Echinocandin analogue and preparation method thereof

Abstract

The invention relates to echinocandin analogs and a preparation method thereof, the compounds can be used for preventing or treating fungal infection, or preventing, stabilizing or inhibiting fungal growth or killing fungi, the example compounds are shown in the formula I, and R1, R2, R3 and G groups are defined in the specification. # imgabs0 #

Description

[0001] This application is a divisional application of the Chinese patent application with application number 202080075108.0, application date December 4, 2020, and invention name “Echinocandin analogs and preparation methods thereof”.

[0002] This application claims priority to 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, and 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 incorporates the entire text of the aforementioned Chinese patent applications. Technical Field

[0003] 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

[0004] The development of antifungal treatment options has been an ongoing challenge for 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 various azole antifungal drugs (e.g., ketoconazole, itraconazole, and fluconazole) that inhibit fungal membrane-sterol biosynthesis (Alexander et al., Drugs, 54:657, 1997). Even though amphotericin B has a broad spectrum of activity and is considered the "gold standard" of 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 by the development of resistant microorganisms and its narrow spectrum of activity. The widespread use of azole antifungals is leading to the emergence of clinically resistant strains of Candida spp.

[0005] Echinocandins are a new class of antifungal drugs, typically consisting of a cyclic hexapeptide and a lipophilic tail, the latter of which is linked to the hexapeptide core via an amide bond. These drugs interfere with the synthesis of β-1,3-glucose in the fungal cell wall by non-competitively inhibiting β-1,3-glucose synthase, leading to changes in the permeability of the fungal cell wall and cell lysis and death. Because human cells lack cell walls, while fungal cells do, echinocandins can act directly on components of the fungal cell wall. Therefore, they exhibit low toxicity to humans and are the safest class of antifungal drugs to date.

[0006] Currently, marketed drugs of this type include caspofungin, micafungin, and anidulafungin. Caspofungin, the first echinocandin antifungal drug, was developed by Merck & Co., Inc. in the United States and approved by the US FDA in 2004 for the treatment of fungal infections and in 2008 for the treatment of Candida infections in children. Micafungin, a novel semisynthetic antifungal drug, was launched in Japan in 2002. Anidulafungin, a third-generation echinocandin semisynthetic antifungal drug, was launched in 2006.

[0007] WO2017049102A and WO2018102407A disclose antifungal echinocandin drugs as shown in Formula 1 below.

[0008] Summary of the Invention

[0009] The present disclosure provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof, or an isomer thereof,

[0010]

[0011] 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)] b CH{CH2[OCH2(CH2) c ] d X1}2 and (OCH2CH2) b (NHCH2CH2) e X2,

[0012] 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,

[0013] R3 is selected from H, OSO3H and CH2NR B1 R B2 ,

[0014] G is C 10-42 lipid unit,

[0015] R A1 、R A2 、R A3 and R A4 independently selected from hydrogen, deuterium, halogen, lower alkyl, cycloalkyl and cycloalkylene

[0016] R B1 and R B2 independently selected from H, -C(O)R J and lower alkyl,

[0017] 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,

[0018] 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 Lower alkyl, and R C1 、R C2 and R C3 At least one of them is not hydrogen,

[0019] Each R F independently 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"),

[0020] X2 is N(R D1 R D2 R D3 ) or X1 structure,

[0021] 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,

[0022] R' and R" are independently selected from hydrogen, hydroxy, alkyl, alkoxy, alkenyl and -C(O)R J ,

[0023] R J Selected from hydrogen, deuterium, C 1-10 Lower alkyl, cycloalkyl and cycloalkylene groups,

[0024] a is an integer from 0 to 5,

[0025] b is an integer from 1 to 5,

[0026] c is an integer from 1 to 2,

[0027] d is an integer from 0 to 3,

[0028] e is an integer from 1 to 5,

[0029] k is an integer from 0 to 20,

[0030] j is an integer from 0 to 5, and

[0031] n is an integer from 1 to 7.

[0032] "Independently selected from" or "independently is" means that the variable groups at each occurrence are independently selected from the defined substituents.

