Echinocandin analogs and preparation methods thereof

Abstract

The invention relates to an echinocandin analog and a preparation method thereof. The compounds can be used to prevent or treat fungal infections, or to prevent, stabilize or inhibit fungal growth or kill fungi. The exemplary compounds are shown in formula I, wherein the definitions of R1, R2, R3 and G groups are as described in the specification.

Description

[0001] This application claims the priority of Chinese Patent Application No. 201911241526.8 filed on December 6, 2019, Chinese Patent Application No. 201911249226.4 filed on December 9, 2019, Chinese Patent Application No. 202010165349.6 filed on March 11, 2020, Chinese Patent Application No. 202010799506.9 filed on August 11, 2020, Chinese Patent Application No. 202011164541.X filed on October 27, 2020, and Chinese Patent Application No. 202011371550.6 filed on November 30, 2020. This application cites the full text of the above Chinese patent applications. Technical Field

[0002] The present disclosure belongs to the field of medicinal chemistry, and in particular relates to a class of echinocandin analogs that can be used to fight fungal infections. Background Art

[0003] The development of antifungal treatment regimens has been a continuing challenge facing society today. Currently available drugs for the treatment of fungal infections include amphotericin B, a macrolide polyene that interacts with fungal membrane sterols: flucytosine, a fluoropyrimidine that interacts with fungal protein and DNA biosynthesis, and a variety of azole antifungal drugs that inhibit fungal membrane-sterol biosynthesis (e.g., ketoconazole, itraconazole, and fluconazole) (Alexander et al., Drugs, 54: 657, 1997). Even though amphotericin B has a wide range of activity and is considered the "gold standard" for antifungal therapy, its use is limited by infusion-related reactions and nephrotoxicity (Warnock, J. Antimicrob. Chemother., 41: 95, 1998). The use of flucytosine is also limited due to the development of resistant microorganisms and its narrow spectrum of activity. The widespread use of azole antifungal drugs is causing the emergence of clinically resistant strains of Candida spp.

[0004] Echinocandins are a new class of antifungal drugs, which usually contain a cyclic hexapeptide and a lipophilic tail, the latter of which is connected to the hexapeptide core via an amide bond. This class of drugs interferes with the synthesis of β-1,3-glucose in the fungal cell wall by non-competitive inhibition of β-1,3-glucose synthase, leading to changes in the permeability of the fungal cell wall and cell lysis and death. Since human cells do not contain cell walls, while fungal cells do, echinocandin antifungal drugs can directly act on the components of the fungal cell wall, so this class of drugs has low toxicity to the human body and is by far the safest class of antifungal drugs.

[0005] Currently, the drugs of this type that have been marketed include caspofungin, micafungin, and anidulafungin. Caspofungin is the first echinocandin antifungal drug, developed by the American pharmaceutical company Merck. It was approved by the US FDA in 2004 for the treatment of fungal infections and in 2008 for the treatment of candidal infections in children. Micafungin (Mycamine) was launched in Japan in 2002 and is a new type of semi-synthetic antifungal drug. Anidulafungin was launched in 2006 and is a semi-synthetic antifungal drug of the third generation of echinocandin.

[0006] WO2017049102A and WO2018102407A disclose antifungal echinocandin drugs as shown in Formula 1 below.

[0007] Summary of the invention

[0008] The present disclosure provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof, or an isomer thereof,

[0009]

[0010] Wherein R1 is selected from hydroxyl, O(C(R A1 )(R A2 )) a (C(R A3 )(R A4 )) j X1、NH(C(R A1 )(R A2 )) a (C(R A3 )(R A4 )) j X1, O(CH2CH2O) b CH2CH2X1, O(CH2CH2CH2O) b CH2CH2X1, O(CH2CH2NH) b CH2CH2X1, NH(CH2CH2O) b CH2CH2X1, NH(CH2CH2NH) b CH2CH2X1, NH(CH2CH2CH2O) b CH2CH2X1, NH[(CH2(CH2) c O)] b CH{CH2[OCH2(CH2) c ] d X1}2、O[(CH2(CH2) c O)] bCH{CH2[OCH2(CH2) c ] d X1}2 and (OCH2CH2) b (NHCH2CH2) e X2,

[0011] R2 is selected from hydrogen, R B1 R B2 N-、CH2CH2NR B1 R B2 、CH2C(O)NR B1 R B2 , C 1-10 Lower alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl and PEG,

[0012] R3 is selected from H, OSO3H and CH2NR B1 R B2 ,

[0013] G is C 10-42 Lipid unit,

[0014] R A1 , R A2 , R A3 and R A4 independently selected from hydrogen, deuterium, halogen, lower alkyl, cycloalkyl and cycloalkylene

[0015] R B1 and R B2 are independently selected from H, -C(O)R J and a lower alkyl group,

[0016] X1 is independently N(R C1 R C2 R C3 ) or the following structure: Ring A is an optionally substituted, saturated or unsaturated monocyclic or condensed ring containing one or more N atoms,

[0017] R C1 , R C2 and R C3 Independently selected from H, C 1-6 Alkyl, halogenated C 1-6 Lower alkyl and deuterated C 1-6 A lower alkyl group, and R C1 , R C2 and R C3 At least one of them is not hydrogen,

[0018] Each R Findependently selected from H, deuterium, hydroxy, hydroxyalkyl, amino, alkoxy, lower alkyl, alkenyl, alkynyl, halogen, SR', SOR', SOR', NR'(R"), COOR' and CONR'(R"), wherein said lower alkyl is optionally substituted with one or more substituents selected from deuterium, alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxy, halogen, SR', NR'(R"), COOR' and CONR'(R"),

[0019] X2 is N(R D1 R D2 R D3 ) or X1 structure,

[0020] R D1 , R D2 and R D3 Independently selected from H, C 1-6 Lower alkyl, halogenated C 1-6 Lower alkyl and deuterated C 1-6 Lower alkyl,

[0021] R' and R" are independently selected from hydrogen, hydroxy, alkyl, alkoxy, alkenyl and -C(O)R J ,

[0022] R J Selected from hydrogen, deuterium, C 1-10 Lower alkyl, cycloalkyl and cycloalkylene,

[0023] a is an integer from 0 to 5,

[0024] b is an integer from 1 to 5,

[0025] c is an integer from 1 to 2,

[0026] d is an integer from 0 to 3,

[0027] e is an integer from 1 to 5,

[0028] k is an integer from 0 to 20,

[0029] j is an integer from 0 to 5, and

[0030] n is an integer from 1 to 7.

[0031] "Independently selected from" or "independently are" means that the variable radicals at each occurrence are independently selected from the defined substituents.

[0032] In some embodiments, R1 can be selected from O(C(R A1 )(R A2 )) a (C(R A3 )(RA4 )) j X1、NH(C(R A1 )(R A2 )) a (C(R A3 )(R A4 )) j X1, O(CH2CH2O) b CH2CH2X1, O(CH2CH2CH2O) b CH2CH2X1, O(CH2CH2NH) b CH2CH2X1, NH(CH2CH2O) b CH2CH2X1, NH(CH2CH2NH) b CH2CH2X1, NH(CH2CH2CH2O) b CH2CH2X1, NH[(CH2(CH2) c O)] b CH{CH2[OCH2(CH2) c ] d X1}2、O[(CH2(CH2) c O)] b CH{CH2[OCH2(CH2) c ] d X1}2 and (OCH2CH2) b (NHCH2CH2) e X2,

[0033] R2 can be selected from hydrogen, R B1 R B2 N-、CH2CH2NR B1 R B2 、CH2C(O)NR B1 R B2 , C 1-10 Lower alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl and PEG,

[0034] R3 can be selected from H, OSO3H and CH2NR B1 R B2 ,

[0035] G can be C 10-36 Lipophilic unit,

[0036] R A1 , R A2 , R A3 and R A4 independently selected from hydrogen, deuterium, halogen, lower alkyl, cycloalkyl and cycloalkylene

[0037] R B1 and R B2 Each independently selected from H, -C(O)R J and a lower alkyl group,

[0038] X1 is independently N(R C1 R C2 R C3 ) or the following structure: Ring A is an optionally substituted, saturated or unsaturated monocyclic or condensed ring containing one or more N atoms,

[0039] R C1 , R C2 and R C3 Each independently selected from H, halogenated C 1-6 Lower alkyl and deuterated C 1-6 A lower alkyl group, and R C1 , R C2 and R C3 At least one of them is not hydrogen,

[0040] Each R F independently selected from H, deuterium, hydroxyl, hydroxyalkyl, amino, alkoxy, lower alkyl, alkenyl, alkynyl, halogen, SR', SOR', SOR', NR'(R"), COOR' and CONR'(R"), wherein the lower alkyl may be optionally substituted with one or more substituents selected from deuterium, alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl,

[0041] X2 is N(R D1 R D2 R D3 ) or X1 structure,

[0042] R D1 , R D2 and R D3 Independently selected from H, C 1-6 Lower alkyl, halogenated C 1-6 Lower alkyl and deuterated C 1-6 Lower alkyl,

[0043] R' and R" are independently selected from hydrogen, hydroxy, alkyl, alkoxy, alkenyl and -C(O)R J ,

[0044] R J are independently selected from hydrogen, C 1-10 Lower alkyl, cycloalkyl and cycloalkylene,

[0045] a is an integer from 0 to 5,

[0046] b is an integer from 1 to 5,

[0047] c is an integer from 1 to 2,

[0048] d is an integer from 0 to 3,

[0049] e is an integer from 1 to 5,

[0050] k is an integer from 0 to 20,

[0051] j is independently an integer from 0 to 5, and

[0052] n is an integer from 1 to 7.

[0053] In some embodiments, X1 can be selected from the following structures:

[0054] Among them, each R F independently selected from H, deuterium, hydroxyl, hydroxyalkyl, amino, alkoxy, lower alkyl, alkenyl, alkynyl, halogen, SR', SOR', SOR', NR'(R"), COOR' and CONR'(R"), wherein the lower alkyl may be optionally substituted with one or more substituents selected from deuterium, alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl,

[0055] R q1 , R q2 Can be independently H or C 1-6 lower alkyl, which is optionally substituted with one or more substituents selected from deuterium, alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxy, halogen, SR', NR'(R"), COOR' and CONR'(R"),

[0056] R' and R" are independently selected from hydrogen, hydroxy, alkyl, alkoxy, alkenyl and -C(O)R J ,

[0057] R J Selected from hydrogen, deuterium, C 1-10 Lower alkyl, cycloalkyl and cycloalkylene,

[0058] f is an integer from 0 to 16,

[0059] g is an integer from 0 to 16,

[0060] h is an integer from 0 to 9,

[0061] i is an integer from 0 to 4,

[0062] n is an integer from 1 to 7, and

[0063] p is an integer from 1 to 3.

