Echinocandin derivative compounds and uses thereof

Abstract

The application belongs to the technical field of medicine, and relates to a echinocandin derivative compound and application thereof. The compound is a compound as shown in formula I or stereoisomers, optical isomers, pharmaceutically acceptable salts thereof, wherein, in formula I, X is a peptide compound with formula II, and Y is a linear or branched acyl group with 6-20 carbon atoms. The compound provided by the application can significantly improve water solubility, maintain good antifungal activity, and has lower toxic side effects.

Description

Technical Field

[0001] This invention relates to the field of biomedicine technology, specifically to an echinocandin derivative compound and its uses, and more particularly to an echinocandin derivative in which a short peptide replaces the aromatic ring structure in an echinocandin drug, its preparation method, and its pharmaceutical uses. Background Technology

[0002] Invasive fungal infections (IFIs) are a major cause of morbidity and mortality in immunocompromised patients, commonly seen in cancer patients undergoing chemotherapy, organ transplant recipients, patients on long-term immunosuppressant therapy, and HIV / AIDS patients. The incidence of IFIs continues to rise, highlighting the urgent need for safe and effective novel antifungal drugs.

[0003] Echinocandins are important antifungal drugs used clinically. They exert their antifungal effect by inhibiting β-1,3-glucan synthase, thus blocking the synthesis of β-1,3-glucan in the fungal cell wall. Currently marketed echinocandins include caspofungin, micafungin, and anidulafungin. These drugs have advantages such as a unique mechanism of action, a broad antifungal spectrum, low toxicity, and few drug interactions, making them first-line drugs for treating invasive candidiasis and aspergillosis.

[0004] However, existing echinocandins still have certain limitations. Some drugs have poor water solubility, often requiring organic solvents or other solubilizing systems during formulation development. This not only increases the difficulty of formulation development but also limits further development and clinical application. Therefore, improving the water solubility of echinocandins while maintaining excellent antifungal activity has become an important research direction for structural optimization of this class of drugs.

[0005] Furthermore, hemolytic toxicity is a concern in the clinical application of echinocandin drugs. Given the hemolytic toxicity of natural echinocandin B, researchers have attempted to reduce it through structural modifications (such as altering the N-acyl side chain). For example, by modifying the side chain of echinocandin B as a lead compound, clinically used drugs such as anidulafungin have been obtained. However, these semi-synthetic modifications have not completely resolved the toxicity issues of echinocandin drugs, and adverse reactions such as liver damage and hemolysis still occur frequently in clinical applications.

[0006] Currently, structural modifications of echinocandin drugs mainly focus on fatty side chains and cyclic peptide backbones, while research on short peptide substitution of their aromatic ring structures is rarely reported. If short peptide fragments can replace traditional aromatic ring structures, improving the compound's water solubility and reducing hemolytic activity while maintaining antifungal activity, it will provide a new technical route for the structural optimization and formulation development of echinocandin drugs.

[0007] Therefore, developing a new type of derivative that replaces the aromatic ring structure of echinocandin drugs with short peptide fragments, while maintaining good antifungal activity, improves the water solubility of the compound and reduces the risk of hemolysis, is of great significance for promoting the further development and application of echinocandin antifungal drugs. Summary of the Invention

[0008] The problem the invention aims to solve: To address the aforementioned deficiencies in the prior art, this invention provides a derivative based on echinocandins, wherein the derivative replaces the aromatic ring structure of echinocandin drugs with a short peptide compound. This compound possesses advantages such as good antifungal activity, excellent water solubility, and good blood compatibility and safety.

[0009] Solution for solving the problem: This invention provides a compound of Formula I or a pharmaceutically acceptable salt, ester, stereoisomer, optical isomer, tautomer, polymorph, solvate, metabolite, or isotopically labeled compound thereof:

[0010] In Formula I, X is a peptide compound having Formula II: Xaa1- Xaa2- Xaa3- Xaa4 (II); Among them, Xaa1 either does not exist or is an L-configuration or a D-configuration Nle; Xaa2 is a substituted or unsubstituted L-configuration or D-configuration Trp, Ser or Lys, wherein the substitution is by being substituted with at least one tert-butyl, tert-butoxycarbonyl and triphenylmethyl substituents; Xaa3 is Pro, Nle, Phe or Arg in the L or D configuration, substituted or unsubstituted, wherein the substitution is by being substituted by at least one nitro or adamantinoxycarbonyl substituent; Xaa4 is absent or is substituted or unsubstituted L or D configuration of Trp, Nle, Phe, Lys or Ser, wherein the substitution is by being substituted by at least one substituent of tert-butyl, tert-butyloxycarbonyl and triphenylmethyl. Y is a straight-chain or branched acyl group with 6 to 20 carbon atoms.

[0011] Preferably, Xaa1 is absent or is an L-configuration Nle; Xaa2 is Trp, Ser, or Ser(tBu) of L configuration; Xaa3 is Pro, Nle, Phe, Arg or Arg(NO2) in the L configuration; Xaa4 either does not exist or is either Trp (L configuration), Lys(Boc), or Phe (D configuration).

[0012] Preferably, Xaa2 is an L-configuration Trp or Ser(tBu); Xaa3 is Nle or Arg(NO2) in the L configuration; Xaa4 is absent or is either an L-configuration Trp or Lys(Boc), preferably an L-configuration Lys(Boc).

[0013] Preferably, X is selected from any of the following: Trp-Pro-dPhe; Nle-Trp-Nle; Nle-Trp-Nle-Lys(Boc); Trp-Phe-Trp; Ser(tBu)-Arg(NO2)-Trp; Ser-Arg(NO2)-Trp.

[0014] Preferably, Y is a straight-chain or branched acyl group with 6 to 16 carbon atoms.

[0015] More preferably, Y is selected from acetyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, and tetradecanoyl.

[0016] More preferably, the Y is selected from octanoyl, decanoyl, dodecanoyl, and tetradecanoyl.

[0017] Most preferably, the Y is selected from octanoyl, decanoyl, and dodecanoyl.

[0018] This invention provides an echinocandin compound or a pharmaceutically acceptable salt, ester, stereoisomer, optical isomer, tautomer, polymorph, solvate, metabolite, or isotopically labeled compound thereof, wherein the compound is selected from any of the following: , , , , , , , , , .

[0019] The present invention provides a pharmaceutical composition comprising a compound as described in any one of the preceding descriptions, or a pharmaceutically acceptable salt, ester, stereoisomer, optical isomer, tautomer, polymorph, solvate, metabolite, or isotopically labeled compound thereof; or, an echinocandin compound as described above, or a pharmaceutically acceptable salt, ester, stereoisomer, optical isomer, tautomer, polymorph, solvate, metabolite, or isotopically labeled compound thereof; and optionally, further comprising a pharmaceutically acceptable carrier.

[0020] This invention provides the use of a compound as described above, or a pharmaceutically acceptable salt, ester, stereoisomer, optical isomer, tautomer, polymorph, solvate, metabolite, or isotopically labeled compound thereof; an echinocandin compound as described above, or a pharmaceutically acceptable salt, ester, stereoisomer, optical isomer, tautomer, polymorph, solvate, metabolite, or isotopically labeled compound thereof; or, the use of a pharmaceutical composition as described above in the preparation of a medicament for treating and / or preventing fungal infections, or a medicament for treating and / or preventing diseases caused by fungal infections.

[0021] Preferably, the fungus includes one or more of Candida albicans, Candida auris, Candida tropicalis, Candida glabrata, Candida parapsilosis, and Candida krusei.