[0033] In some embodiments, R1 can be selected from 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)] b CH{CH2[OCH2(CH2) c ] d X1}2 and (OCH2CH2) b (NHCH2CH2) e X2,

[0034] 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,

[0035] R3 can be selected from H, OSO3H and CH2NR B1 R B2 ,

[0036] G can be C 10-36 Lipophilic unit,

[0037] R A1 、R A2 、R A3 and R A4 independently selected from hydrogen, deuterium, halogen, lower alkyl, cycloalkyl and cycloalkylene

[0038] R B1 and R B2 Each independently selected from H, -C(O)R J and lower alkyl,

[0039] 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,

[0040] R C1 、R C2 and R C3 Each independently selected from H, halogenated C 1-6 Lower alkyl and deuterated C 1-6 Lower alkyl, and R C1 、R C2 and R C3 At least one of them is not hydrogen,

[0041] Each R F are independently selected from H, deuterium, hydroxy, hydroxyalkyl, amino, alkoxy, lower alkyl, alkenyl, alkynyl, halogen, SR', SOR', S02R', NR'(R"), COOR' and CONR'(R"), wherein the lower alkyl group may be optionally substituted with one or more substituents selected from deuterium, alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl,

[0042] X2 is N(R D1 R D2 R D3 ) or X1 structure,

[0043] R D1 、R D2 and R D3 Independently selected from H, C 1-6 Lower alkyl, halogenated C 1-6 Lower alkyl and deuterated C1-6 lower alkyl,

[0044] R' and R" are independently selected from hydrogen, hydroxy, alkyl, alkoxy, alkenyl and -C(O)R J ,

[0045] R J are independently selected from hydrogen, C 1-10 Lower alkyl, cycloalkyl and cycloalkylene groups,

[0046] a is an integer from 0 to 5,

[0047] b is an integer from 1 to 5,

[0048] c is an integer from 1 to 2,

[0049] d is an integer from 0 to 3,

[0050] e is an integer from 1 to 5,

[0051] k is an integer from 0 to 20,

[0052] j is independently an integer from 0 to 5, and

[0053] n is an integer from 1 to 7.

[0054] In some embodiments, X1 can be selected from the following structures:

[0055] Among them, each R F are independently selected from H, deuterium, hydroxy, hydroxyalkyl, amino, alkoxy, lower alkyl, alkenyl, alkynyl, halogen, SR', SOR', S02R', NR'(R"), COOR' and CONR'(R"), wherein the lower alkyl group may be optionally substituted with one or more substituents selected from deuterium, alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl,

[0056] 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"),

[0057] R' and R" are independently selected from hydrogen, hydroxy, alkyl, alkoxy, alkenyl and -C(O)R J ,

[0058] R J Selected from hydrogen, deuterium, C 1-10Lower alkyl, cycloalkyl and cycloalkylene groups,

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

[0060] g is an integer from 0 to 16,

[0061] h is an integer from 0 to 9,

[0062] i is an integer from 0 to 4,

[0063] n is an integer from 1 to 7, and

[0064] p is an integer from 1 to 3.

[0065] 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 radicals selected from deuterium, halogen, alkyl, cycloalkyl, cycloalkylene Substituted by a substituent; 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.

[0066] In some embodiments, G can be selected from:

[0067]

[0068]

[0069] In some embodiments, R1 can be selected from:

[0070]

[0071] In other embodiments, R1 can be selected from:

[0072]

[0073] The present disclosure provides a compound as shown in Formula II, or a pharmaceutically acceptable salt thereof, or an isomer thereof,

[0074]

[0075] G1 can be selected from

[0076] Among them, R p1 、R p2 and R p3 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,

[0077] X is independently selected from O, C(R B1 )(R B2 ),NR p4 - and S,

[0078] R p4 is hydrogen or C 1-3 lower alkyl,

[0079] R T Can be C 1-5 Straight or branched alkyl, wherein the alkyl is optionally substituted by one or more groups selected from deuterium, hydroxy, amino, alkoxy, amino, NR'(R"), halogen, cycloalkyl, cycloalkylene Substituents of

[0080] 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;

[0081] R B1 and RB2 Each independently selected from H, -C(O)R J and C 1-10 lower alkyl,

[0082] R J Selected from hydrogen, C 1-10 Lower alkyl, cycloalkyl and cycloalkylene groups,

[0083] m is an integer from 0 to 4, and

[0084] n is an integer from 1 to 7.

[0085] The present disclosure also provides a compound as shown in Formula III, or a pharmaceutically acceptable salt thereof, or an isomer thereof,

[0086]

[0087] 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.

[0088] The present disclosure provides the following compounds, or pharmaceutically acceptable salts thereof, or isomers thereof,

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096] In certain embodiments, the pharmaceutically acceptable salt of the compound is selected from the group consisting of acetate, trifluoroacetate, and formate.

[0097] The present disclosure also provides a method for preparing the compound or a pharmaceutically acceptable salt thereof.

