Echinocandin analogues and preparation method thereof

Abstract

To provide echinocandin analogs for use in the prevention or treatment of fungal infections, or for use in preventing, stabilizing, or inhibiting fungal growth or killing fungi.SOLUTION: Provided is a compound represented by formula I or a pharmaceutically acceptable salt thereof, or an isomer thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application claims priority from 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. The entire texts of the above Chinese patent applications are incorporated herein by reference. Technical Field The present disclosure is in the field of medicinal chemistry, and specifically relates to echinocandin analogs that can be used to treat fungal infections. [Background technology]

[0002] The development of antifungal therapies is a continuing challenge facing modern society. Currently, drugs available for treating 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 several 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 application is limited by infusion-related reactions and nephrotoxicity (Warnock, J. Antimicrob. Chemother., 41:95, 1998). The development of drug-resistant microorganisms and its narrow spectrum of activity also limit the use of flucytosine. The widespread use of azole antifungal drugs has led to the emergence of clinically drug-resistant strains of Candida spp. Echinocandins are a novel class of antifungal drugs, typically consisting of a cyclic hexapeptide and a lipophilic tail attached to the hexapeptide core by an amide bond. These drugs noncompetitively inhibit β-1,3-glucose synthase, interfering with the synthesis of fungal cell wall β-1,3-glucose, thereby altering the permeability of the fungal cell wall and lysing and killing the cells. Because human cells do not contain cell walls, whereas fungal cells do, and because echinocandins can act directly on fungal cell wall components, these drugs are less toxic to humans and are the safest antifungal drugs to date. Currently available drugs include caspofungin, micafungin, and anidulafungin. Caspofungin, the first echinocandin antifungal drug, was researched and developed by Meso Scale Discovery in the United States and approved by the U.S. FDA for the treatment of fungal infections in 2004 and for the treatment of candidal infections in children in 2008. Micafungin (Mycamine), a novel semisynthetic antifungal drug, was marketed in Japan in 2002. Anidulafungin, a third-generation echinocandin semisynthetic antifungal drug, was marketed in 2006. WO2017049102A and WO2018102407A disclose antifungal echinocandin drugs represented by the following formula 1: [ka] Summary of the Invention [Means for solving the problem]

[0003] The present disclosure provides: TIFF2026001045000002.tif4640, However, R1 is a hydroxyl group, 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 Selected from X2, R2 is hydrogen, R B1 R B2 N-, CH2CH2NR B1 R B2 , CH2C(O)NR B1 R B2 , C 1-10 Lower alkyl group, C 2-10 Alkenyl group, C 2-10 selected from alkynyl groups, aryl groups, heteroaryl groups, cyclohydrocarbyl groups, heterocyclyl groups, and PEG; R3 is H, OSO3H and CH2NR B1 R B2 is selected from G is C 10-42 It is an oily unit, R A1 , R A2 , R A3 and R A4are independently hydrogen, deuterium, halogen, lower alkyl groups, cyclohydrocarbyl groups, and cyclohydrocarbylene groups. Selected from TIFF2026001045000003.tif13150, R B1 and R B2 are independently H, -C(O)R J and a lower alkyl group; X1 is independently N(R C1 R C2 R C3 ) or the following structure: TIFF2026001045000004.tif1721, wherein ring A is an optionally substituted saturated or unsaturated monocyclic or fused ring containing one or more N atoms; R C1 , R C2 and R C3 are independently H, C 1-6 Alkyl groups, halogenated C 1-6 Lower alkyl groups and deuterated C 1-6 lower alkyl groups, and R C1 , R C2 and R C3 At least one of the is not hydrogen, Each R F are independently selected from H, deuterium, hydroxyl, 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, hydroxyl, halogen, SR', NR'(R"), COOR', and CONR'(R"); X2 is N(R D1 R D2 R D3 ) or X1 structure, R D1 , R D2 and RD3 are independently H, C 1-6 Lower alkyl groups, halogenated C 1-6 Lower alkyl groups and deuterated C 1-6 lower alkyl groups, R' and R'' are independently hydrogen, hydroxyl, alkyl, alkoxy, alkenyl, and -C(O)R J is selected from R J are hydrogen, deuterium, and C 1-10 selected from lower alkyl groups, cyclohydrocarbyl groups, and cyclohydrocarbylene groups; 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, k is an integer from 0 to 20, j is an integer from 0 to 5, and The present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, or an isomer thereof, wherein n is an integer from 1 to 7.

[0004] "Independently selected" or "independently" means that each occurrence of a variable is selected from the defined substituents independently of each other.

[0005] In some embodiments, R is 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) bCH2CH2X1, 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 hydrogen, R B1 R B2 N-, CH2CH2NR B1 R B2 , CH2C(O)NR B1 R B2 , C 1-10 Lower alkyl group, C 2-10 Alkenyl group, C 2-10 may be selected from alkynyl groups, aryl groups, heteroaryl groups, cyclohydrocarbyl groups, heterocyclyl groups and PEG; R3 is H, OSO3H and CH2NR B1 R B2 may be selected from G is C 10-36 may be a lipophilic unit, R A1 , R A2 , R A3 and R A4 are independently hydrogen, deuterium, halogen, lower alkyl groups, cyclohydrocarbyl groups, and cyclohydrocarbylene groups. Selected from TIFF2026001045000005.tif13150, R B1 and R B2 are each independently H, -C(O)R J and a lower alkyl group; X1 is independently N(R C1 R C2 R C3 ) or the following structure: TIFF2026001045000006.tif1722, wherein ring A is a saturated or unsaturated monocyclic or fused ring containing one or more optionally substituted N atoms; R C1 , R C2 and R C3 are each independently H, halogenated C 1-6 Lower alkyl groups and deuterated C 1-6 lower alkyl groups, and R C1 , R C2 and R C3 At least one of the is not hydrogen, Each R F are independently selected from H, deuterium, hydroxyl, 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, and alkynyl; X2 is N(R D1 R D2 R D3 ) or X1 structure, R D1 , R D2 and R D3 are independently H, C 1-6 Lower alkyl groups, halogenated C 1-6 Lower alkyl groups and deuterated C 1-6 lower alkyl groups, R' and R'' are independently hydrogen, hydroxyl, alkyl, alkoxy, alkenyl, and -C(O)R J is selected from R J are independently hydrogen, C 1-10 selected from lower alkyl groups, cyclohydrocarbyl groups, and cyclohydrocarbylene groups; 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, k is an integer from 0 to 20, j is independently an integer from 0 to 5, and n is an integer from 1 to 7.

[0006] In some embodiments, X1 has the following structure: TIFF2026001045000007.tif24150, However, each R F are independently selected from H, deuterium, hydroxyl, 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, and alkynyl; R q1 , R q2 are independently H or C 1-6 a lower alkyl group, optionally substituted with one or more substituents selected from deuterium, alkyl groups, cycloalkyl groups, alkoxy groups, hydroxyalkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, nitro groups, nitrile groups, hydroxyl groups, halogen, SR', NR'(R"), COOR', and CONR'(R"); R' and R'' are independently hydrogen, hydroxyl, alkyl, alkoxy, alkenyl, and -C(O)R J is selected from R J are hydrogen, deuterium, and C 1-10 selected from lower alkyl groups, cyclohydrocarbyl groups, and cyclohydrocarbylene 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, n is an integer from 1 to 7, and p is an integer of 1 to 3.

[0007] In some embodiments, G is TIFF2026001045000008.tif21150, wherein X is independently O, C(R B1 )(R B2 ), NR p4 R is selected from - and S; T is C 1-5 wherein the alkyl group is optionally selected from the group consisting of deuterium, halogen, alkyl, cyclohydrocarbyl, cyclohydrocarbylene, TIFF2026001045000009.tif13150, and R p1 , R p2 and R p3 Each occurrence independently represents hydrogen, deuterium, halogen, or C. 1-10 Lower alkyl groups, halogenated C 1-10 Lower alkyl group, C 2-10 Alkenyl group, C 2-10 is selected from an alkynyl group, an aryl group, a heteroaryl group, a cyclohydrocarbyl group, a heterocyclyl group, and PEG; m is an integer of 0 to 4; n is an integer of 1 to 7; R p4 is hydrogen or C 1-6 is a lower alkyl group, and R B1 and R B2 are each independently H, -C(O)R J and C 1-10 lower alkyl groups, R J are hydrogen, deuterium, and C 1-10 It is selected from lower alkyl groups, cyclohydrocarbyl groups and cyclohydrocarbylene groups.

[0008] In some embodiments, G is TIFF2026001045000010.tif147150 may be selected.

[0009] In some embodiments, R1 is TIFF2026001045000011.tif35150 may be selected.

[0010] In another embodiment, R1 is TIFF2026001045000012.tif18150 may be selected.

