Drug-loaded macromolecule of antifungal drug and preparation method of drug-loaded macromolecule

Abstract

The invention relates to a drug-loading macromolecule of an antifungal drug and a preparation method of the drug-loading macromolecule. Specifically, the compound involved in the invention is a dendritic polymer loaded with a drug and a pharmacokinetic modifier, and especially relates to the connection of an antifungal drug to the dendritic polymer through a specific linker. The compound can be used for adjusting the release rate of antifungal drugs, particularly through selection of linkers.

Description

Antifungal drug-carrying macromolecule and preparation method thereof Technical Field

[0001] The present disclosure belongs to the field of medicine and relates to a dendrimer loaded with drugs and pharmacokinetic modifiers, and in particular to linking drugs to dendrimers via specific linkers. Background Art

[0002] Despite significant progress in pharmaceutical research, many drugs remain difficult to formulate into suitable dosage forms for administration during clinical trials due to their physical properties, such as solubility. Furthermore, some drugs can cause toxic effects during periods of high drug concentration after administration or fail due to a poor therapeutic index. Other challenges include poor absorption, low bioavailability, poor in vivo stability, systemic side effects resulting from poor targeting, and the inability to control drug biodistribution, metabolism, and renal or hepatic clearance after administration.

[0003] In recent years, dendrimers have made significant progress in biotechnology and pharmaceutical applications. These polymers have a densely branched structure, similar to a core molecule that repeatedly branches outward, eventually forming a spherical tree. They are characterized by a higher concentration of functional groups per unit molecular volume than conventional polymers. Dendrimers have unique properties such as high branching degree, multivalency, spherical structure, and well-defined molecular weight, making them promising candidates for new scaffolds for drug delivery. Over the past decade, the design and synthesis of biocompatible dendrimers and the exploration of their applications in biosciences such as drug delivery have received increasing attention.

[0004] Starpahrma uses dendrimer-based polylysine technology to deliver anticancer drugs, enhancing their pharmacological properties and ensuring they are delivered to the right part of the body at the right time. This technology is known as "drug delivery" and is The company is currently utilizing Technology to develop three anti-cancer drugs, including -Docetaxel, - Cabazitaxel and -Irinotecan, although both are still in the clinical research stage, have shown good application prospects.

[0005] CN103796684A discloses macromolecules that link drugs to dendrimers via diacid linkers, particularly diacid linkers comprising C1-C10 saturated branched or linear chains interrupted by oxygen, nitrogen, or sulfur atoms.

[0006] Summary of the Invention

[0007] The present disclosure provides a compound, wherein

[0008] i) a dendrimer D having surface amino groups, wherein at least two different end groups are covalently attached to the surface amino groups of the dendrimer:

[0009] ii) a first terminal group, which is a residue A of a pharmaceutically active agent, a derivative thereof, or a precursor thereof containing a carboxyl group, a hydroxyl group, an amino group, or a thiol group;

[0010] iii) a second terminal group which is a pharmacokinetic modifier;

[0011] The first end group is covalently linked to the surface amino group of the dendrimer through an optional linker;

[0012] The residue A of the pharmaceutically active agent, its derivative or its precursor is a residue of a compound having antifungal activity, its derivative or its precursor.

[0013] In some embodiments, the compound has the general structure wherein m is selected from an integer of at least 1, and its upper limit depends on the number of surface amino groups of the dendrimer D; D, Linker, and A are as defined above.

[0014] In some embodiments, the pharmaceutically active agent is selected from antifungal agents, preferably azole antifungal agents.

[0015] In some embodiments, the pharmaceutically active agent is selected from an imidazole antifungal agent or a triazole antifungal agent, preferably a triazole antifungal agent.

[0016] In some embodiments, the antifungal agents include but are not limited to azoles (e.g., fluconazole, isavuconazole, isavuconazole derivatives, itraconazole, ketoconazole, miconazole, clotrimazole, voriconazole, posaconazole, ravuconazole, etc.), polyenes (e.g., natamycin, ruxomicin, nystatin, amphotericin B, etc.), echinocandins (e.g., Cancidas), pramicones (e.g., benamicin, huaguangmycin, sordin, allylamine, etc.), triclosan, piroctone, fenpropimorph, terbinafine, and derivatives and analogs thereof.

[0017] In some embodiments, the linker comprises: a bond, an atom (such as oxygen or sulfur), a spacer group such as NR', C(O), C(O)NH, SO, SO2, SO2NH, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, wherein the alkylene, heteroalkylene, alkenylene, alkynylene is optionally interrupted by one or more selected from cycloalkylene, heterocyclylene, arylene, heteroarylene, wherein R' is hydrogen, acyl, aliphatic or substituted aliphatic.

[0018] In some embodiments, the linker comprises at least one cleavable linking group. Such a cleavable linker can provide sustained release of the antifungal agent from the conjugate, which can provide improved pharmacokinetics. For example, using a lipase-cleavable linker, no or minimal cleavage occurs in the absence of fungi. Consequently, no or minimal drug is released, thereby reducing any toxicity of the drug.

[0019] In some embodiments, the linker can be connected to the ring nitrogen of the azole moiety of the antifungal agent. Alternatively, the linker can be connected to the hydroxyl or carboxyl group of the antifungal agent. The linker can also be connected to a heteroatom of the antifungal agent, such as O, S or N.

[0020] In another aspect, the present disclosure provides a compound comprising:

[0021] i) a dendrimer D having surface amino groups, wherein at least two different end groups are covalently attached to the surface amino groups of the dendrimer:

[0022] ii) a first terminal group, which is a residue A of a pharmaceutically active agent, a derivative thereof, or a precursor thereof containing a carboxyl group, a hydroxyl group, an amino group, or a thiol group;

[0023] iii) a second terminal group which is a pharmacokinetic modifier;

[0024] The first terminal group is connected to the linker -X 1 -LX 2 - covalently linked to the surface amino groups of the dendrimer, X 1 is selected from -C(O)- or -O-, and is linked to the residue A of a pharmaceutically active agent, a derivative thereof, or a precursor thereof, and X 2 is -C(O)-, connected to the dendrimer D via an amide bond, wherein:

[0025] a) L is C 1-10A linear or branched alkylene or heteroalkylene, wherein the alkylene or heteroalkylene is optionally interrupted by one or more cycloalkylene, heterocyclylene, arylene, heteroarylene, and the alkylene or heteroalkylene is optionally substituted by one or more substituents selected from the following groups: deuterium, hydroxyl, C 3-7 Cycloalkyl, C 1-6 Alkoxy, haloalkyl, haloalkoxy, halogen, nitro, cyano, acyl, amino, thiol, sulfinyl, sulfonyl, -NR 1 R 2 , aryl, heteroaryl and heterocyclic groups;

[0026] b) L is C 2-10 A straight or branched alkenylene or alkynylene group, wherein the alkenylene or alkynylene group is optionally substituted by one or more substituents selected from the group consisting of deuterium, hydroxyl, C 3-7 Cycloalkyl, C 1-6 Alkoxy, haloalkyl, haloalkoxy, halogen, nitro, cyano, acyl, amino, thiol, sulfinyl, sulfonyl, -NR 1 R 2 , aryl, heteroaryl and heterocyclic groups;

[0027] The residue A of the pharmaceutically active agent, its derivative or its precursor is a residue of a compound having antifungal activity, its derivative or its precursor;

[0028] R 1 、R 2 The same or different, each independently selected from hydrogen, hydroxyl, C 1-6 Alkyl, cycloalkyl, C 1-6 Alkoxy.

[0029] In some embodiments, L is C 1-10 A straight or branched chain alkylene or heteroalkylene group is optionally substituted with one or more -NR 1 R 2 Substituted, where R 1 、R 2 are each independently selected from hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkoxy is optionally selected from hydroxy, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, amino and C 1-6 The alkylamino group is substituted with one or more substituents.

[0030] In some embodiments, L is C 1-10 A straight or branched chain alkylene or heteroalkylene group is optionally substituted with one or more -NR 1 R 2 Substituted, where R 1 、R 2 are each independently selected from hydrogen, C 1-6 In some embodiments, L is C 1-10 A straight or branched chain alkylene or heteroalkylene group is optionally substituted with one or more -NR 1 R 2 Substituted, where R 1 、R 2 are each independently selected from hydrogen and C 1-6 Alkyl, and R 1 、R 2 Not hydrogen at the same time.

[0031] In some embodiments, the C 1-10 The straight-chain or branched alkylene group is selected from methylene, ethylene, propylene, butylene, pentylene and hexylene, preferably ethylene, propylene, butylene, pentylene and hexylene, and most preferably propylene.

[0032] In some embodiments, Linker-X 1 -LX 2 -Medium, X 1 is -C(O)-, a residue linked to a pharmaceutically active agent, a derivative thereof, or a precursor thereof; X 2 It is -C(O)-, which connects to the surface amino group of the dendrimer D to form an amide bond.

[0033] In some embodiments, the residue A of the pharmaceutically active agent, its derivative, or its precursor comprises a hydroxyl group and is bonded to X via the hydroxyl oxygen atom. 1 Form ester bonds.

[0034] In some specific embodiments, the compound structure is selected from the following:

[0035] In some embodiments, the linkers of the present disclosure are selected to provide a desired rate of drug release, for example, fast release or slow release.

[0036] In some embodiments, the release rate of the pharmaceutically active agent from the compound is faster than that achieved independently of the compound delivery, potentially at least twice as fast. In some embodiments, the release rate of the pharmaceutically active agent from the compound is slower than that achieved independently of the compound delivery, potentially two, three, four, five, six, seven, eight, nine, ten, or more, fifteen, twenty, or thirty times slower. Compounds with a low release rate are suitable for formulating the compound into a drug that releases slowly over an extended period of time, such as from one week to three months, from one month to six months, or more than six months. Rapid release preferably releases greater than 50% of the pharmaceutically active agent within 0-8 hours, particularly within 0-4 hours, more particularly within 0-2 hours, and more particularly within 5-60 minutes. Intermediate release preferably releases greater than 50% of the pharmaceutically active agent within 1-72 hours, particularly within 2-48 hours. The release rate of the pharmaceutically active agent can be controlled by selecting an appropriate linker, and the release rate also depends on the characteristics of the pharmaceutically active agent. In some embodiments, the pharmaceutically active agent is attached to the dendrimer via the same linker. In other embodiments, the pharmaceutically active agent is linked to the dendrimer via two or more linkers such that the pharmaceutically active agent can be released from the compound at different release rates.