[0098] The present disclosure also provides a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0099] The present disclosure also provides a method for treating a fungal infection in a patient, and the method is carried out by giving the patient a pharmaceutical composition of the present disclosure with an amount sufficient to treat infection. In a specific embodiment, the pharmaceutical composition is administered intravenously, topically or orally. The pharmaceutical composition can be given 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 infection: scalp ringworm, tinea corporis, tinea pedis, onychomycosis, perionychia (perionychomycosis), psoriasis versicolor, 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 sinusitis. 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.

[0100] The present disclosure also provides a method for preventing fungal infection in a patient by administering a pharmaceutical composition of the present invention to the patient in an amount sufficient to prevent infection. For example, the methods of the present disclosure can be used to provide preventive treatment in patients preparing for invasive medical procedures (e.g., preparing for surgery, such as undergoing transplantation, stem cell therapy, grafts, prosthetics, 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 taking immunosuppressants), or in patients undergoing long-term antibiotic therapy.

[0101] In one embodiment of the disclosed methods, the pharmaceutical composition comprises Compound 1, or any other compound described herein, or a pharmaceutically acceptable salt thereof.

[0102] 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.

[0103] The terms "sufficient amount" and "sufficient amount" refer to the amount of drug required to treat or prevent an infection. The amount sufficient for practicing the present disclosure to therapeutically treat or prophylactically treat a condition caused or contributed to by an infection varies depending on the mode of administration, the type of infection, and the age, weight, and general health of the patient.

[0104] By "fungal infection" is meant an invasion of a host by pathogenic fungi. For example, an infection can include an overgrowth of fungi normally present in or on a patient's body, or the growth of fungi not normally present in or on a patient's body. More generally, a fungal infection can be any condition in which the presence of a fungal population is harmful to the host organism. Thus, a patient is "suffering from" a fungal infection when an excessive fungal population is present in or on a patient's body, or when the presence of a fungal population damages the patient's cells or other tissues.

[0105] The term "treating" refers to the administration of a pharmaceutical composition for prophylactic and / or therapeutic purposes. For "preventing a disease," this refers to the prophylactic treatment of a subject who is not already suffering from the disease but is susceptible to or at risk for the disease. For "treating a disease," this refers to the treatment of a patient already suffering from the disease to improve or stabilize the patient's condition.

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

[0107] The present disclosure also provides use of the compound or a pharmaceutically acceptable salt thereof in preparing a medicament for preventing fungal infection.

[0108] The present disclosure also provides the use of the compound or its pharmaceutically acceptable salt in the preparation of a medicament for preventing, stabilizing, or inhibiting the growth of fungi or killing fungi. In some embodiments, the use comprises contacting the fungus or a part of the fungus that is prone to growth with the compound or its pharmaceutically acceptable salt, or its isomer.

[0109] 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.

[0110] For the semi-synthetic routes to the disclosed 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).

[0111] The compounds of the present disclosure can be synthesized, for example, using the methods described in the Examples.

[0112] Unless stated otherwise, the following terms used in the specification and claims have the following meanings.

[0113] "Alkyl" refers to a straight or branched chain alkane group, preferably containing 1 to 10 carbon atoms, more preferably containing 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. Unless otherwise specified in the specification, an alkyl group may be optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thioxo, trimethylsilyl, and the like. Unless otherwise specified, "lower alkyl" refers to a straight or branched chain alkane group containing 1 to 10 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. Unless otherwise specified in the specification, a lower alkyl group may be optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thioxo, trimethylsilyl, and the like.

[0114] "Alkenyl" refers to an alkyl compound containing a carbon-carbon double bond, where alkyl is as defined above. Non-limiting examples include ethenyl, 1-propen-2-yl, 1-buten-4-yl, 1-penten-5-yl, and 1-buten-1-yl. Unless otherwise specified in the specification, an alkenyl group may be optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thioxo, trimethylsilyl, and the like.

[0115] "Alkynyl" refers to an alkyl compound containing a carbon-carbon triple bond, where alkyl is as defined above. Non-limiting examples include ethynyl, propynyl, pentynyl, butynyl, and the like. Unless otherwise indicated in the specification, an alkynyl group may be optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thioxo, trimethylsilyl, and the like.

[0116] “C 10-36 The “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.

[0117] "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 include a spirocyclic ring system. Aryl groups include, but are not limited to, those 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, an aryl group may be optionally substituted with one or more substituents independently selected from the following groups: alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, cyano, nitro, etc.

[0118] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting solely of carbon and hydrogen atoms, which may include 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 is attached 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 specified in the specification, cycloalkyl groups may be optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, and the like.

