Echinocandin drug, preparation method therefor, and use thereof

Abstract

Disclosed is a novel compound, such as a compound represented by formula I or a pharmaceutically acceptable salt thereof, or an isomer thereof. Said compound has an excellent effect in inhibiting fungi, can be effectively used for preventing or treating fungal infection, and is a more efficient new generation of echinocandin drug.

Description

An echinocandin drug and its preparation method and use

[0001] Cross-references

[0002] This application claims priority to Chinese patent application CN202310697710.3, filed on June 13, 2023. This application incorporates the entire text of the aforementioned Chinese patent application. Technical Field

[0003] The present invention relates to an echinocandin drug, belonging to the field of pharmaceutical chemistry. Background Art

[0004] Fungal infections are divided into four categories based on the site of infection: superficial fungal infections, skin fungal infections, subcutaneous tissue fungal infections, and systemic fungal infections. The latter two are also known as invasive fungal infections. Fungi can not only invade the skin, mucous membranes, deep tissues, and internal organs, but can also cause systemic disseminated infections with a high mortality rate. In 2022, the WHO published the "Priority List of Fungal Pathogens," listing the common clinically active Aspergillus fumigatus, Cryptococcus neoformans, Candida albicans, and Candida auris as key priority pathogens.

[0005] More than 300 million people worldwide suffer from serious fungal infections, and more than 1.6 million people die from them each year. Invasive fungal infections are an important reason for the continued high morbidity and mortality rates. Such infections are more common in high-risk groups such as those with immunodeficiency, organ or bone marrow transplants, and severe COVID-19. Currently, the antifungal drugs available on the market are very limited, mainly triazoles, polyenes, and echinocandins. In addition, the continuous emergence of drug-resistant strains has exacerbated the challenges posed by invasive fungal infections, and the development of a variety of new antifungal drugs to meet current clinical needs is particularly urgent.

[0006] β-(1,3)-D-glucan is a key component of the fungal cell wall, primarily synthesized by enzymes located in the cell membrane. Echinocandins can non-competitively inhibit β-(1,3)-D-glucan synthase, interfering with β-(1,3)-D-glucan synthesis and thereby disrupting the integrity of the fungal cell wall, leading to lysis and death of the fungal cells. Echinocandins are first-line drugs for the treatment of invasive candidiasis, acting directly on the fungal cell wall. Because human cells do not contain cell walls, these drugs have low toxicity and are relatively safe.

[0007] Caspofungin is the earliest echinocandin drug used clinically to treat fungal infections. It is effective in treating Candida infections and invasive aspergillosis that is ineffective or intolerant to other treatments. The only way to administer this drug is by injection, which is less flexible. It is mostly used in the early stages, and oral preparations such as voriconazole are mainly used for maintenance treatment in the later stages. In addition, the drug needs to be stored at 2 to 8 degrees and has certain requirements for production capacity. Subsequently, micafungin and anidulafungin also appeared. However, the above three drugs mostly have short half-lives and need to be administered daily.

[0008] In 2023, a new-generation echinocandin drug, Rezafungin, was approved for marketing for the treatment of candidemia and invasive candidiasis. While structurally similar to anidulafungin, anidulafungin is susceptible to chemical degradation, where the cysteine ​​residue at C5 ornithine residue is replaced by a choline amino ether, affecting drug stability. Compared to anidulafungin, Rezafungin exhibits greater stability and solubility in plasma, aqueous solutions, and buffered solutions.

[0009] Compared with previous generations of echinocandins, razafungin has a longer half-life, extending the dosing frequency from daily to weekly, which significantly reduces the frequency of dosing for patients and provides significant convenience for them.

[0010] However, the dosage of razafungin is high, at 400 mg in the first week and 200 mg weekly thereafter. This high dosage also leads to a number of side effects, such as abdominal pain, diarrhea, nausea, vomiting, constipation, hypokalemia, hypomagnesemia, and hypophosphatemia.

[0011] Therefore, it is of great significance to develop a new generation of more efficient echinocandins.

[0012] Summary of the Invention

[0013] In order to solve the above problems, the present invention proposes a new compound, such as a compound shown in Formula I or a pharmaceutically acceptable salt or an isomer thereof,

[0014] wherein X, Y, and Z are independently selected from C and N;

[0015] R2, R3, R4, R5, R6, R8, R9, R 10 、R 11 and R 12 are independently selected from hydrogen, deuterium, halogen, cyano, thiocyano, isothiocyano and lower alkyl;

[0016] R7 is selected from C 1-10 Lower alkyl, C2-10 Alkenyl, C 2-10 Alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl;

[0017] R1 is selected from hydroxy, hydrogen, deuterium, halogen, cyano, thiocyano, isothiocyano, 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,

[0018] R A1 、R A2 、R A3 and R A4 independently selected from hydrogen, deuterium, halogen, lower alkyl, cycloalkyl and cycloalkylene

[0019] X1 is independently N(R C1 R C2 R C3 ) or the following structure

[0020] Ring A is an optionally substituted, saturated or unsaturated monocyclic or condensed ring containing one or more N atoms,

[0021] 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,

[0022] 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"),

[0023] X2 is N(R D1 R D2 R D3 ) or X1 structure,

[0024] 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,

[0025] R' and R" are independently selected from hydrogen, hydroxy, alkyl, alkoxy, alkenyl and -C(O)R J ,

[0026] R J Selected from hydrogen, deuterium, C 1-10 Lower alkyl, cycloalkyl and cycloalkylene groups,

[0027] a is an integer of 0-5, b is an integer of 1-5, c is an integer of 1-2, d is an integer of 0-3, e is an integer of 1-5, k is an integer of 0-20, j is an integer of 0-5, and n is an integer of 1-7.

[0028] Further, R1 is selected from O(C(R A1 )(R A2 )) a (C(RA3 )(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,

[0029] R A1 、R A2 、R A3 and R A4 independently selected from hydrogen, deuterium, halogen, lower alkyl, cycloalkyl and cycloalkylene

[0030] X1 is independently N(R C1 R C2 R C3 ) or the following structure

[0031] Ring A is an optionally substituted, saturated or unsaturated monocyclic or condensed ring containing one or more N atoms,

[0032] R C1 、R C2 and R C3 independently selected from H, halogenated C 1-6 Lower alkyl and deuterated C 1-6 Lower alkyl, and R C1 、R C2and R C3 At least one of them is not hydrogen,

[0033] 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,

[0034] X2 is N(R D1 R D2 R D3 ) or X1 structure,

[0035] 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,

[0036] R' and R" are independently selected from hydrogen, hydroxy, alkyl, alkoxy, alkenyl and -C(O)R J ,

[0037] R J Selected from hydrogen, C 1-10 Lower alkyl, cycloalkyl and cycloalkylene groups,

[0038] a is an integer of 0-5, b is an integer of 1-5, c is an integer of 1-2, d is an integer of 0-3, e is an integer of 1-5, k is an integer of 0-20, j is an integer of 0-5, and n is an integer of 1-7.

[0039] Furthermore, X1 is selected from the following structures:

[0040] 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,

[0041] R q1 and R q2 are independently H or C 1-6lower 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"),

[0042] R' and R" are independently selected from hydrogen, hydroxy, alkyl, alkoxy, alkenyl and -C(O)R J ,

[0043] R J Selected from hydrogen, deuterium, C 1-10 Lower alkyl, cycloalkyl and cycloalkylene groups,

[0044] f is an integer of 0 to 16, g is an integer of 0 to 16, h is an integer of 0 to 9, i is an integer of 0 to 4, n is an integer of 1 to 7, and p is an integer of 1 to 3.

[0045] In the present invention, R1 is selected from hydroxyl, hydrogen, deuterium or one of the following structures:

[0046] Furthermore, R1 is selected from hydroxyl, hydrogen or one of the following structures:

[0047] Furthermore, R1 is selected from hydroxyl or one of the following structures:

[0048] Further, R7 is selected from C 3-6 Lower alkyl group: The lower alkyl group may be a straight chain alkyl group.

[0049] Furthermore, R7 is selected from n-butyl or n-pentyl.

[0050] In the present invention, the compound structural formula can be selected from the following:

[0051] The present invention also provides an intermediate II of the compound of formula I:

[0052] Among them, X, Y, Z, R2 to R 12 The definition of corresponds to the compound of formula I;

[0053] -C(=O)-R 13 It consists of carboxyl group, acyl halide group, ester group and anhydride group.

[0054] Furthermore, R 13 Selected from -OH, Cl, -OC(=O)CH3, -R g1 ;

[0055] R g1 Selected from

[0056] The compound of formula I of the present invention can be obtained by reacting an intermediate compound of formula II with a salt of echinocandin B through amidation; or, after the amidation reaction, a substitution reaction occurs at the echinocandin B site corresponding to R1.

[0057] The present invention also provides use of the above-mentioned compound or its pharmaceutically acceptable salt, or its isomer in preparing a drug for treating or preventing fungal infection or a disease caused by fungal infection.

[0058] In the present invention, the fungus is selected from one or more organisms of the following genera: Candida albicans, Candida parapsilosis, Candida glabrata, Candida guilliermondii, Candida krusei, Candida lusitaniae, Candida tropicalis, Aspergillus fumigatus, Aspergillus fumigatus, Aspergillus flavus, Aspergillus terreus, Aspergillus niger, Aspergillus candidus, Aspergillus clavatus or Aspergillus ochraceus.

[0059] In the present invention, the disease caused by fungal infection is selected from scalp ringworm, body ringworm, tinea pedis, onychomycosis, perionychia, psoriasis, thrush, vaginal candidiasis, respiratory tract candidiasis, biliary tract candidiasis, esophageal candidiasis, urethral candidiasis, systemic candidiasis, mucosal and skin candidiasis, aspergillosis, mucormycosis, paracoccidioidomycosis, North American blastomycosis, histoplasmosis, coccidioidomycosis, sporotrichosis, fungal sinusitis or chronic paranasal inflammation.

[0060] Furthermore, the disease caused by fungal infection is selected from candidemia and invasive candidiasis.

[0061] The present invention 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 prophylactic treatment in patients preparing for invasive medical procedures (e.g., preparing for surgery, undergoing transplantation, stem cell therapy, grafts, prosthetic procedures, receiving long-term or frequent intravenous catheterization, or receiving treatment in an intensive care unit), in immunocompromised patients (e.g., patients with cancer, HIV / AIDS, or taking immunosuppressants), or in patients undergoing long-term antibiotic therapy.

[0062] The present invention also provides a method 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.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] The present invention also provides an antifungal pharmaceutical composition comprising the above-mentioned compound or its pharmaceutically acceptable salt or isomer.

[0067] The pharmaceutical composition may contain pharmaceutically acceptable excipients.

[0068] The term "pharmaceutically acceptable" as used herein includes any substance that does not interfere with the effectiveness of the biological activity of the active ingredient and is non-toxic to the host to which it is administered.

[0069] The pharmaceutically acceptable excipients described in the present invention are a general term for all additional materials in a drug other than the main drug. Excipients should have the following properties: (1) be non-toxic to the human body and have almost no side effects; (2) be chemically stable and not easily affected by temperature, pH, storage time, etc.; (3) have no incompatibility with the main drug and do not affect the efficacy and quality inspection of the main drug; (4) do not interact with the packaging material. Excipients in the present invention include but are not limited to fillers (diluents), lubricants (glidants or anti-adhesives), dispersants, wetting agents, adhesives, regulators, solubilizers, antioxidants, antibacterial agents, emulsifiers, disintegrants, etc. Binders include syrup, gum arabic, gelatin, sorbitol, tragacanth, cellulose and its derivatives (such as microcrystalline cellulose, sodium carboxymethyl cellulose, ethyl cellulose or hydroxypropyl methyl cellulose, etc.), gelatin slurry, syrup, starch slurry or polyvinyl pyrrolidone, etc.; fillers include lactose, powdered sugar, dextrin, starch and its derivatives, cellulose and its derivatives, inorganic calcium salts (such as calcium sulfate, calcium phosphate, calcium hydrogen phosphate, precipitated calcium carbonate, etc.), sorbitol or glycine, etc.; lubricants include micropowdered silica gel, magnesium stearate, talc, aluminum hydroxide, boric acid, hydrogenated vegetable oil, polyethylene glycol, etc.; disintegrants include starch and its derivatives (such as sodium carboxymethyl starch, sodium starch glycolate, etc. , pregelatinized starch, modified starch, hydroxypropyl starch, corn starch, etc.), polyvinyl pyrrolidone or microcrystalline cellulose, etc.; wetting agents include sodium lauryl sulfate, water or alcohol, etc.; antioxidants include sodium sulfite, sodium bisulfite, sodium metabisulfite, dibutyl benzoic acid, etc.; antibacterial agents include 0.5% phenol, 0.3% cresol, 0.5% trichlorobutanol, etc.; regulators include hydrochloric acid, citric acid, potassium (sodium) hydroxide, sodium citrate and buffers (including sodium dihydrogen phosphate and disodium hydrogen phosphate), etc.; emulsifiers include polysorbate 80, sorbitan monophosphate, Pluronic F-68, lecithin, soy lecithin, etc.; solubilizers include Tween-80, bile, glycerol, etc.

[0070] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention formed with an acid or base suitable for pharmaceutical use. The aforementioned acids and bases are broadly defined as Lewis acids and bases. Suitable acids for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, phenylmethanesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

[0071] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration methods include, but are not limited to, oral, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration.

[0072] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0073] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0074] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0075] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0076] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0077] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0078] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0079] The compounds of the present invention can also be used in injectable preparations. The injectable preparations are selected from liquid injections (water injections), sterile powders for injection (powder injections), or injectable tablets (which are molded or machine-pressed tablets made using aseptic techniques, dissolved in water for injection, and intended for subcutaneous or intramuscular injection).