[0037] In some embodiments, the first end group and the second end group are present in a ratio of 1:2-2:1, in particular 1:2, 1:1, 2:1. In some embodiments, the first end group and the second end group are present in a ratio of 1:1.

[0038] In some embodiments, the compound comprises a third end group that is a blocking group, a drug, or a targeting group. The blocking group can be an acyl group. In some embodiments, the ratio of the first end group, the second end group, and the third end group is 1:1:1-1:2:2, particularly 1:2:1. In some embodiments, at least 50% of the end groups comprise one of the first end group or the second end group. In specific embodiments, the pharmaceutically active agent is bound to greater than 14%, 25%, 27%, 30%, 39%, 44%, or 48% of the surface amino groups. In some embodiments, the pharmacokinetic modifier is bound to greater than 15%, 25%, 30%, 33%, or 46% of the surface amino groups.

[0039] In some embodiments, the residue A of the pharmaceutically active agent, its derivative, or its precursor has the structure of the compound of formula I,

[0040] in:

[0041] The compound of formula II having antifungal activity contains a nitrogen heterocyclic moiety, which is ** N in the form of quaternary ammonium *C is connected, Q is the part other than the nitrogen heterocyclic part;

[0042] Y is selected from a nitrogen atom or a carbon atom;

[0043] Z - It is a pharmaceutically acceptable monovalent anion;

[0044] Ring A is selected from 3-10 membered carbocyclic ring, 3-10 membered heterocyclic ring, 6-10 membered aromatic ring, 5-10 membered heteroaromatic ring, wherein the carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring is optionally substituted by one or more substituents selected from the following groups: halogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkylamino, oxo, thio, cyano, amino, nitro;

[0045] R A 、R B 、R C 、R D 、R E the same or different, each independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Amino-substituted alkyl, C 1-6 Alkylcarbonyl, haloC 1-6 Alkylcarbonyl, C 1-6 Hydroxyalkylcarbonyl, C 1-6 Alkoxycarbonyl, C 1-6 Haloalkoxycarbonyl, C 1-6 Amino-substituted alkylcarbonyl, C 1-6 Alkylthio, C 1-6 Alkylsulfinyl, C 1-6 alkylsulfonyl, trifluoromethyl, trifluoromethoxy, halogen, hydroxy, nitro, carboxyl, cyano, amino, aminosulfonyl or sulfonic acid,

[0046] or R D 、R E Together with the connected carbon atom, it forms oxo, thio, =NR 3 ;

[0047] “ " represents the compound of formula I through the hydroxyl oxygen atom carried by it and the linker X 1 Ends connected;

[0048] R3 Selected from hydrogen, hydroxyl, C 1-6 Alkyl, cycloalkyl, C 1-6 alkoxy;

[0049] n is selected from 0, 1, 2, 3;

[0050] X 1 As defined above.

[0051] In some embodiments, the compound has the structure shown in Formula III,

[0052] in * , Q, Z - , m, n, ring A, Y, R A 、R B 、R C 、R D 、R E , D, X 1 , L, X 2 As defined above.

[0053] In some embodiments, the ring A is selected from a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring, preferably a benzene ring, a pyridine ring, and most preferably a pyridine ring.

[0054] In some embodiments, the compound of formula I is a compound of formula I-1,

[0055] Among them, *, Q, Y, Z - 、R A 、R B 、R C 、R D 、R E ,n," ” as defined above.

[0056] In some embodiments, the compound has the structure shown in Formula III-1,

[0057] Among them, *, Q, Z - ,m,n,Y,R A 、R B 、R C 、R D 、R E , D, and L are as defined above.

[0058] In some embodiments, when Y is a nitrogen atom, the compound of formula II is a compound of formula II-1 The compound of formula II-1 is a triazole antifungal agent or its residue having antifungal activity, which is **N in the form of quaternary ammonium * C is connected, and Q is the remaining part except the triazole ring part; the compound of formula II-1 is preferably fluconazole, isavuconazole, isavuconazole derivatives, itraconazole, voriconazole, posaconazole, ravuconazole, ravuconazole or their residues, and most preferably isavuconazole residue or isavuconazole derivative residue.

[0059] In some embodiments, wherein the compound of formula I is a compound of formula I-2,

[0060] Among them, *, Q, Z - 、R A 、R B 、R C 、R D 、R E ,n," ” as defined above.

[0061] In some embodiments, the compound has the structure shown in Formula III-2,

[0062] Among them, *, Q, Z - 、m、n、R A 、R B 、R C 、R D 、 R E , D, and L are as defined above.

[0063] In some embodiments, wherein the compound of formula I is a compound of formula I-3,

[0064] where Z - 、R A 、R B 、R C 、R D 、R E ,n," ” as defined above.

[0065] In some embodiments, the compound has the structure shown in Formula III-3,

[0066] where Z - ,m,n,R A 、R B 、R C 、R D 、R E , D, and L are as defined above.

[0067] In some embodiments, wherein R A 、RB the same or different, each independently selected from hydrogen or C 1-6 Alkyl groups are preferably hydrogen, methyl, ethyl, propyl, isopropyl, butyl, and isobutyl, and most preferably hydrogen and methyl.

[0068] In some embodiments, wherein R C Selected from halogen, hydroxy, nitro, carboxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylsulfinyl, C 1-6 Alkylsulfonyl, trifluoromethyl, trifluoromethoxy, aminosulfonyl or sulfonic acid, preferably halogen, hydroxy, nitro, carboxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy.

[0069] In some embodiments, wherein R D 、R E All are hydrogen.

[0070] In some embodiments, wherein n is 0.

[0071] In some embodiments, wherein the compound of formula I is a compound of formula I-4,

[0072] where Z - 、" ” as defined above.

[0073] In some embodiments, the compound has the structure shown in Formula III-4,

[0074] Among them, D, Z - , m, and L are as defined above. In some embodiments, the compound of formula III-4 is selected from formula III-4a, formula III-4b, or formula III-4c, formula III-4d,

[0075] Wherein k is selected from an integer of 1 to 64, D, Z - , m, and L are as defined above.

[0076] In some embodiments, m or k is selected from an integer of 1 to 64, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, or 64. In some embodiments, m or k is selected from 4, 8, 16, 32, or 64. In some embodiments, m or k is selected from 16, 32, or 64.

[0077] In some embodiments, the antifungal agent is an azole-based antifungal agent. An azole-based antifungal agent refers to an antifungal agent that contains at least one azole in its structure. In some embodiments, the antifungal agent is selected from azoles including imidazoles and triazoles. Exemplary azole-based antifungal agents include, but are not limited to, fluconazole, isavuconazole, itraconazole, ketoconazole, miconazole, clotrimazole, voriconazole, posaconazole, and ravuconazole, as well as derivatives and analogs thereof.

[0078] In some embodiments, the antifungal agent is selected from fluconazole, isavuconazole, itraconazole, voriconazole, posaconazole, ravuconazole, ravuconazole, and derivatives and analogs thereof. In some embodiments, the antifungal agent is selected from isavuconazole and its derivatives and analogs.

[0079] In some embodiments, the pharmaceutically active agent is slightly soluble or insoluble in aqueous solution.

[0080] The second end group is a pharmacokinetic modifier that can modify or modulate the pharmacokinetic characteristics of the pharmaceutically active agent or compound, including absorption, distribution, metabolism, and / or excretion. In certain embodiments, the pharmacokinetic modifier extends the plasma half-life of the pharmaceutically active agent, such that the half-life of the pharmaceutically active agent attached to the compound is longer than the half-life of the pharmaceutically active agent alone or in a non-dendritic polymer carrier. Preferably, the half-life of the compound or composition is at least 2 times, and more preferably at least 10 times, longer than the half-life of the pharmaceutically active agent alone or in a non-dendritic polymer carrier.

[0081] The pharmacokinetic modifier can be selected from polyethylene glycol, polyethyloxazoline, polyvinylpyrrolidone, polypropylene glycol, folate, or a folate derivative for a ligand of a cell surface receptor. In some embodiments, the pharmacokinetic modifier is polyethylene glycol. In some embodiments, the polyethylene glycol has a molecular weight in the range of 220 to 5500 Da, for example, 220-2500 Da, 570-2500 Da, 220-1100 Da, 570-1100 Da, 1000-5500 Da, 1000-2500 Da, or 1000-2300 Da. In some embodiments, the pharmacokinetic modifier forms an amide bond with an amino group on the surface of the dendrimer.

[0082] Targeting group is for being bonded to the reagent of biological target cell, organ or tissue with some selectivity, thereby helps to direct compound to specific target in vivo and makes it accumulate in this target cell, organ or tissue.In addition, targeting group can provide mechanism for the compound that enters cell or tissue actively by receptor-mediated endocytosis.Specific example comprises lectin and antibody and other part (comprising small molecule) for cell surface receptor.This interaction can be carried out by any type of key or association (comprising covalent bond, ionic bond and hydrogen bond, van der Waals force).Suitable targeting group comprises those that are bonded to cell surface receptor, for example, folate receptor, adrenergic receptor, growth hormone, luteinizing hormone receptor, estrogen receptor, epidermal growth factor receptor, fibroblast growth factor receptor (such as FGFR2), IL-2 receptor, CFTR and vascular epithelial growth factor (VEGF) receptor.

[0083] In some embodiments, the targeting group may be bound to the dendrimer core directly or, preferably, through a linking group. The linking group may be any divalent group capable of binding to a functional group on the core and a functional group on the targeting group.

[0084] The compounds of the present disclosure include dendrimers in which the outermost generation of the structural unit has surface amino groups. The characteristics of the dendrimer of the compound are not particularly important, provided that it has surface amino groups. For example, the dendrimer can be polylysine, a polylysine analogue, polyamidoamine (PAMAM), polyethyleneimine (PEI) or polyetherhydroxylamine (PEHAM) dendrimers. In some embodiments, the dendrimer is polylysine or a polylysine analogue. Polylysine or a polylysine analogue comprises a core and 2-7 generations of lysine or a lysine analogue, for example, comprising 2 generations, 3 generations, 4 generations, 5 generations, 6 generations or 7 generations of lysine or a lysine analogue.

[0085] In some embodiments, the lysine has the structure shown in 1:

[0086] In some embodiments, the lysine analog has the structure shown in 2:

[0087] In some embodiments, the lysine analog has the structure shown in 3: wherein a is 1 or 2; b and c are the same or different and are integers from 1 to 4.