[0119] "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; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls.

[0120] "Halogen" refers to bromine, chlorine, fluorine or iodine.

[0121] "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, a heterocyclyl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include spirocyclic or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocyclyl group can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl group can be partially or fully saturated. Unless otherwise specified in this specification, a heterocyclyl group includes a heterocyclyl group optionally substituted with one or more substituents selected from the following groups: alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, and the like.

[0122] "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. A 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 a heteroaryl group does not necessarily contain heteroatoms, as long as one of the rings of the heteroaryl group contains heteroatoms. For example, 1,2,3,4-tetrahydroisoquinolin-7-yl is considered a "heteroaryl group." Unless otherwise specified in this specification, heteroaryl groups include heteroaryl groups optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, and the like.

[0123] "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

[0124] Figure 1 : Changes in histamine concentration after intravenous administration of the compound.

[0125] Figure 2 : Comparison of histamine concentrations 30 minutes after intravenous administration of the compounds. DETAILED DESCRIPTION

[0126] 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.

[0127] Experimental methods in the examples of the present invention where specific conditions are not specified are generally performed under conventional conditions or the conditions recommended by the raw material or product manufacturers. Reagents where the specific sources are not specified are conventional reagents purchased from the market.

[0128] Anidulafungin and caspofungin were purchased from Taizhou Kede Chemical. Rezafungin was synthesized according to CN103889221A.

[0129] HPLC purity analysis method:

[0130]

[0131]

[0132] LC-MS analysis method:

[0133]

[0134] Example 1:

[0135] first step

[0136]

[0137] 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. The solid 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%. + ].

[0138] Step 2

[0139]

[0140] 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 in vacuo to dryness. 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 + ].

[0141] 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).

[0142] Example 2:

[0143] first step

[0144]

[0145] 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. The solid 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 + ].

[0146] Step 2

[0147]

[0148] 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, 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 + ].

[0149] 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).

[0150] Example 3:

[0151]

[0152] 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 in vacuo to dryness. 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 + ].

[0153] 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).

[0154] Example 4:

[0155]

[0156] Echinocandin B (50 mg, 0.06 mmol) and octadecanediol mono-tert-butyl ester (24.43 mg, 1.1 eq.) were dissolved in DMF (2 mL) and stirred in an ice-water bath. TBTU (28.9 mg, 1.5 eq.) and DIPEA (15.5 mg, 2 eq.) were added and stirred in an ice-water bath for 1.5 hours. The mixture was quenched with water (5.0 mL) and extracted with ethyl acetate (5 mL x 5). The combined organic phases were washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, and concentrated. Purification by HPLC yielded 55.2 mg of the product with a purity of 97.1% and a yield of 80%. HRMS: 1150.6482 [M+1].

[0157] 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).

[0158] Example 5:

[0159] first step

[0160]

[0161] 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, filter and dry to obtain 4.88 g of white solid compound SM6, yield: 95%. Ms: 130.0 [M + ].

[0162] 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).

[0163] Step 2

[0164]

[0165] 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, and anhydrous acetonitrile (10 mL) was added. Compound SM6 (422.7 mg, 6 eq.) and p-toluenesulfonic acid (340 mg, 7.5 eq.) were added. The mixture was stirred at room temperature for 5 hours under nitrogen protection. An aqueous solution of sodium acetate was added to quench the mixture, and the mixture was concentrated to obtain a crude product. The product was purified by HPLC to obtain 259 mg of the product (acetate salt) with a purity of 96.5% and a yield of 76%. HRMS: 1251.6174 [M + ].

[0166] 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). .

[0167] Example 6:

[0168]

[0169] Echinocandin B (100 mg, 0.12 mmol) and semaglutide side chain (100.9 mg, 1.0 eq.) were dissolved in DMF (4 ml) and stirred in an ice-water bath. TBTU (58 mg, 1.5 eq.) and DIPEA (31 mg, 2 eq.) were added and stirred in an ice-water bath for 1.5 hours. The reaction mixture was added dropwise to 100 mL of ice water to precipitate a solid, which was filtered, dried, and slurried with acetonitrile to yield 120 mg of the product with a purity of 95.8% and a yield of 61.5%. HRMS: 1625.8989 [M+1].

[0170] 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,1 H),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),5.20(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),4.3 7-4.33(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).