[0022] This invention provides the use of a compound as described above, or a pharmaceutically acceptable salt, ester, stereoisomer, optical isomer, tautomer, polymorph, solvate, metabolite, or isotopically labeled compound thereof, as described above, an echinocandin compound, or a pharmaceutically acceptable salt, ester, stereoisomer, optical isomer, tautomer, polymorph, solvate, metabolite, or isotopically labeled compound thereof, or the use of a pharmaceutical composition as described above in the preparation of a β-(1,3)-D-glucan synthase inhibitor.

[0023] The effects of the invention: This invention provides a class of short peptide derivatives of echinocandins and their application in the preparation of antifungal drugs. Compared with existing echinocandin drugs, this invention, by using short peptide fragments to replace the traditional aromatic ring structure, significantly improves the water solubility and physicochemical properties of the compounds while maintaining good antifungal activity, providing a new structural optimization strategy for the formulation development of echinocandin drugs. The short peptide structures have high modifiability and structural diversity, which can further optimize the physicochemical properties and biological performance of the compounds, providing a new technical approach for the development of novel, highly effective, and safe antifungal drugs, and has good application prospects and industrialization value. Detailed Implementation

[0024] To make the technical solution and beneficial effects of the present invention more apparent and understandable, a detailed description is provided below by listing specific embodiments. Unless otherwise defined, the technical and scientific terms used herein have the same meanings as those in the technical field to which this application pertains.

[0025] As used herein, the term “compound” is also intended to cover its pharmaceutically relevant form, namely, the compound as defined herein or its pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotopic label, or prodrug.

[0026] As used herein, the term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds having one or more (e.g., one, two, three, or four) asymmetric centers, racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of this disclosure can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0027] Solid lines can be used in this article ( ), solid wedge ( ) or virtual wedge ( The carbon-carbon bonds of the compounds of this disclosure are depicted. Solid lines are used to depict bonds to asymmetric carbon atoms to indicate all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) at that carbon atom. Solid or imaginary wedges are used to depict bonds to asymmetric carbon atoms to indicate the presence of the indicated stereoisomers. When present in racemic mixtures, solid and imaginary wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise specified, the compounds of this disclosure are intended to exist as stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, trans-blocking isomers, and mixtures thereof. The compounds of this disclosure may exhibit more than one type of isomerism and may consist of mixtures thereof (e.g., racemic mixtures and diastereomer pairs).

[0028] This disclosure also includes all pharmaceutically acceptable isotopically labeled compounds identical to those disclosed, except that one or more atoms are replaced by atoms having the same atomic number but a different atomic mass or mass number than the dominant atomic mass or mass number found in nature. Examples of isotopes suitable for inclusion in compounds of this disclosure include (but are not limited to) isotopes of hydrogen (e.g., deuterium (D, ...). 2 H), tritium (T), 3 H); carbon isotopes (e.g., H); 11 C 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g., Cl); 18 F); isotopes of iodine (e.g., F); 123 I and 125 I); nitrogen isotopes (e.g.) 13 N and 15 N); isotopes of oxygen (e.g., N); 15 O、 17 O and 18 O); isotopes of phosphorus (e.g., O); phosphorus isotopes (e.g., O); 32 P); and isotopes of sulfur (e.g., ... 35 S). Certain isotope-labeled compounds of this disclosure (e.g., those doped with radioisotopes) can be used in drug and / or substrate tissue distribution studies (e.g., analysis). Radioisotope tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) It is particularly suitable for this purpose due to its ease of incorporation and detection. Using positron-emitting isotopes (e.g.) 11 C 18 F, 15 O and 13Substitution of N) can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. Isotopically labeled compounds of this disclosure can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations, by replacing previously used unlabeled reagents with appropriate isotopically labeled reagents. Pharmaceutically acceptable solvates of this disclosure include those in which the crystallization solvent can be isotopically substituted, for example, D2O, acetone-d6, or DMSO-d6.

[0029] It should also be understood that certain compounds of this disclosure may exist in their free form for therapeutic purposes, or, where appropriate, in their pharmaceutically acceptable derivative forms. In this disclosure, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs, which, upon administration to a patient in need, can directly or indirectly provide the compounds of this disclosure or their metabolites or residues. Therefore, when referring to “compounds of this disclosure” herein, it is also intended to encompass the various derivative forms of the compounds described above.

[0030] Pharmaceutically acceptable salts of the compounds disclosed herein include their acid addition salts and base addition salts.

[0031] For a review of suitable salts, see Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds disclosed herein are known to those skilled in the art.

[0032] As used herein, the term "ester" means an ester derived from the various general formula compounds of this application, including physiologically hydrolyzable esters (compounds of this disclosure that can be hydrolyzed under physiological conditions to release free acids or alcohols). The compounds of this disclosure may themselves be esters.

[0033] The compounds disclosed herein may exist as solvates (preferably hydrates), wherein the compounds contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the compound's crystal lattice. The amount of the polar solvent, particularly water, may be stoichiometric or non-stoichiometric.

[0034] The scope of this disclosure also includes metabolites of the compounds of this disclosure, i.e., substances formed in the body upon administration of the compounds of this disclosure. Such products can be generated by, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, etc., of the administered compound. Therefore, this disclosure includes metabolites of the compounds of this disclosure, including compounds prepared by methods that expose the compounds of this disclosure to mammals for a time sufficient to produce their metabolites.

[0035] The term "substitution" refers to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by a designated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound.

[0036] If a substituent is described as “optionally substituted,” then the substituent may be (1) unsubstituted or (2) substituted. If the carbon of the substituent is described as being optionally substituted with one or more of the substituents in the list, then one or more hydrogens on the carbon (to the extent that any hydrogens are present) may be substituted individually and / or together with independently selected optional substituents. If the nitrogen of the substituent is described as being optionally substituted with one or more of the substituents in the list, then one or more hydrogens on the nitrogen (to the extent that any hydrogens are present) may each be substituted with independently selected optional substituents.

[0037] If a substituent is described as being “independently selected” from a group, then each substituent is selected independently of the others. Therefore, each substituent may be the same as or different from another (other) substituent.

[0038] As used herein, the term "one or more" means one or more under reasonable conditions, such as two, three, four, five, or ten.

[0039] Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable location of the substituent.

[0040] When the bond of a substituent is such that it passes through the ring and connects two atoms, then such a substituent can be bonded to any cyclic atom in the substituted ring.

[0041] As used herein, the term "peptide" refers to a sequence of two or more amino acids. "Peptide" may also include amino acid elongations at the N-terminus and / or C-terminus, and / or truncations at the N-terminus and / or C-terminus. Typically, amino acid residues are represented by their full name, their single-letter code, and / or their three-letter code. These three methods are completely equivalent.

[0042] As used herein, the term "amino acid" is a molecule containing an amino and a carboxylic acid group and optionally one or more additional groups, often referred to as side chains. The amino acids in the compound sequences described in this invention are derived from natural amino acids or related amino acid variants and / or derivatives. The abbreviations and codes of the natural amino acids follow generally accepted rules well known to those skilled in the art. Amino acids are typically described using standard single-letter codes (e.g., L = leucine) and α-methyl-substituted residues of natural amino acids (e.g., α-methylleucine, or αMeL) and certain other non-natural amino acids (such as "Nle," etc.). Unless explicitly stated otherwise, all amino acid residues of this invention are preferably in the L-configuration, while in this application, dF or dPhe both denote the D-configuration Phe.