[0080] The powder for injection contains, in addition to the above-mentioned compound, at least an excipient. The excipient herein is an ingredient intentionally added to a drug and should not have pharmacological properties in the amount used. However, the excipient may aid in drug processing, solubility or dissolution, drug delivery via targeted routes of administration, or contribute to drug stability.

[0081] Functional group isomers produced by the rapid movement of an atom in a molecule between two positions are called tautomers.

[0082] The mesomeric compound contains asymmetric atoms in the molecule, but has symmetry factors that make the total optical rotation in the molecule zero, that is, it has no optical activity.

[0083] A racemate is an equimolar mixture of an optically active chiral molecule (see chirality) and its enantiomers.

[0084] Stereoisomers that are non-superimposable mirror images of each other are called enantiomers (enantiomers, abbreviated as enantiomers). Enantiomers have optical activity, one is left-handed and the other is right-handed, so enantiomers are also called optical isomers.

[0085] Diastereoisomers are stereoisomers that have two or more chiral centers and are not mirror images of each other.

[0086] "Independently selected" means that the variable groups at each occurrence are independently selected from the defined substituents.

[0087] "Alkyl" refers to a straight or branched chain alkane group, preferably containing 1 to 10 carbon atoms, more preferably containing 3 to 7 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc. Unless otherwise specified in the specification, an alkyl group may be optionally substituted with one or more of the following substituents: halogen, cyano, thiocyano, isothiocyano, nitro, oxo, thioxo, trimethylsilyl, etc.

[0088] Unless otherwise specified, "lower alkyl" refers to a branched or branched alkane group containing 1 to 10 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc. Unless otherwise specified in the specification, lower alkyl groups may be optionally substituted with one or more of the following substituents: halogen, cyano, thiocyano, isothiocyano, nitro, oxo, thioxo, trimethylsilyl, etc.

[0089] "Alkenyl" refers to an alkyl compound containing a carbon-carbon double bond within the molecule, where alkyl is 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 indicated, alkenyl groups may be optionally substituted with one or more of the following substituents: halogen, cyano, thiocyanato, isothiocyanato, nitro, oxo, thioxo, trimethylsilyl, and the like.

[0090] "Alkynyl" refers to an alkyl compound containing a carbon-carbon triple bond in the molecule, where alkyl is as defined above. Non-limiting examples include ethynyl, propynyl, butynyl, and pentynyl. Unless otherwise indicated, alkynyl groups may be optionally substituted with one or more of the following substituents: halogen, cyano, thiocyanato, isothiocyanato, nitro, oxo, thioxo, trimethylsilyl, and the like.

[0091] "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, phenanthene, and phenanthrene. Unless otherwise specified, an aryl group may be optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, cyano, nitro, and the like.

[0092] "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 indicated, cycloalkyl groups may be optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, and the like.

[0093] "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.

[0094] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0095] "Heterocyclyl" refers to a stable three- to eighteen-membered non-aromatic ring radical 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.

[0096] Typical heterocycloalkyl groups include, but are not limited to:

[0097] "Heteroaryl" refers to a five- to fourteen-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 may include a spirocyclic ring system; and the nitrogen, carbon, or sulfur atoms in the heteroaryl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. The aromatic ring of a heteroaryl group need not contain heteroatoms, as long as one of the heteroaryl rings contains heteroatoms. For example, 1,2,3,4-tetrahydroisoquinolin-7-yl is considered a "heteroaryl group." Unless otherwise specified in this specification, a heteroaryl group includes heteroaryl groups optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, halogenated alkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, and the like.

[0098] Typical heteroaryl groups include, but are not limited to:

[0099] This invention prepares a novel compound by modifying the structure of the lipophilic side chain attached to the cyclic hexapeptide in razafungin. Pharmacokinetic studies revealed that the plasma drug exposure (Cmax and AUC) and half-life (T1 / 2) of this compound in rats were significantly superior to those of razafungin. Experiments in this invention demonstrated that even at a dose half that of razafungin, the compound exhibited significantly higher blood exposure in animals. Compared to razafungin, this invention not only effectively reduces the frequency of medication use but, more importantly, exhibits significantly higher actual bioavailability than razafungin, suggesting that even lower dosages of the compound are possible. This provides a safe and reliable new option for clinical use. BRIEF DESCRIPTION OF THE DRAWINGS

[0100] Figure 1. Blood concentration-time curves of razafungin and Example 16 after intravenous injection in rats

[0101] Figure 2. Blood drug concentration-time curves of rats after intravenous injection of Example 16 and Example 19 DETAILED DESCRIPTION

[0102] The following is a clear and complete description of the technical solution of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0103] 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.

[0104] Caspofungin was purchased from Taizhou Kede Chemical. Razafungin was synthesized according to CN103889221A.

[0105] HPLC purity analysis method:

[0106] LC-MS analysis method:

[0107] Example 1:

[0108] Methyl 6-bromo-2-naphthoate (704 mg, 2.60 mmol, 1 eq.), Pd(PPh3)2Cl2 (186.4 mg, 0.26 mmol, 0.1 eq.), and CuI (50.5 mg, 0.26 mmol, 0.1 eq.) were added to a thick-walled pressure-resistant reaction tube. The reaction was evacuated and replaced with nitrogen. This step was repeated three times. Then, under a nitrogen atmosphere, 4-ethynylphenylpentyl ether (500 mg, 2.00 mmol, 1 eq.), DIPEA (0.92 mL, 5.30 mmol, 2 eq.), and 1,4-dioxane (9 mL) were added to the system. After the addition was complete, the tube was sealed and heated to 80°C with stirring overnight. After the reaction, the solvent was removed using a rotary evaporator to obtain an oily substance, which was dissolved in DCM. The organic phase was washed with water and then brine, and dried over anhydrous sodium sulfate. The crude product obtained after concentration was purified by column chromatography (PE:EA=100:1) to obtain 403.4 mg of yellow solid compound SM1, with a yield of 40%. MS [M+H] + :373.

[0109] SM1 (403.4 mg, 1.08 mmol, 1 eq.) was dissolved in THF (10 mL), and NaOH (86.7 mg, 2.10 mmol, 2 eq.) was dissolved in H2O (10 mL). The NaOH aqueous solution was added to the reaction system, and the reaction was heated in a 60°C oil bath with stirring. After the reaction, 2M HCl (aq.) was added to adjust the pH to acidic. The mixture was filtered, and the filter cake was washed with water to obtain 369.7 mg of yellow solid compound SM2, with a yield of 95%. MS [MH] - :357.

[0110] Echinocandin B hydrochloride (200 mg, 0.23 mmol, 1 eq.), SM2 (85.8 mg, 0.23 mmol, 1 eq.), and CDMT (50.3 mg, 0.28 mmol, 1.2 eq.) were dissolved in DMF (2.4 mL), followed by the addition of NMM (0.078 mL, 0.71 mmol, 3 eq.). The mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction solution was purified by HPLC to obtain 135 mg of a white solid compound with a purity of 97% and a yield of 49%. HRMS [MH] - :1136.5260.

[0111] 1 H NMR (400MHz, CD3OD) δ8.41 (s, 1H), 8.05 (s, 1H), 7.93 (dd, J = 15.7, 5.4Hz, 3H), 7.61 (dd, J=8.5,1.5Hz,1H),7.49(d,J=8.7Hz,2H),7.15(d,J=8.6Hz,2H),6.95(d,J=8.9Hz,2H), 6.76(d,J=8.5Hz,2H),5.36(d,J=3.1Hz,1H),5.02(d,J=3.2Hz,1H),4.70(dd,J=11.8,5 .2Hz,1H),4.57(s,4H),4.35(dd,J=19.1,5.4Hz,3H),4.26(s,3H),4.08(s,1H),4.02(t, J=6.5Hz,3H),3.86(d,J=19.3Hz,2H),3.41(t,J=9.2Hz,1H),2.57–2.40(m,2H),2.25(s,1H),2.18–2.03(m,2H), 1.85–1.76(m,2H),1.51–1.39(m,4H),1.28(dd,J=12.5,6.3Hz,6H),1.07(d,J=6.9Hz,3H),0.96(t,J=7.1Hz,3H).

[0112] Example 2:

[0113] Example 1 (170 mg, 0.14 mmol, 1 eq.) and 3,4-dimethoxyphenylboronic acid (35 mg, 0.19 mmol, 1.3 eq.) were dissolved in dry THF (1.4 mL) and stirred at room temperature for 1 h. The mixture was concentrated to dryness, and choline p-toluenesulfonate (400 mg, 1.40 mmol, 10 eq.) was added. A mixture of TFA (0.425 mL) and acetonitrile (1.5 mL) was then added to dissolve the reactants. The mixture was stirred at room temperature under a nitrogen atmosphere for 6 h. After the reaction was completed, an aqueous sodium acetate solution was added to quench the reaction. The product was purified by HPLC to give 105 mg of the compound (hydrochloride) as a white solid with a purity of 95% and a yield of 57%. HRMS [M] + :1223.6167.

[0114] 1 H NMR (400MHz, CD3OD) δ8.44(s,1H),8.08(s,1H),8.01–7.95(m,3H),7.64(dd,J=8.5,1.4 Hz,1H),7.49(d,J=8.7Hz,2H),7.15(d,J=8.6Hz,2H),6.95(d,J=8.9Hz,2H),6.76(d,J= 8.6Hz,2H),5.43(s,1H),5.05(d,J=3.2Hz,1H),4.77(d,J=5.1Hz,1H),4.59(dd,J=10.7 ,7.1Hz,3H),4.39(d,J=4.2Hz,1H),4.33(d,J=8.6Hz,2H),4.24(dd,J=7.9,1.6Hz,2H), 4.21–4.16(m,1H),4.11(s,1H),4.01(dd,J=13.0,6.6Hz,4H),3.91(dd,J=9.7,7.0Hz,2 H),3.83(d,J=10.8Hz,1H),3.66–3.45(m,4H),3.13(s,9H),2.55–2.43(m,2H),2.31(dd ,J=16.1,7.2Hz,1H),2.08(dd,J=15.4,9.5Hz,2H),1.84–1.77(m,2H),1.46(ddd,J=20. 2,11.3,6.5Hz,4H),1.27(d,J=6.3Hz,6H),1.08(d,J=6.9Hz,3H),0.97(t,J=7.1Hz,3H).

[0115] Example 3:

[0116] Methyl 6-bromo-2-quinolinecarboxylate (500 mg, 1.80 mmol, 1 eq.), 4-ethynylphenylpentyl ether (0.36 mL, 1.80 mmol, 1 eq.), and CuI (35.7 mg, 0.18 mmol, 0.1 eq.) were dissolved in 1,4-dioxane (18 mL). Triethylamine (0.78 mL, 5.60 mmol, 3 eq.) was then added. The mixture was evacuated and replaced with nitrogen, and this process was repeated three times. Under a nitrogen atmosphere, Pd(PPh3)2Cl2 (131 mg, 0.18 mmol, 0.1 eq.) was added to the reaction system. The mixture was refluxed at 80°C overnight. After the reaction, the solvent was removed, and the crude product was purified by column chromatography to obtain 200 mg of compound SM3 as a white solid in a 28% yield. MS [M+H] + :374.2.

[0117] SM3 (200 mg, 0.53 mmol, 1 eq.) was dissolved in THF (5 mL) and heated with stirring at 65°C. A solution of NaOH (43 mg, 1.08 mmol, 4 eq.) in water (0.5 mL) was added to the reaction system. After 1 h, the reaction solution turned from clear to turbid, indicating completion of the reaction by TLC. 2M HCl (aq.) was added to adjust the pH to acidic. Filter the mixture to obtain 160 mg of the green solid compound SM4, with a yield of 83%. MS [M+H] + :360.

[0118] Echinocandin B hydrochloride (371 mg, 0.44 mmol, 1 eq.), SM4 (160 mg, 0.44 mmol, 1 eq.), and CDMT (93.6 mg, 0.53 mmol, 1.2 eq.) were dissolved in DMF (4 mL), followed by the addition of NMM (0.14 mL, 1.30 mmol, 3 eq.). The mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction solution was purified by HPLC to obtain 268 mg of a white solid compound with a purity of 97% and a yield of 52%. HRMS [MH] - :1137.6155.

[0119] 1H NMR (400MHz, CD3OD) δ8.44(d,J=8.6Hz,1H),8.21–8.11(m,3H),7.88(dd,J=8.8,1.7Hz,1H),7.51(d,J=8.7Hz,2H),7.15(d,J=8.5Hz,2H),6.96(d ,J=8.8Hz,2H),6.76(d,J=8.5Hz,2H),5.46(d,J=2.7Hz,1H),5.04(d,J=2.8Hz,1H),4.76(dd,J=11.9,4.8Hz,1H),4.64–4.54(m,4H),4.37(d,J=2 .7Hz,1H),4.32(d,J=7.6Hz,2H),4.26–4.17(m,3H),4.05–3.96(m,4H), 3.92–3.80(m,2H),3.41(t,J=9.1Hz,1H),2.59–2.40(m,2H),2.34(d,J=1 3.6Hz,1H),2.18–2.04(m,2H),1.80(dd,J=13.8,7.2Hz,2H),1.53–1.38 (m,4H),1.29–1.23(m,6H),1.07(d,J=6.8Hz,3H),0.96(t,J=7.1Hz,3H).

[0120] Example 4:

[0121] Example 3 (268 mg, 0.23 mmol, 1 eq.) and 3,4-dimethoxyphenylboronic acid (55.7 mg, 0.30 mmol, 1.3 eq.) were dissolved in dry THF (2.3 mL) and stirred at room temperature for 1 h. The mixture was concentrated to dryness, and choline p-toluenesulfonate (1.94 g, 7.00 mmol, 30 eq.) was added. A mixture of TFA (0.5 mL) and acetonitrile (2.0 mL) was then added to dissolve the reactants. The mixture was stirred at room temperature under a nitrogen atmosphere for 6 h. After the reaction was completed, an aqueous solution of sodium acetate was added to quench the reaction. The product was purified by HPLC to give 151 mg of the white solid compound (acetate salt) with a purity of 91% and a yield of 52%. HRMS [M] + :1224.5755.