[0171] Example 7:

[0172]

[0173] The compound of Example 6 (100 mg, 0.0615 mmol) and phenylboronic acid (15 mg, 2 eq.) were dissolved in THF (4 mL) and stirred at room temperature for 1 hour. The mixture was concentrated to dryness, and compound SM7 (101.6 mg, 6 eq.) and p-toluenesulfonic acid (53 mg, 5 eq.) were added. Stirring was continued at room temperature under nitrogen for 5 hours. An aqueous solution of sodium acetate was added to quench the mixture, and the mixture was concentrated to obtain a crude product. The crude product was purified by HPLC to obtain 44.9 mg of the product (trifluoroacetate salt) with a purity of 96.5% and a yield of 40%. HRMS: 1710.9867 [M + ].

[0174] 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).

[0175] Example 8:

[0176]

[0177] The trifluoroacetic acid salt of Example 7 (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 (trifluoroacetic acid salt) with a purity of 97.8% and a yield of 30%. HRMS: 1598.8629 [M + ].

[0178] Example 9:

[0179] first step

[0180]

[0181] Echinocandin B (200 mg, 0.2397 mmol) and SM8 (89 mg, 1.0 eq.) were dissolved in DMF (5 ml) and stirred in an ice-water bath. TBTU (115 mg, 1.5 eq.) and DIPEA (62 mg, 2 eq.) were added and stirred in an ice-water bath for 1.5 hours. The mixture was purified by reverse-phase column to obtain 234 mg of the product (85% yield). Ms: 1152.5 [M+1].

[0182] 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).

[0183] Step 2

[0184]

[0185] 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, and concentrated to dryness. Compound SM7 (200 mg, 6 eq.), p-toluenesulfonic acid (105 mg, 5 eq.), and anhydrous acetonitrile (5 mL) were added and stirred at room temperature for 5 hours under nitrogen protection. The mixture was quenched by adding an aqueous solution of sodium acetate and concentrated to obtain a crude product. HPLC preparation and purification were performed to obtain 102 mg of the product (acetate salt) with a purity of 95.8% and a yield of 65%. HRMS: 1237.6022 [M + ].

[0186] 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).

[0187] Example 10:

[0188] first step

[0189]

[0190] 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, filter and dry to obtain 12.1 g of white solid compound SM10, yield: 90%. Ms: 144.0 [M + ].

[0191] Step 2

[0192]

[0193] 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 in vacuo to dryness, 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 hours. 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 47.6 mg of the product (acetate) with a purity of 97.1% and a yield of 41%. HRMS: 1265.6324 [M + ].

[0194] 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).

[0195] Example 11:

[0196] first step

[0197]

[0198] Echinocandin B (300 mg, 0.36 mmol) and SM11 (147 mg, 1.1 eq.) were dissolved in DMF (15 ml) and stirred in an ice-water bath. TBTU (174 mg, 1.5 eq.) and DIPEA (141 mg, 3 eq.) were added and stirred in an ice-water bath for 1 hour. The reaction mixture was then 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].

[0199] Step 2

[0200]

[0201] 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 in vacuo to dryness, 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 hours. 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 39.5 mg of the product (formate salt) with a purity of 97.0% and a yield of 35.5%. HRMS: 1243.5936 [M + ].

[0202] 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).

[0203] Example 12:

[0204]

[0205] 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 in vacuo to dryness, 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 hours. 1N sodium acetate aqueous solution (2 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 48.3 mg of the product (acetate) with a purity of 97.7% and a yield of 21.3%. HRMS: 1234.6581 [M + ].

[0206] Example 13:

[0207] first step

[0208]

[0209] 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, filter and dry to obtain 2.44 g of white solid compound SM14, yield: 95%. Ms: 130.0 [M + ].

[0210] Step 2

[0211]

[0212] 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, and 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. The mixture was stirred at room temperature for 5 hours under nitrogen protection. An aqueous solution of sodium acetate was added to quench the mixture, and the mixture was concentrated to obtain a crude product. HPLC purification was performed to obtain 57.5 mg of the product (acetate salt) with a purity of 95.8% and a yield of 50%. HRMS: 1251.6173 [M + ].

[0213] 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).

[0214] Example 14:

[0215] first step

[0216]

[0217] 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 under reflux for 4 h, and the solvent was dried to obtain the crude compound SM16, which was used directly in the next step. + ].

[0218] Step 2

[0219]

[0220] 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 in vacuo to dryness. 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 + ].

[0221] 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).

[0222] Example 15:

[0223] first step

[0224]

[0225] Echinocandin B (250 mg, 0.3 mmol) and SM17 (114 mg, 1.0 eq.) were dissolved in DMF (2.5 ml) and stirred in an ice-water bath. TBTU (145 mg, 1.5 eq.) and DIPEA (78 mg, 2.0 eq.) were added and stirred in an ice-water bath for 1 hour. The reaction mixture was then 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].