[0088] In some embodiments, the lysine analog has the structure shown in 4: wherein a is an integer from 0 to 2; b and c are the same or different and are integers from 2 to 6.

[0089] In some embodiments, the lysine analog has the structure shown in 5: wherein a is an integer from 0 to 5; b and c are the same or different and are integers from 1 to 5.

[0090] In some embodiments, the lysine analog has the structure shown in 6: wherein a is an integer from 0 to 5; b and c are the same or different and are integers from 0 to 5.

[0091] In some embodiments, the lysine analog has the structure shown in 7: wherein a is an integer from 0 to 5; b and c are the same or different and are integers from 1 to 5.

[0092] In some embodiments, the lysine analog has the structure shown in 8: wherein a is an integer from 0 to 5; b, c and d are the same or different and are integers from 1 to 5.

[0093] In some embodiments, the lysine analog has the structure shown in 9: wherein a is an integer from 0 to 5; b and c are the same or different and are integers from 1 to 5.

[0094] The core of the dendrimers of the present disclosure, in particular polylysine or polylysine analogs, may be selected from benzhydrylamine (BHA), benzhydrylamine of lysine (BHALys) or lysine analogs or:

[0095] wherein a is an integer from 1 to 9, preferably from 1 to 5;

[0096] wherein a, b and c may be the same or different and are integers from 1 to 5, d is an integer from 0 to 100, preferably an integer from 1 to 30;

[0097] wherein a and b may be the same or different and are integers from 0 to 5;

[0098] wherein a and c may be the same or different and are integers from 1 to 6, and b is an integer from 0 to 6;

[0099] wherein a and d may be the same or different and are integers from 1 to 6, and b and c may be the same or different and are integers from 0 to 6;

[0100] wherein a and b are identical or different and are integers from 1 to 5, particularly from 1 to 3, especially 1;

[0101] wherein a, b and c are the same or different and are integers selected from 1 to 6;

[0102] wherein a, b and c are the same or different and are integers selected from 0 to 6;

[0103] wherein a, b and c are the same or different and are integers selected from 0 to 6;

[0104] wherein a, b and c may be the same or different and are integers from 0 to 6, and d, e and f may be the same or different and are integers from 1 to 6;

[0105] wherein a, b and c may be the same or different and are integers from 1 to 6;

[0106] wherein a, b, c and d may be the same or different and are integers from 0 to 6;

[0107] wherein a, b, c and d may be the same or different and are integers from 1 to 6; or

[0108] wherein a, b, c and d may be the same or different and are integers from 0 to 6, and e, f, g and h may be the same or different and are integers from 1 to 6.

[0109] In some embodiments, the compound comprises:

[0110] i) a dendrimer D having surface amino groups, wherein at least two different end groups are covalently attached to the surface amino groups of the dendrimer:

[0111] ii) a first terminal group, which is a pharmaceutically active agent or a residue thereof A containing a carboxyl group, a hydroxyl group, an amino group or a thiol group;

[0112] iii) a second terminal group, which is a pharmacokinetic modifier, polyethylene glycol;

[0113] The first end group is covalently linked to the surface amino group of the dendrimer via a linker, and the linker is selected from

[0114] The dendrimer D is selected from BHALys[Lys] 16 、BHALys[Lys] 32 or BHALys[Lys] 64 , the polyethylene glycol has a molecular weight ranging from 1000 to 2500 Da.

[0115] In some embodiments, the number of grafted residues A of the pharmaceutically active agent, its derivative or its precursor is selected from 10 to 64. In some embodiments, the number of grafted residues A of the pharmaceutically active agent, its derivative or its precursor is selected from 20 to 32. In some embodiments, the number of grafted residues A of the pharmaceutically active agent, its derivative or its precursor is selected from 27 to 32. In some embodiments, the number of grafted residues A of the pharmaceutically active agent, its derivative or its precursor is selected from 28 to 31.

[0116] In some embodiments, wherein the dendrimer D is BHALys[Lys] 16 wherein the number of grafted residues A of the pharmaceutically active agent, its derivative or its precursor is selected from 10 to 16. In some embodiments, wherein the dendrimer D is BHALys[Lys] 16 wherein the number of grafted residues A of the pharmaceutically active agent, its derivative or its precursor is selected from 13 to 16. In some embodiments, wherein the dendrimer D is BHALys[Lys] 16 When the grafted number of the residue A of the pharmaceutically active agent, its derivative or its precursor is selected from 14 to 15.

[0117] In some embodiments, wherein the dendrimer D is BHALys[Lys] 32 wherein the number of grafted residues A of the pharmaceutically active agent, its derivative or its precursor is selected from 20 to 32. In some embodiments, wherein the dendrimer D is BHALys[Lys] 32 wherein the number of grafted residues A of the pharmaceutically active agent, its derivative or its precursor is selected from 27 to 32. In some embodiments, wherein the dendrimer D is BHALys[Lys] 32When the grafted number of the residue A of the pharmaceutically active agent, its derivative or its precursor is selected from 28 to 31.

[0118] In some embodiments, wherein the dendrimer D is BHALys[Lys] 64 wherein the number of grafted residues A of the pharmaceutically active agent, its derivative or its precursor is selected from 40 to 64. In some embodiments, wherein the dendrimer D is BHALys[Lys] 16 wherein the number of grafted residues A of the pharmaceutically active agent, its derivative or its precursor is selected from 54 to 64. In some embodiments, wherein the dendrimer D is BHALys[Lys] 16 When the grafted number of the residue A of the pharmaceutically active agent, its derivative or its precursor is selected from 60 to 64.

[0119] On the other hand, the present disclosure also provides a compound selected from

[0120] in:

[0121] x is independently selected from an integer of 2 to 50;

[0122] y represents the number of lysine structural units in the outermost generation of the dendrimer D, selected from 2, 4, 8, 16, 32, and 64;

[0123] Z - As defined above.

[0124] In some embodiments, the Z - Selected from fluoride ion, chloride ion, bromide ion, iodide ion, HCO3 - 、HSO4 - , preferably HSO4 - , chloride ion, iodide ion, and iodide ion is most preferred.

[0125] In some embodiments, x is selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50. In some embodiments, x is selected from the group consisting of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48.

[0126] In some embodiments, when y is 32, the grafting number of isavuconazole is selected from 20 to 32 (including 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 or any number between any two numbers).

[0127] The present disclosure also relates to a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition does not contain a solubilizing excipient, such as polyethoxylated castor oil or polysorbate. In some embodiments, the pharmaceutical composition is administered transdermally, orally, or by injection.

[0128] The compositions of the compounds of the present invention include those suitable for oral, rectal, topical, nasal, inhalation, aerosol, ophthalmic, or parenteral (including intraperitoneal, intravenous, subcutaneous or intramuscular injection) administration. The compositions can be conveniently presented in unit dosage form and can be prepared by any method well known in the pharmaceutical field. All methods include the step of associating the compound with a carrier constituting one or more auxiliary components. Typically, the composition is prepared by associating the compound with a liquid carrier to form a solution or suspension, or alternatively, the compound is associated with a formulation component suitable for forming a solid, optionally granular product, and then, if necessary, the product is shaped into the desired delivery form. The solid preparations of the present invention, when being particles, will generally include a particle size range of about 1 nanometer to about 500 microns. Typically, for solid preparations intended for intravenous administration, the particle diameter range will generally be about 1 nm to about 10 microns. The composition may contain a compound of the present disclosure that is a nanoparticle having a particle diameter of less than 1000 nm, for example, 5 to 1000 nm, particularly 5 to 500 nm, especially 5 to 400 nm (such as 5 to 50 nm and particularly 5 to 20 nm). In a particular embodiment, the composition contains a compound having an average size of 5 to 20 nm. In some embodiments, the compound is polydisperse in the composition, with a PDI of between 1.01 and 1.8, particularly between 1.01 and 1.5, and especially between 1.01 and 1.2. In a particular embodiment, the compound is monodisperse in the composition. Particularly preferred are sterile, lyophilized compositions that are reconstituted in an aqueous vehicle prior to injection.

[0129] In some embodiments, the composition contains a compound having an average size of 5 to 20 nm. In some embodiments, the particle size D of the compound 90 or D 50Less than 1000 nm, for example, 5 to 1000 nm, particularly 5 to 500 nm, especially 5 to 400 nm (such as 5 to 50 nm, particularly 5 to 20 nm). In a particular embodiment, the composition comprises a 50 The compound is 5 to 20 nm.

[0130] The compounds of the present disclosure can also be used to provide controlled-release and / or sustained-release formulations of pharmaceutically active agents. In sustained-release formulations, the formulation ingredients are selected to release the macromolecule from the formulation over an extended period (e.g., days, weeks, or months). Such formulations include transdermal patches or in implantable devices that can be deposited subcutaneously or by intravenous, subcutaneous, intramuscular, intradural, or intracranial injections. In controlled-release formulations, the diacid linker is selected to release most of its pharmaceutically active agent within a given time window. For example, when it is known that most of the macromolecules accumulate in the target organ, tissue, or tumor, a linker can be selected to release most of its pharmaceutically active agent after the accumulation time has passed. This allows for the delivery of a high drug load at the site where its effect is needed at a given time point. Alternatively, a linker is selected to release the pharmaceutically active agent at therapeutic levels over an extended period. In some embodiments, the formulation can have a variety of controlled-release properties. For example, a formulation comprises a compound in which the drugs are linked by different linkers, which allows for a burst of rapid release of the drug followed by a slower release at a lower but constant therapeutic level over an extended period. In some embodiments, the formulation may have both sustained and controlled release properties. For example, the formulation components may be selected to release a macromolecule over an extended period and the linkers may be selected to deliver a constant, low therapeutic level of the pharmaceutically active agent. In some embodiments, the pharmaceutically active agent is linked to the same molecule via different linkers. In some embodiments, each drug-linker combination is linked to a different compound in the same formulation.

[0131] In some embodiments, the pharmaceutical composition comprises a compound that is formulated to release greater than 50% of the pharmaceutically active agent between 5 minutes and 60 minutes. In some embodiments, the pharmaceutical composition comprises a compound that is formulated to release greater than 50% of the pharmaceutically active agent between 2 hours and 48 hours. In some embodiments, the pharmaceutical composition comprises a compound that is formulated to release greater than 50% of the pharmaceutically active agent between 5 days and 30 days.