[0122] 1HNMR(400MHz,CD3OD)δ8.48(d,J=8.6Hz,1H),8.19(dd,J=18.6,8.8Hz,3H),7.9 1(d,J=10.4Hz,1H),7.51(d,J=8.7Hz,2H),7.15(d,J=8.6Hz,2H),6.96(d,J=8.7 Hz,2H),6.76(d,J=8.5Hz,2H),5.64(s,1H),5.08(s,1H),4.84–4.75(m,2H),4.6 0(dd,J=13.7,4.1Hz,3H),4.40(d,J=4.1Hz,1H),4.33(t,J=8.6Hz,2H),4.29–4. 21(m,2H),4.20–4.12(m,1H),4.10–3.97(m,6H),3.93–3.82(m,2H),3.67–3.55 (m,2H),3.50–3.46(m,1H),3.16(s,9H),2.49(ddd,J=22.3,9.7,4.8Hz,2H),2.4 2–2.31(m,1H),2.11–1.99(m,2H),1.90(s,3H),1.86–1.77(m,2H),1.50–1.39(m ,4H),1.24(dd,J=8.8,6.4Hz,6H),1.08(d,J=6.8Hz,3H),0.97(t,J=7.1Hz,3H).

[0123] Example 5:

[0124] Methyl 6-bromo-2-naphthoate (4 g, 15.08 mmol, 1 eq.) was dissolved in dioxane (15 mL), and the nitrogen atmosphere was replaced. Under nitrogen, trimethylethynylsilane (2.08 mL, 15.08 mmol, 1 eq.), Pd(PPh3)2Cl2 (1.05 g, 1.51 mmol, 0.1 eq.), and CuI (288 mg, 1.50 mmol, 0.1 eq.) were added sequentially. Finally, triethylamine (6.29 mL, 45.26 mmol, 3 eq.) was added. The mixture was stirred at room temperature for 2.5 h, extracted with water and EA, and the EA phase was evaporated to dryness. The mixture was separated and purified by column chromatography to obtain 4.14 g of compound SM5 as a yellow solid in a 97% yield. MS [M+H] + :283.0.

[0125] SM2 (1 g, 3.54 mmol, 1 eq.) was dissolved in dioxane (6 mL) and MeOH (6 mL), and potassium carbonate (735 mg, 5.31 mmol, 1.5 eq.) was added. The mixture was stirred at room temperature for 2 h. TLC showed that the reaction was complete. The mixture was filtered and the filtrate was dried to give 413 mg of a yellow solid compound SM6 (yield 55%).

[0126] 2-Bromo-5-hydroxypyridine (1 g, 5.70 mmol, 1 eq.), bromopentane (0.9 ml, 6.80 mmol, 1.2 eq.), and potassium carbonate (2.4 g, 17.00 mmol, 3 eq.) were dissolved in acetonitrile (50 mL) and heated under reflux at 90°C with stirring. After 2 h, TLC showed the formation of new spots and the disappearance of the starting material. The solvent was removed, and the mixture was extracted with ethyl acetate and water. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to yield 1.3 g of compound SM7 as a green oil (92% yield).

[0127] SM6 (156.4 mg, 0.74 mmol, 1 eq.), SM7 (200 mg, 0.81 mmol, 1.1 eq.), and CuI (14 mg, 0.074 mmol, 0.1 eq.) were dissolved in 1,4-dioxane (7 mL). Triethylamine (0.3 mL, 2.20 mmol, 3 eq.) was then added. The mixture was evacuated and replaced with nitrogen, and this process was repeated three times. Under a nitrogen atmosphere, Pd(PPh3)2Cl2 (52 mg, 0.07 mmol, 0.1 eq.) was added to the reaction system. The mixture was heated and stirred at 80°C overnight. After the reaction, the solvent was removed, and the mixture was dissolved in DCM and purified by column chromatography to obtain 167 mg of the yellow solid compound SM8 in a 60% yield.

[0128] SM8 (167 mg, 0.44 mmol, 1 eq.) was dissolved in THF (4 mL) and heated with stirring at 60°C. A 1 mL aqueous solution of NaOH (35.8 mg, 0.89 mmol, 2 eq.) was added to the reaction system. The mixture was heated under reflux at 70°C overnight. After the reaction, 2M HCl (aq.) was added to adjust the pH to acidic. Solid precipitated and was filtered to obtain 100 mg of a yellow solid, compound SM9, in a 62% yield. MS [MH] - :358.

[0129] Echinocandin B hydrochloride (93 mg, 0.11 mmol, 1 eq.), SM9 (40 mg, 0.23 mmol, 1 eq.), and CDMT (23 mg, 0.13 mmol, 1.2 eq.) were dissolved in DMF (1.1 mL), followed by the addition of NMM (0.036 mL, 0.33 mmol, 3 eq.). The mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction solution was purified by HPLC to obtain 67 mg of a white solid compound with a purity of 96% and a yield of 52%. HRMS [MH] - :1137.4491.

[0130] 1 H NMR (400MHz, CD3OD) δ8.46 (s, 2H), 8.26 (s, 1H), 8.05 (d, J = 8.6Hz, 1H), 7.98 (t, J=6.4Hz,3H),7.91(dd,J=8.9,2.8Hz,1H),7.74–7.70(m,1H),7.15(d,J=8.5Hz, 2H),6.76(d,J=8.6Hz,2H),5.36(d,J=3.0Hz,1H),5.02(d,J=3.2Hz,2H),4.71(d d,J=12.9,6.3Hz,1H),4.65–4.53(m,3H),4.39(dd,J=15.0,3.0Hz,1H),4.32(d, J=8.0Hz,2H),4.28–4.19(m,5H),4.14–4.06(m,1H),3.99(d,J=7.8Hz,1H),3.9 3–3.86(m,1H),3.82(d,J=10.8Hz,1H),3.44–3.38(m,1H),2.59–2.41(m,2H),2. 31–2.21(m,1H),2.10(d,J=12.7Hz,2H),1.93–1.84(m,2H),1.56–1.39(m,4H),1 .28(dd,J=12.4,6.3Hz,6H), 1.07(dd,J=6.8,4.1Hz,3H), 0.97(t,J=7.2Hz,3H).

[0131] Example 6:

[0132] 2-Bromo-5-pyrimidinol (1 g, 5.71 mmol, 1 eq.) was dissolved in acetonitrile (30 mL), bromopentane (2.1 mL, 17.14 mmol, 3 eq.) was added, and finally potassium carbonate (2.370 g, 17.14 mmol, 3 eq.) was added. The mixture was heated to 90°C and refluxed with stirring for 4 h. TLC showed that the reaction was complete. The filtrate was filtered and dried, and extracted with water and EA. The EA phase was dried to obtain 1.24 g of brown oily compound SM10, with a yield of 89%.

[0133] SM6 (500 mg, 2.04 mmol, 1 eq.) was dissolved in dioxane (8 mL), and the nitrogen atmosphere was replaced. SM10 (428 mg, 2.04 mmol, 1 eq.), Pd(PPh3)2Cl2 (143 mg, 0.20 mmol, 0.1 eq.), CuI (155 mg, 0.81 mmol, 0.4 eq.), and triethylamine (0.85 mL, 6.12 mmol, 3 eq.) were added sequentially under nitrogen protection. The mixture was stirred at 80°C for 6 h, and the solvent was removed. The mixture was extracted with water and EA. The EA phase was spin-dried and purified by column chromatography to obtain 287 mg of SM11 as a yellow solid (38% yield). MS [M+H] + :375.0.

[0134] SM11 (287 mg, 0.76 mmol, 1 eq.) was dissolved in THF (7 mL). Sodium hydroxide (186 mg, 4.60 mmol, 6 eq.) was dissolved in water (1 mL) and added to the mixture. The mixture was stirred at 60°C for 5 hours, the solvent was removed, and the mixture was extracted with water and DCM. Dilute hydrochloric acid was added to the aqueous phase to adjust the pH to acidic, and the mixture was extracted with DCM. The solvent was removed to obtain the crude product, 270 mg of a yellow-brown liquid SM12, in a 97% yield. MS [M+H] + :361.0.

[0135] Echinocandin B hydrochloride (313 mg, 0.37 mmol, 1 eq.) was dissolved in DMF (4 mL). SM12 (135 mg, 0.37 mmol, 1 eq.), NMM (0.12 mL, 1.12 mmol, 3 eq.), and CDMT (79 mg, 0.45 mmol, 1.2 eq.) were added sequentially. The mixture was reacted at room temperature for 6 h. Purification by HPLC yielded 23.5 mg of the product with a purity of 95% and a yield of 5%. HRMS [MH] - :1138.3973.

[0136] 1HNMR (400MHz, CD3OD) δ8.47–8.39(m,2H),8.24(s,1H),8.06–7.95(m,3H),7.72(d,J=8.6Hz,1H),7.58(d,J=9.2Hz,1H),7.15(d,J=8.5Hz,2H), 6.76(d,J=8.5Hz,2H),5.37(d,J=8.8Hz,1H),5.02(d,J=5.4Hz,2H),4.7 3–4.66(m,1H),4.64–4.54(m,3H),4.39–4.30(m,3H),4.26–4.16(m,5H) ,4.08(s,1H),3.99(d,J=8.2Hz,1H),3.85(dd,J=22.6,9.0Hz,2H),3.45–3.38(m,2H),2.50(ddd,J=36.4,17.3,6.5Hz,2H),2.25(dd,J=18.5,4 .2Hz,1H),2.18–2.03(m,2H),1.90–1.82(m,2H),1.55–1.39(m,4H),1.27(dd,J=10.4,6.4Hz,6H),1.07(d,J=6.9Hz,3H),0.97(t,J=7.1Hz,3H).

[0137] Example 7:

[0138] 4-Bromo-2,3-difluorophenol (0.35 mL, 4.70 mmol, 1 eq.), bromopentane (0.7 mL, 5.70 mmol, 1.2 eq.), and potassium carbonate (2 g, 14.00 mmol, 3 eq.) were dissolved in acetonitrile (47 mL) and heated under reflux at 90°C with stirring. After 1.5 h, TLC showed the formation of new spots and the disappearance of the starting material. The solvent was removed, and the mixture was extracted with ethyl acetate and water. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to yield 1.2 g of compound SM13 as a black oil (92% yield).

[0139] SM6 (378 mg, 1.80 mmol, 1 eq.), SM13 (553 mg, 2.00 mmol, 1.1 eq.), and CuI (14 mg, 0.18 mmol, 0.1 eq.) were dissolved in 1,4-dioxane (7 mL). Triethylamine (0.3 mL, 5.50 mmol, 3 eq.) was then added. Vacuuming and replacing the atmosphere with nitrogen was repeated three times. Under a nitrogen atmosphere, Pd(PPh3)2Cl2 (126 mg, 0.18 mmol, 0.1 eq.) was added. The mixture was heated and stirred at 80°C overnight. TLC revealed a distinct new spot. The solvent was removed, and the mixture was dissolved in DCM and purified by column chromatography to yield SM14 (101 mg) as a white solid in an 11% yield.

[0140] SM14 (101 mg, 0.24 mmol, 1 eq.) was dissolved in THF (2 mL) and heated with stirring at 60°C. A 0.5 mL aqueous solution of NaOH (50 mg, 1.23 mmol, 5 eq.) was added to the reaction system. The mixture was heated under reflux at 75°C overnight. After the reaction, 2M HCl (aq.) was added to adjust the pH to acidic. Solid precipitated and was filtered to obtain 75 mg of SM15 as a white solid, yielding 76%. MS [MH] - :393.

[0141] Echinocandin B hydrochloride (159 mg, 0.19 mmol, 1 eq.), SM15 (75 mg, 0.19 mmol, 1 eq.), and CDMT (40 mg, 0.22 mmol, 1.2 eq.) were dissolved in DMF (2 mL), followed by the addition of NMM (0.06 mL, 0.57 mmol, 3 eq.). The mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction solution was purified by HPLC to obtain 128 mg of a white solid compound with a purity of 96% and a yield of 57%. HRMS [MH] - :1172.4577.

[0142] 1H NMR(400MHz,CD3OD)δ8.41(s,1H),8.09(s,1H),8.00–7.90(m,3H),7.62(dd,J =8.5,1.4Hz,1H),7.35–7.28(m,1H),7.15(d,J=8.5Hz,2H),6.95(t,J=7.5Hz,1 H),6.76(d,J=8.5Hz,2H),5.37(d,J=2.9Hz,1H),5.03(d,J=3.3Hz,1H),4.92( s,1H),4.70(dd,J=11.9,5.2Hz,1H),4.59(dd,J=14.6,7.2Hz,3H),4.34(dd,J= 18.0,5.3Hz,3H),4.28–4.19(m,3H),4.12(t,J=6.4Hz,3H),3.99(d,J=8.1Hz, 1H),3.92–3.80(m,2H),3.44–3.37(m,1H),2.58–2.41(m,2H),2.25(t,J=8.5Hz ,1H),2.18–2.03(m,2H),1.88–1.80(m,2H),1.46(ddd,J=22.2,12.3,6.9Hz,4 H), 1.28 (dd, J = 13.3, 6.3Hz, 6H), 1.06 (d, J = 6.9Hz, 3H), 0.97 (t, J = 7.1Hz, 3H).