[0226] Step 2

[0227]

[0228] 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 in vacuo to dryness, 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 hours. 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 57 mg of the product (formate salt) with a purity of 97.8% and a yield of 34.1%. HRMS: 1243.5928 [M + ].

[0229] 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).

[0230] Example 16:

[0231] first step

[0232]

[0233] Echinocandin B (400 mg, 1.12 mmol) and SM19 (930 mg, 1.0 eq.) were dissolved in DMF (8 ml) and stirred in an ice-water bath. TBTU (359 mg, 1.0 eq.) and DIPEA (288 mg, 2.0 eq.) were added and stirred in an ice-water bath for 1 hour. The reaction mixture was then 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].

[0234] Step 2

[0235]

[0236] 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 hours. 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 123 mg of the product (acetate) with a purity of 97.6% and a yield of 54.6%. HRMS: 1223.6224 [M + ].

[0237] 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).

[0238] Example 17:

[0239] first step

[0240]

[0241] Echinocandin B (162 mg, 0.195 mmol) and SM21 (70 mg, 1.0 eq.) were dissolved in DMF (1.4 ml) and stirred in an ice-water bath. TBTU (84.6 mg, 1.5 eq.) and DIPEA (50 mg, 2.0 eq.) were added and stirred in an ice-water bath for 1 hour. The reaction mixture was then 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].

[0242] Step 2

[0243]

[0244] 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 in vacuo to dryness, 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, and the solvent was removed by rotary evaporation. 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 + ].

[0245] 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).

[0246] Example 18:

[0247]

[0248] 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 in vacuo to dryness, 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, and the solvent was removed by rotary evaporation. 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 + ].

[0249] 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=8.4H z, 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).

[0250] Example 19:

[0251] first step

[0252]

[0253] Echinocandin B (161 mg, 0.193 mmol) and SM24 (80 mg, 1.0 eq.) were dissolved in DMF (3.2 ml) and stirred in an ice-water bath. TBTU (93 mg, 1.5 eq.) and DIPEA (50 mg, 2.0 eq.) were added and stirred in an ice-water bath for 1 hour. The reaction mixture was then 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].

[0254] Step 2

[0255]

[0256] 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 in vacuo to dryness, 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, and the solvent was removed by rotary evaporation. 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 + ].

[0257] 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), 4.73-4.7 8(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).

[0258] Example 20:

[0259] first step

[0260]

[0261] SM-26 (590 mg, 1 eq.) was dissolved in 10% acetonitrile, methyl p-toluenesulfonate (1.2 g, 1.1 eq.) was added, and the mixture was heated under reflux with stirring for 4 hours, concentrated, and slurried with acetone and petroleum ether to obtain 1.6 g of white solid compound SM-27, with a yield of 95%. Ms: 117.1 [M + ].

[0262] Step 2

[0263]

[0264] 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, and concentrated to dryness. Compound SM-27 (151 mg, 6 eq.), p-toluenesulfonic acid (75.4 mg, 5 eq.), and anhydrous dioxane (5 mL) were added. The mixture was stirred at room temperature for 5 hours under nitrogen protection. An aqueous solution of sodium acetate was added to quench the mixture, and the mixture was concentrated to obtain a crude product. The crude product was 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 + ].

[0265] 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).

[0266] Example 21:

[0267]

[0268] The trifluoroacetic acid salt of Example 6 (24 mg, 0.014 mmol) was dissolved in TFA (1 mL) and stirred in an ice-water bath for 5 hours. The mixture was concentrated to dryness and purified by HPLC to obtain 7.2 mg of the product (trifluoroacetic acid salt) with a purity of 97.8% and a yield of 30%. HRMS: 1513.7743 [M+1].

[0269] Example 22:

[0270] first step

[0271]

[0272] 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 mixture was heated under reflux for 2 h to precipitate a white solid. The mixture was cooled to room temperature and filtered. The filter cake was dried under vacuum to obtain 6.5 g of compound SM-30 with a purity of 98% and a yield of 42.9%. Ms: 118.12 [M + ].

[0273] Step 2

[0274]

[0275] 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 hours. 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 + ].

[0276] 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,8 H),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),1.43-1.5 2(m,7H),1.25-1.27(m,6H),1.08(d,J=6.4Hz,3H), 0.97(t,J=7.2Hz,3H).

[0277] Example 23:

[0278] first step

[0279]

[0280] 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 mixture was heated under reflux for 2 h to precipitate a white solid. 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 + ].