[0064] In some embodiments, G may be selected from Wherein, X is independently selected from O, C(R B1 )(R B2 ), NR p4 - and S; R T Can be C 1-5 Straight or branched alkyl, wherein the alkyl is optionally substituted with one or more selected from deuterium, halogen, alkyl, cycloalkyl, cycloalkylene Substituents; R p1 , R p2 and R p3 is independently selected at each occurrence from hydrogen, deuterium, halogen, C 1-10 Lower alkyl, halogenated C 1-10 Lower alkyl, C 2-10 Alkenyl, C 2-10 alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group and PEG; m is an integer from 0 to 4; n is an integer from 1 to 7; R p4 is hydrogen or C 1-6 Lower alkyl; R B1 and R B2 Each independently selected from H, -C(O)R J and C 1-10 Lower alkyl, R J Selected from hydrogen, deuterium, C 1-10 Lower alkyl, cycloalkyl and cycloalkylene.

[0065] In some embodiments, G can be selected from:

[0066]

[0067]

[0068] In some embodiments, R1 can be selected from:

[0069]

[0070] In other embodiments, R1 can be selected from:

[0071]

[0072] The present disclosure provides a compound as shown in Formula II, or a pharmaceutically acceptable salt thereof, or an isomer thereof,

[0073]

[0074] G1 can be selected from

[0075] Among them, R p1 , Rp2 and R p3 are independently selected from hydrogen, deuterium, halogen, C 1-6 Lower alkyl, halogenated C 1-6 Lower alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl and PEG,

[0076] X is independently selected from O, C(R B1 )(R B2 ), NR p4 - and S,

[0077] R p4 is hydrogen or C 1-3 Lower alkyl,

[0078] R T Can be C 1-5 Straight or branched alkyl, wherein the alkyl is optionally substituted by one or more selected from deuterium, hydroxy, amino, alkoxy, amino, NR'(R"), halogen, cycloalkyl, cycloalkylene Substituents of

[0079] And when R p1 , R p2 and R p3 When both are H and X is O, R T Not for—C5H 11 ; When X is O, and R T for—C5H 11 When R p1 , R p2 and R p3 At least one of them is not H; when R T for—C5H 11 , and R p1 , R p2 and R p3 When both are H, X is not O;

[0080] R B1 and R B2 Each independently selected from H, -C(O)R J and C 1-10 Lower alkyl,

[0081] R J Selected from hydrogen, C 1-10 Lower alkyl, cycloalkyl and cycloalkylene,

[0082] m is an integer from 0 to 4, and

[0083] n is an integer from 1 to 7.

[0084] The present disclosure also provides a compound as shown in Formula III, or a pharmaceutically acceptable salt thereof, or an isomer thereof,

[0085]

[0086] Among them, R G1 , R G2 , R G3 and R G4 are independently selected from hydrogen, deuterium, halogen and lower alkyl, and R G1 , R G2 , R G3 and R G4 At least one of them is not hydrogen.

[0087] The present disclosure provides the following compounds, or pharmaceutically acceptable salts thereof, or isomers thereof,

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095] In certain embodiments, the pharmaceutically acceptable salt of the compound is selected from the group consisting of acetate, trifluoroacetate, and formate.

[0096] The present disclosure also provides a method for preparing the compound or a pharmaceutically acceptable salt thereof.

[0097] The present disclosure also provides a pharmaceutical composition, which comprises the compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0098] The present disclosure also provides a method for treating a fungal infection in a patient, which is carried out by administering a pharmaceutical composition of the present disclosure to the patient in an amount sufficient to treat the infection. In a specific embodiment, the pharmaceutical composition is administered intravenously, topically or orally. The pharmaceutical composition can be administered to treat a patient's bloodstream infection, tissue infection (e.g., lung, kidney or liver infection) or other types of infection. The fungal infection to be treated can be selected from the following infections: scalp ringworm, tinea corporis, tinea pedis, onychomycosis, perionychia (perionychomycosis), psoriasis variegata, thrush, vaginal candidiasis, respiratory candidiasis, biliary candidiasis, esophageal candidiasis, urethral candidiasis, systemic candidiasis, mucosal and skin candidiasis, aspergillosis, mucormycosis, paracoccidioidomycosis, North American blastomycosis, histoplasmosis, coccidioidomycosis, sporotrichosis, fungal sinusitis or chronic paranasal inflammation. In certain embodiments, the infection to be treated is an infection caused by Candida albicans, C. parapsilosis, C. glabrata, C. guilliermondii, C. krusei, C. lusitaniae, C. tropicalis, Aspergillus fumigatus, A. flavus, A. terreus, A. niger, A. candidus, A. clavatus, or A. ochraceus.

[0099] The present disclosure also provides a method for preventing fungal infection in a patient, the method being carried out by administering a pharmaceutical composition of the present invention to the patient in an amount sufficient to prevent infection. For example, the method of the present disclosure can be used to perform preventive treatment in patients preparing for invasive medical measures (e.g., preparing for surgery, such as receiving a transplant, stem cell therapy, a graft, a prosthesis, receiving long-term or frequent intravenous catheterization, or receiving treatment in an intensive care unit), in patients with weakened immunity (e.g., patients with cancer, patients with HIV / AIDS, or patients taking immunosuppressants), or patients undergoing long-term antibiotic therapy.

[0100] In a specific embodiment of the methods of the present disclosure, the pharmaceutical composition comprises Compound 1, or any other compound described herein, or a pharmaceutically acceptable salt thereof.

[0101] The present disclosure also provides methods for preventing, stabilizing, or inhibiting the growth of fungi or killing fungi by contacting the fungi or a site susceptible to fungal growth with a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0102] The terms "sufficient amount" and "adequate amount" refer to the amount of drug required to treat or prevent infection. The amount sufficient for practicing the present disclosure to therapeutically treat or prophylactically treat a condition caused or contributed to by infection varies depending on the mode of administration, the type of infection, the age, weight and general health of the patient.

[0103] By "fungal infection" is meant an attack of a host by a pathogenic fungus. For example, an infection may include an overgrowth of fungi that are normally present in or on a patient's body or a growth of fungi that are not normally present in or on a patient's body. More generally, a fungal infection may be any condition in which the presence of a fungal colony is harmful to the host organism. Thus, a patient is "suffering from" a fungal infection when an excessive amount of a fungal colony is present in or on a patient's body, or when the presence of a fungal colony damages a patient's cells or other tissues.

[0104] The term "treating" refers to administering a pharmaceutical composition for preventive and / or therapeutic purposes. For "preventing a disease" it refers to prophylactic treatment of a subject who does not yet have the disease, but is susceptible to or at risk for a particular disease. For "treating a disease" it refers to treating a patient who already has the disease to improve or stabilize the patient's condition.

[0105] The present disclosure also provides use of the compound or a pharmaceutically acceptable salt thereof in preparing a medicament for treating fungal infection.

[0106] The present disclosure also provides use of the compound or a pharmaceutically acceptable salt thereof in preparing a medicament for preventing fungal infection.

[0107] The present disclosure also provides the use of the compound or its pharmaceutically acceptable salt in the preparation of a drug for preventing, stabilizing or inhibiting fungal growth or killing fungi. In some embodiments, the use comprises contacting the fungus or a part where fungi are prone to grow with the compound or its pharmaceutically acceptable salt, or its isomer.

[0108] The compounds of the present disclosure can be synthesized, for example, as described in the Examples, by reacting an echinocandin compound with a suitable acyl, alkyl, carboxyl, hydroxyl and / or amino group under standard reaction conditions.

[0109] For the disclosed semi-synthetic routes to the compounds, the stereochemistry of the compounds will be determined by the starting materials. Thus, the stereochemistry of the non-natural echinocandin derivatives will typically have the same stereochemistry as the naturally occurring echinocandin framework from which they are derived (representative stereochemistries are described in the Examples).

[0110] The compounds of the present disclosure can be synthesized, for example, using the methods described in the Examples.

[0111] Unless stated otherwise, the following terms used in the specification and claims have the following meanings.

[0112] "Alkyl" refers to a straight or branched alkane group, preferably containing 1 to 10 carbon atoms, more preferably containing 1 to 6 carbon atoms, non-limiting examples such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc. Unless otherwise specified in the specification, the alkyl group may be optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thio, trimethylsilyl, etc. Unless otherwise specified, "lower alkyl" refers to a straight or branched alkane group containing 1 to 10 carbon atoms, non-limiting examples such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc. Unless otherwise specified in the specification, the lower alkyl group may be optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thio, trimethylsilyl, etc.

[0113] "Alkenyl" refers to an alkyl compound containing a carbon-carbon double bond in the molecule, wherein the definition of alkyl is as described above. Non-limiting examples include vinyl, 1-propylene-2-yl, 1-butene-4-yl, 1-pentene-5-yl, 1-butene-1-yl, etc. Unless otherwise specified in the specification, alkenyl may be optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thio, trimethylsilyl, etc.

[0114] "Alkynyl" refers to an alkyl compound containing a carbon-carbon triple bond in the molecule, wherein the definition of alkyl is as described above. Non-limiting examples include ethynyl, propynyl, pentynyl, butynyl, etc. Unless otherwise specified in the specification, alkynyl may be optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thio, trimethylsilyl, etc.

[0115] “C 10-36 The term "lipophilic unit" refers to a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, etc. having 10 to 36 carbon atoms.

[0116] "Aryl" refers to a hydrocarbon ring system radical containing hydrogen atoms, 6 to 14 carbon atoms and at least one aromatic ring. It can be a monocyclic, bicyclic or tricyclic ring system, and it can contain a spirocyclic ring system. Aryl includes, but is not limited to, aryl groups derived from acenaphthene, anthracene, azulene, benzene, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, fluorene, indene, naphthalene, phenalene and phenanthrene. Unless otherwise specified in the specification, aryl groups may be optionally substituted by one or more substituents independently selected from the following groups: alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, cyano, nitro, etc.

[0117] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon atoms and hydrogen atoms, which may contain a spirocyclic or bridged ring system, having 3 to 15 carbon atoms, 3 to 10 carbon atoms, or 5 to 7 carbon atoms, and which is saturated or unsaturated and connected to the rest of the molecule by a single bond. Monocyclic cycloalkyl groups include non-bridged hydrocarbon groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include fused, spirocyclic or bridged hydrocarbon groups, such as C10 groups, such as adamantyl (bridged ring) and decalinyl (fused); and C7 groups, such as bicyclo[3.2.0]heptyl (fused), norbornyl and norbornenyl (bridged ring); and substituted polycyclic groups, such as substituted C7 groups, such as 7,7-dimethylbicyclo[2.2.1]heptyl (bridged ring) and the like. Unless otherwise specifically stated in the specification, the cycloalkyl group may be optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thio, cyano, nitro, and the like.

