WO2016050208A1 - Bio-related substance modified by multifunctionalized polyethylene glycol derivative - Google Patents

Abstract

Disclosed is a bio-related substance modified by a multifunctionalized polyethylene glycol derivative (formula 1). The substance has an H-shaped structure and comprises one linear core LPEG and four PEG branch chains, where n₁, n₂, n₃, and n₄ respectively are the degrees of polymerization of the branch chains, U₁ and U₂ are trivalent branching groups connecting the LPEG to two of the PEG branch chains, F₁ and F₂ contain a functional group or a protected form R₀₁ thereof, and the number of R₀₁ is one or more. Any one linking group in the molecule or any linking group formed with an adjacent heteroatom group can either remain stable or be degraded; any one PEG segment in the molecule discretely has polydispersity or monodispersity. various or multiple bio-related substances can be modified by one H-shaped molecule, the modified products are flexible in branching structure, provide high drug loading, optimizable pharmacokinetics and tissue distribution, and also can carry two bio-related substances of different functions, thus producing a fluorescence property or a targeting function.

Description

Bio-related substance modified by polyfunctional polyethylene glycol derivative Technical field

The invention relates to the field of polymer synthesis and biochemical modification, in particular to a bio-related substance modified by a polyfunctional polyethylene glycol derivative.

Background technique

PEGylation is one of the important means of drug modification. Among them, functionalized polyethylene glycol (PEG) can utilize the reactive groups it contains with drug molecules (including protein drugs and small organic drugs), peptides, carbohydrates, lipids, oligonucleotides, affinity Coupling of covalent bonds by bodies, cofactors, liposomes, and biological materials enables the modification of polyethylene glycols for drugs and other biologically relevant substances. The modified drug molecule will possess many of the superior properties of polyethylene glycol (eg, hydrophilicity, flexibility, anticoagulant, etc.). At the same time, due to the spatial repulsion effect, the polyethylene glycol modified drug avoids glomerular filtration and biological reactions such as immune response, which has a longer half-life in the blood than unmodified drugs. For example, Greenwald et al. (J. Org. Chem. 1995, 331-336) modify paclitaxel by means of coupling with polyethylene glycol to increase its water solubility.

Since 1995, Monfardini has two linear methoxy polyethylene glycols attached to the two amino groups of lysine to obtain a bifurcated bimodal (V-type) polyethylene glycol and a carboxyl group of lysine. After activation into succinimide active esters and used in protein modification studies (Bioconjugate Chem. 1995, 6, 62-69), this method has been extended to the most prevalent preparation of monofunctionalized branched polyethylene glycols and their A method of drug derivatives and has been applied in three commercial drugs. Compared with linear polyethylene glycol of the same molecular weight, with a special molecular morphology, branched polyethylene glycol can form an umbrella-shaped protective layer on the surface of the drug, increasing the spatial position around the drug molecule. Resistance, more linear than polyethylene glycol can prevent other macromolecules in the body from attacking the drug, reducing the degree of inactivation or enzymatic hydrolysis of the drug in the organism, and prolonging the action time of the drug in the body.

Branched polyethylene glycol with two polyethylene glycol arms represented by this traditional V-shaped structure, only a single reactive group can react with drug molecules, and the drug loading is low, and the application range is very limited. . In addition, since the reactive group is located in the center of the two polyethylene glycol arms, the active group is embedded in the polyethylene glycol chain, resulting in a modification efficiency when the drug molecule is modified.

In addition, for a drug molecule modified by a PEGylated derivative, since the binding site may be attached to the active site or active site of the drug, or a steric effect is introduced, the drug activity after PEGylation is often caused. Falling or even disappearing. Moreover, in the case of conventional administration, such as injection, oral administration, etc., in addition to acting on the lesion site, the drug molecule usually accumulates in normal tissues, causing certain or even serious side effects. Although the PEGylation modification can greatly reduce the side effects, for some drugs, especially anticancer drugs, the biosafety requirements cannot be met by the existing polyethylene glycol modification.

Therefore, it is necessary to develop a novel structure of functionalized polyethylene glycol modified biologically related substances in the parameters of branch structure, length of branch arms, and pharmacokinetics, tissue distribution and other indicators. Effective combination of high drug loading, high modification rate of PEGylation of drugs, and optimized pharmacokinetics; and how to improve the activity retention of drugs, or how to achieve the release of highly active drugs, etc. There is an urgent need to improve or solve it; and it is necessary to further reduce the side effects of the drug or to increase the distribution in the tissue of the lesion.

Summary of the invention

SUMMARY OF THE INVENTION An object of the present invention is to provide a bio-related substance modified with a polyfunctionalized H-type polyethylene glycol derivative in order to overcome the deficiencies of the prior art.

The present invention discloses a bio-related substance modified with a polyfunctionalized H-type polyethylene glycol derivative. The bio-related substance modified by the polyfunctionalized H-type polyethylene glycol derivative is a stable structure formed by combining a polyfunctionalized H-type polyethylene glycol derivative represented by the general formula (1) with a biologically relevant substance. .

The H-type structure consists of a linear PEG spindle and four PEG branching chains, and the total number of oxidized vinyl units of the linear PEG spindle and the four PEG branch chains does not exceed 5000.

Wherein, LPEG is a linear spindle structure; LPEG is a monoblock, diblock, triblock or 4 to 150 block segment composed of polyethylene glycol or polyethylene glycol; number of oxyethylene units in LPEG The sum is an integer from 2 to 2,000.

n ₁ , n ₂ , n ₃ , and n ₄ are the polymerization degrees of the four PEG branched chains, respectively, each independently satisfying 2 to 2000, and may be the same or different from each other in the same molecule.

The four PEG branched chains corresponding to LPEG and n ₁ , n ₂ , n ₃ , and n ₄ are each independently polydisperse or monodisperse.

U ₁ and U ₂ are each a trivalent branched group linking LPEG and two PEG branching chains;

The structure of U ₁ is

The structure of U ₂ is U ₀₁ and U ₀₂ are each independently a trivalent group. L ₁ , L ₂ , L ₃ , and L ₄ are respectively a linking group of a polyethylene glycol unit in which the number of oxyethylene units is n ₁ , n ₂ , n ₃ , and n ₄ , and L ₅ and L ₆ are connected linear spindles. The linking group of the polyethylene glycol unit, L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ are each independently present or absent, and may be the same or different from each other in the same molecule.

F ₁ and F ₂ contain a functional group or a protected form thereof, and in the same molecule, F ₁ and F ₂ may be the same or different from each other.

The structures of F ₁ and F ₂ are each independently expressed as

among them,

a linker for linking a polyethylene glycol unit; k is an integer of 1 or 2 to 250; g is 0 or 1; G is a linker of a trivalent or higher valence state; when g=0, k=1; g= 1, k is an integer of 2 to 250, and the valence state of G is k+1; L ₀ is a divalent linking group; g ₀ is 0, 1 or 2 to 1000; q and q ₁ are each independently 0 or 1 ; Z ₁ , Z ₂ are each independently a divalent linking group; R ₀₁ is a functional group or a protected form thereof; in the same molecule, k, G, g, L ₀ , g _{0 of} F ₁ and F ₂ , Z ₂ , q, Z ₁ , q ₁ , and R ₀₁ are each independently the same or different.

In the same molecule, LPEG, U ₁ , U ₂ , U ₀₁ , U ₀₂ , L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ , L ₀ (F ₁ ), G(F ₁ ), Z Any one or any of ₁ (F ₁ ), Z ₂ (F ₁ ), L ₀ (F ₂ ), G(F ₂ ), Z ₁ (F ₂ ), Z ₂ (F ₂ ) and adjacent heteroatoms The linker formed by the group can be stably present or degradable.

The bio-related substance modified by the polyfunctionalized H-type polyethylene glycol derivative contains at least one bio-related substance molecule. The type of the bio-related substance to be combined is one or two. The manner in which the polyfunctionalized H-type polyethylene glycol derivative is combined with a biologically relevant substance is a covalently linked or non-covalently linked means. The manner in which any of the functional groups or protected functional groups of the polyfunctionalized H-type polyethylene glycol derivative and the biologically relevant substance are independently stabilized or degradable. Wherein the functional group modified by the polyfunctionalized H-type polyethylene glycol derivative or the protected form thereof may participate in the modification of the biologically relevant substance in whole or in part. A functional group or a protected functional group that is not bound to a biologically relevant substance may retain a structural form before the reaction, may also form a deprotected functional group, or may be blocked by a non-biologically related substance. The F ₁ modified bio-related substance may be the same as or different from the F ₂ modified bio-related substance.

When F ₁ or F _{2 is} combined with a biologically relevant substance, they are each independently expressed as

In the same molecule, they may be the same or different from each other; wherein D is a residue formed by reacting a modified bio-related substance with a polyfunctionalized H-type polyethylene glycol; and L is a polyfunctionalized H-type polyethylene glycol derivative a linking group formed by reacting a functional group or a protected form thereof with a biologically relevant substance; any one of L may be stably present or degradable independently, and a linking group of L and an adjacent hetero atom group may be stably present Or degradable; wherein E ₀₁ is R ₀₁ , protected R ₀₁ , deprotected R ₀₁ or blocked R ₀₁ ; wherein k ₀ is a site in F ₁ or F ₂ that reacts with a biologically relevant substance The number of k ₀ is an integer from 1 to k.

Compared with the prior art, the present invention has the following beneficial effects:

(1) H-type structure design, by adjusting the length of the linear spindle, the distance between the branches on both sides can be adjusted. In the case of a certain overall molecular weight, the length of the main axis and each branch can be separately adjusted, so that the polyethylene glycol modified product It has adjustable, easy-to-control, optimizable pharmacokinetics and tissue distribution properties to improve drug efficacy and reduce side effects. (2) One or more drug molecules can be linked at the end of the polyethylene glycol branching chain, and have a high drug loading amount. (3) It is allowed to contain two different drug molecules or to introduce a functional group which promotes the drug effect, and the drug-loading amount can be greatly enhanced, and the effect of promoting the functional group of the drug effect can be greatly exerted. (4) The structure may contain a degradable group, which allows the steric effect to be weakened by the modification of the product to a low molecular weight product under the stimulation of enzyme, light, temperature, acidity, alkalinity, redox, etc., or by the modified organism. The detachment of the substance from the polyethylene glycol results in a highly active drug molecule; it also improves the pharmacokinetics or tissue distribution. (5) The end of the polyethylene glycol chain of the unmodified bio-related substance can be replaced with a hydroxy end group instead of the conventional methoxy group, thereby reducing the immunogenicity of the modified drug. (6) It can simultaneously modify two kinds of biological related substances, and at the same time modify the drug molecule, it also introduces functional groups such as targeting groups and fluorescent groups; introduction of targeting groups can improve tissue distribution and weaken normal tissues. Influence, reduce toxic side effects; introduction of fluorophores, it is more convenient to achieve detection of pharmacokinetics, tissue distribution and so on.

detailed description

In the present invention, the terms involved are defined as follows.

In the present invention, "hydrocarbon" means a hydrocarbon composed of a carbon atom and a hydrogen atom.

The hydrocarbons in the present invention are classified into aliphatic hydrocarbons and aromatic hydrocarbons. A hydrocarbon having no structure of any one of a benzene ring and a hydrocarbyl-substituted benzene ring is defined as an aliphatic hydrocarbon. A hydrocarbon containing at least one benzene ring or a hydrocarbyl-substituted benzene ring is defined as an aromatic hydrocarbon. Further, the aromatic hydrocarbon may have an aliphatic hydrocarbon group structure such as toluene, diphenylmethane, 2,3-dihydroanthracene or the like.

Hydrocarbons are classified into two types: saturated hydrocarbons and unsaturated hydrocarbons. All aromatic hydrocarbons are unsaturated hydrocarbons. Saturated aliphatic hydrocarbons are also known as alkanes. The degree of unsaturation of the unsaturated aliphatic hydrocarbon is not particularly limited. By way of example, and not limited to, olefins (including double bonds), alkynes (including triple bonds), diolefins (containing two conjugated double bonds), and the like. When the aliphatic hydrocarbon moiety in the aromatic hydrocarbon is a saturated structure, it is also called an aralkyl hydrocarbon such as toluene.

The structure of the hydrocarbon is not particularly limited and may be a linear structure having no pendant group, a branched structure containing a side group, a ring-containing structure, a dendritic structure, a comb structure, a hyperbranched structure or the like. Unless otherwise specified, a linear structure having no pendant group, a branched structure containing a pendant group, and a cyclic containing structure are preferable, and each corresponds to a linear hydrocarbon, a branched hydrocarbon, or a cyclic hydrocarbon. Among them, the hydrocarbons having no cyclic structure are collectively referred to as open-chain hydrocarbons, including but not limited to linear structures having no pendant groups and branched structures having pendant groups. Open chain hydrocarbons are aliphatic hydrocarbons. Therefore, linear hydrocarbons can also be linear aliphatic hydrocarbons. Branched hydrocarbons can also be branched aliphatic hydrocarbons.

The ring structure in the present invention is not particularly limited as long as there is at least one closed loop that is connected end to end. The ring-forming atoms together form a ring skeleton.

Hydrocarbons containing a cyclic structure are referred to as cyclic hydrocarbons, and corresponding cyclic structures are carbocyclic rings, all composed of carbon atoms. Cyclic hydrocarbons are classified into alicyclic hydrocarbons and aromatic hydrocarbons.

Depending on the source, cyclic hydrocarbons are classified into alicyclic hydrocarbons and aromatic hydrocarbons.

Among them, an aliphatic hydrocarbon having a closed carbocyclic ring is called an alicyclic hydrocarbon, and a corresponding cyclic structure is called an alicyclic ring. Alicyclic hydrocarbons are classified into saturated alicyclic hydrocarbons and unsaturated alicyclic hydrocarbons. Saturated alicyclic hydrocarbons are referred to as cycloalkanes. Unsaturated alicyclic hydrocarbons can also be classified into cyclic olefins, cycloalkynes, cyclic diolefins, and the like, depending on the degree of unsaturation.

All aromatic hydrocarbons are cyclic hydrocarbons, contain at least one benzene ring or substituted benzene ring, and may contain no alicyclic ring or alicyclic ring.

The aromatic ring in the present invention specifically means a benzene ring or a fused ring formed of two or more benzene rings.

The structural unit constituting the ring skeleton is not particularly limited and may or may not contain a nested cyclic structure. For example, a ring skeleton of cyclopentane, cyclohexane, cycloheptane, benzene, furan, pyridine, benzotriazole, anthracene, etc. does not contain a nested cyclic structure, and a cyclodextrin is composed of a plurality of D- The glucopyranose monocyclic rings are connected end to end to form a nested cyclic structure.

Non-carbon atoms are defined as heteroatoms. The hetero atom in the present invention is not particularly limited and includes, but not limited to, O, S, N, P, Si, F, Cl, Br, I, B and the like.

The cyclic structure containing a hetero atom in a ring-forming atom is referred to as a heterocyclic ring with respect to a carbocyclic ring. The ring-forming atom of the alicyclic ring is replaced by a hetero atom to form a heteroalicyclic ring, and the ring-forming atom of the aromatic ring is replaced by a hetero atom to form a heteroaromatic ring.

Depending on the type of heteroatoms, the heterocycles can be of different types including, but not limited to, oxa, aza, thia, phosphine, and the like.

Examples of nitrogens such as pyridine, pyran, pyrrole, oxazole, indole, isoindole, pyrimidine, imidazole, indole, pyrazole, pyrazine, pyridazine, oxazole, quinazoline, triazole, tetra Azaindole and the like.

Examples of the oxa group are, for example, ethylene oxide, furan, tetrahydrofuran, pyran, tetrahydropyran, dioxane, ethylene oxide and the like.

Examples of thia, such as thiophene and the like.

The number of hetero atoms is not particularly limited and may be one or more, such as furan, tetrahydrofuran, pyridine, pyran, pyrrole, tetrahydropyran, carbazole, anthracene, isoindole, etc. containing one hetero atom, including two a hetero atom of pyrimidine, isoxazole, imidazole, pyrazole, pyrazine, pyridazine, thiazole, isothiazole, oxazole, quinazoline, etc., triazole containing three heteroatoms, s-triazine, including four A heteroatom of tetraazaindene, anthracene, etc.

When two or more hetero atoms are contained, the types of the hetero atoms may be the same or different.

Examples of the same hetero atom include, but are not limited to, the above-described aza, oxa, thia, and the like.

Examples of the different hetero atoms are, for example, nitroxides such as oxazole, isoxazole, oxirane, etc., nitrogen thia compounds such as thiazole, isothiazole and the like.

When the polycyclic ring contains two or more hetero atoms, the position of the hetero atom is not particularly limited and may be located on the same ring, such as benzotriazole, or may be located on a different ring, such as ruthenium. Can be located on the side of the shared ring, such as

There is no particular limitation on the number of cyclic structures in one molecule. When there is only one closed cyclic structure, it is defined as a monocyclic compound. When having at least two cyclic structures, if any ring shares at least one atom with the ring, it is called a polycyclic compound. According to the number of rings, by way of example, it can be divided into, for example, bicyclo (norbornene, naphthalene, anthracene, isoindole, carbazole, benzotriazole, benzopyran, benzothiophene, quinolinazole), three Rings (such as adamantane, anthracene, phenanthrene, anthracene), four rings (such as ruthenium) and so on.

The manner of connection between two or more annular structures in the plurality of rings is not particularly limited. When two rings are connected by only one common atom, a spiro ring is formed; when the two rings pass through a common ring edge (ie, sharing two adjacent skeleton atoms), a fused ring such as a hydrazine or a benzoheterocyclic ring is formed; When two rings are connected by sharing carbon atoms that are not directly connected, a bridged ring such as norbornene or adamantane is formed. For example, biphenyl has two benzene rings, but does not belong to a polycyclic structure because it does not share any atoms. Atoms that are shared can be shared by two or more rings at the same time, such as 芘.

Any two linked rings in the polycyclic ring may each independently be an alicyclic or heteroalicyclic ring, or may each independently be an aromatic ring or a heteroaromatic ring, or may be independently an alicyclic ring, an aromatic ring or a heteroalicyclic ring. Or a heterocyclic ring.

The hybridized monocyclic ring is referred to as a heteromonocyclic ring or a monoheterocyclic ring such as furan, tetrahydrofuran, pyridine, pyran, dioxane, cyclic glucose isomers and the like.

The hybridized polycyclic ring is called a heteropolycyclic ring, and according to the difference of the polycyclic structure, including a heterospiro ring, a heterobridge ring, and a heterocyclic ring, respectively, a spiro ring, a bridge ring, and a fused ring in which a ring atom is replaced by a hetero atom. .

For fused rings, it is divided into a fused aromatic ring and a fused heterocyclic ring. Among them, the fused aromatic ring is composed of two or more benzene rings. Among them, a heterocyclic ring, that is, a fused ring containing a hetero ring, which is also called a fused heterocyclic ring, is classified into an aromatic fused heterocyclic ring and a hetero fused heterocyclic ring. Among them, the aromatic fused heterocyclic ring is also called an arylheterocyclic ring, and is fused by an aromatic ring and a heterocyclic ring, and is typically represented by a benzoheterocyclic ring such as benzotriazole. The heterocyclic heterocyclic ring is formed by condensing a heterocyclic ring and a heterocyclic ring.

The hybrid fused aromatic ring corresponds to a hetero-fused aromatic ring.

In the present invention, the hydrocarbon-derived ring includes, but is not limited to, an alicyclic ring, an aromatic ring, a monocyclic ring, a polycyclic ring, a spiro ring, a bridged ring, a fused ring, a fused aromatic ring, a fused heterocyclic ring, an aromatic fused heterocyclic ring, and an aromatic heterocyclic ring. , benzoheterocyclic, heterocyclic heterocyclic ring, carbocyclic ring, heterocyclic ring, heterocyclic hetero ring, aromatic heterocyclic ring, heteromonocyclic ring, heteropolycyclic ring, heterospiro ring, hetero bridged ring, heterocyclic ring, heteroalicyclic ring, hetero Any one of an aromatic ring, a saturated alicyclic ring, an unsaturated alicyclic ring, or the like, or a combination of two or more ring types. In the present invention, it is generally classified into two types according to whether or not an aromatic ring or a heteroaryl ring is contained, as follows:

For cyclic hydrocarbons, it is divided into monocyclic hydrocarbons and polycyclic hydrocarbons. Among them, monocyclic hydrocarbons such as cyclobutane, cyclopentane, cyclohexane, benzene, etc., polycyclic hydrocarbons such as hydrazine, hydrazine, and the like. Polycyclic hydrocarbons are classified into spirocyclic hydrocarbons, bridged cyclic hydrocarbons, and fused cyclic hydrocarbons.

For polycyclic hydrocarbons, any two of the linked rings may be alicyclic, such as norbornene, or both benzene rings, such as naphthalene, anthracene, anthracene, phenanthrene, or any of an alicyclic ring and a benzene ring. Combination, such as 2,3-dihydroanthracene. A fused ring hydrocarbon composed of two or more benzene rings is called a condensed aromatic hydrocarbon.

Depending on the degree of unsaturation, cyclic hydrocarbons can also be classified into saturated cyclic hydrocarbons and unsaturated cyclic hydrocarbons. Among them, saturated cyclic hydrocarbons are cycloalkanes. Unsaturated cyclic hydrocarbons are classified into unsaturated alicyclic hydrocarbons and aromatic hydrocarbons.

In the present invention, a compound in which a carbon atom at any position in a hydrocarbon is substituted with a hetero atom is collectively referred to as a hetero hydrocarbon.

Heterocarbons are classified into aliphatic hydrocarbons and aromatic hydrocarbons depending on the source of the hydrocarbon.

The aliphatic hydrocarbon refers to a hetero hydrocarbon derived from an aliphatic hydrocarbon, including an aliphatic heterocyclic hydrocarbon and an aliphatic open chain hydrocarbon. The saturated aliphatic hydrocarbon is a heteroalkane.

Aromatic hydrocarbon refers to a hydrocarbon derived from an aromatic hydrocarbon, including but not limited to a heteroaromatic hydrocarbon, a viscous hydrocarbon. Wherein, the fused heterocyclic hydrocarbon refers to a fused ring hydrocarbon in which a ring atom is replaced by a hetero atom, and is classified into an aromatic fused heterocyclic hydrocarbon, a hetero fused heterocyclic hydrocarbon or the like. The hybrid aralkyl hydrocarbon is a heteroaromatic hydrocarbon.

When a heterocyclic hydrocarbon does not contain a cyclic structure, it is collectively referred to as an open chain hetero hydrocarbon. All open chain heterones are aliphatic hydrocarbons.

When a ring-forming carbon atom in a cyclic hydrocarbon is replaced by a hetero atom, the heterocyclic ring formed is referred to as a heterocyclic hydrocarbon. Heterocyclic hydrocarbons are further classified into aliphatic heteroatoms and aromatic hydrocarbons depending on the source of the cyclic hydrocarbon.

The heteroheterocyclic hydrocarbon refers to a heterocyclic hydrocarbon derived from an alicyclic hydrocarbon such as 1,4-oxetane or 1,4-dioxane.

The heteroatom of the aromatic hydrocarbon may be located on an aromatic ring in the aromatic hydrocarbon, also known as a heteroaromatic hydrocarbon such as pyridine, pyrimidine.

The fused heterocycles are all heterocyclic hydrocarbons including, but not limited to, aromatic fused heterocyclic hydrocarbons (such as benzotriazole, etc.), hetero-fused heterocyclic hydrocarbons, and the like.

A "group" in the present invention contains at least two atoms, meaning that the compound loses free radicals formed by one or more atoms. The group formed after the partial group is lost relative to the compound is also referred to as a residue. The valence state of the group is not particularly limited, and may be, for example, a monovalent group, a divalent group, a trivalent group, a tetravalent group, ..., a one hundred valent group or the like. Among them, groups having a valence of 2 or more are collectively referred to as a linking group. The linker may also contain only one atom, such as an oxy group or a thio group.

"Hydrocarbyl" refers to a residue formed after a hydrocarbon loses at least one hydrogen atom. According to the amount of hydrogen lost, it can be divided into a monovalent hydrocarbon group (loss of one hydrogen atom), a divalent hydrocarbon group (loss of two hydrogen atoms, also called an alkylene group), a trivalent hydrocarbon group (loss of three hydrogen atoms), etc. By analogy, when n hydrogen atoms are lost, the valence state of the hydrocarbon group formed is n. The hydrocarbon group in the present invention is specifically a monovalent hydrocarbon group unless otherwise specified.

The above hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, aromatic hydrocarbons, saturated hydrocarbons, alkanes, unsaturated hydrocarbons, olefins, alkynes, diolefins, open chain hydrocarbons, linear hydrocarbons (linear aliphatic hydrocarbons), branched hydrocarbons (branched aliphatic hydrocarbons) ), cyclic hydrocarbons, alicyclic hydrocarbons, cycloalkanes, unsaturated alicyclic hydrocarbons, cyclic olefins, cycloalkynes, cyclic diolefins, monocyclic hydrocarbons, polycyclic hydrocarbons, spirocyclic hydrocarbons, bridged cyclic hydrocarbons, fused cyclic hydrocarbons, thick One of an aromatic hydrocarbon, a hetero hydrocarbon, a fatty hydrocarbon, an open chain hetero hydrocarbon, a heterocyclic hydrocarbon, an aliphatic heterocyclic hydrocarbon, an aromatic hydrocarbon, a heteroaromatic hydrocarbon, a fused heterocyclic hydrocarbon, an aromatic fused heterocyclic hydrocarbon, a heterofused heterocyclic hydrocarbon, or the like Or a plurality of hydrogen atoms may be substituted by a hetero atom or any group, which in turn corresponds to a substituted hydrocarbon, a substituted aliphatic hydrocarbon, a substituted aromatic hydrocarbon, a substituted aralkyl hydrocarbon, a substituted saturated hydrocarbon, a substituted alkane, a substituted unsaturated group. a hydrocarbon, a substituted olefin, a substituted alkyne, a substituted diolefin, a substituted open chain hydrocarbon, a substituted linear hydrocarbon (substituted linear aliphatic hydrocarbon), a substituted branched hydrocarbon (substituted branched aliphatic hydrocarbon), Substituted cyclic hydrocarbons, substituted alicyclic hydrocarbons, substituted cycloalkanes, substituted unsaturated alicyclic hydrocarbons, substituted cyclic olefins, substitutions a cycloalkyne, a substituted cyclodiene, a substituted monocyclic hydrocarbon, a substituted polycyclic hydrocarbon, a substituted spirocyclic hydrocarbon, a substituted bridged cyclic hydrocarbon, a substituted fused cyclic hydrocarbon, a substituted fused aromatic hydrocarbon, a substituted heterohydrocarbon, Substituted aliphatic hydrocarbons, substituted open chain hetero hydrocarbons, substituted heterocyclic hydrocarbons, substituted aliphatic heterocyclic hydrocarbons, substituted aromatic hydrocarbons, substituted heteroaromatic hydrocarbons, substituted fused heterocyclic hydrocarbons, substituted aromatic fused heterocyclic hydrocarbons Hydrocarbons, substituted hetero-heterocyclic hydrocarbons, and the like. In the present invention, the hetero atom used for substitution is referred to as a "substituted atom", and any group for substitution is referred to as a "substituent".

The hetero atom is not particularly limited, and a halogen atom is preferred.

The substituent is not particularly limited and may be selected from a hydrocarbon group substituent or a hetero atom-containing group. The substituent in the present invention may contain a hetero atom or may not contain a hetero atom, unless otherwise specified.

Wherein two hydrogen atoms in the secondary carbon may be independently substituted by two identical or different heteroatoms or monovalent hydrocarbon groups, such as -C(CH ₃ ) ₂ -, -CH(OCH ₃ ) ₂ -, - CF(OCH ₃ ) ₂ -; can also be substituted by a cyclic structure at the same time, such as

It may also be substituted by only the same hetero atom to form a group including, but not limited to, a carbonyl group, a thiocarbonyl group, an imino group, etc., such as adenine, guanine, cytosine, uracil, thymine, N, N-di Methyl guanine, 1-methylguanine, hypoxanthine, 1-methyl hypoxanthine, and the like.

Here, when a hydrogen atom in a secondary carbon or a tertiary carbon atom in a linear hydrocarbon is substituted with a hydrocarbon group, the hydrocarbon formed is also a branched hydrocarbon, and the monovalent hydrocarbon group exists as a pendant group.

From the above hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, aromatic hydrocarbons, saturated hydrocarbons, alkanes, unsaturated hydrocarbons, olefins, alkynes, diolefins, open chain hydrocarbons, linear hydrocarbons, branched hydrocarbons, cyclic hydrocarbons, alicyclic hydrocarbons, rings Alkanes, unsaturated alicyclic hydrocarbons, monocyclic hydrocarbons, polycyclic hydrocarbons, hetero hydrocarbons, aliphatic hydrocarbons, heteroalkanes, open chain hetero hydrocarbons, heterocyclic hydrocarbons, aliphatic heterocyclocarbons, aromatic hydrocarbons, heteroaromatic hydrocarbons, heteroaromatic hydrocarbons Any one of a condensed hydrocarbon, a condensed aromatic hydrocarbon, a fused heterocyclic hydrocarbon, an aromatic fused heterocyclic hydrocarbon, a hetero fused heterocyclic hydrocarbon, or the like, which may be obtained, but not limited to, a hydrocarbon group, an aliphatic hydrocarbon group, an aryl group, an aromatic hydrocarbon group, an aralkyl group. Base, saturated hydrocarbon group, alkyl group, unsaturated hydrocarbon group, alkenyl group, alkynyl group, dienyl group, alkene group, alkyne group, diolefin group, open chain hydrocarbon group, linear hydrocarbon group, branched hydrocarbon group, cyclic hydrocarbon group, alicyclic hydrocarbon group , cycloalkane group, unsaturated alicyclic hydrocarbon group, monocyclic hydrocarbon group, polycyclic hydrocarbon group, fused ring hydrocarbon group, fused aryl group, hetero hydrocarbon group, heterocyclic hydrocarbon group, aliphatic hydrocarbon group, heteroalkyl group, open chain hetero hydrocarbon group, heteroalicyclic group Hydrocarbyl, arylheteroalkyl, heteroarylalkyl, heteroaryl, heteroaryl, fused cycloalkyl, fused aryl, fused heterocycloalkyl, aromatic Any of a hydrocarbon heterocycloalkyl, heterocycloalkyl fused heteroaryl substituent or the like.

The substituent containing no hetero atom is a hydrocarbon group. Including but not limited to aliphatic hydrocarbon groups, aryl groups, aromatic hydrocarbon groups, aralkyl groups, saturated hydrocarbon groups, alkyl groups, unsaturated hydrocarbon groups, alkenyl groups, alkynyl groups, dienyl groups, alkene groups, alkyne groups, diolefin groups, open chain hydrocarbon groups , a straight-chain hydrocarbon (linear aliphatic hydrocarbon group), a branched hydrocarbon (branched aliphatic hydrocarbon group), a cyclic hydrocarbon group, an alicyclic hydrocarbon group, a cycloalkane group, an unsaturated alicyclic hydrocarbon group, a monocyclic hydrocarbon group, a polycyclic hydrocarbon group, a condensed hydrocarbon group, Any of the thick aryl groups. By way of example, hydrocarbyl groups include, but are not limited to, methyl, ethyl, vinyl, propyl, allyl, propenyl, propargyl, propynyl, isopropyl, butyl, t-butyl, pentyl, g. Base, 2-ethylhexyl, octyl, decyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecane , octadecyl, nonadecyl, eicosyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, benzyl, p-methylphenyl, butyl Phenyl, alkynyl and the like.

In the present invention, in addition to the heteroalkyl group, the hetero atom-containing substituent includes, but is not limited to, a halogenated alkyl group, a nitro group, a silicon group (trimethylsilyl group, tert-butyldimethylsilyl group, trimethoxysilyl group, etc.). ), a hydrocarbon group or a heteroalkyl group and a oxy group, a thio group, an acyl group, an acyloxy group, an oxyacyl group, a -NH-C(=O)-, -C(=O)-NH-, etc. Connected groups and the like. Taking a hydrocarbon group as an example, a hydrocarbyloxy group, a hydrocarbylthio group, an acyl group, an acyloxy group, a hydrocarbyloxyacyl group, an aminoacyl group, an acylamino group or the like is sequentially formed.

The acyl group in the present invention includes a carbonyl group and a non-carbonyl group, and includes, by way of example only, but not limited to, a carbonyl group, a sulfonyl group, a sulfinyl group, a phosphoryl group, a phosphorous group, a hypophosphoryl group, a nitroxyl group, a nitrosyl group, and a thio group. Carbonyl, imidoyl, thiophosphoryl, dithiophosphoryl, trithiophosphoryl, thiophosphoryl, dithiophosphoryl, thiophosphoryl, thiophosphonyl, disulfide Phosphonoyl, thiophosphinyl and the like. It is preferably a carbonyl group, a thiocarbonyl group, a sulfonyl group or a sulfinyl group. The acyl group refers specifically to a carbonyl group unless otherwise specified.

a hydrocarbyloxy group, for example, an alkoxy group formed by an alkyl group and an oxy group (e.g., a methoxy group, an ethoxy group, a t-butoxy group, etc.), an aryloxy group formed by an aromatic ring and an oxy group (e.g., a phenoxy group, etc.) An aryl-substituted aromatic hydrocarbon group (such as a benzyloxy group) formed by linking an aromatic hydrocarbon group and an oxy group, an alkenyl group formed by an alkenyl group and an oxy group, an alkynyl group formed by an alkynyl group and an oxy group, and the like .

A hydrocarbylthio group, for example, an alkylthio group, an arylthio group, an aromatic alkylthio group, an alkenethio group, an alkynethio group or the like.

The acyloxy group, also referred to as an acyloxy group, corresponds to the above acyl group, and includes a sulfonyloxy group, a sulfinyloxy group and the like in addition to the carbonyloxy group, and the description thereof will not be repeated.

The oxyacyl group corresponds to the above acyl group, and includes an oxysulfonyl group in addition to the oxycarboyl group, and corresponds to the type of the acyl group, and the description thereof will not be repeated.

The aminoacyl group and the acylamino group include, in addition to the aminocarbonyl group and the carbonylamino group, a sulfamoyl group or a sulfonylamino group, respectively, and correspond to the type of the acyl group, and the description thereof will not be repeated.

The above substituted hydrocarbyl group includes both a hydrocarbyl-substituted hydrocarbyl group (still belonging to a hydrocarbyl group) and a heterohydrocarbyl-substituted hydrocarbyl group (which belongs to a heterohydrocarbyl group).

The heterohydrocarbyl group is classified into a fatty hydrocarbon group and an aromatic hydrocarbon group depending on the source. Depending on the structure, the heterohydrocarbyl group includes, but is not limited to, an open-chain heterohydrocarbyl group, a heterocycloalkyl group, a heterocyclic-substituted hydrocarbyl group. The aliphatic hydrocarbon group includes an open-chain heteroalkyl group and an aliphatic heterocyclic hydrocarbon group. The aromatic hydrocarbon group includes, but is not limited to, a heteroaryl group, a heteroaryl hydrocarbon group, an aromatic fused heterocyclic hydrocarbon group, and the like. Heterocycloalkyl groups include, but are not limited to, an aliphatic heterocycloalkyl group and an aromatic heterohydrocarbyl group.

For a compound, a group or an atom, it may be substituted and hybridized at the same time, for example, a nitrophenyl group is substituted for a hydrogen atom, and a -CH ₂ -CH ₂ -CH ₂ - is replaced by -CH ₂ -S- CH(CH ₃ )-.

among them,

The hydrocarbon group formed by the aliphatic hydrocarbon is an aliphatic hydrocarbon group.

The hydrocarbon group formed by an alkane is referred to as an alkyl group. The hydrocarbon group formed by the loss of a hydrogen atom by an unsaturated hydrocarbon is an unsaturated hydrocarbon group.

The unsaturated hydrocarbon loses a hydrocarbon group formed by a hydrogen atom on the unsaturated carbon, and may be classified into an alkenyl group, an alkynyl group, a dienyl group or the like, and examples thereof include a propenyl group and a propynyl group. The hydrocarbon group formed by the unsaturated hydrocarbon losing the hydrogen atom on the saturated carbon may be, for example, an olefin group, an alkyne group, a diolefin group or the like depending on the unsaturated bond, specifically, an allyl group, a propargyl group.

The open chain hydrocarbon group is an alkyl group in which an open chain hydrocarbon loses a hydrogen atom.

The linear hydrocarbon loses one hydrogen atom on the primary carbon to form a linear hydrocarbon group, the linear hydrocarbon loses the hydrogen atom on the secondary or tertiary carbon to form a branched hydrocarbon group, and the branched hydrocarbon loses one hydrogen atom at any position to form a branched hydrocarbon group. .

A hydrocarbon group formed by a cyclic hydrocarbon losing one hydrogen atom on the ring is referred to as a cyclic hydrocarbon group.

The alicyclic hydrocarbon loses one hydrogen atom on the ring to form an alicyclic hydrocarbon group.

The hydrocarbon group formed by the aromatic hydrocarbon is classified into an aryl group and an aromatic hydrocarbon group.

The aromatic hydrocarbon loses one hydrogen atom on the aromatic ring to form an aryl group. The aromatic hydrocarbon loses a hydrogen atom on the non-aromatic ring to form an aromatic hydrocarbon group. The aralkyl hydrocarbon loses a hydrogen atom on the non-aromatic ring to form an aralkyl group. The aralkyl group belongs to the category of an aromatic hydrocarbon group. By way of example, the most typical aryl groups are phenyl, phenylene, most typically aromatic hydrocarbon groups such as benzyl.

Hydrocarbons lose hydrogen atoms to form heterohydrocarbyl groups. The heteroalkane forms a heteroalkyl group.

The aliphatic hydrocarbon loses a hydrogen atom to form a fatty hydrocarbon group. The aromatic hydrocarbon loses a hydrogen atom to form an aromatic hydrocarbon group.

The open chain hetero hydrocarbon loses a hydrogen atom to form an open chain heteroalkyl group.

The heterocyclic hydrocarbon loses the heterocyclic hydrocarbon group formed by the hydrogen atom on the ring.

The alicyclic hydrocarbon loses the hydrogen atom on the alicyclic ring to form an aliphatic heterocycloalkyl group.

The aromatic hydrocarbon loses a hydrogen atom on the aromatic ring to form a heteroaryl group, and the aromatic hydrocarbon loses a hydrogen atom on the non-aromatic ring to form a heteroaromatic hydrocarbon group. The heteroaromatic hydrocarbon loses a hydrogen atom on the non-aromatic ring to form a heteroaralkyl group.

The fused ring hydrocarbon loses the hydrogen atom on the ring to form a fused ring hydrocarbon group. Among them, the fused aromatic hydrocarbon loses the hydrogen atom on the benzene ring to form a fused aryl group.

For fused heterocyclic hydrocarbons, the aromatic fused heterocyclic hydrocarbon loses a hydrogen atom to form an aromatic fused heterocycloalkyl group, and the hetero fused heterocyclic hydrocarbon loses a hydrogen atom to form a heterocyclic heterocyclic hydrocarbon group.

The heterohydrocarbyl group in the present invention is not particularly limited. By way of example, but not limited to, heteroatom-containing aliphatic hydrocarbon groups, open chain heterohydrocarbyl groups, aliphatic heterocycloalkyl groups, aromatic heteroalkyl groups, heteroaryl groups, aromatic heteroalkyl groups, aromatic fused heterocycloalkyl groups, hetero fused heterocyclic hydrocarbon groups, oxygen Heterohydrocarbyl, azahydrocarbyl, thiahydrocarbyl, phosphahydrocarbyl, monoheterohydrocarbyl, diheterohydrocarbyl, polyheterohydrocarbyl, and the like.

The source of the alkylene group in the present invention is not particularly limited, and may be, for example, derived from an aliphatic hydrocarbon or an aromatic hydrocarbon, or may be derived from a saturated hydrocarbon or an unsaturated hydrocarbon, or may be derived from a linear hydrocarbon, a branched hydrocarbon or a cyclic hydrocarbon, or a source thereof. From hydrocarbons or hydrocarbons and so on. From the viewpoint of saturation, for example, it may be derived from an alkane, an alkene, an alkyne, a diene or the like; for a cyclic hydrocarbon, for example, it may be derived from an alicyclic hydrocarbon or an aromatic hydrocarbon, a monocyclic hydrocarbon or a polycyclic hydrocarbon; for a heterocyclic hydrocarbon, for example, From an aliphatic heterocyclic hydrocarbon or an aromatic heterocyclic hydrocarbon.

The alkylene group formed by an alkane is also called an alkylene group, and common alkylene groups include, but are not limited to, methylene, 1,2-ethylene, 1,3-propylene, 1,2-propylene, and Propylene, butylene, pentylene, hexylene, heptylene, octylene, fluorene, aa Base and so on.

The alkylene group obtained by the unsaturated aliphatic hydrocarbon includes any one of -CH=CH-, -C≡C-, and the like.

For the cyclocyclic hydrocarbon group, the position of the two hydrogen atoms which are lost is not particularly limited as long as it is not bonded to one carbon atom at the same time. When the same carbon atom is attached, the cyclic structure exists as a substituent of the carbon atom. An alicyclic hydrocarbon loses two hydrogen atoms on the same ring to form an alicyclic hydrocarbon group, such as

Wait. An aromatic hydrocarbon loses two hydrogen atoms on the same aromatic ring to form an arylene group, such as p-phenylene in phenylene

Benzene

O-phenylene

When two hydrogen atoms lost by an aromatic hydrocarbon are located on the aromatic ring and one is located in the aliphatic hydrocarbon group, the aromatic hydrocarbon group, such as

Wait. An example of a cyclic structure as a substituent is as

Wait.

The alkylene group may or may not contain a substituent or a pendant group, including but not limited to a linear chain.

Branch chain (eg

) or a ring structure (such as

).

The two positions of the alkylene group to which other groups are bonded are not particularly limited, and for example, the phenylene group may include p-phenylene, o-phenylene, and m-phenylene, and for example, the propylene group may include 1,3-arylene. Propyl, 1,3-propylene, 1,2-propylene, isopropylidene, and the like.

For the fused ring structure, in addition to the cyclic structure exemplified above, it may also be, for example, phthalimide, phthaloyl hydrazide, phthalic anhydride,

The protecting group (for example, a mercapto protecting group, an alkynyl protecting group, a hydroxy protecting group, an amino protecting group, and the like) in the present invention is not particularly limited. The above-mentioned protecting groups in the published patents and documents can be incorporated into the present invention by reference. The hydroxyl group protected by the hydroxy protecting group is not particularly limited, and may be, for example, a hydroxyl group such as an alcoholic hydroxyl group or a phenolic hydroxyl group. The amino group protecting the amino group is not particularly limited, and may be, for example, a primary amine, a secondary amine, a hydrazine, an amide or the like.

The amino group in the present invention is not particularly limited and includes, but not limited to, a primary amino group, a secondary amino group, and a tertiary amino group.

For the sake of brevity, in the present invention, the range of the number of carbon atoms in the group is also indicated in the subscript position of C, indicating the number of carbon atoms of the group, for example, C _1-10 means "having 1 to 10 The carbon atom", C _3-20 means "having 3 to 20 carbon atoms". The "substituted C _3-20 hydrocarbon group" means a compound obtained by substituting a hydrogen atom of a C _3-20 hydrocarbon group. The "C _3-20 substituted hydrocarbon group" means a compound having a hydrogen atom of a hydrocarbon group substituted with 3 to 20 carbon atoms.

The divalent linking group in the present invention, for example, an alkylene group, an alkylene group, an arylene group, an amide bond or the like, is not particularly limited, and any one of the two linking ends may be selected when it is bonded to another group, for example. When the amide bond is used as a divalent linking group between A-CH ₂ CH ₂ - and -CH ₂ -B, it may be A-CH ₂ CH ₂ -C(=O)NH-CH ₂ -B or A-CH ₂ CH ₂ -NHC(=O)-CH ₂ -B. Some structural formulas are marked with an asterisk as a directional connection.

When the structure involved has an isomer, it may be any one of them unless otherwise specified. For example, for the structure in which a cis-trans isomer exists, it may be either a cis structure or a trans structure. When the alkyl group is not particularly specified, it means a hydrocarbon group formed by losing a hydrogen atom at any position. Specifically, for example, propyl refers to any of n-propyl and isopropyl, and propylene refers to any of 1,3-propylene, 1,2-propylene, and isopropylidene.

In the structural formula, when it is not possible to directly determine the position of the two terminal groups of the divalent linking group, as in the structural formula

Used

To mark the position of other groups in the divalent linking group. In most cases, there is no special mark, such as the following phenylene structure

In the preparation method of the present invention, a dotted line is used for the structural formula of some skeleton groups to indicate that the skeleton is specified. The groups shown in the structural formula are directly linked.

In the present invention, the ring structure is represented by a circle, and is marked differently depending on the ring structure. E.g,

Represents an arbitrary ring structure;

Represents an aliphatic cyclic structure and does not contain any aromatic or heteroaryl rings, also known as aliphatic rings;

An aromatic ring structure having at least one aromatic ring or heteroaryl ring, also called an aromatic ring;

a skeleton representing a sugar or a saccharide derivative having a cyclic monosaccharide skeleton, also referred to as a sugar ring;

a ring representing a chemical bond such as an amide bond, an ester bond, an imide or an acid anhydride in the ring, also called a condensed ring;

The cyclic skeleton of the water-soluble polymer is also referred to as a polymer ring; the molecular weight of the water-soluble polymer is not particularly limited.

As an example, such as

Each represents a cyclic structure containing a nitrogen atom, a double bond, an azo group, a triple bond, a disulfide bond, a conjugated diene bond, an acid anhydride, an imide bond, and a triazole.

The cyclic structure of the present invention includes, but is not limited to, an aliphatic ring, unless otherwise specified.

Aromatic ring

Sugar ring

Condensation ring

Polymer ring

Aliphatic rings include alicyclic and heterocyclic rings including, but not limited to, monocyclic, polycyclic, spiro, bridged, fused, carbocyclic, heterocyclic, heterocyclic, heteromonocyclic, heteropolycyclic, heterohydra Any one of a ring structure, a heterocyclic ring, a heteroalicyclic ring, or a combination of two or more ring types. Among them, a ring structure such as triazole may be a ring formed by a chemical reaction. It should be noted that although

Rings belonging to the nature of the aliphatic heterocycle are sometimes listed as a single class in view of their particularity.

The aliphatic ring is exemplified as follows:

Wait.

Sugar rings, for example:

Cyclodextrin and the like.

The aromatic ring is composed of an aromatic ring and an aromatic heterocyclic ring, including but not limited to a monocyclic ring, a polycyclic ring, a fused ring, a fused aromatic ring, a fused heterocyclic ring, an aromatic fused heterocyclic ring, an aromatic heterocyclic ring, a benzoheterocyclic ring, and a heterocyclic ring. a cyclic structure of any one of a heterocyclic ring, a carbocyclic ring, a heterocyclic ring, an aromatic heterocyclic ring, a heteromonocyclic ring, a heteropolycyclic ring, a heterocyclic ring, and a heteroaryl ring, or a combination of two or more ring types. As an example:

Wait.

Examples of condensed rings are as follows:

Wait.

In the present invention, "substituted", by "substituted" "hydrocarbyl", exemplifies that any one or more hydrogen atoms at any position in the substituted "hydrocarbyl group" may be substituted by any one or any substituent. Replaced. The substituent atom is not particularly limited, and is preferably a halogen atom. The substituents therein are not particularly limited, and include, but are not limited to, all of the substituents recited in the above terms, and are selected from any one of the hydrocarbyl substituent or the hetero atom-containing substituent. In the description, a combination of an optional substituted atom and a substituent is directly described, such as "the substituted atom or substituent is selected from a halogen atom, a hydrocarbyl substituent, or a hetero atom-containing substituent."

The "stably stable" and "degradable" groups of the present invention are a pair of relative concepts.

"Degradable" refers to the occurrence of a break in a chemical bond and the breaks are at least two residues independent of each other. If after chemical changes The structure is changed, but the entire linker is still only a complete linker, and the linker still falls into the category of "stability stable". The conditions for the degradation are not particularly limited, and include, but are not limited to, degradation under conditions of light, heat, enzyme, redox, acid, alkaline, physiological conditions, in vitro simulated environment, etc., preferably in light, heat, enzyme, oxidation. It can be degraded under conditions of reduction, acidity and alkalinity. The light conditions include, but are not limited to, illumination conditions such as visible light, ultraviolet light, infrared light, near-infrared light, and mid-infrared light. The thermal conditions are above normal physiological temperatures, generally referred to as temperature conditions above 37 °C, and typically below 45 °C, preferably below 42 °C. The enzyme conditions are not particularly limited, and enzymes which can be produced under physiological conditions are included, and examples thereof include peptidases, proteases, lyases and the like. The redox condition is not particularly limited, such as a redox transition between a thiol group and a disulfide bond. The physiological condition is not particularly limited, and includes, but not limited to, serum, heart, liver, spleen, lung, kidney, bone, muscle, fat, brain, lymph node, small intestine, gonad, etc., and may be referred to as intracellular or extracellular. In the matrix, it can refer to normal physiological tissues, and can also refer to diseased physiological tissues (such as tumors, inflammation, etc.). The in vitro simulated environment is not particularly limited and includes, but is not limited to, physiological saline, a buffer, a culture medium, and the like. The rate of the degradable is not particularly limited, and may be, for example, rapid degradation under the action of an enzyme, or slow hydrolysis under physiological conditions.

In contrast, as long as the linker remains as a complete linker, it is defined as "stably stable" in which chemical changes that maintain the integrity of the link are allowed to occur. The chemical change is not particularly limited and includes, but not limited to, isomerization conversion, protonation, substitution reaction, and the like. The conditions which can be stably present are not particularly limited, and include, but are not limited to, light, heat, enzyme, redox, neutral, acidic, basic, physiological conditions, in vitro simulated environment, and the like.

In addition, "stable presence" is not an absolute concept for the same linker, for example, the amide bond is more stable than the ester bond under acidic or basic conditions, and the "stable presence" in the present invention The linker contains an amide bond. However, for example, when it encounters a specific enzyme, it can be broken, and thus is also included in the "degradable" linker. Similarly, a urethane group, a thiourethane group, etc. may be a linker which can be stably existed, or a degradable linker.

The type of the amino acid structure in the present invention is not particularly limited unless otherwise specified, and may be either _L -form or _D -form.