[0132] Another aspect of the present disclosure provides a method for treating a fungal infection, comprising administering an effective amount of a compound or pharmaceutical composition of the present disclosure, wherein the pharmaceutically active agent of the first terminal group is an antifungal agent. "Fungi" as used herein includes a variety of nucleated, spore-bearing organisms that lack chlorophyll. Examples include yeast, mildews, molds, rusts, and mushrooms. Examples of fungi include, but are not limited to, Aspergillus fumigates, Aspergillus flavus, Aspergillus nidulans, Candida albicans, Candida glabrata, Candida guilliermondii, Candida krusei, Candida lusitaniae, Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans, Issatchenkia orientalis, Coccidioides, Paracoccidioides, Histoplasma, Blastomyces, and Neurospora crassa. In some embodiments, the fungus is of the genus Malassezia (e.g., M. furfur, M. pachydermatis, M. globosa, M. restricta, M. slooffiae, M. sympodialis, M. nana, M. yamatoensis, M. dermatis, and M. obtuse).

[0133] In another aspect of the present disclosure, there is provided a method of reducing hypersensitivity following treatment with an antifungal agent comprising administering a pharmaceutical composition of the present disclosure, wherein the composition is substantially free of solubilizing excipients such as Cremophor EL and polysorbate 80.

[0134] In another aspect of the present disclosure, a method of reducing the toxicity of an antifungal agent or a formulation of an antifungal agent is provided, comprising administering a compound of the present disclosure, wherein the antifungal agent is a first terminal group of the compound. In some embodiments, the reduced toxicity is hematotoxicity, neurotoxicity, gastrointestinal toxicity, cardiotoxicity, hepatotoxicity, nephrotoxicity, ototoxicity, or encephalopathy.

[0135] In another aspect of the present disclosure, a method for reducing side effects associated with an antifungal agent or a formulation of an antifungal agent is provided, comprising administering a compound of the present disclosure, wherein the antifungal agent is a first terminal group of the compound. In some embodiments, the reduced side effects are selected from the group consisting of neutropenia, leukopenia, thrombocytopenia, bone marrow toxicity, bone marrow suppression, neuropathy, fatigue, nonspecific neurocognitive problems, vertigo, encephalopathy, anemia, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, weakness, pain, nausea, vomiting, mucositis, alopecia, skin reactions, myalgia, and hypersensitivity.

[0136] In some embodiments, the compounds of the present disclosure or pharmaceutical compositions comprising the compounds can reduce or eliminate the need for premedication with agents such as corticosteroids and antihistamines.

[0137] Methods for preparing dendrimers are known in the art. For example, dendrimers of a compound can be prepared by a divergent process or a convergent process, or a mixture thereof.

[0138] In the divergent method, each generation of building blocks is sequentially added to the core or the previous generation. Surface generations with one or two surface amino groups are protected. If one of the amino groups is protected, the free amino group reacts with one of the linker, linker-pharmaceutical active agent, or pharmacokinetic modifier. If both amino groups are protected, they are protected with different protecting groups, so one protecting group can be removed without removing the other protecting group. One of the amino protecting groups is removed and reacted with one of the linker, linker-pharmaceutical active agent, or pharmacokinetic modifier. Once the initial end group has been attached to the dendrimer, the other amino protecting group is removed and the other first and second end groups are added. These groups are attached to the surface amino groups through amide formation known in the art.

[0139] In a convergent approach, each generation of building blocks builds upon the previous generation to form the dendron.The first and second end groups may be attached to the surface amino groups as described above, either before or after the dendron is attached to the core.

[0140] In the hybrid method, each generation of building blocks is added to the core or previous generation of building blocks. However, before the last generation is added to the dendrimer, the surface amino groups are functionalized with the end groups (e.g., first and second end groups, first and third end groups, or second and third end groups). The functionalized last generation is then added to the subsurface layer of the building block and the dendrons are attached to the core.

[0141] The pharmaceutically active agent is reacted with one of the carboxylic acids of the linker by ester formation as is known in the art. For example, an activated carboxylic acid is formed, such as using an acid chloride or anhydride, and reacted with the hydroxyl group of the pharmaceutically active agent. If the pharmaceutically active agent has more than one hydroxyl group, the other hydroxyl groups may be protected.

[0142] In the case where the targeting agent is attached to the core, the functional groups on the core can be protected during dendrimer formation and then deprotected and reacted with the targeting agent, linker, or targeting agent-linker. Alternatively, the core can be reacted with the linker or targeting agent-linker prior to dendrimer formation.

[0143] Suitable protecting groups, methods for their introduction and removal are described in Greene & Wuts, Protecting Groups in Organic Synthesis, 3rd edition, 1999.

[0144] The present disclosure also includes various deuterated forms of the compounds or their pharmaceutically acceptable salts, wherein each available hydrogen atom in the compound can be independently replaced by a deuterium atom. Those skilled in the art will know how to synthesize the deuterated forms of the compounds of the present disclosure or their pharmaceutically acceptable salts.

[0145] The present disclosure also includes isotopically labeled compounds, wherein one or more atoms in the compound are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Examples of isotopes that can be used in the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, iodine, and chlorine, e.g. 3 H. 11 C. 14 C. 18 F. 123 I or 125 I.

[0146] Compounds of the present disclosure can be in the form of pharmaceutically acceptable salts. However, it should be understood that non-pharmaceutically acceptable salts also fall within the scope of the present disclosure, because these can be used as intermediates in the preparation of pharmaceutically acceptable salts or may be useful in storage or transportation. Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids (such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, boric acid, sulfamic acid and hydrobromic acid), or salts of pharmaceutically acceptable organic acids (such as acetic acid, propionic acid, butyric acid, tartaric acid, maleic acid, hydroxymaleic acid, fumaric acid, citric acid, lactic acid, mucic acid, gluconic acid, benzoic acid, succinic acid, oxalic acid, phenylacetic acid, methanesulfonic acid, toluenesulfonic acid (toluenesulphonic), benzenesulfonic acid, salicylic acid, sulfanilic acid (sulphanilic), aspartic acid, glutamic acid, ethylenediaminetetraacetic acid, stearic acid, palmitic acid, oleic acid, lauric acid, pantothenic acid, tannic acid, ascorbic acid and valeric acid). Basic salts include, but are not limited to, those formed with pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, ammonium, and alkylammonium.

[0147] Unless stated otherwise, the following terms used in the specification and claims have the following meanings.

[0148] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0149] The term "hydroxy" refers to -OH.

[0150] The term "amino" refers to -NH2.

[0151] The term "cyano" refers to -CN.

[0152] The term "nitro" refers to -NO2.

[0153] The term "oxo" or "oxo" refers to "=0".

[0154] The term "thio" or "thio" refers to "=S".

[0155] The term "carbonyl" refers to C=O.

[0156] The term "carboxy" refers to -C(O)OH.

[0157] The term "halo" refers to substitution with one or more atoms selected from fluorine, chlorine, bromine, and iodine.

[0158] The term "alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 10 carbon atoms. Where appropriate, the alkyl group may have a specified number of carbon atoms, for example, C 1-4Alkyl, including alkyl groups having 1, 2, 3 or 4 carbon atoms in a straight or branched arrangement. Examples of suitable alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 4-methylbutyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 5-methylpentyl, 2-ethylbutyl, 3-ethylbutyl, heptyl, octyl, nonyl and decyl. Unless otherwise specified, alkyl groups may be substituted or unsubstituted.

[0159] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0160] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens (eg, fluorine, chlorine, bromine, iodine), wherein alkyl is as defined above.

[0161] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy. Unless otherwise specified, alkoxy groups may be substituted or unsubstituted.

[0162] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens (eg, fluorine, chlorine, bromine, iodine), wherein alkoxy is as defined above.

[0163] A "monovalent group" is a compound formed by formally eliminating a monovalent atom or group. A "subunit" is a compound formed by formally eliminating two monovalent or one divalent atom or group.

[0164] The term "alkylene" refers to the portion remaining after removing two hydrogen atoms from an alkane molecule, including straight and branched chain subgroups having 1 to 20 carbon atoms. Non-limiting examples of alkylene groups having 1 to 6 carbon atoms include methylene (-CH2-) and ethylene (e.g., -CH2CH2- or -CH(CH3)-). Unless otherwise specified, alkylene groups may be substituted or unsubstituted.

[0165] The term "heteroalkylene" refers to an alkylene group in which one or more -CH2- groups are replaced by a heteroatom selected from N, O, and S; wherein the alkylene group is as defined above; the heteroalkylene group may be substituted or unsubstituted. Unless otherwise specified, the heteroalkylene group may be substituted or unsubstituted.

[0166] The term "alkenyl" includes branched and straight chain alkenes or alkenes containing aliphatic hydrocarbon groups having from 2 to 12 carbon atoms, or if a specific number of carbon atoms is specified, that specific number is intended. For example, "C 2-6The term "alkenyl" refers to an alkenyl group having 2, 3, 4, 5 or 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3-methylbut-1-enyl, 1-pentenyl, 3-pentenyl and 4-hexenyl. Unless otherwise specified, alkenyl groups may be substituted or unsubstituted.

[0167] The term "alkynyl" includes branched and straight-chain alkynyl groups or alkenes containing aliphatic hydrocarbon groups having 2 to 12 carbon atoms, or if a specific number of carbon atoms is specified, that specific number is intended. Examples include ethynyl, propynyl (e.g., 1-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl, and 1-methylpent-2-ynyl. Unless otherwise specified, alkynyl groups may be substituted or unsubstituted.

[0168] The terms "alkenylene" and "alkynylene" refer to partially unsaturated branched or straight-chain divalent hydrocarbon groups derived from alkenyl or alkynyl groups. In some embodiments, such alkenylene groups are optionally substituted. Non-limiting examples of alkenylene groups include ethenylene, propenylene, butenylene, pentenylene, hexenylene, heptenylene, octenylene, nonenylene, decenylene, and the like; non-limiting examples of alkynylene groups include ethynylene, propynylene, butynylene, pentynylene, hexynylene, and the like. Unless otherwise specified, alkenylene and alkynylene groups may be substituted or unsubstituted.

[0169] The term "cycloalkyl" or "carbocycle" refers to a saturated or unsaturated cyclic hydrocarbon. The cycloalkyl ring may include the specified number of carbon atoms. For example, a 3- to 8-membered cycloalkyl group includes 3, 4, 5, 6, 7, or 8 carbon atoms. Examples of suitable cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, 1,4-cyclohexadienyl, cycloheptyl, and cyclooctyl. Unless otherwise specified, a cycloalkyl group or carbocycle may be substituted or unsubstituted.

