Use of echinocandin compound against tumor

Abstract

Disclosed is use of a compound represented by formula I or a pharmaceutically acceptable salt or an isomer thereof in preparing an anti-tumor drug. The compound has good anti-tumor activity and thus can be effectively used for treating various tumors.

Description

Anti-tumor uses of echinocandin compounds Technical Field

[0001] The present invention relates to a new use of an echinocandin compound and belongs to the field of medicinal chemistry. Background Art

[0002] Echinocandins are a new class of antifungal drugs that non-competitively inhibit β-1,3-glucose synthase, interfering with the synthesis of β-1,3-glucose in the fungal cell wall. This alters the permeability of the fungal cell wall and leads to cell lysis and death. Because human cells lack cell walls, while fungal cells do, echinocandins can act directly on the fungal cell wall. This allows them to have low toxicity to humans, making them the safest class of antifungal drugs to date.

[0003] Echinocandins have a unique mechanism of action, with a broad antibacterial spectrum, strong antifungal effect, long half-life, few and mild adverse reactions, and good patient tolerance. They can be used as potential additive or synergistic drugs and good alternative drugs for polyolefins and azoles, and are worthy of clinical promotion and use.

[0004] The inventors previously developed a new type of echinocandin drug with good antifungal activity.

[0005] However, it is not yet known whether this type of compound has other physiological activities. Summary of the Invention

[0006] According to research findings, the new echinocandin drugs studied by the inventors also have good anti-tumor activity.

[0007] Based on this research, the present invention proposes the use of a compound as shown in Formula I or a pharmaceutically acceptable salt or an isomer thereof in the preparation of an anti-tumor drug:

[0008] wherein X, Y, and Z are independently selected from C and N;

[0009] 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;

[0010] R7 is selected from C 1-10 Lower alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl;

[0011] 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,

[0012] R A1 、R A2 、R A3 and R A4 independently selected from hydrogen, deuterium, halogen, lower alkyl, cycloalkyl and cycloalkylene

[0013] X1 is independently N(R C1 R C2 R C3 ) or the following structure

[0014] Ring A is an optionally substituted, saturated or unsaturated monocyclic or condensed ring containing one or more N atoms,

[0015] R C1 、R C2 and RC3 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,

[0016] 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"),

[0017] X2 is N(R D1 R D2 R D3 ) or X1 structure,

[0018] 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,

[0019] R' and R" are independently selected from hydrogen, hydroxy, alkyl, alkoxy, alkenyl and -C(O)R J ,

[0020] R J Selected from hydrogen, deuterium, C 1-10 Lower alkyl, cycloalkyl and cycloalkylene groups,

[0021] 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.

[0022] Further, R1 is selected from O(C(R A1 )(R A2 )) a (C(R A3 )(R A4 )) j X1、NH(C(R A1 )(R A2 )) a(C(R A3 )(R A4 )) j X1, O(CH2CH2O) b CH2CH2X1, O(CH2CH2CH2O) b CH2CH2X1, O(CH2CH2NH) b CH2CH2X1, NH(CH2CH2O) b CH2CH2X1, NH(CH2CH2NH) b CH2CH2X1, NH(CH2CH2CH2O) b CH2CH2X1, NH[(CH2(CH2) c O)] b CH{CH2[OCH2(CH2) c ] d X1}2、O[(CH2(CH2) c O)] b CH{CH2[OCH2(CH2) c ] d X1}2 and (OCH2CH2) b (NHCH2CH2) e X2,

[0023] R A1 、R A2 、R A3 and R A4 independently selected from hydrogen, deuterium, halogen, lower alkyl, cycloalkyl and cycloalkylene

[0024] X1 is independently N(R C1 R C2 R C3 ) or the following structure

[0025] Ring A is an optionally substituted, saturated or unsaturated monocyclic or condensed ring containing one or more N atoms,

[0026] 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 C2 and R C3 At least one of them is not hydrogen,

[0027] Each R Fare 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,

[0028] X2 is N(R D1 R D2 R D3 ) or X1 structure,

[0029] 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,

[0030] R' and R" are independently selected from hydrogen, hydroxy, alkyl, alkoxy, alkenyl and -C(O)R J ,

[0031] R J Selected from hydrogen, C 1-10 Lower alkyl, cycloalkyl and cycloalkylene groups,

[0032] 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.