[0043] The following table lists some common amino acid names and their three-letter and single-letter abbreviations:

[0044] In this disclosure, the structures of non-natural amino acids and other abbreviations are presented as follows: The Nle structure is as follows ; The Lys(Boc) structure is as follows: ; The Ser(tBu) structure is as follows ; Arg(NO2) structural formula is: ; In this article, when referring to peptides, "amino acid" and "amino acid residue" have the same meaning, referring to the amino acid residues that remain after some groups are lost due to their participation in the formation of the linking bond when amino acids are linked by chemical bonds.

[0045] As used in the context of this disclosure, the term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of this disclosure with a relatively non-toxic acid or base. When a compound of this disclosure contains a relatively acidic functional group (e.g., a carboxyl or sulfonic acid group), a base addition salt can be obtained by contacting it with a sufficient amount of base in a pure solution or a suitable inert solvent in its free form. Non-limiting examples of pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, ammonium, calcium, magnesium, organic amine, or similar salts. When a compound of this disclosure contains a relatively basic functional group (e.g., an amino or guanidinyl group), an acid addition salt can be obtained by contacting it with a sufficient amount of acid in a pure solution or a suitable inert solvent in its free form. Non-limiting examples of pharmaceutically acceptable acid addition salts include, but are not limited to, inorganic acid salts (e.g., hydrochloride, hydrobromide, hydroiodide, nitrate, carbonate, bicarbonate, phosphate, monohydrogen phosphate, dihydrogen phosphate, phosphite, sulfate, hydrogen sulfate, etc.), organic acid salts (e.g., acetate, propionate, isobutyrate, malonate, succinate, octanoate, maleate, fumarate, citrate, tartrate, lactate, mandelate, benzoate, phthalate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, glucuronic acid, etc.), and amino acid salts (e.g., arginine salts). For specific forms of pharmaceutically acceptable salts, see Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66: 1-19.

[0046] This invention provides a compound of Formula I or a pharmaceutically acceptable salt, ester, stereoisomer, optical isomer, tautomer, polymorph, solvate, metabolite, or isotopically labeled compound thereof:

[0047] In Formula I, X is a peptide compound having Formula II: Xaa1- Xaa2- Xaa3- Xaa4 (II); Wherein, Xaa1 is Nle that is non-existent or has an L or D configuration; Xaa2 is a substituted or unsubstituted L-configuration or D-configuration Trp, Ser or Lys, wherein the substitution is by being substituted with at least one tert-butyl, tert-butoxycarbonyl and triphenylmethyl substituents; Xaa3 is Pro, Nle, Phe or Arg in the L or D configuration, substituted or unsubstituted, wherein the substitution is by being substituted by at least one nitro or adamantinoxycarbonyl substituent; Xaa4 is Trp, Nle, Phe, Lys, or Ser in the L or D configuration, which is absent or substituted or unsubstituted, wherein the substitution is by at least one substituent of tert-butyl, tert-butyloxycarbonyl, and triphenylmethyl. Y is a straight-chain or branched acyl group with 6 to 20 carbon atoms.

[0048] In this application, the substitution refers to the modification of the side chain group of an amino acid by a protecting group, which includes, but is not limited to, tert-butyl, tert-butoxycarbonyl, triphenylmethyl, nitro, and adamantyloxycarbonyl.

[0049] In some implementations, Xaa1 is either non-existent or an L-configuration Nle.

[0050] In some implementations, Xaa2 is an L-configuration Trp, Ser, or Ser(tBu).

[0051] In some implementations, Xaa2 is an L-configuration Trp or Ser(tBu); In some implementations, Xaa3 is Pro, Nle, Phe, Arg, or Arg(NO2) in the L configuration.

[0052] In some implementations, Xaa3 is an L-configuration Nle or Arg(NO2); In some implementations, Xaa4 is either absent or is Trp (L configuration), Lys(Boc), or Phe (D configuration).

[0053] In some implementations, Xaa4 is either absent or an L-configuration Trp or Lys(Boc).

[0054] In some implementations, Xaa4 is an L-configuration Lys(Boc).

[0055] In some implementations, Xaa1 is absent, Xaa2 is L-configuration Trp or Ser(tBu), Xaa3 is L-configuration Phe, Pro or Arg(NO2), and Xaa4 is L-configuration Trp or dPhe.

[0056] In some implementations, Xaa4 is non-existent, Xaa1 is Nle of the L configuration, Xaa2 is Trp of the L configuration, and Xaa3 is Nle of the L configuration.

[0057] In some embodiments, when Xaa4 is present, the Y group forms an amide bond with the amino group at the end of the amino acid Xaa4.

[0058] In some embodiments, when Xaa4 is absent, the Y group forms an amide bond with the amino group at the end of the amino group of amino acid Xaa3.

[0059] In some implementations, X is selected from any of the following: Trp-Pro-dPhe; Nle-Trp-Nle; Nle-Trp-Nle-Lys(Boc); Trp-Phe-Trp; Ser(tBu)-Arg(NO2)-Trp; Ser-Arg(NO2)-Trp.

[0060] In some embodiments, Y is a straight-chain or branched acyl group of 6 to 16 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16) carbon atoms.

[0061] In some embodiments, Y is selected from oxyacyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, and tetradecanoyl.

[0062] In some embodiments, Y is selected from octanoyl, decanoyl, dodecanoyl, and tetradecanoyl.

[0063] In some embodiments, Y is selected from octanoyl, decanoyl, and dodecanoyl.

[0064] In some embodiments, X is Nle-Trp-Nle-Lys(Boc), and Y is octanoyl, decanoyl, or dodecanoyl.

[0065] In some embodiments, X is Nle-Trp-Nle, and Y is octanoyl, decanoyl, or dodecanoyl.

[0066] In some embodiments, X is Ser(tBu)-Arg(NO2)-Trp, and Y is octanoyl, decanoyl, or dodecanoyl.

[0067] On the other hand, the present invention provides an echinocandin compound or its stereoisomers, optical isomers, or pharmaceutically acceptable salts thereof, wherein the compound is selected from any of the following compounds. , , , , , , , , , .

[0068] On one hand, the present invention provides a method for preparing the compound or its stereoisomers, optical isomers, or pharmaceutically acceptable salts described in any of the above claims, the method comprising synthesizing the polypeptide compound using a chemical synthesis method.

[0069] In some embodiments, the method of the present invention includes peptide preparation using standard peptide synthesis methods, such as obtaining a short peptide intermediate through standard solid-phase or liquid-phase methods, either stepwise or via fragment assembly, wherein the short peptide intermediate is reacted with echinocandin B hydrochloride (ECBN) to obtain the compound of this application. In this application, the method described is a conventional preparation method in the art.

[0070] On the other hand, the present invention provides a pharmaceutical composition comprising a compound of formula I as described in any of the preceding claims, or a stereoisomer, optical isomer, or pharmaceutically acceptable salt thereof, or an echinocandin compound as described above, or a stereoisomer, optical isomer, or pharmaceutically acceptable salt thereof; and optionally, further comprising a pharmaceutically acceptable carrier.

[0071] As used herein, the term "pharmaceutical composition" refers to a composition that is pharmaceutically usable and comprises one or more compounds as shown in Formula I or in a pharmaceutically acceptable form thereof (e.g., salt, hydrate, solvate, stereoisomer, tautomer, metabolite, prodrug, etc.), and other components (e.g., pharmaceutically acceptable excipients).

[0072] As used herein, the term "pharmaceuticalally acceptable carrier" refers to excipients (excipients) widely used in the pharmaceutical manufacturing industry. The primary purpose of using excipients is to provide a pharmaceutical composition that is safe to use, stable in nature, and / or has specific functionalities, and also to provide a method for the active ingredient to dissolve at a desired rate or to promote the effective absorption of the active ingredient in a subject after administration of the drug. Pharmaceutically acceptable excipients can be inert fillers or functional components that provide a function to the pharmaceutical composition (e.g., stabilizing the overall pH of the composition or preventing degradation of the active ingredient in the composition). Non-limiting examples of pharmaceutically acceptable excipients include, but are not limited to, binders, suspending agents, emulsifiers, diluents (or fillers), granulating agents, adhesives, disintegrants, lubricants, anti-adhesion agents, flow aids, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, sweeteners, etc.