[0118] "Cycloalkyl" refers to a saturated monocyclic or polycyclic hydrocarbon substituent having 3 to 15 carbon atoms, 3 to 10 carbon atoms, or 5 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, etc.; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls.

[0119] "Halogen" refers to bromine, chlorine, fluorine or iodine.

[0120] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring group containing 1 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise specified in this specification, the heterocyclyl can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include a spirocyclic or bridged ring system; and the nitrogen, carbon or sulfur atoms in the heterocyclyl can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl can be partially or completely saturated. Unless otherwise specified in this specification, the heterocyclyl includes a heterocyclyl optionally substituted by one or more substituents selected from the following groups: alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thio, cyano, nitro, etc.

[0121] "Heteroaryl" refers to a 5- to 14-membered ring system radical containing hydrogen atoms, 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur, and at least one aromatic ring. The heteroaryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include a spirocyclic ring system; and the nitrogen, carbon or sulfur atoms in the heteroaryl group can be optionally oxidized; the nitrogen atom can be optionally quaternized. The aromatic ring of the heteroaryl group does not necessarily contain heteroatoms, as long as one ring of the heteroaryl group contains heteroatoms. For example, 1,2,3,4-tetrahydroisoquinolin-7-yl is considered to be a "heteroaryl group". Unless otherwise specifically stated in this specification, the heteroaryl group includes a heteroaryl group optionally substituted by one or more substituents selected from the following groups: alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thio, cyano, nitro, etc.

[0122] "PEG" means polyethylene glycol and, unless otherwise defined, includes ethylene oxide polymers of any length which may be optionally substituted with one or more substituents selected from the group consisting of deuterium, alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thio, cyano, nitro, and the like. BRIEF DESCRIPTION OF THE DRAWINGS

[0123] Figure 1 : Changes of histamine concentration after intravenous administration of the compound.

[0124] Figure 2 : Comparison of histamine concentrations 30 minutes after intravenous administration of the compounds. DETAILED DESCRIPTION

[0125] The present invention is further described below with reference to examples, but these examples are not intended to limit the scope of the present invention.

[0126] The experimental methods in the examples of the present invention that do not specify specific conditions are usually carried out under conventional conditions or under conditions recommended by raw material or product manufacturers. Reagents that do not specify specific sources are conventional reagents purchased from the market.

[0127] Anidulafungin and caspofungin were purchased from Taizhou Kede Chemical. Rezafungin was synthesized according to CN103889221A.

[0128] HPLC purity analysis method:

[0129]

[0130]

[0131] LC-MS analysis method:

[0132]

[0133] Embodiment 1:

[0134] first step

[0135]

[0136] Compound SM1 (510 mg, 5.04 mmol) was dissolved in acetone (5.1 mL), and methyl p-toluenesulfonate (938 mg, 5.04 mmol) was added dropwise. The reaction solution was heated under reflux for 4 h to precipitate a white solid, which was filtered and the filter cake was dried under vacuum to obtain 385 mg of compound SM2 with a purity of 98% and a yield of 26.7%. Ms: 116.1 [M + ].

[0137] Step 2

[0138]

[0139] Under nitrogen protection, anidulafungin (114 mg, 0.1 mmol) was dissolved in tetrahydrofuran (10 mL), phenylboronic acid (24 mg, 0.2 mmol) was added, stirred at room temperature for 2 hours, and the solvent was evaporated to dryness in vacuo. 10 mL of acetonitrile was added, compound SM2 (170 mg, 0.6 mmol) and p-toluenesulfonic acid (86 mg, 0.5 mmol) were added, and stirred at room temperature for 16 h. 1N sodium acetate aqueous solution (1 mL) was added to quench the reaction solution, and the solvent was removed by rotary evaporation. The crude product was purified by preparative chromatography to obtain 79 mg of the product (acetate), with a purity of 97.6% and a yield of 60.8%. HRMS: 1237.6021 [M + ].

[0140] 1H NMR (400MHz, METHANOL-d4) δ7.98-8.01(m,2H),7.82(d,J=8.3Hz,2H),7.71-7.78(m,4H),7.63(d,J=8.8Hz,2H),7.17(d,J=8.6Hz,2H),7.0 3(d,J=8.8Hz,2H),6.79(d,J=8.6Hz,2H),5.40-5.42(m,1H),5.00-5.05(m,1H),4.58-4.80(m,7H),4.41(d,J=4.4Hz,1H),4.34-4.36(m,2H ),4.25-4.32(m,2H),3.97-4.24(m,8H),3.89-3.96(m,1H),3.82-3.87(m,1H),3.48-3.53(m,1H),3.12-3.17(m,6H),2.45-2.57(m,4H),2. 27-2.35(m,1H),2.05-2.15(m,2H),1.79-1.87(m,5H),1.40-1.53(m,4H),1.26-1.32(m,6H),1.10(d,J=6.8Hz,3H),0.99(t,J=7.2Hz,3H).

[0141] Embodiment 2:

[0142] first step

[0143]

[0144] Compound SM3 (1.29 g, 10 mmol) was dissolved in acetone (13 mL), and iodomethane (1.42 g, 10 mmol) was added dropwise. The reaction solution was heated under reflux for 4 h to precipitate a white solid, which was filtered and the filter cake was dried under vacuum to obtain 2.54 g of compound SM4 with a purity of 98% and a yield of 89.2%. Ms: 144.1 [M + ].

[0145] Step 2

[0146]

[0147] Under nitrogen protection, anidulafungin (114 mg, 0.1 mmol) was dissolved in tetrahydrofuran (10 mL), phenylboronic acid (24 mg, 0.2 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated to dryness in vacuo. 10 mL of acetonitrile was added, and compound SM4 (171 mg, 0.6 mmol) and D-(+)-camphorsulfonic acid (120 mg, 0.5 mmol) were added, and the mixture was stirred at room temperature for 16 h. 1N sodium acetate aqueous solution (1 mL) was added to quench the reaction solution, and the solvent was removed by rotary evaporation. The crude product was purified by preparative chromatography to obtain 61 mg of the product (acetate), with a purity of 97.0% and a yield of 46.2%. HRMS: 1265.6327 [M + ].

[0148] 1 H NMR (400MHz, METHANOL-d4) δ8.01(d,J=8.3Hz,2H),7.83(dd,J=0.49,8.3Hz,2H),7.71-7.79(m,4H),7.63(d,J=8.80Hz,2H),7.17(d,J=8.6Hz,2H),7. 03(d,J=8.80Hz,2H),6.79(d,J=8.6Hz,2H),5.34-5.41(m,1H),5.00-5.05 (m,1H),4.58-4.80(m,7H),4.40(d,J=4.4Hz,1H),4.32-4.38(m,2H),4.25- 4.32(m,2H),4.18–4.22(m,1H),4.15-4.24(m,1H),3.81-4.15(m,8H),3.4 3-3.52(m,2H),3.21(d,J=6.6Hz,3H),3.04(d,J=6.6Hz,3H),2.42-2.59(m, 2H),2.24-2.36(m,1H),2.05-2.12(m,2H),1.80-1.88(m,9H),1.42-1.53( m, 5H), 1.28 (d, J = 6.4Hz, 6H), 1.10 (d, J = 6.9Hz, 3H), 0.99 (t, J = 7.1Hz, 3H).

[0149] Embodiment 3:

[0150]

[0151] Under nitrogen protection, anidulafungin (114 mg, 0.1 mmol) was dissolved in tetrahydrofuran (10 mL), phenylboronic acid (24 mg, 0.2 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated to dryness in vacuo. 10 mL of dioxane was added, compound SM5 (73 mg, 0.6 mmol) and p-toluenesulfonic acid (86 mg, 0.5 mmol) were added, and the mixture was stirred at room temperature for 16 h. 1N sodium acetate aqueous solution (1 mL) was added to quench the reaction solution, and the solvent was removed by rotary evaporation. The crude product was purified by preparative chromatography to obtain 68 mg of the product (acetate), with a purity of 97.8% and a yield of 52.3%. HRMS: 1243.5924 [M + ].

[0152] 1 H NMR (400MHz, METHANOL-d4) δ7.97(d,J=8.0Hz,2H),7.79(d,J=8.0Hz,2H),7.69-7.75(m,4H),7.61(d,J=8.4Hz,2H),7.15(d,J=8.0 Hz,2H),7.01(d,J=8.4Hz,2H),6.76(d,J=8.0Hz,2H),5.45(d,J=17.6Hz,2H),5.36(s,1H),5.05(s,1H),4.73-4.77(m,1H),4.58-4 .61(m,3H),4.16-4.40(m,6H),3.81–4.10(m,8H),3.63–3.73(m,2H),3.46-3.50(m,1H),3.20(s,6H),2.42-2.53(m,2H),2.26-2.2 9(m,1H),2.05-2.11(m,2H),1.78-1.84(m,2H),1.40-1.52(m,4H),1.25-1.30(m,7H),1.07(d,J=6.8Hz,3H),0.97(t,J=7.2Hz,3H).

[0153] Embodiment 4:

[0154]

[0155] Echinocandin B (50 mg, 0.06 mmol) and tert-butyl octadecane dioate (24.43 mg, 1.1 eq.) were dissolved in DMF (2 mL), stirred in an ice-water bath, TBTU (28.9 mg, 1.5 eq.) and DIPEA (15.5 mg, 2 eq.) were added, and stirring continued in an ice-water bath for 1.5 hours. Water (5.0 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (5 mL×5). The organic phases were combined, washed with saturated brine (5 mL×2), dried over anhydrous sodium sulfate, concentrated, and purified by HPLC to obtain 55.2 mg of the product with a purity of 97.1% and a yield of 80%. HRMS: 1150.6482 [M+1].