[0143] Example 8:

[0144] Example 7 (347 mg, 0.29 mmol, 1 eq.) and 3,4-dimethoxyphenylboronic acid (70 mg, 0.38 mmol, 1.3 eq.) were dissolved in dry THF (6 mL) and stirred at room temperature for 1 h. The mixture was concentrated to dryness, and choline p-toluenesulfonate (2.4 g, 8.80 mmol, 30 eq.) was added. A mixture of TFA (0.85 mL) and acetonitrile (4.5 mL) was then added to dissolve the reactants. The mixture was stirred at room temperature under a nitrogen atmosphere for 6 h. After the reaction was completed, an aqueous solution of sodium acetate was added to quench the reaction. Purification by HPLC yielded 74 mg of the compound (hydrochloride) as a white solid with a purity of 95% and a yield of 19%. HRMS [M] + :1259.5431.

[0145] 1H NMR (400MHz, CD3OD) δ8.46(s,1H),8.14(s,1H),8.00(dd,J=15.9,5.8Hz,3H),7.66(dd,J =8.5,1.5Hz,1H),7.23(d,J=8.0Hz,1H),7.15(d,J=8.6Hz,2H),6.96(dd,J=12.0,4.5Hz,1 H),6.76(d,J=8.5Hz,2H),5.42(d,J=2.5Hz,1H),5.04(d,J=3.3Hz,1H),4.79(dd,J=12.0, 5.0Hz,2H),4.58(t,J=5.1Hz,3H),4.39(d,J=4.3Hz,1H),4.35–4.31(m,2H),4.25(td,J=7 .1,3.1Hz,2H),4.20–4.16(m,1H),4.12(dd,J=12.6,6.1Hz,3H),4.00(d,J=11.3Hz,2H), 3.91(dd,J=9.8,7.0Hz,2H),3.83(d,J=10.9Hz,1H),3.60(d,J=4.8Hz,1H),3.47(d,J=7.0 Hz,1H),3.13(s,9H),2.53–2.44(m,2H),2.29(d,J=8.9Hz,1H),2.10–2.04(m,2H),1.87–1 .83(m,2H),1.50–1.41(m,4H),1.27(d,J=6.3Hz,6H),1.08(d,J=6.9Hz,3H),0.97(s,3H).

[0146] Example 9:

[0147] 2-Fluoro-4-iodophenol (1 g, 4.20 mmol, 1 eq.) was dissolved in acetonitrile (20 mL), bromopentane (1.56 mL, 12.60 mmol, 3 eq.) was added, and finally potassium carbonate (1.743 g, 12.60 mmol, 3 eq.) was added. The mixture was heated to 90°C and refluxed with stirring for 4 h. TLC showed that the reaction was complete. The filtrate was filtered and dried, and extracted with water and EA. The EA was dried to obtain 1.237 g of yellow liquid SM16, with a yield of 95%.

[0148] SM16 (293 mg, 0.95 mmol, 1 eq.) was dissolved in dioxane (10 mL), and the nitrogen atmosphere was replaced. Under the protection of nitrogen, SM6 (200 mg, 0.95 mmol, 1 eq.), Pd(PPh3)2Cl2 (67 mg, 0.09 mmol, 0.1 eq.), CuI (73 mg, 0.38 mmol, 0.4 eq.), and triethylamine (0.4 mL, 2.85 mmol, 3 eq.) were added in sequence. The mixture was stirred at room temperature overnight. TLC showed that the reaction was complete. The solvent was removed, and the mixture was extracted with water and DCM. After removal of the solvent, the crude product was obtained, which was separated and purified by column chromatography to give 282 mg of white solid SM17 in a yield of 76%.

[0149] SM17 (282 mg, 0.72 mmol, 1 eq.) was dissolved in THF (7 mL), and sodium hydroxide (123 mg, 2.89 mmol, 6 eq.) dissolved in water (1 mL) was added to the system. The mixture was stirred at 60°C for 5 h. TLC indicated completion of the reaction. The solvent was removed, and the mixture was extracted with water and DCM. Dilute hydrochloric acid was added to the aqueous phase to adjust the pH to acidic, and the mixture was extracted with DCM. The solvent was removed to obtain the crude product, 255 mg of SM18 as a white solid, in a 94% yield.

[0150] Echinocandin B hydrochloride (366 mg, 0.43 mmol, 1.2 eq.) was dissolved in DMF (5 mL), and SM18 (138 mg, 0.36 mmol, 1 eq.), NMM (0.13 mL, 1.09 mmol, 3 eq.), and CDMT (77 mg, 0.43 mmol, 1.2 eq.) were added in sequence. The mixture was reacted at room temperature for 6 h and purified by HPLC to obtain 180 mg of the product with a purity of 95% and a yield of 35%. HRMS [M+Na] + :1178.4604.

[0151] 1HNMR(400MHz,CD3OD)δ8.41(d,J=10.8Hz,1H),8.06(s,1H),7.92(dd,J=14.1, 8.5Hz,3H),7.69(d,J=9.5Hz,1H),7.58(d,J=6.8Hz,2H),7.31(dd,J=14.6,4.8 Hz,2H),7.15(t,J=7.1Hz,3H),6.76(d,J=8.5Hz,2H),5.37(d,J=2.8Hz,1H),5. 04(d,J=5.2Hz,2H),4.70(dd,J=11.9,5.1Hz,1H),4.59(dd,J=14.7,7.5Hz,3H) ,4.34(dd,J=18.2,5.3Hz,3H),4.27–4.18(m,3H),4.09(t,J=6.4Hz,3H),3.99 (d,J=8.3Hz,1H),3.92–3.79(m,2H),3.41(t,J=9.0Hz,1H),2.57–2.41(m,2H), 2.25(s,1H),2.11(dd,J=16.3,10.0Hz,2H),1.87–1.78(m,2H),1.51–1.40(m,4 H), 1.28 (dd, J = 13.4, 6.3Hz, 6H), 1.06 (d, J = 6.9Hz, 3H), 0.97 (t, J = 7.2Hz, 3H).

[0152] Example 10:

[0153] Example 9 (100 mg, 0.08 mmol, 1 eq.) and 3,4-dimethoxyphenylboronic acid (20 mg, 0.11 mmol, 1.3 eq.) were dissolved in dry THF (1.5 mL) and stirred at room temperature for 1 h. The mixture was concentrated to dryness, and choline p-toluenesulfonate (238 mg, 0.86 mmol, 10 eq.) was added. A mixture of TFA (0.25 mL) and acetonitrile (1 mL) was then added to dissolve the reactants. The mixture was stirred at room temperature under a nitrogen atmosphere for 6 h. After completion of the reaction, an aqueous solution of sodium acetate was added to quench the reaction. The product was purified by HPLC to give 27.6 mg of the compound (hydrochloride) as a white solid with a purity of 96% and a yield of 25%. HRMS [M] + :1241.5522.

[0154] 1H NMR(400MHz,CD3OD)δ8.45(s,1H),8.11(s,1H),8.02–7.96(m,3H),7.67–7.63(m,1 H),7.34–7.29(m,2H),7.14(t,J=8.8Hz,3H),6.76(d,J=8.5Hz,2H),5.42(d,J=2.4H z,1H),5.04(d,J=3.2Hz,1H),4.79(dd,J=12.1,5.1Hz,1H),4.59(dd,J=10.6,7.4H z,3H),4.39(d,J=4.3Hz,1H),4.33(d,J=8.3Hz,2H),4.25(dd,J=8.3,6.4Hz,2H),4. 20–4.15(m,1H),4.10(t,J=6.5Hz,3H),4.00(d,J=11.4Hz,2H),3.94–3.87(m,2H), 3.83(d,J=10.7Hz,1H),3.65–3.52(m,2H),3.51–3.46(m,1H),3.13(s,9H),2.55–2. 42(m,2H),2.34–2.27(m,1H),2.08(dd,J=24.0,4.3Hz,2H),1.86–1.80(m,2H),1.5 1–1.41(m,4H),1.27(d,J=6.3Hz,6H),1.08(d,J=6.9Hz,3H),0.97(t,J=7.1Hz,3H).

[0155] Example 11:

[0156] 4-Iodo-2-chlorophenol (1 g, 3.90 mmol, 1 eq.), bromopentane (0.6 ml, 4.70 mmol, 1.2 eq.), and potassium carbonate (1.6 g, 11.00 mmol, 3 eq.) were dissolved in acetonitrile (40 mL) and heated under reflux at 90°C with stirring. After 1.5 h, TLC showed the formation of new spots and the disappearance of the starting material. The solvent was removed, and the mixture was extracted with ethyl acetate and water. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to yield 1.0 g of compound SM19 as a yellow oil (78% yield).

[0157] SM6 (432 mg, 2.00 mmol, 1 eq.), SM19 (800 mg, 2.40 mmol, 1.0 eq.), and CuI (39 mg, 0.20 mmol, 0.1 eq.) were dissolved in 1,4-dioxane (24 mL). Triethylamine (0.8 mL, 6.10 mmol, 3 eq.) was then added. Vacuuming and replacing the atmosphere with nitrogen was repeated three times. Under a nitrogen atmosphere, Pd(PPh3)2Cl2 (144 mg, 0.20 mmol, 0.1 eq.) was added. The mixture was heated and stirred at 80°C overnight. TLC showed a distinct new spot, while the signals for the starting materials SM3 and SM25 were weak. The solvent was removed, and the mixture was dissolved in DCM and purified by column chromatography to obtain 261 mg of the white solid compound SM20 in a 25% yield.

[0158] SM20 (261 mg, 0.64 mmol, 1 eq.) was dissolved in THF (7 mL) and heated with stirring at 70°C. A 1.5 mL aqueous solution of NaOH (129 mg, 3.20 mmol, 5 eq.) was then added to the reaction system. The mixture was heated at reflux at 70°C overnight. After the reaction, 2M HCl (aq.) was added to adjust the pH to acidic. Solids precipitated and were filtered to obtain 233 mg of SM21 as a white solid, yielding 92%.

[0159] Echinocandin B hydrochloride (150 mg, 0.17 mmol, 1 eq.), SM21 (75 mg, 0.17 mmol, 1 eq.), and CDMT (38 mg, 0.22 mmol, 1.2 eq.) were dissolved in DMF (1.8 mL), followed by the addition of NMM (0.06 mL, 0.53 mmol, 3 eq.). The mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction solution was purified by HPLC to obtain 138 mg of a white solid compound with a purity of 96% and a yield of 65%. HRMS [MH] - :1170.4768.

[0160] 1H NMR (400MHz, CD3OD) δ8.40(s,1H),8.07(s,1H),7.92(dt,J=13.2,8.7Hz,3H),7.61–7.56(m,2H),7.47(dd,J= 8.6,2.0Hz,1H),7.15(d,J=8.5Hz,2H),7.08(d,J=8.7Hz,1H),6.76(d,J=8.5Hz,2H),5.37(d,J=2.9Hz,1H),5 .03(d,J=3.2Hz,1H),4.74–4.66(m,2H),4.64–4.55(m,3H),4.34(dd,J=18.7,5.3Hz,3H),4.27–4.19(m,3H), 4.10(t,J=6.3Hz,3H),3.99(d,J=8.1Hz,1H),3.85(dd,J=21.2,9.1Hz,2H),3.41(t,J=9.1Hz,1H),2.57–2.41 (m,2H),2.29–2.21(m,1H),2.16–2.04(m,2H),1.84(dd,J=14.5,6.5Hz,2H),1.49(ddd,J=24.5 ,11.7,5.2Hz,4H),1.28(dd,J=12.5,6.3Hz,6H),1.06(d,J=6.9Hz,3H),0.97(t,J=7.2Hz,3H).

[0161] Example 12:

[0162] Example 11 (100 mg, 0.08 mmol, 1 eq.) and 3,4-dimethoxyphenylboronic acid (20 mg, 0.11 mmol, 1.3 eq.) were dissolved in dry THF (1.5 mL) and stirred at room temperature for 1 h. The mixture was concentrated to dryness, and choline p-toluenesulfonate (235 mg, 0.85 mmol, 10 eq.) was added. A mixture of TFA (0.25 mL) and acetonitrile (1.5 mL) was then added to dissolve the reactants. The mixture was stirred at room temperature under a nitrogen atmosphere for 6 h. After the reaction was completed, an aqueous solution of sodium acetate was added to quench the reaction. The mixture was purified by HPLC to give 28 mg of the compound (hydrochloride) as a white solid with a purity of 96% and a yield of 26%. HRMS [M] + :1257.5352.

[0163] 1H NMR(400MHz,CD3OD)δ8.45(s,1H),8.11(s,1H),8.05–7.96(m,3H),7.65(d,J=8.4Hz,1H) ,7.58(d,J=2.0Hz,1H),7.48(dd,J=8.5,2.0Hz,1H),7.15(d,J=8.5Hz,2H),7.09(d,J=8. 6Hz,1H),6.76(d,J=8.6Hz,2H),5.42(d,J=2.4Hz,1H),5.04(d,J=3.2Hz,1H),4.90(s,1H ),4.81–4.75(m,1H),4.58(d,J=6.5Hz,3H),4.39(d,J=4.3Hz,1H),4.33(d,J=7.9Hz,2H) ,4.29–4.23(m,2H),4.21–4.15(m,1H),4.11(t,J=6.3Hz,3H),4.00(d,J=11.3Hz,1H),3. 93–3.88(m,1H),3.83(d,J=10.8Hz,1H),3.68–3.44(m,4H),3.13(s,9H),2.56–2.41(m,2 H),2.35–2.25(m,1H),2.08(dd,J=15.3,9.7Hz,2H),1.88–1.81(m,2H),1.49(ddd,J=24. 5,11.6,5.1Hz,4H),1.27(d,J=6.2Hz,6H),1.08(d,J=6.9Hz,3H),0.97(t,J=7.2Hz,3H).