[0073] The pharmaceutical compositions disclosed herein can be prepared using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulation, emulsification, grinding, encapsulation, embedding, and / or lyophilization processes.

[0074] In this disclosure, the purpose of using the pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and exerting its biological activity. The pharmaceutical compositions of this disclosure can be administered in any form, including injection (intra-arterial, intravenous, intramuscular, intraperitoneal, subcutaneous), mucosal, oral (oral solid dosage forms, oral liquid dosage forms), rectal, inhalation, implantation, and topical (e.g., ocular) administration. Non-limiting examples of oral solid dosage forms include, but are not limited to, powders, capsules, lozenges, granules, tablets, etc. Non-limiting examples of oral or mucosal liquid dosage forms include, but are not limited to, suspensions, tinctures, elixirs, solutions, etc. Non-limiting examples of topical dosage forms include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum preparations. Non-limiting examples of parenteral dosage forms include, but are not limited to, solutions for injection, dry powders for injection, suspensions for injection, emulsions for injection, etc. The pharmaceutical compositions of this disclosure can also be formulated into controlled-release or delayed-release dosage forms (e.g., liposomes or microspheres).

[0075] In this disclosure, the route of administration can be varied or modified in any applicable manner to meet the needs of the properties of the drug, the convenience of patients and healthcare professionals, and other relevant factors.

[0076] On the other hand, the present invention provides the use of a compound of formula I as described in any of the preceding claims, or a stereoisomer, optical isomer, or pharmaceutically acceptable salt thereof, a echinocandin compound as described above, or a stereoisomer, optical isomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, in the preparation of a medicament for treating and / or preventing fungal infections, or a medicament for treating and / or preventing diseases caused by fungal infections.

[0077] In some embodiments, the fungus includes one or more of Candida albicans, Candida auris, Candida tropicalis, Candida glabrata, Candida parapsilosis, and Candida krusei.

[0078] In specific embodiments, the fungi include Candida albicans and Candida tropicalis (Candida tropicalis).

[0079] In a specific and preferred embodiment, the Candida albicans is ATCC 90028 Candida albicans and / or ATCC 10231 Candida albicans.

[0080] In a specific and preferred embodiment, the tropical Candida is ATCC 750 tropical Candida.

[0081] In some embodiments, the disease is an invasive fungal infection; in specific and preferred embodiments, the disease is invasive candidiasis and aspergillosis.

[0082] On the other hand, the present invention provides the use of a compound of formula I as described above, or a stereoisomer, optical isomer, or pharmaceutically acceptable salt thereof, as described above, an echinocandin as described above, or a stereoisomer, optical isomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, in the preparation of a β-(1,3)-D-glucan synthase inhibitor.

[0083] The following specific examples illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and various details in this specification can also be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention.

[0084] Before further describing specific embodiments of the present invention, it should be understood that the scope of protection of the present invention is not limited to the specific embodiments described below; it should also be understood that the terminology used in the embodiments of the present invention is for describing specific embodiments and not for limiting the scope of protection of the present invention.

[0085] Unless otherwise stated, the experimental methods, detection methods, and preparation methods disclosed in this invention all employ conventional techniques in molecular biology, biochemistry, chromatin structure and analysis, analytical chemistry, cell culture, recombinant DNA technology, and related fields. These techniques have been well described in existing literature; see Sam Brook et al., *MOLECULAR CLONING: A LABORATORY MANUAL*, Second edition, Cold Spring Harbor Laboratory Press, 1989 and Third edition, 2001; Ausubel et al., *CURRENT PROTOCOLS IN MOLECULAR BIOLOGY*, John Wiley & Sons, New York, 1987 and periodic updates; *theseries METHODS IN ENZYMOLOGY*, Academic Press, San Diego; Wolffe, *CHROMATINSTRUCTURE AND FUNCTION*, Third edition, Academic Press, San Diego, 1998; *METHODS IN ENZYMOLOGY*, Vol. 304, Chromatin (P.M. Wassarman and A.P. Wolffe, eds.), Academic Press, San Diego, 1999; and *METHODS IN MOLECULAR*. BIOLOGY, Vol. 119, Chromatin Protocols (P. B. Becker, ed.) Humana Press, Totowa, 1999, etc.

[0086] In addition to the specific methods, equipment, and materials used in the embodiments, based on the knowledge of those skilled in the art and the description of this invention, any prior art methods, equipment, and materials similar to or equivalent to those described, used, and materials in the embodiments of this invention can be used to implement this invention. Unless otherwise stated, parts and percentages are parts by weight and weight percentages.

[0087] The raw materials and reagents used in this invention are all common reagents in the art, and unless otherwise specified, they can all be purchased commercially available. Of course, it is not excluded that they can be synthesized according to the methods disclosed in the prior art.

[0088] Example 1: C 10 -dPhe-Pro-Trp-ECBN(A01)

[0089] Using 2-CTC Resin (α, 150.0 mg, SD = 1.06 mmol / g) as a solid support, after swelling, it was reacted with Fmoc-Trp-OH (140.0 mg) The reaction was carried out with 0.318 mmol of DIEA (110 μL, 0.636 mmol), and blocked with anhydrous methanol. The Fmoc protecting group was then removed with 20% PIP / DMF solution to obtain compound b. A condensation reaction was further carried out with Fmoc-Pro-OH (210.0 mg, 0.636 mmol), Oxyma (110.0 mg, 0.795 mmol), and DIC (120 μL, 0.795 mmol). After further removal of the Fmoc protecting group, Fmoc-dPhe-OH was added, yielding compound c. Finally, decanoyl chloride (83 μL, 0.398 mmol) and DIEA (110 μL, 0.636 mmol) were added to complete the fatty chain linkage, yielding compound d with its C-terminus linked to the resin. The resin peptide was cleaved, precipitated, and lyophilized to give 39.6 mg of white solid compound e, with a yield of 41.35%. MS [M + H] + :603.24.

[0090] Echinocandin B hydrochloride (54.9 mg, 0.066 mmol), compound e (39.6 mg, 0.066 mmol), and CDMT (13.9 mg, 0.079 mmol) were dissolved in DMF (0.5 mL), followed by the addition of NMM (22 μL, 0.198 mmol). The mixture was stirred at room temperature for 1 h. After the reaction was complete, 2 mL of H₂O was added to precipitate a solid. The solid was centrifuged and washed twice. Purification by HPLC yielded 21 mg of a white solid, compound A01, with a purity of 97.26% and a yield of 23.12%. MS[M + H] + :1384.6881.

[0091] Example 2: C 12 -dPhe-Pro-Trp-ECBN (A02) Using 2-CTC Resin (a, 150.0 mg, SD = 1.06 mmol / g) as a solid support, after swelling, it was reacted with Fmoc-Trp-OH (140.0 mg, 0.318 mmol) and DIEA (110 μL, 0.636 mmol), blocked with anhydrous methanol, and then the Fmoc protecting group was removed with 20% PIP / DMF solution to obtain Trp-2-CTC Resin. The condensation reaction was further carried out with Fmoc-Pro-OH (210.0 mg, 0.636 mmol), Oxyma (110.0 mg, 0.795 mmol), and DIC (120 μL, 0.795 mmol), followed by removal of the Fmoc protecting group and then attachment of Fmoc-dPhe-OH. After deprotection, D-Phe-Pro-Trp-2-CTC was obtained. Resin was then added, followed by the addition of dodecyl chloride (92 μL, 0.398 mmol) and DIEA (110 μL, 0.636 mmol) to complete the fatty chain linkage, yielding C12-dPhe-Pro-Trp-2-CTC Resin with its C-terminus linked to the resin. The resin peptide was cleaved, precipitated, and lyophilized to obtain 26.3 mg of white solid C12-dPhe-Pro-Trp-OH, with a yield of 26.24%. MS [M + H] + :631.34.