[0033] Furthermore, X1 is selected from the following structures:

[0034] 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,

[0035] R q1 and R q2 are independently H or C 1-6 lower alkyl, which is optionally substituted with one or more substituents selected from deuterium, alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxy, halogen, SR', NR'(R"), COOR' and CONR'(R"),

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

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

[0038] 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.

[0039] In the present invention, R1 is selected from hydroxyl, hydrogen, deuterium or one of the following structures:

[0040] Furthermore, R1 is selected from hydroxyl, hydrogen or one of the following structures:

[0041] Furthermore, R1 is selected from hydroxyl or one of the following structures:

[0042] Further, R7 is selected from C 3-6 Lower alkyl group: The lower alkyl group may be a straight chain alkyl group.

[0043] Furthermore, R7 is selected from n-butyl or n-pentyl.

[0044] In the present invention, the compound structural formula can be selected from the following:

[0045] The tumor is selected from one or more of breast cancer, liver cancer, lung cancer, leukemia, pancreatic cancer, brain tumor, kidney cancer, melanoma, ovarian cancer, colorectal cancer, gastric cancer, thyroid cancer, esophageal cancer, cervical cancer, and prostate cancer.

[0046] Wherein, the leukemia includes at least one of acute myeloid leukemia, chronic myeloid leukemia, and acute lymphocytic leukemia.

[0047] The present invention also provides a method for treating a tumor in a patient by administering a sufficient amount of the medicament of the present invention to the patient.

[0048] "Sufficient amount" refers to the amount of drug required to treat the tumor. The sufficient amount for practicing the present disclosure to achieve therapeutic efficacy varies depending on the mode of administration, the type of tumor, the age, weight and general health of the patient.

[0049] The term "treatment" refers to administering a pharmaceutical composition for therapeutic purposes. "Treatment of a disease" refers to treating a patient already suffering from a disease to improve and / or stabilize the patient's condition, or to prolong the life of a tumor patient.

[0050] In the present invention, the anti-tumor drug includes the above-mentioned compound or its pharmaceutically acceptable salt or isomer.

[0051] The pharmaceutical composition may contain pharmaceutically acceptable excipients.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] 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.

[0058] 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.

[0059] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0060] 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.

[0061] 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.

[0062] 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.

[0063] 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).

[0064] 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.

[0065] Functional group isomers produced by the rapid movement of an atom in a molecule between two positions are called tautomers.

[0066] 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.

[0067] A racemate is an equimolar mixture of an optically active chiral molecule (see chirality) and its enantiomers.

[0068] 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.

[0069] Diastereoisomers are stereoisomers that have two or more chiral centers and are not mirror images of each other.

[0070] "Independently selected" means that the variable groups at each occurrence are independently selected from the defined substituents.

[0071] "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.

[0072] 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.

[0073] "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.

[0074] "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.

[0075] "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.

[0076] "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.

[0077] "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.

[0078] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0079] "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.

[0080] Typical heterocycloalkyl groups include, but are not limited to:

[0081] "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.

[0082] Typical heteroaryl groups include, but are not limited to: DETAILED DESCRIPTION

[0083] 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.

[0084] 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.

[0085] HPLC purity analysis method:

[0086] LC-MS analysis method:

[0087] Example 1:

[0088] 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.

[0089] 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.

[0090] 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.

[0091] 1H 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=8.6 Hz,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).

[0092] Example 2:

[0093] 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.

[0094] 1H 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).

[0095] Example 3:

[0096] 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.

[0097] 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.

[0098] 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.

[0099] 1 H 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).

[0100] Example 4:

[0101] 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.

[0102] 1 H NMR(400MHz,CD3OD)δ8.48(d,J=8.6Hz,1H),8.19(dd,J=18.6,8.8Hz,3H),7.91 (d,J=10.4Hz,1H),7.51(d,J=8.7Hz,2H),7.15(d,J=8.6Hz,2H),6.96(d,J=8.7H z,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).

[0103] Example 5:

[0104] 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.

[0105] 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%).

[0106] 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).

[0107] 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.

[0108] 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.

[0109] 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.

[0110] 1H 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).

[0111] Example 6:

[0112] 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%.

[0113] 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.

[0114] 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.

[0115] 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.

[0116] 1H NMR (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).

[0117] Example 7:

[0118] 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).

[0119] 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. Heat and stir 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 afford SM14 (101 mg) as a white solid in an 11% yield.

[0120] 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.

[0121] 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.

[0122] 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).