[0170] The term "cycloalkylene" refers to a divalent cyclic hydrocarbon radical derived from a cycloalkyl radical. For example Unless otherwise specified, a cycloalkylene group may be substituted or unsubstituted.

[0171] The term "heterocycloalkyl" or "heterocycle" refers to a cyclic hydrocarbon in which one to four carbon atoms have been replaced by heteroatoms independently selected from N, N(R), S, S(O), S(O)2, and O. The heterocycle may be saturated or unsaturated. Examples of suitable heterocyclyl groups include tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolinyl, pyrazolinyl, pyranyl, piperidinyl, pyrazolinyl, dithiole, oxathiole, dioxanyl, dioxinyl, morpholino, and oxazinyl. Unless otherwise specified, the heterocycloalkyl or heterocycle may be substituted or unsubstituted.

[0172] The term "heterocyclylene" refers to a heterocyclic group having two monovalent radical centers, wherein the monovalent radical centers are derived by removing two hydrogen atoms from the same or two different carbon atoms of the parent heterocyclic ring, by removing two hydrogen atoms from two nitrogen atoms of the parent heterocyclic ring, or by removing a hydrogen atom from a nitrogen atom and a hydrogen atom from a carbon atom of the parent heterocyclic ring. Examples include, but are not limited to, piperidine-1,4-diyl, piperazine-1,4-diyl, tetrahydrofuran-2,4-diyl, tetrahydrofuran-3,4-diyl, azetidine-1,3-diyl, and pyrrolidine-1,3-diyl. Wherein, heterocyclic groups are as defined above.

[0173] The term "aryl" or "aromatic ring" refers to any stable, monocyclic or bicyclic carbon ring of up to 7 atoms in each ring, wherein at least one ring is aromatic. Examples of such aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, or binaphthyl. Unless otherwise specified, an aryl group or aromatic ring may be substituted or unsubstituted.

[0174] The term "arylene" refers to a group having two monovalent radical centers derived by removing two hydrogen atoms from the same or two different carbon atoms of a parent aryl group. Such arylene groups include, but are not limited to, phenylene groups. Wherein, aryl is as defined above.

[0175] The term "heteroaryl" or "heteroaromatic ring" refers to stable monocyclic or bicyclic rings of up to 7 atoms in each ring, wherein at least one ring is aromatic and at least one ring contains 1 to 4 heteroatoms selected from O, N and S. Heteroaryl groups within the scope of this definition include, but are not limited to, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, quinazolinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, phenylthio, 3,4-propylenedioxythiophenyl, benzothienyl, benzofuranyl, benzodioxane, benzodioxine, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, imidazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrahydroquinoline, thiazolyl, isothiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,4,5-tetrazinyl, and tetrazolyl. Unless otherwise specified, a heteroaryl group or heteroaryl ring may be substituted or unsubstituted.

[0176] The term "heteroarylene" refers to a heteroaryl system having two points of attachment to the rest of the molecule. Such heteroarylene groups include, but are not limited to, pyridylene, pyrrolylene, thiazolylene, and imidazolylene groups, wherein heteroaryl is as defined above.

[0177] The term "dendrimer" refers to a molecule containing a core and at least one dendron attached to the core. Each dendron is composed of at least one layer, or generation, of branching building blocks, resulting in an increasingly branched structure with branches from each generation of building blocks. The maximum number of dendrons attached to the core is limited by the number of functional groups on the core.

[0178] The term "building block" refers to a branched molecule having at least three functional groups, one functional group for attachment to the core or previous generation of building blocks and at least two functional groups for attachment to the next generation of building blocks or the surface of a dendrimer.

[0179] The term "generation" refers to the number of layers of structural units that make up a dendron or dendrimer. For example, a one-generation dendrimer will have one layer of structural units attached to the core, e.g., core-[[structural unit]]u, where u is the number of dendrons attached to the core. A two-generation dendrimer will have two layers of structural units per dendron attached to the core. When the structural units have one branch point, the dendrimer may be: core[[structural unit][structural unit]2]u. A three-generation dendrimer will have three layers of structural units per dendron attached to the core, e.g., core-[[structural unit][structural unit]2[structural unit]4]u. A six-generation dendrimer will have six layers of structural units attached to the core, e.g., core-[[structural unit][structural unit]2[structural unit]4[structural unit]8[structural unit]16[structural unit]32]u, etc. The last (outermost) generation of structural units provides surface functionalization of the dendrimer and the number of functional groups available for attachment to end groups. For example, in a dendrimer with two dendrons attached to the core (u=2), if each structural unit has one branch point and there are 6 generations, then the outermost generation has 64 structural units and 128 functional groups available for attachment of end groups.

[0180] The term "slightly soluble" refers to a drug or pharmaceutically active agent that has a solubility in water of 1 mg / mL to 10 mg / mL. A drug with a solubility in water of less than 1 mg / mL is considered insoluble.

[0181] The term "solubilizing excipient" refers to a formulation additive used to dissolve an insoluble or slightly soluble pharmaceutically active agent in an aqueous formulation. Examples include surfactants such as polyethoxylated castor oil including Cremophor EL, Cremophor RH40 and Cremophor RH60, D-α-tocopherol-polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, solutol HS15, sorbitan monoleate, poloxamer 407, Labrasol, and the like.

[0182] The term "cleavable linking group" refers to a group that is sensitive to a cleavage agent (e.g., pH, redox potential, or the presence of a degradation molecule). Typically, a cleavage agent is present or found at a higher level or activity in the cell than in serum or blood. The example of such a cleavage agent includes a redox agent that is selected for a specific substrate, or it does not have substrate specificity, including, for example, an oxidase or a reductase or a reducing agent such as a thiol that can degrade the redox cleavable linking group in the cell by reduction; an esterase; an amidase; an endosome or reagent that can produce an acidic environment, for example, those that produce 5 or lower pH; an enzyme that can hydrolyze or degrade the linking group of an acid cleavage by acting as a broad acid, a peptidase (which can be substrate specific) and a protease, and a phosphatase.

[0183] The term "compound having antifungal activity" or "antifungal agent" refers to a substance that is capable of inhibiting or preventing the growth, viability, and / or reproduction of fungal cells. Preferred antifungal agents are those that are capable of preventing or treating fungal infections in animals or plants. A preferred antifungal agent is a broad-spectrum antifungal agent. However, an antifungal agent may also be specific for one or more particular fungal species.

[0184] The term "isavuconazole" refers to Isavuconazole (CAS No. 241479-67-4), which has the structure

[0185] The term "isavuconazonium derivative" or "isavuconazonium sulfate" refers to Isavuconazonium sulfate (CAS No. 946075-13-4), which has the structure

[0186] The term "optional" or "optionally" is intended to mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and where it does not. For example, "the alkylene or heteroalkylene group is optionally interrupted by one or more groups selected from cycloalkylene, heterocyclylene, arylene, and heteroarylene" means that the alkylene or heteroalkylene group may be interrupted by cycloalkylene, heterocyclylene, arylene, or heteroarylene groups but need not be interrupted, and that the description includes instances where the alkylene or heteroalkylene group is interrupted by cycloalkylene, heterocyclylene, arylene, or heteroarylene groups and instances where the alkylene or heteroalkylene group is not interrupted by cycloalkylene, heterocyclylene, arylene, or heteroarylene groups.

[0187] The term "substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort.

[0188] The term "substituent" includes but is not limited to halogen, hydroxy, oxo, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl.

[0189] The term "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0190] With respect to a drug or pharmacologically active agent, the term "effective amount" refers to a non-toxic amount of the drug or agent sufficient to achieve the desired effect. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active agent. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0191] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0192] The term "grafting number of residue A of the pharmaceutically active agent, its derivative or its precursor" (hereinafter referred to as the grafting number of residue A) refers to the number of surface amino groups occupied by residue A in the dendrimer D. For example, the grafting number of residue A is 28, which means that in addition to the surface amino sites occupied by the pharmacokinetic modifier in the dendrimer D, there are 28 sites occupied by residue A among the remaining surface amino sites available for binding. 1 The results were calculated using H NMR detection.

[0193] The terms "grafting number of isavuconazole", "grafting number of isavuconazole derivatives", "grafting number of isavuconazole or its derivatives", and "grafting number of isavuconazole sulfate" are used interchangeably in the present disclosure and all refer to the number of surface amino groups occupied by isavuconazole or its derivatives in the dendrimer D. For example, the grafting number of isavuconazole or its derivatives is 28, indicating that in addition to the surface amino sites occupied by the pharmacokinetic modifier in the dendrimer D, there are 28 remaining surface amino sites that can be bound that are occupied by isavuconazole. The grafting number of isavuconazole is calculated by 1 The amount of surface amino groups occupied by isavuconazole or its derivatives on the dendrimer D was estimated by H NMR detection, i.e., by integrating the aromatic region (8.63-6.48 ppm).

[0194] The term "drug loading" refers to the content ratio of the residue A of the pharmaceutically active agent, its derivative or its precursor (hereinafter referred to as residue A) in the compound of the present invention, which can be calculated by the following formula: drug loading % = [MW (residue A) × number of grafted residues A × purity (compound of the present invention) / MW (compound of the present invention)] × 100%.

[0195] The numerical values ​​in this disclosure are instrumental measurements and are subject to a certain degree of error. Generally speaking, a range of plus or minus 10% is considered within a reasonable error range. Of course, the context in which the numerical value is used must be considered. For example, the grafting number is calculated after measurement, and an error variation of no more than plus or minus 10% is acceptable. The range can be plus or minus 9%, plus or minus 8%, plus or minus 7%, plus or minus 6%, plus or minus 5%, plus or minus 4%, plus or minus 3%, plus or minus 2%, or plus or minus 1%, preferably plus or minus 5%.

[0196] The term "DMF" refers to N,N-dimethylformamide.

[0197] The term "DIPEA" refers to N,N-diisopropylethylamine.

[0198] The term "DMAP" refers to 4-dimethylaminopyridine.

[0199] The term "EDCI" refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[0200] The term "PyBOP" refers to 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate.

[0201] As used herein, the singular form "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0202] In the chemical structures of the compounds disclosed herein, the bond No configuration is specified, i.e. the bond Can be or or include both and Two configurations. In the chemical structure of the compound disclosed in the present invention, the bond The configuration is not specified, that is, it can be Z configuration or E configuration, or contain both configurations.