[0156] 1 HNMR (400 MHz, DMSO d6 ): δ9.31(s,1H),8.06-7.94(m,3H),7.40(s,br,1H),7.29(d,1H,J=9.2Hz), 7.02(d,2H,J=8.4Hz),6.68(d,2H,J=8.0Hz),5.45(d,1H,J=6.4Hz),5.19(d ,1H,J=3.2Hz),5.14(d,1H,J=4.4Hz),5.10(d,1H,J=5.2Hz),5.04-4.91(m, 3H),4.75-4.64(m,4H),4.42(s,1H),4.36-4.28(m,2H),4.21-4.16(m,3H), 4.04-4.01(m,1H),4.00-3.93(m,3H),3.88-3.84(m,1H),3.79-3.77(m,1H) ,3.71-3.68(m,1H),3.19(t,1H,J=8.0Hz),2.35-2.34(m,1H),2.24-2.15(m ,3H),2.08-2.08(m,2H),1.90-1.82(m,2H),1.69-1.59(m,1H),1.47-1.43( m,5H),1.39(s,9H),1.24(s,24H),1.08-1.06(m,6H),0.96(d,3H,J=6.8Hz).

[0157] Embodiment 5:

[0158] first step

[0159]

[0160] Dissolve N-(2-hydroxyethyl)-pyrrolidine (2.30 g, 20 mmol) in 40 ml of acetone, slowly add iodomethane (2.84 g, 1.0 eq.), heat under reflux and stir for 4 hours, concentrate until half of the solvent remains, precipitate solid, filter, and dry to obtain 4.88 g of white solid compound SM6, yield: 95%. Ms: 130.0 [M + ].

[0161] 1 HNMR (400MHz, D2O): δ4.09 (d, 2H, J = 2.0Hz), 3.63-3.56 (m, 6H), 3.15 (s, 3H), 2.26 (s, 4H).

[0162] Step 2

[0163]

[0164] Anidulafungin (300 mg, 0.26 mmol) and phenylboronic acid (64.2 mg, 2 eq.) were dissolved in THF (10 mL), stirred at room temperature for 1 hour, concentrated to dryness, anhydrous acetonitrile (10 mL) was added, compound SM6 (422.7 mg, 6 eq.) and p-toluenesulfonic acid (340 mg, 7.5 eq.) were added, stirred at room temperature for 5 hours under nitrogen protection, sodium acetate aqueous solution was added to quench, concentrated to obtain a crude product, and HPLC preparation and purification were performed to obtain 259 mg of the product (acetate), with a purity of 96.5% and a yield of 76%. HRMS: 1251.6174 [M + ].

[0165] 1HNMR (400MHz, CD3OD): δ8.00(d,2H,J=8.4Hz),7.83(d,2H,J=8.0Hz),7.77(m,4H),7.63(d,2H,J=8.8Hz),7.17(d,2H,J=8.4Hz),7.03(d,2H,J =8.8Hz),6.78(d,2H,J=8.8Hz),5.45(d,1H,J=2.0Hz),5.06(d,1H,J=3.2Hz),4.81-4.76(m,1H),4.62-4.60(m,3H),4.41(d,1H,J=4.4Hz),4. 36-4.33(m,2H),4.28-4.25(m,2H),4.22-4.18(m,1H),4.11-3.83(m,8 H),3.68-3.42(m,8H),3.09(s,3H),2.55-2.44(m,2H),2.33-2.27(m,1 H),2.23-2.03(m,6H),1.92(s,3H),1.87-1.80(m,2H),1.55-1.40(m,4H),1.28(d,6H,J=5.6Hz),1.09(d,3H,J=7.2Hz),0.92(t,3H,J=6.4Hz). .

[0166] Embodiment 6:

[0167]

[0168] Echinocandin B (100 mg, 0.12 mmol) and semaglutide side chain (100.9 mg, 1.0 eq.) were dissolved in DMF (4 ml), stirred in an ice-water bath, TBTU (58 mg, 1.5 eq.) and DIPEA (31 mg, 2 eq.) were added, and stirring continued for 1.5 hours in an ice-water bath. The reaction solution was added dropwise to 100 mL of ice water, solids were precipitated, filtered, dried, and slurried with acetonitrile to obtain 120 mg of product with a purity of 95.8% and a yield of 61.5%. HRMS: 1625.8989 [M+1].

[0169] 1 HNMR (400 MHz, DMSO d6): δ9.31(s,1H),8.05(d,2H,J=7.6Hz),7.95(d,1H,J=8.4Hz),7.90-7.88(m,1H),7.73-7.69(m, 2H),7.43-7.31(m,2H),7.02(d,2H,J=8.4Hz),6.69(d,2H,J=8.0Hz),5.52(d,1H,J=5.6Hz),5.2 0(d,1H,J=2.8Hz),5.15(d,1H,J=3.6Hz),5.10(d,1H,J=5.6Hz),5.01-4.91(m,3H),4.80-4.60( m,4H),4.42(s,1H),4.37-4.33(m,3H),4.22-4.17(m,2H),4.05-3.57(m,11H),3.57(s,br,9H), 3.48-3.45(m,2H),3.43-3.40(m,2H),3.30-3.28(m,2H),3.21-3.18(m,3H),2.36-2.33(m,1H),2.24-2.05(m,7H),1.94 -1.84(m,3H),1.76-1.62(m,2H),1.47(s,br,5H),1.39(s,18H),1.24(s,24H),1.08-1.06(m,6H),0.96(d,3H,J=6.8Hz).

[0170] Embodiment 7:

[0171]

[0172] The compound of Example 6 (100 mg, 0.0615 mmol) and phenylboronic acid (15 mg, 2 eq.) were dissolved in THF (4 mL), stirred at room temperature for 1 hour, concentrated to dryness, added with compound SM7 (101.6 mg, 6 eq.) and p-toluenesulfonic acid (53 mg, 5 eq.), continued to stir at room temperature for 5 hours under nitrogen protection, added with sodium acetate aqueous solution to quench, concentrated to obtain a crude product, prepared and purified by HPLC to obtain 44.9 mg of the product (trifluoroacetate), with a purity of 96.5% and a yield of 40%. HRMS: 1710.9867 [M + ].

[0173] 1HNMR (400MHz, CD3OD): δ8.48(d,1H,J=8.4Hz),8.41(d,1H,J=8.8Hz),8.23(d,1H,J=7.6Hz),8.04-7.99(m,2H),7.60-7.54(m,2H),7.15(d,2H,J=8 .0Hz),6.77(d,2H,J=8.4Hz),5.51(d,1H,J=9.6Hz),5.05-4.89(m,1H),4 .60-4.45(m,4H),4.37-4.32(m,3H),4.28-4.25(m,3H),4.13-3.82(m,10H ),3.76-3.63(m,10H),3.59-3.56(m,3H),3.54-3.56(m,3H),3.53-3.46( m,3H),3.41-3.38(m,3H),3.21(m,9H),2.55-2.44(m,2H),2.36-2.21(m,6 H),2.17-2.06(m,2H),1.92-1.83(m,2H),1.64-1.56(m,4H),1.49(s,9H) ,1.46(s,9H),1.31(s,24H),1.22(d,6H,J=6.4Hz),1.08(d,3H,J=6.4Hz).

[0174] Embodiment 8:

[0175]

[0176] The trifluoroacetate salt of Example 7 compound (24 mg, 0.014 mmol) was dissolved in TFA (1 mL), stirred in an ice-water bath for 5 hours, concentrated to dryness, and purified by HPLC to obtain 7.2 mg of the product (trifluoroacetate salt) with a purity of 97.8% and a yield of 30%. HRMS: 1598.8629 [M + ].

[0177] Embodiment 9:

[0178] first step

[0179]

[0180] Echinocandin B (200 mg, 0.2397 mmol) and SM8 (89 mg, 1.0 eq.) were dissolved in DMF (5 ml), stirred in an ice-water bath, TBTU (115 mg, 1.5 eq.) and DIPEA (62 mg, 2 eq.) were added, and continued to stir in an ice-water bath for 1.5 hours. Purification by reverse phase column gave 234 mg of product with a yield of 85%. Ms: 1152.5 [M+1].

[0181] 1 HNMR (400MHz, CD3OD): δ7.96 (d, 2H, J = 6.0Hz), 7.77-7.69 (m, 6H), 7.62 (d, 2H, J = 8.4Hz), 7.17 (d, 2H, J = 8.4Hz), 7.02 (d, 2H, J = 8.8Hz ),6.78(d,2H,J=8.4Hz),5.37(d,1H,J=2.8Hz),5.05-5.02(m,1H),4.89-4.88(m,1H),4.70-4.58(m,5H),4.39-4.33(m,3H),4.28-4 .22(m,3H),4.10-4.07(m,2H),4.03-4.00(m,1H),3.93-3.83(m,2H),3.45-3.40(m,1H),2.55-2.44(m,2H),2.25-2.06(m,3H),1.98 -1.91(m,2H),1.46-1.37(m,2H),1.31-1.27(m,6H),1.08(d,3H,J=6.8Hz),0.77-0.74(m,1H),0.50-0.46(m,2H),0.10-0.06(m,2H).

[0182] Step 2

[0183]

[0184] SM9 (140 mg, 0.1214 mmol) and phenylboronic acid (0.728 mg, 2 eq.) were dissolved in THF (5 mL), stirred at room temperature for 1 hour, concentrated to dryness, added compound SM7 (200 mg, 6 eq.), p-toluenesulfonic acid (105 mg, 5 eq.) and anhydrous acetonitrile (5 mL), stirred at room temperature for 5 hours under nitrogen protection, added sodium acetate aqueous solution to quench, concentrated to obtain a crude product, HPLC preparation and purification, to obtain 102 mg product (acetate), purity 95.8%, yield 65%. HRMS: 1237.6022 [M + ].

[0185] 1HNMR (400MHz, CD3OD): δ7.99 (d, 2H, J = 8.4Hz), 7.82 (d, 2H, J = 8.0Hz), 7.78-7 .71(m,4H),7.62(d,2H,J=8.4Hz),7.17(d,2H,J=8.4Hz),7.03(d,2H,J=8.4H z), 6.78 (d, 2H, J = 8.4Hz), 5.46 (d, 1H, J = 8.4Hz), 5.08-5.05 (m, 1H), 4.90-4. 77(m,2H),4.63-4.59(m,3H),4.41-4.33(m,3H),4.29-4.26(m,2H),4.21-4.1 8(m,1H),4.11-3.90(m,7H),3.84(d,1H,J=11.2Hz),3.64-3.62(m,1H),3.67 -3.48(m,2H),3.17(s,9H),),2.55-2.44(m,2H),2.34-2.27(m,1H),2.13-2. 02(m,2H),1.97-1.90(m,2H),1.46-1.41(m,2H),1.29(s,3H),1.27(s,3H),1 .10(d,3H,J=6.8Hz)0.80-0.74(m,1H),0.50-0.46(m,2H),0.10-0.06(m,2H).