The amino acid skeleton in the present invention refers to a residue having the essential characteristics of an amino acid, specifically, a carboxyhydroxy group (including all C-terminal carboxyhydroxy groups, and also includes a carboxyhydroxy group such as aspartic acid or a side group in glutamic acid), and a hydroxyl group. a hydrogen atom, a hydrogen atom on a phenolic hydroxyl group (stirine), a hydrogen atom on a sulfhydryl group (such as cysteine), and a hydrogen atom on a nitrogen atom (including all N-terminal hydrogen atoms, including side groups) a hydrogen atom in the amino group such as a hydrogen atom on the ε-amino group on lysine, a hydrogen atom in the amino group on the pendant ring of histidine and tryptophan, etc., and an amino group on the amide (such as aspartame) A residue formed by an amino group in a pendant thiol group or a hydrogen atom in an amino group, such as an acid or glutamic acid. For example, the glycine skeleton structure is

Another example is the lysine skeleton.

The structural formulas are no longer given here one by one.

Similarly, the amino acid derivative skeleton in the present invention refers to an atom or a group portion having an essential feature in addition to an amino acid skeleton, such as a hydroxyproline skeleton.

Another example is the sarcosine (also known as N-methylglycine) skeleton.

The cyclic monosaccharide skeleton in the present invention means a residue formed by losing a monovalent sugar of a monosaccharide having a cyclic structure.

The description of the degree of polymerization of the PEG chain or the PEG block in the patent of the present invention may take the form of "satisfying 2 to 2000" or "integer of 2 to 2000", see n ₁ , n ₂ , n ₃ , n _{4 .} , m ₁ , m ₂ , m ₃ . The compound prepared by the method described in the invention is an aggregate composed of a large number of molecules. For any one of the molecules, n _{1 is} taken as an example, and only an integer can be taken, corresponding to the number of EO units, and for the aggregate, n ₁ behaves. A number average of a series of integers, allowed as a non-integer within the range.

In addition, the patent documents cited in the application No. CN 201510349134.9 (Publication No. CN104877127A, the disclosure of the disclosure of the entire disclosure of Structure (including but not limited to aliphatic rings, aromatic rings, sugar rings, condensed rings, polymer rings, etc.), "stably stable", "degradable", "cyclic monosaccharides", "polydisperse" and "monodisperse", trivalent groups and examples thereof, tetravalent groups and examples thereof, pentavalent groups and examples thereof, hexavalent groups and examples thereof, higher valence groups and examples thereof, in addition to trivalent core structures The other part does not include a trivalent group of a hetero atom and an example thereof, a moiety other than the trivalent core structure, a trivalent group including a hetero atom, and an example thereof, a trivalent branched structure, a functional group, and a protected group thereof Examples of forms, stable divalent linking groups, degradable divalent linking groups, degradable multivalent groups, terminally branched structures, and examples thereof (including but not limited to ring-containing structures, combs, trees) Shape, hyperbranched, branched, etc.), biological phase Substances. It should be noted that the preferred embodiments of the above-described structural examples are also included in the present invention. However, the divalent spacer involved in the above trivalent and higher group does not contain an oxyethylene unit in the present invention.

1.1. The present invention discloses a bio-related substance modified with a polyfunctionalized H-type polyethylene glycol derivative. The bio-related substance modified by the polyfunctionalized H-type polyethylene glycol derivative is a stable structure formed by combining a polyfunctionalized H-type polyethylene glycol derivative represented by the general formula (1) with a biologically relevant substance. .

The H-type structure is composed of a linear PEG main axis and four PEG branching chains, and the total number of oxidized vinyl units of the linear PEG main axis and the four PEG branching chains is not more than 5,000, preferably not more than 4,000, more preferably not more than 3,000. More preferably, it does not exceed 2,500, more preferably does not exceed 2,000, and more preferably does not exceed 1,500.

Wherein, LPEG is a linear spindle structure; and LPEG is a monoblock, diblock, triblock or a fragment of 4 to 150 blocks composed of polyethylene glycol or polyethylene glycol.

The total number of oxyethylene units in the LPEG is an integer of from 2 to 2,000; preferably an integer of from 5 to 2,000; more preferably an integer of from 5 to 1,000; more preferably an integer of from 10 to 1,000; more preferably an integer of from 10 to 500; more preferably 20 An integer of ～500; more preferably an integer of 20 to 250; more preferably an integer of 50 to 250.

n ₁ , n ₂ , n ₃ , and n ₄ are the polymerization degrees of the four PEG branching chains, respectively, each independently satisfying 2 to 2000, and may be the same or different from each other in the same molecule; preferably satisfying 5 to 2000; more preferably satisfying 5 More preferably, it is 10 to 1000; more preferably 20 to 1000; more preferably 20 to 500; more preferably 50 to 500.

In the polyfunctionalized H-type polyethylene glycol derivative of the present invention, any one of the PEG blocks in the molecule is independently polydisperse or monodisperse. LPEG is polydisperse as long as at least one polydisperse PEG block is present in the constituent LPEG. LPEG is monodisperse only if all of the PEG blocks that make up the LPEG are monodisperse. In the present invention, the LPEG and the four PEG branched chains corresponding to n ₁ , n ₂ , n ₃ , and n ₄ are each independently polydisperse or monodisperse.

U ₁ and U ₂ are trivalent branching groups linking LPEG and two PEG branching chains; the structure of U ₁ is

The structure of U ₂ is

U ₀₁ and U ₀₂ are each independently a trivalent group. L ₁ , L ₂ , L ₃ , and L ₄ are respectively a linking group of a polyethylene glycol unit in which the number of oxyethylene units is n ₁ , n ₂ , n ₃ , and n ₄ , and L ₅ and L ₆ are connected linear spindles. The linking group of the polyethylene glycol unit, L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ are each independently present or absent, and may be the same or different from each other in the same molecule.

F ₁ and F ₂ contain a functional group or a protected form thereof, and in the same molecule, F ₁ and F ₂ may be the same or different from each other.

The structures of F ₁ and F ₂ are each independently expressed as

among them,

a linker for linking a polyethylene glycol unit; k is an integer of 1 or 2 to 250; g is 0 or 1; G is a linker of a trivalent or higher valence state; when g=0, k=1; g= 1; k is an integer from 2 to 250, and the valence of G is k+1; L ₀ is a divalent linking group; g ₀ is 0, 1 or 2 to 1000; q and q1 are each independently 0 or 1; Z1, Z2 are each independently a divalent linking group; R ₀₁ is a functional group protected form thereof; in the same molecule, F _1, F k _{2 a, G, g, L 0,} g 0, Z 2, q, Z ₁ , q ₁ , and R ₀₁ are each independently the same or different.

In the same molecule, LPEG, U ₁ , U ₂ , U ₀₁ , U ₀₂ , L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ , L ₀ (F ₁ ), G(F ₁ ), Z Any one or any of ₁ (F ₁ ), Z ₂ (F ₁ ), L ₀ (F ₂ ), G(F ₂ ), Z ₁ (F ₂ ), Z ₂ (F ₂ ) and adjacent heteroatoms The linker formed by the group can be stably present or degradable.

In the same molecule, LPEG, U ₁ , U ₂ , U ₀₁ , U ₀₂ , L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ , L ₀ (F ₁ ), G(F ₁ ), Z Any one or any of ₁ (F ₁ ), Z ₂ (F ₁ ), L ₀ (F ₂ ), G(F ₂ ), Z ₁ (F ₂ ), Z ₂ (F ₂ ) and adjacent heteroatoms The conditions in which the group is formed to be stably present or degradable are not particularly limited, and include, but are not limited to, stable in light, heat, enzyme, redox, acid, alkaline, physiological conditions, in vitro simulated environment, or the like. Degradable, preferably stable or degradable under conditions of light, heat, enzyme, redox, acid, alkaline, and the like.

In the present invention, the position of a certain linker may be stably present or may be degraded, and includes a group consisting of the linker and the linker and the adjacent hetero atom group.

According to the difference in the number of degradable sites and the position of degradable sites in the polyfunctionalized H-type polyethylene glycol, the stability of the polymer and the releasability of the modified drug are important. (1) When degradation occurs between a functional group at the end of four polyethylene glycol chains and a polyethylene glycol chain, including L ₀ (F ₁ ), L ₀ (F ₂ ), Z ₁ (F ₁ ), Z ₁ (F ₂ ), Z ₂ (F ₁ ), Z ₂ (F ₂ ), G(F ₁ ), G(F ₂ ), the drug molecule and the polyethylene glycol structure are separated, Maximizing the active site of the drug molecule; in particular, any of Z ₁ (F ₁ ), Z ₁ (F ₂ ), Z ₂ (F ₁ ), Z ₂ (F ₂ ), more particularly Z _{When any of 1} (F ₁ ) and Z ₁ (F ₂ ) is degraded, the drug molecule can be as close as possible to the state before unmodification. (2) When degradation occurs at the intermediate position of the H-type structure, including U ₁ (including U ₀₁ , L ₁ , L ₂ , L ₅ ), U ₂ (including U ₀₂ , L ₃ , L ₄ , L ₆ ), LPEG At any position (including W ₀ , W ₀₁ , W ₀₂ ), the molecular weight of the drug-attachable polyethylene glycol is decreased, thereby reducing the wrapping of the drug and increasing the efficacy; wherein, when in L ₁ , L ₂ When degradation occurs at any of L ₃ and L ₄ , the drug molecule modified at the end of the polyethylene glycol may be only a linear polyethylene glycol chain, when in L ₅ , L ₆ , W ₀ , W ₀₁ , W When degradation occurs at any of the positions ₀₂ , the two branched chain ends of the V-type polyethylene glycol or the Y-type polyethylene glycol may form a drug molecule.

The polyfunctionalized H-type polyethylene glycol derivative-modified bio-related substance contains at least one molecule of a biologically relevant substance. The manner of binding the polyfunctionalized H-type polyethylene glycol derivative to the bio-related substance is not particularly limited, and may be a covalently linked method or a non-covalently linked method. Preference is given to covalent attachment or hydrogen bonding. More preferably, the covalent attachment means.

The manner in which any of the functional groups or protected functional groups of the polyfunctionalized H-type polyethylene glycol derivative and the biologically relevant substance are independently stabilized or degradable.

The type of the bio-related substance to be combined is one or two. The F ₁ modified bio-related substance may be the same as or different from the F2 modified bio-related substance. When F ₁ and F ₂ have the same R ₀₁ (allowing F ₁ ≠F ₂ due to the difference in the number of R ₀₁ ), F ₁ and F ₂ preferably modify the same biologically relevant substance; when F ₁ ≠F ₂ and have different At R ₀₁ , F ₁ and F ₂ preferably modify different biologically relevant substances.

The functional group modified by the polyfunctionalized H-type polyethylene glycol derivative or a protected form thereof may participate in all or part of the modification of a biologically relevant substance. In a bio-related substance modified by a polyfunctionalized H-type polyethylene glycol derivative, a functional group or a protected functional group that is not bound to a biologically relevant substance may retain a structural form before the reaction, or may form Deprotected functional groups can also be blocked by non-biologically related substances.

When the amount of the bio-related substance that can be modified is greater than 1, the position of the bio-related substance is not particularly limited, and may be located in the same or different polyethylene glycol branched chain, or may be located on the same side or on different sides of the polyethylene glycol. Branch chain.

When F ₁ or F _{2 is} combined with a biologically relevant substance, they are each independently expressed as

They may be the same or different from each other in the same molecule;

Wherein D is a residue formed by reacting a modified bio-related substance with a polyfunctionalized H-type polyethylene glycol. When there are multiple reaction sites in the bio-related substance, the same bio-related substance reacts with the same R ₀₁ to obtain the residue formed by the same or different reaction sites participating in the reaction.

In one molecule, the D content (the number of D with respect to the theoretical reaction site) is not particularly limited and may be more than about 75% or less than about 75%. When a molecule contains two different sources of D, the D content of the two different biologically relevant substances are calculated independently. The D content of each molecule constituting the macroscopic substance of the polyethylene glycol derivative may be the same or different, and is exemplified by, for example, 100%, or as 65 to 90%, or as 75 to 94%. The higher the D content, that is, the higher the drug loading, the more easily the effect of the bio-related substance is, and the higher the homogeneity of the product structure, the better the performance. When there are multiple reaction sites in the biologically relevant substance, the same biologically relevant substance can be reacted with the same R ₀₁ to obtain the same or different residue D, preferably the same residue D is obtained, and the performance of the product is higher. Uniform and stable. Preferably, in one molecule, the D content is greater than about 75%, more preferably greater than about 80%, more preferably greater than about 85%, more preferably greater than about 90%, more preferably greater than about 94%, and most preferably equal to 100%. For macroscopic materials, the average level of D can be greater than about 75% or less than about 75%, preferably greater than about 75%, more preferably greater than about 80%, more preferably greater than about 85%, more preferably greater than about 90%, and even more preferably greater than About 94%, most preferably equal to 100%.

Wherein L is a functional group in the polyfunctionalized H-type polyethylene glycol derivative or a linker formed by reacting the protected form with a biologically relevant substance. L can be a covalent connection or a non-covalent connection. Preference is given to covalent linking groups; it may also be a dihydrogen bond or a multiple hydrogen bond. Any one of L may be independently present or degradable independently, and a linking group of L and an adjacent hetero atom group may be stably present or degradable. Since it is allowed to react with different sites from the same bio-related substance, several PEG chain ends of the same molecule are allowed to correspond to different L, preferably L of the ipsilateral PEG chain end is the same. Any one of L may be independently present or degradable independently, and a linking group of L and an adjacent hetero atom group may be stably present or degradable. Accordingly, any one of (Z ₂ ) _q -L may be independently present or degradable independently, and a linking group of (Z ₂ ) _q -L and an adjacent hetero atom group may be stably present or degradable. Preferably, the L of the ipsilateral PEG chain end has the same stability, that is, both can be stably present or both can be degraded. At this time, (Z ₂ ) _q -L at the end of the ipsilateral PEG chain also has the same stability.

Wherein E ₀₁ is R ₀₁ , protected R ₀₁ , deprotected R ₀₁ or terminated R ₀₁ . E ₀₁ is preferably R ₀₁ . The group for blocking R ₀₁ is not particularly limited, and is preferably blocked with a C _1-6 alkyl group or an amino acid, more preferably with a methyl group, an ethyl group or a glycine group. The definition of R ₀₁ is consistent with the above. Succinimide active ester

Glycine terminated

As another example, the hydroxyl group can be blocked with methyl groups by methanol.

Wherein k ₀ is the number of sites in the F ₁ or F ₂ that react with the bio-related substance; k ₀ is an integer from 1 to k, each independently selected from 1 or 2 to 250, preferably k ₀ = k. In the present invention, it is preferred that one bio-related substance molecule reacts with only one functional group or a protected form thereof. That is, k ₀ also represents the number of bio-related substance molecules bound in F ₁ or F ₂ , and the corresponding quality is controllable.

The bio-related substance modified by the polyfunctionalized H-type polyethylene glycol derivative preferably has the formula represented by formula (2), formula (3), formula (4), formula (5) or formula (6) The structure is more preferably a general structure represented by formula (3) or formula (6), and most preferably has a general structure represented by formula (6).

Wherein, the definitions of LPEG, n ₁ , n ₂ , n ₃ , n ₄ , U ₁ , and U ₂ are the same as those in the above-mentioned polyfunctionalized H-type polyethylene glycol derivative, and are not described herein.

Wherein D ₁ , D ₂ , D ₃ , and D ₄ are each independently represented as

And they may be the same or different from each other in the same molecule.

Wherein, EF ₁ and EF ₂ are each independently expressed as

And they may be the same or different from each other in the same molecule. That is, EF ₁ is F ₁ , protected F ₁ , deprotected F ₁ or blocked F ₁ , EF ₂ is F ₂ , protected F ₂ , deprotected F ₂ or blocked F ₂ . EF ₁ and EF ₂ are preferably F ₁ and F ₂ , respectively. The capped F ₁ , capped F ₂ are each independently preferably capped with a C _1-6 alkyl or amino acid, more preferably terminated with a methyl, ethyl or glycine.

In the same molecule, D ₁ , D ₂ , and EF ₁ are on the right side, and D ₃ , D ₄ , and EF ₂ are on the left side; wherein, i, g, L ₀ , g ₀ , Z ₂ , q, Z _{1 on the same side} , q ₁ , E _{01 are the} same, and D is from the same biologically relevant substance, k, k ₀ , G, L in the same side may be the same or different; wherein, the opposite side k, G, g, L ₀ , g ₀ Z ₂ , q, Z ₁ , q ₁ , E ₀₁ may each independently be the same or different, and the D sides may be derived from the same or different biologically relevant substances. When D is derived from the same biologically relevant substance, residues generated after reaction with R _{01 are} allowed for different reaction sites. Especially when there are multiple identical reactive groups in a biologically relevant substance.

According to the number of blocks in the linear spindle LPEG, the structural form of LPEG includes but is not limited to

Wherein, W ₀ , W ₀₁ , and W ₀₂ are each independently a linking group having 1 to 100 atoms; and W ₀ , W ₀₁ , and W ₀₂ are each independently stable or degradable;

m ₁ , m ₂ , and m ₃ are the degrees of polymerization of the respective PEG blocks, each independently satisfying 0 to 2000, and may be the same or different from each other in the same molecule; preferably, m ₁ , m ₂ , and m ₃ are each independently satisfied. 0 to 1000; and the PEG blocks corresponding to m ₁ , m ₂ , and m ₃ are each independently polydisperse or monodisperse;

j is an integer of 1 or 2 to 100.

LPEG is preferably

for

Then m _{2 is} selected from 2 to 2000 (m ₂ is 0 to 2000, LPEG is 2 to 2000, and the intersection is obtained). m ₂ more preferably satisfies 5 to 2000; more preferably satisfies 5 to 1000; m ₂ more preferably satisfies 10 to 1000; more preferably satisfies 10 to 500; more preferably 20 to 500; more preferably 20 to 250; more preferably 50 ~250.

for

Then m _{1 is} selected from 2 to 2000 (m ₁ is 0 to 2000, LPEG is 2 to 2000, and the intersection is obtained). m ₁ preferably satisfies 5 to 2000; more preferably satisfies 5 to 1000; m ₁ more preferably satisfies 10 to 1000; more preferably 10 to 500; more preferably 20 to 500; more preferably 20 to 250; more preferably 50 to 50 250.

LPEG is most preferably

Taking the general formula (6) as an example, the bio-related substance modified by the polyfunctionalized H-type polyethylene glycol derivative can also be represented by the formula (6-2) or the formula (6-3). The formula (6-2) is preferably represented by the formula (6-4), the formula (6-4b), the formula (6-5), the formula (6-5b) or the formula (6-6). Structure.

Wherein n ₁ , n ₂ , n ₃ , n ₄ , U ₁ , U ₂ , D ₁ , D ₂ , D ₃ , D ₄ , W ₀ , W ₀₁ , W ₀₂ , m ₁ , m ₂ , m ₃ , The definition of j is consistent with the above, and will not be described here.

In the present invention, the general formulae (1) to (6) also include the general formula (6-2), the general formula (6-3), the general formula (6-4), the general formula (6-4b), and the general formula ( 6-5), general formula (6-5b) or general formula (6-6).

1.1.1. Degree of polymerization and dispersion of polyethylene glycol chains

In addition, when it is not specifically limited, the "molecular weight" referred to in this invention is "number average molecular weight", and M _n can be the molecular weight of a polydisperse block or substance, and can also be monodisperse embedded. The molecular weight of a segment or substance, unless otherwise specified, generally refers to a polydisperse polymer.

For the polydisperse PEG chain n _i (i = 1, 2, 3, 4, 5, 6, 7 or 8), the number average molecular weight is preferably from 2 to about 1000; more preferably from 2 to about 500; more preferably from 5 to About 500; more preferably from about 11 to about 500; more preferably from about 22 to about 500; more preferably from about 30 to about 250; more preferably from about 34 to about 150. In the above preferred case, the more conventional the molecular weight of the corresponding PEG segment, the simpler and easier to prepare, the narrower the PDI (polydispersity coefficient) of the molecular weight, and the more uniform the performance. The linear PEG obtained by the usual polymerization method has a number average molecular weight of about 2 kDa to 40 kDa.

For monodisperse PEG blocks, the molecular weight is defined by the number of oxyethylene units (hereinafter referred to as EO units). The monodisperse polyethylene glycol prepared according to the prior art has an EO unit number of between about 1 and 70, including but not limited to the reference "Expert Rev. Mol. Diagn. 2013, 13(4), 315-319. , J. Org. Chem. 2006, 71, 9884-9886, Angew. Chem. 2009, 121, 1274-1278, Bioorganic & Medicinal Chemistry Letters, 2015, 25: 38-42, Angew. .Int. Ed., 2015, 54: 3763-3767 and the number of EO units listed in the documents cited in the above documents. The number of EO units of a typical monodisperse PEG includes, but is not limited to, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 16, 20, 22, 24, 27, 29, 36 44, 48, 56, 62, 64, 67, etc. It should be particularly noted that the monodispersity referred to in the present invention may be a monodisperse mixture in addition to a single component having only one EO unit number, but it is required that the relative content percentage of the different components is determined. That is, the PDI of the mixture is 1, and the corresponding number average degree of polymerization may be an integer or a non-integer. If the content of each component is determined by a monodisperse block or a mixture of substances, the PDI is greater than 1, still forming a polydisperse block or substance. The monodisperse PEG block preferably has 2 to 70 EO units; more preferably 3 to 70; more preferably 3 to 70; more preferably 3 to 50; more preferably 3 to 25. The more preferred the case, the more diverse the preparation process.

The polyfunctionalized H-type polyethylene glycols of the formulas (1) to (6) include, but are not limited to, the following depending on the difference in the dispersibility of the PEG segments in the molecule:

(1) The LPEG is polydisperse.

When the LPEG is polydisperse, the number average molecular weight of the LPEG may preferably be about 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3350, 3500, 4000, 5000, 5500, 6000. ,6500,7000,7500,8000,8500,9000,9500,10000,11000,12000,13000,14000,15000,16000,17000,18000,19000,20000,25000, 30000, 35000, 40000, 50000 or 60000 in Da. More preferably about 1000, 1500, 2000, 2500, 3000, 3350, 3500, 4000, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, 10000, 11000, 12000, 13000, 14000, 15000 , 16000, 17000, 18000, 19000 or 20000Da. More preferably, it is about 1000, 2000, 3000, 3350, 3500, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 12000, 13000, 14000, 15000, 16000, 17000, 18000, 19000 or 20000Da. More preferably, it is about 1000, 2000, 3350, 3500, 4000, 5000, 6000, 8000, 9000, 10000, 12000, 15000 or 20000 Da.

(2) The LPEG is monodisperse.

The linear polyethylene glycol spindle LPEG of the present invention allows for 1, 2, 3 or more PEG blocks, and when LPEG is monodisperse, all of the PEG blocks are required to be monodisperse.

In the case of having one PEG block, the number of EO units of LPEG may preferably be an integer of from 2 to 70; more preferably an integer of from 3 to 70; more preferably an integer of from 5 to 70; more preferably an integer of from 5 to 50.

Wherein, when there are two PEG blocks, the total number of EO units of LPEG may preferably be an integer of from 2 to 140; more preferably an integer of from 3 to 140; more preferably an integer of from 5 to 140; more preferably an integer of from 5 to 70; more preferably An integer from 5 to 50.

Wherein, when there are three PEG blocks, the total number of EO units of LPEG may preferably be an integer of from 3 to 210; more preferably an integer of from 5 to 210; more preferably an integer of from 5 to 150; more preferably an integer of from 5 to 100; more preferably An integer of 5 to 70; more preferably an integer of 5 to 50.

Wherein, when there are 4 or more PEG blocks, the total number of EO units of LPEG may preferably be an integer of 4 to 500; more preferably an integer of 5 to 500; more preferably an integer of 5 to 250; more preferably 5 to 200 An integer; more preferably an integer of 5 to 100; more preferably an integer of 5 to 50.

(3) The PEG branching chain corresponding to the n ₁ , n ₂ , n ₃ or n ₄ is polydisperse.

When the PEG branching chain corresponding to n ₁ , n ₂ , n ₃ or n ₄ is polydisperse, the number average molecular weight of the corresponding PEG branching chain is preferably about 500, 600, 700, 800, 900, 1000, 1500, 2000. , 2500, 3000, 3350, 3500, 4000, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, 10000, 11000, 12000, 13000, 14000, 15000, 16000, 17000, 18000, 19000 , 20000, 25000, 30000, 35000, 40000, 50000 or 60000, in Da. More preferably about 1000, 1500, 2000, 2500, 3000, 3350, 3500, 4000, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, 10000, 11000, 12000, 13000, 14000, 15000 , 16000, 17000, 18000, 19000 or 20000Da. More preferably, it is about 1000, 2000, 3000, 3350, 3500, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 12000, 13000, 14000, 15000, 16000, 17000, 18000, 19000 or 20000Da. More preferably, it is about 1000, 2000, 3350, 3500, 4000, 5000, 6000, 8000, 9000, 10000, 12000, 15000 or 20000 Da.

(4) The PEG branching chain corresponding to the n ₁ , n ₂ , n ₃ or n ₄ is monodisperse.

When the PEG branched chain corresponding to n ₁ , n ₂ , n ₃ or n ₄ is monodisperse, it is preferably an integer of 2 to 70; more preferably an integer of 3 to 70; more preferably an integer of 5 to 70; more preferably 5 An integer of ~50.

(5) The PEG branching chain corresponding to the n ₁ , n ₂ , n ₃ , and n ₄ is polydisperse, and the LPEG is monodisperse. Among them, the number of blocks of LPEG is not particularly limited. Preferably, the LPEG is a monodisperse monoblock, diblock or triblock.

(6) Any two of the PEG branching chains corresponding to n ₁ , n ₂ , n ₃ , and n ₄ are polydisperse, and the other two are monodisperse. LPEG is polydisperse or monodisperse.

(7) The PEG branching chain corresponding to the n ₁ , n ₂ , n ₃ , and n ₄ is monodisperse, and the LPEG is polydisperse. Among them, the number of blocks of LPEG is not particularly limited. Preferably, the LPEG is a monoblock, a diblock or a triblock and contains at least one polydisperse block.

(8) The PEG branching chain and the LPEG corresponding to the n ₁ , n ₂ , n ₃ , and n ₄ are all polydisperse.

(9) The PEG branching chain and the LPEG corresponding to the n ₁ , n ₂ , n ₃ , and n ₄ are monodisperse.

1.1.2. Branched structures U ₁ , U ₂ and G

U ₁ and U ₂ are each independently equal to U ₀₁ , U ₀₂ or each independently contain U ₀₁ , U ₀₂ .

U ₁ and U ₂ are each independently a symmetric type or an asymmetric type.

Unless otherwise specified, for the trivalent groups U ₀₁ , U ₀₂ , either of the connecting ends may be directed to the spindle polyethylene glycol unit. When marked with an asterisk *, the end marked by the asterisk * points to the spindle PEG unit.

Trivalent group

As an example, there are two different types of connectors, e1 and e2. When it is used as the trivalent group U ₀₁ or U ₀₂ , it can be pointed from the e1 end to the main axis polyethylene glycol unit. In this case, it corresponds to the symmetric U ₀₁ or U ₀₂ , and can also be directed to the main axis by any e2 end. The diol unit, which corresponds to the asymmetric U ₀₁ or U ₀₂ at this time.

U ₀₁ and U ₀₂ are each independently selected from any of the trivalent groups in the set G ³ of the trivalent group.

In the same molecule, U ₀₁ and U ₀₂ are each independently a symmetric type or an asymmetric type.

When U ₀₁ and U ₀₂ are of a symmetric type, U ₁ and U ₂ are each independently a symmetric type or an asymmetric type in the same molecule. For symmetrical U ₀₁ , U ₀₂ , when L ₁ = L ₂ and L ₃ = L ₄ , U ₁ and U ₂ are symmetric types. When L ₁ ≠L ₂ or L ₃ ≠L ₄ , U ₁ and U ₂ are of an asymmetric type.

When U ₀₁ and U ₀₂ are of an asymmetric type, U ₁ and U ₂ are asymmetric types.

The stability of U ₁ and U ₂ is not particularly limited, and each is independently a group which is stably present or degradable.

The structure of U ₁ and U ₂ is not particularly limited. The structures of U ₀₁ and U ₀₂ each independently include, but are not limited to, a branched structure or a ring-containing structure.

The stability of U ₀₁ and U ₀₂ is not particularly limited, and each is independently a group which can be stably present or degradable.

The structure of U ₀₁ and U ₀₂ is not particularly limited. The structures of U ₀₁ and U ₀₂ each independently include, but are not limited to, a branched structure or a ring-containing structure.

Unless otherwise specified, for a k+1 (k = 2 to 250) valence group G, a polyethylene glycol unit may be directed to the branched chain by any of the linking ends. When marked with an asterisk *, the junction marked by an asterisk * points to the branched-chain PEG unit.

The structure of G is not particularly limited, and includes, but not limited to, a branch, a ring-containing structure, a comb, a tree, a hyperbranched, and the like.

k is the number of functional groups in a PEG branching chain or a protected form thereof, and is also the number of bio-related material molecules that can be modified by a PEG branching chain.

When k=1, g=0, at which point G does not exist.

When k is an integer of 2 to 250, g=1, at which time G exists, and G is a linker having a valence of k+1. At this time, k may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, An integer of 24, 25, 26, 27, 28, 29, 30, 31, 32 or 33-251. Correspondingly, the valence of G is 3 to 251, that is, G is trivalent, tetravalent, pentavalent, hexavalent, seven-valent, eight-valent, nine-valent, ten-price, eleven-valent, twelve-valent, and thirteen-valent. , fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, two Fifteen, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three or 34-251 .

k is preferably 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 or 9 to 100; more preferably 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 or 33-64; more preferably 1, 2, 3, 4 , 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. .

For any one selected from 2 to 250, G is selected from any one of the k+1-valent groups of the set G ^k+1 of the k+1-valent group.

The stability of any one of the k+1-valent groups of the group G ^k+1 (k=2 to 250) is not particularly limited, and may be a group which is stable or a group which is degradable. The steadily present condition is not particularly limited, and is preferably stable under conditions including, but not limited to, light, heat, enzyme, redox, acid, basic, physiological conditions, in vitro simulated environment, and more preferably, in light and heat. It can be stably present under the conditions of enzyme, redox, acidity and alkalinity. The degradable conditions are also not particularly limited, and are preferably degradable under conditions including, but not limited to, light, heat, enzymes, redox, acid, basic, physiological conditions, in vitro simulated environment, and more preferably, in light, heat, It can be degraded under the conditions of enzyme, redox, acidity and alkali.

U ₀₁ , U ₀₂ , and trivalent G are each independently selected from any one of the trivalent groups of the group G ³ of the trivalent group, and may be the same or different from each other in the same molecule.

1.1.2.1. Trivalent groups

The trivalent group in the set G ³ contains a trivalent core structure. The trivalent core structure may be one atom CM ₃ , one unsaturated bond CB ₃ or one cyclic structure CC ₃ .

Among them, the trivalent nuclear atom CM _{3 is} not particularly limited as long as three covalent single bonds are allowed to be simultaneously formed. For example, a trivalent nitrogen atom nucleus, a trivalent carbon nucleus, a trivalent silicon nucleus, a trivalent phosphorus nucleus, or the like can be mentioned. A trivalent nuclear atom may not be attached to any atom or group, such as a trivalent nitrogen nucleus.

It is also possible to connect other atoms or groups, such as trivalent carbon nuclei.

Trivalent silicon nucleus

Trivalent phosphorus nucleus

Wait.

Wherein R ₁ is a hydrogen atom or a substituent on a carbon atom or a silicon atom.

As a substituent group, R ₁ are not particularly limited. Substituents which are stable in anionic polymerization conditions are preferred.

When the substituent is used, the number of carbon atoms of R ₁ is not particularly limited, but the number of carbon atoms is preferably from 1 to 20, and more preferably from 1 to 10.

As a substituent group, R ₁ may contain a hetero atom, may contain hetero atoms.

As the substituent, the structure of R ₁ is not particularly limited and includes, but not limited to, a linear structure, a branched structure containing a side group, or a cyclic structure. The cyclic structure is not particularly limited and includes, but is not limited to, any of the cyclic structures recited in the terminology.

R ₁ is a hydrogen atom or a group selected from any one of a C _1-20 hydrocarbon group, a substituted C _1-20 hydrocarbon group and the like. Wherein the substituted atom or substituent in R ₁ is not particularly limited, and includes, but is not limited to, any one of the substituted atoms or any of the substituents listed in the term, and is selected from a halogen atom, a hydrocarbon group substituent, and a hetero atom-containing substituent. One.

R ₁ is preferably a hydrogen atom or a C _1-20 alkyl group, an aralkyl group, a C _1-20 open-chain heteroalkyl group, a heteroaryl hydrocarbon group, a substituted C _1-20 alkyl group, a substituted aromatic hydrocarbon group, a substituted C _{1 -} Any one of ₂₀ open-chain heteroalkyl groups, substituted heteroaryl hydrocarbon groups, and the like.

Specifically, as an example, R _{1 is} selected from a hydrogen atom or includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, decyl, Undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, Any one of a benzyl group, a substituted C _1-20 alkyl group, a substituted aromatic hydrocarbon group, a substituted C _1-20 open chain heterohydrocarbyl group, a substituted heteroaryl hydrocarbon group, and the like. Among them, butyl includes, but not limited to, n-butyl group and tert-butyl group. Octyl groups include, but are not limited to, n-octyl, 2-ethylhexyl. Wherein the substituted atom and the substituent are selected from a halogen atom, a hydrocarbyl substituent, and a hetero atom-containing substituent, preferably a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a C _1-6 alkyl group, an alkoxy group. Or nitro.

R ₁ is preferably a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, decyl, C _1-10 halogenated hydrocarbon, halogen An acetyl or alkoxy-substituted C _1-10 aliphatic hydrocarbon group. Wherein the halogen atom is F, Cl, Br or I.

R _{1 is} most preferably a hydrogen atom, a methyl group or an ethyl group.

Wherein R ₃₇ is a substituent of a trivalent silicon branching center selected from a hydrocarbon group, preferably a C _1-20 hydrocarbon group, more preferably a C _1-20 alkyl group, most preferably a methyl group.

Among them, the trivalent unsaturated bond core structure CB _{3 is} not particularly limited as long as three covalent single bonds can be simultaneously formed. The unsaturated bond may have two or more bonding atoms. Preferably 2 or 3 are used. More preferably, two. As an example, such as

Wait.

Among them, the trivalent cyclic core structure CC _{3 is} not particularly limited as long as three covalent single bonds can be simultaneously taken out. The ring-forming atoms which lead to the covalent single bond are not particularly limited, and include, but are not limited to, N, C, Si, P, and the like. The cyclic structure is selected from the group consisting of, but not limited to, an aliphatic ring, an aromatic ring, a sugar ring, and a condensed ring. The annular structure may be a single ring, for example

Can also be multi-ring, for example

It may be a naturally occurring cyclic structure, such as any trivalent monocyclic ring from any cyclic monosaccharide, for example

Etc.; may also be a ring formed by a chemical reaction, such as a cyclic peptide, a lactone, a lactam, a lactide, etc., for example

The extracted covalent single bond can be directly extracted from the ring-forming atom and can be taken out through the unsaturated bond. The three covalent single bonds that are extracted can simultaneously elicit three covalent single bonds from three ring-forming atoms.

Such as

It is also possible that two of the covalent single bonds are from the same ring-forming atom.

Wherein M ₅ , M ₆ , M ₇ and M ₂₃ are ring-forming atoms, that is, atoms located on the ring. M ₅ , M ₆ , M ₇ and M ₂₃ are each independently a carbon atom or a hetero atom, and may be the same or different from each other in the same molecule. M ₅ , M ₆ , M ₇ and M ₂₃ are each independently preferably a carbon atom, a nitrogen atom, a phosphorus atom or a silicon atom. The number of ring-forming atoms of the ring in which M ₅ , M ₆ , M ₇ and M ₂₃ are present is not particularly limited, but is preferably a 3- to 50-membered ring, more preferably 3 to 32, and still more preferably 3 to 18. M ₂₃ is a carbon atom, a nitrogen atom, a phosphorus atom or a silicon atom which leads to two single bonds on the ring. When it is a nitrogen atom, it exists as a quaternary ammonium cation.

M ₅ , M ₆ , M ₇ and M ₂₃ may each independently be a carbon atom or a hetero atom of a ring of 3 to 50 members, preferably a carbon atom or a hetero atom of a ring of 3 to 32 members, more preferably a ring of 3 to 32 members. The carbon atom, the nitrogen atom, the phosphorus atom or the silicon atom is more preferably a carbon atom, a nitrogen atom, a phosphorus atom or a silicon atom on the ring of 3 to 18 members.

A ring in which any one of M ₅ , M ₆ or M ₇ is located, a ring in which M ₅ , M ₆ , and M ₇ are located, and a ring in which M ₂₃ and M ₆ are located are not particularly limited, including but not limited to

Wait.

among them,

Is any alicyclic or aliphatic heterocyclic ring, and the ring-forming atoms are each independently a carbon atom or a hetero atom; the hetero atom is not particularly limited and includes, but not limited to, a nitrogen atom, an oxygen atom, a sulfur atom, a phosphorus atom, and silicon. Atom, boron atom, etc. The hydrogen atom on the ring-forming atom of the alicyclic ring may or may not be substituted by any substituted atom or substituent. The substituted hetero atom or the substituent is not particularly limited and includes, but is not limited to, any one of the substituted hetero atoms or any of the substituents listed in the term, and any one selected from the group consisting of a halogen atom, a hydrocarbon group substituent, and a hetero atom-containing substituent. . The definition of the alicyclic or heteroalicyclic ring is defined in detail in the terminology and will not be repeated here. Briefly, the alicyclic and aliphatic heterocycles include, but are not limited to, monocyclic, polycyclic, spiro, bridged, fused, carbocyclic, heterocyclic, heteroalicyclic, heteromonocyclic, heteropolycyclic, hetero Any one of a spiral structure, a heterocyclic ring, and a heteroalicyclic ring, or a combination of two or more ring types.

among them,

Any one of an aromatic ring or an aromatic heterocyclic ring, and the ring-forming atoms are each independently a carbon atom or a hetero atom; the hetero atom is not particularly limited and includes, but not limited to, a nitrogen atom, a phosphorus atom, a silicon atom, a boron atom and the like. The hydrogen atom on the ring-forming atom of the aromatic ring may or may not be substituted by any of the substituted atoms or any of the substituents. The substituted hetero atom or the substituent is not particularly limited and includes, but is not limited to, any one of the substituted hetero atoms or any of the substituents listed in the term, and any one selected from the group consisting of a halogen atom, a hydrocarbon group substituent, and a hetero atom-containing substituent. . The substituted atom is preferably a halogen atom. The substituent is preferably a group which contributes to the induction and conjugation effect of an unsaturated bond electron. The definitions of the aromatic ring and the aromatic heterocyclic ring are defined in detail in the terminology, and are not described herein again. Generally speaking, the aromatic ring and the aromatic heterocyclic ring include, but are not limited to, a monocyclic ring, a polycyclic ring, a fused ring, a fused aromatic ring, a fused heterocyclic ring, an aromatic fused heterocyclic ring, an aromatic heterocyclic ring, a benzoheterocyclic ring, and a heterocyclic ring. a fused ring, a carbocyclic ring, a heterocyclic ring, an aromatic heterocyclic ring, a heteromonocyclic ring, a heteropolycyclic ring, a hetero fused ring, a heterocyclic ring, or a combination structure of any two or more ring types . The aromatic ring is preferably the above-mentioned benzene, pyridine, pyridazine, pyrimidine, pyrazine, 1,3,5-triazine, tetrazine (1,2,3,4-, 1,2,4,5- and 1, 2,3,5-three isomers), anthracene, anthracene, anthracene, anthracene, anthracene, naphthalene, dihydroanthracene, xanthene (xanthene), thioxanthene, dihydrophenanthrene , 10,11-dihydro-5H-dibenzo[a,d]cycloheptane, dibenzocycloheptene, 5-dibenzocycloheptenone, quinoline, isoquinoline, indole, carbazole , iminodibenzyl, naphthylethylcyclo, dibenzocyclooctyne, azadibenzocyclooctene, etc., in any of the substituted forms, or in any of the hybrid forms.

among them,

It is a skeleton of a saccharide or a saccharide derivative having a cyclic monosaccharide skeleton. The source of the saccharide or saccharide derivative is a natural monosaccharide or a non-natural monosaccharide. The cyclic monosaccharide has the structure of any one of its isomers, chiral isomers, optical isomers, conformational isomers, and rotamers, or any two or more thereof. Combination.

Any one of a skeleton selected from a cyclic monosaccharide or a cyclic monosaccharide derivative, a skeleton of an oligosaccharide or an oligosaccharide derivative, a polysaccharide or a polysaccharide derivative skeleton.

The skeleton of the cyclic monosaccharide or cyclic monosaccharide derivative is represented as

The carbon atom number is 3, 4, 5, 6 or 7, and its structure is any one of an isomer, a chiral isomer, an optical isomer, a conformational isomer, a rotamer or Any combination of two or more forms. Preferred are monosaccharide or monosaccharide derivatives of a cyclic monosaccharide backbone having 6 carbon atoms, including, but not limited to, glucose, allose, altrose, mannose, gulose, idose, and half. Any of monosaccharides such as lactose, talose, psicose, fructose, sorbose, tarulose, and inositol.

The skeleton of the oligosaccharide or oligosaccharide derivative is represented as

The combination between the cyclic monosaccharide skeletons includes, but is not limited to, linear, branched, hyperbranched, dendritic, comb, and cyclic. The number of monosaccharide units is 2 to 10. In the ring form, for example, any of cyclodextrin or a derivative thereof may be formed in combination with α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin.

The polysaccharide or polysaccharide derivative skeleton is expressed as

The combination between the cyclic monosaccharide skeletons includes, but is not limited to, linear, branched, hyperbranched, dendritic, comb, and cyclic. The number of monosaccharide units is greater than 10. By way of example, D-glucopyranose units are sequentially joined by α-1,4 glycosidic bonds to form a linear combination; the above linear structures are connected end to end to form a cyclic combination. For example, when at least one D-glucopyranose unit passes at least two of α-1,2 glycosidic bond, α-1,3 glycosidic bond, α-1,4 glycosidic bond, α-1,6 glycosidic bond. When bonded to a linked glucose unit, a branched or hyperbranched combination is formed. When all of the glucose units are repeatedly joined in a regular manner by a specific three or more glycosidic bonds, a comb combination can be formed. Specifically, as an example, the polysaccharide or the polysaccharide derivative may be any of starch, chitin, cellulose, and dextran.

among them,

It is a ring containing a chemical bond formed by condensation of an amide bond, an ester bond, an imide, an acid anhydride or the like. For example, a lactone, a lactam, a cyclic imide, a cyclic acid anhydride, a cyclic peptide, etc. are mentioned.

CC _{3 is} selected from, but not limited to,

Any of the trivalent cyclic core structures.

Wherein X ₁ and X ₄ are each independently a hydrogen atom to which an oxy group is bonded, a hydroxy protecting group or a group LG ₄ .

When it is a hydroxy protecting group, X ₁ and X _{4 are} selected from the hydroxy protecting group in the combination exemplified by PG ₄ . The protected hydroxy group is referred to as OPG ₄ . The hydroxy protecting group is not particularly limited.

Among them, the number of carbon atoms of LG ₄ is not particularly limited. The number of carbon atoms of LG ₄ is preferably from 1 to 20, and more preferably from 1 to 10.

The structure of LG ₄ is not particularly limited and includes, but is not limited to, a linear structure, a branched structure containing a side group, or a cyclic structure. The cyclic structure is not particularly limited and includes, but is not limited to, any of the cyclic structures recited in the terminology.

LG ₄ may or may not contain heteroatoms.

LG _{4 is} selected from any one of a C _1-20 hydrocarbyl group, a C _1-20 heterohydrocarbyl group, a substituted C _1-20 hydrocarbyl group, and a substituted heterohydrocarbyl group. Wherein the substituted hetero atom or substituent in LG ₄ is not particularly limited, and includes, but is not limited to, any of the substituted hetero atoms or any substituents recited in the terminology, selected from a halogen atom, a hydrocarbyl substituent, a hetero atom-containing substituent. Any of them.

More preferably, LG ₄ is a C _1-20 alkyl group, a C _1-20 unsaturated aliphatic hydrocarbon group, an aryl group, an aromatic hydrocarbon group, a C _1-20 heteroalkyl group, a C _1-20 aliphatic arene group, a C _1-20 aliphatic hydrocarbon group. Acyl, aryl acyl, heteroaryl acyl, C _1-20 hydrocarbyloxyacyl, C _1-20 hydrocarbylthioacyl, C _1-20 hydrocarbylaminoacyl, C _1-20 heteroalkyloxyacyl, C _{1- 20} heterohydrocarbyl thio group, C _1-20 aminoacyl heterohydrocarbyl any one group or any one group are substituted form. The acyl group in LG ₄ is not particularly limited and includes, but is not limited to, any of the acyl groups listed in the terminology. By way of example, the acyl group in LG ₄ may be selected from the group consisting of a carbonyl group, a sulfonyl group, a sulfinyl group, a phosphoryl group, a phosphorous acid group, a phosphoryl group, a nitroxyl group, a nitrosyl group, a thiocarbonyl group, an imido group, a thio group. Phosphoryl, dithiophosphoryl, trithiophosphoryl, thiophosphoryl, dithiophosphoryl, thiophosphoryl, thiophosphonyl, dithiophosphonyl, thiophosphinyl Wait. An acyl group such as a carbonyl group, a thiocarbon group, a sulfonyl group or a sulfinyl group is preferred. The LG ₄ acyl group is more preferably a carbonyl group, a thiocarbonyl group or a sulfonyl group.

More preferably, LG ₄ is C _1-20 alkyl, C _3-20 alkene, aryl, aralkyl, C _1-20 heteroalkyl, heteroaryl, heteroarylalkyl, C _1-20 alkylcarbonyl , arylcarbonyl, aralkylcarbonyl, C _1-20 heteroalkylcarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl, C _1-20 alkoxycarbonyl, aryloxycarbonyl, aralkyloxy Carbonyl, C _1-20 alkylthiocarbonyl, arylthiocarbonyl, aralkylthiocarbonyl, C _1-20 alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, C _1-20 heterocycloalkyl Alkoxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, C _1-20 heteroalkylthiocarbonyl, heteroarylthiocarbonyl, heteroaralkylthiocarbonyl, C _1-20 Heteroalkylaminocarbonyl, heteroarylaminocarbonyl, heteroaralkylaminocarbonyl, C _1-20 alkylthiocarbonyl, arylthiocarbonyl, aralkylthiocarbonyl, C _1-20 heteroalkyl sulfide Carbonyl, heteroarylthiocarbonyl, heteroaralkylthiocarbonyl, C _1-20 alkoxythiocarbonyl, aryloxythiocarbonyl, aralkyloxythiocarbonyl, C _1-20 Alkylthiocarbonyl, arylthiothiocarbonyl, aralkylthiosulfur Carbonyl, C _1-20 alkylaminothiocarbonyl, arylaminothiocarbonyl, aralkylaminothiocarbonyl, C _1-20 heteroalkyloxythiocarbonyl, heteroaryloxythiocarbonyl , heteroaralkyloxythiocarbonyl, C _1-20 heteroalkylthiothiocarbonyl, heteroarylthiothiocarbonyl, heteroaralkylthiothiocarbonyl, C _1-20 heteroalkyl A substituted form of any one of an aminothiocarbonyl group, a heteroarylaminothiocarbonyl group, a heteroarylalkylaminothiocarbonyl group, or a group of any one.

More preferably, LG ₄ is a C _1-20 alkyl group, a C _3-20 alkene group, an aryl group, an aralkyl group, a C _1-20 heteroalkyl group, a heteroaryl group, a heteroarylalkyl group or any A substituted form of a group.

Specifically, LG _{4 is} selected from, but not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, decyl, undecyl, Dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, allyl, benzyl , trityl, benzyl, methylbenzyl, 1-ethoxyethyl, methoxyethoxymethyl, benzyloxymethyl, methylthiomethyl, tetrahydropyranyl, Acetyl, benzoyl, methoxyacyl, ethoxylated, t-butyloxy, phenoxy, benzyloxy, methylthio, ethylthio, tert-butylthio And a substituted form of the phenylthio acyl group, the benzylthio acyl group, the methylamino acyl group, the ethylamino acyl group, the t-butylamino acyl group, the benzylamino acyl group or the like, or a substituted form of any one of the groups. Among them, butyl includes, but not limited to, n-butyl group and tert-butyl group. Octyl groups include, but are not limited to, n-octyl, 2-ethylhexyl. Wherein the substituted atom or substituent is selected from a halogen atom, a hydrocarbyl substituent, and a hetero atom-containing substituent, preferably a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an alkoxy group, an alkenyl group or a nitro group. .

LG _{4 is} further preferably methyl, ethyl, n-propyl, isopropyl, tert-butyl, pentyl, hexyl, heptyl, octyl, decyl, decyl, undecyl, dodecyl, Tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, allyl, benzyl, triphenyl Base, phenyl, benzyl, methylbenzyl, 1-ethoxyethyl, methoxyethoxymethyl, benzyloxymethyl, methylthiomethyl, tetrahydropyranyl, acetyl , benzoyl, methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, methylthiocarbonyl, ethylthiocarbonyl, tert-butylthiocarbonyl, benzene Thiocarbonyl, benzylthiocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, tert-butylaminocarbonyl, benzylaminocarbonyl, ethylthiocarbonyl, phenylmethylthiocarbonyl, methoxythiocarbonyl, Ethoxythiocarbonyl, tert-butyloxythiocarbonyl, phenoxythiocarbonyl, benzyloxythiocarbonyl, methylthiocarbonylcarbonyl, ethylthiothiocarbonyl, tert-butylthiosulfur Carbonyl , Phenylthio thiocarbonyl group, a benzyl group a thiocarbonyl group, a thiocarbonyl group methylamino, ethylamino thiocarbonyl group, tert-butylamino thiocarbonyl, benzylamino thiocarbonyl, C _1-10 haloalkyl a group of a hydrocarbon group, a trifluoroacetyl group, a halogenated phenyl group, a halogenated benzyl group, a nitrobenzyl group, a p-methoxybenzyl group, a trifluoromethylbenzyl group, or the like, or a group of any one of Replace the form. Among them, the substituted atom or the substituent is preferably a fluorine atom, an alkoxy group or a nitro group.

More preferably, LG ₄ is methyl, ethyl, n-propyl, isopropyl, tert-butyl, pentyl, hexyl, allyl, benzyl, trityl, phenyl, benzyl, 1-ethoxy Ethyl ethyl, 2-ethoxyethyl, methoxyethoxymethyl, benzyloxymethyl, methylthiomethyl, tetrahydropyranyl, nitrobenzyl, p-methoxybenzyl Any one of a trifluoromethylbenzyl group, a tert-butyloxycarbonyl group, a phenoxycarbonyl group, a benzyloxycarbonyl group, an acetyl group, a trifluoroacetyl group, and the like.

More preferably, LG ₄ is methyl, ethyl, n-propyl, isopropyl, tert-butyl, pentyl, hexyl, allyl, benzyl, trityl, phenyl, benzyl, nitrobenzyl Any one of p-methoxybenzyl, trifluoromethylbenzyl and the like.