[0203] Any isotope-labeled derivatives of the compounds or pharmaceutically acceptable salts thereof, or isomers thereof, described herein are covered by the present disclosure. Atoms that can be isotopically labeled include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, iodine, and the like. They can be labeled with isotopes. 2 H(D), 3 H. 11 C. 13 C. 14 C. 15 N. 18 F. 31 P. 32 P. 35 S. 36 Cl and 125 Unless otherwise indicated, when a position is specifically designated as deuterium (D), the position is understood to have an abundance of deuterium at least 3000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 45% deuterium incorporation).

[0204] In the present disclosure, the residue A of the pharmaceutically active agent, its derivative or its precursor refers to a molecule or group having pharmaceutical activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0205] FIG1 is the plasma PK curve of beagle dogs in Test Example 1 (0-240 hours). DETAILED DESCRIPTION

[0206] The present disclosure is further described and explained below with reference to examples, but these examples are not intended to limit the scope of the present disclosure.

[0207] Experimental methods in the examples disclosed herein that do not specify specific conditions are generally performed under conventional conditions or according to the conditions recommended by the raw material or product manufacturers. Reagents that do not specify their specific sources are conventional reagents purchased from the market.

[0208] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS). Chemical shifts were calculated based on a 10 -6 The units are given in ppm.

[0209] MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

[0210] High performance liquid chromatography (HPLC) was performed using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150×4.6 mm column).

[0211] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm. The specification of thin layer chromatography separation and purification products adopts 0.4mm-0.5mm silica gel plate.

[0212] Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0213] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organnics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, and other companies.

[0214] Unless otherwise specified in the examples, all reactions were carried out under an argon or nitrogen atmosphere.

[0215] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0216] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0217] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0218] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0219] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0220] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0221] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0222] Room temperature is the most suitable reaction temperature, and the temperature range is 20℃~30℃.

[0223] Preparation of PBS buffer with pH=6.5 in the embodiment: 8.5 g of KH2PO4, 8.56 g of K2HPO4.3H2O, 5.85 g of NaCl, and 1.5 g of EDTA were placed in a bottle, the volume was adjusted to 2 L, and ultrasonication was used to dissolve them all, and the mixture was shaken to obtain the solution.

[0224] The eluent system for column chromatography and the developing solvent system for thin-layer chromatography used to purify the compound include: A: dichloromethane and isopropanol system, B: dichloromethane and methanol system, C: petroleum ether and ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine and acidic or alkaline reagents can also be added for adjustment.

[0225] Some compounds of the present disclosure were characterized by Q-TOF LC / MS using an Agilent 6530 accurate mass quadrupole-time of flight mass spectrometer and an Agilent 1290-Infinity ultra-performance liquid chromatograph (Agilent Poroshell 300SB-C8 5 μm, 2.1×75 mm column).

[0226] Referring to the synthesis method of patent CN 110312531A, the following type of dendrimer was synthesized, wherein the first amino end group is used to connect to the pharmaceutical active agent, and the second end group is used to connect to the pharmacokinetic modifier PEG:

[0227] The dendrimers shown in the examples below include the core of the reference dendrimer and the structural units in the outermost generation of the dendrimer. Generations 1 to subsurface are not depicted. Dendrimer BHAL y s[Lys] 32represents a 5-generation dendrimer having the formula BHALys[Lys]2[Lys]4[Lys]8[Lys] 16 [Lys] 32 , 64 surface amino groups are available for binding to the end groups.

[0228] Dendrimer scaffold BHALys[Lys] 32 [α-NH 2· TFA 32 [ε-PEG 570 ] 32 、BHALys[Lys] 32 [α-NH 2· TFA 32 [ε-PEG 1100 ] 32 、BHALys[Lys] 32 [α-NH 2· TFA 32 [ε-t-PEG 2300 ] 32 、BHALys[Lys] 32 [α-4-HSBA] 32 [ε-PEG 1100 ] 32 、BHALys[Lys] 32 [α-GILGVP-NH2.TFA] 32 [ε-PEG 1100 ] 32 and BHALys[Lys] 32 [α-GILGVP-NH 2· TFA 32 [ε-t-PEG 2300 ] 32 The preparation of can be found in Kaminskas et al., J Control. Release (2011) (doi: 10.1016 / j.jconrel.2011.02.005). Dendrimer scaffold 4-azidobenzamide-PEG 12 -NEOEOEN[Su(NPN)2][Lys] 16 [NH 2· TFA 32 The preparation of can be found in WO08 / 017122.

[0229] 1-A00, 1-B00, and 1-C00 were synthesized according to patent WO2012167309, and the pharmaceutically active agent attached thereto is docetaxel; 2-A00 was synthesized according to patent WO2018154004A, and the pharmaceutically active agent attached thereto is compound 2 (synthesized according to patent WO2012017251). 32 [α-NH 2· TFA 32 [ε-PEG 1100 ] 32 In the examples, it is referred to as dendrimer 1, BHALys[Lys] 32 [α-NH 2· TFA 32 [ε-PEG 2100 ] 32 In the examples, it is referred to as dendrimer 1-PEG2K, which was synthesized according to the method of WO2018154004A:

[0230] General Procedure

[0231] General Procedure A

[0232] Linker and drug installation

[0233] To a magnetically stirred solution of the carboxylic acid linker (0.2–0.5 mmol) in DMF or acetonitrile (1–5 mL) at 0°C was added a coupling agent of EDC or DCC (1.2 equiv). The mixture was left stirring for 5 min, and then a solution containing a mixture of the drug (0.4–1 equiv) and DMAP (0.4–1 equiv) in a solvent (1 mL) was added dropwise. The mixture was maintained at 0°C for 1 hour and then allowed to warm to ambient temperature. The volatiles were then removed in vacuo and the residue was purified by preparative HPLC (BEH300 Waters XBridge C18, 5 μM, 30 x 150 mm, 40–80% ACN / water (5–40 min), without buffer) to obtain the desired product.

[0234] General Procedure B

[0235] Installation of linker and drug

[0236] To a magnetically stirred solution of drug (0.3–1.0 mmol) and anhydride (2 equivalents) in DMF (3–5 mL) was added DIPEA (3 equivalents). The mixture was stirred at ambient temperature overnight. The volatiles were then removed in vacuo and the residue was purified by preparative HPLC (BEH300 Waters XBridge C18, 5 μM, 30 x 150 mm, 40–70% ACN / water (5–40 min), no buffer, RT = 34 min). The appropriate fractions were concentrated in vacuo to yield the desired product.

[0237] General Procedure C

[0238] Dendrimers with drug-linker loading

[0239] At room temperature, a magnetically stirred BHALys[Lys] 32 [α-NH 2· TFA 32 [ε-PEG 1100 ] 32 To a mixture of 1,200 μmol (0.5–1.0 μmol) and DIPEA (1.2 equiv / amine) in DMF was added the linker-drug (1.2 equiv / amine) and PyBOP (1.2 equiv / amine). After stirring at room temperature for 1.5 hours, the volatiles were removed and the residue was purified by SEC (sephadex, LH2O, MeOH). Appropriate fractions (as judged by HPLC) were combined and concentrated to give the desired product.

[0240] General Procedure D

[0241] Click React

[0242] To a magnetically stirred solution of the dendrimer (0.5–1.0 mmol) in a 1:1 H₂O / t-BuOH solution (approximately 0.5 mL) was added the alkyne reagent (2 equivalents), sodium ascorbate solution (2 equivalents), and CuSO₄ solution (20 mol%). The solution was heated to 80°C and monitored by HPLC. Additional sodium ascorbate and CuSO₄ were added as needed to drive the reaction to completion. Once the reaction was judged complete, the reaction was concentrated in vacuo and then purified.

[0243] The compounds disclosed herein can be synthesized according to a route selected from the following, where PG is a carboxylic acid protecting group:

[0244] Example 1 Preparation of Compound 1

[0245] Step 1) Preparation of compound 1b

[0246] In a 50 mL single-necked flask, compound 1a (4.46 g, 14.7 mmol, 1.25 eq, purchased from Shanghai Haohong Biopharmaceutical Technology Co., Ltd., batch number Le041266834) and 2-methylamino-3-pyridinemethanol (1.62 g, 11.8 mmol, 1.0 eq, purchased from Shanghai Haohong Biopharmaceutical Technology Co., Ltd., batch number Lf0810159492) were dissolved in dichloromethane (10 mL). The mixture was cooled to 0°C in an ice bath and purged with nitrogen three times. EDCI (2.82 g, 14.7 mmol, 1.25 eq) and DMAP (432 mg, 3.54 mmol, 0.3 eq) were added, and the mixture was allowed to warm to room temperature and stirred for 2 hours. After the reaction was complete, the reaction solution was diluted with 50 mL of dichloromethane, washed with 10 mL of water, then with 10 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to obtain the crude product. The crude product was purified by normal phase ethyl acetate / petroleum ether system to obtain 4.90 g (yield 98%) of white solid.

[0247] MS (ESI): m / z 424.6 [M+H] + .

[0248] 1 H-NMR (400MHz, CDCl3): 8.17(dd,J=2.0,5.2Hz,1H),7.37(dd,J=2.0,7.2Hz,1H),6.55(dd,J=5.2,7.2Hz,1H),5.10-5.05(m,1H),5.01 (s,2H),4.27-4.19(m,1H),3.02(d,J=4.8Hz,3H),2.50-2.34(m,2H),2.21-2.12(m,1H),1.95-1.85(m,1H),1.46(s,9H),1.44(s,9H).

[0249] Step 2) Preparation of compound 1c

[0250] In a 100 mL single-necked flask, compound 1b (4.90 g, 11.6 mmol, 1.0 eq) was dissolved in DCM (30 mL) and cooled to 0°C. DIPEA (2.99 g, 23.1 mmol, 2.0 eq) and 1-chloroethyl chloroformate (2.48 g, 17.4 mmol, 1.5 eq) were added. Stirring was maintained at 0°C for 1 hour and then at room temperature overnight. TLC confirmed the disappearance of the starting material. The reaction solution was diluted with 50 mL of dichloromethane, washed with 10 mL of water, then with 10 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to obtain the crude product. The crude product was purified with normal-phase ethyl acetate / petroleum ether to afford 4.30 g (70% yield) of a yellow oil.

[0251] MS (ESI): m / z 530.1 [M+H] + .

[0252] 1 H-NMR (400MHz, CDCl3): 8.53-8.42(m,1H),7.88-7.77(m,1H),7.35-7.27(m,1H),6.63-6.52(m,1H),5.25-4.97(m,3H),4.28-4.16 (m,1H),3.44-3.30(m,3H),2.56-2.35(m,2H),2.26-2.10(m,1H),1.97-1.82(m,2H),1.62-1.52(m,2H),1.46(s,9H),1.43(s,9H).