[0123] Example 8:

[0124] 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 sodium acetate solution was added to quench the reaction. The product was purified by HPLC to give 74 mg of the compound (hydrochloride) as a white solid with a purity of 95% and a yield of 19%. HRMS [M] + :1259.5431.

[0125] 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).

[0126] Example 9:

[0127] 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%.

[0128] 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%.

[0129] 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.

[0130] 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.

[0131] 1H NMR(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=14.6,4.8H z,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).

[0132] Example 10:

[0133] 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.

[0134] 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).

[0135] Example 11:

[0136] 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).

[0137] 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.

[0138] 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%.

[0139] 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.

[0140] 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,4 H), 1.28 (dd, J = 12.5, 6.3Hz, 6H), 1.06 (d, J = 6.9Hz, 3H), 0.97 (t, J = 7.2Hz, 3H).

[0141] Example 12:

[0142] 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.

[0143] 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).

[0144] Example 13:

[0145] 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%.

[0146] 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%.

[0147] 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%.

[0148] 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%.

[0149] 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%.

[0150] 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.

[0151] 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).

[0152] Example 14:

[0153] 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.

[0154] 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).

[0155] Example 15:

[0156] 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%.

[0157] 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%.

[0158] 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%.

[0159] 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%.

[0160] 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%.

[0161] 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.

[0162] 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).

[0163] Example 16:

[0164] 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.

[0165] 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).

[0166] Example 17:

[0167] 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%.

[0168] 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%.

[0169] 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%.

[0170] 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.

[0171] 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.

[0172] 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).

[0173] Example 18:

[0174] 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).

[0175] 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).

[0176] 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%.

[0177] 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.

[0178] 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.

[0179] 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.

[0180] 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) and stirred at room temperature for 1 h. The mixture was concentrated to dryness, and choline p-toluenesulfonate (1.7 g, 6.10 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 the reaction was completed, an aqueous sodium acetate solution 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.

[0181] 1H NMR(400MHz,CD3OD)δ8.45(s,1H),8.13(s,1H),8.02–7.96(m,3H),7.65(d,J=8.4 Hz,1H),7.33(dd,J=11.0,6.7Hz,1H),7.15(d,J=8.4Hz,2H),7.03(dd,J=10.7,7.2 Hz,1H),6.76(d,J=8.5Hz,2H),5.42(s,1H),5.05(d,J=2.9Hz,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,1H),4.11(s,1H),4.06(t,J=6.4Hz,3H),4.0 0(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).

[0182] Example 19:

[0183] 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).

[0184] 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).

[0185] 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%.

[0186] 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.

[0187] 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.

[0188] 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.

[0189] 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.

[0190] 1H NMR(400MHz,CD3OD)δ8.45(s,1H),8.13(s,1H),8.03–7.97(m,3H),7.65(dd,J=8.5,1.4H z,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),4.2 5(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).

[0191] Example 20:

[0192] 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%.

[0193] 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%.

[0194] 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%.

[0195] 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%.

[0196] 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%.

[0197] 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.

[0198] 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.

[0199] 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),6.7 6(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=4.3Hz,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).

[0200] Example 21:

[0201] 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%.

[0202] 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%.

[0203] 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%.

[0204] 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%.

[0205] 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.

[0206] 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.

[0207] 1 H NMR (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).

[0208] 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 dried by spin drying. Choline chloride (167 mg, 1.19 mmol, 10 eq.) was added, and a mixture of TFA (0.36 mL) and acetonitrile (3 mL) was 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) as a white solid with a purity of 97% and a yield of 13%. HRMS [M] + :1287.5902.

[0209] 1H NMR (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,2 H),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,1 H),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).

[0210] Example 22:

[0211] 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).

[0212] 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.

[0213] 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).

[0214] 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.

[0215] 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) and stirred at room temperature for 1 h. The mixture was concentrated to dryness, and choline p-toluenesulfonate (2.3 g, 8.30 mmol, 30 eq.) was added. A mixture of TFA (0.85 mL) and acetonitrile (4 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 197 mg of a white solid compound (acetate salt) with a purity of 95% and a yield of 54%. HRMS [M] + :1301.6172.

[0216] 1 H NMR(400MHz,CD3OD)δ8.46(s,1H),8.14(s,1H),8.04–7.97(m,3H),7.66(dd,J=8.4,1.4Hz ,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).

[0217] Example 23:

[0218] 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%.