Most preferably LG _{4 is a} methyl group, an ethyl group, an allyl group or a benzyl group.

Wherein X ₂ is an atom or a group to which a carbon atom is bonded, and may be selected from any one of a hydrogen atom, a hydroxyl group, a protected hydroxyl group OPG ₄ , R ₁ or -CH ₂ -OX ₁ . Wherein, the definitions of R ₁ and X ₁ are consistent with the above, and are not described herein again.

Among them, Q is not particularly limited as long as it contributes to the induction and conjugation effects of unsaturated bond electrons.

When Q is on the ring, it can be one or more. When there are a plurality of, the same structure may be used, or a combination of two or more different structures may be used.

Q can be an atom or a substituent.

When it is an atom, Q is selected from a hydrogen atom or a halogen atom, preferably a hydrogen atom or a fluorine atom.

When in the substituent, Q is selected from the group consisting of, but not limited to, all of the substituents recited in the terminology. It may or may not contain carbon atoms. When a carbon atom is not contained, it may be, for example, a nitro group. When the carbon atom is contained, the number of carbon atoms is not particularly limited, but is preferably 1 to 20 carbon atoms, and more preferably 1 to 10 carbon atoms.

When it is a substituent, the structure of Q is not particularly limited, and includes, but is not limited to, a linear structure, a branched structure containing a side group, or a cyclic structure. The cyclic structure is not particularly limited and includes, but is not limited to, any of the cyclic structures recited in the terminology.

Q may be selected from a hydrogen atom, a halogen atom, a carbon-free substituent, a hydrocarbon group, a heterohydrocarbyl group, a substituted hydrocarbyl group or a substituted heterohydrocarbyl group.

Q is preferably a hydrogen atom, a halogen atom, a nitro group, a nitro group-containing substituent, an acyl group-containing substituent, a C _1-20 haloalkyl group, a C _1-20 alkyl group, a C _2-20 alkenyl group, a C _3-20 opening. Alkenyl group, C _3-20 cycloalkenyl group, aryl group, aromatic hydrocarbon group, C _1-20 heteroalkyl group, heteroaryl group, heteroarylalkyl group, C _1-20 alkoxy group, aryloxy group, aromatic hydrocarbon group Oxyl, C _1-20 heteroalkyloxy, heteroaryloxy, heteroaryloxy, C _1-20 alkylthio, arylthio, arenethio, C _1-20 heteroalkyl Any one or a group of a thio group, a heteroarylthio group, a heteroarylalkylthio group, or the like, or a substituted form of any one of the groups. Wherein the substituted hetero atom or substituent in Q is not particularly limited, and includes, but is not limited to, any substituted hetero atom or any substituent listed in the term portion, selected from a halogen atom, a hydrocarbyl substituent, and a hetero atom-containing substituent. Any one.

More preferably, Q is a hydrogen atom, a halogen atom, a nitro group, a nitro group-containing substituent, an acyl group, a terminal group ester group-containing substituent, a terminal group thioester group-containing substituent, a terminal group amide bond-containing substituent, C _1-20 haloalkyl, C _2-20 alkenyl, C _3-20 open chain olefin group, C _3-20 cycloalkenyl group, aryl group, aromatic hydrocarbon group, C _1-20 heteroalkyl group, heteroaryl group, hetero Aralkyl, C _1-20 alkoxy, aryloxy, arylalkyloxy, C _1-20 heteroalkyloxy, heteroaryloxy, heteroaryloxy, C _1-20 alkane Any one or a group of a group, an arylthio group, an aromatic alkylthio group, a C _1-20 heteroalkylthio group, a heteroarylthio group, a heteroarylalkylthio group, or the like, or a group of any one of Replaced form. Wherein the acyl group is not particularly limited and includes, but is not limited to, any of the acyl groups listed in the terminology. By way of example, the acyl group in Q may be selected from the group consisting of a carbonyl group, a sulfonyl group, a sulfinyl group, a phosphoryl group, a phosphorous group, a hypophosphoryl group, a nitroxyl group, a nitrosyl group, a thiocarbonyl group, an imido group, a thiophosphorus. Acyl, dithiophosphoryl, trithiophosphoryl, thiophosphoryl, dithiophosphoryl, thiophosphoryl, thiophosphonyl, dithiophosphonyl, thiophosphinyl, etc. . An acyl group such as a carbonyl group, a thiocarbon group, a sulfonyl group or a sulfinyl group is preferred. The acyl group is more preferably a carbonyl group, a thiocarbonyl group, a sulfonyl group or a sulfinyl group.

More preferably, Q is a hydrogen atom, a halogen atom, a nitro group, a nitro group-containing substituent, a C _1-20 carbonyl group, a C _1-20 alkylthiocarbonyl group, a C _1-20 sulfonyl group, a C _1-20 alkyl group. Oxycarbonyl, C _1-20 alkylthiocarbonyl, C _1-20 alkylaminocarbonyl, C _1-20 alkyloxythiocarbonyl, C _1-20 alkylthiothiocarbonyl, C _{1- 20} alkylaminothiocarbonyl, C _1-20 alkyloxysulfonyl, C _1-20 alkyloxysulfinyl, arylthiocarbonyl, aryloxycarbonyl, arylthiocarbonyl, aromatic Alkylaminocarbonyl, aryloxythiocarbonyl, arylthiothiocarbonyl, arylaminothiocarbonyl, aryloxysulfonyl, aryloxysulfinyl, aralkylthiocarbonyl, aromatic Alkyloxycarbonyl, aralkylthiocarbonyl, aralkylaminocarbonyl, aralkyloxythiocarbonyl, aralkylthiothiocarbonyl, aralkylaminothiocarbonyl, aralkyloxy Sulfonyl, aralkyloxysulfinyl, C _1-20 alkyl, C _2-20 alkenyl, C _3-20 open chain olefin group, C _3-20 cycloalkenyl group, aryl group, aromatic hydrocarbon group, C _1-20 heteroalkyl, heteroaryl, heteroarylalkyl, C _1-20 alkoxy, aromatic Alkoxy, arylalkyloxy, C _1-20 heteroalkyloxy, heteroaryloxy, heteroaryloxy, C _1-20 alkylthio, arylthio, arylthio, C Any one or a group of a _1-20 heteroalkylthio group, a heteroarylthio group, a heteroarylalkylthio group, a C _1-20 haloalkyl group, or the like, or a substituted form of any one of the groups.

More preferably, Q is a hydrogen atom, a halogen atom, a nitro group, a nitro group-containing substituent, a C _1-10 carbonyl group, a C _1-10 alkylthiocarbonyl group, a C _1-10 sulfonyl group, a C _1-10 alkyl group. Oxycarbonyl, C _1-10 alkylthiocarbonyl, C _1-10 alkylaminocarbonyl, C _1-10 alkyloxythiocarbonyl, C _1-10 alkylthiothiocarbonyl, C _{1- 10} alkylaminothiocarbonyl, C _1-10 alkyloxysulfonyl, C _1-10 alkyloxysulfinyl, arylthiocarbonyl, aryloxycarbonyl, arylthiocarbonyl, aromatic Alkylaminocarbonyl, aryloxythiocarbonyl, arylthiothiocarbonyl, arylaminothiocarbonyl, aryloxysulfonyl, aryloxysulfinyl, aralkylthiocarbonyl, aromatic Alkyloxycarbonyl, aralkylthiocarbonyl, aralkylaminocarbonyl, aralkyloxythiocarbonyl, aralkylthiothiocarbonyl, aralkylaminothiocarbonyl, aralkyloxy Sulfonyl, aralkyloxysulfinyl, C _1-20 alkyl, C _2-10 alkenyl, C _3-10 open chain alkene, C _3-10 cycloalkenyl, aryl, arene, C _1-10 heteroalkyl, heteroaryl, heteroarylalkyl, C _1-10 alkoxy, aromatic Alkoxy, arylalkyloxy, C _{1-10heteroalkyloxy} , heteroaryloxy, heteroaryloxy, C _1-10 alkylthio, arylthio, arylthio, C _1-10 heteroalkyl group, heteroaryl group, heteroarylalkyl group, C _1-10 haloalkyl, like any atom or group, or any one group are substituted form.

Specifically, Q may be selected from a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, a nitrophenyl group, an acetyl group, a benzoyl group, a p-toluenesulfonic acid group, a methanesulfonic acid group, and a methoxy group. Carbocarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, methylthio, ethylthio, tert-butylthiocarbonyl, phenylthiocarbonyl, benzyl Thiocarbonyl, ethylaminoacyl, tert-butylaminocarbonyl, phenylaminocarbonyl, benzylaminocarbonyl, methoxythiocarbonyl, ethoxythiocarbonyl, tert-butyloxythiocarbonyl, phenoxy Thiocarbonylcarbonyl, benzyloxythiocarbonyl, methylthio acyl, ethylthio acyl, tert-butylthiothiocarbonyl, phenylthiothiocarbonyl, benzylthiothiocarbonyl, ethylaminoacyl, tert-Butylaminothiocarbonyl, phenylaminothiocarbonyl, benzylaminothiocarbonyl, methyl, ethyl, n-propyl, isopropyl, butyl, pentyl, hexyl, heptyl, 2-B Hexyl, decyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl Heptadecyl, octadecyl, nonadecyl, eicosyl, vinyl, propenyl, allyl, propynyl, propargyl, cyclopropyl, cyclopropenyl, phenyl, benzyl Base, butylphenyl, p-methylphenyl, methoxy, ethoxy, phenoxy, benzyloxy, methylthio, ethylthio, phenylthio, benzylthio, C _1-20 haloalkane Any of a group or group of atoms or groups, or a substituted form of any of the groups. Among them, butyl includes, but not limited to, n-butyl group and tert-butyl group. Octyl groups include, but are not limited to, n-octyl, 2-ethylhexyl. Wherein the substituted atom or the substituent is selected from any one of a halogen atom, a hydrocarbon group substituent, and a hetero atom-containing substituent, and is preferably a halogen atom, an alkoxy group, an alkenyl group, an aryl group or a nitro group.

Q is preferably a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, a nitrophenyl group, an acetyl group or a benzoyl group. Base, p-toluenesulfonic acid group, methanesulfonic acid group, methoxy acid group, ethoxy group, tert-butyloxycarbonyl group, phenoxycarbonyl group, benzyloxycarbonyl group, methylthio group, ethylthio group, Tert-Butylthiocarbonyl, phenylthiocarbonyl, benzylthiocarbonyl, ethylaminoacyl, tert-butylaminocarbonyl, phenylaminocarbonyl, benzylaminocarbonyl, methyl, ethyl, n-propyl, isopropyl Base, butyl, pentyl, hexyl, heptyl, octyl, decyl, decyl, vinyl, propenyl, allyl, propynyl, propargyl, cyclopropyl, cyclopropenyl, phenyl , benzyl, butylphenyl, p-methylphenyl, methoxy, ethoxy, phenoxy, benzyloxy, methylthio, ethylthio, phenylthio, benzylthio, trifluoromethyl Any one or a group of atoms, 2,2,2-trifluoroethyl, or the like, or a substituted form of any of the groups. Among them, the substituted atom or the substituent is preferably a fluorine atom, an alkoxy group, an alkenyl group, an aryl group or a nitro group.

More preferably, Q is a hydrogen atom, a fluorine atom, a methyl group, a trifluoromethyl group, a methoxy group, a methyloxycarbonyl group, a p-toluenesulfonyl group, a methylsulfonyl group or the like.

More preferably, Q is any atom or group of a hydrogen atom, a fluorine atom, a methyl group, a trifluoromethyl group, a methoxy group, a methyloxycarbonyl group or the like.

among them,

This includes but is not limited to the following structures and their superseded forms:

Wherein M ₁₀ , M ₁₁ , M ₁₂ , M ₁₃ and M ₁₄ are each independently a nitrogen atom or a carbon atom. When any of M ₁₀ , M ₁₁ , M ₁₂ , M ₁₃ and M ₁₄ is a nitrogen atom, the adjacent ring-forming atoms are carbon atoms.

Wherein said

The substituted hetero atom or substituent is not particularly limited and includes, but is not limited to, any of the substituted hetero atoms or any of the substituents recited in the terminology, and any one selected from the group consisting of a halogen atom, a hydrocarbyl substituent, and a hetero atom-containing substituent. The substituted atom is preferably a halogen atom. The substituent is preferably a group which contributes to the induction and conjugation effect of an unsaturated bond electron.

Wherein R ₇ is a hydrogen atom to which an amino group is bonded, an amino protecting group or a group LG ₅ .

Among them, the number of carbon atoms of LG ₅ is not particularly limited. The number of carbon atoms of LG ₅ is preferably from 1 to 20, and more preferably from 1 to 10.

The structure of LG ₅ is not particularly limited and includes, but is not limited to, a linear structure, a branched structure containing a side group, or a cyclic structure. The cyclic structure is not particularly limited and includes, but is not limited to, any of the cyclic structures recited in the terminology.

LG ₅ may or may not contain heteroatoms.

LG _{5 is} selected from any one of a C _1-20 hydrocarbyl group, a C _1-20 heterohydrocarbyl group, a substituted C _1-20 hydrocarbyl group, and a substituted heterohydrocarbyl group. Wherein the substituted hetero atom or substituent in LG ₅ is not particularly limited, and includes, but is not limited to, any substituted hetero atom or any substituent listed in the terminus, selected from a halogen atom, a hydrocarbyl substituent, a hetero atom-containing substituent. Any of them.

More preferably, LG ₅ is a C _1-20 alkyl group, a C _1-20 unsaturated aliphatic hydrocarbon group, an aryl group, an aromatic hydrocarbon group, a C _1-20 heteroalkyl group, a C _1-20 aliphatic arene group, a C _1-20 aliphatic hydrocarbon group. Acyl, aryl acyl, heteroaryl acyl, C _1-20 hydrocarbyloxyacyl, C _1-20 hydrocarbylthioacyl, C _1-20 hydrocarbylaminoacyl, C _1-20 heteroalkyloxyacyl, C _{1- 20} heterohydrocarbyl thio group, C _1-20 aminoacyl heterohydrocarbyl any one group or any one group are substituted form. The acyl group in LG ₅ is not particularly limited and includes, but is not limited to, any of the acyl groups listed in the terminology. By way of example, the acyl group in LG ₅ may be selected from the group consisting of a carbonyl group, a sulfonyl group, a sulfinyl group, a phosphoryl group, a phosphorous group, a hypophosphoryl group, a nitroxyl group, a nitrosyl group, a thiocarbonyl group, an imido group, a thio group. Phosphoryl, dithiophosphoryl, trithiophosphoryl, thiophosphoryl, dithiophosphoryl, thiophosphoryl, thiophosphonyl, dithiophosphonyl, thiophosphinyl Wait. An acyl group such as a carbonyl group, a thiocarbon group, a sulfonyl group or a sulfinyl group is preferred. The LG ₅ acyl group is more preferably a carbonyl group, a thiocarbonyl group or a sulfonyl group.

More preferably, LG ₅ is C _1-20 alkyl, C _1-20 alkenyl, C _1-20 alkene, aryl, aralkyl, C _1-20 heteroalkyl, heteroaryl, heteroarylalkyl, C _1-20 alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, C _1-20 heteroalkylcarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl, C _1-20 alkoxycarbonyl, aryloxy Carbonyl, aralkyloxycarbonyl, C _1-20 alkylthiocarbonyl, arylthiocarbonyl, aralkylthiocarbonyl, C _1-20 alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl , C _1-20 heteroalkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, C _1-20 heteroalkylthiocarbonyl, heteroarylthiocarbonyl, heteroarylalkylsulfide Carbonyl group, C _1-20 heteroalkylaminocarbonyl group, heteroarylaminocarbonyl group, heteroarylalkylaminocarbonyl group, C _1-20 alkylthiocarbonyl group, arylthiocarbonyl group, aralkylthiocarbonyl group, C _1-20 heteroalkylthiocarbonyl, heteroarylthiocarbonyl, heteroaralkylthiocarbonyl, C _1-20 alkoxythiocarbonyl, aryloxythiocarbonyl, aralkyloxysulfur Carbonyl, C _1-20 alkylthiothiocarbonyl, arylthiothiocarbonyl, aromatic Alkylthiothiocarbonyl, C _1-20 alkylaminothiocarbonyl, arylaminothiocarbonyl, aralkylaminothiocarbonyl, C _1-20 heteroalkyloxythiocarbonyl, heteroaryl Oxythiocarbonyl, heteroaralkyloxythiocarbonyl, C _1-20 heteroalkylthiothiocarbonyl, heteroarylthiothiocarbonyl, heteroaralkylthiothiocarbonyl, C ₁ Any substituted group of _-20 heteroalkylaminothiocarbonyl, heteroarylaminothiocarbonyl, heteroarylalkylaminothiocarbonyl or substituted group of any of the groups.

More preferably, LG ₅ is a C _1-20 alkyl group, a C _1-20 alkenyl group, a C _1-20 alkene group, an aryl group, an aralkyl group, a C _1-20 heteroalkyl group, a heteroaryl group or a heteroarylalkyl group. A substituted form of any of the groups or any of the groups.

Specifically, LG _{5 is} selected from, but not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, decyl, undecyl, Dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, allyl, benzyl , trityl, benzyl, methylbenzyl, 1,3,5-dioxane, formyl, acetyl, benzoyl, methoxy acyl, ethoxy acyl, tertiary Butyloxyacyl, phenoxyacyl, benzyloxyacyl, 9-fluorenylmethyloxycarbonyl, 2-methylsulfonylethylcarbonyl, 2-p-toluenesulfonylethyloxycarbonyl, methylsulfide Any one of a acyl group, an ethylthio group, a tert-butylthio acyl group, a phenylthio acyl group, a benzylthio acyl group, a methylamino acyl group, an ethylamino acyl group, a t-butylamino acyl group, a benzylamino acyl group, and the like. A substituted form of a group or any group. Among them, butyl includes, but not limited to, n-butyl group and tert-butyl group. Octyl groups include, but are not limited to, n-octyl, 2-ethylhexyl. Wherein the substituted atom or substituent is selected from a halogen atom, a hydrocarbyl substituent, and a hetero atom-containing substituent, preferably a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an alkoxy group, an alkenyl group or a nitro group. .

LG _{5 is} further preferably methyl, ethyl, n-propyl, isopropyl, tert-butyl, pentyl, hexyl, heptyl, octyl, decyl, decyl, undecyl, dodecyl, Tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, allyl, benzyl, triphenyl Base, phenyl, benzyl, methylbenzyl, 1,3,5-dioxane, formyl, acetyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, tert-butyl Oxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, 2-methylsulfonylethylcarbonyl, 2-p-toluenesulfonylethyloxycarbonyl, methylthiocarbonyl , ethylthiocarbonyl, tert-butylthiocarbonyl, phenylthiocarbonyl, benzylthiocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, tert-butylaminocarbonyl, benzylaminocarbonyl, ethylthiocarbonyl, Phenylmethylthiocarbonyl, methoxythiocarbonyl, ethoxythiocarbonyl, tert-butyloxythiocarbonyl, phenoxythiocarbonyl, benzyloxythiocarbonyl, methylthiocarbonylcarbonyl B Thiocarbonylcarbonyl, tert-butylthiothiocarbonyl, phenylthiothiocarbonyl, benzylthiothiocarbonyl, methylaminothiocarbonyl, ethylaminothiocarbonyl, tert-butylaminothiocarbonyl, Benzylaminothiocarbonyl, 2-methylsulfonylethyloxycarbonyl, C _1-10 halohydrocarbyl, trifluoroacetyl, 2-iodoethoxycarbonyl, halophenyl, halobenzyl, A substituted form of any one of nitrobenzyl, p-methoxybenzyl, trifluoromethylbenzyl, or the like, or a substituted group of any of the groups. Among them, the substituted atom or the substituent is preferably a fluorine atom, an alkoxy group or a nitro group.

More preferably, LG ₅ is methyl, ethyl, n-propyl, isopropyl, tert-butyl, pentyl, hexyl, allyl, benzyl, trityl, phenyl, benzyl, nitrobenzyl , p-methoxybenzyl, trifluoromethylbenzyl, 1,3,5-dioxane, 9-fluorenylmethyloxycarbonyl, 2-methylsulfonylethylcarbonyl, 2- Any one of p-toluenesulfonylethyloxycarbonyl, tert-butyloxycarbonyl, benzyloxycarbonyl, formyl, acetyl, trifluoroacetyl, and the like.

More preferably, LG ₅ is methyl, ethyl, n-propyl, isopropyl, tert-butyl, pentyl, hexyl, allyl, benzyl, trityl, phenyl, benzyl, nitrobenzyl Any one of p-methoxybenzyl, trifluoromethylbenzyl and the like.

Most preferably LG _{5 is a} methyl group, an ethyl group, an allyl group or a benzyl group.

R _{7 is} most preferably a hydrogen atom, a methyl group, an ethyl group or a benzyl group.

The trivalent ring structure of CC ₃ is preferably selected from cyclohexane, furanose ring, pyranose ring, benzene, tetrahydrofuran, pyrrolidine, thiazolidine, cyclohexane, cyclohexene, tetrahydropyran, piperidine, 1, 4-dioxane, pyridine, pyridazine, pyrimidine, pyrazine, 1,3,5-triazine, 1,4,7-triazacyclononane, cyclic tripeptide, hydrazine, indane, hydrazine Bismuth, isoindole, anthracene, naphthalene, dihydroanthracene, xanthene (xanthene), thioxanthene, dihydrophenanthrene, 10,11-dihydro-5H-dibenzo[a,d]cycloheptane Alkane, dibenzocycloheptene, 5-dibenzocycloheptenone, quinoline, isoquinoline, indole, oxazole, iminodibenzyl, naphthyl ring, dibenzocyclooctyne, aza A benzocyclooctyne or the like, a substituted form of either, or a hybridized form of either.

1.1.2.2. Tetravalent group

The tetravalent group in the set G ⁴ contains two trivalent core structures or one tetravalent core structure.

The trivalent core structure is as defined in the above G ³ and will not be described herein.

The tetravalent core structure may be one atom CM ₄ , one unsaturated bond CB ₄ or one cyclic structure CC ₄ .

Among them, the tetravalent nuclear atom CM _{4 is} not particularly limited as long as four covalent single bonds can be simultaneously formed. For example, a tetravalent carbon atom nucleus, a tetravalent silicon nucleus, a tetravalent phosphorus nucleus, or the like can be mentioned. A tetravalent nuclear atom may not be attached to any atom or group, such as a tetravalent nucleus.

Other atoms or groups may also be attached.

Among them, the tetravalent unsaturated bond core structure CB _{4 is} not particularly limited as long as four covalent single bonds can be simultaneously formed. The unsaturated bond may have two or more bonding atoms. Preferably 2 or 3 are used. More preferably, two. As an example, such as

Wait.

Among them, the tetravalent cyclic core structure CC _{4 is} not particularly limited as long as four covalent bonds can be simultaneously extracted. The ring-forming atoms which lead to the covalent bond are not particularly limited, and include, but are not limited to, N, C, Si, P, and the like. The cyclic structure may be an aliphatic ring or an aromatic ring, for example

Etc.; it can also be a sugar ring, for example

Etc.; can also be a condensed ring, for example

Wait. It may be a naturally occurring cyclic structure, such as a sugar ring; it may also be a ring formed by a chemical reaction, such as

Wait. The ejected covalent single bond can be taken directly from the ring-forming atom or from the unsaturated bond. Either one of the introduced covalent single bonds is taken from a ring-forming atom alone, or two covalent single bonds can be simultaneously taken from the same ring-forming atom. A more typical CC ₄ structure is the simultaneous extraction of four covalent single bonds from four ring-forming atoms.

CC _{4 is} selected from, but not limited to,

A tetravalent cyclic core structure of any one of them.

The tetravalent nuclear structure also includes but is not limited to

Wait.

The tetravalent ring structure of CC ₄ preferably includes, but is not limited to, a furanose ring, a pyranose ring, a cyclamate, a cyclotetrapeptide, tetrahydrofuran, pyrrolidine, a thiazolidine, cyclohexane, benzene, cyclohexene, tetrahydrogen. Pyran, piperidine, 1,4-dioxane, pyridine, pyridazine, pyrimidine, pyrazine, indene, indane, hydrazine, isoindole, indole, naphthalene, indoline, xanthene ( Xanthene), thioxanthene, dihydrophenanthrene, 10,11-dihydro-5H-dibenzo[a,d]cycloheptane, dibenzocycloheptene, 5-dibenzocycloheptenone , quinoline, isoquinoline, anthracene, oxazole, iminodibenzyl, tetramethyltetrahydrobifluorene, dipyridammine skeleton, tetracyclic triglyoxal hydrate ring skeleton, tetravalent 2 a six-membered ring skeleton of D-sorbitol in which two hydroxyl groups are protected at the 4-position, or a substituted form of any one, or a hybridized form of either.

1.1.2.3.k+1 (k≥4) valence group

The k+1 valence group in any set G ^k+1 ( ^k ≥ 4) may contain a k+1 valence ring core structure CC _k+1 or 2 or more 3 to k A low-cost ring-shaped nuclear structure. As an example,

Wherein, when k=4, in the set G ⁵ , the cyclic core structure CC ₅ is a cyclic core structure which leads to five covalent single bonds from five ring-forming atoms, including but not limited to a cyclic monosaccharide core structure and a ring. Peptides, azacycloalkanes, and the like. By way of example, such as from a cyclic monosaccharide

Also derived from cyclic peptides

Wait.

Wherein, when ^k ≥ 5, in the set G ^k+1 ( ^k ≥ 5), the cyclic core structure CC _k+1 includes, but is not limited to, a cyclic peptide, an azacycloalkane, a polymer ring or the like. Take G ⁶ as an example, as an example, such as:

Wait.

1.1.2.4. Examples of k+1 valence groups in the set G ^k+1 (k ≥ 2)

The k+1 valent group in any of the sets G ^k+1 (k ≥ 2) may contain a portion other than the 3 to k +1 nucleus structure when it contains a 3 to k +1 nucleus structure.

Taking k=2 as an example, U ₀₁ and U ₀₂ each independently contain any of the above trivalent core structures, preferably containing

Any of the trivalent core structures.

When a moiety other than the k+1 valence core structure is contained, it may or may not contain a carbon atom and may or may not contain a hetero atom. The moiety other than the k+1 valence core structure may be a group containing a hetero atom or an alkylene group not containing a hetero atom. The heteroatoms include, but are not limited to, O, S, N, P, Si, F, Cl, Br, I, B, and the like. The number of hetero atoms may be one or two or more. The hetero atom may independently exist as a divalent linking group, such as -O-(oxy or ether linkage), -S-(thio or thioether linkage), -N(R ₇ )-(secondary amino or divalent) Tertiary amino) and the like; may also exist as a divalent substituent, such as -C(=O)-, -C(=S)-, -P(=O)-, -S(=O) ₂ -, - S(=O)-etc; can also be combined to form some specific covalent bonds, such as -C(=O)-N(R ₇ )-, -N(R ₇ )-C(=O)-,- SS-, -C(=O)-O-, -OC(=O)-, -C(=O)-S-, -SC(=O)-, -C(=S)-O-,- OC(=S)-, -C(=S)-S-, -SC(=S)-, -OC(=O)-O-, -SC(=O)-O-, -OC(=S )-O-, -OC(=O)-S-, -SC(=S)-O-, -OC(=S)-S-, -SC(=O)-S-, -SC(=S )-S-, -N(R ₇ )-C(=O)-O-, -OC(=O)-N(R ₇ )-, -N(R ₇ )-C(=S)-O- , -OC(=S)-N(R ₇ )-, -N(R ₇ )-C(=O)-S-, -SC(=O)-N(R ₇ )-, -N(R ₇ )-C(=S)-S-, -SC(=S)-N(R ₇ )-, -N(R ₁₉ )-N(R ₁₈ )-, -N(R ₁₉ )-C(=O )-N(R ₁₈ )-, -N(R ₁₉ )-C(=S)-N(R ₁₈ )-, -N(R ₁₈ )-N(R ₁₉ )-C(=O)-,- C(=O)-N(R ₁₉ )-N(R ₁₈ )-, -N(R ₁₈ )-N(R ₁₉ )-C(=S)-, -C(=S)-N(R ₁₉ )-N(R ₁₈ )-, -(R ₁₅ )C=N-, -N=C( R ₁₅ )-, -(R ₁₅ )C=NN(R ₇ )-, -N(R ₇ )-N=C(R ₁₅ )-, -(R ₁₅ )C=NN(R ₇ )-C( =O)-, -C(=O)-N(R ₇ )-N=C(R ₁₅ )-, -(R ₁₅ )C=NO-, -ON=C(R ₁₅ )-, -(R ₁₅ ) C=NS-, -SN=C(R ₁₅ )-, -N=N-, -N(R ₁₈ )-N(R ₁₉ )-C(=O)-N=N-, -N= NC(=O)-N(R ₁₉ )-N(R ₁₈ )-, -N(R ₁₈ )-C(=O)-N(R ₁₉ )-, -C(=NR ₇ )-N(R ₂₃ )-, -N(R ₂₃ )-C(=NR ₇ )-, -N(R ₇ )-C(=NH ₂ ⁺ )-, -C(=NH ₂ ⁺ )-N(R ₇ )- , -C(=NR ₇ )-O-, -OC(=NR ₇ )-, -OC(=NH ₂ ⁺ )-, -C(=NH ₂ ⁺ )-O-, -C(=NR ₇ ) -S-, -SC(=NR ₇ )-, -SC(=NH ₂ ⁺ )-, -C(=NH ₂ ⁺ )-S-, -S(=O) ₂ -O-, -OS(= O) ₂ -, -S(=O)-O-, -OS(=O)-, -S(=O) ₂ -N(R ₇ )-, -N(R ₇ )-S(=O) ₂ -, -S(=O) ₂ -N(R ₁₈ )-N(R ₁₉ )-, -N(R ₁₉ )-N(R ₁₈ )-S(=O) ₂ - and the like. The hetero atom-free hydrocarbylene group is not particularly limited, and a C _1-10 alkylene group is preferred.

a moiety other than the core structure, preferably a C _1-6 alkylene group, an ether bond, a thioether bond, a secondary amino group, a divalent tertiary amino group, an amide bond, a urethane bond, a thiourethane bond or a C ₁ a divalent linking group of _-6 alkylene groups in combination with any of the others. More preferably, C _1-6 alkylene, -O-, -N(R ₇ )-, -C(=O)-N(R ₇ )-, -N(R ₇ )-C(=O)-, -N(R ₇ )-C(=O)-O- or -OC(=O)-N(R ₇ )-.

Wherein, R ₇ , R ₁₈ , R ₁₉ and R ₂₃ are the same as defined in the above R ₇ , and are not described herein again. And in the same molecule, R ₇ , R ₁₈ , R ₁₉ , R ₂₃ may be the same or different from each other.

R ₁₅ is a hydrogen atom, a substituted atom or a substituent on C in the structure containing a C=N bond. By way of example, structures containing C=N bonds include, but are not limited to, -C=N-, -C=N ⁺ =N-, -C=N-NH-, -C=N-NH-C(=O)- and many more. In the present invention, C=N is referred to as an imine bond.

When the atom is substituted, R _{15 is} selected from any of halogen atoms. A fluorine atom is preferred.

When it is a substituent, the number of carbon atoms of R ₁₅ is not particularly limited, but the number of carbon atoms is preferably from 1 to 20, and more preferably from 1 to 10.

As the substituent, the structure of R ₁₅ is not particularly limited and includes, but is not limited to, a linear structure, a branched structure containing a side group, or a cyclic structure. The cyclic structure is not particularly limited and includes, but is not limited to, any of the cyclic structures recited in the terminology.

As a substituent, R ₁₅ may contain a hetero atom, may contain hetero atoms.

R _{15 is} selected from a hydrogen atom, a halogen atom, a C _1-20 hydrocarbon group, a C _1-20 heteroalkyl group, a substituted C _1-20 hydrocarbon group or a substituted heterohydrocarbyl group. Wherein the substituted atom or substituent in R ₁₅ is not particularly limited, and includes, but is not limited to, any one of the substituted atoms or any of the substituents listed in the term, and is selected from a halogen atom, a hydrocarbon group substituent, and a hetero atom-containing substituent. One.

R ₁₅ is preferably a hydrogen atom, a halogen atom, a C _1-20 hydrocarbon group, a C _1-20 heteroalkyl group, a substituted C _1-20 hydrocarbon group or a substituted heterohydrocarbyl group.

R _{15 is} more preferably a hydrogen atom, a halogen atom, a C _1-20 alkyl group, a C _1-20 unsaturated aliphatic hydrocarbon group, an aryl group, an aromatic hydrocarbon group, a C _1-20 heteroalkyl group, a C _1-20 hydrocarbyloxyacyl group, C Any one or a group of a _1-20 hydrocarbylthioacyl group, a C _1-20 hydrocarbylaminoacyl group, or a substituted form of any one of the groups. Wherein the acyl group in R ₁₅ is not particularly limited and includes, but is not limited to, any of the acyl groups listed in the terminology. By way of example, the acyl group in R ₁₅ may be selected from the group consisting of a carbonyl group, a sulfonyl group, a sulfinyl group, a phosphoryl group, a phosphorous group, a hypophosphoryl group, a nitroxyl group, a nitrosyl group, a thiocarbonyl group, an imido group, a thio group. Phosphoryl, dithiophosphoryl, trithiophosphoryl, thiophosphoryl, dithiophosphoryl, thiophosphoryl, thiophosphonyl, dithiophosphonyl, thiophosphinyl Wait. An acyl group such as a carbonyl group, a thiocarbon group, a sulfonyl group or a sulfinyl group is preferred. The acyl group in R ₁₅ is more preferably a carbonyl group or a thiocarbonyl group.

More preferably, R ₁₅ is a hydrogen atom, a halogen atom, a C _1-20 alkyl group, a C _1-20 alkenyl group, an aryl group, an aromatic hydrocarbon group, a C _1-20 aliphatic hydrocarbon group, a heteroaryl group, a heteroaryl hydrocarbon group, C _1- Any atom or group of ₂₀ alkoxyacyl, aryloxyacyl, C _1-20 alkylthioacyl, arylthioacyl, C _1-20 alkylaminoacyl, arylaminoacyl, Or a substituted form of any of the groups. Here, the substituted atom or the substituent is selected from any one of a halogen atom, a hydrocarbon group substituent, and a hetero atom-containing substituent, and is preferably a halogen atom, an alkenyl group or a nitro group.

More preferably, R ₁₅ is a hydrogen atom, a halogen atom, a C _1-20 alkyl group, a C _1-20 alkenyl group, an aryl group, an aromatic hydrocarbon group, a C _1-20 aliphatic hydrocarbon group, a heteroaryl group, a heteroaryl hydrocarbon group, C _{1- 20} alkoxycarbonyl, aryloxycarbonyl, C _1-20 alkylthiocarbonyl, arylthiocarbonyl, C _1-20 alkylaminocarbonyl, arylaminocarbonyl, C _1-20 alkoxy sulfide Carbonyl, aryloxythiocarbonyl, C _1-20 alkylthiothiocarbonyl, arylthiothiocarbonyl, C _1-20 alkylaminothiocarbonyl, arylaminothiocarbonyl An atom or group, or a substituted form of any of the groups. Here, the substituted atom or the substituent is any one selected from the group consisting of a halogen atom, a hydrocarbon group substituent, and a hetero atom-containing substituent, and is preferably a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an alkenyl group or a nitro group.

Specifically, R _{15 is} selected from, but not limited to, a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group. , octyl, decyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, N-nonyl, eicosyl, allyl, propenyl, vinyl, phenyl, methylphenyl, butylphenyl, benzyl, methoxycarbonyl, ethoxycarbonyl, phenoxycarbonyl , benzyloxycarbonyl, methylthiocarbonyl, ethylthiocarbonyl, phenylthiocarbonyl, benzylthiocarbonyl, ethylaminocarbonyl, benzylaminocarbonyl, methoxythiocarbonyl, ethoxythiocarbonyl, phenoxy Thiocarbonylcarbonyl, benzyloxythiocarbonyl, methylthiocarbonylcarbonyl, ethylthiothiocarbonyl, phenylthiothiocarbonyl, benzylthiothiocarbonyl, ethylaminothiocarbonyl, benzylaminothio a carbonyl group, a substituted C _1-20 alkyl group, a substituted C _1-20 alkenyl group, a substituted aryl group, a substituted aromatic hydrocarbon group, a substituted C _1-20 aliphatic heterohydrocarbyl, substituted heteroaryl, Substituted heteroarylalkyl, substituted C _1-20 alkoxycarbonyl group, a substituted aryloxycarbonyl group, substituted C _1-20 alkylthio group, a substituted aryl thiocarbonyl group, a substituted C _{1- 20} alkylaminocarbonyl, substituted arylaminocarbonyl, substituted C _1-20 alkoxythiocarbonyl, substituted aryloxythiocarbonyl, substituted C _1-20 alkylthiothiocarbonyl, Any one or a group of a substituted arylthiothiocarbonyl group, a substituted C _1-20 alkylaminothiocarbonyl group, a substituted arylaminothiocarbonyl group, or the like. Among them, butyl includes, but not limited to, n-butyl group and tert-butyl group. Octyl groups include, but are not limited to, n-octyl, 2-ethylhexyl. Here, the substituted atom or the substituent is selected from any one of a halogen atom, a hydrocarbon group substituent, and a hetero atom-containing substituent, and is preferably a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or a nitro group.

R _{15 is} further preferably a hydrogen atom, a fluorine atom, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a decyl group, a decyl group, an allyl group, or a propylene group. Base, vinyl, phenyl, methylphenyl, butylphenyl, benzyl, C _1-10 halohydrocarbyl, halophenyl, halobenzyl, nitrophenyl, methoxycarbonyl, B Oxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, methylthiocarbonyl, ethylthiocarbonyl, phenylthiocarbonyl, benzylthiocarbonyl, ethylaminocarbonyl, benzylaminocarbonyl, methoxythiocarbonyl, B Oxythiocarbonyl, phenoxythiocarbonyl, benzyloxythiocarbonyl, methylthiocarbonylcarbonyl, ethylthiothiocarbonyl, phenylthiothiocarbonyl, benzylthiothiocarbonyl, ethylamino Any one or a group of a thiocarbonyl group, a benzylaminothiocarbonyl group, or the like, or a substituted form of any one of the groups.

R _{15 is} most preferably a hydrogen atom, a fluorine atom or a methyl group.

Taking a trivalent group of k=2 as an example, a moiety other than the trivalent core structure does not include a trivalent group of a hetero atom, for example,

Wait. Also included, but not limited to, the following structure disclosed in paragraph [0199] of the patent document CN104877127A:

Wait.

The moiety other than the trivalent core structure includes a trivalent group of a hetero atom, for example:

Wait. Also included but not limited to the following structures disclosed in paragraphs [0201]-[0202] of the patent document CN104877127A:

Wait. To better illustrate the above example, the set of features in a trivalent group G ^3, and G ³ is not set to the range defined.

Wherein, the definitions of R ₁ , X ₁ , X ₂ , X ₄ , and Q are as described above, and are not described herein again.

To better illustrate the above example, the set of features in a trivalent group G ^3, and G ³ is not set to the range defined.

Take the tetravalent group of k=3 as an example.

The moiety other than the tetravalent core structure does not include a tetravalent group of a hetero atom, for example:

Wait.

The moiety other than the tetravalent core structure includes a tetravalent group of a hetero atom, for example,

Wait.

When k≥3, that is, the valence state of G≥4, the k+1 valence group in the set G ^k+1 contains the corresponding k+1 valence ring core structure CC _k+1 , or from 2 to k- One low-valent group having a 3 to k-valent group is directly linked or combined or indirectly combined with one or more divalent spacers L ₁₀ . For example, when k=3, for a tetravalent group, two three groups may be combined; for a pentavalent group, three trivalent groups may be combined, or one trivalent group may be used. The group is combined with a tetravalent group.

When two or more L ₁₀ are contained, they may be the same or different from each other.

The L _{10 is} not particularly limited. L ₁₀ may contain a carbon atom or may not contain a carbon atom; L ₁₀ may contain a hetero atom or may not contain a hetero atom; L ₁₀ may be a subunit formed by a single atom, or may be a subunit composed of two or more atoms. base.

L ₁₀ may be a monoatomic subunit, such as -O- or -S-;

L ₁₀ may also be a hetero atom-free hydrocarbylene group, preferably a C _1-20 alkylene group, a C _1-20 divalent alkenyl group, a C _1-20 divalent alkene group, a C _1-20 divalent alkynyl group, C _{a 1-20} divalent alkyne group, a C _1-20 divalent cycloalkyl group, a C _1-20 divalent cycloalkane group, a phenylene group, a divalent condensed aryl group, or a divalent aromatic hydrocarbon group;

L ₁₀ may also be -C(=O)-N(R ₇ )-, -N(R ₇ )-C(=O)-, -SS-, -C(=O)-O-, -OC( =O)-, -C(=O)-S-, -SC(=O)-, -C(=S)-O-, -OC(=S)-, -C(=S)-S- , -SC(=S)-, -OC(=O)-O-, -SC(=O)-O-, -OC(=S)-O-, -OC(=O)-S-,- SC(=S)-O-, -OC(=S)-S-, -SC(=O)-S-, -SC(=S)-S-, -N(R ₇ )-C(=O )-O-, -OC(=O)-N(R ₇ )-, -N(R ₇ )-C(=S)-O-, -OC(=S)-N(R ₇ )-,- N(R ₇ )-C(=O)-S-, -SC(=O)-N(R ₇ )-, -N(R ₇ )-C(=S)-S-, -SC(=S )-N(R ₇ )-, -N(R ₁₉ )-N(R ₁₈ )-, -N(R ₁₉ )-C(=O)-N(R ₁₈ )-, -N(R ₁₉ )- C(=S)-N(R ₁₈ )-, -N(R ₁₈ )-N(R ₁₉ )-C(=O)-, -C(=O)-N(R ₁₉ )-N(R ₁₈ )-, -N(R ₁₈ )-N(R ₁₉ )-C(=S)-, -C(=S)-N(R ₁₉ )-N(R ₁₈ )-, -(R ₁₅ )C= N-, -N=C(R ₁₅ )-, -(R ₁₅ )C=NN(R ₇ )-, -N(R ₇ )-N=C(R ₁₅ )-, -(R ₁₅ )C= NN(R ₇ )-C(=O)-, -C(=O)-N(R ₇ )-N=C(R ₁₅ )-, -(R ₁₅ )C=NO-, -ON=C( R ₁₅ )-, -(R ₁₅ )C=NS-, -SN=C(R ₁₅ )-, -N=N-, -N(R ₁₈ )-N(R ₁₉ )-C(=O)- N = N -, - N = NC (= O) -N (R 19) -N (R 18) -, - N (R 18) -C (= O) -N (R 19) -, - C ( _{NR 7) -N (R 23)} -, - N (R 23) -C (= NR 7) -, - N (R 7) -C (= NH 2 +) -, - C (= NH 2 +) -N(R ₇ )-, -C(=NR ₇ )-O-, -OC(=NR ₇ )-, -OC(=NH ₂ ⁺ )-, -C(=NH ₂ ⁺ )-O-, -C(=NR ₇ )-S-, -SC(=NR ₇ )-, -SC(=NH ₂ ⁺ )-, -C(=NH ₂ ⁺ )-S-, -S(=O) ₂ - O-, -OS(=O) ₂ -, -S(=O)-O-, -OS(=O)-, -S(=O) ₂ -N(R ₇ )-, -N(R ₇ )-S(=O) ₂ -, -S(=O) ₂ -N(R ₁₈ )-N(R ₁₉ )-, -N(R ₁₉ )-N(R ₁₈ )-S(=O) ₂ - a divalent linkage of a covalent bond containing a hetero atom, such as -CH ₂ -O-, -O-CH ₂ -, -OR ₂₉ -, -R ₂₉ -O-, -OR ₂₉ -O-, etc. Base or its substituted form. Wherein, the definitions of R ₇ , R ₁₈ , R ₁₉ , R ₂₃ and R ₁₅ are the same as above, and the definitions are not repeated here. Wherein R _{29 is} selected from a C _3-20 alkylene group, and its structure is not particularly limited, and may be a linear, branched or cyclic structure; the number of carbon atoms of R ₂₉ is preferably a C _3-12 hydrocarbon group; and the structure of R ₂₉ A linear structure is preferred.

The L _{10 is} more preferably an oxy group, a thio group, a secondary amino group or a divalent tertiary amino group, at which time a stable linkage is formed.

The L _{10 is} most preferably an oxy group, such as an alcoholic hydroxyl group condensed with an alcoholic hydroxyl group to form an ether linkage.

L ₁₀ may also be a monodisperse multimeric form of any of -CH ₂ CH ₂ -O-, -O-CH ₂ CH ₂ -, -OR ₂₉ -, -R ₂₉ -O-, repeating unit number selection From 2 to 20, preferably from 2 to 10. However, such structures do not appear in the branch centers U ₀₁ and U ₀₂ .

Taking the tetravalent group of k=3 as an example, the tetravalent group in the aggregate G ⁴ may be composed of any two trivalent groups in the aggregate G ³ in addition to the tetravalent core structure.

The combination may be a direct linkage, such as a tetravalent group derived from erythritol.

It can be seen as a connection of two trivalent groups separated by a broken line.

Another example is a tetravalent group formed by directly linking two molecular amino acid skeletons.

Wait.

The combination may be indirectly connected by one or more divalent spacers L ₁₀ . When the tetravalent group in the aggregate G ⁴ contains two or more L ₁₀ groups, they may be the same or different from each other. Some common tetrahydric alcohols are condensed by a tetrahydric alcohol. The corresponding tetravalent group after deamination of a hydroxyl group or a hydroxyl hydrogen atom belongs to this type. As an example, for example,

Wait.

The tetravalent G may be selected from any of the above-mentioned aggregates G ⁴ and a tetravalent group. The tetravalent G also includes, but is not limited to, the following structure disclosed in paragraph [0231] of the patent document CN104877127A:

Wait. Among them, the definition of X ₁ is consistent with the above.

Take the pentavalent group of k=4 as an example. For example,

Wait.

Also included, but not limited to the following structure disclosed in paragraph [0233] of the patent document CN104877127A:

Wait.

among them,

The isomeric structure includes, but is not limited to, a pentavalent carbon skeleton of D-ribose, D-arabinose, D-xylose, D-lyxose. Pentavalent groups also include, but are not limited to, six-membered cyclic monosaccharides such as glucose, allose, altrose, mannose, gulose, idose, galactose, talose, psicose, fructose The pentavalent skeleton structure of sorbose, tartarose and the like.

Take the hexavalent group of k=5 as an example. For example,

Wait. Also included but not limited to

From inositol, sorbitol, mannitol, D-glucosamine, 1-mercaptosorbitol, N-methyl-D-glucosamine, tris(2,3-dichloropropyl) phosphate or 3 - removal of a hexavalent backbone structure of D-sorbitol esters at six hydrogen atoms of a hydroxyl group, an amino group or/and a sulfhydryl group, from D-allose, D-aldose, D-glucose, D- A hexavalent carbon skeleton of mannose, D-gulose, D-idose, D-galactose, D-talose, D-psicose, and the like.

Take the seven-valent group of k=6 as an example. For example,

Wait.

Take the octavalent group of k=7 as an example. For example,

Wait.

When k ≥ 4, that is, the valence state of G ≥ 5, a combination of 3 to k-1 low-valent groups having a 3 to k valence group or one or more divalent spacers L ₁₀ Indirect combination of k+1 groups of G ^k+1 . The combination between 3 and k-1 low-cost groups is not particularly limited. By way of example, it may include, but is not limited to, a comb combination method, a tree combination method, a branch combination method, a hyperbranched combination, a ring combination method, and the like. For comb, dendritic or hyperbranched groups in which a plurality of low-cost groups are combined, the plurality of lower-valent groups may be the same or different from each other, preferably from the same low-valent group.

The comb combination method, the tree combination method, the branch combination method, the hyperbranched combination, and the ring combination method of the low-cost groups constituting the k+1-valent group in the set G ^k+1 (k≥4) The number of medium and low-priced groups is from 3 to 150; preferably from 3 to 100.

The dendritic combination is 2 to 6 generations; preferably 2 to 5 generations, more preferably 2, 3 or 4 generations.

The combination of branches is as follows:

Wait.

A comb-like combination method is exemplified by hexaglycerin, trimeric pentaerythritol, and the like.

The algebra of the dendritic combination is not particularly limited, and is preferably 1 to 6 generations, more preferably 1 to 5 generations, and most preferably 2, 3 or 4 generations. The dendritic combination formed by the dendritic combination can be represented by DENR (U _denr , NONE, d) or DENR (U _denr , L ₁₀ , d), and can also be expressed as [U _denr ,] _d . Wherein, U _denr represents a polyvalent group repeating unit, NONE, indicating that the multivalent repeating unit is directly connected, L ₁₀ represents that the multivalent repeating unit is indirectly connected by the divalent linking group L ₁₀ , and d represents an algebra of the dendritic combination manner. For example:

Wait. Where ng is 1, 2, 3, 4, 5 or 6.

Hyperbranched combination method, for example, has the following repeating unit structure

Hyperbranched structure:

Wait.

Ring combination, as for example

Cyclodextrin skeleton and the like.

Wherein n ₅ is an integer of from 3 to 250; preferably an integer of from 3 to 150; more preferably an integer of from 3 to 100.

Wherein n ₆ is an integer of from 2 to 250; preferably an integer of from 2 to 150; more preferably an integer of from 5 to 100.

Wherein M ₉ is O, S or NX ₁₀ .

Wherein X ₁₀ is a hydrogen atom or a hydrocarbon group having 1 to 20 carbon atoms.

The structure of X ₁₀ is not particularly limited and includes, but is not limited to, a linear structure, a branched structure, or a cyclic structure.

The type of X ₁₀ is not particularly limited and includes, but not limited to, a linear alkyl group, a branched alkyl group, a cycloalkyl group, an aryl group, an arylalkyl group, a substituted cycloalkyl group, a substituted aryl group, a substituted aralkyl group, etc. .

X ₁₀ is preferably hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, heptyl, 2-ethylhexyl, octyl, decyl, decyl, ten Monoalkyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, C _3-20 cycloalkyl, aryl, phenyl, arene, aralkyl, benzyl, butylphenyl, C _3-20 substituted cycloalkyl, substituted aryl, C _7-20 substituted aromatic a group, a C _7-20 substituted aralkyl group, and the like. More preferably, it is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, heptyl, 2-ethylhexyl, octyl, decyl, decyl, undecyl, ten Dialkyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, benzyl or butylbenzene Base.

More preferably, X ₁₀ is a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, including but not limited to a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a t-butyl group, a pentyl group, a heptyl group. , 2-ethylhexyl, octyl, decyl, decyl, benzyl, butylphenyl, and the like.