[0092] Echinocandin B hydrochloride (34.8 mg, 0.042 mmol), C 12 -dPhe-Pro-Trp-OH (26.3 mg, 0.042 mmol) and CDMT (8.8 mg, 0.051 mmol) were dissolved in DMF (0.5 mL), and then NMM (14 μL, 0.126 mmol) was added. The mixture was stirred at room temperature for 1 h. After the reaction was complete, 2 mL of H2O was added to precipitate the solid. The solid was centrifuged and washed twice. 14.5 mg of a white solid compound A02 was obtained by HPLC purification, with a purity of 97.16% and a yield of 24.70%. MS[M + H] + :1410.7128.

[0093] Example 3: C 10 -Nle-Trp-Nle-ECBN(A03) Using 2-CTC Resin (a, 150.0 mg, SD = 1.06 mmol / g) as a solid support, after swelling, it was reacted with Fmoc-Nle-OH (110.0 mg, 0.318 mmol) and DIEA (110 μL, 0.636 mmol), blocked with anhydrous methanol, and then the Fmoc protecting group was removed with 20% PIP / DMF solution to obtain Nle-2-CTC Resin. The condensation reaction was further carried out with Fmoc-Trp-OH (280.0 mg, 0.636 mmol), Oxyma (110.0 mg, 0.795 mmol), and DIC (120 μL, 0.795 mmol), followed by removal of the Fmoc protecting group, and then reattach Fmoc-Nle-OH. After deprotection, Nle-Trp-Nle-2-CTC was obtained. Resin was then added, followed by the addition of decanoyl chloride (83 μL, 0.398 mmol) and DIEA (110 μL, 0.636 mmol) to complete the fatty chain linkage, resulting in C-terminal C-terminal linked to the resin. 10 -Nle-Trp-Nle-2-CTC Resin, the resin peptide was cleaved, precipitated, and lyophilized to obtain 35.5 mg of white solid C. 10 -Nle-Trp-Nle-OH, yield 38.2%. MS[M + H] + :585.31.

[0094] Echinocandin B hydrochloride (50.7 mg, 0.061 mmol), C 10 -Nle-Trp-Nle-OH (35.5 mg, 0.061 mmol) and CDMT (12.8 mg, 0.073 mmol) were dissolved in DMF (0.5 mL), and then NMM (20 μL, 0.183 mmol) was added. The mixture was stirred at room temperature for 1 h. After the reaction was complete, 2 mL of H2O was added to precipitate the solid. The solid was centrifuged and washed twice. Purification by HPLC yielded 28.3 mg of a white solid compound A03 with a purity of 99.14% and a yield of 34.16%. MS[M+H] + 1364.7296

[0095] Example 4: C 12 -Nle-Trp-Nle-ECBN (A04) Using 2-CTC Resin (a, 150.0 mg, SD = 1.06 mmol / g) as a solid support, after swelling, it was reacted with Fmoc-Nle-OH (110.0 mg, 0.318 mmol) and DIEA (110 μL, 0.636 mmol), blocked with anhydrous methanol, and then the Fmoc protecting group was removed with 20% PIP / DMF solution to obtain Nle-2-CTC Resin. The condensation reaction was further carried out with Fmoc-Trp-OH (280.0 mg, 0.636 mmol), Oxyma (110.0 mg, 0.795 mmol), and DIC (120 μL, 0.795 mmol), followed by removal of the Fmoc protecting group, and then ligation with Fmoc-Nle-OH. After deprotection, Nle-Trp-Nle-2-CTC was obtained. Resin was then added, followed by the addition of dodecyl chloride (92 μL, 0.398 mmol) and DIEA (110 μL, 0.636 mmol) to complete the fatty chain linkage, resulting in C-terminal C-terminal linked to the resin. 12 -Nle-Trp-Nle-2-CTC Resin, the resin peptide was cleaved, precipitated, and lyophilized to obtain 55.8 mg of a white solid C. 12 -Nle-Trp-Nle-OH, yield 57.30%. MS[M + H] + :613.54.

[0096] Echinocandin B hydrochloride (76.0 mg, 0.091 mmol), C 12 -Nle-Trp-Nle-OH (55.8 mg, 0.091 mmol) and CDMT (19.2 mg, 0.109 mmol) were dissolved in DMF (0.5 mL), and then NMM (30 μL, 0.273 mmol) was added. The mixture was stirred at room temperature for 1 h. After the reaction was complete, 2 mL of H2O was added to precipitate the solid. The solid was centrifuged and washed twice. 48.3 mg of a white solid compound A04 was obtained by HPLC purification, with a purity of 95.58% and a yield of 38.10%. MS[M+H] + :1393.7632.

[0097] Example 5: C8-Lys(Boc)-Nle-Trp-Nle-ECBN (A05) Using 2-CTC Resin (a, 150.0 mg, SD = 1.06 mmol / g) as a solid support, after swelling, it was reacted with Fmoc-Nle-OH (110.0 mg, 0.318 mmol) and DIEA (110 μL, 0.636 mmol), blocked with anhydrous methanol, and then the Fmoc protecting group was removed with 20% PIP / DMF solution to obtain Nle-2-CTC Resin. A condensation reaction was further carried out with Fmoc-Trp-OH (280.0 mg, 0.636 mmol), Oxyma (110.0 mg, 0.795 mmol), and DIC (120 μL, 0.795 mmol), followed by removal of the Fmoc protecting group. Then, Fmoc-Nle-OH and Fmoc-Lys(Boc)-OH were linked, and after deprotection, Lys(Boc)-Nle-Trp-Nle-2-CTC was obtained. Resin was then added, followed by the addition of octanoyl chloride (68 μL, 0.398 mmol) and DIEA (110 μL, 0.636 mmol) to complete the fatty chain linkage, yielding C8-Lys(Boc)-Nle-Trp-Nle-2-CTC Resin with its C-terminus linked to the resin. The resin peptide was cleaved, precipitated, and lyophilized to obtain 51.8 mg of white solid C8-Lys(Boc)-Nle-Trp-Nle-OH, with a yield of 41.53%. MS [M+H] + :785.63.

[0098] Echinocandin B hydrochloride (55.6 mg, 0.066 mmol), C8-Lys(Boc)-Nle-Trp-Nle-OH (51.8 mg, 0.066 mmol), and CDMT (14.1 mg, 0.079 mmol) were dissolved in DMF (0.5 mL), followed by the addition of NMM (22 μL, 0.198 mmol). The mixture was stirred at room temperature for 1 h. After the reaction was complete, 2 mL of H2O was added to precipitate the solid. The solid was centrifuged and washed twice. Purification by HPLC yielded 34.3 mg of a white solid compound A05 with a purity of 97.17% and a yield of 26.80%. MS[M+H] + : 1566.8547.