[0011] The present disclosure provides: TIFF2026001045000013.tif5541 G1 is It can be selected from TIFF2026001045000014.tif23150, However, R p1 , R p2 and R p3 are independently hydrogen, deuterium, halogen, C 1-6 Lower alkyl groups, halogenated C 1-6 Lower alkyl group, C 2-10 Alkenyl group, C 2-10 selected from alkynyl groups, aryl groups, heteroaryl groups, cyclohydrocarbyl groups, heterocyclyl groups, and PEG; X is independently O, C(R B1 )(R B2 ), NR p4 and S, R p4 is hydrogen or C 1-3 is a lower alkyl group, R T is C 1-5 wherein the alkyl group is optionally selected from the group consisting of deuterium, hydroxyl, amino, alkoxy, amino, NR'(R"), halogen, cyclohydrocarbyl, cyclohydrocarbylene. TIFF2026001045000015.tif13150, And R p1 , R p2 and R p3 is simultaneously H and X is O, then R T Ha -CH11 Instead, X is O and R T -CH 11 If R p1 , R p2 and R p3 At least one of the following is R, not H. T -CH 11 and R p1 , R p2 and R p3 is simultaneously H, then X is not O, R B1 and R B2 are each independently H, -C(O)R J and C 1-10 lower alkyl groups, R J is hydrogen, C 1-10 selected from lower alkyl groups, cyclohydrocarbyl groups, and cyclohydrocarbylene groups; m is an integer from 0 to 4, and The present invention provides a compound represented by Formula II, or a pharmaceutically acceptable salt thereof, or an isomer thereof, wherein n is an integer from 1 to 7.

[0012] The present disclosure provides: TIFF2026001045000016.tif6795However, R G1 , R G2 , R G3 and R G4 are independently selected from hydrogen, deuterium, halogen, and lower alkyl groups, and R G1 , R G2 , R G3 and R G4 is not hydrogen.

[0013] The present disclosure provides a compound shown below, or a pharmaceutically acceptable salt thereof, or an isomer thereof: TIFF2026001045000017.tif102150 TIFF2026001045000018.tif77150 TIFF2026001045000019.tif115150 TIFF2026001045000020.tif108150 TIFF2026001045000021.tif102150 TIFF2026001045000022.tif113150 TIFF2026001045000023.tif111150 TIFF2026001045000024.tif115150 TIFF2026001045000025.tif102150 TIFF2026001045000026.tif108150 TIFF2026001045000027.tif96150 TIFF2026001045000028.tif102150 TIFF2026001045000029.tif49150

[0014] In some embodiments, the pharmaceutically acceptable salt of the compound is selected from acetate, trifluoroacetate, and formate.

[0015] The present disclosure further provides methods for preparing the compounds or pharmaceutically acceptable salts thereof.

[0016] The present disclosure further provides a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0017] The present disclosure further provides a method for treating a fungal infection in a patient by administering to the patient a pharmaceutical composition of the present disclosure in an amount sufficient to treat the infection. In specific embodiments, the pharmaceutical composition is administered intravenously, topically, or orally. The pharmaceutical composition can be administered to treat a bloodstream infection, a tissue infection (e.g., a lung, kidney, or liver infection), or other types of infection in a patient. The fungal infection to be treated may be an infection selected from tinea capitis, tinea corporis, tinea pedis, tinea unguium, perionychomycosis, tinea versicolor, thrush, vaginal candidiasis, respiratory candidiasis, biliary candidiasis, esophageal candidiasis, urinary candidiasis, systemic candidiasis, mucocutaneous candidiasis, aspergillosis, mucormycosis, paracoccidioidomycosis, North American blastomycosis, histoplasmosis, coccidioidomycosis, sporotrichosis, fungal sinusitis, or chronic sinusitis. In some embodiments, the infection being treated is Candida albicans, C. parapsilosis, C. glabrata, C. guilliermondii, C. krusei, C. lusitaniae, C. tropicalis, Aspergillus fumigatus, Aspergillus flavus, Aspergillus terreus, Aspergillus niger, Aspergillus candidus, Aspergillus clavatus, or Aspergillus ochraceus. ochraceus) is an infection caused by the bacterium.

[0018] The present disclosure further provides a method for preventing a fungal infection in a patient, comprising administering to the patient a pharmaceutical composition of the present invention in an amount sufficient to prevent the infection. For example, the method of the present disclosure can be used to provide prophylactic treatment in patients preparing for an invasive medical procedure (e.g., preparing for surgery, undergoing, for example, a transplant, stem cell therapy, implant, or repair surgery, undergoing long-term or frequent intravenous catheter placement, or receiving treatment in an intensive care unit), immunocompromised patients (e.g., patients with cancer, HIV / AIDS, or taking immunosuppressants), or patients undergoing long-term antibiotic therapy.

[0019] In one specific embodiment of the disclosed method, the pharmaceutical composition comprises Compound 1, or any other compound described herein, or a pharmaceutically acceptable salt thereof.

[0020] The present disclosure also provides a method of preventing, stabilizing, or inhibiting fungal growth or killing a fungus by contacting a fungus or a site prone to fungal growth with a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0021] The terms "sufficient amount" and "amount sufficient" refer to the amount of drug needed to treat or prevent an infection. The amount sufficient to practice the present disclosure to effectively or prophylactically treat symptoms caused by or resulting from an infection will vary depending on the mode of administration, the type of infection, and the age, weight, and general health of the patient.

[0022] The term "fungal infection" refers to the invasion of a host by a pathogenic fungus. For example, the infection can include an overgrowth of a fungus normally present in or on a patient's body or the growth of a fungus not normally present in or on a patient's body. More generally, a fungal infection can be any situation in which the presence of a fungal population is damaging to the host's body. Thus, a patient is "suffering from" a fungal infection when an excessive amount of a fungal population is present in or on a patient's body, or when the presence of a fungal population is damaging to the patient's cells or other tissues.

[0023] The term "treatment" refers to the administration of a pharmaceutical composition for prophylactic and / or therapeutic purposes. "Prevention of disease" refers to prophylactic treatment of a subject who is not yet ill, but who is susceptible to or at risk of developing a particular disease. "Treatment of disease" refers to treating a patient suffering from a disease to ameliorate or stabilize the patient's symptoms.

[0024] The disclosure further provides the use of the compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a fungal infection.

[0025] The present disclosure further provides the use of the compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing a fungal infection.

[0026] The present disclosure further provides a use of the compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing, stabilizing, or inhibiting fungal growth or killing a fungus, in some embodiments, the use comprising contacting the fungus or a site prone to fungal growth with the compound or a pharmaceutically acceptable salt thereof, or an isomer thereof.

[0027] The compounds of the present disclosure may be synthesized by reacting an echinocandin compound with an appropriate acyl group, alkyl group, carboxyl group, hydroxyl group, and / or amino group under standard reaction conditions, for example, as illustrated in the Examples.

[0028] For the semisynthetic routes to the disclosed compounds, the stereochemistry of the compounds is determined by the starting materials. Thus, the stereochemistry of the unnatural echinocandin derivatives typically has the same stereochemistry as the naturally occurring echinocandin skeleton from which they are derived (representative stereochemistries are illustrated in the Examples).

[0029] The compounds of the present disclosure are synthesized, for example, by the methods illustrated in the Examples.

[0030] Unless otherwise stated to the contrary, the following terms used in the specification and claims have the following meanings.

[0031] "Alkyl group" refers to a straight-chain or branched-chain alkane group, preferably containing 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms; non-limiting examples include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl groups. Unless otherwise specified in the specification, alkyl groups may be optionally substituted with one or more substituents such as halogen, cyano, nitro, oxo, thioxo, and trimethylsilyl groups. Unless otherwise specified, "lower alkyl group" refers to a straight-chain or branched-chain alkane group containing 1 to 10 carbon atoms; non-limiting examples include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl groups. Unless stated otherwise in the specification, lower alkyl groups may be optionally substituted with one or more substituents such as halogen, cyano, nitro, oxo, thioxo, trimethylsilyl, and the like.

[0032] An "alkenyl group" refers to an alkyl group compound containing a carbon-carbon double bond in the molecule, where alkyl is defined as above. Non-limiting examples include vinyl, 1-propen-2-yl, 1-buten-4-yl, 1-penten-5-yl, 1-buten-1-yl, and the like. Unless otherwise specified in the specification, an alkenyl group may be optionally substituted with one or more substituents such as halogen, cyano, nitro, oxo, thioxo, or trimethylsilyl.

[0033] An "alkynyl group" refers to an alkyl group compound containing a carbon-carbon triple bond in the molecule, where alkyl is defined above. Non-limiting examples include ethynyl, propynyl, pentynyl, butynyl, and the like. Unless otherwise specified in the specification, an alkynyl group may be optionally substituted with one or more substituents such as halogen, cyano, nitro, oxo, thioxo, or trimethylsilyl.

[0034] "C 10-36 The term "lipophilic unit" refers to a substituted or unsubstituted alkyl group having 10 to 36 carbon atoms, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cyclohydrocarbyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclyl group, or the like.

[0035] The term "aryl group" refers to a hydrocarbon ring system containing a hydrogen atom, 6 to 14 carbon atoms, and at least one aromatic ring, and may be monocyclic, bicyclic, or tricyclic, and may include a spirocyclic ring system. Aryl groups include, but are 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 with one or more substituents independently selected from alkyl groups, alkenyl groups, alkynyl groups, halogens, haloalkyl groups, haloalkenyl groups, haloalkynyl groups, cyano groups, nitro groups, and the like.