More preferably, X ₁₀ is a hydrocarbon group having a hydrogen atom or 1 to 5 carbon atoms, including but not limited to a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a t-butyl group, a pentyl group and the like.

X _{10 is} more preferably a hydrogen atom or a methyl group.

Wherein R ₃ is a terminal group to which an oxy group or a thio group is bonded.

The number of carbon atoms of R ₃ is not particularly limited, but is preferably from 1 to 20, and more preferably from 1 to 10.

The structure of R ₃ is not particularly limited and includes, but not limited to, a linear structure, a branched structure containing a side group, or a cyclic structure. The cyclic structure is not particularly limited and includes, but is not limited to, any of the cyclic structures recited in the terminology.

R ₃ may or may not contain a hetero atom.

R _{3 is} selected from any one of a C _1-20 hydrocarbon group, a C _1-20 heteroalkyl group, a C _1-20 substituted hydrocarbon group, and a C _1-20 substituted heteroalkyl group. The hetero atom or substituent for substituting R ₃ is not particularly limited and includes, but is not limited to, any one of the hetero atoms or any of the substituents listed in the terminology, preferably any one of a halogen atom, a hydrocarbon group, and a hetero atom-containing substituent. .

R ₃ is preferably C _1-20 alkyl, C _3-20 alkene, aryl, arene, C _1-20 aliphatic, heteroaryl, heteroaryl, substituted C _1-20 alkyl, substituted Any one of a C _3-20 alkene group, a substituted aryl group, a substituted aromatic hydrocarbon group, a substituted C _1-20 aliphatic hydrocarbon group, a substituted heteroaryl group, or a substituted heteroaryl hydrocarbon group. Wherein the substituted atom or the substituent is selected from any one of a halogen atom, a hydrocarbon group substituent, and a hetero atom-containing substituent.

R ₃ is preferably a C _1-20 linear alkyl group, a C _1-20 branched alkyl group, a C _3-20 cycloalkyl group, an aryl group, an aromatic hydrocarbon group, a C _1-20 aliphatic hydrocarbon group, a heteroaryl group or a heteroaromatic hydrocarbon. , substituted C _1-20 linear alkyl, substituted C _1-20 branched alkyl, substituted C _3-20 cycloalkyl, substituted aryl, substituted arene, substituted C _1-20 Any one of a fatty hydrocarbon group, a substituted heteroaryl group, or a substituted heteroaryl hydrocarbon group. Wherein the substituted atom or the substituent is any one selected from the group consisting of a halogen atom, a hydrocarbon group substituent, and a hetero atom-containing substituent, and a halogen atom, an alkoxy group, a hydrocarbon group, an aryl group or a nitro group is preferred.

More preferably, R ₃ is a C _1-10 linear alkyl group, a C _1-10 branched alkyl group, a C _3-10 cycloalkyl group, an aryl group, an aromatic hydrocarbon group, a C _1-20 aliphatic hydrocarbon group, a heteroaryl group, or a heterocyclic group. Aromatic hydrocarbon group, substituted C _1-10 linear alkyl group, substituted C _1-10 branched alkyl group, substituted C _3-10 cycloalkyl group, substituted aryl group, substituted aromatic hydrocarbon group, substituted C _1- Any one of ₁₀ aliphatic hydrocarbon groups, substituted heteroaryl groups, substituted heteroaryl hydrocarbon groups. Wherein the substituted atom or substituent is selected from the group consisting of a halogen atom, a hydrocarbyl substituent, and a hetero atom-containing substituent, preferably a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydrocarbon group, an aryl group or a nitro group; A halogen atom, an alkoxy group or a nitro group is preferred.

Specifically, R _{3 is} selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, decyl, benzyl, allyl, and the like. A substituted form of one or any of them. Among them, butyl includes, but not limited to, n-butyl group and tert-butyl group. Octyl groups include, but are not limited to, n-octyl, 2-ethylhexyl. Wherein the substituted atom or substituent is selected from the group consisting of a halogen atom, a hydrocarbyl substituent, and a hetero atom-containing substituent, preferably a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydrocarbon group, an aryl group or a nitro group; A halogen atom, an alkoxy group or a nitro group is preferred.

Most preferably R _{3 is a} methyl group, an ethyl group or a benzyl group.

Wherein R ₈ is a hydrogen atom, a substituted atom or a substituent on the double bond (-C=C-).

When it is a substituted atom, R _{8 is} selected from any of halogen atoms of F, Cl, Br, and I. Each is preferably independently a fluorine atom.

When it is a substituent, the number of carbon atoms of R ₈ is not particularly limited. The number of carbon atoms of R ₈ is each independently preferably from 1 to 20, and more preferably from 1 to 10.

When it is a substituent, the structure of R ₈ is not particularly limited, and each independently includes, but is not limited to, a linear structure, a branched structure containing a side group, or a cyclic structure. Here, the cyclic structure is not particularly limited and includes, but is not limited to, any of the cyclic structures recited in the terminology.

When it is a substituent, R ₈ may or may not contain a hetero atom.

R _{8 is} selected from a hydrogen atom, a halogen atom, a C _1-20 hydrocarbon group, a C _1-20 heteroalkyl group, a substituted C _1-20 hydrocarbon group or a substituted heterohydrocarbyl group. Wherein the substituted atom or substituent in R ₈ is not particularly limited, and includes, but is not limited to, any one of the substituted atoms or any of the substituents listed in the term, and is selected from a halogen atom, a hydrocarbon group substituent, and a hetero atom-containing substituent. One.

More preferably, R ₈ is a hydrogen atom, a halogen atom, a C _1-20 alkyl group, a C _1-20 unsaturated aliphatic hydrocarbon group, an aryl group, an aromatic hydrocarbon group, a C _1-20 heteroalkyl group, a C _1-20 hydrocarbyloxy group, C Any one or a group of a _1-20 hydrocarbylthioacyl group, a C _1-20 hydrocarbylaminoacyl group, or a substituted form of any one of the groups. Wherein the acyl group in R ₈ is not particularly limited and includes, but is not limited to, any of the acyl groups listed in the terminology.

R _{8 is} more preferably a hydrogen atom, a halogen atom, a C _1-20 alkyl group, a C _1-20 alkenyl group, an aryl group, an aromatic hydrocarbon group, a C _1-20 aliphatic hydrocarbon group, a heteroaryl group, a heteroaryl hydrocarbon group, C _1- Any atom or group of ₂₀ alkoxyacyl, aryloxyacyl, C _1-20 alkylthioacyl, arylthioacyl, C _1-20 alkylaminoacyl, arylaminoacyl, Or a substituted form of any of the groups. The substituted atom or the substituent is selected from any one of a halogen atom, a hydrocarbon group substituent, and a hetero atom-containing substituent, and is preferably a halogen atom, an alkenyl group or a nitro group.

R _{8 is} more preferably a hydrogen atom, a halogen atom, a C _1-20 alkyl group, a C _1-20 alkenyl group, an aryl group, an aromatic hydrocarbon group, a C _1-20 aliphatic hydrocarbon group, a heteroaryl group, a heteroaryl hydrocarbon group, C _{1- 20} alkoxycarbonyl, aryloxycarbonyl, C _1-20 alkylthiocarbonyl, arylthiocarbonyl, C _1-20 alkylaminocarbonyl, arylaminocarbonyl, C _1-20 alkoxy sulfide Carbonyl, aryloxythiocarbonyl, C _1-20 alkylthiothiocarbonyl, arylthiothiocarbonyl, C _1-20 alkylaminothiocarbonyl, arylaminothiocarbonyl An atom or group, or a substituted form of any of the groups. The acyl group in R ₈ is more preferably a carbonyl group or a thiocarbonyl group. Here, the substituted atom or the substituent is any one selected from the group consisting of a halogen atom, a hydrocarbon group substituent, and a hetero atom-containing substituent, and is preferably a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an alkenyl group or a nitro group.

Specifically, R _{8 is} selected from, but not limited to, a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group. , octyl, decyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, N-nonyl, eicosyl, allyl, propenyl, vinyl, phenyl, methylphenyl, butylphenyl, benzyl, methoxycarbonyl, ethoxycarbonyl, phenoxycarbonyl , benzyloxycarbonyl, methylthiocarbonyl, ethylthiocarbonyl, phenylthiocarbonyl, benzylthiocarbonyl, ethylaminocarbonyl, benzylaminocarbonyl, methoxythiocarbonyl, ethoxythiocarbonyl, phenoxy Thiocarbonylcarbonyl, benzyloxythiocarbonyl, methylthiocarbonylcarbonyl, ethylthiothiocarbonyl, phenylthiothiocarbonyl, benzylthiothiocarbonyl, ethylaminothiocarbonyl, benzylaminothio a carbonyl group, a substituted C _1-20 alkyl group, a substituted C _1-20 alkenyl group, a substituted aryl group, a substituted aromatic hydrocarbon group, a substituted C _1-20 aliphatic heterohydrocarbyl, substituted heteroaryl, taking Heteroarylalkyl, substituted C _1-20 alkoxycarbonyl group, a substituted aryloxycarbonyl group, substituted C _1-20 alkylthio group, a substituted aryl thiocarbonyl group, a substituted C _1-20 Alkylaminocarbonyl, substituted arylaminocarbonyl, substituted C _1-20 alkoxythiocarbonyl, substituted aryloxythiocarbonyl, substituted C _1-20 alkylthiothiocarbonyl, substituted Any one of an arylthiothiocarbonyl group, a substituted C _1-20 alkylaminothiocarbonyl group, a substituted arylaminothiocarbonyl group, and the like. Among them, butyl includes, but not limited to, n-butyl group and tert-butyl group. Octyl groups include, but are not limited to, n-octyl, 2-ethylhexyl. Here, the substituted atom or the substituent is selected from any one of a halogen atom, a hydrocarbon group substituent, and a hetero atom-containing substituent, and is preferably a halogen atom, an alkenyl group or a nitro group.

R _{8 is} further preferably a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, decyl, allyl, propenyl, ethylene Base, phenyl, methylphenyl, butylphenyl, benzyl, methoxycarbonyl, ethoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, methylthiocarbonyl, ethylthiocarbonyl, phenylsulfonate Carbocarbonyl, benzylthiocarbonyl, ethylaminocarbonyl, benzylaminocarbonyl, methoxythiocarbonyl, ethoxythiocarbonyl, phenoxythiocarbonyl, benzyloxythiocarbonyl, methylthiocarbonylcarbonyl , ethylthiothiocarbonyl, phenylthiothiocarbonyl, benzylthiothiocarbonyl, ethylaminothiocarbonyl, benzylaminothiocarbonyl, C _1-10 halogenated hydrocarbon, halophenyl, halobenzyl Any of a group or group of a group, a nitrophenyl group, or the like, or a substituted form of any of the groups. Here, the substituted atom or the substituent is any one selected from the group consisting of a halogen atom, a hydrocarbon group substituent, and a hetero atom-containing substituent, and is preferably a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an alkenyl group or a nitro group.

R _{8 is} more preferably a hydrogen atom, a fluorine atom or a methyl group.

among them,

It is a ring structure containing a water-soluble block in the ring skeleton, and the valence state is n ₅ +1, and all the branching points are derived from ring-forming atoms.

The structure of the water-soluble block is not particularly limited, and a linear structure is preferred.

The stability of the water-soluble block is not particularly limited and may be stably present or degradable.

The ring backbone contains at least one water soluble block.

When the amount of the water-soluble block is more than 1, the kinds of the water-soluble blocks may be the same or different from each other. At this time, the connection mode between the adjacent water-soluble blocks is not particularly limited, and may be directly connected or may be connected by any divalent linking group. The stability of the divalent linking group is not particularly limited and may be stably present or degradable.

The water soluble block may be a water soluble oligomer or a water soluble polymer.

The source of the water-soluble block is not particularly limited and may be a natural, modified or synthetic water-soluble oligomer or a water-soluble polymer.

The kind of the water-soluble polymer block is not particularly limited, and includes, but not limited to, polyalkylene oxides and derivatives (preferably polyethylene glycol and derivatives thereof), polyvinyl alcohol, polyacrylic acid, and derivatives thereof. , polymethyl methacrylate and its derivatives, polyethyl methacrylate and its derivatives, polyacrylamide, poly N-isopropyl acrylamide, polyhydroxyethyl methacrylate, polyglycolic acid, polyhydroxyl Butyrate, propylene glycol fumarate, polyvinylpyrrolidone, water-soluble polysaccharide, chitosan, dextran, polyamino acid, polypeptide, carboxymethyl starch, starch acetate, hydroxymethyl cellulose, carboxymethyl Cellulose, polyhydroxyalkylmethacrylamide, polyhydroxyalkyl methacrylate, poly-α-hydroxy acid, polyphosphazene, polyoxazoline, poly N-acryloylmorpholine, and the like. Preference is given to polyethylene glycols, polyamino acids, cyclodextrins or polypeptides. Among them, the polyamino acid is preferably polylysine.

Accordingly, the monomer units or "monomer unit pairs" constituting the water-soluble oligomer and the water-soluble polymer block include, but are not limited to, ethylene oxide, substituted ethylene oxide, ethylene glycol, vinyl alcohol, Acrylic acid and its derivatives, methyl methacrylate and its derivatives, ethyl methacrylate and its derivatives, acrylamide, N-isopropyl acrylamide, hydroxyethyl methacrylate, glycolic acid, hydroxybutyric acid , fumaric acid and propylene glycol, vinyl pyrrolidone, chain glucose unit, cyclic glucose unit water-soluble polysaccharide, natural amino acid and its derivatives, polypeptide, hydroxyalkyl methacrylamide, hydroxyalkyl methacrylate, α- Any one or a combination of two or more of a hydroxy acid, a phosphazene, an oxazoline, and an N-acryloylmorpholine.

Wherein, the structural formula of the substituted ethylene oxide is

X _{9 is} not particularly limited as long as it can be stably present under anionic polymerization conditions.

The water-soluble oligomer block includes, but is not limited to, a cyclic oligomer composed of the above monomer units (e.g., cyclodextrin). For example, a water-soluble cyclic peptide or the like can also be included.

specifically,

Water soluble blocks include, but are not limited to, cyclic structures derived from oligomers or polymers: polyethylene glycol, polyvinyl alcohol, polyacrylic acid, polymethyl methacrylate, polyethyl methacrylate, poly Acrylamide, poly N-isopropylacrylamide, polyhydroxyethyl methacrylate, polyglycolic acid, polyhydroxybutyrate, propylene glycol fumarate, polyvinylpyrrolidone, water-soluble polysaccharide, chitosan, Portuguese Glycans, polyamino acids, polypeptides, carboxymethyl starch, starch acetate, hydroxymethylcellulose, carboxymethylcellulose, cyclodextrin, cyclic peptides, and the like. Preferred are polyethylene glycol, polyamino acid, cyclodextrin, polypeptide, cyclodextrin, cyclic peptide, polyhydroxyalkylmethacrylamide, polyhydroxyalkyl methacrylate, poly-α-hydroxy acid, polyphosphazene , polyoxazoline, poly N-acryloylmorpholine and the like. Preference is given to polyethylene glycol, substituted polyethylene glycols, polylysines, polypeptides, cyclodextrins or cyclic peptides.

1.1.3. Functional group or its protected form

1.1.3.1. Definition of functional group R ₀₁

In the general formulae (1) to (6), R ₀₁ is a functional group or a protected form thereof.

R ₀₁ may be a functional group capable of interacting with a biologically relevant substance or a protected form thereof, or may be a functional group or a derivative thereof which does not react with a biologically relevant substance.

The functional group disclosed in paragraphs [0280] to [0506] of the patent document CN104877127A, a variant of a reactive group, a functional group having a therapeutic targeting property, a functional group such as a fluorescent functional group, and the like (including the corresponding protected form) and corresponding examples and preferred structures are included in the R ₀₁ range of the present invention. Wherein, the reactive group is active, can form a linkage with a bio-related substance to form a linkage, and mainly refers to a reaction that forms a covalent bond, and forms a non-covalent bond through a dihydrogen bond or multiple hydrogen. The key is complexed. The covalent bond includes, but is not limited to, a covalent bond that can be stably present, a degradable covalent bond, and a dynamic covalent bond. Such variations include, but are not limited to, precursors of reactive groups, active forms thereof as precursors, substituted active forms, protected forms, deprotected forms, and the like. The precursor of the reactive group refers to at least one process of oxidation, reduction, hydration, dehydration, electron rearrangement, structural rearrangement, salt complexation and decomplexation, ionization, protonation, deprotonation, and the like. Converted to the structure of the reactive group. The precursor can be active or inactive. The variant of the reactive group refers to a reactive group undergoing oxidation, reduction, hydration, dehydration, electron rearrangement, structural rearrangement, salt complexation and decomplexation, ionization, protonation, deprotonation. An inactive form (still a reactive group) after at least one process, such as substitution, deprotection, or the like, or a protected inactive form. Fluorescent functional groups are classified as long as they fluoresce, or emit fluorescence (such as fluorescein diacetate) through the action of the microenvironment in the body, or can fluoresce (such as light stimulation, thermal stimulation, etc.) through clinical stimulation.

When it is possible to react with a biologically relevant substance, R ₀₁ includes, but is not limited to, any of the functional groups of the class A to the class H, or a variation thereof, and R ₀₁ of these classes is a reactive group or a variant thereof is a reaction. Sex group.

Class A: Active esters (including but not limited to succinimide active ester, p-nitrophenyl active ester, o-nitrophenyl active ester, benzotriazole active ester, 1,3,5-trichlorobenzene active ester , 1,3,5-trifluorobenzene active ester, pentafluorobenzene active ester, imidazole active ester, etc., and similar structures of active ester groups (such as 2-thione-3-thiazolidinecarboxylate (tetrahydrothiazole) -2-thione-N-formate), 2-thioxothiazolidine-3-carboxylate, 2-thioketopyrrolidine-N-carboxylate, 2-thioketopyrrolidine-N-A An acid ester, 2-thione benzothiazole-N-formate, 1-oxo-3-thioxoisoindoline-N-formate, etc.);

Class B: sulfonate, sulfinate, sulfone, sulfoxide, 1,3-disulfonyl-2-propylcarbonylphenyl, sulfone methacryloyl, etc.;

Class C: hydroxylamine, mercapto, amino (primary or secondary), azide, halogenated hydrocarbon, haloacetamide (such as iodoacetamide), tetramethylpiperidinyloxy, dioxapiperidinyloxy (3,5-dioxo-1-cyclohexylamine-N-oxyl), ammonium salt (amine salt), hydrazine, disulfide compound (such as lipoic acid, etc.)

Class D: amide, hydrazide, carboxamide, carboxyl, aldehyde, glyoxal, acid halide, acetal, hemiacetal, hydrated aldehyde, ketal, hemi-ketal, hemi-ketal, ketal, hydration Ketones, orthoesters, cyanates, isocyanates, esters, siloxanes, silicates, silyls, thioesters, thioesters, dithioesters (dithioesters), trithioesters (three Thiocarbonate), thiohemiacetal, monothiohydrate, dithiohydrate, disulfide (such as dithiopyridine, etc.), thiol hydrate, thioketone, thioacetal, thioketone Hydrate, keto mercaptan, hemi-ketal, dihydrooxazole, isothiocyanate, sulfhydryl, ureido, thiourea, sulfhydryl, anhydride, squaric acid (squaraine), square acid ester Acid ester)

Class E: maleimide, N-acrylamide, acrylate, N-methyl acrylamide, methacrylate, norbornene-2-3-dicarboxyimino, maleamic acid, protected Maleimide, 1,2,4-triazoline-3,5-dione, etc.;

Class F: cyano, alkenyl (including vinyl, propenyl, etc.), olefinic (such as allyl, etc.), cycloalkenyl (such as cyclooctene, norbornene, etc.), alkynyl, alkyne (such as Propargyl), epoxy (glycidyl ether), azo (such as linear azo compound, cyclic F10, etc.), diazo, dienyl, diolefin, tetrazolium, linear a conjugated diene (such as a linear butadienyl group), a nitrile oxide/cyanide oxide, or the like;

Class G: cycloalkynyl or cycloalkynyl, cyclodiene (eg conjugated cyclopentadiene, 2,5-norbornadiene, bicycloheptadiene/2,5-norbornadiene, 7 -oxabicycloheptadiene, 7-oxa-bicyclo[2.2.1]hept-5-en-2-yl, etc.), hybrid conjugated diene (such as furan), 1,2,4, 5-tetrazinyl group;

Class H: hydroxyl (including but not limited to alcoholic hydroxyl, phenolic hydroxyl, enoloxy, hemiacetal, etc.), protected hydroxyl, siloxy, protected bis, trihydroxysilyl, protected Trishydroxysilane and the like.

In addition, but not limited to imides, sulfonyl hydrazides, hydrazines, imines, enamines, acetylene amines, xanthates, perthiocarbonates, tetrathiodiesters, sulfonates, sulfenic acid groups , hydroxamic acid, thiohydroxamic acid, xanthogen, sulfonyl chloride, ortho acid, cyanate, thiocyanate, thiocarboxylic acid (monothiocarboxylic acid (thiocarbonyl or thiol) ), dithiocarboxylic acid), mercapto and its protonated form, semi-squaric acid, hemi-succinate, N-carbamoyl-3-imidazole or N-carbamoyl-3-methylimidazolium iodide Anthraquinone, imidic acid, imidate, nitrone, hydrazine, urea, thiourea, pseudourea, isocyano, aldoxime, diazo, diazonium ion, azo, nitrile, N- Oxidized aldimine, tetrazolium, 4-acetyl-2-methoxy-5-nitrophenoxy and its diazotized form; others can undergo 1,3-dipolar cycloaddition functionalization Groups are also included in the invention and are defined as class (AH)'.

Further, the above-mentioned class A to class H also includes a precursor of any reactive group, a substituted form, and a protected form such as a protected hydroxyl group, a protected thiol group, a protected alkynyl group, and a protected form. Amino group, protected carboxyl group, etc. Functional groups related to the click reaction and their referenced click reactions reported in the literature Adv. Funct. Mater., 2014, 24, 2572 are incorporated herein by reference. CN is a precursor of the oxidized form C=N ⁺ O ^- , -NH ₂ is a precursor of ammonium ion -NH ₃ ⁺ , amine salt -NH ₂ HCl, -COOH is its sodium salt -COONa, negative ion -COO ^- Precursor, etc. Protected forms include, but are not limited to, protected hydroxyl groups, protected dihydroxy groups, protected trihydroxy groups, protected orthocarbonic acids, protected sulfhydryl groups, protected amino groups, protected carboxyl groups, protected aldehyde groups. Protected maleimide group (such as E4), protected alkynyl group (such as F4), and the like. The substituted forms are also included in A15, A16, G4-G10. -NH(C=NH ₂ ⁺ )NH ₂ is a protonated form of a thiol group. A functional group can belong to two subcategories at the same time. The ortho-pyridine disulfide in C13 is also a protected form of a thiol group. C9 is both a protected amino group and a protected dihydroxy group. Esters, thioesters, thioesters, carbonates, thiocarbonates may also belong to a protected hydroxy or thiol group.

The use of the above functional groups, including variations thereof, by way of example, includes but is not limited to:

The group of class A can be amino modified to form an amide bond or a urethane bond;

The sulfonate or sulfinate in the group of the class B can be used for the alkylation modification, and the sulfone group or sulfoxide group can be used for the modification of the thiol or disulfide bond.

Some groups are also frequently found in modified sites of biologically relevant substances, such as sulfhydryl groups, amino groups, disulfide bonds, and the like. In this category, mainly groups having similar reactivity (such as hydroxylamine, hydrazine), protected forms, salt forms and the like, in addition to halogens which are easily removed, and the like. For example, iodoacetamide can also be modified with a thiol group.

Some groups or their deprotected forms may interact with a hydroxyl group or a group such as CD, such as a carboxyl group, a sulfonic acid group, a hydroxamic acid, an acid halide, an aldehyde group, an isocyanate group, an isothiocyanate group, Oxycarbonylcarbonyl halide, dihydrooxazole, thiocarboxylic acid, ureido, thioureido, thiol and its protonated form, N-carbamoyl-3-imidazole or N-carbamoyl-3-methyl Imidazolium iodide, or a deprotected form of an acetal, a trihydroxy protecting group, a carboxylate (D11), a thiohemiacetal, a squaric acid ester, a hemi- succinate, a thioester, and an amino group, a thiol group, A suitable group in the hydroxy or halo is reacted. Further, for example, N-carbamoyl-3-imidazole can be reacted with a carboxyl group, and dihydrooxazole can react with a carboxyl group or an acid halide. Among them, a mercapto group can form a dihydrogen bond with two carbonyl groups of tanshinone IIa.

The group of the group E contains an α,β-unsaturated bond, and a 1,2-addition reaction can occur, for example, it can react with an amino group, a mercapto group or a hydroxyl group. The dihalo-substituted maleimide can also undergo a substitution reaction with a bis-indenyl group.

Groups of class F, the most common of which are similar in their preparation, can be obtained by substitution reactions of the corresponding halides. Among them, the epoxy group includes, but is not limited to, a naked bishydroxy group obtained by ring opening, a ring-opening addition reaction with an amino group, and the like. An alkenyl group of F2 may undergo an addition reaction. Alkynyl and deprotected alkynyl groups are common groups for the click reaction.

Functional groups of the invention also include reactive groups that can undergo a click reaction. Cycloalkyne and its precursors, conjugated dienes, 1,2,4,5-tetrazinyl group can undergo cycloaddition or Diels-Alder addition reaction, allyl, propargyl, propadiene and the like The group can undergo a 1,3-dipolar cycloaddition reaction. Further, G10 can be converted into a reactive group in a diazo form by treatment with a hydrazine or the like, and further reacts with a carboxyl group to form an ester bond.

The group of the group H is a protected form of a hydroxyl group, a bishydroxy group, a trihydroxy group, or any of them, and is an important functional group starting group (such as from a PEG terminal), a hydroxyl group or a deproton thereof. The group of the chemical form is also an essential component of the initiator center for initiating the polymerization of ethylene oxide in the present invention. Hydroxyl groups in the class H may also be present at the modified site of the biologically relevant substance. Further, H6 and H7 can be converted into an enol-type hydroxyl group under light conditions, and further subjected to an addition reaction with an α,β-unsaturated bond such as E.

When not reacting with a biologically relevant substance, it means a non-bonding reaction, which has a special function at this time, and R ₀₁ includes, but is not limited to, a targeting molecule (for example, folic acid, etc.), and a photosensitive group (such as a fluorescent group). And other special functional molecules and their derivatives. The substituted form still needs to have corresponding specific functions and can be classified into corresponding targeting groups and photo-sensitive groups. Such R ₀₁ includes, but is not limited to, class I to class J:

Class I: Targeting groups and pharmaceutically acceptable salts thereof, such as folic acid and its derivatives, cholesterol and its derivatives, biotin and its derivatives, and the like. Derivatives of biotin such as D-desulfurized biotin, 2-iminobiotin, and the like.

Class J: Fluorescent groups, such as fluorescein, rhodamine, guanidine, guanidine, coumarin, fluorescein 3G, carbazole, imidazole, guanidine, anthraquinone, etc., and the functionality of any of the above Derivatives. Among them, derivatives of rhodamine include, but are not limited to, tetramethylrhodamine, tetraethylrhodamine (rhodamine B, RB200), rhodamine 3G, rhodamine 6G (rhodamine 590), 5-carboxy-X-rhodan Ming, 6-carboxy-X-rhodamine, sulforhodamine B, sulforhodamine G, sulforhodamine 101, rhodamine X (R101), rhodamine 101, rhodamine 110, rhodamine 123, rhodamine 700, Rhodamine 800, etc., but also include, but are not limited to, the rhodamine derivatives described in the literature "Progress in Chemistry, 2010, 22 (10): 1929-1939" and references cited therein.

In the present invention,

As a whole of a functional group or a protected form thereof. As an example,

If R ₀₁ is an active ester,

Including, but not limited to, carbonates, acetates, propionates, butyrates, valerates, hexanoates, heptanoates, caprylates, phthalates, phthalates, of any of the active esters, Oxalate, malonate, methylmalonate, ethylmalonate, butylmalonate, succinate, 2-methylsuccinate, 2,2-di Methyl succinate, 2-ethyl-2-methyl-succinate, 2,3-dimethylsuccinate, glutarate, 2-methylglutarate, 3- Methyl glutarate, 2,2-dimethylglutarate, 2,3-dimethylglutarate, 3,3-dimethylglutarate, adipate, Gem Any one of an acid ester, a suberate, a sebacate, a sebacate, a maleate, a fumarate, an amino acid ester, a polypeptide acid ester, or a polyamino acid ester;

If R ₀₁ is an amino group,

The primary amine, including but not limited to methylamine, ethylamine, propylamine, butylamine, pentylamine, hexylamine, heptylamine, octylamine, cyclohexylamine, aniline, etc., loses the primary amino group obtained by the non-amino hydrogen atom or loses the amino hydrogen atom. Secondary amino group obtained, and dimethylamine, diethylamine, dipropylamine, dibutylamine, diamylamine, dihexylamine, diheptylamine, dioctylamine, dicyclohexylamine, N-methylaniline, N- Secondary amines such as ethylaniline, N-propylaniline, N-isopropylaniline, N-butylaniline, N-cyclohexylaniline, azetidine, pyrrolidine, piperidine, etc., lose non-amino hydrogen atoms Secondary amino group.

It can also lose C- for amino acids, amino acid derivatives, ω-aminocarboxylic acids (such as β-alanine, γ-butyric acid, δ-valerine, ε-hexidine, etc.), polypeptides or polypeptide derivatives. A residue formed after the carboxyl group or a hydroxyl group of a pendant carboxyl group, in which case R ₀₁ is an N-amino group or an amino group of a pendant group.

When R ₀₁ is an aldehyde group,

Including but not limited to formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde, valeraldehyde, hexanal, heptaldehyde, octanal, furfural, furfural, crotonaldehyde, acrolein, methacrolein, 2-ethyl acrolein, Chloroacetaldehyde, iodoacetaldehyde, dichloroacetaldehyde, benzaldehyde, phenylacetaldehyde, methyl benzaldehyde, cinnamaldehyde, nitrocinnamaldehyde, bromobenzaldehyde, chlorobenzaldehyde, etc. loses a non-aldehyde-based hydrogen atom (formaldehyde) The corresponding monovalent functional group corresponding to formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde, valeraldehyde, hexanal, heptaldehyde, octanal, furfural, furfural, croton Aldehyde, acrolein, methacrolein, 2-ethylpropenyl, monochloroacetaldehyde, iodoacetaldehyde, dichloroacetaldehyde, benzaldehyde, phenylacetaldehyde, methyl benzaldehyde , cinnamaldehyde group, nitrocinnamaldehyde group, bromobenzaldehyde group, chlorobenzaldehyde group and the like. As described in the terminology, when two or more structural forms such as isomers are present, any one of them may be employed. By way of example, butyraldehyde includes, but is not limited to, n-butyraldehyde, isobutyraldehyde, 2-methylpropanal, 2,2-dimethylacetaldehyde. For example, the valeraldehyde includes, but is not limited to, n-pentanal, 2-methylbutanal, isovaleraldehyde. The octanal as described includes, but is not limited to, n-octanal, 2-ethylhexanal. The methyl benzaldehyde includes o-methylbenzaldehyde, m-methylbenzaldehyde, and p-methylbenzaldehyde. For example, cinnamaldehyde includes, but is not limited to, anti-cinnamaldehyde. The nitrocinnamaldehyde includes, but is not limited to, trans-2-nitrocinnamaldehyde. The bromobenzaldehyde includes 2-bromobenzaldehyde, 3-bromobenzaldehyde, 4-bromobenzaldehyde. Such chlorobenzaldehyde includes 2-chlorobenzaldehyde, 3-chlorobenzaldehyde, 4-chlorobenzaldehyde. Acrolein as described

Benzaldehyde is

Such as m-methylbenzaldehyde

Such as the anti-cinnamaldehyde, including but not limited to

When R ₀₁ is a carboxyl group,

Including but not limited to formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, heptanoic acid, caprylic acid, capric acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, arachidic acid , behenic acid, behenic acid, isobutyric acid, 3-methylbutyric acid, acrylic acid, methacrylic acid, citric acid, vinyl acetic acid, cis citric acid, 6-heptenoic acid, itaconic acid, fragrant Monoacid, monochloroacetic acid, dichloroacetic acid, monofluoroacetic acid, difluoroacetic acid, benzoic acid, methylbenzoic acid, monofluorobenzoic acid, ethoxybenzoic acid, methoxybenzoic acid, ethylbenzoic acid, Vinyl benzoic acid, propyl benzoic acid, 2-isopropylbenzoic acid, 2-butyl benzoic acid, 2-isobutyl benzoic acid, carbamoyl maleic acid, N-phenyl maleic acid, Malay Amidic acid, arachidonic acid, tetracosanoic acid, tetracosenoic acid (neric acid), glycolic acid, lactic acid, isonicotinic acid, ascorbic acid, gentisic acid, gluconic acid, uronic acid, sorbic acid, a monovalent functional group in which a monobasic acid such as N-(ω-aminocarboxylic acid) group loses a non-carboxyl hydrogen atom, and a dibasic acid obtained by removing a molecular hydroxyl group a functional group, including but not limited to oxalic acid, malonic acid, methylmalonic acid, ethylmalonic acid, butylmalonic acid, succinic acid, 2-methylbutyl Acid, 2,2-dimethylsuccinic acid, 2-ethyl-2-methyl-succinic acid, 2,3-dimethylsuccinic acid, glutaric acid, 2-methylglutaric acid, 3-methylglutaric acid, 2,2-dimethylglutaric acid, 2,3-dimethylglutaric acid, 3,3-dimethylglutaric acid, adipic acid, pimelic acid, octane Diacid, azelaic acid, sebacic acid, maleic acid, fumaric acid, oxaloacetic acid, dimethylmalonic acid, isopropylmalonic acid, benzylmalonic acid, 1,1-epoxy Dicarboxylic acid, 1,1-cyclobutyldicarboxylic acid, dibutylmalonic acid, ethyl(1-methylpropyl)malonic acid,ethyl(1-methylbutyl)malonic acid, Ethyl (isopentyl)malonic acid, phenylmalonic acid, 2,2-dimethylsuccinic acid, 2-oxoglutaric acid, 3-oxoglutaric acid, 5-norbornene- Endo-2,3-dicarboxylic acid, 1,4-cyclohexanedicarboxylic acid, 1,3-cyclohexanedicarboxylic acid, 1,2-cyclohexanedioic acid, pyrrolidine-3,4-dicarboxylic acid, camphor Acid, chloric acid, cyclic acid, 5-methylisophthalic acid, phthalic acid 4-methyl-1,2-benzenedicarboxylic acid, 4-chlorophthalic acid, 3,4-pyridinedicarboxylic acid, 2,3-pyridinedicarboxylic acid, 2,4-pyridinedicarboxylic acid, 3 , 5-pyridinedicarboxylic acid, 2,6-pyridinedicarboxylic acid, 2,4-dimethylpyrrole-3,5-dicarboxylic acid, pyridine-2,3-dicarboxylic acid, 5-methylpyridine- 2,3-dicarboxylic acid, 5-ethylpyridine-2,3-dicarboxylic acid, 5-methoxymethyl-2,3-pyridinedicarboxylic acid, 4,5-pyridazine dicarboxylic acid, 2 , 3-pyrazinedicarboxylic acid, 5-methylpyrazine-2,3-dicarboxylic acid, 4,5-imidazoledicarboxylic acid, 2-propylimidazoledicarboxylic acid, 2-propylimidazoledicarboxylic acid ,diphenyl phthalic acid, 4,4'-stilbene dicarboxylic acid, 2,7-naphthalene dicarboxylic acid, 4,4'-diphenyl ether dicarboxylic acid, 2,2'-bipyridyl-5,5' -dicarboxylic acid, 2,2'-bipyridyl-3,3'-dicarboxylic acid, 4-pyrone-2,6-dicarboxylic acid, catechol-O, O'-diacetic acid, thiophene -2,3-dicarboxylic acid, 2,5-thiophene dicarboxylic acid, 2,5-dicarboxylic acid-3,4-ethylenedioxythiophene, 1,3-acetone dicarboxylic acid, methylene butadiene Acid, 2-methyl-2-butenedioic acid (citraconic acid and mesaconic acid), 1,3-butadiene-1,4-dicarboxylic acid, butynedioic acid, norbornene-2, 3 -dicarboxylic acid (bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid), bicyclo[2.2.1]hept-2-ene-2,3-dicarboxylic acid, diglycolic acid , dithiol dihydroxyacetic acid, malic acid, tartaric acid, 2,3-dimercaptosuccinic acid, 2,3-dibromosuccinic acid, pyrazole oxalic acid, 4,4'-dichloro-2,2' -dicarboxybiphenyl, 4,4'-dibromo-2,2'-dicarboxybiphenyl, gluconic acid, sucrose, pamoate, 2-bromosuccinic acid, 2-mercaptosuccinic acid, 1,3-adamantane dicarboxylic acid, 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid, carbonylmalonic acid, 3-oxoglutaric acid, ethoxylate Methylene malonic acid, 3,3'-dithiodipropionic acid, 5-exo-methyl-2-norbornene-5, 6-endo-cis-dicarboxylic acid, acetylmalonic acid, and the like. The above structures include various isomeric forms such as cis, trans, D, and L. For example, malic acid includes D and L types. Methylbenzoic acid includes o-methylbenzoic acid, m-methylbenzoic acid, p-methylbenzoic acid; monofluorobenzoic acid includes 2-fluorobenzoic acid, 3-fluorobenzoic acid, 4-fluorobenzoic acid; ethoxylate Benzoic acid includes o-ethoxybenzoic acid, m-ethoxybenzoic acid, p-ethoxybenzoic acid; methoxybenzoic acid includes o-methoxybenzoic acid, m-methoxybenzoic acid, p-methoxybenzoic acid Ethyl benzoic acid includes o-ethyl benzoic acid, m-ethyl benzoic acid, and p-ethyl benzoic acid. An example of a dibasic acid that removes one molecule of a hydroxyl group, such as malonic acid,

correspond

Succinic acid corresponding

Maleic acid

Wait.

It may also be a residue formed by losing an N-amino group or a hydrogen atom of a pendant amino group to an amino acid, an amino acid derivative, a polypeptide or a polypeptide derivative, in which case R ₀₁ is a C-carboxy group or a carboxyl group of a pendant group.

When R ₀₁ is an acid halide, the halogen atom may be a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a chlorine atom and a bromine atom. at this time,

Including but not limited to acetyl chloride, acetyl bromide, monochloroacetyl chloride, dichloroacetyl chloride, propionyl chloride, propionyl bromide, butyryl chloride, 3-cyclopentylpropionyl chloride, 2-chloropropionyl chloride, 3-chloropropane Acyl, tert-butylacetyl chloride, valeryl chloride, hexanoyl chloride, heptanoyl chloride, octanoyl chloride, decanoyl chloride, decanoyl chloride, lauroyl chloride, myristoyl chloride, palmitoyl chloride, stearoyl chloride, oleoyl chloride, behenyl chloride, cyclopentane a monovalent group obtained by removing one hydrogen atom, such as formyl chloride, methoxyacetyl chloride, acetoxyacetyl chloride, etc., and oxalyl, malonyl, methylmalonyl, ethylmalonyl, butyl Malonyl, succinyl, 2-methylsuccinyl, 2,2-dimethylsuccinyl, 2-ethyl-2-methyl-succinyl, 2,3-dimethyl Diacyl, glutaryl, 2-methylglutaryl, 3-methylglutaryl, 2,2-dimethylglutaryl, 2,3-dimethylglutaryl, 3,3-di An acyl group formed by combining a diacyl group such as methylglutaryl, adipoyl, pimeloyl, suberyl, azelayl, sebacyl, maleoyl or fumaryl with a halogen atom Halogen. Here, the acyl group of the dibasic acid refers to a residue obtained by removing two hydroxyl groups, such as a malonyl group.

When R ₀₁ is an acid anhydride, it may be an open chain or an intramolecular acid anhydride, for example,

Including but not limited to acetic anhydride, propionic anhydride, butyric anhydride, valeric anhydride, hexanoic anhydride, heptanoic anhydride, caprylic anhydride, phthalic anhydride, phthalic anhydride, lauric anhydride, myristic acid anhydride, palmitic anhydride, stearic anhydride, behenic anhydride, croton Anhydride, methacrylic anhydride, oleic anhydride, linoleic anhydride, linoleic anhydride, chloroacetic anhydride, iodoacetic anhydride, dichloroacetic anhydride, succinic anhydride, methyl succinic anhydride, 2,2-dimethylsuccinic anhydride, Anhydrides such as itaconic anhydride, maleic anhydride, glutaric anhydride, diethanol anhydride, benzoic anhydride, phenyl succinic anhydride, phenyl maleic anhydride, phthalic anhydride, isatoic anhydride, phthalic anhydride, etc. lose one hydrogen atom A corresponding monovalent functional group. The intramolecular acid anhydride also includes, but is not limited to, derived from succinic anhydride, 2,2-dimethyl succinic anhydride, cyclopentane-1,1-diacetic anhydride, 1,1-cyclohexyl diacetic anhydride, 2- Methylene succinic anhydride, glutaric anhydride, karonic anhydride, cyclobutane-1,2-dicarboxylic anhydride, hexahydrophthalic anhydride, methylhexahydrophthalic anhydride, 1,2,3 ,6-tetrahydrophthalic anhydride, 1,2,5,6-tetrahydrophthalic anhydride, 3-methyltetrahydrophthalic anhydride, methyltetrahydrophthalic anhydride, citraconic anhydride, 2,3-dimethyl Kamaine anhydride, 2,3-dichloromaleic anhydride, 3,4,5,6-tetrahydrophthalic anhydride, 3-methylphthalic anhydride, 4-tert-butylphthalic anhydride, 1,8- Naphthalic anhydride, 2,2'-tetraphthalic anhydride, 4-fluorophthalic anhydride, 3-fluorophthalic anhydride, 4-bromophthalic anhydride, 4-chlorophthalic acid Anhydride, 3,6-dichlorophthalic anhydride, 3-nitrophthalic anhydride, 4-nitrophthalic anhydride, 4-bromo-1,8-naphthalic anhydride, 4,5 -dichloro-1,8-naphthalic anhydride, 4-nitro-1,8-naphthalic anhydride, norbornene dianhydride, methyl endomethylene tetrahydrophthalic anhydride, demethylation Alizarin (7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic anhydride), 2,3-pyridinedicarboxylic anhydride, 2,3-pyrazine dianhydride, benzothioxanthene dicarboxylate An acid anhydride such as an acid anhydride.

If R ₀₁ is an intramolecular carbon imide,

Including but not limited to the imide form corresponding to any of the above-mentioned intramolecular acid anhydrides, such as succinimide corresponding succinimide, maleic anhydride corresponding maleimide, phthalic anhydride corresponding to phthalic acid Imide, etc., will not be repeated one by one. Also included, but not limited to, sulfonylbenzimide.

When R ₀₁ is a maleimide group,

Including but not limited to from 3,4,5,6-tetrahydrophthalimide, maleimidoacetyl, 3-maleimidopropionyl, 4-maleimide Butyryl, 5-maleimidopentanoyl, 6-(maleimido)hexanoyl, 3-maleimidobenzoyl, 4-maleimidobenzoyl, 4-(N-maleimidomethyl)cyclohexane-1-formyl, 4-(4-maleimidophenyl)butanoyl, 11-(maleimido) Undecanoic acid acyl, 4-(4-maleimidophenyl)butanoyl, 11-(maleimido)undecanoyl acyl, N-(2-aminoethyl)male A maleimide group such as an imide, N-(4-aminophenyl)maleimide or 2-maleimidoethyl.

If R ₀₁ is a cyano group,

Including but not limited to carbonitrile, acetonitrile, butyronitrile, valeronitrile, hexanenitrile, heptonitrile, octonitrile, phthalonitrile, phthalonitrile, undecylnitrile, allyl, acrylonitrile, crotononitrile, methacrylonitrile A monovalent functional group corresponding to a cyano compound such as dichloroacetonitrile, fluoroacetonitrile, benzonitrile, benzyl nitrile, methylbenzyl nitrile, chlorobenzonitrile or methyl benzonitrile loses a hydrogen atom.

When R ₀₁ is an alkynyl group,

These include, but are not limited to, ethynyl, propynyl, propargyl, cycloalkynyl, and the like.

If R ₀₁ is a hydroxyl group,

Including but not limited to methanol, ethanol, propanol, butanol, pentanol, hexanol, heptanol, octanol, decyl alcohol, decyl alcohol, undecyl alcohol, dodecanol, tridecyl alcohol, tetradecanol, fifteen Alcohol, cetyl alcohol, heptadecyl alcohol, stearyl alcohol, stearyl alcohol, oleyl alcohol, benzyl alcohol, cumene alcohol, phenol, cresol, phenol, propanol, cinnamyl phenol, naphthol, cyclopentanol, A monohydric alcohol such as cyclohexanol loses a corresponding monovalent functional group after a non-hydroxyl hydrogen atom.

When R ₀₁ is cholesterol or a derivative thereof,

A molecule such as, but not limited to, a derivative of cholesterol, a cholesteryl hydrosuccinate, or the like, is modified at the end of the PEG.

When R ₀₁ is biotin or a derivative thereof,

Including but not limited to biotin-N-succinimidyl ester, 3-[3-[2-(biotinamide)ethyl]amino-3-oxopropyl]dithio]propionic acid succinyl Amine, 3-[[2-(biotinamide)ethyl]dithio]propionic acid sulfosuccinimide, N-(3-azidopropyl) biotinamine, N-biotin -3,6-dioxooctane-1,8-diamine, N-biotin-3,6,9-trioxadecane-1,11-diamine, biotinyl-6-aminoquin Porphyrin, N-(6-[biotinamine]hexyl)-3'-(2'-pyridinedithio)propanamide, 15-[D-(+)-biotinamino]-4,7,10,13 -tetraoxapentadecanoic acid, 3-(4-(N-biotin-6-aminohexylcarboxy)phenyl)propionic acid, N-Fmoc-N'-biotin-L-lysine, D- A molecule formed by modification of a molecule such as biotin hydrazide, biotin-aspartyl-glutamyl-prolyl-aspartic acid to the PEG terminal.

When R ₀₁ is fluorescein or a derivative thereof,

Including but not limited to 5-carboxyfluorescein succinimide ester, 6-carboxyfluorescein succinimide ester, 5-aminofluorescein, 6-aminofluorescein, 5(6)-aminofluorescein, 5-( Aminomethyl)fluorescein hydrochloride, 6-([4,6-dichlorotriazin-2-yl]amino)fluorescein hydrochloride, 5'-fluorescein phosphoramidate, fluorescein 5-maleamide Amine, fluorescein 6-maleimide, 5-carboxyfluorescein, 6-carboxyfluorescein, 2,7-bis(2-carboxyethyl)-5(6)-carboxyfluorescein, 5-(4 , 6-dichlorotriazine) aminofluorescein, CI 45350 and other molecules modified at the end of the PEG formed residues.

When R ₀₁ is rhodamine or a derivative thereof,

Including but not limited to tetramethylrhodamine, tetraethylrhodamine (rhodamine B, RB200), rhodamine 3G, rhodamine 6G (rhodamine 590), 5-carboxy-X-rhodamine, 6-carboxy-X - rhodamine, sulforhodamine B, sulforhodamine G, sulforhodamine 101, rhodamine X (R101), rhodamine 101, rhodamine 110, rhodamine 123, rhodamine 700, rhodamine 800, 5 -carboxytetramethylrhodamine, 6-carboxytetramethylrhodamine, 5-carboxytetramethylrhodamine succinimide ester, 6-carboxytetramethylrhodamine succinimide ester, 5-carboxyrhodamine 6G succinimide ester, 6-carboxyrhodamine 6G succinimide ester, tetramethylrhodamine-5-maleimide, tetramethylrhodamine-6-maleimide, 6-carboxyl -X-rhodamine succinimide ester, tetramethylrhodamine-5-isothiocyanate, tetramethylrhodamine-6-isothiocyanate, tetramethylrhodamine B-5-isosulfide A residue formed by modifying a molecule such as a cyanate ester, a tetramethylrhodamine B-6-isothiocyanate, a rhodamine 101 chloride, or a sulfonated rhodamine B to the PEG terminal.

When R ₀₁ is hydrazine or a derivative thereof,

Including but not limited to 9-oxime methanol, 1-aminoindole, 2-aminoindole, 9-nonanoxine, 10-methylindole-9-formaldehyde, 9-anthracenecarboxylic acid, 9-fluorene methyl acrylate, methacrylic acid A residue formed by modifying a molecule such as methyl-9-methyl ester, 9-valeraldoxime or 9-fluorenyl acrolein at the end of the PEG.

When R ₀₁ is hydrazine or a derivative thereof,

Including but not limited to 1-indole methanol, 7,8,9,10-tetrahydrobenzo[a]indol-7-ol, N-hydroxysuccinimide ester 1-indolyl butyric acid, 1-indolyl formaldehyde, 1 - indolebutyric acid, 1-indolecarboxylic acid (1-indolecarboxylic acid), 1-indole acetic acid, 10-(1-indolyl) decanoic acid, 1-decanoic acid, Fmoc-3-(1-indenyl)- L-alanine, tert-butyloxycarbonyl-3-(1-indolyl)-D-alanine, tert-butyloxycarbonyl-3-(1-indolyl)-L-alanine, 1- Molecular modification of aminoguanidine, 1,3-diaminopurine, 1,8-diaminopurine, 1,6-diaminopurine, 1-indolylmethylamine, N-(1-indolyl)maleimide Residue formed after the end of PEG.

When R ₀₁ is oxazolium or a derivative thereof,

Including but not limited to carbazole, 9-oxazole ethanol, 2-hydroxycarbazole, 2-(9H-carbazolyl)ethylboronic acid pinacol ester, 2-(9H-carbazolyl)ethylboronic acid diethanolamine A residue formed by modifying a molecule such as an ester, N-aminocarbazole, 9-(4-aminophenyl)oxazole or 9-carbazoleacetic acid at the end of the PEG.

When R ₀₁ is imidazole or a derivative thereof,

Including but not limited to 4-(hydroxymethyl)imidazole, 4-hydroxyethylimidazole, 1-(2-hydroxyethyl)imidazole, 1-methyl-2-hydroxymethyl-1H-imidazole, 1-(2 -Hydroxypropyl ester)imidazole, 1-(β-hydroxyethyl)-2-methylimidazole, 4-hydroxymethyl-5-methyl-2-phenylimidazole, 1-hydroxyethyl-3-methyl Imidazole, 1-hydroxyethyl-3-methylimidazolium chloride, 4-hydroxymethyl-5-methylimidazole, 4-bromo-1H-imidazole, 2-bromo-1H-imidazole, 1-methyl-2 -bromo-1H-imidazole, 5-chloro-1-methylimidazole, 2-aminoimidazole, 4-aminoimidazole, 1-(3-aminopropyl)imidazole, 1-methyl-4-imidazolium, 4- Imidazole formaldehyde (4-formyl imidazole), 1-formyl imidazole, 2-formyl imidazole, 4-(imidazol-1-yl)benzaldehyde, 1-methyl-2-imidazolecarboxaldehyde, 2-butyl-1H -Imidazole-4-carbaldehyde, 5-methylimidazole-4-carbaldehyde, 2-ethyl-4-formylimidazole, 2-ethyl-4-methyl-5-imidazolecarboxaldehyde, 1-benzyl-1H- Molecules such as imidazole-5-formaldehyde, 2-ethyl-4-formyl imidazole, 5-amino-1H-imidazole-4-carbonitrile, histidine and the like are modified at the end of the PEG.