[0099] Example 6: C 10 -Trp-Phe-Trp-ECBN (A06) Using 2-CTC Resin (a, 150.0 mg, SD = 1.06 mmol / g) as a solid support, after swelling, it was reacted with Fmoc-Trp-OH (140.0 mg, 0.318 mmol) and DIEA (110 μL, 0.636 mmol), blocked with anhydrous methanol, and then the Fmoc protecting group was removed with 20% PIP / DMF solution to obtain Trp-2-CTC Resin. The condensation reaction was further carried out with Fmoc-Phe-OH (250.0 mg, 0.636 mmol), Oxyma (110.0 mg, 0.795 mmol), and DIC (120 μL, 0.795 mmol), followed by removal of the Fmoc protecting group, and then ligation with Fmoc-Trp-OH. After deprotection, Trp-Phe-Trp-2-CTC was obtained. Resin was then added, followed by the addition of decanoyl chloride (83 μL, 0.398 mmol) and DIEA (110 μL, 0.636 mmol) to complete the fatty chain linkage, resulting in C-terminal C-terminal linked to the resin. 10 -Trp-Phe-Trp-2-CTC Resin, the resin peptide was cleaved, precipitated, and lyophilized to obtain 42.3 mg of white solid C. 10 -Trp-Phe-Trp-OH, yield 38.48%. MS[M + H] + :692.37.

[0100] Echinocandin B hydrochloride (51.1 mg, 0.061 mmol), C 10 -Trp-Phe-Trp-OH (42.3 mg, 0.061 mmol) and CDMT (12.9 mg, 0.073 mmol) were dissolved in DMF (0.5 mL), and then NMM (20 μL, 0.183 mmol) was added. The mixture was stirred at room temperature for 1 h. After the reaction was complete, 2 mL of H2O was added to precipitate the solid. The solid was centrifuged and washed twice. 18.4 mg of a white solid compound A06 was obtained by HPLC purification, with a purity of 92.57% and a yield of 20.45%. MS[M+H] + :1472.7114.

[0101] Example 7: C 12 -Trp-Phe-Trp-ECBN (A07) Using 2-CTC Resin (a, 150.0 mg, SD = 1.06 mmol / g) as a solid support, after swelling, it was reacted with Fmoc-Trp-OH (140.0 mg, 0.318 mmol) and DIEA (110 μL, 0.636 mmol), blocked with anhydrous methanol, and then the Fmoc protecting group was removed with 20% PIP / DMF solution to obtain Trp-2-CTC Resin. The condensation reaction was further carried out with Fmoc-Phe-OH (250.0 mg, 0.636 mmol), Oxyma (110.0 mg, 0.795 mmol), and DIC (120 μL, 0.795 mmol), followed by removal of the Fmoc protecting group, and then ligation with Fmoc-Trp-OH. After deprotection, Trp-Phe-Trp-2-CTC was obtained. Resin was then added, followed by the addition of dodecyl chloride (92 μL, 0.398 mmol) and DIEA (110 μL, 0.636 mmol) to complete the fatty chain linkage, resulting in C-terminal C-terminal linked to the resin. 12- Trp-Phe-Trp-2-CTC Resin, the resin peptide was cleaved, precipitated, and lyophilized to obtain 63.2 mg of a white solid C. 12 -Trp-Phe-Trp-OH, yield 55.25%. MS[M + H] + :720.41.

[0102] Echinocandin B hydrochloride (73.3 mg, 0.088 mmol), C 12 -Trp-Phe-Trp-OH (63.2 mg, 0.088 mmol) and CDMT (18.5 mg, 0.106 mmol) were dissolved in DMF (0.5 mL), and then NMM (29 μL, 0.264 mmol) was added. The mixture was stirred at room temperature for 1 h. After the reaction was complete, 2 mL of H2O was added to precipitate the solid. The solid was centrifuged and washed twice. 18.9 mg of a white solid compound A07 was obtained by HPLC purification, with a purity of 95.60% and a yield of 14.40%. MS[M+H] + :1500.7427.

[0103] Example 8: C 10 -Trp-Arg(NO2)-Ser(tBu)-ECBN(A08) Using 2-CTC Resin (a, 150.0 mg, SD = 1.06 mmol / g) as a solid support, after swelling, it was reacted with Fmoc-Ser(tBu)-OH (120.0 mg, 0.318 mmol) and DIEA (110 μL, 0.636 mmol), blocked with anhydrous methanol, and then the Fmoc protecting group was removed with 20% PIP / DMF solution to obtain Ser(tBu)-2-CTC Resin. The condensation reaction was further carried out with Fmoc-Arg(NO2)-OH (280.0 mg, 0.636 mmol), Oxyma (110.0 mg, 0.795 mmol), and DIC (120 μL, 0.795 mmol). After further removal of the Fmoc protecting group, Fmoc-Trp-OH was ligated, and after deprotection, Trp-Arg(NO2)-Ser(tBu)-2-CTC was obtained. Resin was then added, followed by the addition of decanoyl chloride (83 μL, 0.398 mmol) and DIEA (110 μL, 0.636 mmol) to complete the fatty chain linkage, yielding C10-Trp-Arg(NO2)-Ser(tBu)-2-CTC Resin with its C-terminus linked to the resin. The resin peptide was cleaved, precipitated, and lyophilized to obtain 47.5 mg of white solid C10-Trp-Arg(NO2)-Ser(tBu)-OH, with a yield of 42.53%. MS [M + H] + :703.41.

[0104] Echinocandin B hydrochloride (56.4 mg, 0.068 mmol), C10-Trp-Arg(NO2)-Ser(tBu)-OH (39.6 mg, 0.068 mmol), and CDMT (13.9 mg, 0.082 mmol) were dissolved in DMF (0.5 mL), followed by the addition of NMM (22 μL, 0.204 mmol). The mixture was stirred at room temperature for 1 h. After the reaction was complete, 2 mL of H2O was added to precipitate the solid. The solid was centrifuged and washed twice. 48 mg of a white solid compound A08 was obtained by HPLC purification, with a purity of 81.11% and a yield of 47.90%. MS[M+H] + :1484.7472.

[0105] Example 9: C 12 -Trp-Arg(NO2)-Ser(tBu)-ECBN(A09) Using 2-CTC Resin (a, 150.0 mg, SD = 1.06 mmol / g) as a solid support, after swelling, it was reacted with Fmoc-Ser(tBu)-OH (120.0 mg, 0.318 mmol) and DIEA (110 μL, 0.636 mmol), blocked with anhydrous methanol, and then the Fmoc protecting group was removed with 20% PIP / DMF solution to obtain Ser(tBu)-2-CTC Resin. The condensation reaction was further carried out with Fmoc-Arg(NO2)-OH (280.0 mg, 0.636 mmol), Oxyma (110.0 mg, 0.795 mmol), and DIC (120 μL, 0.795 mmol). After further removal of the Fmoc protecting group, Fmoc-Trp-OH was ligated, and after deprotection, Trp-Arg(NO2)-Ser(tBu)-2-CTC was obtained. Resin was then added, followed by the addition of dodecyl chloride (92 μL, 0.398 mmol) and DIEA (110 μL, 0.636 mmol) to complete the fatty chain linkage, resulting in C-terminal C-terminal linked to the resin. 12 -Trp-Arg(NO2)-Ser(tBu)-2-CTC Resin, the resin peptide was cleaved, precipitated, and lyophilized to obtain 48.7 mg of white solid C. 12 -Trp-Arg(NO2)-Ser(tBu)-OH, yield 43.65%. MS[M+H] + :731.63.