[0219] 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.

[0220] 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).

[0221] Example 24:

[0222] 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.

[0223] 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).

[0224] Test Example 1: Antitumor Activity Test Method

[0225] Tumor cell lines: human lung cancer cells A549, human breast cancer cells HCC1806, human liver cancer cells HepG2, human liver cancer cells HuH7, human gastric cancer cells AGS, human gastric cancer cells MKN74, human breast cancer cells MDA-MB-231, and human colon cancer cells HT-29.

[0226] Cell culture method: HepG2, HuH7, and MDA-MB-231 cells were cultured in DMEM medium (containing 10% fetal bovine serum, 100 U / mL penicillin and streptomycin); HCC1806 and MKN74 cells were cultured in 1640 medium (containing 10% fetal bovine serum, 100 U / mL penicillin and streptomycin); HT-29 cells were cultured in McCoy's 5A medium (containing 10% fetal bovine serum, 100 U / mL penicillin and streptomycin); A549 cells were cultured in Ham's F-12K medium (containing 10% fetal bovine serum, 100 U / mL penicillin and streptomycin); AGS cells were cultured in Ham's F-12 medium (containing 10% fetal bovine serum, 100 U / mL penicillin and streptomycin). When the cell confluence reached 90%, trypsin was used for digestion. When the cells shrank and became round and the intercellular spaces were obvious, the digestion was immediately terminated with culture medium. The cells were broken up and blown evenly into a single suspension state, divided into bottles and passaged, and cultured in a cell culture incubator at 37°C with 5% CO2. Subsequent experiments were carried out using cells in the logarithmic growth phase.

[0227] Example 19 was divided into multiple concentration groups, with the concentrations in the cancer cells being 0.14, 0.4, 1.2, 3.7, 11.1, 33.3, and 100 μM, respectively. A vehicle control group and a blank control group were set up. The blank control group received only the same volume of culture medium and was treated for 72 hours. Cell viability was assessed using a CCK-8 assay to evaluate the inhibitory effect of the drug on tumor cell growth.

[0228] Example 19 Inhibitory Effect on Tumor Cell Growth

[0229] Experiments have shown that the compounds of the present invention have good inhibitory activity against the above-mentioned tumor cells and can be effectively used in the treatment of tumor patients.

Claims

1. Use of a compound represented by formula I, or a pharmaceutically acceptable salt thereof, or an isomer thereof, in the preparation of an anti-tumor drug: Among them, X, Y, and Z are each independently selected from C and N; R2, R3, R4, R5, R6, R8, R9, R 10 , R 11 and R 12 are each independently selected from hydrogen, deuterium, halogen, cyano, thiocyano, isothiocyano, and C 1-10 lower alkyl; R7 is selected from C 1-10 lower alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group; R1 is selected from the group consisting of 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,​​ R A1 、R A2 、R A3 and R A4 are independently selected from hydrogen, deuterium, halogen, C 1-10 lower alkyl, cycloalkyl and cycloalkylene X1 is independently N(R C1 R C2 R C3 ) or has the following structure Ring A is an optionally substituted, saturated or unsaturated monocyclic or fused ring containing one or more N atoms; R C1 、R C2 and R C3 are independently selected from H, C 1-6 alkyl, halo-C 1-6 lower alkyl, and deuterated C 1-6 lower alkyl, and at least one of R C1 、R C2 and R C3 is not hydrogen Each R F is independently selected from H, deuterium, hydroxyl, hydroxyalkyl, amino, alkoxy, lower alkyl, alkenyl, alkynyl, halogen, SR', SOR', SO2R', NR'(R"), COOR' and CONR'(R"), where the lower alkyl is optionally substituted with one or more substituents selected from deuterium, alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxyl, halogen, SR', NR'(R"), COOR' and CONR'(R") X2 is N(R D1 R D2 R D3 ) or the X1 structure 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, R' and R” are independently selected from hydrogen, hydroxy, alkyl, alkoxy, alkenyl and -C(O)R J , R J selected from hydrogen, deuterium, C 1-10 lower alkyl, cycloalkyl and cycloalkylene, a is an integer from 0 to 5, b is an integer from 1 to 5, c is an integer from 1 to 2, d is an integer from 0 to 3, e is an integer from 1 to 5, k is an integer from 0 to 20, j is an integer from 0 to 5, and n is an integer from 1 to 7.