[0186] Embodiment 10:

[0187] first step

[0188]

[0189] Dissolve N-(2-hydroxyethyl)-pyrrolidine (6.5 g, 50 mmol) in 25 ml of acetonitrile, slowly add iodomethane (7.09 g, 1.0 eq.), heat under reflux and stir for 4 hours, concentrate until half of the solvent remains, precipitate solid, filter, and dry to obtain 12.1 g of white solid compound SM10, yield: 90%. Ms: 144.0 [M + ].

[0190] Step 2

[0191]

[0192] Under nitrogen protection, anidulafungin (100 mg, 0.0877 mmol) was dissolved in tetrahydrofuran (10 mL), phenylboronic acid (21.4 mg, 0.1754 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated to dryness in vacuo, 10 mL of dioxane was added, compound SM10 (162.6 mg, 0.6 mmol) and p-toluenesulfonic acid (75.5 mg, 0.44 mmol) were added, and the mixture was stirred at room temperature for 16 h. 1N sodium acetate aqueous solution (1 mL) was added to quench the reaction solution, the solvent was removed by rotary evaporation, and the crude product was purified by preparative chromatography to obtain 47.6 mg (acetate) of the product, with a purity of 97.1% and a yield of 41%. HRMS: 1265.6324 [M + ].

[0193] 1 H NMR (400MHz, METHANOL-d4) δ7.98(d,J=8.4Hz,2H),7.81(d,J=8.4Hz,2H),7.70-7.76(m,4H),7.61(d,J=8.8Hz,2H),7.15(d,J=8 .4Hz,2H),7.01(d,J=8.8Hz,2H),6.76(d,J=8.4Hz,2H),5.42(d,J=1.6Hz,1H),5.04(d,J=3.2Hz,1H),4.74-4.78(m,1H),4.58-4 .61(m,3H),4.16-4.40(m,6H),3.81–4.10(m,8H),3.38–3.65(m,7H),3.09(s,3H),2.42-2.53(m,2H),2.26-2.28(m,1H),2.03-2 .12(m,2H),1.90(s,3H),1.78–1.83(m,6H),1.38-1.63(m,6H),1.26-1.30(m,7H),1.08(d,J=7.2Hz,3H),0.97(t,J=7.2Hz,3H).

[0194] Embodiment 11:

[0195] first step

[0196]

[0197] Echinocandin B (300 mg, 0.36 mmol) and SM11 (147 mg, 1.1 eq.) were dissolved in DMF (15 ml), stirred in an ice-water bath, TBTU (174 mg, 1.5 eq.) and DIPEA (141 mg, 3 eq.) were added, and stirring was continued in an ice-water bath for 1 hour. The reaction solution was passed through a reverse phase column (MECN / H2O) to obtain 392 mg of compound SM12 with a purity of 96% and a yield of 70.6%. MS: 1158.5 [M+1].

[0198] Step 2

[0199]

[0200] Under nitrogen protection, SM12 (100 mg, 0.086 mmol) was dissolved in tetrahydrofuran (10 mL), phenylboronic acid (21.3 mg, 0.173 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated to dryness in vacuo, 10 mL of dioxane was added, compound SM7 (108 mg, 0.777 mmol) and camphorsulfonic acid (100 mg, 0.43 mmol) were added, and the mixture was stirred at room temperature for 16 h. 1N sodium acetate aqueous solution (1 mL) was added to quench the reaction solution, the solvent was removed by rotary evaporation, and the crude product was purified by preparative chromatography to obtain 39.5 mg of the product (formate), with a purity of 97.0% and a yield of 35.5%. HRMS: 1243.5936 [M + ].

[0201] 1 H NMR (400MHz, METHANOL-d4) δ8.54(s,1H),7.98(d,J=8.0Hz,2H),7.81(d,J=8.0Hz,2H),7.70-7.76(m,4H),7.61(d,J=8.4Hz ,2H),7.15(d,J=8.4Hz,2H),7.02(d,J=8.0Hz,2H),6.76(d,J=8.4Hz,2H),5.42(s,1H),5.04(s,1H),4.71-4.78(m,1H),4.4 8-4.58(m,4H),4.16-4.42(m,7H),4.05(t,J=6.4Hz,3H),3.81–4.01(m,3H),3.47–3.65(m,4H),3.22(s,9H),2.42-2.53(m, 2H),2.25-2.32(m,1H),2.00-2.11(m,2H),1.73-1.88(m,4H),1.59-1.66(m,2H),1.26-1.37(m,8H),1.08(d,J=6.8Hz,3H).

[0202] Embodiment 12:

[0203]

[0204] Under nitrogen protection, anidulafungin (200 mg, 0.175 mmol) was dissolved in tetrahydrofuran (20 mL), phenylboronic acid (42.8 mg, 0.351 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated to dryness in vacuo, 20 mL of dioxane was added, compound SM13 (235 mg, 1.58 mmol) and p-toluenesulfonic acid (151 mg, 0.877 mmol) were added, and the mixture was stirred at room temperature for 16 h. 1N sodium acetate aqueous solution (2 mL) was added to quench the reaction solution, the solvent was removed by rotary evaporation, and the crude product was purified by preparative chromatography to obtain 48.3 mg (acetate), with a purity of 97.7% and a yield of 21.3%. HRMS: 1234.6581 [M + ].

[0205] Embodiment 13:

[0206] first step

[0207]

[0208] Dissolve N-methyl-D-prolinol (1.15 g, 10 mmol) in 20 ml of acetone, slowly add iodomethane (1.56 g, 1.1 eq.), heat under reflux and stir for 4 hours, concentrate until half of the solvent remains, precipitate solid, filter, and dry to obtain 2.44 g of white solid compound SM14, yield: 95%. Ms: 130.0 [M + ].

[0209] Step 2

[0210]

[0211] Anidulafungin (100 mg, 0.0877 mmol) and phenylboronic acid (21.39 mg, 2 eq.) were dissolved in THF (5 mL), stirred at room temperature for 1 hour, concentrated to dryness, compound SM14 (135.2 mg, 6 eq.), p-toluenesulfonic acid (75.6 mg, 5 eq.) and anhydrous dioxane (5 mL) were added, stirred at room temperature for 5 hours under nitrogen protection, quenched by adding sodium acetate aqueous solution, concentrated to obtain a crude product, and purified by HPLC to obtain 57.5 mg of the product (acetate), with a purity of 95.8% and a yield of 50%. HRMS: 1251.6173 [M + ].

[0212] 1H NMR(400MHz,METHANOL-d4)δ7.98(d,J=8.8Hz,2H),7.81(d,J=8.0Hz,2H),7.69- 7.76(m,4H),7.61(d,J=9.2Hz,2H),7.15(d,J=8.8Hz,2H),7.01(d,J=8.8Hz,2H) ,6.76(d,J=8.4Hz,2H),5.42(d,J=2.4Hz,1H),5.03(d,J=3.2Hz,1H),4.92-4.93 (m,1H),4.74-4.78(m,1H),4.57-4.61(m,3H),4.38(d,J=4.0Hz,1H),4.32-4.34( m,2H),4.24-4.28(m,2H),4.16-4.20(m,1H),4.06-4.10(m,1H),3.97-4.04(m,4 H),3.81-3.92(m,4H),3.46-3.63(m,3H),3.21(s,3H),3.00(s,3H),2.42-2.52( m,2H),2.26-2.31(m,2H),1.92–2.15(m,5H),1.90(s,3H),1.78–1.85(m,2H),1. 40-1.52(m,4H),1.25-1.28(m,6H),1.08(d,J=6.8Hz,3H),0.97(t,J=6.8Hz,3H).

[0213] Embodiment 14:

[0214] first step

[0215]

[0216] Compound SM15 (1.02 g, 10.08 mmol) was dissolved in acetonitrile (10 mL), and methyl p-toluenesulfonate (1.88 g, 10.08 mmol) was added dropwise. The reaction solution was heated to reflux for 4 h, and the solvent was dried to obtain a crude compound SM16, which was directly used in the next step. Ms: 116.1 [M + ].

[0217] Step 2

[0218]

[0219] Under nitrogen protection, anidulafungin (1.14 g, 1 mmol) was dissolved in tetrahydrofuran (40 mL), phenylboronic acid (244 mg, 2 mmol) was added, stirred at room temperature for 2 hours, and the solvent was evaporated to dryness in vacuo. 50 mL of dioxane was added, compound SM16 (2.86 g, 10 mmol) and camphorsulfonic acid (1.16 g, 5 mmol) were added, and stirred at room temperature for 16 h. 1N sodium acetate aqueous solution (10 mL) was added to quench the reaction solution, and the solvent was removed by rotary evaporation. The crude product was purified by preparative chromatography to obtain 563 mg of the product (acetate), with a purity of 95.4% and a yield of 43.4%. HRMS: 1237.6023 [M + ].

[0220] 1 H NMR (400MHz, METHANOL-d4) δ7.97 (d, J = 8.3Hz, 2H), 7.80-7.82 (m, 2H), 7.69-7. 76(m,4H),7.61(d,J=8.8Hz,2H),7.14(d,J=8.6Hz,2H),7.01(d,J=8.8Hz,2H),6 .76(d,J=8.6Hz,2H),5.35-5.36(m,1H),5.02-5.03(m,1H),4.86(d,J=5.1Hz,1H ),4.74(dd,J=5.3,12.1Hz,1H),4.44-4.65(m,5H),4.39(d,J=4.4Hz,1H),4.31- 4.33(m,2H),4.22-4.26(m,2H),4.06-4.20(m,4H),4.02(t,J=6.5Hz,3H),3.81- 3.98(m,4H),3.51-3.69(m,2H),3.43-3.50(m,1H),3.19(s,3H),2.60-2.72(m,1 H),2.34-2.56(m,3H),2.21-2.33(m,1H),1.97-2.14(m,2H),1.75-1.87(m,5H), 1.39-1.52(m,4H),1.24-1.28(m,6H),1.07(d,J=6.8Hz,3H),0.92-1.01(m,3H).

[0221] Embodiment 15:

[0222] first step

[0223]

[0224] Echinocandin B (250 mg, 0.3 mmol) and SM17 (114 mg, 1.0 eq.) were dissolved in DMF (2.5 ml), stirred in an ice-water bath, TBTU (145 mg, 1.5 eq.) and DIPEA (78 mg, 2.0 eq.) were added, and stirring was continued in an ice-water bath for 1 hour. The reaction solution was passed through a reverse phase column (MECN / H2O) to obtain 298 mg of compound SM18 with a purity of 97% and a yield of 72.6%. MS: 1158.5 [M+1].