When R ₀₁ is hydrazine or a derivative thereof,

Including but not limited to 4-hydroxyindole, 5-hydroxyindole, 6-hydroxyindole, 7-hydroxyindole, 5-hydroxy-2-methylindole, 4-hydroxy-2-methylindole, 3-(2-methylaminoethyl)anthracene, 2-(2-aminoethyl)anthracene, 3-(2-aminoethyl)-6-methoxyindole, 4-aminoindole, 5-aminoindole, 6-aminopurine, 7-aminopurine, 4-methyl-5-aminopurine, 3-bromoindole, 4-bromoindole, 5-bromoindole, 6-bromo吲哚, 7-bromoindole, 5-bromo-1-methyl-1H-indole, 3-(2-aminoethyl)indol-5-ol, 5-hydroxyindole-2-carboxylic acid, 6 -hydroxy-2-indolecarboxylic acid, 7-hydroxyindole-2-carboxylic acid, 5-bromoindole-2-carboxylic acid, 6-bromoindole-2-carboxylic acid, 7-bromoindole-2-carboxylic acid, 5 -bromoindole-3-carboxylic acid, 6-bromoindole-3-carboxylic acid, 4-bromoindole-3-carbaldehyde, 6-bromoindole-3-carbaldehyde, 5-bromo-1H-indole-3- A molecule such as ethanol is modified to form a residue after the end of the PEG.

1.1.3.2. Structural classification of the functional group R ₀₁

Specifically, R ₀₁ includes, but is not limited to, any one of the following categories A to J:

Class A:

Or class B:

Or class C:

Or class D:

Or class E:

Or class F:

Or class G:

Or class H:

Or class I:

Or class J:

Wait.

Wherein E ₀₂ and E ₀₃ correspond to a carbonyl group and the other is bonded to OH.

Wherein X ₆ is a terminal group attached to an ester group or an oxygen atom in a thioester group, and is selected from a hydroxy protecting group or a group LG ₄ .

Wherein, the rings in which R ₃ , LG ₄ , Q, M ₅ and M ₅ are located are consistent with the above definitions, and are not described herein again.

Wherein Y ₁ is a leaving group to which a sulfonyl group, a sulfinyl group, an oxysulfonyl group or an oxysulfinyl group is bonded.

Y _{1 is} not particularly limited.

Y ₁ preferably has a C _1-10 hydrocarbyl group or a fluoro C _1-10 hydrocarbyl group.

More preferably, Y ₁ has any one of a C _1-10 alkyl group, a C _1-10 alkenyl group, a phenyl group, and the like, or a substituted form thereof. Wherein the substituted atom or the substituent group is a halogen atom, an alkenyl group, an alkoxy group or a nitro group.

Specifically, as an example, Y ₁ may be selected from, but not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, decyl, vinyl Any one of phenyl, benzyl, p-methylphenyl, 4-(trifluoromethoxy)phenyl, trifluoromethyl, 2,2,2-trifluoroethyl, and the like. Among them, butyl includes, but not limited to, n-butyl group and tert-butyl group. Octyl includes, but is not limited to, n-octyl, 2-ethylhexyl.

Y ₁ is preferably any of a methyl group, a p-methylphenyl group, a 2,2,2-trifluoroethyl group, a trifluoromethyl group, and a vinyl group.

Wherein W is F, Cl, Br or I, preferably Br or Cl.

Wherein W ₂ is F, Cl, Br or I, preferably I.

among them,

Ring structures containing a nitrogen atom, a double bond, an azo, a triple bond, a disulfide bond, an acid anhydride, and a diene, respectively, including but not limited to a carbocyclic ring, a heterocyclic ring, a benzoheterocyclic ring, a substituted carbocyclic ring. a substituted heterocyclic ring or a substituted benzoheterocyclic ring or the like.

Wherein M is a carbon atom or a hetero atom on the ring, including but not limited to a carbon atom, a nitrogen atom, a phosphorus atom, or a silicon atom.

Wherein M ₈ is a carbon atom or a hetero atom located on the ring. M ₈ is preferably a carbon atom, a nitrogen atom, a phosphorus atom or a silicon atom. The number of ring atoms of the ring in which M ₈ is present is not particularly limited, but is preferably 4 to 50, more preferably 4 to 32, still more preferably 5 to 32, and still more preferably 5 to 18. M ₈ may be a carbon atom or a hetero atom on a ring of 4 to 50 members, preferably a carbon atom, a nitrogen atom, a phosphorus atom or a silicon atom on a ring of 4 to 32 members, more preferably a carbon atom or a nitrogen atom on a ring of 5 to 32 members. The atom, the phosphorus atom or the silicon atom is more preferably a carbon atom, a nitrogen atom, a phosphorus atom or a silicon atom on a ring of 5 to 18 members.

Wherein R ₈ , R ₉ , R ₁₀ , R ₁₁ and R _{12 are the} same as defined in the above R ₈ , and are not described herein again. Further, in the same molecule, R ₈ , R ₉ , R ₁₀ , R ₁₁ and R ₁₂ may be the same as or different from each other.

In the class E3, R _{8 is} most preferably a methyl group.

Wherein R ₂ is an acetal, a ketal, a hemiacetal, a hemi-ketal, an orthoester, a thioacetal, a thioketal, a thio hemiacetal, a thiosemi-ketal, a thioorthoester An end group or a divalent linking group to which an oxygen or sulfur atom is attached, such as D7, D8, D12, D18.

R _{2 is} selected from a hydrogen atom, any one of R ₂₁ or R ₃ or a group.

Wherein R ₂₁ is a divalent linking group and participates in ring formation.

The number of carbon atoms of R ₂₁ is not particularly limited, and is preferably from 1 to 20, and more preferably from 1 to 10.

The structure of R ₂₁ is not particularly limited and includes, but not limited to, a linear structure, a branched structure containing a side group, or a cyclic structure. The cyclic structure is not particularly limited and includes, but is not limited to, any of the cyclic structures recited in the terminology. The above aliphatic ring, aromatic ring, sugar ring, and condensed ring are preferred.

R ₂₁ may or may not contain a hetero atom.

R _{21 is} selected from a C _1-20 alkylene group, a divalent C _1-20 heteroalkyl group, a substituted C _1-20 alkylene group, a substituted divalent C _1-20 heteroalkyl group, or a divalent linking group. A divalent linking group formed by a combination of any three or three. The substituent atom or the substituent is not particularly limited and includes, but is not limited to, any of the substituted atoms or any substituents recited in the terminology, and any one selected from the group consisting of a halogen atom, a hydrocarbon group substituent, and a hetero atom-containing substituent.

R ₂₁ is preferably a C _1-20 open chain alkylene group, a C _1-20 open chain alkenylene group, a C _1-20 cycloalkylene group, a C _1-20 cycloalkylene group, an arylene group, an arylene group, Divalent C _1-20 fattyalkyl, divalent C _1-20 aliphatic heteroalkenyl, divalent heteroaryl, divalent heteroaryl, substituted alkylene, substituted C _1-20 open chain alkylene , substituted C _1-20 cycloalkylene, substituted C _1-20 cycloalkylene, substituted arylene, substituted arylene, substituted divalent C _1-20 heteroalkyl, substituted a divalent C _1-20 oligoalkenyl group, a substituted divalent heteroaryl group, a substituted divalent heteroaryl group, a divalent linking group, a combination of any two, or a combination of any three A divalent linking group. Among them, a substituted atom or a substituent is preferably a halogen atom, an alkoxy group and a nitro group.

More preferably, R ₂₁ is a C _1-10 open chain alkylene group, a C _1-10 open chain alkenylene group, a C _3-10 cycloalkylene group, a C _1-10 cycloalkylene group, an arylene group, or an arylene group. , divalent C _1-10 oxaalkyl, divalent C _1-10 alialkenyl, divalent heteroaryl, divalent heteroaryl, substituted alkylene, substituted C _1-10 open chain Alkenyl, substituted C _1-10 cycloalkylene, substituted C _1-10 cycloalkylene, substituted arylene, substituted aralkyl, substituted divalent C _1-10 oxaalkyl a divalent linking group of a substituted divalent C _1-10 alicyclic alkenyl group, a substituted divalent heteroaryl group, a substituted divalent heteroaryl group, or a combination of any two or any three Valence link.

Specifically, R _{21 is} selected from the group consisting of methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, fluorenylene, fluorenylene, 1,2- Any one of a phenyl group, a benzylidene group, a C _{1-20 oxaalkylene} group, a C _1-20 thiaalkylene group, a C _1-20 azaalkylene group, an azaheteroaryl group, or any of A substituted form of a group or a combination of any two or more of the same or different groups or groups substituted forms. Here, the substituted atom or the substituent is selected from any one of a halogen atom, a hydrocarbon group substituent, and a hetero atom-containing substituent, and a halogen atom, an alkoxy group or a nitro group is preferable.

R ₂₁ is preferably selected from the group consisting of methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, fluorenylene, fluorenylene, 1,2-phenylene, Any one of a benzylidene group, a C _{1-20 oxaalkylene} group, a C _1-20 thiaalkylene group, a C _1-20 azaalkylene group, an azaheteroaryl group, or a group thereof A substituted form or a combination of any two or more than two identical or different groups or groups substituted forms. Here, the substituted atom or the substituent is selected from any one of a halogen atom, a hydrocarbon group substituent, and a hetero atom-containing substituent, and a halogen atom, an alkoxy group or a nitro group is preferable.

R _{21 is} more preferably 1,2-ethylene, 1,3-propylene.

Wherein R ₄ is a hydrogen atom, a substituted atom or a substituent on C in the structure of -(R ₄ )C=N ⁺ =N ^- .

When the atom is substituted, R _{4 is} selected from any of halogen atoms. A fluorine atom is preferred.

When it is a substituent, the number of carbon atoms of R ₄ is not particularly limited, but the number of carbon atoms is preferably from 1 to 20, and more preferably from 1 to 10.

As the substituent, the structure of R ₄ is not particularly limited and includes, but is not limited to, a linear structure, a branched structure containing a side group, or a cyclic structure. The cyclic structure is not particularly limited and includes, but is not limited to, any of the cyclic structures recited in the terminology.

As a substituent, R ₄ may contain a hetero atom, may contain hetero atoms.

R _{4 is} selected from a hydrogen atom, a halogen atom, a C _1-20 hydrocarbon group, a C _1-20 heteroalkyl group, a substituted C _1-20 hydrocarbon group or a substituted heterohydrocarbyl group. Wherein the substituted atom or substituent in R ₄ is not particularly limited, and includes, but is not limited to, any one of the substituted atoms or any of the substituents listed in the term, and is selected from a halogen atom, a hydrocarbon group substituent, and a hetero atom-containing substituent. One.

More preferably, R ₄ is a hydrogen atom, a halogen atom, a C _1-20 alkyl group, a C _1-20 unsaturated aliphatic hydrocarbon group, an aryl group, an aromatic hydrocarbon group, a C _1-20 heteroalkyl group, a C _1-20 hydrocarbyloxy group, C Any one or a group of a _1-20 hydrocarbylthioacyl group, a C _1-20 hydrocarbylaminoacyl group, or a substituted form of any one of the groups. Wherein the acyl group in R ₄ is not particularly limited and includes, but is not limited to, any of the acyl groups listed in the terminology. The acyl group in R ₄ is more preferably a carbonyl group or a thiocarbonyl group.

R _{4 is} more preferably a hydrogen atom, a halogen atom, a C _1-20 alkyl group, a C _1-20 alkenyl group, an aryl group, an aromatic hydrocarbon group, a C _1-20 aliphatic hydrocarbon group, a heteroaryl group, a heteroaryl hydrocarbon group, C _1- Any atom or group of ₂₀ alkoxyacyl, aryloxyacyl, C _1-20 alkylthioacyl, arylthioacyl, C _1-20 alkylaminoacyl, arylaminoacyl, Or a substituted form of any of the groups.

R _{4 is} more preferably a hydrogen atom, a halogen atom, a C _1-20 alkyl group, a C _1-20 alkenyl group, an aryl group, an aromatic hydrocarbon group, a C _1-20 aliphatic hydrocarbon group, a heteroaryl group, a heteroaryl hydrocarbon group, C _{1- 20} alkoxycarbonyl, aryloxycarbonyl, C _1-20 alkylthiocarbonyl, arylthiocarbonyl, C _1-20 alkylaminocarbonyl, arylaminocarbonyl, C _1-20 alkoxy sulfide Carbonyl, aryloxythiocarbonyl, C _1-20 alkylthiothiocarbonyl, arylthiothiocarbonyl, C _1-20 alkylaminothiocarbonyl, arylaminothiocarbonyl An atom or group, or a substituted form of any of the groups.

Specifically, R _{4 is} selected from, but not limited to, a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group. , octyl, decyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, N-nonyl, eicosyl, allyl, propenyl, vinyl, phenyl, methylphenyl, butylphenyl, benzyl, methoxycarbonyl, ethoxycarbonyl, phenoxycarbonyl , benzyloxycarbonyl, methylthiocarbonyl, ethylthiocarbonyl, phenylthiocarbonyl, benzylthiocarbonyl, ethylaminocarbonyl, benzylaminocarbonyl, methoxythiocarbonyl, ethoxythiocarbonyl, phenoxy Thiocarbonylcarbonyl, benzyloxythiocarbonyl, methylthiocarbonylcarbonyl, ethylthiothiocarbonyl, phenylthiothiocarbonyl, benzylthiothiocarbonyl, ethylaminothiocarbonyl, benzylaminothio a carbonyl group, a substituted C _1-20 alkyl group, a substituted C _1-20 alkenyl group, a substituted aryl group, a substituted aromatic hydrocarbon group, a substituted C _1-20 aliphatic heterohydrocarbyl, substituted heteroaryl, taking Heteroarylalkyl, substituted C _1-20 alkoxycarbonyl group, a substituted aryloxycarbonyl group, substituted C _1-20 alkylthio group, a substituted aryl thiocarbonyl group, a substituted C _1-20 Alkylaminocarbonyl, substituted arylaminocarbonyl, substituted C _1-20 alkoxythiocarbonyl, substituted aryloxythiocarbonyl, substituted C _1-20 alkylthiothiocarbonyl, substituted Any one of an arylthiothiocarbonyl group, a substituted C _1-20 alkylaminothiocarbonyl group, a substituted arylaminothiocarbonyl group, and the like. Among them, butyl includes, but not limited to, n-butyl group and tert-butyl group. Octyl groups include, but are not limited to, n-octyl, 2-ethylhexyl. Here, the substituted atom or the substituent is any one selected from the group consisting of a halogen atom, a hydrocarbon group substituent, and a hetero atom-containing substituent, and is preferably a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an alkenyl group or a nitro group.

R _{4 is} further preferably a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, decyl, allyl, propenyl, ethylene Base, phenyl, methylphenyl, butylphenyl, benzyl, methoxycarbonyl, ethoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, methylthiocarbonyl, ethylthiocarbonyl, phenylsulfonate Carbocarbonyl, benzylthiocarbonyl, ethylaminocarbonyl, benzylaminocarbonyl, methoxythiocarbonyl, ethoxythiocarbonyl, phenoxythiocarbonyl, benzyloxythiocarbonyl, methylthiocarbonylcarbonyl , ethylthiothiocarbonyl, phenylthiothiocarbonyl, benzylthiothiocarbonyl, ethylaminothiocarbonyl, benzylaminothiocarbonyl, C _1-10 halogenated hydrocarbon, halophenyl, halobenzyl Any of a group or group of a group, a nitrophenyl group, or the like, or a substituted form of any of the groups.

R ₄ is preferably hydrogen atom, methyl, ethyl, n-propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, allyl, propenyl, vinyl Any one or a group of a phenyl group, a methylphenyl group, a butylphenyl group or a benzyl group.

R _{4 is} most preferably a hydrogen atom, a methyl group or a benzyl group.

Wherein R ₂₄ is a terminal group attached to a disulfide bond, preferably a C _1-20 alkyl group, an aryl group, an aromatic hydrocarbon group, a hybrid phenyl group or the like, such as an ortho-pyridyl group.

Wherein R ₂₇ is a substituent attached to azo, preferably a phenyl group, a substituted phenyl group or a hybrid phenyl group.

Wherein R ₃₀ is a hydrocarbon group, preferably a benzyl group in which a C _1-20 alkyl group, a benzyl group, or a benzene ring hydrogen atom is substituted with a C _1-20 hydrocarbon group.

Wherein M ₁₉ , M ₂₀ and M ₂₁ are each independently an oxygen atom or a sulfur atom, and may be the same or different from each other in the same molecule.

Wherein X ₁₁ is a terminal group to which a carbonyl group or a thiocarbonyl group is bonded, preferably a C _1-20 alkyl group, more preferably a methyl group, an ethyl group, an isopropyl group or a t-butyl group.

Wherein X ₁₂ is a terminal group to which a carbonate group or a thiocarbonate group is bonded, and is selected from a hydrocarbon group (which may or may not include a benzene ring), preferably a C _1-20 hydrocarbon group, more preferably a C _1-20 alkyl group, a phenyl group. A hydrocarbyl or hydrocarbyl substituted phenyl group.

Wherein X ₅ is a terminal group attached to a thio group, and is selected from a thiol protecting group or a group LG ₂ .

When in the thiol protecting group, X _{5 is} selected from the group consisting of fluorenyl protecting groups in the combinations exemplified for PG ₂ .

Among them, the number of carbon atoms of LG ₂ is not particularly limited. The number of carbon atoms of LG ₂ is preferably from 1 to 20, and more preferably from 1 to 10.

The structure of LG ₂ is not particularly limited and includes, but is not limited to, a linear structure, a branched structure containing a side group, or a cyclic structure. The cyclic structure is not particularly limited and includes, but is not limited to, any of the cyclic structures recited in the terminology.

LG ₂ may or may not contain a hetero atom.

LG _{2 is} selected from any one of a C _1-20 hydrocarbyl group, a C _1-20 heterohydrocarbyl group, a substituted C _1-20 hydrocarbyl group, and a substituted heterohydrocarbyl group. Wherein the substituted hetero atom or substituent in LG ₂ is not particularly limited, and includes, but is not limited to, any substituted hetero atom or any substituent listed in the terminology, and is selected from a halogen atom, a hydrocarbon group substituent, and a hetero atom-containing substituent. Any of them.

LG _{2 is} more preferably C _1-20 alkyl, C _1-20 unsaturated aliphatic hydrocarbon, aryl, aromatic hydrocarbon, C _1-20 heteroalkyl, C _1-20 alkylthio, C _1-20 aliphatic hydrocarbon sulfur , arylthio, arenethio, C _1-20 aliphatic arehenyl, C _1-20 aliphatic acyl, aryl acyl, heteroaryl acyl, C _1-20 hydrocarbyl acyl, C ₁ Any one of a _-20 hydrocarbylthioacyl group, a C _1-20 hydrocarbylaminoacyl group, a C _1-20 heteroalkyloxyacyl group, a C _1-20 heteroalkylthioacyl group, a C _1-20 heteroalkylaminoacyl group or A substituted form of any of the groups. Wherein the acyl group in LG ₂ is not particularly limited and includes, but is not limited to, any of the acyl groups listed in the terminology. By way of example, the acyl group in LG ₂ may be selected from the group consisting of a carbonyl group, a sulfonyl group, a sulfinyl group, a phosphoryl group, a phosphorous group, a hypophosphoryl group, a nitroxyl group, a nitrosyl group, a thiocarbonyl group, an imido group, a thio group. Phosphoryl, dithiophosphoryl, trithiophosphoryl, thiophosphoryl, dithiophosphoryl, thiophosphoryl, thiophosphonyl, dithiophosphonyl, thiophosphinyl Wait. An acyl group such as a carbonyl group, a thiocarbon group, a sulfonyl group or a sulfinyl group is preferred. The acyl group in LG ₂ is more preferably a carbonyl group, a thiocarbonyl group or a sulfonyl group.

More preferably, LG ₂ is C _1-20 alkyl, aryl, aralkyl, C _1-20 heteroalkyl, heteroaryl, heteroarylalkyl, C _1-20 alkylthio, arylthio, aromatic Alkylthio, C _1-20 heteroalkylthio, heteroarylthio, heteroaralkylthio, C _1-20 alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, C _1-20 Alkylcarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl, C _1-20 alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, C _1-20 alkylthiocarbonyl, arylthio Carbonyl, aralkylthiocarbonyl, C _1-20 alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, C _1-20 heteroalkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyl Alkoxycarbonyl, C _1-20 heteroalkylthiocarbonyl, heteroarylthiocarbonyl, heteroaralkylthiocarbonyl, C _1-20 heteroalkylaminocarbonyl, heteroarylaminocarbonyl, heteroaralkyl Alkylaminocarbonyl, C _1-20 alkylthiocarbonyl, arylthiocarbonyl, aralkylthiocarbonyl, C _1-20 heteroalkylthiocarbonyl, heteroarylthiocarbonyl, heteroarylalkylsulfide thiocarbonyl group, C _1-20 alkoxy-thiocarbonyl group, aryloxy thiocarbonyl group, an aralkyl Thiocarbonyl group, C _1-20 alkylthio thiocarbonyl group, thiocarbonyl arylthio, aralkylthio thiocarbonyl, C _1-20 alkylamino thiocarbonyl group, an aryl thio group Carbonyl, aralkylaminothiocarbonyl, C _1-20 heteroalkyloxythiocarbonyl, heteroaryloxythiocarbonyl, heteroaralkyloxythiocarbonyl, C _1-20 heteroalkyl sulfide Thiocarbonylcarbonyl, heteroarylthiothiocarbonyl, heteroaralkylthiothiocarbonyl, C _1-20 heteroalkylaminothiocarbonyl, heteroarylaminothiocarbonyl, heteroaralkylaminosulfur Any substituted group or substituted form of any of the groups.

More preferably, LG ₂ is C _1-20 alkyl, aryl, aralkyl, C _1-20 heteroalkyl, heteroaryl, heteroarylalkyl, C _1-20 alkylthio, arylthio, aromatic A substituted form of any one of alkylthio, C _1-20 heteroalkylthio, heteroarylthio, heteroarylalkylthio or any of the groups.

Specifically, LG _{2 is} selected from, but not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, decyl, undecyl, Dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, allyl, benzyl , trityl, phenyl, benzyl, methylbenzyl, nitrobenzyl, tert-butylthio, benzylthio, 2-pyridylthio, ethylacyl, phenylyl, Methoxy, ethoxy, t-butyloxy, phenoxy, benzyloxy, methylthio, ethylthio, tert-butylthio, phenylthio, benzyl A substituted form of any one of a thioyl group, a 2-pyridylcarbonyl group, a methylamino acyl group, an ethylamino acyl group, a t-butylamino acyl group, a benzylamino acyl group, or the like, or a substituted group of any one. Among them, butyl includes, but not limited to, n-butyl group and tert-butyl group. Octyl groups include, but are not limited to, n-octyl, 2-ethylhexyl. Here, the substituted atom or the substituent is selected from any one of a halogen atom, a hydrocarbon group substituent, and a hetero atom-containing substituent, and is preferably a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or a nitro group.

LG _{2 is} further preferably methyl, ethyl, n-propyl, isopropyl, tert-butyl, pentyl, hexyl, heptyl, octyl, decyl, decyl, undecyl, dodecyl, Tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, allyl, benzyl, triphenyl Base, phenyl, benzyl, methylbenzyl, nitrobenzyl, tert-butylthio, benzylthio, 2-pyridylthio, acetyl, benzoyl, methoxycarbonyl, ethoxy Carbocarbonyl, tert-butyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, methylthiocarbonyl, ethylthiocarbonyl, tert-butylthiocarbonyl, phenylthiocarbonyl, benzylthiocarbonyl, 2-pyridine Carbocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, tert-butylaminocarbonyl, benzylaminocarbonyl, ethylthiocarbonyl, phenylmethylthiocarbonyl, methoxythiocarbonyl, ethoxythiocarbonyl , tert-Butyloxythiocarbonyl, phenoxythiocarbonyl, benzyloxythiocarbonyl, methylthiocarbonylcarbonyl, ethylthiothiocarbonyl, tert-butylthiothiocarbonyl, phenylsulfonate Thiocarbonyl group, a benzyl group a thiocarbonyl group, a thiocarbonyl group methylamino, ethylamino thiocarbonyl group, tert-butylamino thiocarbonyl, benzylamino thiocarbonyl group, C _1-10 halogenated hydrocarbon group, a trifluoromethyl Any of a group of acetyl, halophenyl, halobenzyl, nitrophenyl, nitrobenzyl, or the like, or a substituted form of any of the groups. Among them, the substituted atom or the substituent is preferably a fluorine atom, an alkoxy group or a nitro group.

More preferably, LG ₂ is tert-butyl, benzyl, trityl, phenyl, benzyl, methylbenzyl, tert-butylthio, benzylthio, 2-pyridylthio, 2-pyridyl Carbonyl, tert-butyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, tert-butyloxythiocarbonyl, phenoxythiocarbonyl, benzyloxythiocarbonyl, tert-butylthiothiocarbonyl Any one of a phenylthiothiocarbonyl group, a benzylthiothiocarbonyl group, a trifluoroacetyl group, and the like.

More preferably, LG ₂ is a t-butyl group, a benzyl group, a trityl group, a phenyl group, a benzyl group, a methylbenzyl group, a t-butylthio group, a benzylthio group or a 2-pyridylthio group. Group.

Most preferably LG _{2 is a} methyl group, an ethyl group, an allyl group or a benzyl group.

Wherein Q ₃ is a H atom or a group which contributes to the induction and conjugation effect of an unsaturated bond electron;

Q _{3 is} selected from all but substituted atoms and combinations of substituents including, but not limited to, the terminology, as long as it contributes to the induction and conjugation effects of the unsaturated bond electrons.

Q ₃ may contain carbon atoms or no atoms. When a carbon atom is not contained, it may be, for example, a nitro group. When the carbon atom is contained, the number of carbon atoms is not particularly limited, but is preferably 1 to 20 carbon atoms, and more preferably 1 to 10 carbon atoms.

The structure of Q ₃ is not particularly limited and includes, but is not limited to, a linear structure, a branched structure containing a side group, or a cyclic structure. The cyclic structure is not particularly limited and includes, but is not limited to, any of the cyclic structures recited in the terminology.

Q ₃ may be selected from any one of a hydrogen atom, a halogen atom, a carbon-free substituent, a hydrocarbon group, a heteroalkyl group, a substituted hydrocarbon group or a substituted heteroalkyl group. Wherein the substituted hetero atom or substituent in Q ₃ is not particularly limited, and includes but is not limited to any substituted hetero atom or any substituent listed in the terminology, and is selected from a halogen atom, a hydrocarbyl substituent, and a hetero atom-containing substituent. Any of them.

More preferably, Q ₃ is a hydrogen atom, a halogen atom, a C _1-20 alkyl group, a C _2-20 alkenyl group, a C _3-20 open chain olefin group, a C _3-20 cycloalkene group, an aryl group, an aromatic hydrocarbon group, C _{1 . -20} heteroalkyl, heteroaryl, heteroarylalkyl, C _1-20 alkoxy, aryloxy, arylalkyloxy, C _1-20 heteroalkyloxy, heteroaryloxy, hetero Any one or a group of an aromatic hydrocarbonoxy group, a C _1-20 heteroalkylthio group, a heteroarylthio group, a heteroarylalkylthio group, a C _1-20 haloalkyl group, or the like, or a group of any one of Replaced form.

More preferably, Q ₃ is a hydrogen atom, a halogen atom, a C _1-10 haloalkyl group, a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _3-10 open chain olefin group, a C _3-10 cycloalkene group, and an aromatic group. a base, an aromatic hydrocarbon group, a C _1-10 heteroalkyl group, a heteroaryl group, a heteroarylalkyl group, a C _1-10 alkoxy group, an aryloxy group, an aromatic hydrocarbonoxy group, a C _1-10 heteroalkyloxy group, Any one or a group of a heteroaryloxy group, a heteroarylalkyloxy group, or the like, or a substituted form of any one of the groups.

Specifically, Q ₃ may be selected from a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, and a 2- Ethylhexyl, decyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, N-nonyl, eicosyl, vinyl, propenyl, allyl, propynyl, propargyl, cyclopropyl, cyclopropenyl, phenyl, benzyl, butylphenyl, p-methyl Phenyl, nitrophenyl, p-methoxyphenyl, azaphenyl, methoxy, ethoxy, phenoxy, benzyloxy, methylthio, ethylthio, phenylthio, benzyl sulfide Any one or a group of a C _1-20 haloalkyl group, or a substituted form of any of the groups. Among them, butyl includes, but not limited to, n-butyl group and tert-butyl group. Octyl groups include, but are not limited to, n-octyl, 2-ethylhexyl. Here, the substituted atom or the substituent is selected from any one of a halogen atom, a hydrocarbon group substituent, and a hetero atom-containing substituent, and is preferably a halogen atom, an alkoxy group, an alkenyl group or a nitro group.

Q ₃ is preferably a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a decyl group or a fluorenyl group. Base, vinyl, propenyl, allyl, propynyl, propargyl, cyclopropyl, cyclopropenyl, phenyl, benzyl, butylphenyl, p-methylphenyl, p-nitrophenyl , o-nitrophenyl, p-methoxyphenyl, pyridyl, methoxy, ethoxy, phenoxy, benzyloxy, methylthio, ethylthio, phenylthio, benzylthio, tri Any atom or group of fluoromethyl, 2,2,2-trifluoroethyl, or the like, or a substituted form of any of the groups. Among them, the substituted atom or the substituent is preferably a fluorine atom, an alkoxy group, an alkenyl group or a nitro group.

More preferably, Q ₃ is any atom or group of a hydrogen atom, a methyl group, a trifluoromethyl group, a phenyl group, a p-nitrophenyl group, an o-nitrophenyl group, a pyridyl group or the like.

More preferably, Q ₃ is a hydrogen atom, a methyl group, a phenyl group, a pyridyl group, a diazaphenyl group or a triazaphenyl group.

More preferably, Q ₃ is a hydrogen atom, a methyl group, a phenyl group or a pyridyl group.

Q _{3 is} most preferably a hydrogen atom, a phenyl group or a pyridyl group.

Wherein Q _{5 is} selected from a hydrogen atom, a substituted atom or a substituent, and is not particularly limited, and is preferably selected from a H atom, a methyl group, an ethyl group or a propyl group. When Q ₅ is on the ring, it may be one or more. When it is more than one, it may be the same structure, or a combination of two or more different structures. The ring in which Q ₅ is present includes but is limited to hydrazine, carbazole, norbornene, 7-oxa-bicyclo[2.2.1]hept-5-en-2-yl.

Wherein Q ₆ is a hydrogen atom or a methyl group. Q ₇ is a hydrogen atom, a methyl group, a phenyl group or a substituted phenyl group. The substituted phenyl group, such as p-methoxyphenyl. In the same molecule, Q ₆ and Q ₇ may be the same or different.

Here, Q ₈ is a substituted atom or a substituent on the imidazole group, and is not particularly limited, and is preferably a hydrogen atom, a methyl group, a methyl group, a propyl group, a butyl group or a phenyl group. When Q ₈ can be one or more. When it is more than one, it may be the same structure, or a combination of two or more different structures.

Wherein Q ₁₁ is a substituent on the nitrogen atom of the tetrazole, preferably a phenyl group, a substituted phenyl group or an azaphenyl group.

Wherein, PG ₂ is a thiol protecting group, and the structure after sulfhydryl protection is represented by SPG ₂ .

Wherein PG ₃ is an alkynyl protecting group.

Wherein, PG ₄ is a hydroxy protecting group, and the structure in which the hydroxy group is protected is represented by OPG ₄ .

Wherein, PG ₅ is an amino-protecting group, and the structure in which the amino group is protected is represented by NPG ₅ .

Wherein PG ₆ is a bishydroxy protecting group, and PG ₆ and two oxygen atoms constitute a five-membered or six-membered ring acetal structure. PG _{6 is} selected from a methylene group or a substituted methylene group. The substituent of PG ₆ is a hydrocarbyl substituent or a hetero atom-containing substituent including, but not limited to, the following groups: methylene, 1-methylmethylene, 1,1-dimethylmethylene, 1,1-cyclopentylene group, 1,1-cyclohexylene group, 1-phenylmethylene group, 3,4-dimethylphenylmethylene group and the like.

Wherein PG ₈ is a protected group of orthocarbonic acid or orthosilicate, D8 is a protected form of ortho acid, and H5 is a protected form of ortho silicic acid. PG ₈ can be a single trivalent end group such as

Take D8 as an example, corresponding to

PG ₈ can also be two or three independent end groups, and correspondingly, D8 corresponds to

H5 corresponds to

The PG ₂ is a thiol protecting group, and is not particularly limited. SPG ₂ is a structure in which a mercapto group is protected, and is not limited to a specific structure, and is preferably a structure such as a sulfide, a disulfide, a silyl sulfide, or a thioester, including but not limited to the following structures: methyl sulfide, ethyl sulfur Ether, propyl sulfide, tert-butyl sulfide, butyl sulfide, isobutyl sulfide, benzyl sulfide, p-methoxybenzyl sulfide, o-hydroxybenzyl sulfide, p-hydroxybenzyl sulfide Ether, o-acetoxybenzyl sulfide, p-acetoxybenzyl sulfide, p-nitrobenzyl sulfide, 2,4,6-trimethylbenzyl sulfide, 2,4,6-trimethoxy Base benzyl sulfide, 4-pyridine methyl sulfide, 2-quinoline methyl sulfide, 2-pyridine N-oxide methyl sulfide, 9-fluorene methyl sulfide, 9-fluorene methyl sulfide , S-ferrocenylmethyl ether, diphenylmethyl sulfide, trityl sulfide, bis(4-methoxyphenyl)methyl sulfide, bis(4-methoxyphenyl) Benzyl sulfide, 5-dibenzocycloheptyl sulfide, diphenyl-4-pyridylmethyl sulfide, 2,4-dinitrophenyl sulfide, 1-adamantyl sulfide, A Oxymethyl sulfide, isobutoxymethyl sulfide, benzyloxymethyl sulfide, 2-tetrahydrofuryl sulfide, benzylthiomethyl Ether, phenylthiomethyl sulfide, tetrahydrothiazole sulfide, acetamidomethyl sulfide, trimethylacetamidomethyl sulfide, benzamide methyl sulfide, allyloxycarbonylamino Thioether, phenylacetamidomethyl sulfide, phthalimidomethyl sulfide, acetyl methyl sulfide, (2-nitrophenyl) ethyl sulfide, 2-( 2,4-Dinitrophenyl)ethyl sulfide, 2(4'-pyridyl)ethyl sulfide, 2-cyanoethyl sulfide, 2-(trimethylsilyl)ethyl sulfide , 2,2-bis(ethoxycarbonyl)ethyl sulfide, 2-benzenesulfonyl yl ethyl sulfide, 1-(4-methylphenylsulfonyl)-2-methyl-2-propyl sulfide Ether, acetyl thioester, benzoyl thioester, trifluoroacetyl thioester, N-[(p-biphenyl)isopropoxycarbonyl]-N-methyl-γ-aminothiobutyrate Acid ester, N-(tert-butoxycarbonyl)-N-methyl-γ-aminothiobutyrate, 2,2,2-trichloroethoxycarbonylthiocarbonate, tert-butoxycarbonylthiocarbonate Benzyloxycarbonylthiocarbonate, p-methoxybenzyloxycarbonylthiocarbonate, N-ethylcarbamate, N-methoxymethylcarbamate, ethyl disulfide, tert-butyl two Thioether, substituted phenyl disulfide, 2-pyridine disulfide.

The SPG ₂ is preferably tert-butyl sulfide, trityl sulfide, substituted trityl sulfide, tert-butyldimethylsilyl sulfide, triisopropylsilyl sulfide, benzyl sulfide Ether, substituted benzyl sulfide, p-nitrobenzyl sulfide, o-nitrobenzyl sulfide, acetyl thioester, benzoyl thioester, trifluoroacetyl thioester, tert-butyl Any of thioether, substituted phenyl disulfide, 2-pyridine disulfide, and the like.

The PG ₃ is an alkynyl protecting group, and is not particularly limited. PG _{3 is} not limited to a specific structure, and is preferably a silicon group including, but not limited to, the following structures: trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethyl (1,1,2- Trimethylpropyl)silyl, dimethyl[1,1-dimethyl-3-(tetrahydrofuran-2H-2-oxy)propyl]silyl, biphenyldimethylsilyl, triisopropyl A silyl group, a biphenyldiisopropylsilyl group, a tert-butyldiphenylsilyl group, a 2-(2-hydroxy)propyl group or the like.

The PG ₄ is a hydroxy protecting group, and is not particularly limited. Among them, PG ₄ may be a protective group of an alcoholic hydroxyl group or a phenolic hydroxyl group. OPG ₄ is a structure in which a hydroxyl group is protected, and is not limited to a specific structure, and is preferably an ether, a silyl ether, an ester, a carbonate, a sulfonate or the like, including but not limited to the following structures: methyl ether, methoxymethyl ether , methylthiomethyl ether, (phenyldimethylsilyl)methoxymethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, p-nitrobenzyloxy Methyl ether, o-nitrobenzyloxymethyl ether, (4-methoxybenzyloxy) methyl ether, o-methoxyphenol methyl ether, tert-butoxymethyl ether, 4-pentyl Alkenyloxymethyl ether, siloxymethyl ether, 2-methoxyethoxymethyl ether, 2,2,2-trichloroethoxymethyl ether, bis(2-chloroethoxy) Methyl ether, 2-(trimethylsilyl)ethoxymethyl ether,

Oxymethyl methyl ether, tetrahydropyranyl ether, 3-bromotetrahydropyranyl ether, 1-methoxycyclohexyl ether, 4-methoxytetrahydropyran cyclohexyl ether, 4-methoxy Tetrahydrothiopyranyl ether, S,S-dioxy-4-methoxy-tetrahydrothiopyranyl ether, 1-[(2-chloro-4-methyl)phenyl]-4-methoxyphene Pyridin-4-yl ether, 1-(2-fluorophenyl)-4-methoxypiperidin-4-yl ether, 1,4-dioxan-2-yl ether, tetrahydrofuranyl ether, tetrahydrothiophene Ether, ethoxy ether, 1-ethoxyethyl ether, 1-(2-chloroethoxy)ethyl ether, 1-[2-(trimethylsilyl)ethoxy]ethyl ether, 1 -methyl-1-methylethyl ether, 1-methyl-1-benzylethyl ether, 1-methyl-1-benzyl-2-fluoroethyl ether, 1-methyl-1-benzene Oxyethyl ether, 2,2,2-trichloroethyl ether, 1,1-dimethoxyphenyl-2,2,2-trichloroethyl ether, 1,1,1,3,3, 3-hexafluoro-2-phenylisopropyl ether, 2-trimethylsilyl ethyl ether, 2-(benzyl sulfide) ethyl ether, 2-phenylselenethyl ether, tert-butyl ether, allyl ether , propargyl ether, p-chlorophenyl ether, p-methoxyphenyl ether, p-nitrophenyl ether, 2,4-dinitrophenyl ether, 2,3,5,6-tetrafluoro-4 -(trifluoromethyl)phenyl ether, benzyl Ether, p-methoxybenzyl ether, 3,4-dimethoxybenzyl ether, o-nitrobenzyl ether, p-nitrobenzyl ether, p-bromobenzyl ether, p-chlorobenzyl ether, 2,6-dichlorobenzyl ether, p-cyanobenzyl ether, p-phenylbenzyl ether, 2,6-difluorobenzyl ether, p-acetamide benzyl ether, p-azidobenzyl ether, 2 -trifluoromethylbenzyl ether, p-(methylsulfinyl)benzyl ether, 2-pyridylmethyl ether, 4-pyridylmethyl ether, 3-methyl-2-pyridylmethyl-N-oxide Ether, 2-quinolinyl methyl ether, 1-mercaptomethyl ether, benzhydryl ether, di(p-nitrophenyl)methyl ether, 5-dibenzocycloheptyl ether, triphenyl Ether, α-naphthyldiphenylmethyl ether, p-methoxyphenyl diphenyl methyl ether, di(p-nitrophenyl)methyl ether, tris(p-methoxyphenyl)methyl ether , 4-(4'-bromophenoxy)phenyl diphenyl methyl ether, 4-(4'-bromophenoxy)phenyl diphenyl methyl ether, 4,4'4"- Tris(4,5-dichlorophthalimidophenyl)methyl ether, 4,4'4"-tris(levulinic acid phenyl)methyl ether, 4,4'4"-tris (benzoic acid) Acylphenyl)methyl ether, 4,4'-(dimethoxy-3"-N-imidazolidinylmethyl)trityl ether 4,4'-(Dimethoxy-3"-[N-(imidazolidinyl)carbamoyl]trityl ether, 1,1'-bis(4-methoxyphenyl)-1'- Methyl ether, 4-(17-tetrabenzo[a,c,g,i]fluorenylmethyl)-4,4'-dimethoxytrityl ether, 9-mercaptoether, 9- (9-phenyl-10 oxo)nonyl ether, 1,3-benzodithiolan-2-yl ether, benzisothiazolyl-S,S-dioxane, trimethyl Silyl ether, triethylsilyl ether, triisopropylsilyl ether, dimethyl isopropyl silyl ether, diethyl isopropyl silyl ether, 1,1,2-trimethylpropyl Dimethylsilyl ether, tert-butyldimethylsilyl ether, tert-butyldiphenylsilyl ether, tribenzylsilyl ether, tri-p-methylbenzylsilyl ether, triphenylsilyl ether, Diphenylmethylsilyl ether, di-tert-butylmethylsilyl ether, tris(trimethylsilyl)silyl ether, 2-hydroxystyryl-dimethylsilyl ether, 2-hydroxystyryl- Diisopropylsilyl ether, tert-butylmethoxyphenyl silicon ether, tert-butoxy diphenyl silicon ether, formate, benzoylformate, acetate, chloroacetate, two Chloroacetate, trichloroacetate, trifluoroacetate, methoxy Acid ester, triphenylmethoxyacetate, phenolic oxyacetate, p-chlorophenoxyacetate, phenylacetate, diphenylacetate, nicotine, 3-phenylpropionate, 4- Pentenoate, 4-acetylpropionate, 4,4-(ethylenedidecyl)valerate, 5-[3-bis(4-methoxyphenyl)hydroxymethylphenol] levulinate, Pivalate, 1-adamantate, crotonate, 4-methoxy crotonate, benzoate, p-phenyl benzoate, 2,4,6-trimethylphenyl Benzoate, alkyl methyl carbonate, methoxymethyl carbonate, 9-methyl ester carbonate, alkyl ethyl carbonate, 2,2,2-trichloroethyl carbonate, 1,1 - dimethyl-2,2,2-trichloroethyl carbonate, 2-(trimethylsilyl)ethyl carbonate, 2-(phenylsulfonyl)ethyl carbonate, 2-(triphenylphosphine) Ethyl carbonate, isobutyl ester carbonate, vinyl ester carbonate, allyl carbonate, p-nitrophenyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate Ester, o-nitrobenzyl ester carbonate, p-benzyl benzyl carbonate, 2-dansyl ethyl carbonate, 2-(4-nitrophenyl)ethyl carbonate, 2-(2,4-dinitrate base Ethyl carbonate, 2-cyano-1-phenylethyl carbonate, S-benzyl thioester carbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate , 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylvalerate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate , 2-(methylthiomethoxy)ethyl carbonate, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2-( Chloroacyloxymethyl)benzoate, 2-[2-(chloroacetoxy)ethyl]benzoate, 2-[2-(benzyloxy)ethyl]benzoate, 2-[2-(4-Methoxybenzyloxy)ethyl]benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-( 1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate , isobutyrate, succinic acid monoester, (E)-2-methyl-2-butenoate, crotonate, o-(methoxycarbonyl)benzoate, benzoate, alpha -naphthoate, nitrate, N,N,N',N'-tetramethylphosphoryl diamine, 2-chlorobenzoate, 4-bromobenzoate, 4-nitrobenzoic acid Ester, 3'-5'-dimethoxybenzoin carbonate, N-phenylcarbamate, borate, dimethyl thiophosphonate, 2,4-dinitrobenzene sulfinate, sulfate, Allyl sulfonate, mesylate, benzyl sulfonate, p-methylsulfonate, 2-(4-nitrophenylethyl) sulfonate.

The OPG ₄ is preferably methyl ether, 1-ethoxyethyl ether, tert-butyl ether, allyl ether, benzyl ether, p-methoxybenzyl ether, o-nitrobenzyl ether, p-nitro Benzyl ether, 2-trifluoromethylbenzyl ether, methoxymethyl ether, 2-methoxyethoxymethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, Methylthiomethyl ether, tetrahydropyranyl ether, trimethylsilyl ether, triethylsilyl ether, triisopropylsilyl ether, tert-butyldimethylsilyl ether, acetate, chlorine Any of acetate, trifluoroacetate, carbonate, and the like.

The PG ₅ is an amino-protecting group, and is not particularly limited. PG ₅ may be a protecting group such as a primary amine, a secondary amine, or a hydrazine. NPG ₅ is a structure in which an amino group is protected, and is not limited to a specific structure, and is preferably a carbamate, an amide, an imide, an N-alkylamine, an N-arylamine, an imine, an enamine, an imidazole, a pyrrole, or an anthracene.哚 and other structures, including but not limited to the following structures: methyl carbamate, urethane, 9-methyl carbamic acid methyl ester, 9-(2-thio) fluorene carbamate, 9-(2) carbamic acid ,7-dibromo)methyl ester, 17-tetrabenzo[a,c,g,i]methyl carbamate, 2-chloro-3-indolyl carbamate, 1,1-dicarbamic acid Oxobenzo[b]thiophene-2-methyl ester, 2,2,2-trichloroethyl carbamate, 2-trimethylsilyl carbamate, 2-phenylethyl carbamate, carbamic acid 1, 1-Dimethyl-2-chloroethyl ester, 1,1-dimethyl-2-bromoethyl carbamate, 1,1-dimethyl-2-fluoroethyl carbamate, 1,1-carbamic acid Dimethyl-2,2-dibromoethyl ester, 1,1-dimethyl-2,2,2-trichloroethyl carbamate, 1-methyl-1-(4-biphenyl carbamic acid) 1-methylethyl ester, 1-(3,5-di-tert-butylphenyl)-1-methylethyl carbamate, 2-(2',4'-pyridyl)carbamic acid , 2,2-bis(4'-nitrophenyl)ethyl carbamate, N-(2-pivaloyl)-1,1-dimethylethyl carbamate, 2-[(2) Nitrophenyl)dithio]-1-phenylethyl ester, 2-(N,N-dicyclohexylcarbamido)ethyl carbamate, tert-butyl carbamate, 1-adamantyl carbamate, 2-adamantyl carbamate, vinyl carbamate, allyl carbamate, 1-isopropylallyl carbamate, cinnamyl carbamate, 4-nitrocinnamyl carbamate, carbamate 3 -(3'-pyridyl)allyl ester, 8-quinolinyl carbamate, N-hydroxypiperidinyl carbamate, methyl dithiocarbamate, ethyl dithiocarbamate, Tert-butyl dithiocarbamate, isopropyl dithiocarbamate, phenyl dithiocarbamate, benzyl carbamate, p-methoxybenzyl carbamate, carbamate Base benzyl ester, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinyl benzyl carbamate, carbamate 9- Mercapto methyl ester, ammonia Diphenylmethyl ester, 2-methylthioethyl carbamate, 2-methylsulfonyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, carbamic acid [2-(1,3) -dithiahexyl)]methyl ester, 4-methylthiophenyl carbamate, 2,4-dimethylthiophenyl carbamate, 2-phosphonyl carbamate, carbamic acid 1- Methyl-1-(triphenylphosphonium)ethyl ester, 1,1-dimethyl-2-cyanoethyl carbamate, 2-dansyl ethyl carbamate, 2-(4-nitro carbamate Phenyl)ethyl ester, 4-phenylacetoxybenzyl carbamate, 4-azidomethoxybenzyl carbamate, p-(dihydroxyboranyl)benzyl carbamate, 5-benzidine carbamate Methyl oxazole, methyl 2-(trifluoromethyl)-6-chromone, m-nitrophenyl carbamate, 3,5-dimethylbenzyl carbamate, 1-methyl carbamate 1-(3,5-Dimethoxyphenyl)ethyl ester, α-methylnitropiperonium carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitro carbamate Benzyl, o-nitrophenyl methyl carbamate, 2-(2-nitrophenyl)ethyl carbamate, 6-nitro-3 carbamate, 4-dimethoxybenzyl ester, 4-methoxybenzoylmethyl carbamate, 3',5'-dimethoxybenzoin, t-amyl carbamate, S-benzylthio Carbamate, butynyl carbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropyl methyl carbamate, carbamate Isopropyl methyl ester, 2,2-dimethoxycarbonyl vinyl carbamate, o-(N,N'-dimethylamido)propyl carbamate, 1,1-dimethylpropane carbamate Ester, bis(2-pyridyl)methyl carbamate, 2-furanmethyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate, isonicotinoyl carbamate, carbamic acid p-- Oxyphenylazo)benzyl ester, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropyl methyl carbamate, 1-methyl carbamate 1-(p-phenylazophenyl)ethyl ester, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4'-pyridyl)ethyl carbamate, carbamate Phenyl ester, p-phenylazobenzyl carbamate, 2,4,6-tri-tert-butylphenyl carbamate, 4-(trimethylammonium) benzyl carbamate, 2,4,6-trimethylbenzyl carbamate, formamide, acetamide, chloroacetamide, Trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropionamide, 4-pentenamide, 2-pyridine amide, 3-pyridine amide, benzamide, p-phenylbenzamide, o-nitro Phenylacetamide, o-nitrophenoxyacetamide, 3-o-nitrophenylpropionamide, 2-methyl-2-o-nitrophenoxypropionamide, 3-methyl-3-nitrobutanamide, O-nitrocinnamamide, o-nitrobenzamide, 2,2-dimethyl-3-(4-tert-butyl-2,6-dinitrophenyl)propanamide, o-benzoyloxy Benzoyl, (2-acetoxymethyl)benzoyl, 2-[(tert-butyldiphenylsilyloxy)methyl]benzoyl, 3-(2',3',5'-trimethyl-3',6'-dioxo-1',4'-cyclohexadienyl)-3,3-dimethylpropanamide; o-hydroxy-trans-cinnamamide, 2-methyl- 2-o-phenylazophenoxypropionamide, 4-chlorobutyramide, acetoacetamide, 3-p-hydroxyphenylpropionamide, (N'-dithiobenzyloxycarbonylamino)acetamide, phthalic acid Imide, Tetrachlorophthalimide, 4-nitrophthalimide, dithiosuccinimide, 2,3-diphenyl maleimide, 2,5- Dimethylpyrrole, 2,5-bis(triisopropylsilyloxy)pyrrole, 1,1,4,4-tetramethyldimethylazepine, 1,1,3,3 -tetramethyl-1,3-disilaisoindoline, 5-substituted-1,3-dimethyl-1,3,5-triazacyclo-2-one, 5-substituted- 1,3-Dibenzyl-1,3,5-triazacyclopentan-2-one, 1-substituted-3,5-dinitro-4-pyridone, 1,3,5-dioxo Azacyclohexane, methylamino, tert-butylamino, allylamino, [2-(trimethylsilyl)ethoxy]methylamino, 3-acetoxypropylamino, cyanomethyl Amino, 1-isopropyl-4-nitro-2-oxo-3-pyrrolineamino, 2,4-dimethoxybenzylamino, 2-azanorborneneamino, 2,4-di Nitrophenylamino, quaternary ammonium, benzylamino, 4-methoxybenzylamino, 2,4-dimethoxybenzylamino, 2-hydroxybenzylamino, diphenylmethylamino, 2, 4-dimethoxybenzylamino, 2-hydroxybenzylamino, diphenylmethylamino, (4-methoxyphenyl)methylamino, 5-dibenzocycloheptylamino, triphenylmethylamino, (4-methoxyphenyl)diphenylmethylamino, 9-phenylindole Amino group, ferrocenylmethylamino group, 2-pyridylmethylamine-N'-oxide, 1,1-dimethylthiomethyleneamine, benzylimine, p-methoxybenzylimine, two Phenylmethyleneamine, [(2-pyridyl)trimethylphenyl]methyleneamine, N',N'-dimethylaminomethyleneamine, N',N'-dibenzylamino Methylamine, N'-tert-butylaminomethyleneamine, isopropylenediamine, p-nitrobenzylimine, salicylaldimine, 5-chlorosalicyl imine, (5-chloro-2-hydroxyphenyl) Benzimimine, cyclohexylimine, tert-butylmethyleneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-2,7-dichloro- 9-mercaptomethylamine, N-2-(4,4-dimethyl-2,6-dioxocyclohexylylene)ethylamine, N-4,4,4-trifluoro-3-oxo Generation of 1-butenamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrroline)amine.