[0106] Echinocandin B hydrochloride (55.6 mg, 0.067 mmol), C12-Trp-Arg(NO2)-Ser(tBu)-OH (48.7 mg, 0.067 mmol), and CDMT (14.1 mg, 0.080 mmol) were dissolved in DMF (0.5 mL), followed by the addition of NMM (22 μL, 0.201 mmol). The mixture was stirred at room temperature for 1 h. After the reaction was complete, 2 mL of H2O was added to precipitate the solid. The solid was centrifuged and washed twice. Purification by HPLC yielded 26 mg of a white solid compound A09 with a purity of 97.17% and a yield of 26.80%. MS[M+H] + :1512.7787.

[0107] Example 10: C 12 -Trp-Arg(NO2)-Ser-ECBN(A10) Using 2-CTC Resin (a, 150.0 mg, SD = 1.06 mmol / g) as a solid support, after swelling, it was reacted with Fmoc-Ser(tBu)-OH (120.0 mg, 0.318 mmol) and DIEA (110 μL, 0.636 mmol), blocked with anhydrous methanol, and then the Fmoc protecting group was removed with 20% PIP / DMF solution to obtain Ser(tBu)-2-CTC Resin. The condensation reaction was further carried out with Fmoc-Arg(NO2)-OH (280.0 mg, 0.636 mmol), Oxyma (110.0 mg, 0.795 mmol), and DIC (120 μL, 0.795 mmol). After further removal of the Fmoc protecting group, Fmoc-Trp-OH was ligated, and after deprotection, Trp-Arg(NO2)-Ser(tBu)-2-CTC was obtained. Resin was then added, followed by the addition of dodecyl chloride (92 μL, 0.398 mmol) and DIEA (110 μL, 0.636 mmol) to complete the fatty chain linkage, resulting in C-terminal C-terminal linked to the resin. 12 -Trp-Arg(NO2)-Ser(tBu)-2-CTC Resin, the resin peptide was cleaved, precipitated, and lyophilized to obtain 40.0 mg of white solid C. 12 -Trp-Arg(NO2)-Ser-OH, yield 37.30%. MS[M + H] + :675.52.

[0108] Echinocandin B hydrochloride (49.5 mg, 0.055 mmol), C 12 Trp-Arg(NO2)-Ser-OH (40.0 mg, 0.055 mmol) and CDMT (12.5 mg, 0.066 mmol) were dissolved in DMF (0.5 mL), and then NMM (20 μL, 0.165 mmol) was added. The mixture was stirred at room temperature for 1 h. After the reaction was complete, 2 mL of H2O was added to precipitate a solid. The solid was centrifuged and washed twice. 56.7 mg of a white solid compound A10 was obtained by HPLC purification, with a purity of 75.57% and a yield of 71.22%. MS[M + H] + :1455.7133.

[0109] Example 1: Pharmacological study of the compounds of this invention. The in vitro antifungal activity of compounds A1-A10 prepared in Examples 1-10 above was determined using the double dilution method.

[0110] The experiment was conducted in accordance with the 2003 edition of the antifungal susceptibility testing protocol for sporogenic filamentous fungi published by the National Committee for Clinical Laboratory Standards (NCCLS) in the United States. YPD medium was used for both culture and dilution.

[0111] Positive control drugs: Fluconazole and Caspofungin.

[0112] Test strains: Candida albicans (ATCC90028 and ATCC10231) and Candida tropicalis (ATCC750).

[0113] Preparation of stock solutions for target compound and control drug: Weigh 4 mg of the target compound and positive control drug respectively, dissolve them in 5 mL of DMSO, add 5 mL of Tween 80 and 4.0 mL of distilled water to prepare stock solutions, and store them at 4℃ for later use.

[0114] Determination of minimum inhibitory concentration (MIC) in vitro: YPD medium was added to a 96 plate. 180 μL was added to well 1, 100 μL to the growth control and experimental wells, and 200 μL to the blank control wells. Then, 20 μL of drug stock solution was added to well 1, mixed well, and 100 μL was transferred to well 2. Another 100 μL was added to well 2 and transferred to well 3, and so on, until all experimental wells were reached. No drug stock solution was added to the growth control and blank control wells. Finally, 100 μL of the prepared drug stock solution, diluted to 1×10⁻⁶, was added to each experimental and growth control well. 3 ~5×10 3 A bacterial suspension of cuf / mL was prepared. 96 plates were incubated at 30℃. The MIC values ​​for *Candida albicans* and *Candida tropicalis* were read after 24 hours of incubation. All experiments were performed at least three times independently, with an experimental error not exceeding 10%. The results are shown in Table 1. Here, MIC represents the minimum inhibitory concentration, fluconazole is the standard concentration, caspofungin is the standard concentration for *Candida albicans*, and *Candida tropicalis* is the standard concentration for *Candida albicans*.

[0115] Table 1

[0116] The results of in vitro antifungal activity experiments (Table 1) show that the echinocandin short peptide derivatives designed in this invention have good inhibitory activity against a variety of common clinical pathogenic fungi. Among them, most compounds showed varying degrees of antifungal activity against the standard strain of Candida albicans C. alb 10231, the clinical strain of Candida albicans C. alb 90028, and Candida tropicalis C. tro 750.

[0117] Specifically, compounds A04, A05, and A09 exhibited significant antifungal activity, with MIC values ​​reaching 2–4 μg / mL. Compound A05, in particular, showed an MIC of 2 μg / mL against both the clinical strains of Candida albicans (C. alb 90028) and Candida tropicalis (C. tro 750), comparable to the activity of the positive control, caspofungin. In contrast, the negative control ECBN showed no significant antifungal activity (MIC > 128 μg / mL), indicating that the short peptide structural modification introduced in this invention plays a crucial role in the formation of antifungal activity.

[0118] Furthermore, fluconazole has an MIC of 64 μg / mL against Candida tropicalis C. tro 750, while some of the compounds of this invention maintain lower MIC values, indicating that they have a potential advantage against some drug-resistant or low-susceptibility fungal strains. This suggests that these compounds may exert their antifungal effects through a mechanism of action different from azole drugs.

[0119] Example 2: Study on the water solubility of the compounds of the present invention This experiment used the external curve method to determine the water solubility of echinocandin-derived peptides A1-A10. The specific implementation method is as follows: (1) Accurately weigh the lyophilized powders of compounds A1 to A10, dissolve and dilute them with methanol to prepare concentration gradient solutions of 100 μg / mL, 50 μg / mL, 25 μg / mL, 12.5 μg / mL and 6.25 μg / mL, and filter them for later use.

[0120] (2) Weigh 0.5 mg of lyophilized compound A1~A10, add 0.2 mL of ultrapure water, disperse by ultrasonic oscillation, centrifuge, take the supernatant, filter and use for later use.

[0121] (3) All the above samples were determined using the following method: Instrument: Hitachi Chromaster 5000 high performance liquid chromatograph; Column: Huapu Xinchuang ACCHROM XAqua-C18 column (4.6mm×250mm, 100Å, 5µm); Mobile phase: A: 0.1% TFA ultrapure aqueous solution; B: 0.1% TFA acetonitrile solution; Program: Mobile phase B 40%~100%, 20min; Wavelength: 215nm; Flow rate: 1mL / min; Injection volume: 5μL; Column temperature: 40℃.

[0122] (4) Integrate the sample analysis results from (1) using the area normalization method, plot a standard curve with concentration versus peak area, and fit a linear equation. Integrate the sample analysis results from (2) using the area normalization method, substitute the peak area into the linear equation, and calculate the concentration, which is the solubility of the compound in aqueous solution under these conditions.

[0123] The solubility results of the compounds in this invention are shown in Table 2.

[0124] Table 2

[0125] As shown in Table 2, replacing the traditional aromatic ring structure with short peptide fragments can significantly improve the water solubility and physicochemical properties of echinocandin compounds, providing favorable conditions for the formulation development and further application of this class of drugs.