[0036] "Cyclohydrocarbyl group" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbyl group composed solely of carbon and hydrogen atoms, which may include spirocyclic or bridged ring systems, contains 3 to 15 carbon atoms, 3 to 10 carbon atoms, or 5 to 7 carbon atoms, is saturated or unsaturated, and is attached to the remainder of the molecule by a single bond. Monocyclic cyclohydrocarbyl groups include unbridged ring hydrocarbyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. Polycyclic groups include C groups such as adamantyl groups (bridged rings) and decahydronaphthyl groups (fused rings), and fused, spiro, or bridged ring hydrocarbyl groups such as C groups such as bicyclo[3.2.0]heptyl groups (fused rings), norbornane groups and norbornenyl groups (bridged rings), as well as substituted polycyclic groups such as substituted C groups such as 7,7-dimethylbicyclo[2.2.1]heptyl groups (bridged rings). Unless otherwise specified in the specification, cyclohydrocarbyl groups may be optionally substituted with one or more substituents independently selected from alkyl groups, alkenyl groups, alkynyl groups, halogens, haloalkyl groups, haloalkenyl groups, haloalkynyl groups, oxo groups, thioxo groups, cyano groups, nitro groups, and the like.

[0037] "Cycloalkyl group" refers to a saturated monocyclic or polycyclic cyclic hydrocarbon substituent having 3 to 15 carbon atoms, 3 to 10 carbon atoms, or 5 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups, and polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups.

[0038] "Halogen" refers to bromine, chlorine, fluorine or iodine.

[0039] A "heterocyclyl group" 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 the specification, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, may include a spirocyclic or bridged ring system, and the nitrogen, carbon, or sulfur atoms in the heterocyclyl group may be optionally oxidized, the nitrogen atom may be optionally quaternized, and the heterocyclyl group may be partially or fully saturated. Unless otherwise specified in the specification, a heterocyclyl group includes a heterocyclyl group optionally substituted with one or more substituents selected from alkyl groups, alkenyl groups, alkynyl groups, halogens, haloalkyl groups, haloalkenyl groups, haloalkynyl groups, oxo groups, thioxo groups, cyano groups, nitro groups, and the like.

[0040] A "heteroaryl group" refers to a 5- to 14-membered ring system containing a hydrogen atom, 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur, and at least one aromatic ring. Heteroaryl groups may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, and may include spirocyclic ring systems. The nitrogen, carbon, or sulfur atoms in the heteroaryl group may be optionally oxidized, and the nitrogen atom may be optionally quaternized. The aromatic ring of a heteroaryl group does not necessarily contain a heteroatom; only one ring of the heteroaryl group may contain a heteroatom. For example, 1,2,3,4-tetrahydroquinolin-7-yl is considered a "heteroaryl group." Unless stated otherwise in this specification, heteroaryl groups include heteroaryl groups optionally substituted with one or more substituents selected from alkyl groups, alkenyl groups, alkynyl groups, halogen, haloalkyl groups, haloalkenyl groups, haloalkynyl groups, oxo groups, thioxo groups, cyano groups, nitro groups, and the like.

[0041] "PEG" refers to polyethylene glycol, and unless otherwise defined, "PEG" includes ethylene oxide polymers of any length, which may be further optionally substituted with one or more substituents selected from deuterium, alkyl groups, alkenyl groups, alkynyl groups, halogens, haloalkyl groups, haloalkenyl groups, haloalkynyl groups, oxo groups, thioxo groups, cyano groups, nitro groups, and the like. [Brief explanation of the drawings]

[0042] [Figure 1] 1 shows the change in histamine concentration after intravenous administration of the compound. [Figure 2] This is a comparison of histamine concentrations 30 minutes after intravenous administration of the compounds. DETAILED DESCRIPTION OF THE INVENTION

[0043] The present invention will be further described below with reference to examples, but these examples are not intended to limit the scope of the present invention.

[0044] In the examples of the present invention, experimental methods for which specific conditions are not specified generally follow conventional conditions or conditions recommended by the manufacturers of raw materials or products. Reagents for which no specific source is specified are conventional reagents purchased from the market.

[0045] Anidulafungin and caspofungin are all purchased from Taizhou Kede Chemical Co., Ltd. Rezafungin is synthesized according to CN103889221A.

[0046] HPLC purity analysis method: [Table 1] LC-MS analysis method: [Table 1] [Example]

[0047] Example 1: Step 1 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 mixture was heated to reflux for 4 h. A white solid precipitated, which was filtered. The filter cake was dried under vacuum to give 385 mg of compound SM2, with a purity of 98% and a yield of 26.7%. Ms: 116.1 [M + ].

[0048] Step 2 TIFF2026001045000033.tif44150 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 under vacuum. 10 mL of acetonitrile was added, and compound SM2 (170 mg, 0.6 mmol) and p-toluenesulfonic acid (86 mg, 0.5 mmol) were added, followed by stirring at room temperature for 16 hours. The reaction was quenched by the addition of 1 N aqueous sodium acetate (1 mL). The solvent was removed by rotary evaporation, and the resulting crude product was purified by preparative chromatography to give 79 mg of the product (acetate salt) with a purity of 97.6% and a yield of 60.8%. HRMS: 1237.6021 [M + ].

[0049] 1H NMR (400 MHz, METHANOL-d4) δ 7.98 - 8.01 (m, 2H), 7.82 (d, J = 8.3 Hz, 2H), 7.71 - 7.78 (m, 4H), 7.63 (d, J = 8.8 Hz, 2H), 7.17 (d, J = 8.6 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 6.79 (d, J = 8.6 Hz, 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 = 6.8 Hz, 3H), 0.99 (t, J = 7.2 Hz, 3H).

[0050] Example 2: Step 1 Compound SM3 (1.29 g, 10 mmol) was dissolved in acetone (13 mL), iodomethane (1.42 g, 10 mmol) was added dropwise, and the reaction mixture was heated to reflux for 4 h. A white solid precipitated, which was filtered, and the filter cake was dried under vacuum to give 2.54 g of compound SM4, 98% pure, in 89.2% yield. Ms: 144.1 [M + ].

[0051] Step 2 TIFF2026001045000035.tif44150 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 under vacuum. 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, followed by stirring at room temperature for 16 hours. The reaction was quenched by the addition of 1 N aqueous sodium acetate solution (1 mL). The solvent was removed by rotary evaporation, and the resulting crude product was purified by preparative chromatography to give 61 mg of the product (acetate salt), with a purity of 97.0% and a yield of 46.2%. HRMS: 1265.6327 [M + ].

[0052] 11H NMR (400 MHz, METHANOL-d4) δ 8.01 (d, J = 8.3 Hz, 2H), 7.83 (dd, J = 0.49, 8.3 Hz, 2H), 7.71 - 7.79 (m, 4H), 7.63 (d, J = 8.80Hz, 2H), 7.17 (d, J = 8.6 Hz, 2H), 7.03 (d, J = 8.80Hz, 2H), 6.79 (d, J = 8.6 Hz, 2H), 5.34 - 5.41 (m, 1H), 5.00 - 5.05 (m, 1H), 4.58 - 4.80 (m, 7H), 4.40 (d, J = 4.4 Hz, 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), 3.43 - 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 = 6.4 Hz, 6H), 1.10 (d, J = 6.9 Hz, 3H), 0.99 (t, J = 7.1Hz, 3H).

[0053] Example 3: TIFF2026001045000036.tif44150 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 under vacuum. 10 mL of dioxane was added, and 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 hours. The reaction was quenched by the addition of 1 N aqueous sodium acetate solution (1 mL). The solvent was removed by rotary evaporation, and the resulting crude product was purified by preparative chromatography to give 68 mg of the product (acetate salt) with a purity of 97.8% and a yield of 52.3%. HRMS: 1243.5924 [M + ].

[0054] 1 H NMR (400 MHz, METHANOL-d4) δ 7.97 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H), 7.69 - 7.75 (m, 4H), 7.61 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 7.01 (d, J = 8.4Hz, 2H), 6.76 (d, J = 8.0 Hz, 2H), 5.45(d, J =17.6 Hz, 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), 2.26-2.29 (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 = 6.8 Hz, 3H),0.97 (t, J = 7.2 Hz) ,3H).

[0055] Example 4: Echinocandin B (50 mg, 0.06 mmol) and octadecanedioic acid 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. The mixture was stirred in an ice-water bath for 1.5 h, quenched with water (5.0 mL), and extracted with ethyl acetate (5 mL × 5). The combined organic phases were washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC to give 55.2 mg of product with a purity of 97.1% and a yield of 80%. HRMS: 1150.6482 [M+1].