After the amino protective structure NPG ₅ is preferably formamide, acetamide, trifluoroacetamide, carbamate, carbamic acid 2-iodo-ethyl carbamate, benzyl carbamate, 9-fluorenylmethyl ester, 2-trimethylsilylcarbamate, 2-methylsulfonylcarbamate, 2-(p-toluenesulfonyl)carbamate, phthalimide, diphenylmethyleneamine, 1 , 3,5-dioxane, methylamino, triphenylmethylamino, tert-butylamino, allylamino, benzylamino, 4-methoxybenzylamino, benzylimine Any of them.

1.1.3.3. Examples of functional groups - (Z ₁ ) _{q1 -} R ₀₁

Z ₁ is a divalent linking group, which is defined in detail later, and is not disclosed in detail here. As an example,

Including but not limited to any of the following categories A to J:

Class A:

Or class B:

Or class C:

Or class D:

Or class E:

Or class F:

Or class G:

Or class H:

Or class I:

Or class J:

Wait.

In the above class A to class J:

Wherein either E ₂ or E ₃ is

The other is OH;

Where Z ₃ is

Where Z ₄ is

Where Z ₅ is

Where Z ₆ is

Where q is 0 or 1.

Among them, Z ₂ is a divalent linking group which can be stably present or degradable, and is hereinafter defined in detail, and is not disclosed in detail herein.

Wherein M ₉ is O, S or NX ₁₀ .

Wherein Y ₁ , R ₁ , R ₂ , R ₃ , R ₄ , R ₂₁ , R ₇ , R ₁₈ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₂₄ , R ₂₇ , R ₃₀ , X ₄ , X ₅ , X ₆ , Q, Q ₃ , Q ₅ , Q ₆ , Q ₇ , Q ₁₁ , W, W ₂ , PG ₂ , PG ₃ , PG ₄ , PG ₅ , PG ₆ , PG ₈ , X ₁₀ , M ₁₉ , M ₂₀ , M ₂₁ , M ₂₂ , M, M ₅ , M ₆ , M ₈ and M ₅ , M ₆ , M ₈ are located in the same ring as the above definition, and will not be described again here.

Wherein M ₁₆ is C, N, P or Si.

Wherein Q ₉ and Q ₁₀ are each independently selected from the group consisting of hydrogen, C _1-20 alkyl, C _6-20 aryl, C _6-20 aromatic hydrocarbon, hybrid C _6-20 aryl, hybrid C _{6 -20} aromatic hydrocarbon group. In the same molecule, Q ₉ and Q ₁₀ may be the same or different from each other. Each of Q ₉ and Q _{10 is} independently preferably a hydrogen atom, a C _1-6 alkyl group, a phenyl group, a hybrid phenyl group or a substituted phenyl group.

Wherein X ₃ is a hydrocarbon group, a heteroalkyl group, a substituted hydrocarbon group or a substituted heteroalkyl group in the acyl group.

The number of carbon atoms of X ₃ is not particularly limited. The number of carbon atoms of X ₃ is preferably from 1 to 20, and more preferably from 1 to 10.

The structure of X ₃ is not particularly limited, and each independently includes, but is not limited to, a linear structure, a branched structure containing a side group, or a cyclic structure. The cyclic structure is not particularly limited and includes, but is not limited to, any of the cyclic structures recited in the terminology.

X _{3 is} selected from a C _1-20 hydrocarbyl group, a C _1-20 heterohydrocarbyl group, a substituted C _1-20 hydrocarbyl group or a substituted heterohydrocarbyl group. Wherein the substituted hetero atom or substituent in X ₃ is not particularly limited, and includes, but is not limited to, any substituted hetero atom or any substituent listed in the terminus, selected from a halogen atom, a hydrocarbyl substituent, a hetero atom-containing substituent. Any of them.

More preferably, X ₃ is a C _1-20 alkyl group, a C _1-20 unsaturated aliphatic hydrocarbon group, an aryl group, an aromatic hydrocarbon group, a C _1-20 heteroalkyl group, a C _1-20 hydrocarbyloxy group, an aryloxy group, an aromatic hydrocarbon group. Base, C _1-20 fatty hydrocarbonoxy, heteroaryloxy, heteroaryloxy, C _1-20 hydrocarbylthio, arylthio, arenethio, C _1-20 aliphatic hydrocarbyl sulfur Any of a heteroarylthio group, a heteroarylthio group, a C _1-20 hydrocarbylamino group, an arylamino group, an aromatic alkyl group, a C _1-20 alicyclic amino group, a heteroarylamino group, or a heteroarylamino group. a substituted group or a substituted form of any of the groups.

More preferably, X ₃ is C _1-20 alkyl, C _3-20 alkenyl, C _3-20 alkynyl, C _5-20 dienyl, C _3-20 alkene, C _3-20 alkyne, C _{5- 20} diolefin, aryl, aromatic hydrocarbon, C _3-20 aliphatic hydrocarbon, heteroaryl, heteroaryl, C _1-20 alkoxy, C _2-20 alkenyloxy, C _2-20 alkynyloxy , C _2-20 alkoxy, C _2-20 alkoxy, aryloxy, areneoxy, C _1-20 alkylthio, C _2-20 alkenethio, C _2-20 alkyne Any one of a thio group, an arylthio group, an aromatic thio group, a C _1-20 alkylamino group, a C _2-20 alkenylamino group, a C _2-20 alkylamino group, an arylamino group, an aromatic alkyl group or the like. A substituted form of a group or any group.

More preferably, X ₃ is C _1-20 alkyl, C _3-20 alkenyl, C _3-20 alkynyl, C _5-20 dienyl, C _3-20 alkene, C _3-20 alkyne, C _5- A substituted form of any one or any of the groups of ₂₀ diolefin, aryl, arene, C _3-20 aliphatic, heteroaryl, heteroaryl, and the like.

Specifically, as an example, X ₃ may be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, decyl, undecyl, and ten. Dialkyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, cyclopropyl, cyclohexyl , vinyl, propenyl, allyl, propynyl, propargyl, phenyl, benzyl, butylphenyl, p-methylphenyl, methoxy, ethoxy, phenoxy, benzyloxy A substituted form of any one of the group, methylthio group, ethylthio group, phenylthio group, benzylthio group, methylamino group, ethylamino group, benzylamino group, or the like, or a substituted group of any one of them. Among them, butyl includes, but not limited to, n-butyl group and tert-butyl group. Octyl groups include, but are not limited to, n-octyl, 2-ethylhexyl. Here, the substituted atom or the substituent is selected from any one of a halogen atom, a hydrocarbon group substituent, and a hetero atom-containing substituent, and is preferably a fluorine atom, an alkoxy group, an alkenyl group or a nitro group.

More preferably, X ₃ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, vinyl, allyl, phenyl, benzyl, butylphenyl, p-methylphenyl Any one of C _1-10 fluoroalkyl, nitrophenyl, vinylphenyl, methoxyphenyl, fluorophenyl, and the like.

X _{3 is} most preferably methyl, trifluoromethyl, 2,2,2-trifluoroethyl, p-methylphenyl or vinyl.

Wherein R ₂₀ is a pendant group of an amino acid and a derivative thereof, a protected form of a pendant group or a substituted form of a pendant group.

The amino acid derived from R ₂₀ is a derivative of an amino acid or an amino acid, and the amino acid is an L-form or a D-form.

By way of example, R ₂₀ is selected from any of the following including but not limited to any category of an amino acid side groups and derivatives thereof, the side groups are in protected form or in the form of side groups is substituted with:

Neutral amino acids and derivatives thereof: glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline, sarcosine;

A hydroxyl or sulfur containing amino acid and derivatives thereof: serine, threonine, cysteine, methionine, tyrosine, hydroxyproline;

Acidic amino acids and derivatives thereof: aspartic acid, glutamic acid, asparagine, glutamine;

Basic amino acids and derivatives thereof: lysine, arginine, histidine, tryptophan.

Wherein R ₂₅ and R ₂₆ are each independently a hydrogen atom or a methyl group.

Wherein R ₃₁ , R ₃₂ , R ₃₃ and R ₃₄ are each independently a hydrogen atom or a C _1-6 hydrocarbon group, and may be the same or different from each other in the same part. R ₃₁ , R ₃₂ , R ₃₃ and R ₃₄ are each independently preferably a hydrogen atom or a methyl group.

Z ₁ in the above example,

For example, R ₀₁ is NH ₂ and q ₁ =1, while the former Z ₁ is a methylene group and the latter Z ₁ is an ethylene group.

The portion in which Z ₂ is bonded to Z ₁ in the present invention is not particularly limited. The end of Z ₁ directly bonded to Z ₂ may be a hetero atom (such as -O-, -S-, -NH-, etc.), a substituted hetero atom (such as -N(LG ₅ )-, -S(=O). )-, -S(=O)-, -S(=O) ₂ -, -P(=O)-, etc., -CH ₂ -, -CH(LG ₅ )-, -CR ₂₂ -, carbonyl, Thiocarbonyl, -C(=NR ₇ )-, and the like. The definition of LG ₅ is consistent with the above, and will not be described here. Wherein R ₂₂ is a divalent linking group and forms a cyclic substituent, preferably a ring atom of from 3 to 8, more preferably a C _3-8 ring, more preferably a C _3-8 saturated ring. Taking g=0, and R _{01 is the} same as an example, for example, F ₁ and F ₂ are respectively succinimide propionate and succinimide acetate (corresponding to the class A1, R ₀₁ is a succinimide group, -(Z ₂ ) _q -(Z ₁ ) _q1 - 1,2-ethylene, methylene), propionaldehyde and butyraldehyde (corresponding to D5, R ₀₁ are both CHO, -(Z ₂ ) _q - (Z ₁ ) _q1 - 1,2-ethylene, 1,3-propylene), acetic acid and propionic acid (corresponding to D4, R ₀₁ is COOH, -(Z ₂ ) _q -(Z ₁ ) _{When q1} - methylene and 1,2-ethylene, respectively, q = q, q ₁ = 1, Z ₂ are absent, have different Z ₁ , or take q = 1, q ₁ = 0 Z ₁ is absent and has a different Z ₂ .

1.1.4. Divalent linkage

In the general formulae (1) to (6), L ₀ , L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ in D ₁ , D ₂ , D ₃ , D ₄ , EF ₁ or EF ₂ , W ₀ , W ₀₁ , W ₀₂ , Z ₁ , and Z ₂ are all divalent linking groups, and are independent of each other, and may be the same or different in the same molecule. Wherein L ₀ , Z ₁ , and Z ₂ are groups in D ₁ , D ₂ , D ₃ , D ₄ , EF ₁ or EF ₂ , and L _{0 is taken} as an example, and may be represented as L ₀ (D ₁ ), L ₀ (D ₂ ), L ₀ (D ₃ ), L ₀ (D ₄ ), L ₀ (EF ₁ ), L ₀ (EF ₂ ), and the like.

The structures of L ₀ , L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ , W ₀ , W ₀₁ , W ₀₂ , Z ₁ , Z ₂ are not particularly limited, and each independently includes, but is not limited to, a linear chain. Structure, branched structure or ring-containing structure.

The number of non-hydrogen atoms of L ₀ , L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ , W ₀ , W ₀₁ , W ₀₂ , Z ₁ , and Z ₂ is not particularly limited, and each is preferably 1 to 1 independently. 50 non-hydrogen atoms; more preferably 1 to 20 non-hydrogen atoms; more preferably 1 to 10 non-hydrogen atoms. The non-hydrogen atom is a carbon atom or a hetero atom. The heteroatoms include, but are not limited to, O, S, N, P, Si, B, and the like. When the number of non-hydrogen atoms is 1, the non-hydrogen atom may be a carbon atom or a hetero atom. When the number of non-hydrogen atoms is more than 1, the type of the non-hydrogen atom is not particularly limited, and may be one type or two or more types. When the number of non-hydrogen atoms is more than 1, carbon atoms and carbon may be used. An atom, a carbon atom and a hetero atom, a hetero atom and a hetero atom are combined.

L ₀ , L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ , W ₀ , W ₀₁ , W ₀₂ , Z ₁ , Z ₂ each independently preferably have 1 to 50 non-hydrogen atoms; The non-hydrogen atom is C, O, S, N, P, Si or B; when the number of non-hydrogen atoms is more than 1, the type of the non-hydrogen atom is one type, or two types, or two or more types, and the non-hydrogen atom is A carbon atom is combined with a carbon atom, a carbon atom and a hetero atom, and a hetero atom or a hetero atom.

Any one or one of L ₀ , L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ , W ₀ , W ₀₁ , W ₀₂ , Z ₁ , Z ₂ and adjacent hetero atom groups The divalent linking group is a linker STAG or a degradable linker DEGG which is stable in existence. The conditions for the stable presence are not particularly limited, and include, but are not limited to, stable in light, heat, enzyme, redox, acid, alkaline, physiological conditions, in vitro simulated environment, etc., preferably in light, heat, enzyme It can be stably present under conditions such as redox, acidity and alkalinity. The conditions for the degradation are not particularly limited, and include, but are not limited to, degradation under conditions of light, heat, enzyme, redox, acid, alkaline, physiological conditions, in vitro simulated environment, etc., preferably in light, heat, enzyme, oxidation. It can be degraded under conditions of reduction, acidity and alkalinity.

₀ , ₁ , ₂ , ₂ or more of L ₀ , L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ , W ₀ , W ₀₁ , W ₀₂ , Z ₁ , Z ₂ a valency linker or a divalent linker of the divalent linker to an adjacent heteroatom group is a stable linker STAG, and the remaining divalent linker or the divalent linker and an adjacent heteroatom group The divalent linking group is a linking group DEGG which is a degradable linker.

By way of example, adjacent hetero atom groups such as oxy, thio, -NX ₁₀ -, carbonyl, thiocarbonyl, -C(=NX ₁₀ )-, -C(=NH ₂ ⁺ )-, -S(= O)-, -S(=O) ₂ -, -P(=O)-, -Si(R ₃₇ ) ₂ -, -C(=O)-M ₉ -, -M ₉ -C(=O) -, - C (= S) -M 9 -, - M 9 -C (= S) -, - C (= NX 10) -M 9 -, - M 9 -C (= NX 10) -, - C (=NH ₂ ⁺ ))-M ₉ -, -M ₉ -C(=NH ₂ ⁺ ))- and the like. The definitions of M ₉ , X ₁₀ , and R ₃₇ are the same as those described above, and are not described herein again.

The U ₁ (O-) ₃ and U ₂ (O-) ₃ of the present invention preferably do not contain a -OCH ₂ CH ₂ O- unit.

The -O(L ₀ ) _g0 --, -O(Z ₂ ) _q -(Z ₁ ) _q1 -- of the present invention preferably does not contain an -OCH ₂ CH ₂ O- unit.

1.1.5. Degradability

The polyfunctionalized H-type polyethylene glycol derivative can be stably present or degradable. When degradable, the number of degradable sites in the same molecule may be one or more. According to the difference between the number of degradable sites and the position of degradable sites, including but not limited to the following situations:

(1) Degradation may occur at any of Z ₁ (F ₁ ) and Z ₂ (F ₁ ), and the remaining divalent link positions may be independently present or degradable independently; or Z ₁ (F ₂ ), Z Degradation may occur at any of ₂ (F ₂ ), and the remaining divalent link positions may be independently present or degradable independently;

(2) any one of Z ₁ (F ₁ ), Z ₂ (F ₁ ), and any one of Z ₁ (F ₂ ) and Z ₂ (F ₂ ), degradation may occur, and the remaining divalent linking groups may be The positions are each independently stable or degradable;

(3) Degradation may occur at any one of L ₀ (F ₁ ) and L ₀ (F ₂ ), and the remaining positions of the above-mentioned divalent linking groups may be stably present or degradable independently;

(4) Both L ₀ (F ₁ ) and L ₀ (F ₂ ) can be degraded, and the remaining divalent linking sites are independently stable or degradable;

(5) Degradation may occur at any of L ₅ and L ₆ , and the remaining positions of the above divalent linking groups may be stably present or degradable independently;

(6) Both L ₅ and L ₆ can be degraded, and the remaining divalent linking sites are independently stable or degradable;

(7) Degradation may occur at any of W ₀ , W ₀₁ , and W ₀₂ , and the remaining positions of the above-mentioned divalent linking groups may be independently present or degradable independently.

Regarding the position of degradability: (1) may be located at U ₀₁ , U ₀₂ , L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ , W ₀ , W ₀₁ , W ₀₂ , (L ₀ ) _g0 , In any of the degradable groups of G, (Z ₂ ) _q -L, (2) may also occur at the junction of any of the above groups with an adjacent group, but not for Z ₁ -R ₀₁ The degradability of the connection position is limited. In the first case, the degradable group contains a degradable divalent linking group such as an ester group or a carbonate group. For the second case, then U ₀₁ -L _i (i=1,2 or 5), U ₀₂ -L _i (i=3,4 or 6), L _i (i=1,2,3,4 Any one of 5or6)-O, O-(L ₀ ) _g0 , (L ₀ ) _g0 -G, GZ ₂ , and Z ₂ -Z ₁ may be independently degraded.

According to the difference in the number of degradable sites and the position of degradable sites in the polyfunctionalized H-type polyethylene glycol derivatives, the stability of the polymer and the releasability of the modified drug are important. (1) When degradation occurs between a functional group at the end of a polyethylene glycol chain and a polyethylene glycol chain, that is, the position of -(Z ₂ ) _q -L-, a drug molecule and a polyethylene glycol structure The detachment exposes the active site of the drug molecule to the maximum extent, and the drug molecule can be maximally close to the state before unmodification. (2) When degradation occurs at the position of the trivalent branching center, including U ₀₁ , U ₀₂ , L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ , U ₀₁ -L _i (i=1, 2 or 5), U ₀₂ -L _i (i=3,4 or 6), L _i (i=1,2,3,4,5 or6)-O in any position, at this time the drug can be connected to the poly The molecular weight of the diol is reduced, thereby reducing the encapsulation of the drug and increasing the efficacy.

Some typical degradation methods are as follows:

(a) g = 0 or 1, and degrading at the divalent junction between the trivalent core structure of the trivalent branched structure and the PEG branching chain, wherein U ₁ (O-) _{3 is} in U ₀₁ -L ₁ At least one of -O, U ₀₁ -L ₂ -O is degradable, and U ₂ (O-) ₃ is degradable at least one position of U ₀₂ -L ₃ -O in U ₀₂ -L ₄ -O;

(b) g = 0 or 1, and degradation occurs at the divalent junction between the trivalent core structure of the trivalent branched structure and the PEG backbone, wherein U ₁ (O-) _{3 is} in U ₀₁ -L ₅ The -O position is degradable and U ₂ (O-) ₃ is degradable at the U ₀₂ -L ₆ -O position;

(c) g = 0 or 1, the trivalent branched structure contains a cyclic trivalent core structure CC ₃ , and CC ₃ is degradable;

(d) g = 0 or 1, degradation occurs in LPEG, where m ₁ × j ≠ 0 or m ₁ + m ₃ ≠ 0, when m ₁ × j ≠ 0, degradable at -OW ₀ O- position When m ₁ +m ₃ ≠0, at least one of -OW ₀₁ O-, -OW ₀₂ O- is degradable;

(e) g = 0 or 1, degrading only at the position of -(Z ₂ ) _q -L-, the position comprising a linker formed with an adjacent group on the PEG side;

(f) g = 1, only the position (L0) _G0 of degradation, comprising (L0) within _g0, O- (L0) _g0 connection, (L0) _g0 -G connection;

(g) g = 1, degradation occurs only in G.

When F ₁ and F ₂ have the same R ₀₁ , three degradation modes of e, f, and g occur, and the degradation of the branched chains on both sides is the same. When U ₁ = U ₂ , if the degradation modes of a, b, and c occur, the degradability of the corresponding positions of the two branched center structures is the same.

When F ₁ and F ₂ have different R ₀₁ , the degradability of the two sides is independent, that is, the trivalent nuclear structure of the two branched central structures, the divalent connection between the trivalent nuclear structure and the PEG branching chain, and the third The divalent linkage between the valency core structure and the PEG backbone, and the degradability of (L ₀ ) _g0 -G-((Z ₂ ) _q -L) _k0 at the end of the PEG branch chain are independent and may be the same or different.

One or more types of degradation modes are allowed in the polyfunctional polyethylene glycol derivative. When there is more than one degradation mode, gradient degradation can occur, and the degradation kinetics of the modified product can be more flexibly controlled; for PEG-modified drugs, the pharmacokinetic control in the body is more flexible and fine. More able to meet the needs of complex therapeutic effects.

1.1.6. Description of stable and degradable groups

The stable linker STAG or the degradable linker DEGG in the present invention may be present in the above L ₀ , L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ , W ₀ , W ₀₁ , Any of divalent linking groups of W ₀₂ , Z ₁ , and Z ₂ , or a divalent linking group present in any of the divalent linking groups and adjacent hetero atomic groups, may also be present in any of the branching centers The structure U ₁ , U ₂ , U ₀₁ , U ₀₂ , the terminal branching structure G, or any divalent linking group formed by a polyvalent group and an adjacent group.

1.1.6.1. Stable bivalent linker STAG in the present invention

The conditions in which the STAG can be stably existed are not particularly limited, and can be stably present under any conditions including, but not limited to, light, heat, enzyme, redox, acidity, alkaline conditions, physiological conditions, in vitro simulated environment, and the like, preferably in light or heat. It can be stably present under any conditions such as enzyme, redox, acidity and alkalinity.

The type of STAG is not particularly limited, and includes but is not limited to an alkylene group, a divalent heteroalkyl group, a double bond, a triple bond, and a divalent two. Alkenyl, divalent cycloalkyl, divalent cycloalkenyl, divalent cycloalkenyl, divalent cycloalkynyl, aromatic, heterocyclic, heterocyclic, heterocyclic, heterocyclic, substituted Alkylene, substituted heteroalkyl, substituted divalent heteroalkyl, substituted double bond, substituted triple bond, substituted diene, substituted divalent cycloalkyl, substituted divalent cycloalkenyl, substituted Divalent cycloalkenyl group, substituted divalent cycloalkynyl group, substituted aromatic ring, substituted aliphatic heterocyclic ring, substituted hetero benzene ring, substituted aryl heterocyclic ring, substituted hetero fused heterocyclic ring, ether bond, sulfur Ether bond, urea bond, thiourea bond, carbamate group, thiocarbamate group, -P(=O)-, -P(=S)-, divalent silicon group without active hydrogen, a divalent linking group containing a boron atom, a secondary amino group, a tertiary amino group, a carbonyl group, a thiocarbonyl group, an amide group, a thioamide group, a sulfonamide group, an enamine group, a triazole, a 4,5-dihydroisoxazole A divalent linking group consisting of any one of amino acid and its derivative skeleton or of two or more kinds of atoms or groups.

Specifically, the STAG includes, but is not limited to, any one of the following structures or a combination of two or more of the following:

-L ₁₁ -, -(R ₅ ) _r1 -C(R ₈ )=C(R ₉ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -C≡C-(R ₆ ) _r2 -,

-(R ₅ ) _r1 -C(R ₈ )=C(R ₉ )-C(R ₁₀ )=C(R ₁₁ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -S-(R ₆ ) _r2 -,

-(R ₅ ) _r1 -N(R ₁₈ )-C(=O)-N(R ₁₉ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₁₈ )-C(=S) -N(R ₁₉ )-(R ₆ ) _r2 -,

-(R ₅ ) _r1 -N(R ₇ )-C(=O)-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -OC(=O)-N(R ₇ )-(R ₆ ) _r2 -,

-(R ₅ ) _r1 -N(R ₇ )-C(=S)-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -OC(=S)-N(R ₇ )-(R ₆ ) _r2 -,

-(R ₅ ) _r1 -N(R ₇ )-C(=O)-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -SC(=O)-N(R ₇ )-(R ₆ ) _r2 -,

-(R ₅ ) _r1 -N(R ₇ )-C(=S)-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -SC(=S)-N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-(R ₆ ) _r2 -,

-(R ₅ ) _r1 -C(=O)-(R ₆ ) _r2 -, -(R ₅ ) _r1 -C(=S)-(R ₆ ) _r2 -, -(R ₅ ) _r1 -P(= O)-(R ₆ ) _r2 -,

-(R ₅ ) _r1 -(R ₃₈ )P(=O)-(R ₆ ) _r2 -, -(R ₅ ) _r1 -(R ₃₈ O)P(=O)-(R ₆ ) _r2 -,- (R ₅ ) _r1 -P(=S)-(R ₆ ) _r2 -,

-(R ₅ ) _r1 -(R ₃₈ )P(=S)-(R ₆ ) _r2 -, -(R ₅ ) _r1 -(R ₃₈ O)P(=S)-(R ₆ ) _r2 -,- (R ₅ ) _r1 -C(=O)N(R ₇ )-(R ₆ ) _r2 -,

-(R ₅ ) _r1 -N(R ₇ )C(=O)-(R ₆ ) _r2 -, -(R ₅ ) _r1 -CH ₂ N(R ₇ )CH ₂ -(R ₆ ) _r2 -,- (R ₅ ) _r1 -NHCH ₂ -(R ₆ ) _r2 -,

-(R ₅ ) _r1 -CH ₂ NH-(R ₆ ) _r2 -, -(R ₅ ) _r1 -CH ₂ -N(R ₇ )-CH ₂ -(R ₆ ) _r2 -, -(R ₅ ) _r1 -C(R ₈ )=C(R ₉ )-(R ₆ ) _r2 -,

-(R ₅ ) _r1 -C≡C-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )C(=O)CH ₂ -S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -S-CH ₂ C(=O)N(R ₇ )-(R ₆ ) _r2 -,

-(R ₅ ) _r1 -S(=O) ₂ -(R ₆ ) _r2 -, -(R ₅ ) _r1 -S(=O)-(R ₆ ) _r2 -, -(R ₅ ) _r1 -(R ₈ ) C=C(NR ₇ R ₃₉ )-(R ₆ ) _r2 -,

-(R ₅ ) _r1 -(NR ₇ R ₃₉ )C=C(R ₈ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -M ₁₇ (R ₂₂ )-(R ₆ ) _r2 -,

a skeleton of an ω-aminocarboxylic acid, a divalent linking group containing at least one amino acid skeleton amino acid or an amino acid derivative of the aggregate SG. The ω-aminocarboxylic acid is preferably H ₂ N(CH ₂ ) _j1 COOH, wherein the integer j _{1 is} selected from 2 to 20, preferably 2 to 12, more preferably 2 to 6, most preferably 2.

Wherein r1 and r2 are each independently 0 or 1. Typically it is r1=0.

Wherein, the definitions of the rings in which R ₇ , R ₁₈ , R ₁₉ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , M ₅ , M ₆ and M ₅ and M ₆ are located are as described above, and are not described herein again. Among them, typical STAG examples include, but are not limited to, R ₁ is a hydrogen atom, a methyl group or an ethyl group; R ₃ is a methyl group, an ethyl group or a benzyl group; and R ₇ , R ₁₈ and R ₁₉ are each independently a methyl group. , ethyl, n-propyl, isopropyl, tert-butyl, pentyl, hexyl, allyl, benzyl, trityl, phenyl, benzyl, nitrobenzyl, p-methoxybenzyl Or a trifluoromethylbenzyl group; R ₈ , R ₉ , R ₁₀ and R ₁₁ are a hydrogen atom or a methyl group.

Wherein L ₁₁ is an alkylene group or a substituted alkylene group which is stable in existence. Wherein the substituted hetero atom or the substituent is not particularly limited, and includes, but is not limited to, any one of the substituted hetero atoms or any of the substituents listed in the term, and any one selected from the group consisting of a halogen atom, a hydrocarbon group substituent, and a hetero atom-containing substituent. .

The structure of L ₁₁ is not particularly limited and includes, but not limited to, a linear structure, a branched structure, or a cyclic structure.

The number of carbon atoms of L ₁₁ is not particularly limited, and is preferably 1 to 20 carbon atoms, more preferably 1 to 10 carbon atoms.

L ₁₁ is preferably a C _1-20 alkylene group or a substituted C _1-20 alkylene group which is stable in existence. The steadily present condition is not particularly limited, and is preferably stable under conditions of light, heat, enzyme, redox, acid, basic, physiological conditions, in vitro simulated environment, and the like.

More preferably, L ₁₁ is a C _1-20 alkylene group or a substituted C _1-20 alkylene group which is stably present under conditions of light, heat, enzyme, redox, acid, basic, physiological conditions, in vitro simulated environment and the like.

Taking an alkylene group having a cyclic structure as an example, L ₁₁ includes but is not limited to:

Taking methylene or substituted methylene as an example, the structure of L ₁₁ includes but is not limited to:

Wherein, the definitions of R ₃ , R ₇ , R ₁₈ , R ₁₉ , R ₁₉ , R ₂₃ , R ₂₁ , PG ₂ , and PG ₄ are the same as those described above, and are not described herein again.

Among them, as an example,

The structure includes but is not limited to: methylene,

More preferably, L ₁₁ is methylene, 1,1-ethylene, 1,2-ethylene, 1,3-propylene, 1,2-propylene, isopropylidene, butylene, or Pentyl, hexylene, heptylene, octylene, fluorenylene, fluorenylene, undecylene, dodecylene, tridecylene, tetradecyl, heptadecane , hexadecyl, heptadecyl, octadecyl, undecylene, decylene, cyclopropylene, cyclopentylene, cyclohexylene, cyclohexene a substituted alkylene group, a cyclooctylene group, a cyclopentylene group, a p-phenylene group, an phenylene group, an isophenylene group, a benzylidene group, or a substituted form of any one, or any two or two thereof A combination of the above alkylene groups or substituted alkylene groups. Among them, the substituent is preferably any one of a C _1-6 alkyl group, a phenyl group, a benzyl group, a methylphenyl group, and a butylphenyl group.

Wherein X ₇ and X _{8 are} present in the same molecule, each independently linking an oxy or a thio group, any of which is R ₃ and the other is X ₄ when attached to the oxy group, and when attached to the thio group X ₅ . The definitions of R ₃ , X ₄ , and X ₅ are consistent with the above, and are not described herein again.

Wherein R ₁₃ and R ₁₄ are each independently a hydrogen atom, a hetero atom or a substituent on a secondary or tertiary carbon.

The hetero atom and the substituent in R ₁₃ and R ₁₄ are not particularly limited.

The number of carbon atoms of R ₁₃ and R ₁₄ is not particularly limited. The aliphatic hydrocarbon group or the aliphatic hydrocarbon group is preferably independently independently a carbon number of from 1 to 20, more preferably from 1 to 10. The number of carbon atoms of the aryl group, the aromatic hydrocarbon group, the heteroaryl group, the heteroaryl hydrocarbon group and the fused heterocyclic hydrocarbon group is not particularly limited.

R ₁₃ and R ₁₄ are each independently selected from, but not limited to, a hydrogen atom, a halogen atom, a C _1-20 hydrocarbon group, a C _1-20 heteroalkyl group, a substituted C _1-20 hydrocarbon group, a substituted C _1-20 heteroalkyl group, and the like. An atom or group of any of them.

The substituent atom or the substituent is not particularly limited and includes, but is not limited to, all of the substituent atoms and substituents recited in the terminology, and any one selected from the group consisting of a halogen atom, a hydrocarbon group substituent, and a hetero atom-containing substituent.

R ₁₃ and R ₁₄ are each independently preferably a hydrogen atom, a halogen atom, a C ₁₁₂₀ alkyl group, a C _3-20 unsaturated hydrocarbon group, a C _1-20 linear aliphatic hydrocarbon group, a C _3-20 branched aliphatic hydrocarbon group, or a C _3-20 group. Alicyclic hydrocarbon group, aryl group, aromatic hydrocarbon group, C _1-20 open chain heterohydrocarbyl group, C _3-20 aliphatic heterocycloalkyl group, heteroaryl group, heteroaryl hydrocarbon group, fused heterocyclic hydrocarbon group, C _1-20 hydrocarbyloxy group, C _1-20 hydrocarbylthio, C _1-20 hydrocarbylamino, C _1-20 aliphatic arenyl acyl, aryl acyl, aryl hydroacyl, C _1-20 alicyclic acyl, heteroaryl acyl, heteroaromatic acyl, C _1-20 hydrocarbyloxyacyl group, C _1-20 hydrocarbylthioacyl group, C _1-20 hydrocarbylaminoacyl group, C _1-20 hydrocarbyl acyloxy group, C _1-20 hydrocarbyl thiol group, C _1-20 hydrocarbyl acyl group Any atom or group of amino groups or the like, or a substituted form of any of the groups. Among them, the substituted atom and the substituent are preferably a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a C _1-6 alkyl group, a C _1-6 alkenyl group, an aryl group, an alkoxy group or a nitro group.

Wherein the acyl group is not particularly limited and includes, but is not limited to, any of the acyl groups listed in the terminology. Preferred are carbonyl, sulfonyl, sulfinyl, phosphoryl, phosphoryl, hypophosphoryl, nitroxyl, nitrosyl, thiocarbonyl, imidoyl, thiophosphoryl, dithiophosphoryl, tri A thiophosphoryl group, a thiophosphoryl group, a dithiophosphoryl group, a thiophosphoryl group, a thiophosphonyl group, a dithiophosphonyl group, a thiophosphinyl group, and the like. More preferably, any one of a carbonyl group, a thiocarbonoyl group, a sulfonyl group, and a sulfinyl group is used.

R ₁₃ and R ₁₄ are each independently more preferably a hydrogen atom, a halogen atom, a C _1-20 alkyl group, a C ₂₂₀ alkenyl group, a C _2-20 alkynyl group, a C _4-20 dienyl group, a C _3-20 alkene group, C _3-20 alkyne group, C _5-20 diolefin group, C _1-20 linear aliphatic hydrocarbon group, C _3-20 branched aliphatic hydrocarbon group, C _3-20 cycloalkyl group, C _3-20 cycloalkenyl group, C _3-20 cycloalkyne, C _{5-20 cyclodienyl} , phenyl, fused ring hydrocarbon, aromatic hydrocarbon, C _1-20 open chain heteroalkyl, C _3-10 aliphatic heterocycloalkyl, heteroaryl, heteroaromatic Base, aryl fused heterocycloalkyl, hetero fused heterocyclic hydrocarbon, C _1-20 alkoxy, C _2-20 alkenyloxy, C _2-20 alkynyloxy, aryloxy, aryloxyoxy, C _{1 -20} alkylthio, C _2-20 olefin thio, C _2-20 alkynylthio, arylalkylthio, C _1-20 alkylamino, C _2-20 alkenylamino, C _1-20 alkyl acyl , C _2-20 alkenyl group, C _2-20 alkynyl group, aryl acyl group, arylalkyl acyl group, C _1-20 alicyclic acyl group, heteroaryl acyl group, heteroaromatic acyl group, C _1-20 alkoxy group an acyl group, aryloxy group, C _1-20 alkylthio group, arylthio group, C _1-20 alkylamino group, C _1-20 acyloxy group, an acyl group, an aryl group C _1-20 alkyl thio group, aryl thio group, C _1-20 alkyl acylamino like any atom or group, or any of which groups are substituted form.

Specifically, R ₁₃ and R ₁₄ each independently may be selected from a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a butyl group, a pentyl group, and a hexyl group. , heptyl, octyl, decyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl Alkyl, nonadecyl, eicosyl, cyclopropyl, cyclohexyl, phenyl, benzyl, butylphenyl, p-methylphenyl, vinyl, propenyl, allyl, propynyl , propargyl, methoxy, ethoxy, phenoxy, benzyloxy, methylthio, ethylthio, phenylthio, benzylthio, methylamino, ethylamino, benzylamino, ethyl acyl, Phenyl, methoxy, ethoxy, phenoxy, benzyloxy, methylthio, ethylthio, phenylthio, benzylthio, methylthio, B Thioacyl, phenylthioacyl, benzylthioacyl, methylaminoacyl, ethylaminoacyl, phenylaminoacyl, benzylaminoacyl, ethylacyloxy, phenylacyloxy Ethyl thio group, phenyl thio group, ethyl group, phenyl amino group, C _1-20 haloalkyl, like any atom or group, or any of which groups are substituted form. Among them, butyl includes, but not limited to, n-butyl group and tert-butyl group. Octyl groups include, but are not limited to, n-octyl, 2-ethylhexyl. The acyl group is any of the above acyl groups. Wherein the substituted atom or the substituent is selected from a halogen atom, a hydrocarbon group substituent, and a hetero atom-containing substituent, and is preferably a halogen atom, a C _1-6 alkyl group, an alkoxy group, a C _1-6 alkenyl group, Any of the nitro groups.

R ₁₃ and R ₁₄ are each independently more preferably a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a butyl group, a pentyl group, a hexyl group or a heptyl group. , octyl, decyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, N-nonyl, eicosyl, cyclopropyl, cyclohexyl, phenyl, benzyl, butylphenyl, p-methylphenyl, vinylphenyl, vinyl, propenyl, allyl, propyl Alkynyl, propargyl, nitrophenyl, p-methoxyphenyl, methoxy, ethoxy, phenoxy, benzyloxy, methylthio, ethylthio, phenylthio, benzylthio , methylamino, ethylamino, benzylamino, acetyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, methylthiocarbonyl, ethylthiocarbonyl, phenylthio Carbonyl, benzylthiocarbonyl, methylthiocarbonyl, ethylthiocarbonyl, phenylthiocarbonyl, benzylthiocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, benzylaminocarbonyl Methoxysulfonyl, ethoxysulfonyl, phenoxysulfonyl, benzyloxysulfonyl, acetyloxy, benzoyloxy, acetylthio, benzoylthio, acetylamino, Benzoylamino, ethylthiocarbonyl, phenylthiocarbonyl, methoxythiocarbonyl, ethoxythiocarbonyl, phenoxythiocarbonyl, benzyloxythiocarbonyl, methylthiothio Carbonyl, ethylthiothiocarbonyl, phenylthiothiocarbonyl, benzylthiothiocarbonyl, methylthiocarbonylcarbonyl, ethylthiothiocarbonyl, phenylthiothiocarbonyl, benzylthiothiocarbonyl , methylaminothiocarbonyl, ethylaminothiocarbonyl, phenylaminothiocarbonyl, benzylaminothiocarbonyl, ethylthiocarbonyloxy, phenylthiocarbonyloxy, ethylthiocarbonyl Any one or a group of a thio group, a phenylthiocarbonylthio group, an ethylthiocarbonylamino group, a phenylthiocarbonylamino group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, or the like, Or a substituted form of any of the groups. Among them, butyl includes, but not limited to, n-butyl group and tert-butyl group. Octyl groups include, but are not limited to, n-octyl, 2-ethylhexyl.

R ₁₃ and R ₁₄ are each independently more preferably a hydrogen atom, a fluorine atom, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a decyl group or a fluorenyl group. , undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl , cyclopropyl, cyclohexyl, phenyl, benzyl, butylphenyl, p-methylphenyl, vinylphenyl, vinyl, propenyl, allyl, nitrophenyl, p-methoxybenzene Base, methoxy, ethoxy, phenoxy, benzyloxy, methylthio, ethylthio, phenylthio, benzylthio, methylamino, ethylamino, benzylamino, trifluoromethyl, 2, Any one or a group of 2,2-trifluoroethyl or the like, or a substituted form of any of the groups. Among them, the substituted atom or the substituent is preferably a fluorine atom, a C _1-6 alkyl group, an alkoxy group, a C _1-6 alkenyl group or a nitro group.

R ₁₃ and R ₁₄ are each independently more preferably a hydrogen atom, a fluorine atom, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a butyl group, a phenyl group, a benzyl group, a butylphenyl group or a p-methylphenyl group. Any one or a group of a trifluoromethyl group, a 2,2,2-trifluoroethyl group, or a substituted form of any one of them.

R ₁₃ and R ₁₄ are each independently most preferably a hydrogen atom or a methyl group.

By way of example, the structure of -NR ₇ - includes, but is not limited to, -NH-,

Wherein R ₅ and R ₆ are each independently a hydrocarbylene group or a substituted alkylene group which may be stably present; and in the same molecule, R ₅ and R ₆ may be the same as or different from each other. The conditions in which the stability can be present are not particularly limited.

The structures of R ₅ and R ₆ are not particularly limited, and each independently includes, but is not limited to, a linear structure, a branched structure, or a cyclic structure.

The number of carbon atoms of R ₅ and R ₆ is not particularly limited, and each independently is preferably 1 to 20 carbon atoms, more preferably 1 to 10 carbon atoms.

R ₅ and R ₆ may each independently be selected from any one of a C _1-20 alkylene group or a substituted C _1-20 alkylene group which may be stably present. The steadily present condition is not particularly limited, and is preferably stable under conditions of light, heat, enzyme, redox, acid, basic, physiological conditions, in vitro simulated environment, and the like.

R ₅ and R ₆ are each independently more preferably any one of a linear alkylene group, a branched alkylene group, a cycloalkyl group, a phenyl group, a fused aryl group, and an aralkyl group, or any one of them is C. _{A 1-6} alkyl, phenyl, benzyl, methylphenyl or butylphenyl substituted alkylene group.

R ₅ and R ₆ each independently preferably have 1 to 10 carbon atoms.

Specifically, by way of example, R ₅ and R ₆ may each independently be selected from the group consisting of, but not limited to, methylene, 1,1-ethylene, 1,2-ethylene, 1,3-propylene, 1,2-propylene, isopropylidene, butylene, pentylene, hexylene, heptylene, octylene, fluorenylene, fluorenylene, undecylene, dodecylene , tridecylene, tetradecylene, pentadecyl, hexadecyl, heptadecyl, octadecyl, undecylene, decylene, sub a substituted alkyl, a cyclohexylene group, a cyclohexylene group, a cyclopentylene group, a p-phenylene group, an o-phenylene group, an isophenylene group, a benzylidene group, or a substituted form of any one, or A combination of any two or more of an alkylene group or a substituted alkylene group. Wherein the substituent is selected from any one of a C _1-6 alkyl group, a phenyl group, a benzyl group, a methylphenyl group, and a butylphenyl group. Among them, the pentylene group includes, but is not limited to, 1,5-pentylene, 3,3-pentylene. among them. The heptylene group includes, but is not limited to, 1,7-heptylene, 1,1-diisopropylmethylene.

R ₅ and R ₆ are each independently more preferably methylene, 1,2-ethylene, 1,3-propylene, 1,2-propylene, isopropylidene, butylene, pentylene. , hexylene, 1,7-heptylene, 1,1-diisopropylmethylene, octylene, cyclopropylene, p-phenylene, o-phenylene, m-phenylene, benzylidene, 1 -benzylmethylene, 1-phenylmethylene and the like.

R ₅ and R ₆ are each independently most preferably methylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene, 1,5-pentylene, 1,6- Any of the sub-hexyl groups.

-M ₁₇ (R ₂₂ )- is a 1,1-cyclic divalent linking group, and the number of ring atoms is preferably from 3 to 8 (3, 4, 5, 6, 7, or 8).

Wherein M ₁₇ is a carbon atom or a hetero atom located on the ring. A carbon atom, a phosphorus atom or a silicon atom located on the ring is preferred.

-(R ₅ ) _r1 -M ₁₇ (R ₂₂ )-(R ₆ ) _r2 - can also be expressed as

among them,

a substituted form containing a ring structure of M _{17 in} a ring-forming atom and selected from any one or any one of a C _1-20 alicyclic ring, a C _1-20 alicyclic ring, and a C _1-20 fused heterocyclic ring. . Wherein the substituted hetero atom or the substituent is not particularly limited, and includes, but is not limited to, any one of the substituted hetero atoms or any of the substituents listed in the term, and any one selected from the group consisting of a halogen atom, a hydrocarbon group substituent, and a hetero atom-containing substituent. .

Wherein R ₂₂ is a divalent linking group and participates in ring formation.

The number of carbon atoms of R ₂₂ is not particularly limited, and is preferably from 1 to 20, and more preferably from 1 to 10.

The structure of R ₂₂ is not particularly limited and includes, but not limited to, a linear structure, a branched structure containing a side group, or a cyclic structure. The cyclic structure is not particularly limited and includes, but is not limited to, any of the cyclic structures recited in the terminology.

R ₂₂ may or may not contain a hetero atom.

R _{22 is} selected from the group consisting of a C _1-20 alkylene group, a C _1-20 divalent heteroalkyl group, a substituted C _1-20 alkylene group, a substituted C _1-20 divalent heteroalkyl group, or any two of the divalent linking groups. A divalent linking group formed by a combination of any three or three. The substituent atom or the substituent is not particularly limited and includes, but is not limited to, any of the substituted atoms or any substituents recited in the terminology, and any one selected from the group consisting of a halogen atom, a hydrocarbon group substituent, and a hetero atom-containing substituent.

More preferably, R ₂₂ is a C _1-20 open chain alkylene group, a C _1-20 open chain alkenylene group, a C _3-20 cycloalkylene group, a C _1-20 cycloalkylene group, an arylene group, C _{1- 20} divalent fatty alkyl, C _1-20 divalent heteroalkenyl, divalent heteroaryl, substituted alkylene, substituted C _1-20 open alkenylene, substituted C _1-20 Cycloalkyl, substituted C _1-20 cycloalkylene, substituted aralkyl, substituted C _1-20 divalent heteroalkyl, substituted C _1-20 divalent heteroalkenyl, substituted A divalent linking group formed by any one of divalent linking groups or a combination of two or any three of the divalent heteroaromatic hydrocarbon groups. Among them, the hetero atom is not particularly limited, and any of O, S, N, P, and Si is preferable.

R _{22 is} more preferably C _1-10 open chain alkylene, C _1-10 open alkenylene, C _3-10 cycloalkylene, C _1-10 cycloalkylene, arylene, C _{1- 10} divalent fatty alkyl, C _1-10 divalent heteroalkenyl, divalent heteroaryl, substituted alkylene, substituted C _1-10 open alkenylene, substituted C _1-10 Cycloalkyl, substituted C _1-10 cycloalkylene, substituted aralkyl, substituted C _1-10 divalent heteroalkyl, substituted C _1-10 divalent heteroalkenyl, substituted A divalent linking group formed by any one of divalent linking groups or a combination of two or any three of the divalent heteroaromatic hydrocarbon groups.

Specifically, R _{22 is} selected from the group consisting of methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, fluorenylene, fluorenylene, C _1-20 a substituted form of a valent oxaalkyl group, a C _1-20 divalent thiaalkyl group, a C _1-20 divalent azaalkyl group, a divalent aza heteroaryl group, or a group of any one Or a combination of any two or more than two identical or different groups or groups substituted forms. Here, the substituted atom or the substituent is selected from any one of a halogen atom, a hydrocarbon group substituent, and a hetero atom-containing substituent, and a halogen atom, an alkoxy group or a nitro group is preferable.

R ₂₂ is preferably 1,2-ethylene, 1,2-vinylidene or 1,3-propylene.

Wherein, as an example, when R ₂₂ is 1,2-ethylene, corresponding

Corresponding when R ₂₂ is 1,2-vinylidene

Wherein R ₃₈ is a hydrocarbon group, preferably a C _1-20 hydrocarbon group, more preferably a C _1-20 alkyl group, more preferably a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group or a hexyl group.

Wherein R ₃₉ is a hydrogen atom or a substituent to which a nitrogen atom is bonded, preferably a hydrogen atom or a C _1-20 hydrocarbon group, further preferably a hydrogen atom, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, an n-butyl group or a benzyl group. base. In the above -NR ₇ R ₃₉ , R ₇ and R ₃₉ may be the same or different. NR ₇ R ₃₉ is preferably NH ₂ , NHR ₃₉ or N(R ₃₉ ) ₂ .

Wherein, SG is a collection of amino acid skeletons; any one of amino acid skeletons in SG is derived from derivatives of amino acids or amino acids; and the amino acids are _L -form or _D -form. Wherein, SG is a collection of amino acid skeletons; any one of amino acid skeletons in SG is derived from derivatives of amino acids or amino acids; and the amino acids are _L -form or _D -form.

By way of example, any of the amino acid backbones in SG are derived from derivatives including, but not limited to, any one of the following classes of amino acids or any of the amino acids:

Neutral amino acids: glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline, sarcosine;

Amino acid having a hydroxyl group or sulfur: serine, threonine, cysteine, methionine, tyrosine, hydroxyproline;

Acidic amino acids: aspartic acid, glutamic acid, asparagine, glutamine;

Basic amino acids: lysine, arginine, histidine, tryptophan.