[0225] Step 2

[0226]

[0227] Under nitrogen protection, SM18 (150 mg, 0.13 mmol) was dissolved in tetrahydrofuran (7.5 mL), phenylboronic acid (31.6 mg, 0.259 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated to dryness in vacuo, 7.5 mL of dioxane was added, compound SM7 (108 mg, 0.777 mmol) and camphorsulfonic acid (150 mg, 0.65 mmol) were added, and the mixture was stirred at room temperature for 16 h. 1N sodium acetate aqueous solution (1 mL) was added to quench the reaction solution, the solvent was removed by rotary evaporation, and the crude product was purified by preparative chromatography to obtain 57 mg of the product (formate), with a purity of 97.8% and a yield of 34.1%. HRMS: 1243.5928 [M + ].

[0228] 1 H NMR (400MHz, METHANOL-d4) δ8.55(s,1H),7.61-7.81(m,9H),7.15(d,J=8.8Hz,2H),7.02(d,J=8.8Hz,2H),6.7 6(d,J=8.4Hz,2H),5.37(d,J=2.4Hz,1H),5.03(d,J=3.2Hz,1H),4.71-4.76(m,1H),4.58-4.61(m,4H),4.14-4. 40(m,6H),3.81–4.08(m,8H),3.46–3.65(m,3H),3.16(s,9H),2.42-2.54(m,2H),2.25-2.31(m,1H),2.01-2.1 2(m,2H),1.78–1.85(m,2H),1.38-1.53(m,4H),1.25-127(m,6H),1.08(d,J=6.8Hz,3H),0.97(t,J=7.2Hz,3H).

[0229] Embodiment 16:

[0230] first step

[0231]

[0232] Echinocandin B (400 mg, 1.12 mmol) and SM19 (930 mg, 1.0 eq.) were dissolved in DMF (8 ml), stirred in an ice-water bath, TBTU (359 mg, 1.0 eq.) and DIPEA (288 mg, 2.0 eq.) were added, and stirring was continued in an ice-water bath for 1 hour. The reaction solution was passed through a reverse phase column (MECN / H2O) to obtain 890 mg of compound SM20 with a purity of 89.6% and a yield of 70.1%. MS: 1138.5 [M+1].

[0233] Step 2

[0234]

[0235] Under nitrogen protection, SM20 (200 mg, 0.18 mmol) was dissolved in tetrahydrofuran (4 mL), phenylboronic acid (42.8 mg, 0.351 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated in vacuo to dryness, 8 mL of dioxane was added, compound SM7 (146 mg, 1.05 mmol) and camphorsulfonic acid (204 mg, 0.88 mmol) were added, and the mixture was stirred at room temperature for 16 h. 1N sodium acetate aqueous solution (1 mL) was added to quench the reaction solution, the solvent was removed by rotary evaporation, and the crude product was purified by preparative chromatography to obtain 123 mg of the product (acetate), with a purity of 97.6% and a yield of 54.6%. HRMS: 1223.6224 [M + ].

[0236] 1H NMR (400MHz, METHANOL-d4) δ7.98(d,J=8.4Hz,2H),7.80(d,J=8.4Hz,2H),7.72-7.78(m,4H),7.59(d,J=8.0Hz,2H),7.28(d,J=8.0Hz,2 H),7.15(d,J=8.4Hz,2H),6.76(d,J=8.8Hz,2H),5.42(d,J=2.0Hz,1H),5.04(d,J=3.2Hz,1H),4.87(s,1H),4.74-4.78(m,1H),4.56-4.6 1(m,3H),4.16-4.40(m,6H),3.81–4.11(m,6H),3.46-3.62(m,3H),3.14(s,9H),2.64-2.68(m,2H),2.42-2.53(m,2H),2.26-2.29(m,1H) ,2.04–2.12(m,2H),1.91(s,3H),1.62–1.68(m,2H),1.35-1.40(m,6H),1.26-1.27(m,6H),1.07(d,J=7.2Hz,3H),0.91(t,J=6.8Hz,3H).

[0237] Embodiment 17:

[0238] first step

[0239]

[0240] Echinocandin B (162 mg, 0.195 mmol) and SM21 (70 mg, 1.0 eq.) were dissolved in DMF (1.4 ml), stirred in an ice-water bath, TBTU (84.6 mg, 1.5 eq.) and DIPEA (50 mg, 2.0 eq.) were added, and stirring was continued in an ice-water bath for 1 hour. The reaction solution was passed through a reverse phase column (MECN / H2O) to obtain 94 mg of compound SM22 with a purity of 73% and a yield of 32.9%. MS: 1139.5 [M+1].

[0241] Step 2

[0242]

[0243] Under nitrogen protection, SM22 (100 mg, 0.18 mmol) was dissolved in tetrahydrofuran (2 mL), phenylboronic acid (21.4 mg, 2.0 eq) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated to dryness in vacuo, 4 mL of dioxane was added, compound SM7 (73.5 mg, 6.0 eq) and camphorsulfonic acid (102 mg, 5.0 eq) were added, and the mixture was stirred at room temperature for 16 h. 1N sodium acetate aqueous solution (1 mL) was added to quench the reaction solution, the solvent was removed by rotary evaporation, and the crude product was purified by preparative chromatography to obtain 31 mg of the product (acetate), with a purity of 96.1% and a yield of 27.5%. HRMS: 1224.6163 [M + ].

[0244] 1 H NMR(400MHz, METHANOL-d4)δ7.96(d,J=8.4Hz,2H),7.79(d,J=8.0Hz,2H),7.65-7.72(m,4H),7.48(d,J=8.8Hz,2H),7.15(d,J=8 .4Hz,2H),6.71-6.78(m,4H),5.43(d,J=2.0Hz,1H),5.04(d,J=3.6Hz,1H),4.91-4.93(m,1H),4.73-4.78(m,1H),4.57-4.61(m,3 H),4.16-4.40(m,6H),3.81–4.10(m,6H),3.46-3.62(m,3H),3.11-3.14(m,11H),2.42-2.53(m,2H),2.26-2.31(m,1H),2.02–2.1 2(m,2H),1.91(s,3H),1.62-1.67(m,2H),1.38-1.44(m,4H),1.26(d,J=6.0Hz,6H),1.08(d,J=6.8Hz,3H),0.96(t,J=6.8Hz,3H).

[0245] Embodiment 18:

[0246]

[0247] Under nitrogen protection, anidulafungin (100 mg, 0.088 mmol) was dissolved in tetrahydrofuran (4 mL), phenylboronic acid (21.4 mg, 0.175 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated to dryness in vacuo, 4 mL of dioxane was added, compound SM23 (75.6 mg, 0.526 mmol) and p-toluenesulfonic acid (75.5 mg, 0.438 mmol) were added, and the mixture was stirred at room temperature for 16 h. 1N sodium acetate aqueous solution (2 mL) was added to quench the reaction solution, the solvent was removed by rotary evaporation, and the crude product was purified by preparative chromatography to obtain 35 mg of the product (acetate), with a purity of 97.3% and a yield of 30.9%. HRMS: 1229.6268 [M + ].

[0248] 1 H NMR (400MHz, METHANOL-d4) δ7.97(d,J=8.4Hz,2H),7.79(d,J=8.4Hz,2H),7.69-7.76(m,4H),7.61(d,J=8.8Hz,2H),7.15(d,J=8.4Hz,2H),7.00(d,J= 8.8Hz, 2H), 6.76 (d, J = 8.4Hz, 2H), 5.42 (d, J = 2.4Hz, 1H), 5.04 (d, J = 2.8Hz, 1H), 4.88 (s, 1H), 4 .74-4.78(m,1H),4.57-4.61(m,3H),4.15-4.40(m,6H),3.81–4.11(m,6H),3.46-3.50(m,1H), 3.14(s,9H),2.42-2.54(m,2H),2.25-2.32(m,1H),2.01–2.11(m,2H),1.91(s,3H),1.77–1.84 (m,2H),1.38-1.53(m,4H),1.27(d,J=5.6Hz,6H),1.07(d,J=7.6Hz,3H),0.97(t,J=6.8Hz,3H).

[0249] Embodiment 19:

[0250] first step

[0251]

[0252] Echinocandin B (161 mg, 0.193 mmol) and SM24 (80 mg, 1.0 eq.) were dissolved in DMF (3.2 ml), stirred in an ice-water bath, TBTU (93 mg, 1.5 eq.) and DIPEA (50 mg, 2.0 eq.) were added, and stirring was continued in an ice-water bath for 1 hour. The reaction solution was passed through a reverse phase column (MECN / H2O) to obtain 165 mg of compound SM25 with a purity of 95.9% and a yield of 71.6%. MS: 1194.5 [M+1].

[0253] Step 2

[0254]

[0255] Under nitrogen protection, SM25 (100 mg, 0.084 mmol) was dissolved in tetrahydrofuran (4 mL), phenylboronic acid (20.4 mg, 2.0 eq) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated to dryness in vacuo, 4 mL of dioxane was added, compound SM7 (70 mg, 6.0 eq) and camphorsulfonic acid (97.6 mg, 5.0 eq) were added, and the mixture was stirred at room temperature for 16 h. 1N sodium acetate aqueous solution (1 mL) was added to quench the reaction solution, the solvent was removed by rotary evaporation, and the crude product was purified by preparative chromatography to obtain 33 mg of the product (acetate), with a purity of 97.2% and a yield of 29.4%. HRMS: 1279.5720 [M + ].

[0256] 1 H NMR(400MHz, METHANOL-d4)δ7.97(d,J=8.0Hz,2H),7.80(d,J=8.4Hz,2H),7.69-7.76(m,4H),7.62(d,J=8.4Hz,2H),7.15 (d,J=8.4Hz,2H),7.03(d,J=8.8Hz,2H),6.76(d,J=8.4Hz,2H),5.42(d,J=2.0Hz,1H),5.04(d,J=3.2Hz,1H),4.88(s,1H) ,4.73-4.78(m,1H),4.57-4.61(m,3H),4.16-4.40(m,6H),3.81–4.11(m,8H),3.46-3.62(m,3H),3.15(s,9H),2.42-2.53 (m,2H),2.23-2.32(m,3H),2.04–2.11(m,2H),1.93(s,3H),1.87–1.90(m,2H),1.76–1.82(m,2H),1.26(d,J=6.4Hz,6H), 1.08 (d, J=6.8Hz, 3H).

[0257] Embodiment 20:

[0258] first step

[0259]

[0260] SM-26 (590 mg, 1 eq.) was dissolved in 10 acetonitrile, methyl p-toluenesulfonate (1.2 g, 1.1 eq.) was added, heated under reflux and stirred for 4 hours, concentrated, and slurried with acetone petroleum ether to obtain 1.6 g of white solid compound SM-27, yield: 95%. Ms: 117.1 [M + ].