[0056] 1 HNMR (400 MHz, DMSO d6):δ 9.31 (s, 1H), 8.06-7.94 (m, 3H), 7.40(s, br, 1H), 7.29 (d, 1H, J = 9.2 Hz), 7.02 (d, 2H, J = 8.4 Hz), 6.68 (d, 2H, J = 8.0 Hz), 5.45 (d, 1H, J = 6.4 Hz), 5.19 (d, 1H, J = 3.2 Hz), 5.14 (d, 1H, J = 4.4 Hz), 5.10 (d, 1H, J = 5.2 Hz), 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 = 8.0 Hz), 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 = 6.8 Hz).

[0057] Example 5: Step 1 N-(2-hydroxyethyl)-pyrrolidine (2.30 g, 20 mmol) was dissolved in 40 mL of acetone, and iodomethane (2.84 g, 1.0 eq.) was added slowly. The mixture was heated under reflux for 4 hours, and the solvent was concentrated until half of the solvent remained. The solid precipitated, filtered, and dried to give 4.88 g of a white solid, compound SM6, in a 95% yield. Ms: 130.0 [M + ].

[0058] 1HNMR (400 MHz, D2O): δ 4.09 (d, 2H, J = 2.0 Hz), 3.63-3.56 (m, 6H), 3.15(s, 3H), 2.26 (s, 4H).

[0059] Step 2 TIFF2026001045000039.tif51150 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, and concentrated to dryness. Anhydrous acetonitrile (10 mL) was added, and 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. The mixture was quenched with aqueous sodium acetate and concentrated to obtain the crude product. The crude product was purified by preparative HPLC to give 259 mg of the product (acetate salt), with a purity of 96.5% and a yield of 76%. HRMS: 1251.6174 [M + ].

[0060] 1HNMR (400 MHz, CD3OD):δ 8.00 (d, 2H, J = 8.4 Hz), 7.83 (d, 2H, J = 8.0 Hz), 7.77 (m, 4H), 7.63 (d, 2H, J = 8.8 Hz), 7.17 (d, 2H, J = 8.4 Hz), 7.03 (d, 2H, J = 8.8 Hz), 6.78 (d, 2H, J = 8.8 Hz), 5.45 (d, 1H, J = 2.0 Hz), 5.06 (d, 1H, J = 3.2 Hz), 4.81-4.76 (m, 1H), 4.62-4.60 (m, 3H), 4.41 (d, 1H, J = 4.4 Hz), 4.36-4.33 (m, 2H), 4.28-4.25 (m, 2H), 4.22-4.18 (m, 1H), 4.11-3.83 (m, 8H), 3.68-3.42 (m, 8H), 3.09 (s, 3H), 2.55-2.44 (m, 2H), 2.33-2.27 (m, 1H), 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 = 5.6 Hz), 1.09 (d, 3H, J = 7.2 Hz), 0.92 (t, 3H, J = 6.4 Hz).

[0061] Example 6: 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 the mixture was 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. The solid was filtered, dried, and triturated with acetonitrile to give 120 mg of product with a purity of 95.8% and a yield of 61.5%. HRMS: 1625.8989 [M+1].

[0062] 1HNMR (400 MHz, DMSO d6 ): δ 9.31 (s, 1H), 8.05 (d, 2H, J = 7.6 Hz), 7.95 (d, 1H, J = 8.4 Hz), 7.90 - 7.88 (m, 1H), 7.73 - 7.69 (m, 2H), 7.43 - 7.31 (m, 2H), 7.02 (d, 2H, J = 8.4 Hz), 6.69 (d, 2H, J = 8.0 Hz), 5.52 (d, 1H, J = 5.6 Hz), 5.20 (d, 1H, J = 2.8 Hz), 5.15 (d, 1H, J = 3.6 Hz), 5.10 (d, 1H, J = 5.6 Hz), 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 = 6.8 Hz).

[0063] Example 7: TIFF2026001045000041.tif30127 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, and concentrated to dryness. Compound SM7 (101.6 mg, 6 eq.) and p-toluenesulfonic acid (53 mg, 5 eq.) were added, and the mixture was stirred at room temperature for 5 hours under nitrogen protection. The mixture was quenched with aqueous sodium acetate and concentrated to obtain the crude product, which was purified by preparative 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 + ].

[0064] 1 HNMR (400 MHz, CD3OD):δ 8.48 (d, 1H, J = 8.4 Hz), 8.41 (d, 1H, J = 8.8 Hz), 8.23 ​​(d, 1H, J = 7.6 Hz), 8.04-7.99 (m, 2H), 7.60-7.54 (m, 2H), 7.15 (d, 2H, J = 8.0 Hz), 6.77 (d, 2H, J = 8.4 Hz), 5.51 (d, 1H, J = 9.6 Hz), 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, 6H), 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 = 6.4 Hz), 1.08 (d, 3H, J = 6.4 Hz).

[0065] Example 8: The trifluoroacetate salt of the compound from 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 preparative HPLC to give 7.2 mg of the product (trifluoroacetate salt), with a purity of 97.8% and a yield of 30%. HRMS: 1598.8629 [M + ].

[0066] Example 9: Step 1 TIFF2026001045000043.tif47150 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 the mixture was stirred in an ice-water bath for 1.5 hours. The mixture was purified using a reverse-phase column to give 234 mg of product in 85% yield. Ms: 1152.5 [M+1].

[0067] 1HNMR (400 MHz, CD3OD):δ 7.96 (d, 2H, J = 6.0 Hz), 7.77-7.69 (m, 6H), 7.62 (d, 2H, J = 8.4 Hz), 7.17 (d, 2H, J = 8.4 Hz), 7.02 (d, 2H, J = 8.8 Hz), 6.78 (d, 2H, J = 8.4 Hz), 5.37 (d, 1H, J = 2.8 Hz), 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 = 6.8 Hz), 0.77-0.74 (m, 1H), 0.50-0.46 (m, 2H), 0.10-0.06 (m, 2H).

[0068] Step 2 TIFF2026001045000044.tif41119 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 h, 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 h under nitrogen protection. The mixture was quenched with aqueous sodium acetate and concentrated to give the crude product, which was purified by preparative HPLC to give 102 mg of the product (acetate salt), with a purity of 95.8% and a yield of 65%. HRMS: 1237.6022 [M + ].

[0069] 1HNMR (400 MHz, CD3OD):δ 7.99 (d, 2H, J = 8.4Hz), 7.82 (d, 2H, J = 8.0Hz), 7.78-7.71 (m, 4H), 7.62 (d, 2H, J = 8.4 Hz), 7.17 (d, 2H, J = 8.4Hz), 7.03 (d, 2H, J = 8.4Hz), 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), 4.21-4.18 (m, 1H), 4.11-3.90 (m, 7H), 3.84 (d, 1H, J = 11.2 Hz), 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 = 6.8 Hz) 0.80-0.74 (m, 1H), 0.50-0.46 (m, 2H), 0.10-0.06 (m, 2H).

[0070] Example 10: Step 1 N-(2-hydroxyethyl)-pyrrolidine (6.5 g, 50 mmol) was dissolved in 25 mL of acetonitrile, and iodomethane (7.09 g, 1.0 eq.) was added slowly. The mixture was heated under reflux for 4 hours, and the solvent was concentrated until half of the solvent remained. The solid precipitated, filtered, and dried to give 12.1 g of compound SM10 as a white solid in 90% yield. Ms: 144.0 [M + ].

[0071] Step 2 TIFF2026001045000046.tif42150 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 under vacuum, and 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. The reaction was quenched by the addition of 1 N aqueous sodium acetate solution (1 mL). The solvent was removed by rotary evaporation, and the resulting crude product was purified by preparative chromatography to give 47.6 mg of the product (acetate salt), with a purity of 97.1% and a yield of 41%. HRMS: 1265.6324 [M + ].

[0072] 1 H NMR (400 MHz, METHANOL-d4) δ 7.98 (d, J = 8.4 Hz, 2H), 7.81 (d, J = 8.4Hz, 2H), 7.70 - 7.76 (m, 4H), 7.61 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 6.76 (d, J = 8.4 Hz, 2H), 5.42 (d, J =1.6 Hz, 1H),5.04(d, J =3.2 Hz, 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 = 7.2 Hz) ,3H).

[0073] Example 11: Step 1 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 the mixture was stirred in an ice-water bath for 1 h. The reaction mixture was then loaded onto a reverse-phase column (MECN / HO) to give 392 mg of compound SM12 with a purity of 96% and a yield of 70.6%. MS: 1158.5 [M+1].

[0074] Step 2 TIFF2026001045000048.tif41131 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 h. The solvent was evaporated to dryness under vacuum, and 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. The reaction was quenched by the addition of 1 N aqueous sodium acetate solution (1 mL). The solvent was removed by rotary evaporation, and the resulting crude product was purified by preparative chromatography to give 39.5 mg of the product (formate salt), with a purity of 97.0% and a yield of 35.5%. HRMS: 1243.5936 [M + ].

[0075] 1H NMR (400 MHz, METHANOL-d4) δ 8.54 (s, 1H),7.98(d, J = 8.0 Hz, 2H), 7.81 (d, J = 8.0 Hz, 2H), 7.70 - 7.76 (m, 4H), 7.61 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 8.0 Hz, 2H), 6.76 (d, J = 8.4 Hz, 2H), 5.42 (s, 1H), 5.04 (s, 1H), 4.71-4.78 (m, 1H), 4.48 - 4.58 (m, 4H), 4.16-4.42 (m, 7H), 4.05 (t, J = 6.4 Hz ,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 = 6.8 Hz, 3H).