Wherein SG includes, but is not limited to, a collection of the following amino acid backbones:

Neutral amino acid skeleton:

-C(=O)-CH(R ₂₀ )-NH- or -NH-CH(R ₂₀ )-C(=O)-; wherein R ₂₀ is -H, -CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ -CH(CH ₃ ) ₂ or -CH(CH ₃ )-CH ₂ CH ₃ ;

Amino acid skeleton containing hydroxyl or sulfur:

-C(=O)-CH(R ₂₀ )-NH- or -NH-CH(R ₂₀ )-C(=O)-; wherein R ₂₀ is -CH ₂ -OH, -CH ₂ -OPG ₄ , -CH ₂ -OR ₃ , -CH(CH ₃ )-OH, -CH(CH ₃ )-OPG ₄ , -CH(CH ₃ )-OR ₃ , -CH ₂ -SH, -CH ₂ -SPG ₂ ,- CH ₂ -SR ₃ or -CH ₂ CH ₂ -S-CH ₃ ;

Acidic amino acid skeleton:

-C(=O)-CH ₂ -CH(COOH)-NH-, -NH-CH(COOH)-CH ₂ -C(=O)-, -C(=O)-CH ₂ -CH(COOR ₃ )-NH-, -NH-CH(COOR ₃ )-CH ₂ -C(=O)-, -C(=O)-CH ₂ -CH ₂ -CH(COOH)-NH-, -NH-CH( COOH)-CH ₂ -CH ₂ -C(=O)-, -C(=O)-CH ₂ -CH ₂ -CH(COOR ₃ )-NH-, -NH-CH(COOR ₃ )-CH ₂ - CH ₂ -C(=O)-, -NH-C(=O)-CH ₂ -CH(COOH)-NH-, -NH-CH(COOH)-CH ₂ -C(=O)-NH-, -NH-C(=O)-CH ₂ -CH(COOR ₃ )-NH-, -NH-CH(COOR ₃ )-CH ₂ -C(=O)-NH-, -NH-C(=O) -CH ₂ -CH ₂ -CH(COOH)-NH-, -NH-CH(COOH)-CH ₂ -CH ₂ -C(=O)-NH-, -NH-C(=O)-CH ₂ - CH ₂ -CH(COOR ₃ )-NH-, -NH-CH(COOR ₃ )-CH ₂ -CH ₂ -C(=O)-NH-, -C(=O)-CH(R ₂₀ )-NH - or -NH-CH(R ₂₀ )-C(=O)-; wherein R ₂₀ is -CH ₂ -COOH, -CH ₂ -C(=O)-OR ₃ , -CH ₂ -CH ₂ -C (=O)-OR ₃ , -CH ₂ -C(=O)-NH ₂ , -CH ₂ -CH ₂ -C(=O)-NH ₂ ;

Basic amino acid skeleton:

-C(=O)-CH(NH ₂ )-(CH ₂ ) ₄ -NH-, -NH-(CH ₂ ) ₄ -CH(NH ₂ )-C(=O)-, -C(=O) -CH(NH ₂ )-(CH ₂ ) ₃ -NH-C(=NH)-NH-, -NH-C(=NH)-NH-(CH ₂ ) ₃ -CH(NH ₂ )-C(= O)-, -C(=O)-CH(NH ₂ )-(CH ₂ ) ₃ -NH-C(=NH ₂ ⁺ )-NH-, -NH-C(=NH ₂ ⁺ )-NH-( CH ₂ ) ₃ -CH(NH ₂ )-C(=O)-, -C(=O)-CH(R ₂₀ )-NH- or -NH-CH(R ₂₀ )-C(=O)-;

Wherein R ₂₀ is -(CH ₂ ) ₄ -NH ₂ , -(CH ₂ ) ₄ -NH ₃ ⁺ , -(CH ₂ ) ₄ -NPG ₅ , -(CH ₂ ) ₄ -NR ₇ (R ₁₈ ), -(CH ₂ ) ₃ -NH-C(=NH)-NH ₂ or -(CH ₂ ) ₃ -NH-C(=NH ₂ ⁺ )-NH ₂ ;

Among the above-exemplified amino acid skeletons, R ₃ , R ₇ , R ₁₈ , PG ₄ , and PG ₅ are as defined above, and will not be described herein.

As an example,

These include, but are not limited to, the following cyclic linkers:

Where R ₅ , R ₁₃ ,

The definition is consistent with the above, and will not be repeated here.

Wherein R ₇ is a hydrogen atom, PG ₅ or LG ₅ . Among them, the definitions of PG ₅ and LG ₅ are consistent with the above. Wherein, Q ₂ is consistent with the above definition of O, and details are not described herein again. Wherein M ₄ is a carbon atom or a hetero atom located on the ring, including but not limited to a carbon atom, a nitrogen atom, a phosphorus atom, a silicon atom or the like. among them,

Represents a heteroaromatic ring containing a triazole structure, a fused heterocyclic ring, a substituted heteroaryl ring or a substituted fused heterocyclic ring.

As a combination of any two or more than two or more structures, for example, -CH ₂ O-, -OCH ₂ -, -CH ₂ CH ₂ O-, -OCH ₂ CH ₂ -, -OCH ₂ CH ₂ O-, - (CH ₂ ) ₃ O-, -O(CH ₂ ) ₃ -, -(CH ₂ ) ₃ O-, -O(CH ₂ ) ₃ -, and the like. As an example, L ₀ may comprise an oligopeptide or a polypeptide formed by N- and C-terminal ends of a plurality of amino acids, which may be the same or different, but does not include a polypeptide fragment which is degradable by an in vivo biological enzyme. Further, L ₀ may also contain -(L ₁₁ O) _nj -, -(OL ₁₁ ) _nj -, -(R ₂₉ O) _nj -, -(OR ₂₉ ) _nj -, -(CH ₂ CH ₂ O) Any of _nj -, -(OCH ₂ CH ₂ ) _nj - and the like. Among them, the definitions of L ₁₁ and R ₂₉ are consistent with the above. Wherein the integer nj is the number of repeating units of the monodisperse structure, and is selected from 2 to 20, preferably 2 to 10.

Also exemplified as follows: -(R ₅ ) _r1 -S-CH ₂ CH ₂ CH ₂ -O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -O-CH ₂ CH ₂ CH ₂ -S-(R ₆ ) _r2 -,

1.1.6.2. Degradable divalent linker DEGG in the present invention

The DEGG degradable condition is not particularly limited, and may be degraded under any conditions including, but not limited to, light, heat, enzyme, redox, acid, alkaline, physiological conditions, in vitro simulated environment, etc., preferably in light, heat, enzyme, It can be degraded under any conditions such as redox, acidity and alkalinity.

The divalent linking group formed by combining any of DEGG with any of the STAGs is a degradable linking group.

The type of DEGG is not particularly limited and includes, but is not limited to, containing a disulfide bond, a vinyl ether bond, an ester group, a thioester group, sulfur Ester group, dithioester group, carbonate group, thiocarbonate group, dithiocarbonate group, trithiocarbonate group, urethane group, thiocarbamate group, disulfide A carbamate group, an acetal, a cyclic acetal, a thioacetal, an azaacetal, a nitrogen heterocyclic acetal, a nitrogen thioacetal, a dithioacetal, a hemiacetal, a thio hemiacetal Aza-hemiacetal, ketal, sulfur-thione, aza- ketal, azacyclohexanone, azathioketal, imine bond, hydrazone bond, hydrazide bond, hydrazone bond, thiol ether group, Semicarbazone, thioscarbazide, sulfhydryl, hydrazide, thiocarbonylhydrazide, azocarbonylhydrazide, thioazocarbonylcarbonyl, carbazate, hydrazine Thiocarbamate group, carbazone, thiocarbazone, azo group, isoureido group, isothiourea group, allophanate group, thiourea group, sulfhydryl group, fluorenyl group, Aminoguanidino, aminoguanidino, imido group, imidate thioester, sulfonate, sulfinate, sulfonyl sulfonyl, sulfonylurea, maleimide, orthoester Base, phosphate group, phosphite group, phosphite group, phosphine Ester, phosphosilyl, silane ester, carboxamide, thioamide, sulfonamide, polyamide, phosphoramide, phosphoramidite, pyrophosphoramide, cyclophosphamide, ifosfamide, thiophosphoramide , aconityl group, benzyloxycarbonyl group, polypeptide fragment, nucleotide and its derivative skeleton, deoxynucleotide and its derivative skeleton, any one of divalent linking groups, any two or more than two kinds of divalent linkage The combination of bases.

Here, the carbamate group, the thiourethane group, the carboxamide, the phosphoramide or the like can be used as a linker which can be stably present or as a degradable linker.

Specifically, the optional structure of DEGG includes, but is not limited to, a structure containing any one of the following structures, or a combination of any two or more of the structures, or any one or more structures and a divalent linking group L which can be stably present ₉ formed combination:

-(R ₅ ) _r1 -SS-(R ₆ ) _r2 -, -(R ₅ ) _r1 -C(R ₈ )=C(R ₉ )-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -OC(R ₉ )=C(R ₈ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -C(=O)-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -C (=O)-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -C(=O)-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -SC(=O)-( R ₆ ) _r2 -, -(R ₅ ) _r1 -C(=S)-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -OC(=S)-(R ₆ ) _r2 -, -(( R ₅ ) _r1 -C(=S)-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -SC(=S)-(R ₆ ) _r2 -, -(R ₅ ) _r1 -OC(= O)-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -SC(=O)-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -OC(=S)-O-( R ₆ ) _r2 -, -(R ₅ ) _r1 -OC(=O)-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -SC(=S)-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -OC(=S)-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -SC(=O)-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -SC(=S)-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-C(=O)-O-(R ₆ ) _r2 -, -(R ₅ )r ₁ -OC(=O)-N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-C(=S)-O-(R ₆ ) _r2 -,- (R ₅ ) _r1 -OC(=S)-N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-C(=O)-S-(R ₆ ) _R2 -, -(R ₅ ) _r1 -SC(=O)-N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-C(=S)-S- (R ₆ ) _{r 2} -, -(R ₅ ) _r1 -SC(=S)-N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -CH(OR ₃ )-O-(R ₆ ) _r2 - , -(R ₅ ) _r1 -O-CH(OR ₃ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -CH(OR ₃ )-S-(R ₆ ) _r2 -, -(R ₅ ) _R1 -S-CH(OR ₃ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -CH(SR ₃ )-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -O-CH( SR ₃ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -CH(SR ₃ )-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -S-CH(SR ₃ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -CH(OR ₃ )-N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-CH(OR ₃ )- (R ₆ ) _r2 -, -(R ₅ ) _r1 -CH(NR ₁₈ R ₁₉ )-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -O-CH(NR ₁₈ R ₁₉ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -CH(NR ₁₈ R ₁₉ )-N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-CH(NR ₁₈ R ₁₉ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -(R ₁₈ R ₁₉ N)C(SR ₃ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -CH(SR ₃ ) -N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-CH(SR ₃ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -CH(NR ₁₈ R ₁₉ )-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -S-CH(NR ₁₈ R ₁₉ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -CH(OH)- O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -O-CH(OH)-(R ₆ ) _r2 -, -(R ₅ ) _r1 -CH(OH)-S-(R ₆ ) _r2 - , -(R ₅ ) _r1 -S-CH(OH)-(R ₆ ) _r2 -, -(R ₅ ) _R1 -CH(OH)-N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-CH(OH)-(R ₆ ) _r2 -, -(R ₅ ) _R1 -CR ₁₃ (OR ₃ )-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -O-CR ₁₃ (OR ₃ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -CR ₁₃ (OR ₃ )-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -S-CR ₁₃ (OR ₃ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -CR ₁₃ (SR ₃ ) -O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -O-CR ₁₃ (SR ₃ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -CR ₁₃ (SR ₃ )-S-( R ₆ ) _r2 -, -(R ₅ ) _r1 -S-CR ₁₃ (SR ₃ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -CR ₁₃ (OR ₃ )-N(R ₇ )-( R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-CR ₁₃ (OR ₃ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -CR ₁₃ (NR ₁₈ R ₁₉ )-O -(R ₆ ) _r2 -, -(R ₅ ) _r1 -O-CR ₁₃ (NR ₁₈ R ₁₉ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -CR ₁₃ (NR ₁₈ R ₁₉ ))- N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-CR ₁₃ (NR ₁₈ R ₁₉ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -CR ₁₃ (SR ₃ )-N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-CR ₁₃ (SR ₃ )-(R ₆ ) _r2 -, -(R _{5 R1} -CR ₁₃ (NR ₁₈ R ₁₉ )-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -S-CR ₁₃ (NR ₁₈ R ₁₉ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -CR ₁₃ (OH)-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -O-CR ₁₃ (OH)-(R ₆ ) _r2 -, -(R ₅ ) _r1 -CR ₁₃ (OH)-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -S-CR ₁₃ (OH)-(R ₆ ) _r2 -, -(R ₅ ) _r1 -CR ₁₃ (OH)-N( R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-CR ₁₃ (OH)-(R ₆ ) _r2 -, -(R ₅ ) _r1 -(R ₁₅ )C= N-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N=C(R ₁₅ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -(R ₁₅ )C=NN(R ₇ )- (R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-N=C(R ₁₅ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -(R ₁₅ )C=NN( R ₇ )-C(=O)-(R ₆ ) _r2 -, -(R ₅ ) _r1 -C(=O)-N(R ₇ )-N=C(R ₁₅ )-(R ₆ ) _r2 - , -(R ₅ ) _r1 -(R ₁₅ )C=NO-(R ₆ ) _r2 -, -(R ₅ ) _r1 -ON=C(R ₁₅ )-(R ₆ ) _r2 -, -(R ₅ ) _R1 -(R ₁₅ )C=NS-(R ₆ ) _r2 -, -(R ₅ ) _r1 -SN=C(R ₁₅ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-C(=O)-N(R ₁₈ )-N=C-(R ₆ ) _r2 -, -(R ₅ ) _r1 -C=NN(R ₁₈ )-C(=O)-N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-C(=S)-N(R ₁₈ )-N=C-(R ₆ ) _r2 -, -(R ₅ ) _R1 -C=NN(R ₁₈ )-C(=S)-N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-N(R ₁₈ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-N(R ₁₈ )-C(=O)-(R ₆ ) _r2 -, -(R ₅ ) _r1 -C(=O)- N(R ₁₈ )-N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-N(R ₁₈ )-C(=S)-( R ₆ ) _r2 -, -(R ₅ ) _r1 -C(=S)-N(R ₁₈ )-N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ ) -N(R ₁₈ )-C(=O)-N=N-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N=NC(=O)-N(R ₁₈ )-N(R ₇ ) -(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-N(R ₁₈ )-C(=S)-N=N-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N=NC(=S)-N(R ₁₈ )-N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₁₈ )-N(R ₇ )-C(= O)-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -OC(=O)-N(R ₇ )-N(R ₁₈ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₁₈ )-N(R ₇ )-C(=S)-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -OC(=S)-N(R ₇ )-N(R ₁₈ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₁₈ )-N(R ₇ )-C(=O)-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -SC(=O)-N(R ₇ )-N(R ₁₈ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₁₈ )-N(R ₇ )-C(=S) -S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -SC(=S)-N(R ₇ )-N(R ₁₈ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N (R ₇ )-N(R ₁₈ )-C(=O)-N(R ₁₉ )-N(R ₂₃ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-N (R ₁₈ )-C(=S)-N(R ₁₉ )-N(R ₂₃ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N=N-(R ₆ ) _r2 -, -( R ₅ ) _r1 -OC(=NR ₁₈ )-N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-C(=NR ₁₈ )-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -OC(=NH ₂ ⁺ )-N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-C(=NH ₂ ⁺ )-O-(R ₆ ) _r2 -, -(R _{5 R1} - N(R ₇ )-C(=NR ₁₈ )-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -SC(=NR ₁₈ )-N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-C(=NH ₂ ⁺ )-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -SC(=NH ₂ ⁺ )-N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₁₈ )-C(=O)-N(R ₇ )-C(=O)-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -OC(=O)-N(R ₇ )-C(=O)-N(R ₁₈ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₁₈ ) -C(=S)-N(R ₇ )-C(=O)-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -OC(=O)-N(R ₇ )-C(= S)-N(R ₁₈ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₁₈ )-C(=NR ₇ )-N(R ₁₉ )-(R ₆ ) _r2 -,- (R ₅ ) _r1 -N(R ₁₈ )-C(=NH ₂ ⁺ )-N(R ₁₉ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -C(=NR ₇ )-N(R ₁₉ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₁₉ )-C(=NR ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₁₈ )- C(=NH ₂ ⁺ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -C(=NH ₂ ⁺ )-N(R ₁₈ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 - N(R ₂₃ )-N(R ₁₈ )-C(=NR ₇ )-N(R ₁₉ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₁₉ )-C(=NR ₇ )-N(R ₁₈ )-N(R ₂₃ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-N(R ₁₈ )-C(=NH ₂ ⁺ )-N( R ₁₉ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₁₉ )-C(=NH ₂ ⁺ )-N(R ₁₈ )-N(R ₇ )-(R ₆ ) _r2 -,- (R ₅ ) _r1 -C(=NR ₇ )-N(R ₁₈ )-N(R ₁₉ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₁₉ )-N(R ₁₈ ) -C(=NR ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₁₉ )-N(R ₁₈ )-C(=NH ₂ ⁺ )-, -(R ₅ ) _r1 - C(=NH ₂ ⁺ )-N(R ₁₈ )-N(R ₁₉ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -C(=NR ₇ )-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -OC(=NR ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -OC(=NH ₂ ⁺ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 - C(=NH ₂ ⁺ )-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -C(=NR ₇ )-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -SC(= NR ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -SC(=NH ₂ ⁺ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -C(=NH ₂ ⁺ )-S- (R ₆ ) _r2 -, -(R ₅ ) _r1 -S(=O) ₂ -O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -OS(=O) ₂ -(R ₆ ) _r2 - , -(R ₅ ) _r1 -S(=O)-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -OS(=O)-(R ₆ ) _r2 -, -(R ₅ ) _r1 - S(=O) ₂ -N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-S(=O) ₂ -(R ₆ ) _r2 -, -(R ₅ ) _r1 - N(R ₁₉ )-S(=O) ₂ -N(R ₁₈ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -S(=O) ₂ -N(R ₁₈ )- N(R ₁₉ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₁₉ )-N(R ₁₈ ) -S(=O) ₂ -(R ₆ ) _r2 -, -(R ₅ ) _r1 -S(=O) ₂ -N(R ₁₈ )-C(=O)-N(R ₇ )-(R _{6 R2} -, -(R ₅ ) _r1 -N(R ₇ )-C(=O)-N(R ₁₈ )-S(=O) ₂ -(R ₆ ) _r2 -, -(R ₅ ) _r1 - N(R ₇ )-(CH ₂ ) _r3 -OC(=O)-, -(R ₅ ) _r1 -N(R ₇ )-(CH ₂ ) _r3 -OC(=O)-(R ₆ ) _r2 - , -(R ₅ ) _r1 -O-Si(R ₄₁ R ₄₂ )-O-(R ₆ ) _r2 -, orthoester group, phosphate group, phosphite group, phosphite group, phosphonate group , phosphosilyl ester, silyl ester, carbonamide, thioamide, sulfonamide, polyamide, phosphoramide, phosphoramidite, pyrophosphamide, cyclophosphamide, ifosfamide, thiophosphoramide, a divalent linking group of a head acyl group, a benzyloxycarbonyl group, a polypeptide fragment, a nucleotide and a derivative thereof, a divalent linking group of a deoxynucleotide and a derivative thereof,

In addition, such as

The linker is stable under physiological conditions, but can be degraded under special lighting conditions. Ordinary ester bonds are degradable except under acid and alkali conditions. And such as benzyloxycarbonyl,

The ester group in the case can also be degraded under special light conditions (Journal of Polymer Science: Part A: Polymer Chemistry, 2008, 46, 6896-6906).

Wherein, L ₉ is any divalent linking group which can be stably present, and may be any of the above STAGs.

Wherein r1 and r2 are each independently 0 or 1.

Wherein r3 is 2, 3, 4, 5 or 6;

Wherein R ₃ , R ₅ , R ₆ , R ₇ , R ₁₈ , R ₁₉ , R ₂₃ , R ₈ , R ₉ , R ₁₃ , R ₁₄ , R ₁₅ , M ₅ , M ₆ have the same meanings as defined above, here No longer.

Wherein R ₄₁ and R ₄₂ are each independently selected from C _1-20 alkyl, phenyl, benzyl, C _1-20 alkyl substituted phenyl, C _1-20 alkyl substituted benzyl, C ₁ Any one of _-20 alkoxy groups, preferably C _1-6 alkyl, phenyl, benzyl, C _1-6 alkyl substituted phenyl, C _1-6 alkyl substituted benzyl, C _1-6 Any one of alkoxy groups, more preferably any one of a C _1-6 alkyl group, a phenyl group, and a benzyl group.

Wherein M ₁₉ and M ₂₀ are each independently an oxygen atom or a sulfur atom, and in the same molecule, the two may be the same or different from each other.

Wherein, M ₁₅ is a hetero atom selected from an oxygen atom, a sulfur atom, and a nitrogen atom; PG ₉ is a protecting group corresponding to M ₁₅ , and deprotection occurs under the action of acid basicity, enzyme, redox, light, temperature; When M ₁₅ is O, PG ₉ corresponds to the hydroxy protecting group PG ₄ , when M ₁₅ is S, PG ₉ corresponds to the thiol protecting group PG ₂ , and when M ₁₅ is N, PG ₉ corresponds to the amino protecting group PG ₅ .

Wherein n ₇ is the number of double bonds selected from a natural number of 0 or 1-10. among them,

It is a cyclic structure that can be degraded into at least two separate fragments. As an example, for example, a lactide ring.

For example, r1=r2=0, R ₇ =R ₁₈ =R ₁₉ =R ₂₃ =R ₈ =R ₉ =R ₁₃ =R ₁₄ =R ₁₅ =H, DEGG may contain any of the following structures or any two Or a combination of two or more structures: -SS-, -CH=CH-O-, -O-CH=CH-, -C(=O)-O-, -OC(=O)-, -C(= O)-O-CH ₂ -, -CH ₂ -OC(=O)-, -C(=O)-O-CH ₂ -, -CH ₂ -OC(=O)-, -C(=O) -O-CH ₂ -OC(=O)-, -C(=O)-O-CH ₂ -NH-C(=O)-, -OC(=O)-R ₅ -C(=O)- O-, -C(=O)-S-, -SC(=O)-, -C(=S)-O-, -OC(=S)-, -C(=S)-S-,- SC(=S)-, -OC(=O)-O-, -SC(=O)-O-, -OC(=S)-O-, -OC(=O)-S-, -SC( =S)-O-, -OC(=S)-S-, -SC(=O)-S-, -SC(=S)-S-, -NH-C(=O)-O-,- OC(=O)-NH-, -NH-C(=S)-O-, -OC(=S)-NH-, -NH-C(=O)-S-, -SC(=O)- NH-, -NH-C(=S)-S-, -SC(=S)-NH-, -CH(OR ₃ )-O-, -O-CH(OR ₃ )-, -CH(OR ₃ )-S-, -S-CH(OR ₃ )-, -CH(SR ₃ )-O-, -O-CH(SR ₃ )-, -CH(SR ₃ )-S-, -S-CH( SR ₃ )-, -CH(OR ₃ )-NH-, -NH-CH(OR ₃ )-, -CH(NPG ₅ )-O-, -O-CH(NH ₂ )-, -CH(NH ₂ ) -NH -, - NH-CH (NH 2) -, - (NH 2) C (SR 3) -, - CH (SR 3) -NH- _{-NH-CH (SR 3) -} , - CH (NH 2) -S -, - S-CH (NH 2) -, - CH (OH) -NH -, - NH-CH (OH) -, - CH (OR ₃ )-O-, -O-CH(OR ₃ )-, -CH(OR ₃ )-S-, -S-CH(OR ₃ )-, -CH(SR ₃ )-O-, -O -CH(SR ₃ )-, -CH(SR ₃ )-S-, -S-CH(SR ₃ )-, -CH(OR ₃ )-NH-, -NH-CH(OR ₃ )-, -CH (NH ₂ )-O-, -O-CH(NH ₂ )-, -CH(NH ₂ )-NH-, -NH-CH(NH ₂ )-, -CH(SR ₃ )-NH-, -NH -CH(SR ₃ )-, -CH(NH ₂ )-S-, -S-CH(NH ₂ )-, -CH(OH)-O-, -O-CH(OH)-, -CH(OH )-S-, -S-CH(OH)-, -CH(OH)-NH-, -NH-CH(OH)-, -HC=N-, -N=CH-, -HC=N-NH -, -NH-N=CH-, -HC=N-NH-C(=O)-, -C(=O)-NH-N=CH-, -HC=NO-, -ON=CH-, -HC=NS-, -SN=CH-, -NH-C(=O)-NH-N=CH-, -HC=N-NH-C(=O)-NH-, -NH-C(= S)-NH-N=CH-, -HC=N-NH-C(=S)-NH-, -NH-NH-, -NH-NH-C(=O)-, -C(=O) -NH-NH-, -NH-NH-C(=S)-, -C(=S)-NH-NH-, -NH-NH-C(=O)-N=N-, -N=NC (=O)-NH-NH-, -NH-NH-C(=S)-N=N-, -N=NC(=S)-NH-NH-, -NH-NH-C(=O) -O-, -OC(=O)-NH-NH-, -NH-NH-C(=S)-O-, -OC(=S)-NH-NH-, -NH-NH-C(= O)-S-, -SC(=O)-NH-NH-, -NH-NH-C( S)-S-, -SC(=S)-NH-NH-, -NH-NH-C(=O)-NH-NH-, -NH-NH-C(=S)-NH-NH-, -N=N-, -OC(=NH)-NH-, -NH-C(=NH)-O-, -OC(=NH ₂ ⁺ )-NH-, -NH-C(=NH ₂ ⁺ ) -O-, -NH-C(=NH)-S-, -SC(=NH)-NH-, -NH-C(=NH ₂ ⁺ )-S-, -SC(=NH ₂ ⁺ )-NH -, -NH-C(=O)-NH-C(=O)-O-, -OC(=O)-NH-C(=O)-NH-, -NH-C(=S)-NH -C(=O)-O-, -OC(=O)-NH-C(=S)-NH-, -NH-C(=NH-NH-, -NH-C(=NH ₂ ⁺ )- NH--NH-C(=O)-NH-C(=O)-O-, -OC(=O)-NH-C(=O)-NH-, -NH-C(=S)-NH -C(=O)-O-, -OC(=O)-NH-C(=S)-NH-, -NH-C(=NH)-NH-, -NH-C(=NH ₂ ⁺ ) -NH-, -C(=NH)-NH-, -NH-C(=NH)-, -NH-C(=NH ₂ ⁺ )-, -C(=NH ₂ ⁺ )-NH-, -NH -NH-C(=NH)-NH-, -NH-C(=NH)-NH-NH-, -NH-NH-C(=NH ₂ ⁺ )-NH-, -NH-C(=NH ₂ ⁺ )-NH-NH-, -C(=NH)-NH-NH-, -NH-NH-C(=NH)-, -NH-NH-C(=NH ₂ ⁺ )-, -C(= NH ₂ ⁺ )-NH-NH-, -C(=NH)-O-, -OC(=NH)-, -OC(=NH ₂ ⁺ )-, -C(=NH ₂ ⁺ )-O-, -C(=NH)-S-, -SC(=NH)-, -SC(=NH ₂ ⁺ )-, -C(=NH ₂ ⁺ )-S-, -S(=O) ₂ -O- _{, -OS (= O) 2 -} , - S (= O) -O -, - OS (= O) - _{-S (= O) 2 -NH -} , - NH-S (= O) 2 -, - NH-S (= O) 2 -NH -, - S (= O) 2 -NH-NH -, - NH -NH-S(=O) ₂ -, -S(=O) ₂ -NH-C(=O)-NH-, -NH-C(=O)-NH-S(=O) ₂ -,- NH-(CH ₂ ) _r3 -OC(=O)-, -N(CH ₃ )-(CH ₂ ) _r3 -OC(=O)-. Where r3 is 2, 3, 4, 5 or 6. R _{3 is} selected from methyl, ethyl or benzyl. The definitions of M ₁₅ , PG ₉ , M ₁₉ , M ₂₀ , and n ₇ are the same as those described above, and are not described herein again.

DEGG also includes combinations of any of the above-described degradable divalent linking groups with any suitable stable divalent linking group.

For the divalent linking group in which DEGG is combined with any of the above STAGs, examples are as follows:

Wherein r1 and r2 are each independently 0 or 1.

Wherein, the definitions of R ₅ , R ₆ , R ₇ , and Q are consistent with the above, and are not described herein again.

For a degradable divalent linking group containing an aromatic ring, it can also be derived from an aromatic ring (such as

) combined with a degradable divalent linking group, for example:

Wherein, the definitions of Q, Q ₂ , R ₁₃ , R ₁₄ , X ₁₀ , M ₁₉ , M ₂₀ , M ₁₅ , PG ₉ , and n ₇ are the same as those described above, and are not described herein again.

1.1.6.3. Degradable multivalent groups

The degradable trivalent or tetravalent or higher valent group needs to contain at least one degradable divalent linking group DEGG.

For degradable trivalent groups, including but not limited to a stable trivalent group containing a trivalent nuclear structure and a degradable divalent linking group, a trivalent aromatic ring and a degradable divalent linking group a group, a combination of a degradable trivalent ring structure and a stable divalent linking group, a combination of a degradable trivalent ring structure and a degradable divalent linking group, and any of the above degradable divalent groups The trivalent form of the linker. Wherein the degradable trivalent ring structure refers to a trivalent cyclic structure which is degradable into at least two independent fragments. It may be a trivalent closed ring structure in which two or more degradable groups are connected in series. For example, a cyclic peptide, such as a cyclic structure in which two or more ester bonds are connected in series.

For the degradable trivalent group U, it may be composed of a trivalent aromatic ring and a degradable divalent linking group, or a combination of a degradable trivalent ring structure and a divalent linking group which may be stably present or degradable. It may also be a trivalent form of any of the above-described degradable divalent linking groups.

Among them, by a trivalent aromatic ring (such as

The degradable U composed of a degradable divalent linking group can be exemplified as follows:

Wherein, the definitions of Q, Q ₂ , R ₁₃ , R ₁₄ , X ₁₀ , M ₁₉ , M ₂₀ , M ₁₅ , PG ₉ , and n ₇ are the same as those described above, and are not described herein again.

Wherein the degradable trivalent ring structure refers to a trivalent cyclic structure which is degradable into at least two independent fragments. It may be a trivalent closed ring structure in which two or more degradable groups are connected in series. For example, a cyclic peptide, such as a cyclic structure in which two or more ester bonds are connected in series.

Wherein, the trivalent form of the above degradable divalent linking group can be exemplified as follows:

The definitions of M ₁₉ , M ₂₀ , M ₁₅ , PG ₉ , and n ₇ are the same as those described above, and are not described herein again.

1.1.7. Preferred structure of the trivalent branched center structure U ₁ , U ₂ , U ₀₁ , U ₀₂

U ₀₁ and U ₀₂ each independently preferably contain any of the following structures:

Wait. Further, U ₀₁ and U _{02 are} further independently independently contained in the above structure, and are selected from one, two or three identical or different divalent linking groups selected from the group consisting of an oxy group, a thio group, a secondary amino group, a divalent tertiary amino group and a carbonyl group. Structure; when participating in an initiator molecule constituting living anionic polymerization, a structure containing no carbonyl group or secondary amino group is further preferred. As an example, U ₀₁ , U ₀₂ may be selected from any of the following structures:

Wait. When the initiator molecule constituting the living anionic polymerization is used, a structure containing no carbonyl group or secondary amino group is further preferred. The definition of Q ₅ is consistent with the above.

The branching groups U ₀₁ and U ₀₂ are each independently optimized

U ₀₁ and U ₀₂ may each independently be selected from a trivalent skeleton structure of an amino acid or a derivative thereof, but are not involved in an initiator molecule constituting living anionic polymerization; wherein the amino acid is an _L -form or a _D -form. By way of example, it may be derived from, but not limited to, the following amino acids or derivatives thereof: hydroxyl or sulfur containing amino acids and derivatives thereof: serine, threonine, cysteine, tyrosine, hydroxyproline; Amino acids and their derivatives: aspartic acid, glutamic acid, asparagine, glutamine; basic amino acids and their derivatives: lysine, arginine, citrulline, histidine, tryptophan .

Specifically, in the above formulas (1) to (6), the branching groups U ₁ and U ₂ are each independently include, but are not limited to:

Wait. Wherein Q ₅ is a H atom, a methyl group, an ethyl group or a propyl group; and R ₂₈ is a methyl group, an isopropyl group or an isobutyl group.

The branching groups U ₁ and U ₂ are each independently preferably

1.1.8. Terminal branching structure G and examples thereof

The structure of G is not particularly limited, and each independently includes, but is not limited to, a branched, a ring-containing structure, a comb, a tree, a hyperbranched, and the like. G is degradable or stable.

L ₀ is a divalent linking group linking the PEG segment to the terminal branching structure G, which may or may not be present. L ₀ can be stably present or degradable. L ₀ may be selected from any of the above STAG or DEGG.

The structural types of the terminal branching groups G may be the same or different. When they have the same structure type, for example, they are three-branched structures, or the same four-branched structure, or the same comb-like structure, or the same tree-like structure, or the same hyperbranched structure, or the same ring structure. In the case of the same type of structure, the structure of the end of the PEG chain is not completely consistent, and is mainly directed to a special structure such as a comb, a tree, a hyperbranched, or a ring. For example, for a comb structure, the difference in valence state due to the inconsistent number of repeating units is allowed; for the hyperbranched structure, the number of branching units is not required to be strictly uniform, and each branching unit is allowed to be randomly connected. Therefore, in the same molecule, when the end of the PEG chain is a comb or hyperbranched structure, the terminal k may be unequal. For tree and ring structures, the structure is required to be completely consistent, and the corresponding k is also completely equal.

When the terminal reaction site k=2, G is a trivalent group, including but not limited to the trivalent group in the above set G ³ , U ₀₁ , U ₀₂ , U ₁ , U ₂ . (L ₀ ) _g0 -G preferably contains a structure selected from the group consisting of any of the above U ₀₁ , U ₀₂ , U ₁ , U ₂ ,

Any of the structures.

When the terminal reaction site k=3, G is a tetravalent group, including but not limited to the tetravalent group in the above set G ⁴ ; the tetravalent G preferably contains an atom CM ₄ , an unsaturated bond CB ₄ , a cyclic structure Any of the four-valent nuclear structures in CC ₄ , or contain two trivalent nuclear structures. (L ₀ ) _g0 -G further preferably contains any of the following structures:

Wait.

When the terminal reaction site k ≥ 3, that is, when the valence state of G ≥ 4, the G of the k+1 valence includes, but is not limited to, the k+1 valent group in the above set G ^k+1 . The G+1 valence G may contain one k+1 valence core structure, or may be directly linked or combined by 2 to k-1 3 to k valence low valence groups or one or more of two The valence spacer L _{10 is} indirectly combined. The low-valent groups of 3 to k valence may be the same or different, and their valence states may be the same or different. For example, two different trivalent groups are combined into

For the k+1 valence core structure, when k ≥ 4, when the k+1 valence core structure is contained, the k+1 valence core structure is preferably a ring structure. When two or more L ₁₀ are contained, L ₁₀ may be the same or different from each other. The definition of L ₁₀ is consistent with the above.

The G+1 (k≥4) valence G, which is directly or indirectly combined, includes but is not limited to a comb combination mode, a tree combination mode, a branch combination mode, a hyperbranched combination release, and a ring Form combination, etc. For example, for comb, dendritic or hyperbranched groups in which a plurality of low-cost groups are combined, the plurality of lower-valent groups may be the same or different from each other, preferably by combining the same low-cost groups.

Among them, the basic unit of the polyvalent G constituting the dendritic structure is preferably a trivalent G or a tetravalent G.

The tree-like combination structure is for example

Wait. Where ng represents the algebra of the tree combination. d represents an algebra of a dendritic combination, and d is preferably 2 to 6 generations, more preferably 2 to 5 generations, and most preferably 2, 3 or 4 generations. Wherein M ₉ is O, S or NX ₁₀ , wherein the definition of X ₁₀ is consistent with the above.

Among them, the basic unit of the polyvalent G constituting the branched or hyperbranched combination structure is preferably a trivalent G or a tetravalent G. The preferred basic unit includes, but is not limited to, the above-described tree combination, and includes

Wait. The branched or hyperbranched combination structure differs from the above-described tree-like combination structure in that it is a hybrid combination of multivalent G and its low-cost form. The low-cost form of the multivalent G, for example

Low price form

Among them, the basic unit of the polyvalent G constituting the comb-shaped combined structure is preferably trivalent G, tetravalent G or pentavalent G. Composed of comb The basic units of the multivalent G of the combined structure include, but are not limited to, glycerin, pentaerythritol, substituted propylene oxide, substituted propylene oxide and carbon dioxide groups, acrylates and derivatives thereof, methacrylates and derivatives thereof, The basic unit of the acetal structure (such as (1→6) β-D glucopyranoside), amino acid or thio group-containing amino acid and derivatives thereof, acidic amino acid and derivatives thereof, basic amino acid and derivatives thereof, and the like. G may also be a D-glucopyranose unit through a β-1,6 glycosidic bond, an α-1,6 glycosidic bond, a β-1,4 glycosidic bond, an α-1,4 glycosidic bond, a β-1,3 glycoside The acetalized dextran formed by the end-to-end linkage of any of the bond, the α-1,3 glycosidic bond, or the oxidized form of the above polymer. The repeating unit of the comb-like combination structure may also be a suitable trihydric alcohol, a suitable tetrahydric alcohol, an open-chain pentitol, an open-chain hexitol, and the corresponding raw materials are preferably other than the ether bond hydroxyl group. The hydroxy group is in a protected form, such as glycerol, trishydroxyethylethane, trishydroxyethylpropane. As a typical example, including but not limited to the following structure:

Wherein n ₅ , X ₄ , and R ₇ are as defined above, wherein X ₄ is a hydrogen atom to which an oxy group is bonded, a hydroxy protecting group or a group LG ₄ ; R ₇ is a hydrogen atom to which an amino group is bonded, an amino protecting group or Group LG ₅ .

Wherein the multivalent G of the cyclic combination is preferably a residue of a cyclic peptide or a derivative thereof, a residue of a cyclic monosaccharide or a derivative thereof, a cyclic polysaccharide or a derivative thereof (such as a functional derivative of a cyclodextrin) , the residue of 1,4,7-tri-tert-butoxycarbonyl-1,4,7,10-tetraazacyclododecane, 2-hydroxymethylpiperidine-3,4,5-three The skeleton of the alcohol, the skeleton of 6-amino-4-(hydroxymethyl)-4-cyclohexyl-[4H,5H]-1,2,3-triol, and the like.

For example, when the terminal reaction site k=4, G is a pentavalent group including, but not limited to, a pentavalent group in the above-described set G5. The pentavalent G may include one pentavalent nuclear structure, one tetravalent nuclear structure and one trivalent nuclear structure, or three trivalent nuclear structures. (L ₀ ) _g0 -G preferably contains any of the following structures:

A dendritic structure in which three trivalent Gs are directly or indirectly combined, and a comb structure in which three trivalent Gs are directly or indirectly combined. Among them, a dendritic structure in which three trivalent Gs are directly or indirectly combined is, for example, a structure in which the above algebra d=2. A comb-like structure in which three trivalent groups are directly combined, including but not limited to a trimeric lysine skeleton, a trimeric glutamic acid skeleton, a trimeric aspartic acid skeleton, a trimeric glycerol skeleton, and the like, such as

A comb-like structure in which three trivalent groups are indirectly combined, such as three lysines in which amino acids such as glycine and alanine are combined as a spacer.

For example, when the terminal reaction site k=5, G is a hexavalent group including, but not limited to, the hexavalent group in the above set G ⁶ . Hexavalent G may include a hexavalent nuclear structure, a pentavalent nuclear structure and a trivalent nuclear structure, two tetravalent nuclear structures, one tetravalent nuclear structure and two trivalent nuclear structures, or 4 A trivalent nuclear structure. (L ₀ ) _g0 -G preferably contains any of the following structures: a comb structure in which four trivalent Gs are directly or indirectly combined (for example, tetrameric glycerol, tetrameric lysine, tetrameric aspartic acid, Tetraglutamic acid, etc.),

Wait.

1.1.9. Biologically relevant substances

The bio-related substance modified by the polyfunctionalized H-type polyethylene glycol derivative disclosed in the present invention may be a biologically related substance or a modified biologically related substance; the biologically related substance may be a naturally occurring organism Related substances can also be synthetic bio-related substances.

The manner of obtaining the biologically relevant substance is not particularly limited, and includes, but is not limited to, natural extracts and derivatives thereof, degradation products of natural extracts, genetically recombinant products (molecular cloning products), chemical synthetic substances, and the like.

The hydrophilicity of the bio-related substance is not particularly limited, and may be hydrophilic or water-soluble, or may be hydrophobic or fat-soluble.

The biologically relevant substance may be a biologically related substance itself, or may be a dimer or a polymer thereof, a partial subunit or a fragment or the like.

The biologically relevant substance may be a biologically related substance itself, or a precursor, an activated state, a derivative, an isomer, a mutant, an analog, a mimetic, a polymorph, a pharmaceutically acceptable salt, Fusion proteins, chemically modified substances, genetically recombinant substances, etc., may also be corresponding agonists, activators, activators, inhibitors, antagonists, modulators, receptors, ligands or ligands, antibodies and fragments thereof, Action enzymes (such as kinases, hydrolases, lyases, oxygen reductases, isomerases, transferases, deaminase, deiminase, invertase, synthetase, etc.), enzyme substrates (such as coagulation cascade proteases) Substrate, etc.). Such derivatives include, but are not limited to, terpenoids, nucleosides, amino acids, and polypeptide derivatives. The chemically modified product forming a new reactive group, and the modified product formed by additionally introducing a functional group, a reactive group, an amino acid or an amino acid derivative, a polypeptide, etc., are all chemically modified by a biologically relevant substance. substance. The bio-related substance may also allow a target molecule, an appendage or a carrier to be bound thereto to form a modified organism before or after binding to the polyfunctionalized H-type polyethylene glycol. Related substances or complex biologically relevant substances.

There are no particular restrictions on the source of biologically relevant substances, including but not limited to human sources, rabbit sources, mouse sources, sheep sources, cattle sources, and pig sources.

The application fields of the above biological related substances are not particularly limited, including but not limited to medicine, regenerative medicine, tissue engineering, stem cell engineering, bioengineering, genetic engineering, polymer engineering, surface engineering, nano engineering, detection and diagnosis, chemical staining, fluorescence Marking, cosmetics, food, food additives, nutrients and other fields. Among them, for medical biological related substances, including but not limited to drugs, drug carriers, medical devices, can be used for disease treatment and prevention, wound treatment, tissue repair and replacement, imaging diagnosis and the like. By way of example, related substances may also include: dye molecules for quantitative or semi-quantitative analysis; for example, fluorocarbon molecules that can be used for contrast diagnosis, blood substitutes, and the like; for example, antiparasitic drugs such as primaquine; It is used as a carrier for antidote, such as chelating agent ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA) and the like. When a biologically relevant substance is used as a drug, there are no particular restrictions on the therapeutic field, including but not limited to drugs for treating cancer, tumor, liver disease, hepatitis, diabetes, gout, rheumatism, rheumatoid, senile dementia, cardiovascular diseases and the like. , anti-allergic drugs, anti-infectives, antibiotics, antivirals, antifungals, vaccines, central nervous system inhibitors, central nervous system stimulants, psychotropic drugs, respiratory drugs, peripheral nervous system drugs, at synaptic junctions Drugs, smooth muscle active drugs, histaminative agents, antihistamines, blood and hematopoietic drugs, gastrointestinal drugs, steroids, cytostatics, and intestinal mites that act on point or neuroeffector junction sites Agent, antimalarial agent, antiprotozoal agent, antimicrobial agent, anti-inflammatory agent, immunosuppressant, Alzheimer's disease drug or compound, imaging agent, antidote, anticonvulsant, muscle relaxant, anti-inflammatory drug, Appetite suppressant, migraine treatment, muscle contraction, antimalarial, anti-vomiting agent / antiemetic, tracheal dilator, antithrombotic, anti-high Blood pressure drugs, antiarrhythmic drugs, antioxidants, anti-asthma drugs, diuretics, lipid regulators, antiandrogens, antiparasitic drugs, anticoagulants, antibiotics, hypoglycemic agents, nutraceuticals, additives , growth supplements, anti-enteric agents, vaccines, antibodies, diagnostics (including but not limited to contrast agents), contrast agents, hypnotics, sedatives, psychostimulants, tranquilizers, anti-Parkinson's drugs, analgesics, anti-anxiety Drugs, muscle infections, etc. Among them, typical anti-cancer or anti-tumor drugs include, but are not limited to, breast cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, gastrointestinal cancer, intestinal cancer, metastatic colorectal cancer, rectal cancer, colon cancer, colorectal Cancer, gastric cancer, squamous cell carcinoma, laryngeal cancer, esophageal cancer, esophageal cancer, malignant tumor, lung cancer, small unit lung cancer (small cell lung cancer), non-small cell lung cancer, liver cancer, thyroid cancer, kidney cancer, cholangiocarcinoma, brain cancer , skin cancer, pancreatic cancer, prostate cancer, bladder cancer, testicular cancer, nasopharyngeal carcinoma, head and neck cancer, gallbladder and cholangiocarcinoma, retinal cancer, renal cell carcinoma, gallbladder adenocarcinoma, multidrug resistant cancer, melanoma, Lymphoma, non-Hodgkin's lymphoma, adenoma, leukemia, chronic lymphocytic leukemia, multiple myeloma, brain tumor, Wilms' tumor, liposarcoma, endometrial sarcoma, rhabdomyosarcoma, neuroblastoma, Primary or secondary cancer, sarcoma or carcinosarcoma such as cancer associated with AIDS (eg Kaposi's sarcoma).

"Pharmaceutical" as used in the present invention includes any agent, compound, composition or mixture that provides a physiological or pharmacological effect in vivo or in vitro, and often provides a beneficial effect. The type thereof is not particularly limited and includes, but not limited to, drugs, vaccines, antibodies, vitamins, foods, food additives, nutrients, nutraceuticals, and other agents that provide a beneficial effect. The range in which the "drug" produces a physiological or pharmacological action in the body is not particularly limited, and may be a systemic effect or may be produced only locally. The activity of the "drug" is not particularly limited, and may be an active substance that can interact with other substances, or an inert substance that does not interact; but an inert drug can be converted into an active form by in vivo action or certain stimulation. .

The kind of the biologically relevant substance is not particularly limited, and includes but is not limited to the following substances: drugs, proteins, polypeptides, oligopeptides, protein mimetics, fragments and analogs, enzymes, antigens, antibodies and fragments thereof, receptors, small molecules Drugs, nucleosides, nucleotides, oligonucleotides, antisense oligonucleotides, polynucleotides, nucleic acids, aptamers, polysaccharides, proteoglycans, glycoproteins, steroids, terpenoids, lipids, hormones , vitamins, vesicles, liposomes, phospholipids, glycolipids, dyes, fluorescent substances, targeting factors, cytokines, neurotransmitters, extracellular matrix substances, plant or animal extracts, viruses, vaccines, cells, vesicles , micelles, etc.

The bio-related substances are classified and enumerated as follows. A biologically relevant substance can occur in one or more of the following categories.