[0126] Example 3: Hemolytic toxicity study of the compounds of the present invention In this experiment, healthy Japanese white rabbits were selected, and blood was collected through the marginal ear vein. Sodium citrate was added as an anticoagulant, and the mixture was stirred thoroughly to prevent clotting. The blood was centrifuged at 1200 rpm for 10 minutes, and the red blood cell pellet was collected. Subsequently, the red blood cell pellet was washed 4-5 times with physiological saline until the supernatant was clear and colorless. Finally, the red blood cell suspension was diluted with physiological saline to the required concentration to prepare a 2% red blood cell suspension. 100 µL of the 2% red blood cell suspension was added to each well of a 96-well plate. Different concentrations of the test sample were added to different wells to set up a solvent control group (test sample solvent), a positive control group (distilled water), and a negative control group (physiological saline). The system was incubated at 37°C for 1 hour to ensure that the hemolysis reaction proceeded fully. After incubation, the plate was centrifuged, the supernatant was collected, and the absorbance was measured using a microplate reader (405 nm). The hemolysis rate was calculated based on the degree of hemolysis of different concentrations of the test sample. The results are shown in Table 3.

[0127] Table 3

[0128] The hemolysis test results showed that the half-maximal hemolytic concentration (HC50) of the positive control drug Anidulafungin was significantly lower than that of the control drug. 50 The concentration of HbA1c was 58.23 μg / mL, exhibiting significant hemolytic activity. In contrast, compounds A05 and A09, at the highest tested concentration of 64 μg / mL, showed hemolysis rates of less than 5% in rabbit erythrocytes, and no significant hemolysis was observed in either (HC). 50 >64 μg / mL). This result indicates that A05 and A09 have significantly lower hemolytic toxicity compared to the positive control, demonstrating good blood compatibility and safety advantages.

[0129] In summary, the results of this invention demonstrate that by replacing the aromatic ring structure in echinocandin drugs with short peptide fragments, the compound's water solubility, blood compatibility, and safety are significantly improved while maintaining good antifungal activity. This also enhances its physicochemical properties and provides a new technical approach for the structural optimization and formulation development of echinocandin drugs, showing promising application prospects and industrialization value.

[0130] It should be understood that the above embodiments are exemplary and are not intended to encompass all possible implementations included in the claims. Various modifications and changes can be made to the above embodiments without departing from the scope of this disclosure. Similarly, the various technical features of the above embodiments can be arbitrarily combined to form other embodiments of the present invention that may not be explicitly described. Therefore, the above embodiments only illustrate several implementations of the present invention and do not limit the scope of protection of this patent.

Claims

1. A compound of Formula I or a pharmaceutically acceptable salt, ester, stereoisomer, optical isomer, tautomer, polymorph, solvate, metabolite, or isotopically labeled compound thereof: ； in, In Formula I, X is a peptide compound having Formula II: Xaa1- Xaa2- Xaa3- Xaa4 (II); Among them, Xaa1 either does not exist or is an L-configuration or a D-configuration Nle; Xaa2 is a substituted or unsubstituted L-configuration or D-configuration Trp, Ser or Lys, wherein the substitution is by being substituted with at least one tert-butyl, tert-butoxycarbonyl and triphenylmethyl substituents; Xaa3 is Pro, Nle, Phe or Arg in the L or D configuration, substituted or unsubstituted, wherein the substitution is by being substituted by at least one nitro or adamantinoxycarbonyl substituent; Xaa4 is absent or is substituted or unsubstituted L or D configuration of Trp, Nle, Phe, Lys or Ser, wherein the substitution is by being substituted by at least one substituent of tert-butyl, tert-butyloxycarbonyl and triphenylmethyl. Y is a straight-chain or branched acyl group with 6 to 20 carbon atoms.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, optical isomer, tautomer, polymorph, solvate, metabolite, or isotopically labeled compound thereof, characterized in that, Xaa1 either does not exist or is an L-configuration Nle; Xaa2 is Trp, Ser, or Ser(tBu) of L configuration; Xaa3 is Pro, Nle, Phe, Arg or Arg(NO2) in the L configuration; Xaa4 either does not exist or is either Trp (L configuration), Lys(Boc), or Phe (D configuration).

3. The compound according to claim 2, or a pharmaceutically acceptable salt, ester, stereoisomer, optical isomer, tautomer, polymorph, solvate, metabolite, or isotopically labeled compound thereof, characterized in that, Xaa2 is either Trp or Ser(tBu) of the L configuration; Xaa3 is Nle or Arg(NO2) in the L configuration; Xaa4 is absent or is either an L-configuration Trp or Lys(Boc), preferably an L-configuration Lys(Boc).

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester, stereoisomer, optical isomer, tautomer, polymorph, solvate, metabolite, or isotopically labeled compound thereof, characterized in that, X is selected from any of the following: Trp-Pro-dPhe; Nle-Trp-Nle; Nle-Trp-Nle-Lys(Boc); Trp-Phe-Trp; Ser(tBu)-Arg(NO2)-Trp; Ser-Arg(NO2)-Trp.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, ester, stereoisomer, optical isomer, tautomer, polymorph, solvate, metabolite, or isotopically labeled compound thereof, characterized in that, The Y is a straight-chain or branched acyl group with 6 to 16 carbon atoms; preferably, the Y is selected from acyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, and tetradecanoyl; more preferably from octanoyl, decanoyl, dodecanoyl, and tetradecanoyl; most preferably from octanoyl, decanoyl, and dodecanoyl.

6. A echinocandin compound or a pharmaceutically acceptable salt, ester, stereoisomer, optical isomer, tautomer, polymorph, solvate, metabolite, or isotopically labeled compound thereof, said compound being selected from any of the following: 、 、 、 、 、 、 、 、 、 。 7. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises a compound as described in any one of claims 1 to 5, or a pharmaceutically acceptable salt, ester, stereoisomer, optical isomer, tautomer, polymorph, solvate, metabolite, or isotopically labeled compound thereof; or, an echinocandin compound as described in claim 6, or a pharmaceutically acceptable salt, ester, stereoisomer, optical isomer, tautomer, polymorph, solvate, metabolite, or isotopically labeled compound thereof; and optionally, further comprising a pharmaceutically acceptable carrier.

8. The use of a compound as described in any one of claims 1 to 5, or a pharmaceutically acceptable salt, ester, stereoisomer, optical isomer, tautomer, polymorph, solvate, metabolite, or isotopically labeled compound thereof; an echinocandin compound as described in claim 6, or a pharmaceutically acceptable salt, ester, stereoisomer, optical isomer, tautomer, polymorph, solvate, metabolite, or isotopically labeled compound thereof; or, the use of the pharmaceutical composition as described in claim 7 in the preparation of a medicament for treating and / or preventing fungal infections, or a medicament for treating and / or preventing diseases caused by fungal infections.

9. The application according to claim 8, characterized in that, The fungi include one or more of Candida albicans, Candida auris, Candida tropicalis, Candida glabrata, Candida parapsilosis, and Candida krusei.

10. The use of a compound as described in any one of claims 1 to 5, or a pharmaceutically acceptable salt, ester, stereoisomer, optical isomer, tautomer, polymorph, solvate, metabolite, or isotopically labeled compound thereof; an echinocandin compound as described in claim 6, or a pharmaceutically acceptable salt, ester, stereoisomer, optical isomer, tautomer, polymorph, solvate, metabolite, or isotopically labeled compound thereof; or, the use of the pharmaceutical composition as described in claim 7 in the preparation of a β-(1,3)-D-glucan synthase inhibitor.

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