[0076] Example 12: TIFF2026001045000049.tif41150 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 under vacuum, and 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. The reaction was quenched by the addition of 1N aqueous sodium acetate (2 mL). The solvent was removed by rotary evaporation, and the resulting crude product was purified by preparative chromatography to give 48.3 mg of the product (acetate salt), with a purity of 97.7% and a yield of 21.3%. HRMS: 1234.6581 [M + ].

[0077] Example 13: Step 1 N-Methyl-D-prolinol (1.15 g, 10 mmol) was dissolved in 20 mL of acetone, iodomethane (1.56 g, 1.1 eq.) was added slowly, and the mixture was refluxed for 4 hours. The solvent was concentrated until half of the solid remained, and the precipitate was filtered and dried to give 2.44 g of a white solid, compound SM14, in 95% yield. Ms: 130.0 [M + ].

[0078] Step 2 TIFF2026001045000051.tif44150 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 and stirred at room temperature for 5 hours under nitrogen protection. The mixture was quenched with aqueous sodium acetate and concentrated to obtain the crude product, which was purified by preparative HPLC to give 57.5 mg of the product (acetate salt), with a purity of 95.8% and a yield of 50%. HRMS: 1251.6173 [M + ].

[0079] 1H NMR (400 MHz, METHANOL-d4) δ 7.98 (d, J = 8.8 Hz, 2H), 7.81 (d,J=8.0Hz, 2H), 7.69 - 7.76 (m, 4H), 7.61 (d, J = 9.2 Hz, 2H), 7.15 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 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,4H), 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 = 6.8 Hz, 3H).

[0080] Example 14: Step 1 Compound SM15 (1.02 g, 10.08 mmol) was dissolved in acetonitrile (10 mL), methyl p-toluenesulfonate (1.88 g, 10.08 mmol) was added dropwise, and the reaction mixture was heated to reflux for 4 h. The solvent was evaporated to dryness to give crude compound SM16, which was used directly in the next step. Ms: 116.1 [M + ].

[0081] Step 2 TIFF2026001045000053.tif44150 Under nitrogen protection, anidulafungin (1.14 g, 1 mmol) was dissolved in tetrahydrofuran (40 mL), phenylboronic acid (244 mg, 2 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated to dryness under vacuum. 50 mL of dioxane was added, and compound SM16 (2.86 g, 10 mmol) and camphorsulfonic acid (1.16 g, 5 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The reaction was quenched by the addition of 1 N aqueous sodium acetate (10 mL). The solvent was removed by rotary evaporation, and the resulting crude product was purified by preparative chromatography to give 563 mg of the product (acetate salt) with a purity of 95.4% and a yield of 43.4%. HRMS: 1237.6023 [M + ].

[0082] 1H NMR (400 MHz, METHANOL-d4) δ 7.97 (d, J = 8.3 Hz, 2H), 7.80 - 7.82 (m, 2H), 7.69 - 7.76 (m, 4H), 7.61 (d, J = 8.8 Hz, 2H), 7.14 (d, J = 8.6 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 6.76 (d, J = 8.6 Hz, 2H), 5.35 - 5.36 (m, 1H), 5.02 - 5.03 (m, 1H), 4.86 (d, J = 5.1 Hz, 1H), 4.74 (dd, J = 5.3, 12.1 Hz, 1H), 4.44 - 4.65 (m, 5H), 4.39 (d, J = 4.4 Hz, 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, 1H), 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 = 6.8 Hz, 3H), 0.92 - 1.01 (m, 3H).

[0083] Example 15: ステップ1 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 the mixture was stirred in an ice-water bath for 1 h. The reaction mixture was then loaded onto a reverse-phase column (MECN / HO) to give 298 mg of compound SM18 with a purity of 97% and a yield of 72.6%. MS: 1158.5 [M+1].

[0084] Step 2 TIFF2026001045000055.tif41129 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 h. The solvent was evaporated to dryness under vacuum, and 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. The reaction was quenched by the addition of 1 N aqueous sodium acetate (1 mL). The solvent was removed by rotary evaporation, and the resulting crude product was purified by preparative chromatography to give 57 mg of the product (formate salt), with a purity of 97.8% and a yield of 34.1%. HRMS: 1243.5928 [M + ].

[0085] 1H NMR (400 MHz, METHANOL-d4) δ 8.55(s, 1H), 7.61 - 7.81 (m, 9H), 7.15(d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 6.76 (d, J = 8.4 Hz, 2H), 5.37 (d, J = 2.4 Hz, 1H), 5.03 (d, J = 3.2 Hz, 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 - 2.12 (m, 2H), 1.78 - 1.85(m, 2H),1.38-1.53 ​​(m, 4H), 1.25-127(m,6H),1.08 (d, J = 6.8 Hz, 3H),0.97(t,J =7.2 Hz, 3H).

[0086] Example 16: Step 1 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 the mixture was stirred in an ice-water bath for 1 h. The reaction mixture was then loaded onto a reverse-phase column (MECN / HO) to give 890 mg of compound SM20 with a purity of 89.6% and a yield of 70.1%. MS: 1138.5 [M+1].

[0087] Step 2 TIFF2026001045000057.tif41129 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 h. The solvent was evaporated to dryness under vacuum, and 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. The reaction was quenched by the addition of 1 N aqueous sodium acetate solution (1 mL). The solvent was removed by rotary evaporation, and the resulting crude product was purified by preparative chromatography to give 123 mg of the product (acetate salt), with a purity of 97.6% and a yield of 54.6%. HRMS: 1223.6224 [M + ].

[0088] 1 H NMR (400 MHz, METHANOL-d4) δ 7.98 (d, J = 8.4 Hz, 2H), 7.80 (d,J=8.4Hz, 2H), 7.72 - 7.78 (m, 4H), 7.59 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.4 Hz, 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 - 4.61 (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 = 6.8 Hz, 3H).

[0089] Example 17: Step 1 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 the mixture was stirred in an ice-water bath for 1 h. The reaction mixture was then loaded onto a reverse-phase column (MECN / HO) to give 94 mg of compound SM22 with a purity of 73% and a yield of 32.9%. MS: 1139.5 [M+1].

[0090] Step 2 TIFF2026001045000059.tif41129 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 h. The solvent was evaporated to dryness under vacuum, and 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. The reaction was quenched by the addition of 1 N aqueous sodium acetate (1 mL). The solvent was removed by rotary evaporation, and the resulting crude product was purified by preparative chromatography to give 31 mg of the product (acetate salt) with a purity of 96.1% and a yield of 27.5%. HRMS: 1224.6163 [M + ].

[0091] 1H NMR (400 MHz, METHANOL-d4) δ 7.96 (d, J = 8.4 Hz, 2H), 7.79 (d,J=8.0Hz, 2H), 7.65 - 7.72 (m, 4H), 7.48(d, J = 8.8 Hz, 2H), 7.15 (d, J = 8.4 Hz, 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, 3H), 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 - 2.12 (m, 2H), 1.91(s,3H),1.62 - 1.67(m, 2H), 1.38- 1.44 (m, 4H), 1.26 (d, J =6.0 Hz,6H), 1.08 (d,J=6.8Hz, 3H),0.96 (t, J = 6.8 Hz, 3H).

[0092] Example 18: TIFF2026001045000060.tif44150 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 under vacuum, and 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 hours. The reaction was quenched by the addition of 1 N aqueous sodium acetate (2 mL). The solvent was removed by rotary evaporation, and the resulting crude product was purified by preparative chromatography to give 35 mg of the product (acetate salt) with a purity of 97.3% and a yield of 30.9%. HRMS: 1229.6268 [M + ].

[0093] 1 H NMR (400 MHz, METHANOL-d4) δ 7.97 (d, J = 8.4 Hz, 2H), 7.79 (d,J=8.4Hz, 2H), 7.69- 7.76 (m, 4H), 7.61(d, J = 8.8 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.00(d, J = 8.8 Hz, 2H), 6.76(d, J = 8.4 Hz, 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 =5.6 Hz,6H), 1.07 (d,J=7.6Hz, 3H),0.97(t, J = 6.8 Hz, 3H).

[0094] Example 19: Step 1 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 the mixture was stirred in an ice-water bath for 1 h. The reaction mixture was then loaded onto a reverse-phase column (MECN / HO) to give 165 mg of compound SM25 with a purity of 95.9% and a yield of 71.6%. MS: 1194.5 [M+1].

[0095] Step 2 TIFF2026001045000062.tif41132 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 h. The solvent was evaporated to dryness under vacuum, and 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. The reaction was quenched by the addition of 1 N aqueous sodium acetate (1 mL). The solvent was removed by rotary evaporation, and the resulting crude product was purified by preparative chromatography to give 33 mg of the product (acetate salt) with a purity of 97.2% and a yield of 29.4%. HRMS: 1279.5720 [M + ].