[0281] Step 2

[0282]

[0283] 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 the mixture was stirred at room temperature for 16 hours. 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 + ].

[0284] 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),7.15(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),2.25-2.3 1(m,1H),2.03-2.11(m,2H),1.89(s,3H),1.78-1.84(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).

[0285] Example 24:

[0286] first step

[0287]

[0288] 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 mixture was heated under reflux for 2 h to precipitate a white solid. 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 + ].

[0289] Step 2

[0290]

[0291] 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 the mixture was stirred at room temperature for 16 hours. 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 + ].

[0292] 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).

[0293] Example 25:

[0294] first step

[0295]

[0296] SM-35 (505 mg, 1 eq.) was dissolved in 5 mL of acetone, and methyl p-toluenesulfonate (1.02 g, 1.1 eq.) was added. The mixture was 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. The yield was 85%. Ms: 116.2 [M + ].

[0297] Step 2

[0298]

[0299] 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 hours. 1N sodium acetate aqueous solution (1 mL) was added to quench the reaction solution and concentrate to obtain a crude product. HPLC preparation and purification were performed to obtain 50 mg of the product (acetate salt) with a purity of 96.2% and a yield of 44%. HRMS: 1238.4225 [M + ].

[0300] 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).

[0301] Example 26:

[0302] first step

[0303]

[0304] SM-37 (505 mg, 1 eq.) was dissolved in 5 mL of acetone, and methyl p-toluenesulfonate (1.02 g, 1.1 eq.) was added. The mixture was 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. The yield was 90%. Ms: 116.2 [M + ].

[0305] Step 2

[0306]

[0307] 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 hours. The reaction solution was quenched with 1N sodium acetate aqueous solution (1 mL) and concentrated to obtain a crude product, which was purified by HPLC to obtain 40 mg of the product (acetate salt) with a purity of 96.2% and a yield of 34%. HRMS: 1238.4225 [M + ].

[0308] 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).

[0309] High-resolution mass spectrometry methods:

[0310]

[0311] Test Example 1: Antifungal Activity Test Method

[0312] After serial dilution of the test compound, MIC determination was performed against Candida albicans standard strains, and MEC determination was performed against Aspergillus standard strains. Minimum inhibitory concentration (MIC) determinations were performed according to the guidelines of the Clinical Laboratory Standards Institute (CLSIM27-A3), and minimum effective concentration (MEC) determinations were performed according to the guidelines of the Clinical Laboratory Standards Institute (CLSIM38-A2).

[0313] Fungal inoculum preparation

[0314] Candida:

[0315] The frozen strain was passaged at least twice, and a single colony was picked and resuspended in physiological saline or sterile water. The suspension was vortexed and the concentration of the bacterial suspension was 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 Take 10 μL and spread it on SDA plate to count the colonies, which range from 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. 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 48 hours to 7 days to induce sporulation. Overlay the colonies on the plate with approximately 1 mL of 0.85% physiologically pressurized 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 medium) and transfer the resuspended spore mycelium to a sterile test tube. Let it sit for 3-5 minutes to allow the heavier particles to settle. Transfer the homogenized upper layer to a new sterile test tube, securely cap the tube, and vortex for 15 seconds (caution: the suspension may produce aerosols when reopening the tube). Using a spectrophotometer, adjust the suspension concentration to an OD value of 0.09-0.13 at 530 nm. Dilute the suspension 50-fold with 1× RPMI 1640. Within 2 hours after dilution, add 100 μL of sample 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-fold again, apply 10 μL to SDA plates, incubate at 28°C and observe daily. Count colonies immediately after visible colonies appear.

[0320] nourish

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

[0322] MIC or MEC interpretation

[0323] Yeast fungi: Cover a 96-well plate with disposable sealing film, shake and mix thoroughly. Visually inspect the plate using a plate reader. The minimum compound concentration that results in ≥50% growth inhibition compared to the control is defined as the MIC. Use an automated plate reader to photograph and save the image.

[0324] Aspergillus: For echinocandins, the MEC is the lowest concentration of drug that results in the formation of small, round, compact hyphal granules as compared to the growth control as measured by a plate reader. To accurately determine the MEC, do not vortex the plate before reading.

