyl is substituted with a substituent selected from D, F, Cl, Br, I; R3 is selected from the group consisting of OH and NH2; R4and R5are each independently selected from the group consisting of H, -(C=0)-0-(CH2) n6 -(CH2) n7 -(CH2) n8 -R 41 -(CH2) n42 -R 42 -(CH2) n43 -Y4-R 43 ; said -CH2- is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I; Each R 41 and R 43 Each independently selected from C 1-5 Alkyl group; the alkyl group is substituted with a substituent selected from D, F, Cl, Br, I; R 42 is hydroxyl or amino; R 23 , R 24 , and R 25 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; R 26 is hydroxyl; Ring A is a three- to six-membered cycloalkyl or a three- to six-membered heterocycloalkyl; the heterocycloalkyl contains 1 or 2 heteroatoms selected from the group consisting of N, O, and S; optionally, the cycloalkyl or heterocycloalkyl is substituted with a substituent selected from the group consisting of D, F, Cl, Br, and I; Y1 is selected from the group consisting of -O-, -S-, and -NH-; Y3 is selected from the group consisting of a bond and -NH-; X is selected from the group consisting of O and NH; Z is Cl - , Br - , I - ; each of n1, n2, n3, n5, n6, and n7 is independently 1, 2, 3, 4, or 5; n8 is 5, 6, 7, 8, 9, or 10; each of n11 and n12 is independently 0, 1, 2, or 3.

10. The amphotericin B hydrazide derivative of claim 1, or a stereoisomer, a pharmaceutically acceptable salt, or a deuterated form thereof, wherein, R1is selected from -(CH2) n1 -OH, -CO-O-R 21 , -CO-S-R 21 , -CO-NH-R 21 , -CO-R 22 or -(CH2) n5 -Y3-C(=X)-R3; optionally, said -CH2- is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I, or OH; R 21 selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, OH, NH2, methoxy, ethoxy, propoxy, butoxy, pentoxy, methylamino, ethylamino, propylamino, butylamino, pentoxyamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heterocyclopropyl, heterocyclobutyl, heterocyclopentyl, heterocyclohexyl, or -(CH2) n4 -NR 23 R 24 -(CH2) n4 -cyclopropyl, -(CH2) n4 -cyclobutyl, -(CH2) n4 -cyclopentyl, -(CH2) n4 -cyclohexyl, -(CH2) n4 -O-C(=O)O(CH2CH2O) n8 -R 41 -(CH2) n1 -N + R 23 R 24 R 25 Z - 、 optionally, the methyl, ethyl, propyl, butyl, pentyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, methylamino, ethylamino, propylamino, butylamino, pentylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heterocyclopropyl, heterocyclobutyl, heterocyclopentyl, heterocyclohexyl are substituted with a substituent selected from the group consisting of D, F, Cl, Br, and I; optionally, the methoxy, ethoxy, propoxy, butoxy, pentoxy, methylamino, ethylamino, propylamino, butylamino, pentylamino are substituted with a substituent selected from the group consisting of hydroxyl and amino; the heterocyclopropyl, heterocyclobutyl, heterocyclopentyl, heterocyclohexyl contains 1 or 2 heteroatoms selected from the group consisting of N, O, and S; R 22 selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, OH, or NH2; optionally, said methyl, ethyl, propyl, butyl, pentyl is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I; R3 is selected from the group consisting of OH and NH2; R4and R5are each independently selected from the group consisting of H, -(C=0)-0-(CH2) n6 -(CH2) n7 -(CH2) n8 -R 41 -(CH2) n42 -R 42 -(CH2) n43 -Y4-R 43 ; said -CH2- is substituted with a substituent selected from the group consisting of D, F, Cl, Br, I; each R is independently selected from the group consisting of H, F, Cl, Br, I, and C1-C5 alkyl; 41 each R is independently selected from the group consisting of H, F, Cl, Br, I, and C1-C5 alkyl; 43 each R is independently selected from the group consisting of H, F, Cl, Br, I, and C1-C5 alkyl; R 42 is hydroxyl or amino; R 23 , R 24 , and R 25 are each independently selected from H or methyl, ethyl, propyl, butyl, pentyl; optionally, said methyl, ethyl, propyl, butyl, pentyl is substituted with a substituent selected from D, F, Cl, Br, I; R 26 is hydroxyl; Ring A is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heterocyclopropyl, heterocyclobutyl, heterocyclopentyl, or heterocyclohexyl; the heterocycloalkyl contains 1 or 2 heteroatoms selected from the group consisting of N, O, and S; optionally, the cycloalkyl or heterocycloalkyl is substituted with a substituent selected from the group consisting of D, F, Cl, Br, and I; Y1 is selected from the group consisting of -O-, -S-, and -NH-; Y3 is selected from the group consisting of a bond and -NH-; X is selected from the group consisting of O and NH; Z is Cl - , Br - , I - ; each of n1, n2, n3, n5, n6, n7 is independently 1, 2, 3, 4, or 5; n8 is 5, 6, 7, 8, 9, or 10; each of n11 and n12 is independently 0, 1, 2, or 3.

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

12. A pharmaceutical composition comprising a therapeutically effective amount of the amphotericin B hydrazide derivative of any one of claims 1-11, or a stereoisomer, a pharmaceutically acceptable salt, or a deuterated form thereof, and a pharmaceutically acceptable carrier.

13. Use of the amphotericin B hydrazide derivative or a stereoisomer, a pharmaceutically acceptable salt or deuterated form thereof of any one of claims 1 to 11, or the pharmaceutical composition of claim 12 in the manufacture of an antifungal medicament.

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