[0096] 1 H NMR (400 MHz, METHANOL-d4) δ 7.97 (d, J = 8.0 Hz, 2H), 7.80 (d,J=8.4Hz, 2H), 7.69- 7.76 (m, 4H), 7.62(d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.03(d, J = 8.8 Hz, 2H), 6.76(d, J = 8.4 Hz, 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 =6.4 Hz,6H), 1.08 (d,J=6.8Hz, 3H).

[0097] Example 20: Step 1 SM-26 (590 mg, 1 eq.) was dissolved in 10 mL of acetonitrile, and methyl p-toluenesulfonate (1.2 g, 1.1 eq.) was added. The mixture was refluxed for 4 hours, concentrated, and triturated with acetone and petroleum ether to give 1.6 g of a white solid, compound SM-27, in a 95% yield. Ms: 117.1 [M + ].

[0098] Step 2 TIFF2026001045000064.tif48150 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 and stirred at room temperature for 5 hours under nitrogen protection. The mixture was quenched with aqueous sodium acetate and concentrated to obtain the crude product, which was purified by preparative 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 + ].

[0099] 1HNMR (400 MHz, CD3OD):δ 8.56(s, 1H), 8.02 (d, 2H, J = 10.8 Hz), 7.82 (d, 2H, J = 8.4 Hz), 7.77 (m, 4H), 7.63 (d, 2H, J = 8.4 Hz), 7.17 (d, 2H, J = 8.8 Hz), 7.03 (d, 2H, J = 8.8 Hz), 6.78 (d, 2H, J = 8.8 Hz), 5.42 (d, 1H, J = 2.4 Hz), 5.06 (d, 1H, J = 2.8 Hz), 4.92-4.88 (m, 2H), 4.81-4.72 (m, 2H), 4.63-4.58 (m, 3H), 4.42 (d, 1H, J = 4.0 Hz), 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 = 6.0 Hz), 1.08 (d, 3H, J = 6.8 Hz), 0.99 (t, 3H, J = 6.8 Hz).

[0100] Example 21: 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 h, concentrated to dryness, and purified by preparative HPLC to give 7.2 mg of the product (trifluoroacetate salt), with a purity of 97.8% and a yield of 30%. HRMS: 1513.7743 [M+1].

[0101] Example 22: Step 1 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 to reflux for 2 h to precipitate a white solid. The solid was cooled to room temperature and filtered. The filter cake was dried under vacuum to give 6.5 g of compound SM-30, with a purity of 98% and a yield of 42.9%. Ms: 118.12 [M + ].

[0102] Step 2 TIFF2026001045000067.tif46150 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 h. The solvent was evaporated to dryness under vacuum, and 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, followed by stirring at room temperature for 16 h. The reaction was quenched by the addition of 1 N aqueous sodium acetate solution (1 mL). The solvent was removed by rotary evaporation, and the resulting crude product was purified by preparative chromatography to give 53 mg of the product (acetate salt) with a purity of 96.1% and a yield of 46.5%. HRMS: 1239.6225 [M + ].

[0103] 1H NMR (400 MHz, METHANOL-d4) δ 7.98 (d, J = 8.4 Hz, 2H), 7.81 (d,J=7.2Hz, 2H), 7.69 - 7.76 (m, 4H), 7.61 (d, J =8.8 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.8 Hz, 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 = 7.2 Hz, 3H).

[0104] Example 23: Step 1 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 to reflux for 2 h to precipitate a white solid. The solid was cooled to room temperature and filtered. The filter cake was dried under vacuum to give 3.2 g of compound SM-32, with a purity of 98% and a yield of 53%. Ms: 118.12 [M + ].

[0105] Step 2 TIFF2026001045000069.tif45150 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 h. The solvent was evaporated to dryness under vacuum, and 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, followed by stirring at room temperature for 16 h. The reaction was quenched by the addition of 1 N aqueous sodium acetate (1 mL). The solvent was removed by rotary evaporation, and the resulting crude product was purified by preparative chromatography to give 39 mg of the product (acetate salt) with a purity of 99.6% and a yield of 34.2%. HRMS: 1239.6226 [M + ].

[0106] 1H NMR (400 MHz, METHANOL-d4) δ 7.97 (d, J = 8.4 Hz, 2H), 7.69 - 7.81 (m, 6H), 7.61 (d, J =8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 6.76 (d, J = 8.4Hz, 2H), 5.34(d,J = 2.8 Hz,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 - 1.84 (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 = 7.2 Hz, 3H).

[0107] Example 24: Step 1 TIFF2026001045000070.tif2591 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 to reflux for 2 h to precipitate a white solid. The solid was cooled to room temperature and filtered. The filter cake was dried under vacuum to give 2.05 g of compound SM-34, with a purity of 98% and a yield of 33%. Ms: 118.12 [M + ].

[0108] Step 2 TIFF2026001045000071.tif48150 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 h. The solvent was evaporated to dryness under vacuum, and 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, followed by stirring at room temperature for 16 h. The reaction was quenched by the addition of 1 N aqueous sodium acetate solution (1 mL). The solvent was removed by rotary evaporation, and the resulting crude product was purified by preparative chromatography to give 29 mg of the product (acetate salt) with a purity of 97.5% and a yield of 25.4%. HRMS: 1239.6223 [M + ].

[0109] 1H NMR (400 MHz, METHANOL-d4) δ 7.96 (d, J = 7.2 Hz, 2H), 7.69 - 7.80 (m, 6H), 7.61 (d, J =8.4 Hz, 2H), 7.15 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 7.6 Hz, 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, 2H), 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 = 7.2 Hz, 6H),1.20 (d,J=5.2Hz, 3H),1.07 (d,J=7.2Hz, 3H),0.97 (t, J = 6.8 Hz, 3H).

[0110] Example 25: Step 1 TIFF2026001045000072.tif2047SM-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 a white solid, compound SM-36, in an 85% yield. Ms: 116.2 [M + ].

[0111] Step 2 TIFF2026001045000073.tif47150 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 h. The solvent was evaporated to dryness under vacuum, and 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, followed by stirring at room temperature for 16 h. The reaction was quenched with 1 N aqueous sodium acetate solution (1 mL) and concentrated to give the crude product. The crude product was purified by preparative HPLC to give 50 mg of the product (acetate salt) with a purity of 96.2% and a yield of 44%. HRMS: 1238.4225 [M + ].

[0112] 1HNMR (400 MHz, METHANOL-d4): δ 8.02 (d, 2H, J = 8.4 Hz), 7.84 (d, 2H, J = 8.0 Hz), 7.78-7.71 (m, 4H), 7.63 (d, 2H, J = 6.8 Hz), 7.17 (d, 2H, J = 8.8 Hz), 7.03 (d, 2H, J = 8.8 Hz), 6.81 (d, 2H, J = 7.2 Hz), 5.52 (d, 1H, J = 1.6 Hz), 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 = 4.4 Hz), 4.36-4.33 (m, 2H), 4.27-4.23(m, 2H), 4.18-4.15 (m, 1H), 4.06-4.00(m, 4H), 3.96-3.90 (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 = 7.2 Hz), 0.99(t, 3H, J = 7.2 Hz).

[0113] Example 26: Step 1 TIFF2026001045000074.tif2047SM-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 a white solid, compound SM-38, in a 90% yield. Ms: 116.2 [M + ].

[0114] Step 2 TIFF2026001045000075.tif47150 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 h. The solvent was evaporated to dryness under vacuum, and 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, followed by stirring at room temperature for 16 h. The reaction was quenched with 1 N aqueous sodium acetate (1 mL) and concentrated to give the crude product, which was purified by preparative HPLC to give 40 mg of the product (acetate salt) with a purity of 96.2% and a yield of 34%. HRMS: 1238.4225 [M + ].

[0115] 1HNMR (400 MHz, METHANOL-d4): δ 8.00 (d, 2H, J = 8.4 Hz), 7.82 (d, 2H, J = 8.4 Hz), 7.78-7.71 (m, 4H), 7.63 (d, 2H, J = 8.8 Hz), 7.17 (d, 2H, J = 8.8 Hz), 7.03 (d, 2H, J = 8.8 Hz), 6.78 (d, 2H, J = 8.4 Hz), 5.44 (d, 1H, J = 2.4 Hz), 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 = 4.0 Hz), 4.36-4.33 (m, 2H), 4.27-4.25(m, 2H), 4.20-4.18 (m, 1H), 4.06-4.00 (m, 4H), 3.94-3.90 (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 = 7.2 Hz), 0.99 (t, 3H, J = 7.2 Hz).

[0116] High-energy decomposition mass analysis methods: Table 1

[0117] Test Example 1: Test Method for Antifungal Activity After gradient dilution of the test compounds, MIC detection was performed against the Candida standard strain, and MEC detection was performed against the Aspergillus standard strain. The minimum inhibitory concentration (MIC) detection method was performed in accordance with the guidelines of the American Clinical Laboratory Standards Institute (CLSI M27-A3), and the minimum effective concentration (MEC) detection method was performed in accordance with the guidelines of the American Clinical Laboratory Standards Institute (CLSI M38-A2).