[0164] Example 13:

[0165] 4-Bromo-2,6-difluorophenol (1 g, 4.78 mmol, 1 eq.) was dissolved in acetonitrile (20 mL), bromopentane (1.8 mL, 14.35 mmol, 3 eq.) was added, and finally potassium carbonate (1.984 g, 14.35 mmol, 3 eq.) was added. The mixture was heated to 90°C and refluxed with stirring for 4 h. TLC showed that the reaction was complete. The filtrate was filtered and dried, and extracted with water and EA. The EA was dried to obtain 1.317 g of yellow liquid SM22, with a yield of 99%.

[0166] SM22 (1 g, 3.58 mmol, 1 eq.) was dissolved in triethylamine (17 mL), and trimethylethynylsilane (0.51 mL, 3.58 mmol, 1 eq.), Pd(PPh3)2Cl2 (252 mg, 0.35 mmol, 0.1 eq.), and CuI (68 mg, 0.35 mmol, 0.1 eq.) were added. The nitrogen atmosphere was replaced, and the mixture was stirred at 90°C for 2 h using a microwave reactor. TLC showed that the reaction was complete and new spots were generated. The mixture was separated and purified by column chromatography to obtain 922 mg of a yellow liquid compound SM23 with a yield of 87%.

[0167] SM23 (922 mg, 3.11 mmol, 1 eq.) was dissolved in MeOH (10 mL) and THF (10 mL), and potassium carbonate (654 mg, 4.66 mmol, 1.5 eq.) was added. The mixture was stirred at room temperature for 3 h. TLC showed that the reaction was complete, new spots were generated, and the starting material disappeared. The mixture was extracted with water and DCM. After removing the solvent, the crude product was obtained to obtain 600 mg of yellow oily compound SM24, with a yield of 86%.

[0168] Methyl 6-bromo-2-naphthoate (639 mg, 2.41 mmol, 1 eq.) was dissolved in triethylamine (12 mL), and SM24 (540 mg, 2.41 mmol, 1 eq.), (PPh3)2PdCl2 (169 mg, 0.24 mmol, 0.1 eq.), and CuI (46 mg, 0.24 mmol, 0.1 eq.) were added. The nitrogen atmosphere was replaced by microwave reaction at 90°C and stirred for 2 h. TLC showed the generation of new spots and the disappearance of the raw materials. The mixture was separated and purified by column chromatography to obtain 662 mg of yellow solid compound SM25 in a yield of 67%.

[0169] SM25 (662 mg, 1.62 mmol, 1 eq.) was dissolved in THF (9 mL), and NaOH (259 mg, 6.48 mmol, 4 eq.) was dissolved in water (1 mL) and added to the reaction system. The mixture was stirred at 60°C overnight. TLC showed a product spot. After the THF was dried, the mixture was extracted with water and EA for the first time. The aqueous phase was acidified and a solid precipitated. It was filtered and dried to obtain 621 mg of a yellow solid compound SM26 in a yield of 97%.

[0170] SM26 (236 mg, 0.59 mmol, 1 eq.) was dissolved in DMF (6 mL). Echinocandin B hydrochloride (500 mg, 0.59 mmol, 1 eq.) and CDMT (126 mg, 0.71 mmol, 1.2 eq.) were added sequentially. Finally, NMM (0.20 mL, 1.79 mmol, 3 eq.) was added. The mixture was stirred at room temperature for 4 h. The product was purified by HPLC to give 211 mg of a white solid with a purity of 96% and a yield of 30%. HRMS [M+Na] + :1196.4405.

[0171] 1 H NMR (400MHz, CD3OD) δ8.41(s,1H),8.10(s,1H),7.94(dd,J=16.1,7.7Hz,3H),7.65–7.61(m,1H),7.23(d,J=8.4Hz,2H),7.15(d,J= 8.5Hz,2H),6.76(d,J=8.5Hz,2H),5.36(s,1H),5.03(s,2H),4.70(dd,J=11.8,5.1Hz,1H),4.64–4.53(m,3H),4.39–4.30(m,3H),4 .27–4.15(m,5H),4.09(s,1H),3.99(d,J=8.4Hz,1H),3.93–3.80(m,2H),3.41(t,J=9.1Hz,1H),2.58–2.40(m,2H),2.25(s,1H),2. 18–2.04(m,2H),1.81–1.72(m,2H),1.54–1.39(m,4H),1.28(dd,J=13.2,6.2Hz,6H),1.06(d,J=6.9Hz,3H),0.96(t,J=7.2Hz,3H).

[0172] Example 14:

[0173] Example 13 (150 mg, 0.12 mmol, 1 eq.) was dissolved in dry THF (3 mL), and 3,4-dimethoxyphenylboronic acid (30 mg, 0.16 mmol, 1.3 eq.) was added. After stirring at room temperature for 1 h, the solvent was removed and dry THF (3 mL) was added and the mixture was spin-dried. Choline p-toluenesulfonate (352 mg, 1.27 mmol, 10 eq.) was added. TFA (0.38 mL) and acetonitrile (3 mL) were mixed and added to the system. The mixture was stirred at room temperature for 3 h. LCMS showed the presence of product. HPLC preparative purification gave 57 mg of a white solid (acetate salt) with a purity of 98% and a yield of 28%. HRMS [M] +:1259.5494.

[0174] 1 H NMR(400MHz,CD3OD)δ8.45(s,1H),8.14(s,1H),8.02–7.97(m,3H),7.66(d,J =8.5Hz,1H),7.23(d,J=8.4Hz,2H),7.15(d,J=8.5Hz,2H),6.76(d,J=8.4Hz,2 H),5.42(s,1H),5.05(d,J=3.0Hz,1H),4.81–4.77(m,1H),4.60(d,J=11.6Hz ,4H),4.39(d,J=4.3Hz,1H),4.34(s,2H),4.25(dd,J=10.0,5.7Hz,3H),4.19( t,J=6.4Hz,3H),4.11(s,1H),4.00(d,J=10.9Hz,2H),3.94–3.88(m,2H),3.8 3(d,J=10.6Hz,1H),3.50(d,J=6.9Hz,1H),3.13(s,9H),2.54–2.43(m,2H),2. 30(s,1H),2.07(d,J=12.8Hz,2H),1.90(s,3H),1.79–1.74(m,2H),1.48–1.3 9(m,4H),1.27(d,J=6.2Hz,6H),1.08(d,J=6.9Hz,3H),0.96(t,J=7.2Hz,3H).

[0175] Example 15:

[0176] 4-Bromo-2,5-difluorophenol (1 g, 4.78 mmol, 1 eq.) was dissolved in acetonitrile (25 mL), bromopentane (1.8 mL, 14.35 mmol, 3 eq.) was added, and finally potassium carbonate (1.984 g, 14.35 mmol, 3 eq.) was added. The mixture was heated to 90°C and refluxed with stirring for 4 h. TLC showed that the reaction was complete. The filtrate was filtered and dried, and extracted with water and EA. The EA was dried to obtain 1.280 g of yellow liquid crude product SM27, with a yield of 96%.

[0177] SM27 (500 mg, 1.79 mmol, 1 eq.) was dissolved in triethylamine (15 mL) and added to a sealed tube. Nitrogen was replaced by bubbling. Trimethylethynylsilane (0.38 mL, 2.68 mmol, 1.5 eq.), Pd(PPh3)2Cl2 (126 mg, 0.17 mmol, 0.1 eq.), and CuI (34 mg, 0.17 mmol, 0.1 eq.) were added. The mixture was stirred in an oil bath at 90°C overnight. TLC showed that the reaction was complete and new spots were generated. After removing the solvent, the mixture was dissolved in DCM and the organic phase was washed with ammonium chloride solution, dilute hydrochloric acid, and saturated brine in sequence. The crude product was obtained after removal of the solvent. The product was separated and purified by column chromatography to obtain 537 mg of yellow oily compound SM28 in a yield of 99%.

[0178] SM28 (537 mg, 1.81 mmol, 1 eq.) was dissolved in MeOH (9 mL) and THF (9 mL), and potassium carbonate (376 mg, 2.71 mmol, 1.5 eq.) was added. The mixture was stirred at room temperature for 3 h. TLC showed that the reaction was complete, new spots were generated, and the starting material disappeared. The mixture was extracted with water and DCM, and after removing the solvent, 402.5 mg of crude product, yellow oily compound SM29, was obtained in a yield of 99%.

[0179] Methyl 6-bromo-2-naphthoate (592 mg, 2.23 mmol, 1 eq.) was dissolved in triethylamine (10 mL), and SM29 (500 mg, 2.23 mmol, 1 eq.), (PPh3)2PdCl2 (157 mg, 0.22 mmol, 0.1 eq.), and CuI (43 mg, 0.22 mmol, 0.1 eq.) were added. The atmosphere was replaced with nitrogen, and the mixture was stirred in an oil bath at 90°C overnight. TLC showed that new spots appeared and the raw material disappeared. The solvent was removed and the mixture was extracted with water and DCM. After removal of the solvent, the crude product was obtained. The product was separated and purified by column chromatography to obtain 678 mg of yellow solid compound SM30 in a yield of 74%.

[0180] SM30 (678 mg, 1.66 mmol, 1 eq.) was dissolved in THF (16 mL), and NaOH (266 mg, 6.64 mmol, 4 eq.) was dissolved in water (2 mL) and added to the reaction system. The mixture was stirred at 60°C overnight. TLC showed a product spot. After the THF was dried, the mixture was extracted with water and DCM for the first time. The aqueous phase was acidified and then extracted with DCM to remove the solvent to obtain a crude product. 418.6 mg of yellow solid compound SM31 was obtained with a yield of 64%.

[0181] SM31 (71 mg, 0.18 mmol, 1 eq.) was dissolved in DMF (2 mL). Echinocandin B hydrochloride (150 mg, 0.18 mmol, 1 eq.) and CDMT (38 mg, 0.21 mmol, 1.2 eq.) were added sequentially. Finally, NMM (0.06 mL, 0.54 mmol, 3 eq.) was added. The mixture was stirred at room temperature for 4 h. HPLC purification was performed to obtain 83 mg of a white solid compound with a purity of 96% and a yield of 39%. HRMS [M+Na] + :1196.4617.

[0182] 1 H NMR (400MHz, CD3OD) δ8.42(s,1H),8.10(s,1H),8.01–7.92(m,3H),7.62(dd,J=8.5,1.2Hz,1H),7.33(dd,J=11.1,6.7Hz,1H),7.15(d,J=8.5Hz,2H),7 .02(dd,J=10.7,7.2Hz,1H),6.76(d,J=8.5Hz,2H),5.36(s,1H),5.02(s,2 H),4.69(d,J=6.2Hz,1H),4.61(dd,J=14.9,10.6Hz,3H),4.34(dd,J=18.9, 5.7Hz,3H),4.26–4.18(m,3H),4.09(t,J=6.4Hz,3H),3.99(d,J=10.9Hz,1 H),3.88(dd,J=18.5,10.7Hz,2H),3.43–3.38(m,1H),2.60–2.39(m,2H),2. 30–2.20(m,1H),2.18–2.03(m,2H),1.88–1.80(m,2H),1.52–1.39(m,4H), 1.28(dd,J=11.6,6.3Hz,6H), 1.06(d,J=6.8Hz,3H), 0.97(t,J=7.1Hz,3H).

[0183] Example 16:

[0184] Example 15 (250 mg, 0.21 mmol, 1 eq.) was dissolved in dry THF (5 mL), and 3,4-dimethoxyphenylboronic acid (50 mg, 0.27 mmol, 1.3 eq.) was added. After stirring at room temperature for 1 hour, the solvent was removed and dry THF (5 mL) was added and the mixture was spin-dried. Choline chloride (297 mg, 2.12 mmol, 10 eq.) was added, and TFA (0.63 mL) and acetonitrile (5 mL) were mixed and added to the system. The mixture was stirred at room temperature for 3 hours. LCMS showed the presence of product. HPLC preparative purification gave 57 mg of the compound (hydrochloride) as a white solid with a purity of 97% and a yield of 21%. HRMS [M] + :1259.5494.

[0185] 1 H NMR(400MHz,CD3OD)δ8.45(s,1H),8.12(s,1H),8.02–7.95(m,3H),7.65(dd,J=8.5, 1.1Hz,1H),7.33(dd,J=11.0,6.7Hz,1H),7.15(d,J=8.4Hz,2H),7.02(dd,J=10.7,7. 2Hz,1H),6.76(d,J=8.4Hz,2H),5.42(s,1H),5.05(s,1H),4.81–4.75(m,1H),4.60( d,J=11.3Hz,3H),4.39(d,J=4.1Hz,1H),4.33(d,J=8.1Hz,2H),4.24(d,J=8.0Hz,2H) ,4.21–4.16(m,1H),4.09(t,J=6.4Hz,3H),4.00(d,J=8.6Hz,2H),3.96–3.88(m,2H) ,3.82(d,J=10.9Hz,1H),3.58(d,J=26.0Hz,2H),3.51–3.46(m,1H),3.13(s,9H),2.5 5–2.41(m,2H),2.30(s,1H),2.09(t,J=13.4Hz,2H),1.83(dd,J=14.3,6.7Hz,2H),1. 50–1.40(m,4H),1.27(d,J=6.2Hz,6H),1.08(d,J=6.8Hz,3H),0.97(t,J=7.1Hz,3H).

[0186] Example 17:

[0187] 4-Bromo-2,6-difluorophenol (2 g, 9.56 mmol, 1 eq.) was dissolved in acetonitrile (45 mL), bromooctane (1.65 mL, 9.56 mmol, 1 eq.) was added, and finally potassium carbonate (3.969 g, 28.70 mmol, 3 eq.) was added. The mixture was heated to 90°C and refluxed with stirring for 4 h. TLC showed that the reaction was complete. The filtrate was filtered and dried, and extracted with water and EA. The EA was dried to obtain 3.092 g of a transparent liquid crude product SM32, with a yield of 99%.