[0253] Step 3) Preparation of compound 1e

[0254] In a 50 mL single-necked vial, compound 1d (700 mg, 1.60 mmol, 1.0 eq, purchased from Chengdu Baite Wanhe Pharmaceutical, batch number T001-M9-220201), compound 1c (1.19 g, 2.24 mmol, 1.4 eq), and sodium iodide (336 mg, 2.24 mmol, 1.4 eq) were dispersed in 5 mL of acetonitrile. The atmosphere was purged with nitrogen three times, heated to 70°C, and stirred for 3 hours. The reaction mixture was then cooled to room temperature and filtered. The filter cake was washed twice with 5 mL of ethyl acetate. The filtrate was then spin-dried and purified using normal-phase methanol / dichloromethane to obtain 2.1 g of a yellow solid (yield: >100%). The crude product was used directly in the next step.

[0255] MS(ESI):m / z 931.4[MI] + .

[0256] Step 4) Preparation of Compound 1f

[0257] In a 50 mL single-necked flask, compound 1e (2.1 g, 1.60 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL). Dioxane hydrochloride (5 mL, 4 N, 20 mmol) was added and stirred at room temperature for 2.5 hours. The resulting solid was concentrated and washed twice with dichloromethane. The solid was then pumped dry to afford 2 g of a yellow solid. The crude product was used directly in the next step.

[0258] MS (ESI): m / z 776.2 [MI-HCl] + .

[0259] Step 5) Preparation of Compound 1g

[0260] In a 100 mL single-necked flask, compound 1f (3.2 g, 2.92 mmol, 1.0 eq) was dissolved in methanol (50 mL). 37% aqueous formaldehyde (10 mL) was added and the mixture was cooled to 0°C in an ice bath. Sodium triacetylborohydride (4.02 g, 19.0 mmol, 6.5 eq) was added portionwise. The mixture was returned to room temperature and stirred for 3 hours. The reaction solution was evaporated under reduced pressure to approximately 20 mL and then purified by reverse phase purification to afford 2.5 g (88% yield) of a white solid.

[0261] Ms(ESI):m / z 803.5[MI-HCl] + .

[0262] 1 H-NMR (400MHz, CD3OD): 9.06-8.84(m,1H),8.48-8.38(m,1H),8.20-8.15(m,3H),7.99-7.96(m,1H),7 .83-7.81(m,2H),7.49-7.42(m,1H),7.23-7.14(m,4H),6.87-6.72(m,1H),5.19-5.05(m,3H),4.76-4 .67(m,1H),4.40-4.27(m,1H),4.06-3.92(m,1H),3.27-3.23(m,3H),2.95-2.92(m,6H),2.77-2.60(m ,3H),2.36-2.25(m,1H),2.19-2.08(m,1H),1.97-1.86(m,1H),1.62-1.57(m,2H),1.29-1.28(m,3H).

[0263] Step 6) Preparation of Compound 1

[0264] In a 100 mL single-necked flask, compound 1g (1.72 g, 1.77 mmol, 65 eq) and PyBOP (1.0 g, 1.90 mmol, 70 eq) were dissolved in DMF (20 mL) under nitrogen and stirred at room temperature. Compound 1h (2.1 g, 0.0272 mmol, 1.0 eq) and DMAP (1.0 g, 8.16 mmol, 300 eq) were dissolved in DMF (20 mL) and added to the above solution. The temperature was then raised to 35°C and stirred overnight. When the central control panel indicated the reaction was complete, the reaction solution was cooled to room temperature and then added dropwise to water (800 mL). Filtered, the filtrate was purified by ultrafiltration three times with pure water, and lyophilized to yield 2.8 g of a white solid (91.2% yield, 91% purity).

[0265] through 1H NMR analysis (estimate of the grafted isavuconazole content by integration in the aromatic region (8.63-6.48 ppm)): 28 isavuconazole / dendrimer. Actual molecular weight is approximately 99.2 kDa (11.2% wt.% isavuconazole).

[0266] 1 H NMR (400MHz, CD3OD): 8.63-6.48(m,412H), 5.29-4.83(m,137H), 4.45-4.11(m,109H), 4.06-3. 44(m,5900H),3.35(s,104H),3.30-2.83(m,182H),2.65-2.12(m,205H),2.09-0.97(m,666H).

[0267] Example 2 Preparation of Compound 2

[0268] Step 1) Preparation of compound 2b

[0269] In a 50 mL single-necked flask, compound 2a (2.35 g, 12.5 mmol, 1.25 eq, purchased from Shanghai Shaoyuan Reagent Co., Ltd., batch number R22010813) and 2-methylamino-3-pyridinemethanol (1.38 g, 10.0 mmol, 1.0 eq, purchased from Shanghai Haohong Biopharmaceutical Technology Co., Ltd., batch number Lf0810159492) were dissolved in dichloromethane (10 mL). The mixture was cooled to 0°C in an ice bath and purged with nitrogen three times. EDCI (2.4 g, 12.5 mmol, 1.25 eq) and DMAP (366 mg, 3.0 mmol, 0.3 eq) were added, and the mixture was stirred at 0°C for 1 hour. After the reaction was complete, the reaction solution was diluted with 30 mL of dichloromethane, washed with 10 mL of water, then with 10 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to obtain the crude product. The crude product was purified by normal phase ethyl acetate / petroleum ether system to obtain 2.76 g (yield: 89%) of colorless oil.

[0270] MS (ESI): m / z 309.4 [M+H] + .

[0271] 1H-NMR (400MHz, CDCl3): 8.16 (d, J=4.8Hz, 1H), 7.36 (d, J=7.2Hz, 1H), 6.55 (dd, J=4.8, 7.2Hz, 1H), 5.07 (brs, 1H), 5.00(s,2H),3.02(d,J=4.4Hz,3H),2.39(t,J=7.2Hz,2H),2.27(t,J=7.2Hz,1H),1.95-1.88(m,2H),1.44(s,9H).

[0272] Step 2) Preparation of compound 2c

[0273] In a 100 mL single-necked flask, compound 2b (2.76 g, 8.96 mmol, 1.0 eq) was dissolved in dichloromethane (30 mL). The mixture was cooled to 0°C, and DIPEA (2.3 g, 17.8 mmol, 2.0 eq) and 1-chloroethyl chloroformate (1.92 g, 13.4 mmol, 1.5 eq) were added. The mixture was then warmed to room temperature and stirred overnight. After the reaction was complete, the reaction solution was diluted with 30 mL of dichloromethane, washed with 10 mL of water, then with 10 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to obtain the crude product. The crude product was purified using normal-phase ethyl acetate / petroleum ether to obtain 3.1 g (yield: 83%) of a yellow oil.

[0274] MS (ESI): m / z 437.0 [M+Na] + .

[0275] 1 H-NMR (400MHz, CDCl3): 8.54-8.42(m,1H),7.84-7.77(m,1H),7.34-7.26(m,1H),6.62-6.52(m,1H),5.19-5 .02(m,3H),3.44-3.35(m,3H),2.43(t,J=7.2Hz,2H),2.28(t,J=7.2Hz,1H),1.96-1.88(m,2H),1.44(s,9H).

[0276] Step 3) Preparation of compound 2d

[0277] In a 50 mL single-necked vial, compound 1d (1.13 g, 2.58 mmol, 1.0 eq, purchased from Chengdu Baite Wanhe Pharmaceutical, batch number T001-M9-220201), compound 2c (1.5 g, 3.62 mmol, 1.4 eq), and sodium iodide (543 mg, 3.62 mmol, 1.4 eq) were dispersed in 10 mL of acetonitrile. The atmosphere was purged with nitrogen three times, heated to 80°C, and stirred overnight. The reaction mixture was then cooled to room temperature, filtered, and washed twice with 5 mL of acetonitrile. The filtrate was then spin-dried to dryness to yield 2.5 g of a yellow solid, which was used directly in the next step.

[0278] MS(ESI):m / z 816.3[MI] + and 760.3[MI-tBu] + .

[0279] Step 4) Preparation of compound 2e

[0280] In a 50 mL single-necked vial, compound 2d (2.5 g, 2.58 mmol, 1.0 eq) was dispersed in dioxane hydrochloride (20 mL, 4 N, 80 mmol) and stirred at room temperature (18°C) for 2 hours. The reaction was complete at the intermediate control. The reaction solution was spin-dried and purified with reverse-phase CH3CN / H2O to obtain 1.8 g of a white solid (92% yield).

[0281] MS(ESI):m / z 760.7[MI] + .

[0282] Step 5) Preparation of Compound 2

[0283] In a 100 mL single-necked flask, compound 2e (1.8 g, 2.03 mmol, 80 eq) and PyBOP (1.18 g, 2.28 mmol, 90 eq) were dissolved in DMF (20 mL) under nitrogen and stirred at room temperature. Compound 1h (1.9 g, 0.0253 mmol, 1.0 eq) and DMAP (927 mg, 7.59 mmol, 300 eq) were dissolved in 20 mL of DMF and added to the solution. The mixture was then heated to 35°C and stirred overnight. The reaction mixture was cooled to room temperature and then added dropwise to 200 mL of water. The mixture was filtered and the filtrate was purified by ultrafiltration three times with pure water. The solution was lyophilized to afford 1.9 g of a yellow solid (yield 67.0%, purity 88%).

[0284] through 1 H NMR analysis (estimate of the grafted isavuconazole content by integration in the aromatic region (8.63-6.48 ppm)): 31 isavuconazole / dendrimer. Actual molecular weight is approximately 100.6 kDa (11.8% wt.% isavuconazole).

[0285] 1 H NMR (400MHz, CD3OD): 8.68-6.65(m,431H), 4.58-4.11(m,107H), 4.05-3.43(m,5900 H),3.35(s,108H),3.24-2.81(m,193H),2.60-2.11(m,205H),2.05-0.97(m,771H).

[0286] Example 3 Preparation of Compound 3

[0287] The preparation was carried out according to the method of Example 1 to obtain 2.3 g of compound 3 (yield 85.6%, purity 97.37%).

[0288] through 1 H NMR analysis (estimate of the grafted isavuconazole amount by integration in the aromatic region (8.63-6.48 ppm)): 27 isavuconazole / dendrimer. Actual molecular weight is approximately 95.8 kDa (12.0% wt.% isavuconazole).

[0289] Biological evaluation

[0290] The present disclosure is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present disclosure.