2. The use according to claim 1, wherein: R1 is selected from O(C(R A1 )(R A2 )) a (C(R A3 )(R A4 )) j X1, NH(C(R A1 )(R A2 )) a (C(R A3 )(R A4 )) j X1, O(CH2CH2O) b CH2CH2X1, O(CH2CH2CH2O) b CH2CH2X1, O(CH2CH2NH) b CH2CH2X1, NH(CH2CH2O) b CH2CH2X1, NH(CH2CH2NH) b CH2CH2X1, NH(CH2CH2CH2O) b CH2CH2X1, NH[(CH2(CH2) c O)] b CH{CH2[OCH2(CH2) c d X1}2, O[(CH2(CH2) c O)] b CH{CH2[OCH2(CH2) c d X1}2 and (OCH2CH2) b (NHCH2CH2) e X2,​​ R A1 、R A2 、R A3 and R A4 are independently selected from hydrogen, deuterium, halogen, C 1-10 lower alkyl, cycloalkyl and cycloalkylene X1 is independently N(R C1 R C2 R C3 ) or has the following structure Ring A is an optionally substituted, saturated or unsaturated monocyclic or fused ring containing one or more N atoms; R C1 、R C2 and R C3 are independently selected from H, halo C 1-6 lower alkyl, and deuterated C 1-6 lower alkyl, and at least one of R C1 、R C2 and R C3 is not hydrogen Each R F is independently selected from H, deuterium, hydroxyl, hydroxyalkyl, amino, alkoxy, lower alkyl, alkenyl, alkynyl, halogen, SR', SOR', SO2R', 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 X2 is N(R D1 R D2 R D3 ) or the X1 structure, R D1 、R D2 and R D3 are independently selected from H, C1-6 lower alkyl, halo C1-6 lower alkyl, and deuterated C1-6 lower alkyl, R' and R” are independently selected from hydrogen, hydroxy, alkyl, alkoxy, alkenyl, and -C(O)R J , R J selected from hydrogen, C 1-10 lower alkyl, cycloalkyl and cycloalkylene, a is an integer from 0 to 5, b is an integer from 1 to 5, c is an integer from 1 to 2, d is an integer from 0 to 3, e is an integer from 1 to 5, k is an integer from 0 to 20, j is an integer from 0 to 5, and n is an integer from 1 to 7.

3. The use according to claim 1, wherein: X1 is selected from the following structures: wherein each R F is independently selected from H, deuterium, hydroxyl, hydroxyalkyl, amino, alkoxy, lower alkyl, alkenyl, alkynyl, halogen, SR', SOR', SO2R', NR'(R”), COOR' and CONR'(R”), wherein the lower alkyl is optionally substituted with one or more substituents selected from deuterium, alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl R q1 and R q2 are independently H or C 1-6 lower alkyl, said lower alkyl optionally being substituted by one or more substituents selected from deuterium, alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxy, halogen, SR', NR'(R"), COOR' and CONR'(R") R' and R” are independently selected from hydrogen, hydroxy, alkyl, alkoxy, alkenyl and -C(O)R J , R J selected from hydrogen, deuterium, C 1-10 lower alkyl, cycloalkyl and cycloalkylene, f is an integer from 0 to 16, g is an integer from 0 to 16, h is an integer from 0 to 9, i is an integer from 0 to 4, n is an integer from 1 to 7, and p is an integer from 1 to 3.

4. The use according to claim 1, wherein: R1 is selected from a hydroxyl group, hydrogen, deuterium, or one of the following structures:

5. The use according to claim 4, characterized in that: R1 is selected from a hydroxyl group, hydrogen, or one of the following structures:

6. The use according to claim 4, wherein: R1 is selected from a hydroxyl group or one of the following structures:

7. The use according to claim 1, characterized in that: R7 is selected from C 3-6 lower alkyl.

8. The use according to claim 1, characterized in that: R7 is selected from n-butyl or n-pentyl.

9. The use according to claim 1, characterized in that: The structural formula of the said compound is as follows:

10. The use according to claim 1, characterized in that, The tumor is selected from one or more of breast cancer, liver cancer, lung cancer, leukemia, pancreatic cancer, brain tumor, kidney cancer, melanoma, ovarian cancer, colorectal cancer, gastric cancer, thyroid cancer, esophageal cancer, cervical cancer, and prostate cancer.

11. The use according to claim 1, characterized in that, The tumor is selected from tumors with simultaneous fungal infections.

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