[0188] SM6 (1 g, 4.76 mmol, 1 eq.) and SM32 (1.53 g, 4.76 mmol, 1 eq.) were dissolved in triethylamine (20 mL), and (PPh3)2PdCl2 (330 mg, 0.47 mmol, 0.1 eq.) and CuI (90 mg, 0.47 mmol, 0.1 eq.) were added. The nitrogen was replaced and the mixture was reacted at 90°C in a microwave oven for 2.5 h. TLC showed that new spots were generated and the raw materials disappeared. The solvent was removed and the mixture was extracted with water and DCM. After removing the solvent, the crude product was obtained. The product was separated and purified by column chromatography to obtain 766 mg of yellow solid compound SM33 in a yield of 32%.

[0189] SM33 (766 mg, 1.70 mmol, 1 eq.) was dissolved in THF (9 mL), and NaOH (272 mg, 6.80 mmol, 4 eq.) was dissolved in water (1 mL) and added to the reaction system. The mixture was stirred at 60°C for 5 h. TLC showed a product spot. After the THF was dried, the mixture was extracted with water and EA for the first time. The aqueous phase was acidified and then extracted with DCM to remove the solvent to obtain a crude product. 531 mg of yellow solid compound SM34 was obtained with a yield of 71%.

[0190] SM34 (391 mg, 0.89 mmol, 1 eq.) was dissolved in DMF (6 mL). Echinocandin B hydrochloride (500 mg, 0.89 mmol, 1 eq.) and CDMT (126 mg, 1.07 mmol, 1.2 eq.) were added sequentially. Finally, NMM (0.2 mL, 2.69 mmol, 3 eq.) was added. The mixture was stirred at room temperature for 4 h. HPLC purification was performed to obtain 409 mg of SM35 as a white solid with a purity of 96% and a yield of 53%. HRMS [M+Na] + :1238.4876.

[0191] SM35 (150 mg, 0.12 mmol, 1 eq.) was dissolved in dry THF (3 mL), and 3,4-dimethoxyphenylboronic acid (29 mg, 0.16 mmol, 1.3 eq.) was added. After stirring at room temperature for 1 hour, the solvent was removed and dry THF (3 mL) was added and the mixture was spin-dried. Choline chloride (344 mg, 1.23 mmol, 10 eq.) was added. TFA (0.38 mL) and acetonitrile (3 mL) were mixed and added to the system. Stirring at room temperature for 3 hours, LCMS showed the presence of product. HPLC preparative purification gave 34 mg of the compound (hydrochloride) as a white solid with a purity of 98% and a yield of 28%. HRMS [M+H] + :1301.5963.

[0192] 1 H NMR(400MHz,CD3OD)δ8.45(s,1H),8.14(s,1H),8.02–7.96(m,3H),7.67–7.64(m ,1H),7.23(d,J=8.5Hz,2H),7.15(d,J=8.5Hz,2H),6.76(d,J=8.5Hz,2H),5.42(d ,J=2.2Hz,1H),5.05(d,J=3.1Hz,1H),4.78(d,J=5.0Hz,1H),4.58(d,J=5.3Hz,3 H),4.39(d,J=4.3Hz,1H),4.33(d,J=7.8Hz,2H),4.25(dd,J=9.9,5.6Hz,2H),4.1 9(t,J=6.3Hz,3H),4.11(s,1H),4.00(d,J=11.0Hz,2H),3.94–3.88(m,2H),3.82 (d,J=10.8Hz,1H),3.60–3.47(m,3H),3.13(s,9H),2.53–2.42(m,2H),2.33–2.26 (m,1H),2.08(t,J=12.2Hz,2H),1.79–1.73(m,2H),1.50(d,J=7.6Hz,2H),1.37– 1.31(m,8H),1.27(d,J=6.2Hz,6H),1.08(d,J=6.9Hz,3H),0.92(t,J=6.7Hz,3H).

[0193] Example 18:

[0194] Dissolve 4-bromo-2,5-difluorophenol (2 g, 9.50 mmol, 1 eq.), bromopropane (1 ml, 11.00 mmol, 1.2 eq.), and potassium carbonate (3.9 g, 28.00 mmol, 3 eq.) in acetonitrile (45 mL) and heat under reflux at 90°C with stirring. After 1.5 h, TLC showed the formation of new spots and the disappearance of the starting material. Remove the solvent, extract with ethyl acetate and water, and combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to yield 2.2 g of compound SM36 as a yellow oil (95% yield).

[0195] SM36 (1 g, 4.00 mmol, 1 eq.), trimethylsilylacetylene (393 mg, 4.00 mmol, 1 eq.), Pd(PPh3)2Cl2 (280 mg, 0.40 mmol, 0.1 eq.), and CuI (70 mg, 0.40 mmol, 0.1 eq.) were placed in a microwave reaction vial. Triethylamine (15 mL) was added and nitrogen was bubbled in, purging the air. After 15 minutes, the vial was quickly sealed and microwaved at 90°C for 3 h. After completion of the reaction, no starting material was observed on a TLC plate. The solvent was removed, and the mixture was dissolved in DCM. Column chromatography afforded 690 mg of SM37 as a yellow oil (64% yield).

[0196] SM37 (690 mg, 2.50 mmol, 1 eq.) and potassium carbonate (535 mg, 3.80 mmol, 1.5 eq.) were dissolved in THF (5 mL) and CH3OH (5 mL) and stirred at room temperature overnight. TLC showed that the reaction was complete. The solvent was removed, and the mixture was extracted with water and EA. The organic phase was dried and concentrated to obtain 471 mg of a yellow oil SM38, with a yield of 93%.

[0197] SM38 (471 mg, 2.40 mmol, 1.2 eq.), methyl 6-bromo-2-naphthoate (533 mg, 2.00 mmol, 1 eq.), Pd(PPh3)2Cl2 (141 mg, 0.20 mmol, 0.1 eq.), and CuI (38 mg, 0.20 mmol, 0.1 eq.) were weighed into a microwave reaction vial. Triethylamine (15 mL) was added and nitrogen was bubbled in, purging the air. After approximately 15 minutes, the vial was quickly sealed and microwaved at 90°C for 3 h. After completion of the reaction, no starting material was observed on a TLC plate. The solvent was removed, and the mixture was dissolved in DCM. Column chromatography afforded 555 mg of SM39 as a yellow solid in a 72% yield.

[0198] SM39 (555 mg, 1.40 mmol, 1 eq.) was dissolved in THF (5 mL) and heated with stirring at 70°C. A 1 mL aqueous solution of NaOH (234 mg, 5.80 mmol, 4 eq.) was then added to the reaction system. The mixture was heated at reflux at 70°C overnight. After the reaction, 2 M HCl (aq.) was added to adjust the pH to acidic. Solids precipitated and were filtered to obtain 457 mg of SM40, a white solid, in an 85% yield.

[0199] Echinocandin B hydrochloride (300 mg, 0.35 mmol, 1 eq.), SM40 (131 mg, 0.35 mmol, 1 eq.), and CDMT (75 mg, 0.43 mmol, 1.2 eq.) were dissolved in DMF (3.5 mL), followed by the addition of NMM (0.118 mL, 1.07 mmol, 3 eq.). The mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction solution was purified by HPLC to obtain 235 mg of SM41, a white solid with a purity of 86% and a yield of 57%. MS [M+H] + :1146.

[0200] SM41 (235 mg, 0.20 mmol, 1 eq.) and 3,4-dimethoxyphenylboronic acid (49 mg, 0.26 mmol, 1.3 eq.) were dissolved in dry THF (3 mL), stirred at room temperature for 1 h, and concentrated to dryness. Choline p-toluenesulfonate (1.7 g, 6.10 mmol, 30 eq.) was added, followed by a mixture of TFA (0.5 mL) and acetonitrile (3 mL) to dissolve the reactants. The mixture was stirred at room temperature under a nitrogen atmosphere for 5 h. After completion of the reaction, an aqueous solution of sodium acetate was added to quench the reaction. The product was purified by HPLC to give 160 mg of a white solid compound (hydrochloride salt) with a purity of 96% and a yield of 63%. HRMS [M] + :1231.5424.

[0201] 1H NMR (400MHz, CD3OD) δ8.45(s,1H),8.13(s,1H),8.02–7.96(m,3H),7.65(d,J= 8.4Hz,1H),7.33(dd,J=11.0,6.7Hz,1H),7.15(d,J=8.4Hz,2H),7.03(dd,J=10.7,7.2Hz,1H),6.76(d,J=8.5Hz,2H),5.42(s,1H),5.05(d,J=2.9 Hz,1H),4.79(dd,J=12.0,5.0Hz,1H),4.60(d,J=11.5Hz,3H),4.39(d,J=4.2Hz,1H),4.33(d,J=8.1Hz,2H),4.25(t,J=7.5Hz,2H),4.21–4.16(m,1 H),4.11(s,1H),4.06(t,J=6.4Hz,3H),4.00(d,J=11.0Hz,1H),3.95–3. 88(m,2H),3.83(d,J=11.0Hz,1H),3.55–3.47(m,2H),3.13(s,9H),2.55– 2.42(m,2H),2.30(dd,J=11.5,6.1Hz,1H),2.08(dd,J=15.1,10.5Hz,2H),1.86(dd,J=14.0,6.7Hz,2H),1.27(d,J=6.2Hz,6H),1.10–1.05(m,6H).

[0202] Example 19:

[0203] Dissolve 4-bromo-2,5-difluorophenol (2 g, 9.50 mmol, 1 eq.), bromobutane (1 ml, 11.00 mmol, 1.2 eq.), and potassium carbonate (3.9 g, 28.00 mmol, 3 eq.) in acetonitrile (45 mL) and heat under reflux at 90°C with stirring. After 1.5 h, TLC showed the formation of new spots and the disappearance of the starting material. Remove the solvent, extract with ethyl acetate and water, and combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to yield 2.28 g of compound SM51 as a yellow oil (90% yield).

[0204] SM42 (1 g, 3.70 mmol, 1 eq.), trimethylsilylacetylene (446 mg, 4.50 mmol, 1.2 eq.), Pd(PPh3)2Cl2 (265 mg, 0.37 mmol, 0.1 eq.), and CuI (72 mg, 0.37 mmol, 0.1 eq.) were placed in a microwave reaction vial. Triethylamine (15 mL) was added and nitrogen was bubbled in, purging the air. After 15 minutes, the reaction was quickly sealed and microwaved at 90°C for 3 h. After completion of the reaction, no starting material was observed on a TLC plate. The solvent was removed, and the mixture was dissolved in DCM. Column chromatography afforded 992 mg of SM43 as a yellow oil (93% yield).

[0205] SM43 (992 mg, 3.50 mmol, 1 eq.) and potassium carbonate (731 mg, 5.20 mmol, 1.5 eq.) were dissolved in THF (5 mL) and CH3OH (5 mL) and stirred at room temperature overnight. TLC showed that the reaction was complete. The solvent was removed, and the mixture was extracted with water and EA. The organic phase was dried and concentrated to obtain 672 mg of a yellow oil SM44, with a yield of 91%.

[0206] SM44 (672 mg, 3.20 mmol, 1.5 eq.), methyl 6-bromo-2-naphthoate (568 mg, 2.10 mmol, 1 eq.), Pd(PPh3)2Cl2 (150 mg, 0.20 mmol, 0.1 eq.), and CuI (40 mg, 0.20 mmol, 0.1 eq.) were weighed into a microwave reaction vial. Triethylamine (15 mL) was added and nitrogen was bubbled in, purging the air. After 15 minutes, the vial was quickly sealed and microwaved at 90°C for 3 h. After completion of the reaction, no starting material was observed on a TLC plate. The solvent was removed, and the mixture was dissolved in DCM. Column chromatography afforded 635 mg of SM45 as a yellow solid in a 75% yield.

[0207] SM45 (635 mg, 1.60 mmol, 1 eq.) was dissolved in THF (7 mL) and heated with stirring at 70°C. A 1.5 mL aqueous solution of NaOH (258 mg, 6.40 mmol, 4 eq.) was then added to the reaction system. The mixture was heated at reflux at 70°C overnight. After the reaction, 2M HCl (aq.) was added to adjust the pH to acidic. Solids precipitated and were filtered to afford 586 mg of SM46, a yellow solid, in a 95% yield.

[0208] Echinocandin B hydrochloride (300 mg, 0.35 mmol, 1 eq.), SM46 (136 mg, 0.35 mmol, 1 eq.), and CDMT (75 mg, 0.43 mmol, 1.2 eq.) were dissolved in DMF (3.5 mL), followed by the addition of NMM (0.118 mL, 1.07 mmol, 3 eq.). The mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction solution was purified by HPLC to obtain 252 mg of SM47 as a white solid with a purity of 99% and a yield of 60%. MS [M+H] + :1161.

[0209] SM47 (252 mg, 0.20 mmol, 1 eq.) and 3,4-dimethoxyphenylboronic acid (51 mg, 0.28 mmol, 1.3 eq.) were dissolved in dry THF (3 mL) and stirred at room temperature for 1 h. The mixture was concentrated to dryness, and choline p-toluenesulfonate (1.79 g, 6.50 mmol, 30 eq.) was added. A mixture of TFA (0.5 mL) and acetonitrile (3 mL) was then added to dissolve the reactants. The mixture was stirred at room temperature under a nitrogen atmosphere for 5 h. After completion of the reaction, an aqueous solution of sodium acetate was added to quench the reaction. The product was purified by HPLC to give 93 mg of a white solid compound (hydrochloride salt) with a purity of 96% and a yield of 34%. HRMS [M] + :1245.5582.