[0118] Preparation of fungal inoculum Candida: The cryopreserved strains were passaged at least twice, and single colonies were selected and resuspended in saline or sterile water. The colonies were vortexed and the bacterial suspension was measured at a wavelength of 530 nm using a spectrophotometer to obtain a 0.5 McF (1 × 10 6 ~5×10 6 After diluting 50-fold with saline, the culture was diluted 20-fold (1 × 10 CFU / mL) with 1 × RPMI 1640 broth. 3 ~5×10 3 CFU / mL) was diluted. 10 μL was plated on an SDA plate and colonies were counted, ranging from 10 to 50 single colonies.

[0119] After the prepared drug susceptibility plate was completely dissolved at room temperature, the bacterial suspension was added to a 96-well plate using a multichannel pipette at a concentration of 100 μL per well. The bacterial concentration in each well was 0.5 × 10 3 ~2.5×10 3 It should be expressed as CFU / mL.

[0120] Aspergillus (operate in a Class II biological safety cabinet): Aspergillus was subcultured onto SDA plates and cultured at 35°C for 48 h–7 d to induce sporulation. Approximately 1 mL of 0.85% saline or sterile water was used to cover the colonies on the plates (polysorbate 20 was added to a final concentration of 0.1%–0.01%). The surface of the medium was gently wiped using a tip or sterile cotton swab (taking care not to puncture the medium), and the resuspended spore mycelium was transferred to a sterile test tube. The tube was left to stand for 3–5 min to allow the heavier particles to settle. The resulting homogenous suspension was transferred to a new sterile test tube, tightly capped, and vortexed for 15 s (Caution: Reopening the cap can generate aerosols). The suspension was then diluted 50-fold with 1x RPMI 1640 until the OD at 530 nm was measured spectrophotometrically at 0.09–0.13. Within 2 h after dilution, 100 μL of sample was added to each well of a 96-well plate (the final concentration of spores in the drug susceptibility plate was 0.4 × 10 4 ~5×10 4 CFU / mL) was added.

[0121] Colony counting: The suspension diluted with RPMI 1640 was further diluted 10-fold, and 10 μL was taken and applied to an SDA plate. The plate was cultured at 28°C and observed daily. Colonies were counted immediately after they appeared with the naked eye.

[0122] culture The yeast detection plate was placed in an incubator at 35°C and 85% humidity for 24 hours before reading the MIC values. For echinocandins, the Aspergillus was incubated at 28°C for 21-26 hours before reading the MEC results.

[0123] MIC or MEC reading Yeast-type fungi: A disposable sealing film was attached to a 96-well plate, and the plate was shaken to mix uniformly. The plate was then visually observed using a plate reading mirror. The lowest compound concentration corresponding to ≥50% growth inhibition compared to the growth control was defined as the MIC. Photographs were taken using an automated plate reader and saved.

[0124] Aspergillus: For echinocandins, the minimum drug concentration that causes the mycelia to form small, round, and dense hyphal particles compared to the growth control under the plate reading mirror is defined as the MEC. To accurately measure the MEC value, do not vortex the plate before reading it.

[0125] Table 1. Bacteriostatic activity test results of compounds (batch 1) [Table 1] Note: 1. Candida parapsilosis ATCC 22019 and Candida krusei ATCC 6258 are the control strains. Based on CLSI-M60, the 24-h MICs of ANI against ATCC 22019 are 0.25-2 μg / mL, and those of CAS are 0.25-1 μg / mL. The 24-h MICs of ANI against ATCC 6258 are 0.03-0.12 μg / mL, and those of CAS are 0.12-1 μg / mL.

[0126] Table 2. Bacteriostatic activity test results of compounds (Patch 2) [Table 1] Test data show that a significant portion of the compounds in the examples according to the present disclosure have excellent antifungal activity, and some compounds have antifungal activity superior to that of positive drugs.

[0127] Test Example 2: Plasma histamine concentration and pharmacokinetics test of compounds Test Method: Twelve SD rats were divided into two groups, with six animals per group, half male and half female. Observations were conducted at least once daily. Body weight was measured once before administration. Administration was by single intravenous injection, with each animal receiving the drug for 20 minutes. PK analysis was performed once 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 analysis was performed once before administration and at 30 minutes, 4 hours, 8 hours, and 24 hours after administration.

[0128] The doses were designed as shown in the table below: [Table 1]

[0129] The main results are as follows: General condition observation On the day of dosing, two females (2 / 3) in Group 2 had a slight transient decrease in activity.

[0130] Other than that, the SD rats in each group were in good general condition, had normal spontaneous movement, clean skin and hair, normal feces and urine, and no other abnormal reactions were observed.

[0131] Histamine test As shown in Figure 1, intravenous administration of both Group 1 and Group 2 caused a transient elevation of histamine in rats. Plasma histamine concentrations peaked at 30 min, showed a tendency to recover after 4 h, and essentially returned to normal after 8–24 h. As shown in Figure 2, at 30 min after administration, the mean histamine concentration in the plasma of rats in Group 1 was 296.6 ng / mL, while that in Group 2 was 1333.0 ng / mL. The mean histamine concentration was 4.5 times higher than that of Group 1, significantly higher than that of Group 1 (p = 0.046). At the same dose, the ability of Group 1 to elevate histamine in rats was significantly lower than that of Group 2.

[0132] Pharmacokinetics The in vivo pharmacokinetic parameters of the animals after dosing in Group 1 or Group 2 are shown in the table below: [Table 1]

[0133] The study data showed that plasma drug exposure levels (C max and AUC) were the same, with no clear gender differences, and all other pharmacokinetic parameters were shown to be nearly identical.

[0134] In summary, after a single intravenous injection of the final product of Example 13 at 10 mg / kg, the plasma drug exposure was the same as that of Rezafungin acetate at the same dose, but its ability to increase 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 clinically allergic reactions than Rezafungin.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, or an isomer thereof, 、 However, R 1 is a hydroxyl group, O(C(R A1 )(R A2 )) a (C(R A3 (R A4 )) j X 1 , NH(C(R A1 (R A2 )) a (C(R A3 (R A4 )) j X 1 , O(CH 2 CH 2 O) b CH 2 CH 2 X 1 , O(CH 2 CH 2 CH 2 O) b CH<00,00026>CH 2 X 1 , O(CH 2 CH 2 NH) b CH 2 CH 2 X 1 , NH(CH 2 CH 2 O) b CH 2 CH 2 X 1 , NH(CH 2 CH 2 NH) b CH 2 CH 2 X 1 , NH(CH 2 CH 2 CH 2 O) b CH 2 CH 2 X 1 , NH[(CH 2 () c O)] b CH{CH 2 [OCH 2 (CH 2 ) c} d X 1} 2 , O[(CH 2 (CH 2 ) c O)] b CH{CH 2 [OCH 2 (CH 2 ) c ] d X 1 } 2 and (OCH 2 CH 2 ) b (NHCH 2 CH 2 ) e X 2 is selected from R 2 is hydrogen, R B1 R B2 N-, CH 2 CH 2 NR B1 R B2 , C.H. 2 C(O)NR B1 R B2 , C 1-10 Lower alkyl group, C 2-10 Alkenyl group, C 2-10 selected from alkynyl groups, aryl groups, heteroaryl groups, cyclohydrocarbyl groups, heterocyclyl groups, and PEG; R 3 H, OSO 3 H and CH 2 NR B1 R B2 is selected from G is C 10-42 It is an oily unit, R A1 , R A2 , R A3 and R A4 are independently hydrogen, deuterium, halogen, lower alkyl groups, cyclohydrocarbyl groups, and cyclohydrocarbylene groups. is selected from R B1 and R B2 are independently H, -C(O)R J and a lower alkyl group; X 1 are independently N(R C1 R C2 R C3 ) or the following structure: wherein ring A is an optionally substituted saturated or unsaturated monocyclic or fused ring containing one or more N atoms; R C1 , R C2 and R C3 are independently H, C 1-6 Alkyl groups, halogenated C 1-6 Lower alkyl groups and deuterated C 1-6 lower alkyl groups, and R C1 , R C2 and R C3 At least one of the is not hydrogen, Each R F are independently H, deuterium, hydroxyl group, hydroxyalkyl group, amino group, alkoxy group, lower alkyl group, alkenyl group, alkynyl group, halogen, SR', SOR', SO 2 R', NR'(R"), COOR', and CONR'(R"), wherein the lower alkyl group is optionally substituted with one or more substituents selected from deuterium, alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxyl, halogen, SR', NR'(R"), COOR', and CONR'(R"); X 2 is N(R D1 R D2 R D3 ) or X 1 It is a structure, R D1 , R D2 and R D3 are independently H, C 1-6 Lower alkyl groups, halogenated C 1-6 Lower alkyl groups and deuterated C 1-6 lower alkyl groups, R' and R'' are independently hydrogen, hydroxyl, alkyl, alkoxy, alkenyl, and -C(O)R J is selected from R J are hydrogen, deuterium, and C 1-10 selected from lower alkyl groups, cyclohydrocarbyl groups, and cyclohydrocarbylene groups; a is an integer from 0 to 5, b is an integer from 1 to 5; c is an integer between 1 and 2, d is an integer from 0 to 3, e is an integer from 1 to 5, k is an integer from 0 to 20, j is an integer from 0 to 5, and n is an integer from 1 to 7; A compound of formula I or a pharmaceutically acceptable salt thereof, or an isomer thereof.