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

[0326]

[0327] Note: 1. Candida parapsilosis ATCC 22019 and Candida krusei ATCC 6258 are quality control strains. According to CLSI-M60, the 24-hour MICs of ANI against ATCC 22019 are (0.25-2) μg / mL, and CAS are (0.25-1) μg / mL. The 24-hour MICs of ANI against ATCC 6258 are (0.03-0.12) μg / mL, and CAS are (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 Pharmacokinetics Test

[0333] Test method:

[0334] Twelve Sprague-Dawley rats were divided into two groups, each consisting of six animals, half male and half female. Animals were observed at least once daily. Body weight was measured before dosing. The drug was administered intravenously as a single injection 20 minutes before administration. PK testing was performed before administration and at 5 minutes, 30 minutes, 1 hour, 4 hours, 8 hours, 24 hours, 48 hours, 72 hours, and 96 hours after administration. Histamine testing was performed before administration and at 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 good general condition, with normal autonomous activities, clean skin and fur, normal feces and urine, and no other abnormal reactions were observed.

[0341] Histamine test

[0342] Intravenous administration of group 1 and group 2 could induce transient histamine elevation in rats, with plasma histamine concentration reaching a peak at 30 minutes; a recovery trend was observed at 4 hours, and the concentration 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 table below:

[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, plasma drug exposure was comparable to that of rezafungin acetate at the same dose, but its ability to elevate histamine in rats was significantly lower than that of rezafungin acetate. This suggests that the final product of Example 13 is less likely to cause allergic reactions clinically than rezafungin.

Claims

1. A compound as shown in formula I or a pharmaceutically acceptable salt thereof, or an isomer thereof, in, R1 is selected from 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)] b CH{CH2[OCH2(CH2) c ] d X1}2 and (OCH2CH2) b (NHCH2CH2) e X2, R2 is selected from C 1-10 lower alkyl, R3 is selected from H, G is C 10-42 lipid unit, R A1 、R A2 、R A3 and R A4 independently selected from hydrogen, deuterium, halogen, lower alkyl, cycloalkyl and cycloalkylene X1 is selected from the following structures: Among them, each R F are independently selected from H, deuterium, hydroxy, hydroxyalkyl, amino, alkoxy, lower alkyl, alkenyl, alkynyl, halogen, SR', SOR', S02R', NR'(R"), COOR' and CONR'(R"), wherein the lower alkyl is optionally substituted with one or more substituents selected from deuterium, alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, R q1 and R q2 are 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"), R' and R" are independently selected from hydrogen, hydroxy, alkyl, alkoxy, alkenyl and -C(O)R J , R J Selected from hydrogen, deuterium, C 1-10 Lower alkyl, cycloalkyl and cycloalkylene groups, f is an integer from 0 to 16, g is an integer from 0 to 16, h is an integer from 0 to 9, i is an integer from 0 to 4, and p is an integer from 1 to 3; X2 is the structure of X1, R' and R" are independently selected from hydrogen, hydroxy, alkyl, alkoxy, alkenyl and -C(O)R J , a is an integer from 0 to 5, b is an integer from 1 to 5, c is an integer from 1 to 2, d is an integer from 0 to 3, e is an integer from 1 to 5, j is an integer from 0 to 5, and n is an integer from 1 to 7.

2. The compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, or an isomer thereof, wherein G is selected from in, X is independently selected from O, C(R B1 )(R B2 ),NR p4 - and S; R T C 1-5 Straight or branched alkyl, wherein the alkyl is optionally substituted with one or more radicals selected from deuterium, halogen, alkyl, cycloalkyl, cycloalkylene Substituted by a substituent; R p1 、R p2 and R p3 independently selected 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.

3. The compound of formula I according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, or an isomer thereof, wherein G is selected from:

4. The compound of formula I according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or an isomer thereof, wherein G is selected from:

5. The compound of formula I according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or an isomer thereof, wherein G is selected from:

6. The compound of formula I according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or an isomer thereof, wherein G is selected from:

7. The compound of formula I according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or an isomer thereof, wherein R1 is selected from 8. The compound of formula I according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or an isomer thereof, wherein R1 is selected from:

9. The compound of formula I according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or an isomer thereof, wherein R1 is selected from:

10. The compound of formula I according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, or an isomer thereof, wherein R1 is selected from:

11. The compound of formula I according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or an isomer thereof, wherein R1 is selected from:

12. The compound of formula I according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, or an isomer thereof, wherein the compound of formula I is:

13. The compound according to any one of claims 1 to 12, wherein the pharmaceutically acceptable salt thereof is selected from acetate, trifluoroacetate and formate.

14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, or an isomer thereof, and a pharmaceutically acceptable excipient.

15. Use of the compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or an isomer thereof, in the preparation of a medicament for treating and / or preventing fungal infection.

16. Use of the compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or an isomer thereof, in the preparation of a medicament for preventing, stabilizing or inhibiting the growth of fungi or killing fungi.

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