[0261] Step 2

[0262]

[0263] Anidulafungin (100 mg, 0.0877 mmol) and phenylboronic acid (21.39 mg, 2 eq.) were dissolved in THF (5 mL), stirred at room temperature for 1 hour, concentrated to dryness, added with compound SM-27 (151 mg, 6 eq.), p-toluenesulfonic acid (75.4 mg, 5 eq.) and anhydrous dioxane (5 mL), stirred at room temperature for 5 hours under nitrogen protection, quenched with an aqueous solution of sodium acetate, concentrated to obtain a crude product, and purified by HPLC to obtain 60 mg of the product (formate salt), with a purity of 97.8% and a yield of 55.6%. HRMS: 1237.6024 [M + ].

[0264] 1HNMR (400MHz, CD3OD): δ8.56 (s, 1H), 8.02 (d, 2H, J = 10.8Hz), 7.82 (d, 2H, J = 8.4Hz), 7.77 (m, 4H), 7.63 (d, 2H, J = 8.4Hz), 7.17 (d, 2H, J=8.8Hz),7.03(d,2H,J=8.8Hz),6.78(d,2H,J=8.8Hz),5.42(d,1H,J=2.4Hz),5.06(d,1H,J=2.8Hz),4.92-4.88(m,2H),4.81-4.72( m,2H),4.63-4.58(m,3H),4.42(d,1H,J=4.0Hz),4.29-3.81(m,14H),3.52-3.38(m,1H),3.19(s,6H),2.57-2.43(m,4H),2.34-2.27( m,1H),2.13-2.04(m,2H),1.87-1.80(m,2H),1.55-1.40(m,4H),1.29(d,6H,J=6.0Hz),1.08(d,3H,J=6.8Hz),0.99(t,3H,J=6.8Hz).

[0265] Embodiment 21:

[0266]

[0267] The trifluoroacetate salt of the compound of Example 6 (24 mg, 0.014 mmol) was dissolved in TFA (1 mL), stirred in an ice-water bath for 5 hours, concentrated to dryness, and purified by HPLC to obtain 7.2 mg of the product (trifluoroacetate salt) with a purity of 97.8% and a yield of 30%. HRMS: 1513.7743 [M+1].

[0268] Embodiment 22:

[0269] first step

[0270]

[0271] Compound SM-29 (5.4 g, 52.3 mmol) was dissolved in acetone (54 mL), and methyl p-toluenesulfonate (10.23 g, 54 mmol) was added dropwise. The reaction solution was heated to reflux for 2 h, and a white solid was precipitated. The mixture was cooled to room temperature and filtered. The filter cake was vacuum dried to obtain 6.5 g of compound SM-30 with a purity of 98% and a yield of 42.9%. Ms: 118.12 [M + ].

[0272] Step 2

[0273]

[0274] Under nitrogen protection, anidulafungin (100 mg, 0.0877 mmol) and phenylboronic acid (21.39 mg, 2 eq.) were dissolved in tetrahydrofuran (4 mL) and stirred at room temperature for 2 hours. The solvent was evaporated to dryness in vacuo, 4 mL of dioxane was added, compound SM-30 (152.3 mg, 0.526 mmol) and camphorsulfonic acid (102 mg, 0.44 mmol) were added, and stirred at room temperature for 16 h. 1N sodium acetate aqueous solution (1 mL) was added to quench the reaction solution, and the solvent was removed by rotary evaporation. The crude product was purified by preparative chromatography to obtain 53 mg of the product (acetate), with a purity of 96.1% and a yield of 46.5%. HRMS: 1239.6225 [M + ].

[0275] 1 H NMR (400MHz, METHANOL-d4) δ7.98(d,J=8.4Hz,2H),7.81(d,J=7.2Hz,2H),7.69-7.76(m,4H),7.61(d,J=8.8Hz,2H),7.15(d,J=8.4Hz,2H),7.01(d,J= 8.8Hz,2H),6.76(d,J=8.4Hz,2H),5.44(s,1H),5.04(d,J=3.2Hz,1H),4.85(m,1H),4.74-4.78(m,1H),4.57-4 .61(m,3H),4.39(d,J=4.0Hz,1H),4.32-4.34(m,2H),4.24-4.27(m,2H),4.16-4.20(m,1H),3.81-4.07(m,8H) ,3.74(m,1H),3.46-3.50(m,1H),3.11(s,9H),2.42-2.53(m,2H),2.28-2.36(m,1H),2.02–2.11(m,2H),1.90( s, 3H), 1.78–1.85 (m, 2H), 1.43-1.52 (m, 7H), 1.25-1.27 (m, 6H), 1.08 (d, J = 6.4Hz, 3H), 0.97 (t, J = 7.2Hz, 3H).

[0276] Embodiment 23:

[0277] first step

[0278]

[0279] Compound SM-31 (2.15 g, 20.84 mmol) was dissolved in acetone (21.5 mL), and methyl p-toluenesulfonate (4.08 g, 22 mmol) was added dropwise. The reaction solution was heated to reflux for 2 h, and a white solid was precipitated. The mixture was cooled to room temperature and filtered. The filter cake was dried under vacuum to obtain 3.2 g of compound SM-32 with a purity of 98% and a yield of 53%. Ms: 118.12 [M + ].

[0280] Step 2

[0281]

[0282] Under nitrogen protection, anidulafungin (100 mg, 0.0877 mmol) and phenylboronic acid (21.39 mg, 2 eq.) were dissolved in tetrahydrofuran (4 mL) and stirred at room temperature for 2 hours. The solvent was evaporated to dryness in vacuo, 4 mL of dioxane was added, compound SM-32 (152.3 mg, 0.526 mmol) and camphorsulfonic acid (102 mg, 0.44 mmol) were added, and stirred at room temperature for 16 h. 1N sodium acetate aqueous solution (1 mL) was added to quench the reaction solution, and the solvent was removed by rotary evaporation. The crude product was purified by preparative chromatography to obtain 39 mg of the product (acetate), with a purity of 99.6% and a yield of 34.2%. HRMS: 1239.6226 [M + ].

[0283] 1H NMR(400MHz,METHANOL-d4)δ7.97(d,J=8.4Hz,2H),7.69-7.81(m,6H),7.61(d,J=8.4Hz,2H),7.1 5(d,J=8.4Hz,2H),7.01(d,J=8.4Hz,2H),6.76(d,J=8.4Hz,2H),5.34(d,J=2.8Hz,1H),5.02(d,J= 2.4Hz, 1H), 4.85 (m, 1H), 4.73-4.78 (m, 1H), 4.57-4.61 (m, 3H), 4.39 (d, J = 4.4Hz, 1H), 4.32-4.34 (m,2H),4.24-4.28(m,2H),4.17-4.21(m,1H),3.79-4.10(m,8H),3.66(m,1H),3.46-3.50(m,1H), 3.12(s,9H),2.42-2.53(m,2H),2.25-2.31(m,1H),2.03–2.11(m,2H),1.89(s,3H),1.78–1.8 4(m,2H),1.37-1.53(m,7H),1.25-1.28(m,6H),1.08(d,J=6.8Hz,3H),0.97(t,J=7.2Hz,3H).

[0284] Embodiment 24:

[0285] first step

[0286]

[0287] Compound SM-33 (2.2 g, 21.3 mmol) was dissolved in acetone (22 mL), and methyl p-toluenesulfonate (4.17 g, 22.4 mmol) was added dropwise. The reaction solution was heated to reflux for 2 h, and a white solid was precipitated. The mixture was cooled to room temperature and filtered. The filter cake was dried under vacuum to obtain 2.05 g of compound SM-34 with a purity of 98% and a yield of 33%. Ms: 118.12 [M + ].

[0288] Step 2

[0289]

[0290] Under nitrogen protection, anidulafungin (100 mg, 0.0877 mmol) and phenylboronic acid (21.39 mg, 2 eq.) were dissolved in tetrahydrofuran (4 mL) and stirred at room temperature for 2 hours. The solvent was evaporated to dryness in vacuo, 4 mL of dioxane was added, compound SM-34 (152.3 mg, 0.526 mmol) and camphorsulfonic acid (102 mg, 0.44 mmol) were added, and stirred at room temperature for 16 h. 1N sodium acetate aqueous solution (1 mL) was added to quench the reaction solution, and the solvent was removed by rotary evaporation. The crude product was purified by preparative chromatography to obtain 29 mg of the product (acetate), with a purity of 97.5% and a yield of 25.4%. HRMS: 1239.6223 [M + ].

[0291] 1 H NMR (400MHz, METHANOL-d4) δ7.96(d,J=7.2Hz,2H),7.69-7.80(m,6H),7.61(d,J=8.4Hz,2H),7.15(d,J=8.8Hz,2H),7.01(d,J=7.6Hz,2H),6.76 (d,J=8.4Hz,2H),5.50(s,1H),5.04(d,J=3.2Hz,1H),4.85(m,1H),4.78 -4.79(m,1H),4.55-4.60(m,3H),4.30-4.36(m,4H),4.22-4.27(m,2H),4 .16-4.20(m,1H),3.80-4.10(m,6H),3.52-3.55(m,1H),3.34-3.43(m,2 H),3.18(s,9H),2.42-2.51(m,2H),2.24-2.30(m,1H),2.05–2.13(m,2H ),1.90(s,3H),1.78–1.84(m,2H),1.40-1.51(m,4H),1.27(t,J=7.2Hz, 6H), 1.20 (d, J=5.2Hz, 3H), 1.07 (d, J=7.2Hz, 3H), 0.97 (t, J=6.8Hz, 3H).

[0292] Embodiment 25:

[0293] first step

[0294]

[0295] SM-35 (505 mg, 1 eq.) was dissolved in 5 mL of acetone, methyl p-toluenesulfonate (1.02 g, 1.1 eq.) was added, stirred at room temperature for 2 hours, filtered, and the filter cake was rinsed with acetone to obtain 1.22 g of white solid compound SM-36, yield: 85%. Ms: 116.2 [M + ].

[0296] Step 2

[0297]

[0298] Under nitrogen protection, anidulafungin (100 mg, 0.0877 mmol) and phenylboronic acid (21.39 mg, 2 eq.) were dissolved in tetrahydrofuran (4 mL) and stirred at room temperature for 2 hours. The solvent was evaporated to dryness in vacuo, 4 mL of dioxane was added, compound SM-36 (151.2 mg, 0.526 mmol) and camphorsulfonic acid (102 mg, 0.44 mmol) were added, and stirred at room temperature for 16 h. 1N sodium acetate aqueous solution (1 mL) was added to quench the reaction solution, concentrated to obtain a crude product, and HPLC preparation and purification were performed to obtain 50 mg of the product (acetate), with a purity of 96.2% and a yield of 44%. HRMS: 1238.4225 [M + ].