2. R 1 は、O(C(R A1 (R) A2 )) a (C(R) A3 (R) A4 )) j X 1 NH(C(R) A1 (R) A2 )) a (C(R) A3 (R) A4 )) j X 1 O (CH) 2 CH 2 O) b CH 2 CH 2 X 1 O (CH) 2 CH 2 CH 2 O) b CH 2 CH 2 X 1 O (CH) 2 CH 2 NH) b CH 2 CH 2 X 1 NH(CH) 2 CH 2 O) b CH 2 CH 2 X 1 NH(CH) 2 CH 2 NH) b CH 2 CH 2 X 1 NH(CH) 2 CH 2 CH 2 O) b CH 2 CH 2 X 1 NH[(CH) 2 ( ) c O)] b CH{CH 2 [OCH 2 (CH 2 ) c ] d X 1 } 2 O[(CH 2 (CH 2 ) c O)] b CH{CH 2 [OCH 2 (CH 2 ) c ] d X 1 } 2 and (OCH 2 CH 2 ) b (NHCH 2 CH 2 ) e X 2 is selected from R 2 is hydrogen, R B1 R B2 N-, CH 2 CH 2 NR B1 R B2 , C.H. 2 C(O)NR B1 R B2 , C 1-10 Lower alkyl group, C 2-10 Alkenyl group, C 2-10 selected from alkynyl groups, aryl groups, heteroaryl groups, cyclohydrocarbyl groups, heterocyclyl groups, and PEG; R 3 H, OSO 3 H and CH 2 NR B1 R B2 is selected from G is C 10-36 is a lipophilic unit, R A1 , R A2 , R A3 and R A4 are independently hydrogen, deuterium, halogen, lower alkyl groups, cyclohydrocarbyl groups, and cyclohydrocarbylene groups. is selected from R B1 and R B2 are independently H, -C(O)R J and a lower alkyl group; X 1 are independently N(R C1 R C2 R C3 ) or the following structure: wherein ring A is an optionally substituted saturated or unsaturated monocyclic or fused ring containing one or more N atoms; R C1 , R C2 and R C3 are independently H, halogenated C 1-6 Lower alkyl groups and deuterated C 1-6 lower alkyl groups, and R C1 , R C2 and R C3 At least one of the is not hydrogen, Each R F are independently H, deuterium, hydroxyl group, hydroxyalkyl group, amino group, alkoxy group, lower alkyl group, alkenyl group, alkynyl group, halogen, SR', SOR', SO 2 R', NR'(R"), COOR', and CONR'(R"), wherein the lower alkyl group is optionally substituted with one or more substituents selected from deuterium, alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, and alkynyl groups; X 2 is N(R D1 R D2 R D3 ) or X 1 It is a structure, R D1 , R D2 and R D3 are independently H, C 1-6 Lower alkyl groups, halogenated C 1-6 Lower alkyl groups and deuterated C 1-6 lower alkyl groups, R' and R'' are independently hydrogen, hydroxyl, alkyl, alkoxy, alkenyl, and -C(O)R J is selected from R J is hydrogen, C 1-10 selected from lower alkyl groups, cyclohydrocarbyl groups, and cyclohydrocarbylene groups; a is an integer from 0 to 5, b is an integer from 1 to 5; c is an integer between 1 and 2, d is an integer from 0 to 3, e is an integer from 1 to 5, k is an integer from 0 to 20, j is an integer from 0 to 5, and n is an integer from 1 to 7; 2. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, or an isomer thereof.

3. X 1 has the following structure: is selected from However, each R F are independently H, deuterium, hydroxyl group, hydroxyalkyl group, amino group, alkoxy group, lower alkyl group, alkenyl group, alkynyl group, halogen, SR', SOR', SO 2 R', NR'(R"), COOR', and CONR'(R"), wherein the lower alkyl group is optionally substituted with one or more substituents selected from deuterium, alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, and alkynyl groups; R q1 and R q2 are independently H or C 1-6 a lower alkyl group, optionally substituted with one or more substituents selected from deuterium, alkyl groups, cycloalkyl groups, alkoxy groups, hydroxyalkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, nitro groups, nitrile groups, hydroxyl groups, halogens, SR', NR'(R"), COOR', and CONR'(R"); R' and R'' are independently hydrogen, hydroxyl, alkyl, alkoxy, alkenyl, and -C(O)R J is selected from R J are hydrogen, deuterium, and C 1-10 selected from lower alkyl groups, cyclohydrocarbyl groups, and cyclohydrocarbylene 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, n is an integer from 1 to 7, and p is an integer from 1 to 3; 3. A compound of formula I according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, or an isomer thereof.

4. G is wherein X is independently selected from O, C(R B1 ) (R B2 ), NR p4 R is selected from - and S; T is C 1-5 wherein the alkyl group is optionally selected from the group consisting of deuterium, halogen, alkyl, cyclohydrocarbyl, cyclohydrocarbylene groups, and R is substituted with one or more substituents selected from p1 , R p2 and R p3 are independently hydrogen, deuterium, halogen, C 1-10 Lower alkyl groups, halogenated C 1-10 Lower alkyl group, C 2-10 Alkenyl group, C 2-10 is selected from alkynyl groups, aryl groups, heteroaryl groups, cyclohydrocarbyl groups, heterocyclyl groups, and PEG; m is an integer from 0 to 4; n is an integer from 1 to 7; and R p4 is hydrogen or C 1-6 is a lower alkyl group, and R B1 and R B2 are each independently H, -C(O)R J and C 1-10 lower alkyl groups, R J are hydrogen, deuterium, and C 1-10 selected from lower alkyl groups, cyclohydrocarbyl groups, and cyclohydrocarbylene groups; A compound of formula I according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or an isomer thereof.

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

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

7. G is Selected from: A compound of formula I according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or an isomer thereof.

8. G is is selected from, preferably and more preferably That is, A compound of formula I according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or an isomer thereof.

9. R 1 teeth, Selected from: A compound of formula I according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or an isomer thereof.

10. R 1 teeth, Selected from: A compound of formula I according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, or an isomer thereof.

11. R 1 teeth, Selected from: A compound of formula I according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or an isomer thereof.

12. R 1 teeth, Selected from: A compound of formula I according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, or an isomer thereof.

13. R 1 teeth, is selected from, preferably and more preferably That is, A compound of formula I according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or an isomer thereof.

14. R 1 teeth, is selected from, preferably and more preferably That is, A compound of formula I according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or an isomer thereof.

15. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, or an isomer thereof, wherein the compound of formula I is as follows: G 1 teeth, is selected from However, R p1 , R p2 and R p3 are independently hydrogen, deuterium, halogen, C 1-6 Lower alkyl groups, halogenated C 1-6 Lower alkyl group, C 2-10 Alkenyl group, C 2-10 selected from alkynyl groups, aryl groups, heteroaryl groups, cyclohydrocarbyl groups, heterocyclyl groups, and PEG; X is independently O, C(R B1 ) (R B2 ), NR p4 and S, R p4 is hydrogen or C 1-3 is a lower alkyl group, R T is C 1-5 wherein the alkyl group is optionally selected from the group consisting of deuterium, hydroxyl, amino, alkoxy, amino, NR' (R"), halogen, cyclohydrocarbyl, cyclohydrocarbylene. and is substituted with one or more substituents selected from And R p1 , R p2 and R p3 is simultaneously H and X is O, then R T Ha-C 5 H 11 Instead, X is O and R T Ga-C 5 H 11 If R p1 , R p2 and R p3 At least one of the following is R, not H. T Ga-C 5 H 11 and R p1 , R p2 and R p3 is simultaneously H, then X is not O, R B1 and R B2 are each independently H, -C(O)R J and C 1-10 lower alkyl groups, R J is hydrogen, C 1-10 selected from lower alkyl groups, cyclohydrocarbyl groups, and cyclohydrocarbylene groups; m is independently an integer from 0 to 4; n is an integer from 1 to 7.

16. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, or an isomer thereof, wherein the compound of formula I is as follows: However, R G1 , R G2 , R G3 and R G4 are independently selected from hydrogen, deuterium, halogen, and lower alkyl groups, and R G1 , R G2 , R G3 and R G4 At least one of these is not hydrogen.

17. A compound of formula I according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, or an isomer thereof, wherein the compound of formula I is as follows:

18. Pharmaceutically acceptable salts are selected from acetate, trifluoroacetate and formate salts. A compound according to any one of claims 1 to 17.

19. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, or an isomer thereof, and a pharmaceutically acceptable excipient. Drug composition.

20. 20. Use of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, or an isomer thereof, in the preparation of a medicament for treating and / or preventing a fungal infection.

21. 20. Use of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, or an isomer thereof, in the preparation of a medicament for preventing, stabilizing or inhibiting fungal growth or killing fungi.

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