[0210] 1H NMR(400MHz,CD3OD)δ8.45(s,1H),8.13(s,1H),8.03–7.97(m,3H),7.65(dd, J=8.5,1.4Hz,1H),7.33(dd,J=11.1,6.7Hz,1H),7.15(d,J=8.5Hz,2H),7.03 (dd,J=10.7,7.2Hz,1H),6.76(d,J=8.5Hz,2H),5.42(d,J=2.5Hz,1H),5.04( d,J=3.2Hz,1H),4.79(dd,J=12.0,5.1Hz,1H),4.59(dd,J=10.7,7.2Hz,4H), 4.39(d,J=4.3Hz,1H),4.33(d,J=8.3Hz,2H),4.25(dd,J=8.2,6.4Hz,2H),4. 20–4.16(m,1H),4.10(t,J=6.4Hz,3H),4.00(d,J=11.2Hz,1H),3.95–3.88(m ,2H),3.83(d,J=10.5Hz,1H),3.60(s,1H),3.49(d,J=9.6Hz,2H),3.13(s,9H ),2.53–2.42(m,2H),2.30(s,1H),2.10(d,J=12.1Hz,2H),1.85–1.79(m,2H), 1.54(dd,J=15.1,7.5Hz,2H), 1.27(d,J=6.3Hz,6H), 1.08(d,J=6.9Hz,3H), 1.01(t,J=7.4Hz,3H).

[0211] Example 20:

[0212] 4-Bromo-2,5-difluorophenol (2 g, 9.56 mmol, 1 eq.) was dissolved in acetonitrile (45 mL), and bromohexane (2.01 mL, 14.35 mmol, 1.5 eq.) was added, and finally potassium carbonate (3.969 g, 28.70 mmol, 3 eq.) was added. The mixture was heated to 90°C and refluxed with stirring for 4 h. TLC showed that the reaction was complete. The filtrate was filtered and dried, and extracted with water and EA. The EA was dried to obtain 2.551 g of a transparent liquid crude product SM48, with a yield of 91%.

[0213] SM48 (1 g, 3.41 mmol, 1 eq.) was dissolved in triethylamine (17 mL), and trimethylethynylsilane (0.48 mL, 3.41 mmol, 1 eq.), Pd(PPh3)2Cl2 (239 mg, 0.34 mmol, 0.1 eq.), and CuI (65 mg, 0.34 mmol, 0.1 eq.) were added. The mixture was reacted at 90°C in a microwave oven for 3 h. TLC showed that the reaction was complete and new spots were generated. The mixture was separated and purified by column chromatography to obtain 851 mg of light yellow liquid compound SM49 with a yield of 80%.

[0214] SM49 (851 mg, 2.74 mmol, 1 eq.) was dissolved in MeOH (13 mL) and THF (13 mL), and potassium carbonate (569 mg, 4.11 mmol, 1.5 eq.) was added. The mixture was stirred at room temperature for 3 h. TLC showed that the reaction was complete, new spots were generated, and the starting material disappeared. The mixture was extracted with water and EA, and the EA phase was spin-dried to obtain 578 mg of oily liquid SM50, with a yield of 88%.

[0215] Methyl 6-bromo-2-naphthoate (644 mg, 2.42 mmol, 1 eq.) was dissolved in triethylamine (12 mL), and SM50 (578 mg, 2.42 mmol, 1 eq.), (PPh3)2PdCl2 (170 mg, 0.24 mmol, 0.1 eq.), and CuI (46 mg, 0.24 mmol, 0.1 eq.) were added. The atmosphere was replaced with nitrogen, and the mixture was stirred in a microwave at 90°C for 3 h. TLC showed that new spots were generated and the raw material disappeared. The mixture was separated and purified by column chromatography to obtain 854 mg of yellow solid compound SM51 in a yield of 83%.

[0216] SM51 (854 mg, 2.02 mmol, 1 eq.) was dissolved in THF (10 mL), and NaOH (324 mg, 8.09 mmol, 4 eq.) was dissolved in water (1 mL) and added to the reaction system. The mixture was stirred at 60°C overnight. TLC showed the presence of a product spot. After acidification, a solid precipitated and was filtered and dried to obtain 698 mg of a yellow solid compound SM52 in a yield of 84%.

[0217] SM52 (300 mg, 0.73 mmol, 1 eq.) was dissolved in DMF (7 mL), and echinocandin B hydrochloride (613 mg, 0.73 mmol, 1 eq.) and CDMT (155 mg, 0.88 mmol, 1.2 eq.) were added sequentially. Finally, NMM (0.24 mL, 2.20 mmol, 3 eq.) was added. The mixture was stirred at room temperature for 4 h. HPLC purification was performed to obtain 435 mg of SM53 as a white solid with a purity of 91% and a yield of 50%. HRMS [M+H] + :1210.4887.

[0218] SM53 (335 mg, 0.28 mmol, 1 eq.) was dissolved in dry THF (7 mL), and 3,4-dimethoxyphenylboronic acid (67 mg, 0.36 mmol, 1.3 eq.) was added. After stirring at room temperature for 1 hour, the solvent was removed and dry THF (7 mL) was added and the mixture was spin-dried. Choline chloride (394 mg, 2.82 mmol, 10 eq.) was added. TFA (0.84 mL) and acetonitrile (7 mL) were mixed and added to the system. The mixture was stirred at room temperature for 3 hours. LCMS showed the presence of product. HPLC preparative purification gave 9 mg of the compound (hydrochloride) as a white solid with a purity of 99% and a yield of 2%. HRMS [M] + :1273.5882.

[0219] 1H NMR(400MHz,CD3OD)δ8.45(s,1H),8.12(s,1H),8.01–7.96(m,3H),7.70(d,J =8.2Hz,1H),7.33(dd,J=11.0,6.7Hz,1H),7.15(d,J=8.6Hz,2H),7.02(dd,J =10.8,7.2Hz,1H),6.76(d,J=8.6Hz,2H),5.42(d,J=2.4Hz,1H),5.05(d,J=3 .2Hz,1H),4.79(dd,J=12.1,5.1Hz,1H),4.58(d,J=6.4Hz,3H),4.39(d,J=4.3 Hz,1H),4.33(d,J=8.0Hz,2H),4.27–4.22(m,2H),4.20–4.16(m,1H),4.09(t ,J=6.4Hz,3H),4.00(d,J=11.2Hz,1H),3.94–3.87(m,2H),3.82(d,J=10.9Hz ,1H),3.64–3.46(m,4H),3.13(s,9H),2.53–2.42(m,2H),2.34–2.27(m,1H), 2.08(t,J=13.4Hz,2H),1.84(dd,J=14.3,7.3Hz,2H),1.54–1.48(m,2H),1.38 (dd,J=7.2,3.5Hz,4H),1.27(d,J=6.3Hz,6H),1.07(d,J=6.9Hz,3H),0.94(t,J=7.0Hz,3H).

[0220] Example 21:

[0221] 4-Bromo-2,5-difluorophenol (2 g, 9.56 mmol, 1 eq.) was dissolved in acetonitrile (45 mL), bromoheptane (2.25 mL, 14.35 mmol, 1.5 eq.) was added, and finally potassium carbonate (3.969 g, 28.70 mmol, 3 eq.) was added. The mixture was heated to 90°C and refluxed with stirring for 4 h. TLC showed that the reaction was complete. The filtrate was filtered and dried, and extracted with water and EA. The EA was dried to obtain 2.905 g of a transparent liquid crude product SM54, with a yield of 97%.

[0222] SM54 (1 g, 3.25 mmol, 1 eq.) was dissolved in triethylamine (15 mL), and trimethylethynylsilane (0.46 mL, 3.25 mmol, 1 eq.), Pd(PPh3)2Cl2 (229 mg, 0.32 mmol, 0.1 eq.), and CuI (62 mg, 0.32 mmol, 0.1 eq.) were added. The mixture was reacted at 90°C in a microwave oven for 3 h. TLC showed that the reaction was complete and new spots were generated. The mixture was separated and purified by column chromatography to obtain 740 mg of a light yellow liquid compound SM55 with a yield of 70%.

[0223] SM55 (740 mg, 2.28 mmol, 1 eq.) was dissolved in MeOH (11 mL) and THF (11 mL), and potassium carbonate (473 mg, 3.42 mmol, 1.5 eq.) was added. The mixture was stirred at room temperature for 3 h. TLC showed that the reaction was complete. The mixture was extracted with water and EA, and the EA phase was spin-dried to obtain 495 mg of yellow oily compound SM56, with a yield of 86%.

[0224] Methyl 6-bromo-2-naphthoate (521 mg, 1.96 mmol, 1 eq.) was dissolved in triethylamine (15 mL), and SM56 (495 mg, 1.96 mmol, 1 eq.), (PPh3)2PdCl2 (138 mg, 0.19 mmol, 0.1 eq.), and CuI (37 mg, 0.19 mmol, 0.1 eq.) were added. The atmosphere was replaced with nitrogen, and the mixture was stirred in a microwave at 90°C for 3 h. TLC showed that new spots were generated and the raw material disappeared. The mixture was separated and purified by column chromatography to obtain 584 mg of yellow solid compound SM57 in a yield of 68%.

[0225] SM57 (584 mg, 2.02 mmol, 1 eq.) was dissolved in THF (5 mL), and NaOH (214 mg, 8.09 mmol, 4 eq.) was dissolved in water (1 mL) and added to the reaction system. The mixture was stirred at 60°C for 3 h. TLC showed that the reaction was complete. After acidification, the mixture was filtered and dried to obtain 683 mg of a yellow solid compound SM58 in an 80% yield.

[0226] SM58 (300 mg, 0.73 mmol, 1 eq.) was dissolved in DMF (7 mL). Echinocandin B hydrochloride (593 mg, 0.73 mmol, 1 eq.) and CDMT (150 mg, 0.88 mmol, 1.2 eq.) were added sequentially. Finally, NMM (0.23 mL, 2.20 mmol, 3 eq.) was added. The mixture was stirred at room temperature for 4 h. HPLC purification was performed to obtain 144 mg of SM59 as a white solid with a purity of 91% and a yield of 16%. HRMS [M+Na]+ :1224.4853.

[0227] 1 HNMR(400MHz,CD3OD)δ8.41(s,1H),8.09(s,1H),7.94(dd,J=17.0,5.8Hz,3H),7.62 (d,J=9.9Hz,1H),7.33(dd,J=11.0,6.7Hz,1H),7.15(d,J=8.5Hz,2H),7.02(dd,J=10 .7,7.2Hz,1H),6.76(d,J=8.5Hz,2H),5.39–5.34(m,1H),5.03(d,J=5.6Hz,1H),4.84 (s,1H),4.70(dd,J=11.9,5.2Hz,1H),4.64–4.53(m,3H),4.34(dd,J=18.3,5.2Hz,3H ),4.23(dd,J=12.7,7.0Hz,3H),4.09(t,J=6.4Hz,3H),3.99(d,J=8.1Hz,1H),3.93– 3.80(m,2H),3.41(t,J=9.2Hz,1H),2.58–2.40(m,2H),2.28–2.20(m,1H),2.10(ddd, J=25.0,16.8,8.2Hz,2H),1.87–1.79(m,2H),1.50(dd,J=15.2,7.4Hz,2H),1.43–1.3 2(m,6H),1.28(dd,J=12.2,6.2Hz,6H),1.06(d,J=6.9Hz,3H),0.93(t,J=6.8Hz,3H).

[0228] SM59 (144 mg, 0.11 mmol, 1 eq.) was dissolved in dry THF (3 mL), and 3,4-dimethoxyphenylboronic acid (28 mg, 0.15 mmol, 1.3 eq.) was added. After stirring at room temperature for 1 hour, the solvent was removed and dry THF (7 mL) was added and the mixture was spin-dried. Choline chloride (167 mg, 1.19 mmol, 10 eq.) was added. TFA (0.36 mL) and acetonitrile (3 mL) were mixed and added to the system. The mixture was stirred at room temperature for 3 hours. LCMS showed the presence of product. HPLC preparative purification gave 21 mg of the compound (hydrochloride salt) as a white solid with a purity of 97% and a yield of 13%. HRMS [M] + :1287.5902.

[0229] 1HNMR(400MHz,CD3OD)δ8.43(s,1H),8.10(s,1H),7.98–7.91(m,3H),7.63(dd,J=8.5,1.3Hz,1H),7 .32(dd,J=11.0,6.7Hz,1H),7.15(d,J=8.5Hz,2H),7.02(dd,J=10.8,7.2Hz,1H),6.76(d,J=8.5Hz, 2H),5.44–5.37(m,1H),5.06(dd,J=8.3,3.0Hz,1H),4.79(dd,J=12.1,4.9Hz,1H),4.59(dd,J=11.5 ,6.8Hz,3H),4.39(d,J=4.2Hz,1H),4.37–4.31(m,2H),4.25(dd,J=11.6,3.3Hz,2H),4.22–4.17(m, 1H),4.12(d,J=8.7Hz,1H),4.08(t,J=6.4Hz,2H),3.99(d,J=7.8Hz,2H),3.95–3.88(m,2H),3.82(d ,J=10.8Hz,1H),3.61(dd,J=11.9,7.3Hz,1H),3.55–3.45(m,2H),3.12(s,9H),2.54–2.41(m,2H),2 .29(t,J=8.9Hz,1H),2.08(dd,J=12.0,8.7Hz,2H),1.82(dd,J=14.6,6.6Hz,2H),1.51(dd,J=14.8, 7.1Hz,2H),1.42–1.32(m,6H),1.27(d,J=6.1Hz,6H),1.07(d,J=6.9Hz,3H),0.92(t,J=6.8Hz,3H).