[0299] 1HNMR (400MHz, METHANOL-d4): δ8.02(d,2H,J=8.4Hz),7.84(d,2H,J=8.0Hz),7.78-7.71(m,4H),7.63(d,2H,J=6.8Hz),7.17(d,2H,J=8.8Hz),7.03(d,2H ,J=8.8Hz),6.81(d,2H,J=7.2Hz),5.52(d,1H,J=1.6Hz),5.08(d,1H,J=3.2 Hz),4.84-4.76(m,1H),4.63-4.60(m,6H),4.42(d,1H,J=4.4Hz),4.36-4.33 (m,2H),4.27-4.23(m,2H),4.18-4.15(m,1H),4.06-4.00(m,4H),3.96-3.9 0(m,2H),3.86-3.83(m,1H),3.74-3.46(m,4H),3.18(s,3H),3.11(s,3H),2. 60-2.30(m,4H),2.10-2.04(m,2H),1.91(s,3H),1.85-1.80(m,2H),1.53-1 .40(m,4H),1.29-1.26(m,6H),1.10(d,3H,J=7.2Hz),0.99(t,3H,J=7.2Hz).

[0300] Embodiment 26:

[0301] first step

[0302]

[0303] SM-37 (505 mg, 1 eq.) was dissolved in 5 mL of acetone, methyl p-toluenesulfonate (1.02 g, 1.1 eq.) was added, stirred at room temperature for 2 hours, filtered, and the filter cake was rinsed with acetone to obtain 1.29 g of white solid compound SM-38, yield: 90%. Ms: 116.2 [M + ].

[0304] Step 2

[0305]

[0306] Under nitrogen protection, anidulafungin (100 mg, 0.0877 mmol) and phenylboronic acid (21.39 mg, 2 eq.) were dissolved in tetrahydrofuran (4 mL) and stirred at room temperature for 2 hours. The solvent was evaporated to dryness in vacuo, 4 mL of dioxane was added, compound SM-38 (151.2 mg, 0.526 mmol) and camphorsulfonic acid (102 mg, 0.44 mmol) were added, and stirred at room temperature for 16 h. 1N sodium acetate aqueous solution (1 mL) was added to quench the reaction solution, and the crude product was concentrated to obtain a crude product, which was prepared and purified by HPLC to obtain 40 mg of the product (acetate), with a purity of 96.2% and a yield of 34%. HRMS: 1238.4225 [M + ].

[0307] 1 HNMR (400MHz, METHANOL-d4): δ8.00(d,2H,J=8.4Hz),7.82(d,2H,J=8.4Hz),7.78-7.71(m,4H),7.63(d,2H,J=8.8Hz),7.17(d,2H,J=8.8Hz),7.03(d,2H ,J=8.8Hz),6.78(d,2H,J=8.4Hz),5.44(d,1H,J=2.4Hz),5.06(d,1H,J=2.8 Hz),4.83-4.77(m,1H),4.63-4.60(m,6H),4.42(d,1H,J=4.0Hz),4.36-4.33 (m,2H),4.27-4.25(m,2H),4.20-4.18(m,1H),4.06-4.00(m,4H),3.94-3.9 0(m,2H),3.86-3.78(m,1H),3.71-3.46(m,4H),3.25(s,3H),3.19(s,3H),2. 58-2.41(m,4H),2.32-2.28(m,2H),1.92(s,3H),1.86-1.80(m,2H),1.53-1 .40(m,4H),1.32-1.27(m,6H),1.10(d,3H,J=7.2Hz),0.99(t,3H,J=7.2Hz).

[0308] High resolution mass spectrometry method:

[0309]

[0310]

[0311] Test Example 1: Antifungal Activity Test Method

[0312] After the test compound was diluted in series, the MIC test was performed on the Candida albicans standard strain, and the MEC test was performed on the Aspergillus standard strain. The minimum inhibitory concentration (MIC) test method was operated in accordance with the guidelines of the Clinical Laboratory Standards Institute of the United States (CLSI M27-A3), and the minimum effective concentration (MEC) test method was operated in accordance with the guidelines of the Clinical Laboratory Standards Institute of the United States (CLSI M38-A2).

[0313] Fungal inoculum preparation

[0314] Candida:

[0315] The frozen strains were subcultured at least twice, and a single colony was picked and resuspended in physiological saline or sterile water. The suspension was vortexed and adjusted to 0.5 McF (1×10 6 ~5×10 6 CFU / mL). After diluting 50 times with normal saline, dilute 20 times with 1×RPMI 1640 broth (1×10 3 ~5×10 3 CFU / mL). Take 10 μL and spread it on SDA plate for colony counting, the range is about 10 to 50 single colonies.

[0316] After the prepared drug sensitivity plate is completely dissolved at room temperature, add the bacterial suspension to the 96-well plate using a spray gun, 100 μL per well. At this point, the bacterial concentration in each well should be 0.5×10 3 ~2.5×10 3 CFU / mL.

[0317] Aspergillus (operation is carried out in a Class II biosafety cabinet):

[0318] Subculture Aspergillus onto SDA plates and culture at 35°C for 48h-7d to induce spore formation. Cover the colonies on the plate with about 1mL of 0.85% physiological pressurized water or sterile water (add polysorbate 20 to a final concentration of 0.1%-0.01%). Gently wipe the surface of the culture medium with a tip or sterile cotton swab (be careful not to puncture the culture medium), and transfer the spore hyphae resuspension into a sterile test tube, let it stand for 3-5min to allow the heavier particles to settle, transfer the upper homogenized suspension into a new sterile test tube, cover the bottle cap tightly, and vortex for 15s (note: the suspension can produce aerosols when the bottle cap is reopened). Use a spectrophotometer to increase the concentration of the suspension to an OD value of 0.09-0.13 at 530nm. Dilute the suspension 50 times with 1×RPMI 1640. Within 2 hours after dilution, add 100 μL to each well of a 96-well plate (the final spore concentration in the drug sensitivity plate should be 0.4×10 4 ~5×10 4 CFU / mL).

[0319] Colony count: dilute the suspension diluted with RPMI 1640 10 times again, apply 10 μL to SDA plate, culture at 28°C and observe every day. Count colonies immediately after visible colonies appear.

[0320] nourish

[0321] Place the yeast fungus test plate in an incubator at 35°C and 85% humidity, and read the MIC value after incubation for 24 hours. For echinocandin drugs, place Aspergillus at 28°C and read the MEC result after incubation for 21-26 hours.

[0322] MIC or MEC interpretation

[0323] Yeast fungi: Attach a disposable airtight sealing film to a 96-well plate, shake and mix, and observe with the naked eye using a plate reader. The minimum compound concentration corresponding to >=50% growth inhibition compared to the growth control is defined as the MIC. Use an automatic plate reader to take pictures and save the images.

[0324] Aspergillus: For the echinocandins, the lowest drug concentration that results in the formation of small, round, compact hyphal particles compared to the growth control under a plate reader is defined as the MEC. To accurately determine the MEC, the plate should not be vortexed before reading.

[0325] Table 1 Antibacterial activity test results of compounds (first batch)

[0326]

[0327] Note: 1. Candida parapsilosis ATCC 22019 and Candida krusei ATCC6258 are quality control strains. According to CLSI-M60, the 24h MIC of ANI for ATCC 22019 is (0.25-2) μg / mL, and CAS is (0.25-1) μg / mL. The 24h MIC of ANI for ATCC6258 is (0.03-0.12) μg / mL, and CAS is (0.12-1) μg / mL.

[0328] Table 2 Antibacterial activity test results of compounds (second batch)

[0329]

[0330]

[0331] The experimental data show that a considerable number of the example compounds disclosed in the present invention have excellent antifungal activity, and some compounds have better antifungal activity than positive drugs.

[0332] Test Example 2: Compound plasma histamine concentration and pharmacokinetic test

[0333] Test method:

[0334] 12 SD rats were divided into 2 groups, 6 animals in each group, half of them were male and half were female. The rats were observed at least once a day. The body weight was measured once before administration. A single intravenous injection was given to each animal for 20 minutes. PK tests were performed once before administration and 5 minutes, 30 minutes, 1 hour, 4 hours, 8 hours, 24 hours, 48 ​​hours, 72 hours, and 96 hours after administration. Histamine tests were performed once before administration and 30 minutes, 4 hours, 8 hours, and 24 hours after administration.

[0335] The dosage design is shown in the table below:

[0336]

[0337] The main results are as follows:

[0338] General status observation

[0339] On the day of drug administration, two females (2 / 3 ratio) in Group 2 showed transient slight decrease in activity.

[0340] In addition, the SD rats in each group were in general good condition, with normal autonomous activities, clean skin and fur, normal feces and urine, and no other abnormal reactions.

[0341] Histamine test

[0342] Intravenous administration of group 1 and group 2 could cause transient histamine elevation in rats, with plasma histamine concentration reaching a peak at 30 minutes; a recovery trend was seen at 4 hours, and it basically returned to normal at 8 to 24 hours. Figure 1 . 30 minutes after administration, the average histamine concentration in the plasma of rats in group 1 was 296.6 ng / mL; the average histamine concentration in the plasma of rats in group 2 was 1333.0 ng / mL, which was 4.5 times that of group 1 and significantly higher than that of group 1 (p=0.046). Figure 2 At the same dose, the ability of group 1 to induce histamine elevation in rats was significantly lower than that of group 2.

[0343] Pharmacokinetics

[0344] After administration to group 1 or group 2, the pharmacokinetic parameters in animals are shown in the following table:

[0345]

[0346] The experimental data showed that after a single intravenous injection of the same dose in Group 1 and Group 2, the plasma drug exposure level (C max There was no significant gender difference and the other pharmacokinetic parameters were basically the same.

[0347] In summary, after a single intravenous injection of 10 mg / kg of the final product of Example 13, the plasma drug exposure was comparable to that of Rezafungin acetate at the same dose, but the ability to cause histamine elevation in rats was significantly lower than that of Rezafungin acetate, suggesting that compared with Rezafungin, the final product of Example 13 is less likely to cause allergic reactions in clinical practice.

Claims

1. A compound as shown below or a pharmaceutically acceptable salt thereof, 、 。 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is selected from acetate, trifluoroacetate and formate.

3. A pharmaceutical composition comprising the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

4. Use of the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing fungal infection.

5. Use of the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing, stabilizing or inhibiting fungal growth.

6. Use of the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for killing fungi.

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