[0291] Test Example 1 Pharmacokinetic Study of Different Compounds in Beagle Dogs after Single Intravenous Injection

[0292] 1. Test sample

[0293] The disclosed compounds are Isavuconazole (analytical standard, purchased from Chengdu Baite Wanhe Pharmaceutical, batch number T001-M9-220201, purity 98%), Isavuconazonium sulfate (purchased from Dalian Boglin Biotechnology Co., Ltd., batch number 22102704, Isavuconazole content 52.5%), Compound 1 (prepared in Example 1, with a drug loading of 11.0% based on Isavuconazole), and Compound 2 (prepared in Example 2, with a drug loading of 11.8% based on Isavuconazole).

[0294] Sample preparation method:

[0295] 1) Solvent preparation: Dissolve 1.27 g of disodium hydrogen phosphate and 1.2 g of citric acid monohydrate in 100 mL of water. The pH value is measured to be in the range of 4 to 5.

[0296] 2) Test sample preparation: Weigh the required amount of test sample (need to convert the drug loading), add an appropriate volume of blank solvent, and slowly stir until completely dissolved to prepare a solution with a concentration of 1 mg / mL. After filtering through a 0.22 μm filter membrane, administer the solution by slow intravenous injection over 1 hour.

[0297] 2. Experimental Animals

[0298] Beagle, naive level, sourced from Shanghai Hengling Pharmaceutical Technology Co., Ltd., certificate numbers: 202280145, 202301739.

[0299] 3. Test methods

[0300] Dosing: Weigh patients before dosing, calculate the dose based on body weight, and administer slowly via intravenous injection. One mL of blood was collected from a limb vein and placed in an EDTA-K2 anticoagulant tube in an ice bath. Plasma was separated by centrifugation within 30 minutes (1800 g, 2-8°C, 10 minutes). Plasma was aliquoted into two tubes and temporarily stored in an ice bath. Within 30 minutes, the plasma was transferred to a -80°C freezer for storage. Maintain low temperatures throughout the collection and aliquoting process. Plasma samples were collected before and at various time points after dosing to measure free isavuconazole levels. For the isavuconazonium sulfate group, plasma samples were collected before dosing and at 0.5, 1, 1.17, 1.5, 2, 4, 8, 24, 48, and 72 hours after the start of dosing; for the other test groups, plasma samples were collected before dosing and at 0.5, 1, 1.17, 1.5, 4, 8, 24, 48, 72, 96, 168, 240, and 336 hours after the start of dosing.

[0301] Table 1 Dosage regimen

[0302] 4. Test results

[0303] The pharmacokinetic parameters and curves of each group of animals are shown in Table 2 and Figure 1.

[0304] Table 2 Pharmacokinetic data

[0305] The test results showed that after administration at the same dose, the C maxThe plasma half-life of Compound 1 and Compound 2 was 9 times and 6 times longer than that of Isavuconazonium sulfate group, respectively. The above results show that the compounds disclosed herein can effectively reduce the drug C level compared with Isavuconazonium sulfate. max While increasing drug exposure; drug release is slower, the release behavior is more stable, and it has a significant sustained release effect. Indicator Compound 1 and Compound 2 have the ability to reduce drug C max related adverse reactions and the potential to increase the therapeutic window.

Claims

1. A compound comprising: i) a dendrimer D having surface amino groups, wherein at least two different end groups are covalently attached to the surface amino groups of the dendrimer: ii) a first terminal group, which is a residue A of a pharmaceutically active agent, a derivative thereof, or a precursor thereof containing a carboxyl group, a hydroxyl group, an amino group, or a thiol group; iii) a second terminal group which is a pharmacokinetic modifier; The first terminal group is connected by a linker -X 1 -LX 2 - covalently linked to the surface amino groups of the dendrimer, X 1 is selected from -C(O)- or -O-, and is linked to the residue A of a pharmaceutically active agent, a derivative thereof or a precursor thereof, and X 2 is -C(O)-, connected to the dendrimer D via an amide bond, wherein: a) L is C 1-10 A straight or branched alkylene or heteroalkylene, wherein the alkylene or heteroalkylene is optionally interrupted by one or more cycloalkylene, heterocyclylene, arylene, heteroarylene, and the alkylene or heteroalkylene is optionally substituted by one or more substituents selected from the following groups: deuterium, hydroxyl, C 3-7 Cycloalkyl, C 1-6 Alkoxy, haloalkyl, haloalkoxy, halogen, nitro, cyano, acyl, amino, thiol, sulfinyl, sulfonyl, -NR 1 R 2 , aryl, heteroaryl and heterocyclyl; b) L is C 2-10 A straight or branched alkenylene or alkynylene group, wherein the alkenylene or alkynylene group is optionally substituted by one or more substituents selected from the following groups: deuterium, hydroxyl, C 3-7 Cycloalkyl, C 1-6 Alkoxy, haloalkyl, haloalkoxy, halogen, nitro, cyano, acyl, amino, thiol, sulfinyl, sulfonyl, -NR 1 R 2 , aryl, heteroaryl and heterocyclyl; The residue A of the pharmaceutically active agent, its derivative or its precursor is a residue of a compound having antifungal activity, its derivative or its precursor; R 1 , R 2 are the same or different, each independently selected from hydrogen, hydroxyl, C 1-6 Alkyl, cycloalkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkoxy is optionally selected from hydroxy, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, amino and C 1-6 The alkylamino group is substituted with one or more substituents.

2. The compound according to claim 1, wherein L is C 1-10 A straight or branched chain alkylene or heteroalkylene group is optionally substituted with one or more -NR 1 R 2 substituted, preferably methylene, ethylene, propylene, butylene, pentylene, hexylene, more preferably ethylene, propylene, butylene, pentylene, hexylene, most preferably propylene, The R 1 , R 2 As defined in claim 1.

3. The compound according to claim 1 or 2, selected from the following structures:

4. The compound according to any one of claims 1 to 3, wherein the pharmaceutically active agent is selected from fluconazole, isavuconazole, isavuconazole derivatives, itraconazole, voriconazole, posaconazole and ravuconazole, ravuconazole, preferably isavuconazole or isavuconazole derivatives.

5. The compound according to any one of claims 1 to 4, wherein the residue A of the pharmaceutically active agent, its derivative or its precursor has the structure of the compound of formula I-3, in Z - It is a pharmaceutically acceptable monovalent anion; R A , RB , R C , R D , R E are the same or different, each independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Amino-substituted alkyl, C 1-6 Alkylcarbonyl, haloC 1-6 Alkylcarbonyl, C 1-6 Hydroxyalkylcarbonyl, C 1-6 Alkoxycarbonyl, C 1-6 Haloalkoxycarbonyl, C 1-6 Amino-substituted alkylcarbonyl, C 1-6 Alkylthio, C 1-6 Alkylsulfinyl, C 1-6 alkylsulfonyl, trifluoromethyl, trifluoromethoxy, halogen, hydroxy, nitro, carboxyl, cyano, amino, aminosulfonyl or sulfonic acid, or R D , R E Together with the connected carbon atom, it forms oxo, thio, =NR 3 ; The compound represented by formula I-3 is connected to the linker X through the hydroxyl oxygen atom carried by it. 1 The ends are connected; R 3 Selected from hydrogen, hydroxyl, C 1-6 Alkyl, cycloalkyl, C 1-6 Alkoxy; n is selected from 0, 1, 2, 3; X 1 As defined in claim 1.

6. The compound according to claim 5, wherein R A , R B the same or different, each independently selected from hydrogen or C 1-6 The alkyl group is preferably hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and most preferably hydrogen and methyl.

7. The compound according to claim 5 or 6, wherein R C Selected from halogen, hydroxy, nitro, carboxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylsulfinyl, C 1-6alkylsulfonyl, trifluoromethyl, trifluoromethoxy, aminosulfonyl or sulfonic acid, preferably halogen, hydroxyl, nitro, carboxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy.

8. A compound according to any one of claims 5 to 7, wherein R D , R E All are hydrogen.

9. The compound according to any one of claims 5 to 8, wherein n is 0.

10. The compound according to any one of claims 5 to 9, wherein the residue A of the pharmaceutically active agent, its derivative or its precursor has the structure of the compound of formula I-4, Where Z - , As defined in claim 5.

11. A compound according to any one of claims 5 to 10, wherein Z - Selected from fluoride ion, chloride ion, bromide ion, iodide ion, HCO3 - 、HSO4 - , preferably HSO4 - , chloride ion, iodide ion, with iodide ion being most preferred.

12. A compound according to any one of claims 1 to 11, wherein the pharmacokinetic modifier is selected from polyethylene glycol, polyethyloxazoline, polyvinylpyrrolidone, polypropylene glycol, folate or a folate derivative for a ligand of a cell surface receptor, preferably polyethylene glycol; Further, the polyethylene glycol has a molecular weight ranging from 220 to 5500 Da, preferably 1000-5500 Da, more preferably 1000-2500 Da, most preferably 1000-2300 Da.

13. The compound according to any one of claims 1 to 12, wherein the dendrimer D is selected from polylysine, polylysine analogs, polyamidoamine (PAMAM), polyethyleneimine (PEI) or polyetherhydroxylamine (PEHAM) dendrimers, preferably polylysine or polylysine analogs, more preferably polylysine or polylysine analogs comprising a core and 2-7 generations of lysine or lysine analogs.

14. The compound according to any one of claims 1 to 13, wherein the first end group and the second end group are present in a ratio of 1:

1.

15. The compound of any one of claims 1 to 14, wherein at least 50% of the end groups comprise one of the first end group or the second end group.

16. The compound according to any one of claims 1 to 15, wherein the dendrimer D is selected from BHALys[Lys] 16 , BHALys[Lys] 32 or BHALys[Lys] 64 .

17. The compound according to any one of claims 1 to 16, wherein the grafted number of the residue A of the pharmaceutically active agent, its derivative or its precursor is selected from 20 to 32, preferably 27 to 32, most preferably 28 to 31.

18. A compound selected from in: x is independently selected from an integer of 2 to 50; y is selected from 2, 4, 8, 16, 32, 64; Z - As defined in claim 5.

19. The compound according to claim 18, wherein when said y is 32, the grafting number of isavuconazole is selected from 20 to 32, preferably 27 to 32, and most preferably 28 to 31.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19 and a pharmaceutically acceptable carrier.

21. Use of a compound according to any one of claims 1 to 20 in the preparation of a medicament for the treatment of antifungal diseases.

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