[0230] Example 22:

[0231] 4-Bromo-2,3-difluorophenol (2 g, 9.50 mmol, 1 eq.), 1-bromooctane (1.98 ml, 11.00 mmol, 1.2 eq.), and potassium carbonate (4 g, 28.00 mmol, 3 eq.) were dissolved in acetonitrile (47 mL) and heated under reflux at 90°C with stirring. After 1.5 h, TLC showed the formation of new spots and the disappearance of the starting material. The solvent was removed, and the mixture was extracted with ethyl acetate and water. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to yield 3 g of compound SM60 as a black oil (97% yield).

[0232] SM6 (2 g, 9.50 mmol, 1 eq.), SM60 (3 g, 9.50 mmol, 1 eq.), and CuI (550 mg, 0.47 mmol, 0.05 eq.) were dissolved in 1,4-dioxane (10 mL). DIPEA (3.3 mL, 19.00 mmol, 3 eq.) was then added. Vacuum and nitrogen were replaced three times. Pd(PPh3)2Cl2 (550 mg, 0.47 mmol, 0.05 eq.) was added under a nitrogen atmosphere. The mixture was heated and stirred at 80°C overnight. TLC revealed a distinct new spot. The solvent was removed, and the mixture was dissolved in DCM and purified by column chromatography to obtain 681 mg of SM61 as a white solid in a 16% yield.

[0233] SM61 (681 mg, 1.50 mmol, 1 eq.) was dissolved in THF (6 mL) and heated with stirring at 60°C. A 1 mL solution of NaOH (242 mg, 6.00 mmol, 5 eq.) was added to the reaction system. The mixture was heated under reflux at 75°C overnight. After the reaction, 2M HCl (aq.) was added to adjust the pH to acidic. Solid precipitated and was filtered to obtain 595 mg of SM62 as a white solid (89% yield).

[0234] Echinocandin B hydrochloride (600 mg, 0.71 mmol, 1 eq.), SM62 (315 mg, 0.71 mmol, 1 eq.), and CDMT (40 mg, 0.22 mmol, 1.2 eq.) were dissolved in DMF (2 mL), followed by the addition of NMM (0.06 mL, 0.57 mmol, 3 eq.). The mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction solution was purified by HPLC to obtain 579 mg of SM63 as a white solid with a purity of 96% and a yield of 57%. MS [M+H] + :1216.

[0235] SM63 (337 mg, 0.27 mmol, 1 eq.) and 3,4-dimethoxyphenylboronic acid (65 mg, 0.36 mmol, 1.3 eq.) were dissolved in dry THF (4 mL), stirred at room temperature for 1 h, and concentrated to dryness. Choline p-toluenesulfonate (2.3 g, 8.30 mmol, 30 eq.) was added, followed by a mixture of TFA (0.85 mL) and acetonitrile (4 mL) to dissolve the reactants. The mixture was stirred at room temperature under a nitrogen atmosphere for 6 h. After completion of the reaction, an aqueous solution of sodium acetate was added to quench the reaction. The product was purified by HPLC to give 197 mg of a white solid compound (acetate salt) with a purity of 95% and a yield of 54%. HRMS [M] + :1301.6172.

[0236] 1 HNMR(400MHz,CD3OD)δ8.46(s,1H),8.14(s,1H),8.04–7.97(m,3H),7.66(dd,J=8.4,1.4H z,1H),7.34–7.30(m,1H),7.15(d,J=8.5Hz,2H),6.97(d,J=7.5Hz,1H),6.76(d,J=8.6Hz,2 H),5.42(d,J=2.4Hz,1H),5.04(d,J=3.2Hz,1H),4.79(dd,J=12.0,5.1Hz,2H),4.61–4.56 (m,3H),4.39(d,J=4.3Hz,1H),4.33(d,J=8.2Hz,2H),4.27–4.22(m,2H),4.20–4.16(m,1H) ,4.13(t,J=6.4Hz,3H),4.00(d,J=11.4Hz,1H),3.94–3.87(m,2H),3.83(d,J=11.4Hz,1H) ,3.60(d,J=4.9Hz,1H),3.52–3.46(m,2H),3.13(s,9H),2.52–2.43(m,2H),2.30(t,J=9.0H z,1H),2.08(dd,J=15.4,9.4Hz,2H),1.89(s,3H),1.86–1.81(m,2H),1.50(d,J=8.0Hz,2H ),1.35(d,J=16.1Hz,8H),1.29–1.26(m,6H),1.08(d,J=6.9Hz,3H),0.91(t,J=6.9Hz,3H).

[0237] Example 23:

[0238] N-methyl-D-prolinol (3 g, 26.04 mmol, 1 eq.) was dissolved in acetone (30 mL), and methyl p-toluenesulfonate (4.851 g, 26.04 mmol, 1 eq.) was slowly added. The mixture was refluxed at 60°C for 3 h. LCMS showed that most of the product was produced. Solids precipitated after adding petroleum ether. The product was filtered, and the filter cake was washed with petroleum ether and dried to obtain 6.69 g of product SM64 in a yield of 85%.

[0239] Example 15 (300 mg, 0.25 mmol, 1 eq.) was dissolved in dry THF (3 mL), and 3,4-dimethoxyphenylboronic acid (60 mg, 0.33 mmol, 1.3 eq.) was added. After stirring at room temperature for 1 hour, the solvent was evaporated and dry THF (3 mL) was added and dried. SM64 (2.308 g, 7.66 mmol, 30 eq.) was added. TFA (0.75 mL) and dry MeCN (3 mL) were mixed and added to the system. The system was stirred at room temperature for 3 hours. LCMS showed the presence of product. HPLC preparative purification gave 40 mg of the compound (hydrochloride) as a white solid with a purity of 88% and a yield of 12%. HRMS [M] + :1285.5715.

[0240] 1 H NMR(400MHz,CD3OD)δ8.45(s,1H),8.12(s,1H),8.03–7.95(m,3H),7.65(d,J=8.6Hz, 1H),7.33(dd,J=11.0,6.7Hz,1H),7.15(d,J=8.5Hz,2H),7.02(dd,J=10.7,7.2Hz,1H ),6.76(d,J=8.5Hz,2H),5.42(d,J=6.8Hz,1H),5.04(d,J=5.3Hz,1H),4.80(s,1H),4 .60(d,J=12.0Hz,3H),4.39(d,J=4.2Hz,1H),4.34(d,J=8.0Hz,2H),4.27(dd,J=13.1, 6.3Hz,2H),4.21–4.17(m,1H),4.09(t,J=6.4Hz,3H),4.00(d,J=8.8Hz,2H),3.87(dt ,J=16.9,9.4Hz,4H),3.62–3.46(m,3H),3.20(s,3H),2.99(s,3H),2.55–2.41(m,2H) ,2.34–2.21(m,2H),2.14–2.03(m,4H),1.97–1.89(m,1H),1.87–1.80(m,2H),1.51–1 .40(m,4H),1.27(dd,J=6.1,3.3Hz,6H),1.08(d,J=6.9Hz,3H),0.97(t,J=7.1Hz,3H).

[0241] Example 24:

[0242] SM47 (50 mg, 0.04 mmol, 1 eq.) and 3,4-dimethoxyphenylboronic acid (10 mg, 0.05 mmol, 1.3 eq.) were dissolved in dry THF (1 mL), stirred at room temperature for 1 h, and then concentrated to dryness. SM64 (389 mg, 1.2 mmol, 30 eq.) was added, followed by a mixture of TFA (0.1 mL) and CH3CN (2 mL) to dissolve the reactants. The mixture was stirred at room temperature under a nitrogen atmosphere for 5 h. After completion of the reaction, an aqueous solution of sodium acetate was added to quench the reaction. The product was purified by HPLC to give 25 mg of a white solid compound (hydrochloride salt) with a purity of 90% and a yield of 45%. HRMS [M] + :1271.5322.

[0243] 1 H NMR(400MHz,CD3OD)δ8.46(s,1H),8.13(s,1H),8.05–7.94(m,3H),7.65(dd,J=8.5,1.5 Hz,1H),7.33(dd,J=11.0,6.7Hz,1H),7.15(d,J=8.6Hz,2H),7.03(dd,J=10.8,7.2Hz,1 H),6.76(d,J=8.6Hz,2H),5.41(s,1H),5.07–5.01(m,1H),4.79(dd,J=11.8,5.2Hz,2H) ,4.59(dd,J=10.8,7.4Hz,3H),4.39(d,J=4.3Hz,1H),4.36–4.30(m,2H),4.30–4.22(m, 2H),4.21–4.15(m,1H),4.10(t,J=6.4Hz,3H),4.00(d,J=8.4Hz,2H),3.93–3.79(m,4H) ,3.67–3.41(m,4H),3.20(s,3H),2.99(s,3H),2.54–2.41(m,2H),2.34–2.20(m,2H),2. 09(t,J=10.7Hz,3H),1.97–1.88(m,1H),1.82(dt,J=12.4,6.4Hz,2H),1.54(dq,J=14.8 ,7.4Hz,2H),1.27(dd,J=6.2,3.0Hz,6H),1.08(d,J=6.9Hz,3H),1.01(t,J=7.4Hz,3H).

[0244] Test Example 1: Antifungal Activity Test Method

[0245] After serial dilution of the test compound, MIC assays were performed against Candida albicans standard strains, and MEC assays were performed against Aspergillus standard strains. Minimum inhibitory concentration (MIC) assays were performed according to the Clinical Laboratory Standards Institute (CLSIM27-A3) guidelines, and minimum effective concentration (MEC) assays were performed according to the Clinical Laboratory Standards Institute (CLSIM38-A2) guidelines.

[0246] Fungal inoculum preparation

[0247] Candida:

[0248] 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.

[0249] 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.

[0250] Aspergillus (operation is carried out in a Class II biosafety cabinet):

[0251] Subculture Aspergillus onto SDA plates and culture at 35°C for 48 h to 7 d to induce spore formation. Overlay the colonies on the plates with 0.85% saline (1 mL) or sterile water (add polysorbate 20 to a final concentration of 0.1% to 0.01%). Gently wipe the surface of the culture medium with a sterile cotton swab (be careful not to puncture the culture medium) and transfer the resuspended spore mycelium to a sterile test tube. Let it sit for 3 to 5 min to allow the heavier particles to settle. Transfer the homogenized upper layer of the suspension to a new sterile test tube, secure the cap, and vortex for 15 s (note: the suspension may produce aerosols when the cap is reopened). Use a spectrophotometer to increase the suspension concentration to an OD value of 0.09 to 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).

[0252] Colony count: Dilute the suspension diluted with RPMI 1640 10-fold, apply 10 μL to SDA plates, culture at 28°C and observe daily. Count colonies immediately after visible colonies appear.

[0253] nourish

[0254] 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 Aspergillus plate at 28°C and read the MEC value after 21-26 hours.

[0255] MIC or MEC interpretation

[0256] 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.

[0257] Aspergillus: For the 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 seen on a microplate reader. To accurately determine the MEC, do not vortex the plate before reading.

[0258] Table 1 Antibacterial activity test results of compounds

[0259] Note: 1. Candida parapsilosis ATCC 22019 and Candida krusei ATCC 6258 are quality control strains. According to CLSI-M60, the 24-hour MIC of caspofungin against ATCC 22019 is 0.25-1 μg / mL, and the 24-hour MIC of caspofungin against ATCC 6258 is 0.12-1 μg / mL.

[0260] Table 2 Antibacterial activity test results of compounds

[0261] Table 3 Antibacterial activity test results of compounds

[0262] Table 4 Antibacterial activity test results of compounds

[0263] Experimental Example 2: Study on Pharmacokinetic Properties in Rats

[0264] SPF SD rats were used as test animals to study the pharmacokinetic properties of razafungin, Example 16 and Example 19 in rat plasma after intravenous administration.

[0265] Table 5 Experimental plan for the study of pharmacokinetic properties in rats

[0266] Pharmacokinetic parameters are shown in the table below

[0267] Table 6 Pharmacokinetic parameters in rats

[0268] The experimental data showed that after a single intravenous injection of Example 16 and Example 19 at the same dose, the plasma drug exposure level (Cmax and AUC) and half-life (T 1 / 2 ) is significantly higher than that of razafungin, providing a new option for clinical medication.

Claims

1. A compound as shown in formula I or a pharmaceutically acceptable salt thereof, characterized in that: Wherein, X, Y, and Z are independently selected from C; R1 is selected from one of the following structures: R2, R3, R4, R5, R6, R8, R9, R 10 , R 11 and R 12 are independently selected from hydrogen, deuterium, halogen, cyano, thiocyano, isothiocyano and C 1-10 Lower alkyl; R7 is selected from C 1-10 Lower alkyl.

2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R1 is selected from one of the following structures:

3. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R7 is selected from C 3-6 Lower alkyl.

4. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R7 is selected from n-butyl or n-pentyl.

5. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound structural formula is as follows:

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

7. The use according to claim 6, characterized in that The medicine is a medicine for treating or preventing fungal infection or a disease caused by fungal infection.

8. The use according to claim 6, characterized in that: The fungus is selected from one or more organisms of the following genera: 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.

9. The use according to claim 7, characterized in that: The disease caused by fungal infection is selected from scalp ringworm, body ringworm, tinea pedis, onychomycosis, perionychia, psoriasis, thrush, vaginal candidiasis, respiratory tract candidiasis, biliary tract candidiasis, esophageal candidiasis, urethral candidiasis, systemic candidiasis, mucosal and skin candidiasis, aspergillosis, mucormycosis, paracoccidioidomycosis, North American blastomycosis, histoplasmosis, coccidioidomycosis, sporotrichosis, fungal sinusitis or chronic paranasal inflammation.

10. The use according to claim 7, characterized in that: The disease caused by fungal infection is selected from candidemia and invasive candidiasis.

11. An antifungal pharmaceutical composition, characterized in that: It comprises the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

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