(1) Proteins and peptides and related substances

Protein is the foundation of life. The proteins and polypeptides which can be modified are not particularly limited, and specific examples are as follows:

Hormones such as growth hormone, growth hormone releasing hormone, luteinizing hormone, luteinizing hormone releasing hormone, pituitary hormone, thyroid hormone, androgen, estrogen, adrenaline, amylin, gonadotropin, follicle stimulating hormone, thyroid Gland hormone, thymosin (such as thymosin α1, thymosin β, thymosin β4, thymosin β9, thymosin β10, thymosin α1, thymosin iib/iiia, etc.), 1-dihydrotestosterone, glucocorticoid, antibiotic Diuretic hormone, small stimulator, bicalutamide, diethylstilbestrol, etc.;

Serum protein, hemoglobin, serum albumin, blood factor, coagulation factor (coagulation factor I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, X III, etc., such as factor VIIa) , von Willebrand factor, fibrinogen, etc.;

Cytokines and fragments thereof, such as interleukin (interleukin-2, interleukin-3, interleukin-4, interleukin-6, interleukin-8, interleukin-11, interleukin-12, interleukin-13, interleukin-17, etc.), interferon ( Including interferon-α, interferon-β, interferon-γ, interferon-ε, interferon-κ, interferon-ω, interferon-δ, interferon-τ, interferon λ, interferon α-2a , interferon alpha-2b, interferon beta-1a, interferon n1, interferon n3, interferon alpha 5, interferon gamma-1b, complex interferon, etc.), granulocyte colony stimulating factor, filgrastim, giant Phagocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, chemokine, monocyte chemoattractant protein, platelet-derived growth factor (platelet-derived growth factor), thrombopoietin, phospholipase-activating protein, insulin, insulin Pro-, C-peptide, glucagon, insulin-like growth factor, insulin opsonin, glucagon-like peptides and analogs thereof (eg GLP-1, liraglutide, exenatide, exenatide, Bydureon, Lixirapin, lozena peptide, etc.), lectin, ricin, tumor necrosis (such as TNF-α), transforming growth factors (such as TGF-α, TFG-β, etc.), bone morphogenetic proteins (such as BMP-2, BMP-6, OP-1, etc.), osteoprotegerin, tissue growth factor, Connective tissue growth factor, epidermal growth factor, hepatocyte growth factor, keratinocyte growth factor, endothelial growth factor, vascular endothelial growth factor, nerve growth factor, bone growth factor, insulin-like growth factor, heparin-binding growth factor, tumor growth Factor, acidic fibroblast growth factor, basic fibroblast growth factor, glial cell line-derived neurotrophic factor, glial growth factor, macrophage differentiation factor, differentiation inducing factor, leukemia inhibitory factor, amphiregulin , growth regulator, erythropoietin, new erythropoiesis stimulating protein (NESP), hematopoietin, angiotensin, calcitonin, ecalcitonin, lactoferrin, cystic fibrosis transmembrane conductance regulator Wait;

a polypeptide, such as an anti-ovulation peptide;

Enzymes and corresponding zymogens, such as proteolytic enzymes, oxidoreductases, transferases, hydrolases, lyases, phenylalanine ammonia lyase, isomerase, ligase, aspartase, arginase , arginine deaminase, arginine deiminase, adenosine deaminase, deoxyribonuclease (such as deoxyribonuclease alpha), superoxide dismutase, endotoxin, catalase, Chymotrypsin, lipase, uricase, elastase, streptokinase, urokinase, adenosine diphosphatase, tyrosinase, bilirubin oxidase, glucose oxidase, glucosease, staphylokinase, galactosidase ( Such as α-galactosidase, β-galactosidase, etc., glucosidase (such as α-glucosidase, β-glucosidase, etc.), imiglucerase, arabinosidase, defibrase, fiber Lysozyme, hyaluronidase, alteplase, reteplase, lantipase, tenecteplase, tenipeptase, ranopeptidase, monteplase, streptococcus, alpha 1 anti-pancreas Protease, phosphodiesterase, asparaginase, pegoltinase, batroxobin, pamiteplase, streptococcal deoxyribonuclease alpha, neprilysin Phospho-oligopeptide, leukotriene A4 hydrolase, endothelin converting enzyme, ste24 protease, mitochondrial intermediate peptidase, interstitial collagenase, collagenase, macrophage elastase, gelatinase, transmembrane peptidase , procollagen C-endopeptidase, procollagen N-endopeptidase, ADAM and ADAMT metalloproteinase, myelin-related metalloproteinase, enamel lysin, tumor necrosis factor alpha-converting enzyme, insulin lysozyme, nardilysin, mitochondria treatment Peptidase, magnolysin, dactylysin-like metalloproteinase, neutrophil collagenase, matrix metalloproteinase, membrane-type matrix metalloproteinase, SP2 endopeptidase, trypsin, calpain, pancreatic elastase, pancreatic endopeptidase, Enterokinase, leukocyte elastase, chymotrypsin, tryptase, granzyme, stratum corneum chymotrypsin, acrosome protease, kallikrein, alternative complement pathway c3/c5 convertase, mannose binding protein-associated serine protease , thrombin, cathepsin G, hepatic serine, serine proteolytic enzyme, hepatocyte growth factor activated endopeptidase, subtilisin/kexin type White invertase, furin, proprotein convertase, prolyl peptidase, acylaminoacyl peptidase, peptidyl-glycaminase, signal peptidase, N-terminal nucleophile aminohydrolase, 20s proteasome, γ- Glutamyltranspeptidylase, mitochondrial peptidase, mitochondrial peptidase Ia, htra2 peptidase, site 1 protease, asparagine endopeptidase, cathepsin, cathepsin D, cysteine Cathepsin, calpain, ubiquitin isoeptidase T, caspase, glycosylphosphatidylinositol transamidase, prohormone thiol protease, γ-glutamyl hydrolase, bleomycin hydrolase, Pepsin, chymosin, gastric protease, yeast aspartase (memapsin), cyclosporin synthase, etc.;

Immunoglobulins such as IgG, IgE, IgM, IgA, and IgD;

Monoclonal or polyclonal antibodies and fragments thereof, such as tumor necrosis factor alpha antibody, GRO-beta antibody, anti-CMV antibody, anti-CD3 monoclonal antibody, anti-human interleukin-8 monoclonal antibody, anti-Tac monoclonal antibody, respiratory polysaccharide virus antibody, Infliximab, rituximab, trastuzumab, temimumab, tocilizumab, alemtuzumab, gemtuzumab, cetuximab, bevacizumab , adalimumab, golimumab, basiliximab, infliximab, panitumumab, olvazumab, daclizumab, uzutuzumab, nimotuzumab Anti-, iodine [131I] rituximab, belimumab, ranibizumab, inotuzumab, obinutuzumab, ustekinumab, cetuximab, pertuzumab, nimotuzumab, edrecolomab, omalizumab, ipilimumab, etanercept, certolizumab, tocilizumab, natalizumab, palivizumab, muromonab-CD3, siplizumab, Eculizumab, canakinumab, afelimomab, mitumomab, olizumab, nofetumomab, arcitumomab, capromab, denosumab, efalizumab, afutuzumab, ramucirumab, raxibacumab, siltuximab, fanolesomab, vedolizumab, dorlimomab arit Ox, imciromab penetetate, alefacept, abatacept, belatacept, aflibercept, Zinapax, abagovomab, abx-il8, actoxumab, adecatunumab, alirocumab, anifrolumab, anrukinzumab, anti-LAG-3, apolizumab, bapineuzumab, bavituximab, benralizumab, bertilimumab, bezlotoxumab, bispecific Antibody MDX-447, blinatumomab, blosozumab, briakinumab, brodalumab, cantuzumab ravtansine, caplacizumab, carlumab, cd28-supermab, cuxutumumab, clazakizumab, clenoliximab, clivatuzumab tetraxetan, conatumumab, crenezumab, dacetuzumab, dalotuzumab, daratumumab, demcizumab, dupilumab, ecromeximab, efungumab , eldelumab, elotuzumab/HuLuc63, enokizumab, ensituximab, epratuzumab, ertumaxomab, etaracizumab/etaratuzumab, etrolizumab, evolocumab, farletuzumab, fezakinumab, ficlatuzumab, figitumumab, flanvotumab, fontolizumab, fresolimumab, galiximab, ganitumab, gantenerumab, gavilimomab, girentuximab, glembatumumab vedotin, Gomiliximab/lumiliximab, guselkuma b, ibalizumab/Hu5A8, icrucumab, inclacumab, intetumumab, iratumumab, labetuzumab, lampalizumab, lebrikizumab, lebrikizumab, lerdelimumab, lexatumumab, lirilumab, lorvotuzumab mertansine, lucatumumab, mapatumumab, margetuximab, matuzumab, mavrilimumab, metelimumab, milatuzumab, mitumomab, mogamulizumab, motavizumab , moxetumomab pasudotox, MSB0010718C, namilumab, naptumomab estafenatox, narnatumab, necitumumab, nesvacumab, nivolumab, ocaratuzumab, ocrelizumab, olaratumab, olokizumab, onartuzumab, oregovomab, otelixizumab, otlertuzumab, ozanezumab, pagibaximab, pascolizumab, pateclizumab, patritumab, pembrolizumab (lambrolizumab), Pemtumomab, pexelizumab, pidilizumab, ponezumab, PRO 140, quilizumab, racotumomab, reslizumab, rilotumumab, romosozumab, rontalizumab, ruplizumab, sarilumab, secukinumab, sevirumab, sibrotuzumab, sifalimumab, simtuzumab, sirukumab, solanezumab, stamulumab, tabalumab, tanezumab, tefibazumab Tenatumomab, teplizumab, teprotumumab, tigatuzumab, tildrakizumab, toralizumab, tralkinumab, tregalizumab, tremelimumab, tucotuzumab celmoleukin, tuvirumab, ublituximab, urelumab, vantictumab, visilizumab, volociximab, zalutumumab, zanolimumab, dorlimomab aritox, aducanumab, alacizumab pegol, anatumomab mafenatox, aselizumab, Aselizumab, attumumab, atorolimumab, bectumomab, bivatuzumab mertansine, cantuzumab mertansine, cantuzumab mertansine, cedelizumab, cedelizumab, citatuzumab, bogatox, detumomab, drozitumab, duligotumab, dusigitumab, edobacomab, elsilimomab, enoticumab, erlizumab, exbivirumab, faralimomab, fasinumab, felvizumab, foravirumab , fulranumab, futuximab, imgatuzumab, indatuximab ravtansine, indium (111in)altumomabpentetate, indium(111in)biciromab, indium(111In)biciromab, indium(111In)igovomab, indium(111In))satumomab pendetide, inolimomab, iodine(125I)CC49, Toliizumab, keliximab, keliximab, Lemalesomab, libivirumab, liligizumab, maslimomab, minretumomab, moromumumab, nacolomab tafenatox, nebacumab, nerelimomab, odulimomab, ontuxizumab, oportuzumab monatox, orticumab, oxelumab, ozoralizumab, panobacumab, parsatuzumab, perakizumab, placulumab, priliximab (CMT 412), pritumumab, radretumab, Rafivirumab, regavirumab, robatumumab, rovelizumab/leukarrest/Hu23F2G, samalizumab, solitomab, suvizumab, tacatuzumab tetraxetan, tadocizumab, talizumab/TNX-901, taplitumomab paptox, technetium (99mTc) pintumomab, technetium (99mTc) sulesomab, technetium (99mTc) votumumab, Telimomab aritox, teneliximab, tovetumab, urtoxazumab, vatelizumab, vepalimomab, vesencumab, zolimomab aritox, bactericidal/permeability enhancing protein, antibody fragments (eg heavy chain, light chain, Fc fragment, Fv fragment, Fab fragment, antibody variable region, etc.) );

Antigens such as VLA-4, CD molecules, etc.;

Polyamino acids, such as poly-L-lysine, poly-D-lysine, etc.;

Vaccines, including inactivated vaccines, live attenuated vaccines, toxoids, and corresponding conjugate vaccines and combination vaccines, such as hepatitis B vaccine, malaria vaccine, melanoma vaccine, HIV-1 vaccine, influenza vaccine, adsorption Tetanus vaccine, meningococcal polysaccharide vaccine, pneumonia vaccine, pneumococcal polysaccharide conjugate vaccine, polio vaccine, rotavirus gene reassortment vaccine, DNA-Tianjin vaccinia compound AIDS vaccine, human dendritic cell vaccine, SARS vaccine , typhoid vaccine, cancer, lung cancer vaccine, intestinal vaccine, Japanese encephalitis vaccine, hepatitis A vaccine, hepatitis B vaccine, hepatitis A and hepatitis hepatitis combined vaccine, herpes zoster vaccine, rabies vaccine, blood heat vaccine, varicella vaccine, tuberculosis Vaccine, rubella vaccine, diarrhea vaccine, AIDS vaccine, cholera vaccine, measles and rubella combination vaccine, immunotherapy for Alzheimer's disease synthetic vaccine, vaccinia vaccine, avian influenza vaccine, mumps vaccine, plague vaccine, hand, foot and mouth disease vaccine, etc.;

Related substances of the above proteins and polypeptides include, but are not limited to, dimers and multimers, subunits and fragments thereof, precursors, activated states, derivatives, isomers, mutants, analogs, mimetics, polymorphs , pharmaceutically acceptable salts, fusion proteins, chemically modified substances, genetically modified substances, and the like, and corresponding agonists, activators, activators, inhibitors, antagonists, modulators, receptors, ligands or Ligands, antibodies and fragments thereof, enzymes (such as kinases, hydrolases, lyases, oxygen reductases, isomerases, transferases, deaminase, deiminase, invertase, synthetase, etc.), enzymes Substrate, etc. Some examples can be as follows:

Fusion protein, such as interleukin 2-Fc fusion protein

Antagonists, such as growth factor antagonists, growth hormone antagonists, receptor antagonists (such as opioid receptor antagonists; as well as chemokine receptor antagonists, interleukin receptor-1 antagonist Rilonacept), antibody antagonists, Kinase antagonists and the like; wherein opioid antagonists include, but are not limited to, naloxone, N-methylnaloxone, hydromorphone, oxymorphone, 6-amino-6-deoxy-naloxone, cyclopropane Hydroxymorphomtone, levomorphin methylnaltrexone, N-methylnaltrexone, 6-amino-14-hydroxy-17-allylnodoxorphine, buprenorphine, morphine, dihydrogen Morphine, salt diacetylmorphine, acid ethylmorphine, medihydromorphine, naltrexone, naltrexone, naltrexone, naprofen, levomorphin and naprofen, nabufen, pentane Zozocine, oxazoxine, tezoxine, codeine, dihydrocodeine, norpinatoxin, butorphanol, oxyxantane, sedclofen, oxconcidine, and the like.

Inhibitors such as reverse transcriptase inhibitors (eg amdoxovir, etc.), cyclosporine, somatostatin, VLA-4 inhibitors, endostatin, alpha-1 protease inhibitors, tyrosine phosphorylation inhibitors, etc. ;

An agonist such as a platelet-derived growth factor agonist, an EPO agonist, or the like;

An activator such as a plasminogen activator;

Receptors: such as tumor necrosis factor receptor, interleukin receptor (such as interleukin-1 receptor), T cell receptor and the like.

(2) Small molecule drugs

The type of small molecule drug is not particularly limited, including but not limited to flavonoids, terpenoids, carotenoids, saponins, steroids, steroids, guanidines, guanidines, fluoroquines, coumarins, alkaloids, porphyrins, Polyphenols, macrolides, monolactams, phenylpropanoids, anthracene, amino sugars, and the like.

The field of treatment of small molecule drugs is not particularly limited. Anticancer or antitumor drugs and antifungal drugs are preferred.

Anticancer or antitumor drugs including, but not limited to, taxanes, paclitaxel and its derivatives, docetaxel, docetaxel, camptothecin and its derivatives (including but not limited to 7-ethyl-10- Hydroxycamptothecin, 9-nitrocamptothecin, 9-aminocamptothecin, etc., irinotecan, SN38, topotecan, topotecan hydrochloride, topotecan, belocommide, acetacetate Kang, Lutotic, Giniconol, difluenticol, carniticon, rupibotecan, ezetidine, Karenitecin, jigitotecan, jimatidine, ixaticom, aficicon, letoticon , cisplatin, oxaliplatin, hydroxycamptothecin (including but not limited to 10-hydroxycamptothecin, etc.), vinblastine, vincristine, ipecaine, ipecaine hydrochloride, colchicine, doxorubicin Star, epirubicin, pirarubicin, valrubicin, doxorubicin or doxorubicin hydrochloride, epirubicin, daunorubicin, daunorubicin, mitomycin, aclaramicin , Idamycin, bleomycin, pilomycin, daunorubicin, luminoxin, rapamycin, bleomycin, streptozotocin, podophyllotoxin, actinomycin D (regeneration) Phytomycin), maytansinoids, amikacin, mitoxantrone, all-trans retinoic acid, vindesine, vinorelbine, gemcitabine, capecitabine, cladribine, pemetrexed Disodium, tegafur, letrozole, anastrozole, fulvestrant, goserelin, triptorelin, leuprolide, buserelin, temozolomide, cyclophosphamide, ifosfamide Gefitinib, Shuni Nie, erlotinib, ectinib, lapatinib, sorafenib, imatinib, dasatinib, nilotinib, sirolimus, everolimus, thiophene, Methotrexate, 5-fluorouracil, dacarbazine, hydroxyurea, vorinostat, ixabepilone, bortezomib, cytarabine, etoposide, azacytidine, teniposide, pu Napronol, procaine, tetracaine, lidocaine, valsaratin, carmustine (dichloroethyl nitrosourea), chlorambucil, benzyl hydrazine, thiotepa , topotecan, erlotinib, plitidepsin, ramustine, genistein, etc.;

Antibiotics, antiviral agents, antifungal agents, including but not limited to macrolides, defensins, polymyxin E methanesulfonic acid, polymyxin, polymyxin B, capreomycin, bacitracin, Brevibacterium, amphotericin B, aminoglycoside antibiotics, gentamicin, paramecium, tobramycin, kanamycin, amikacin, neomycin, streptomycin , nystatin, echinomycin, carbenicillin, penicillin, penicillin sensitive agent, penicillin G, penicillin V, penicillin enzyme resistance (such as methicillin, oxacillin, o-chloropenicillin, diclofenac, Flucloxacillin, nafcillin, etc.), penem, amoxicillin, vancomycin, daptomycin, anthracycline, chloramphenicol, cyclic erythromycin, flavomycin, oleandomycin , oleandomycin, clarithromycin, dafaxin, erythromycin, dirithromycin, roxithromycin, erythromycin, azithromycin, fluoroerythromycin, josamycin, spiramycin, Medicamycin, dexamethasone, leucomycin, miokamycin, rotamycin, doxycycline, swinolide A Teicoplanin, lanpranin, pirarine, statin, polymyxin E methanesulfonic acid, fluorocytosine, miconazole, econazole, fluconazole, itraconazole, Ketoconazole, voriconazole, fluconazole, clotrimazole, bifonazole, netilmicin, amikacin, caspofungin, micafungin, terbinafine, fluoroquinolone, lomefloxacin , norfloxacin, ciprofloxacin, enoxacin, ofloxacin, levofloxacin, troxafloxacin, alafloxacin, moxifloxacin, norfloxacin, gepafloxacin, gatifloxacin Star, sparfloxacin, temafloxacin, pefloxacin, amloxacin, fleroxacin, toloxacin, prulifloxacin, iloxacin, pazufloxacin, clinfloxacin, cisplatin Sand star, idarubicin, tosufloxacin, iloxacin, teicoplanin, rampolanin, daptomycin, colitimethate, nucleoside antiviral, ribavirin, anti-monospora penicillin, Ticarcillin, azlocillin, mezlocillin, piperacillin, gram (negative) negative microbial active agent, ampicillin, hetacillin, gravizine, amoxicillin, Sporomycin (such as cefpodoxime, cefprozil, cefbutene, ceftizoxime, ceftriaxone, cefotaxime, cefpirin, cephalexin, cefradine, cefoxitin, ceftime, cefazolin, cephalosporin Indomethacin, cefaclor, cefadroxil, ceftriaxone, cefuroxime, ceftriaxone, cefotaxime, ceftriaxone, cefotaxime, cefepime, cefaclor, cefonicid, cefoperazone Ketone, cefotetan, cefmetazole, ceftazidime, chlorocephalosporin, deoxycephalosporin, ceftibuten, cephalosporin, cephalosporin II, ceftriaxone, cyanoacetyl cephalosporin, etc.), monolactam ring , aztreonam, carbapenem, imipenem, pentamidine isethionate, imipenem, meropenem, pentamidine thiourea, salbutamol sulfate, lidocaine, Ocininaline sulfate, beclomethasone, beclomethasone dipropionate, meta-isoproterenol sulfate, dimethicone dipropionate, triamcinolone acetoacetate, butadiene, budesonide acetonide , fluticasone, fluticasone propionate, ipratropium bromide, fluni Pine, cromolyn sodium, ergotamine tartrate, pentamidine, pentamidine isethionate, chlorogenic acid and the like.

Other anticancer drugs, antitumor drugs, antibiotics, antiviral agents, antifungal drugs and other small molecule drugs, including but not limited to cytochalasin B, aminotoluic acid, sodium urate, aminoglutethimide, aminoketone Valeric acid, aminosalicylic acid, pamidronic acid, amsacrine, anagrelide, anatoxazole, levamisole, busulfan, cabergoline, ligulin, carboplatin, cilastatin sodium, Disodium clodronate, amiodarone, ondansetron, deacetylcyclopropionate, megestrol, testosterone, estramustine, exemestane, fluoromethylol testosterone, diethylstilbestrol , fexofenadine, fludarabine, hydrocortisone, 16α-methyl hydrocortisone, deferoxamine, flutamide, citracamide, thalidomide, L-dopa , formyltetrahydrofolate, resino Puli, levothyroxine sodium, nitrogen mustard, Angong lutein, m-hydroxynorphedrine ditartrate, metoclopramide, mexiletine, mitoxantrone, nicotine, nicotine tartrate, nilum , octreotide, pentastatin, pilcamycin, porphyrin, prednisone, procarbazine, prochlorperazine, raltitrexe, streptozotocin, sirolimus, tacrolimus, Tamoxifen, teniposide, tetrahydrocannabinol, thioguanine, thiotepa, dolasetron, granisetron, formoterol, formoterol fumarate, melphalan, imi Dazolam, alprazolam, podophylotoxins, sumatriptan, low molecular weight heparin, amifostine, carmustine, gemcitabine, lomustine, tyrostin, osteoarthritis treatment ( Including but not limited to aspirin, salicylic acid, phenylbutazone, indomethacin, naproxen, diclofenac, meloxicam, nabumetone, etodolac, sulindac, acemetine, double vinegar Rein et al), amdoxovir, cyanuric blue/aminoaryl ketone, aminocaproic acid, aminophenididone, aminolevulinic acid, butanediol diesterate, Chloroformate/disodium chloroformate, L-dihydroxyphenylalanine, lovothyroxine sodium, dichloromethyldiethylamine, meta-hydroxylamine tartrate, o-p-dichlorophenyldichloroethane, Pru Chlorazine, ondansetron, raltitrexed, tacrolimus, tamoxifen, taniposide, tetrahydrocannabinol, fluticasone, aroyl hydrazone, sumatriptan, mecomycin, spirulina, malt Aflatoxin, isorhamnetin, myricetin, dicyanoprenamin, catechin, epicatechin, phlorizin, acarbose, salmeterol, salmeterol, naloxone Opioid preparations (such as mu-opiates, kappa-opiates, etc.), phenytoin, cinacalcet, diphenhydramine, and the like.

(3) Gene-related substances

The gene-related substance is not particularly limited and may be enumerated as follows: nucleoside, nucleotide, oligonucleotide, polynucleotide, antisense oligonucleotide, nucleic acid, DNA, RNA, aptamer, related aptamer or ligand Wait.

Among them, nucleic acid is a biomacromolecular compound polymerized from many nucleotides and is one of the most basic substances in life. Nucleic acids are widely present in all animals, plant cells, microorganisms, and nucleic acids often bind to proteins to form nuclear proteins. Depending on the chemical composition, nucleic acids can be divided into ribonucleic acid and deoxyribonucleic acid.

As examples, such as GRO-β, CD-40 ligand, CFrR gene and the like.

By way of example, nucleotides and nucleosides such as 8-azaguanine, 6-mercaptopurine, azathioprine, thioinosinate, 6-methylthioinosinate, 6-thiouric acid, 6-sulfur bird嘌呤, adenosine, cladribine, ampicitabine, fludarabine, aza-cytosine, erythro-9-(2-hydroxy-3-indolyl) adenine, gemcitabine and the like.

(4) Vitamins

Vitamins are a kind of trace organic substances that humans and animals must obtain from foods to maintain normal physiological functions, and play an important role in human growth, metabolism and development. Specifically, but not limited to, vitamin A (including but not limited to vitamin A, vitamin A acid, isotretinoin, retinal, 3-dehydroretinol, 13-cis-retinoic acid, all-trans yellow Acid, α-carotene, β-carotene, γ-carotene, δ-carotene, cryptoxanthin, etretinate, eretin, etc., vitamin B (such as folic acid, etc.) , vitamin C, vitamin D, vitamin E, vitamin K, vitamin H, vitamin M, vitamin T, vitamin U, vitamin P, vitamin PP and so on.

(5) Sugar

The saccharide is a main component constituting cells and organs, and is not particularly limited, and mainly includes glycolipids, glycoproteins, glycogens, and the like. Glycolipids are widely distributed in organisms, mainly including glycosylglycerols and glycosphingolipids, including ceramides, cerebrosides, sphingosine, gangliosides, and glyceryl glycolipids; glycoproteins are A complex carbohydrate composed of a branched oligosaccharide chain covalently linked to a polypeptide, usually secreted into a body fluid or a component of a membrane protein, including but not limited to transferrin, ceruloplasmin, membrane-bound protein, and tissue-compatible Sex antigens, hormones, carriers, lectins, heparin, and antibodies.

(6) lipids

Lipids mainly include fatty acid esters and lipids.

Typical fatty acid esters are oils and fats and refer to esters of fatty acids with glycerol. Fatty acid esters also include esters of non-glycerol alcohols with fatty acids including, but not limited to, coconut oil fatty acid esters, polyglycerin fatty acid esters, sucrose fatty acid esters, and the like. Among them, the component of the fatty acid is not particularly limited, but a fatty acid having 12 to 24 carbon atoms is preferable, and the fatty acid may be a saturated fatty acid or an unsaturated fatty acid.

Lipids include glycolipids, phospholipids, and sterol esters.

Glycolipids mainly include glyceroglycolipids, glycosphingolipids (sphingolipids), sophorolipids, cerebrosides, ceramide trihexose, sphingosine-1-phosphate, rhamnolipids, double rhamnose Fat and so on.

The phospholipid may be a natural phospholipid material or a semi-synthetic or synthetic phospholipid compound.

Natural phospholipids include, but are not limited to, phosphatidic acid, lecithin (which belongs to phosphatidylcholine, derived from egg yolk, soybean, etc., eg egg yolk lecithin, soy lecithin), cephalin (belongs to phosphatidylethanolamine, derived from brain, nerve, soybean) Etc., inositol phospholipid (phosphatidylinositol), phosphatidylserine, sphingomyelin, lysophospholipid, lysolecithin, lysophosphatidic acid, lysophosphatidic acid, myelin, cardiolipin (diphosphatidylglycerol), heparin, Small molecular weight heparin, other phospholipids derived from soybean or egg yolk, and the like.

Semi-synthetic or synthetic phospholipid compounds include, but are not limited to, phosphatidic acid (PA), plasmalogen, phosphatidylglycerol (PG), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS) , phosphatidylinositol (PI), ceramide, ceramide phospholipids (including but not limited to ceramide phosphatidylcholine, ceramide phosphatidylethanolamine, ceramide phosphatidylglycerol, ceramide phosphatidylserine, ceramide phosphatidyl phosphatase An alcohol, a ceramide phosphatidylglyceride or the like, a lysophospholipid isomer, a hydrogenated natural natural phospholipid, an O-amino acid ester of phosphatidylglycerol, or the like. The number of fatty acyl groups in the synthetic phospholipid may be one or two; when two, the two fatty acyl groups may be the same or different. Among them, the fatty acyl group in the synthetic phospholipid may be derived from a saturated fatty acid or an unsaturated fatty acid. The source of the fatty acyl group is not particularly limited and includes, but not limited to, butyric acid, t-butyric acid, valeric acid, heptanoic acid, 2-ethylhexanoic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, heptadecane. Acid, stearic acid, isostearic acid, oleic acid, elaidic acid, linoleic acid, linolenic acid, arachidic acid, arachidonic acid, behenic acid, erucic acid, lauric acid, waxy acid, twenty-eight An acyl group derived from a fatty acid such as an alkanoic acid, a bee acylic acid or a lacquer wax. By way of example, phosphatidic acid includes, but is not limited to, dilauroyl phosphatidic acid, dimyristoyl phosphatidic acid, dipalmitoyl phosphatidic acid, and the like; phosphatidylglycerols include, but are not limited to, dihexanoylphosphatidylglycerol, dioctanoylphosphatidylglycerol, Diacetyl phosphatidylglycerol, dilauroylphosphatidylglycerol, dimyristoyl phosphatidylglycerol, dipalmitoylphosphatidylglycerol, distearoylphosphatidylglycerol, dioleoylphosphatidylglycerol, etc.; phosphatidylcholine includes But not limited to dihexanoylphosphatidylcholine, dioctanoylphosphatidylcholine, diacetyl phosphatidylcholine, dilauroylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine Base, distearoylphosphatidylcholine, dioleoylphosphatidylcholine, hydrogenated soybean phosphatidylcholine, etc.; phosphatidylethanolamines include, but are not limited to, N-glutaryl-phosphatidylethanolamine, dilauroylphosphatidylethanolamine , dimyristoyl phosphatidylethanolamine, dipalmitoylphosphatidylethanolamine, distearoylphosphatidylethanolamine, dioleoylphosphatidylethanolamine, dilinoleylphosphatidylethanolamine, di-erucylphosphatidylethanolamine, etc.; phosphatidylinositol Kinases include, but are not limited to, dilauroylphosphatidylinositol, dimyristoylphosphatidylinositol, dipalmitoylphosphatidylinositol, distearoylphosphatidylinositol, dioleoylphosphatidylinositol, lysophosphatidyl Inositol, etc.; hydrogenated natural phospholipids include, but are not limited to, hydrogenated soy lecithin, hydrogenated egg yolk lecithin, etc.; synthetic phospholipids containing two different acyl groups, including but not limited to 1-palmitoyl-2-oleoylphosphatidylethanolamine, 1 - palmitoyl-2-linoleoylphosphatidylcholine, 1-stearoyl-2-linoleoylphosphatidylcholine, 1-stearoyl-2-oleoylphosphatidylcholine, 1-stearoyl -2-Arachidonic acid phosphatidylcholine, 1-palmitoyl-2-oleoylphosphatidylcholine, 1-palmitoyl-2-stearoylphosphatidylcholine, and the like.

Cholesterol and terpenoids (steroids, steroids) and other substances play an important role in regulating the normal metabolism and reproductive processes of organisms. Including but not limited to cholesterol, dihydrocholesterol, sitosterol, beta-sitosterol, lanolin alcohol, lanosterol, annalsterol, oat sterol, rapeseed sterol, ergosterol, ergocalciferol, dihydroergocalciferol, ergot Sterols, dihydroergosterol, campesterol, chalinosterol, chinasterol, cholesterol, fecal sterol, cycloartenol, dehydrocholesterol, streptitol, black sea sterol, epicholinol, fucoidol, hexahydrofurfuryl alcohol, Hydroxycholesterol, photosterol, Parkerol, porous sterol, trehalol, sitostanol, stiganool, stigmasterol, weinbersterol, yeast sterol, bile alcohol, bile acid (including but not limited to bile acid, goose cholic acid, Glycocholic acid, taurocholic acid, deoxycholic acid and lithocholic acid), sex hormones, vitamin D, aldosterone, deoxycorticosterone, clobetasol, hydrocortisone, cortisone, hydrogenated Pine, prednisone, hydroxybutazone, methylprednisone, cyromidazole, beclomethasone, betamethasone, dexamethasone, diflupiron, diflumethasone, triamcinolone, mometasone, Deoxymetazone, fluocinolone, flunisin Parra betamethasone, halcinonide, amcinonide, the ciclesonide, prednisolone, methyl prednisolone, clocortolone, hydrocortisone acetonide fluoro dragon.

(7) Neurotransmitters

Neurotransmitters, also known as neurotransmitters, are a class of specific chemicals that act as informational transmissions between neuronal synapses, and are classified into monoamines, peptides, and amino acids. Among them, monoamines include dopamine, norepinephrine, adrenaline, serotonin (also known as serotonin); peptides include vasopressin, cholecystokinin, vasoactive intestinal peptide, blood vessels Vasopressin, endogenous opioid peptide, somatostatin, neuropeptide y, etc.; other classes include nucleotides, anandamide, sigma receptor (sigma receptor) and the like.

Related drugs include, but are not limited to, diphenhydramine, bromophenhydramine, doxylamine, carbisamin, clemastine, diphenhydramine, tripyridamamine, pilamine, methacetin, and suzola Sensitive, non-neiramin, chlorpheniramine, dextropheniramine, bromfenibamine, dextrobromopyramine, pyrrazine, triptoridine, promethazine, alimazine, a Diazine, cyprozine, chlorcyclizine, diphenyl larin, benzoguanamine, dimethylhydrazine, kekejing, buctorizine, anatazole, cyproheptadine, azastatin, terfena Dingsone, fexofenadine, astemizole, cetirizine, azelastine, azastatin, loratadine, desloratadine, etc.

(8) extracellular matrix substance

The extracellular matrix is an important component of the cellular microenvironment, including but not limited to collagen (such as type I collagen, type II collagen, etc.), hyaluronic acid, glycoprotein, proteoglycan, laminin, fibronectin, elastin, etc. Biomacromolecule;

(9) Dyes and fluorescent substances

Dyes include, but are not limited to, trypan blue, Coomassie brilliant blue, crystal violet, pyrogallol red, benzopentone, and the like.

Fluorescent substances can be used for fluorescent staining methods such as chemical fluorescence staining, immunofluorescence staining, and fluorescent labeling and tracing. Fluorescent substances include, but are not limited to, fluorescent proteins (such as green fluorescent protein, red fluorescent protein, etc.), rhodamines (such as TRITC, Texas Red, HAMRA, R101, RB200, etc.), phalloidin and its derivatives, Ruodan Ming, cyanine dyes (such as thiazole orange, oxazole orange), acridine (such as acridine red, acridine yellow, acridine orange, etc.), phycoerythrin, phycocyanin, methyl green, alizarin red, Aniline blue, pyronine, fluorescein (including but not limited to standard fluorescein, isocyanate fluorescein FITC, fluorescein diacetate FDA, FAM, TET, HEX, JOE, etc.), hematoxylin, eosin, neutral red , Basic Fuchsin, Alexa Fluor Series, Oregon Green Series, BODIPY Series, Cy3, Cy3.5, Cy5, Cy5.5, Cy7, Cy7.5, Hex, PerCP, DAPI, Hoechst Series, Cascade Blue, Astrazon Series, SYTO series, stilbene, naphthalimide, coumarin, anthraquinone, phenanthridine, porphyrin, anthracene derivative, chromomycin A, ethidium bromide, purpurin and the like.

All of the fluorescent compound materials disclosed in the patents CN1969190A, CN101679849B, and US14/526901 (US20150119281A1) are incorporated herein by reference. The rhodamine derivatives described in the literature "Progress in Chemistry, 2010, 22(10): 1929-1939" and the citations thereof are incorporated herein by reference. The coumarins also include, but are not limited to, 4,5,7-trihydroxycoumarin. The functional group of the formula J in the formula (1) also belongs to the biologically relevant substance herein.

(10) Targeting factor

The targeting factor is not particularly limited. It can be a single target class or a multi-target class. It may be a single molecule or an aggregate of a plurality of molecules. It may be the targeting factor itself, and also includes molecules, molecular aggregates, self-assemblers, nanoparticles, liposomes, vesicles, drugs, and the like modified with the targeting factor.

The site to be targeted is not particularly limited. Including but not limited to brain, lung, kidney, stomach, liver, pancreas, breast, prostate, thyroid, uterus, ovary, nasopharynx, esophagus, rectum, colon, small intestine, gallbladder, bladder, bone, sweat gland, skin, blood vessels, lymph , joints, soft tissue and other parts.

The targeted tissue characteristics are not particularly limited, and include, but are not limited to, tumor tissue, inflammatory tissue, diseased tissue, and the like.

Targeting factors include, but are not limited to, class I in the above functional groups, polypeptide ligands, small molecule ligands, other ligands and ligand variants that are recognized by cell surface receptors, tumor angiogenesis targeting ligands , tumor cell apoptosis targeting ligand, disease cell cycle targeting ligand, disease receptor targeting ligand, kinase inhibitor or proteasome inhibitor, PI3K/Akt/mTOR inhibitor, angiogenesis inhibitor, cytoskeleton Signal Inhibitors, Stem Cells and Wnt Gene Inhibitors, Protease Inhibitors, Protein Tyrosine Kinase Inhibitors, Apoptosis Inhibitors, MAPK Inhibitors, Cell Cycle Regulators, TGF-beta/Smad Inhibitors, Neural Signal Inhibition Agents, endocrine and hormone inhibitors, metabolic inhibitors, microbial inhibitors, epigenetic inhibitors, JAK/STAT inhibitors, DNA damage inhibitors, NF-κB inhibitors, GPCR&G Protein inhibitors, transmembrane transporters Inhibitors, autophagy inhibitors, ubiquitin Ubiquitin inhibitors, multi-target inhibitors, receptors, antibodies, gene targeting molecules, viruses, vaccines, biomacromolecular targeting factors, Any one of antibiotics, drugs targeted.

Specifically, targeting factors include, but are not limited to:

Polypeptide ligands such as RGD peptides and cyclic peptides, LPR peptides, NGR peptides, tumor vascular targeting peptides GX1, transferrin receptors Binding peptide, GE11, H24, LINGO-1 polypeptide, somatostatin analogue RC160, bombesin, gastrin releasing peptide (GRP peptide), stilbene SynB3, oligopeptide (K)16GRGDSPC, dhvar5, FHS001, octreotide , cell penetrating peptide CPPs (such as TAT peptide, ACPP), vasoactive intestinal peptide (VIP), LyP-1 (CGNKRTRGC), angiogenic homing peptide (such as GPLPLR, APRPG), Angiopep-2, F3, PR_b, ARA Peptide, etc.

Small molecule ligands such as carnitine, doxorubicin, amifostine, bortezomib, cholic acid (eg glycine cholic acid-cisplatin complex, ursodeoxycholic acid-cisplatin chelate), GDC-0449, triptolide, etc.;

Other ligands and ligand variants that are recognized by cell surface receptors, such as phosphorescent complexes targeting tumor cell surface integrin αvβ3, tumor targeting tumor necrosis factor-related apoptosis ligand variants, and the like;

Tumor angiogenesis targeting ligands, including endogenous anti-angiogenic molecules Angiostatin, Endostatin (Endostatin, Endo), Fumagillin derivatives (TNP-470), Shali Degree amine (Tnalidomide, reaction stop), cyclooxygenase-2 (COX-2), zactima (ZD6474), NGR, COX-2, anti-EGF, Herceptin, angiostatin, thalidomide, calcium adhesion Antagonists, alphastatin, PSMA, anti-CD44, endoglin, endosialin, matrix metalloproteinases (eg MMP2, MMP9), VCAM-1 E-selectin, tissue factor phosphatidylserine, silililil, etc.

Disease cell cycle targeting ligands such as adenosine, penciclovir, FIAU, FIRU, IVFRU, GCV, PCV, FGCV, FPCV, PHPG, PHBG, guanine, etc.;

Tumor cell apoptosis targeting ligands, including but not limited to TRAIL, caspase-3 targeting ligands, etc.;

Disease receptor targeting ligands such as estrogen, androgen, luteinizing hormone, transferrin, progesterone, etc.;

Kinase inhibitors or proteasome inhibitors, including tyrosine kinase inhibitors (eg, imatinib, gefitinib, erlotinib, sorafenib, dasatinib, sunitinib, lapa Tinidinib, nilotinib, pazopanib, vandetanib, etc.;

PI3K/Akt/mTOR inhibitors, including but not limited to ATM/ATR inhibitors (eg KU-55933 (ATM Kinase Inhibitor), KU-55933, KU-60019, VE-821, CP-466722, VE-822, AZ20, ETP-46464, Chloroquine Phosphate, CGK 733), PI3K inhibitors (eg PI-103, GDC-0980, CH5132799, CAL-101, GDC-0941, LY294002, BKM120, HS-173, CZC24832, NU7441, TGX-221, IC-87114, Wortmannin, XL147, ZSTK474, BYY719, AS-605240, PIK-75, 3-Methyladenine, A66, PIK-93, PIK-90, AZD6482, GDC-0980, IPI-145, TG100-115, AS- 252424, CUDC-907, PIK-294, AS-604850, GSK2636771, BAY80-6946, YM201636, CH5132799, CAY10505, PIK-293, TG100713), mTOR inhibitors (eg CCI-779, Ridaforolimus, Rapamycin, everolimus) , AZD8055, KU-0063794, XL388, PP242, INK128, Torin1, GSK2126458, OSI-027, WYE-354, AZD2014, Torin2, WYE-125132, Palomid529, WYE-687, WAY-600, Chrysophanic Acid, GDC-0349) , Akt inhibitors (eg A-674563, MK-2206, Perifosine, GSK690693, Ipatasertib, AZD5363, PF-04691502, AT7867, Triciribine, CCT128930, PHT-427, Miltefosine, Honokiol, TIC10, Triciribine phosphate), GSK-3 inhibitors (eg CHIR-99021 HCl, SB216763, CHIR-98014, TWS119, Tideglusib, 1-Azakenpaullone, AR-A014418, BIO, AZD2858, SB415286, AZD1080, Indirubin), DNA-PK inhibitors (eg NU7441, NU7026, KU-0060648, PIK-75), PDK-1 inhibitors (eg OSU-03012, BX-795, BX-912, GSK2334470), S6 Kinase inhibitors (eg BI-D1870, PF-4708671);

Angiogenesis inhibitors, including but not limited to Bcr-Abl inhibitors (eg imatinib, punatinib, nilotinib, sectinib, Degrasyn, dasatinib, Bafetinib, PD173955, GNF-5 , Danusertib, DCC-2036, GNF-2, GZD824, etc.), Src inhibitors (eg, dasatinib, sectinib, bosutinib, KX2-391, PP2, PP1), vascular endothelial growth factor receptor Inhibitors (eg endostatin, rivastatin, squalamine, thalidomide, compudidine phosphate disodium, Endo, vandetanib, vatarani, bevacizumab, PTK787/ ZK2222584, apatinib, Thrombospondins, SU5416, Orantinib, ZD4190, zactima, AEE788, Enzastaurin, Mortensini, Carbotinib, Citriani, Nintedanib, SKLB1002, Foretinib, linifanib, RAF265, Brinicib , OSI-930, Ki8751, Telatinib, Semaxanib, ZM 306416, ZM 323881 HCl, Tivozanib/AV-951, etc.), EGFR inhibitors (eg Erlotinib HCl, Gefitinib, Afatinib, Canertinib, Lapatinib, AZD9291, CO-1686, AG -1478/Tyrphostin, Neratinib, AG-490, CP-724714, Dacomitinib/PF299804, WZ4002, AZD8931/Sapitinib, PD153035 HCl, Pelitinib, AC480/BMS-599626, AEE788, OSI-420, WZ3146, WZ8040, ARRY-380, AST-1306, Genistein, Varinitinib, Icotinib, Desmethyl Erlotinib, Tyrphostin9, CNX-2006, AG-18, etc.), an interstitial lymphoma kinase inhibitor (ALK inhibitors such as TAE684, Alectinib, LDK378, AP26113, GSK1838705A, ASP3026, AZD3463), Syk inhibitors (eg R406, R788 (Fostamatinib) Disodium, PRT062607, Fostamatinib, GS-9973, Piceatannol), HER2 inhibitors (eg CP-724714, Sapitinib, Mubritinib, AC480/BMS- 599626, ARRY-380, etc.), fibroblast growth factor receptor inhibitors (FGFR inhibitors such as BGJ398, PD173074, AZD4547, SSR128129E, Brivanib Alaninate), HIF inhibitors (eg FG-459, 2-Methoxyestradiol, IOX2, BAY 87-2243), VDA inhibitors (eg DMXAA/Vadimezan, Plinabulin), JAK inhibitors (eg Ruxolitinib/INCB018424, Tofacitinib, AZD1480, TG101348, GLPG0634, Pacritinib, XL019, Momelotinib, Tofacitinib, TG101209, LY2784544, NVP-BSK8052HCl , Baricitinib, AZ 960, CEP-33779, S-Ruxolitinib, ZM 39923 HCl), platelet-derived growth factor receptor inhibitor (PDGFR inhibitor, such as Cr Enolanib/CP-868596, CP-673451, Nintedanib/BIBF 1120, Masititinib/AB1010, TSU-68/SU6668/Orantinib, Tyrphostin AG 1296), FLT3 inhibitors (eg Quizartinib, Tandutinib, KW-2449, TCS 359, ENMD- 2076L-(+)-Tartaric acid), FAK inhibitors (eg PF-00562271, PF-562271, PF-573228, TAE226, PF-562271HCl), BTK inhibitors (eg Ibrutinib, AVL-292, CNX-774, CGI1746) );

Cytoskeletal signaling inhibitors, including integrin inhibitors (such as Cilengitide, RGD (Arg-Gly-Asp) Peptides), Dynamin inhibitors (such as Dynasore, Mdivi-1), Bcr-Abl inhibitors, Wnt/beta-catenin inhibition Agents (eg XAV-939, ICG-001, IWR-1-endo, Wnt-C59, LGK-974, FH535, IWP-2, IWP-L6, KY02111), PAK inhibitors (eg IPA-3, PF-3758309) , Akt inhibitors, HSP inhibitors (such as HSP90 inhibitors, such as Tanespimycin, AUY922, Alvespimycin, Ganetespib, Elesclomol, VER-50589, CH5138303, PU-H71, NMS-E973, VER-49009, BIIB021, AT13387, NVP- BEP800, Geldanamycin, SNX-2112, PF-04929113, KW-2478, XL888), Kinesin inhibitors (eg Ispinesib, SB743921, GSK923295, MPI-0479605), Tubulin-related inhibitors (eg Paclitaxel, Docetaxel, Vincristine, Epothilone) B, ABT-751, INH6, INH1, Vinorelbine Tartrate, CK-636, CW069, Nocodazole, Vinblastine, CYT997, Epothilone, Fosbretabulin, Vinflunine Tartrate, Griseofulvin), PKC inhibitors (eg Enzastaurin, Sotrastaurin, Staurosporine, Go 6983, GF109203X) ,Ro31-8220M Esylate, Dequalinium Chloride), FAK inhibitor;

Stem cells and Wnt gene inhibitors, including but not limited to Wnt/beta-catenin inhibitors, Hedgehog/Smoothened inhibitors (eg Vismodegib, Cyclopamine, LDE225, LY2940680, Purmorphamine, BMS-833923, PF-5274857, GANT61, SANT-1) , GSK-3 inhibitors (such as CHIR-99021, CHIR-99021, CHIR-98014, TWS119, Tideglusib, AR-A014418, AZD2858, SB415286), JAK inhibitors, STAT inhibitors (such as S3I-201, Fludarabine, Niclosamide, Stattic, Cryptotanshinone, HO-3867), ROCK inhibitors (eg Y-27632 2HCl, Thiazovivin, GSK429286A, RKI-1447), TGF-beta/Smad inhibitors (eg SB431542, LY2157299, LY2109761, SB525334, DMH1, LDN-212854) , ML347, LDN193189 HCl, K02288, SB505124, Pirfenidone, GW788388, LY364947, RepSox), γ-secretase inhibitors (eg DAPT, RO4929097, Semagacestat, MK-0752, Avagacesta, FLI-06, YO-01027, LY411575);

Protease inhibitors, including but not limited to DPP-4 inhibitors (such as Sitagliptin phosphate monohydrate, Linagliptin, Vildagliptin, Glimepiride, Saxagliptin, Trelagliptin, Alogliptin), HIV protease inhibitors (such as Ritonavir, Lopinavir, Atazanavir Sulfate, Darunavir Ethanolate, Amprenavir, Nelfinavir Mesylate), MMP inhibitors (eg Sulfamerazine, Batimastat, NSC 405020, Ilomastat, SB-3CT), Caspase inhibitors (eg VX-765, PAC-1, Apoptosis Activator 2, Tasisulam, Z-VAD-FMK), serine Protease inhibitors (eg Avelestat, AEBSF HCl, Aprotinin, Gabexate Mesylate), γ-secretase inhibitors, proteasome inhibitors (eg Bortezomib, MG-132, Carfilzomib, MLN9708, MLN2238, PI-1840, ONX-0914, Opizomib) , CEP-18770, Nafamostat Mesylate), HCV protease inhibitors (eg Dacalatasvir, Telaprevir, VX-222, Danoprevir), cysteine protease inhibitors (eg Odanacatib, E-64, Aloxistatin, Z-FA-FMK, Loxistatin) Acid (E-64C), Leupeptin Hemisulfate), Fms-like tyrosine kinase inhibitor, Aurora Kinase inhibitors, Abelson kinase inhibitors, etc.;

Protein tyrosine kinase inhibitors, including but not limited to Axl inhibitors (eg R428/BGB324, BMS-777607, Cabozantinib malate), c-Kit inhibitors (eg Dasatinib), Tie-2 inhibitors (eg Tie2 kinase inhibitor) , CSF-1R inhibitors (eg GW2580), Ephrin Receptor inhibitors, vascular endothelial growth factor receptor inhibitors, EGFR inhibitors, IGF-1R inhibitors (eg OSI-906, NVP-AEW541, GSK1904529A, NVP-ADW742, BMS-536924, GSK1838705A, AG-1024, BMS-754807, PQ 401), c-Met inhibitors (eg Crizotinib, Foretinib, PHA-665752, SU11274, SGX-523, EMD 1214063, JNJ-38877605, Tivantinib, PF- 04217903, INCB28060, BMS-794833, AMG-208, AMG-458, NVP-BVU972), ALK inhibitor, HER2 inhibitor, FGFR inhibitor, PDGFR inhibitor c-RET inhibitor, FLT3 inhibitor, Trk receptor inhibitor (eg GW441756);

Inhibitors of apoptosis, including but not limited to Caspase inhibitors, Bcl-2 inhibitors (eg ABT-737, ABT-263, Obatoclax Mesylate, TW-37, ABT-199, AT101, HA14-1, BAM7), p53 Inhibitors (eg JNJ-26854165, Pifithrin-α, RITA, Tenovin-1, NSC 319726, Tenovin-6, Pifithrin-μ, NSC 207895), Survivin inhibitors (eg YM155), TNF-alpha inhibitors (eg Lenalidomide, Pomalidomide, Thalidomide, Necrostatin-1, QNZ), PERK inhibitors (eg GSK2606414, GSK2656157, ISRIB), Mdm2 inhibitors (eg Nutlin-3, Nutlin-3a, Nutlin-3b, YH239-EE), c-RET inhibitors , IAP inhibitors (eg Birinapant, GDC-0152, Embelin, BV6);

MAPK inhibitors, including but not limited to Raf inhibitors (eg, Vemurafenib, PLX-4720, Dabrafenib, GDC-0879, Encorafenib, TAK-632, SB590885, ZM 336372, GW5074, Raf265 derivative), ERK inhibitors (eg XMD8-92) , SCH772984, FR 180204), MEK inhibitors (eg Selumtinib, PD0325901, Trametinib, U0126-EtOH, PD184352, RDEA119, MEK162, PD98059, BIX 02189, Pimasertib), p38 MAPK inhibitors (eg SB203580, BIRB 796, SB202190, LY2228820) , VX-702, Losmapimod, Skepone-L, PH-797804, VX-745, TAK-715, Asiatic acid), JNK inhibitors (eg SP600125, JNK-IN-8, JNK inhibitor IX);

Inhibitors of cell cycle regulation, including but not limited to c-Myc inhibitors (such as 10058-F4), Wee1 inhibitors (such as MK-1775), Rho inhibitors (such as Zoledronic Acid, NSC 23766, EHop-016, ZCL278, K- Ras (G12C) inhibitor 6, EHT 1864), Aurora Kinase inhibitors (eg Alistipib, VX-680, Barasertib, ZM 447439, MLN8054, Danusertib, Hesperadin, Aurora A Inhibitor, SNS-314 Mesylate, PHA-680632, MK-5108 , AMG-900, CCT129202, PF-03814735, GSK1070916, TAK-901, CCT137690), CDK inhibitors (eg Palbociclib, Roscovitine, SNS-032, Dinaciclib, Flavopiridol, XL413, LDC000067, ML167, LEE011, TG003, AT7519, Flavopiridol HCl, JNJ-7706621, AZD5438, MK-8776, PHA-793887, BS-181 HCl, Palbociclib, A-674563, LY2835219, BMS-265246, PHA-767491, Milciclib, R547, NU6027, P276-00), Chk inhibition Agents (eg AZD7762, LY2603618, MK-8776, CHIR-124), ROCK inhibitors, PLK inhibitors (eg BI 2536, Volasertib, Rigosertib, GSK461364, HMN-214, Ro3280, MLN0905), APC inhibitors (eg TAME) ;

TGF-beta/Smad inhibitors, including but not limited to Bcr-Abl inhibitors, ROCK inhibitors, TGF-beta/Smad inhibitors, PKC inhibitors;

Neuronal signaling inhibitors, including BACE inhibitors (such as LY2811376), dopamine receptor inhibitors (such as Quetiapine Fumarate, Benztropine mesylate, Chlorpromazine HCl, Amantadine HCl, Domperidone, Alizapride, Olanzapine, Amfebutamone HCl, Amisulpride, Paliperidone, Rotundine, Chlorprothixene, Pramipexole 2HCl Monohydrate, Levosulpiride, Lurasidone HCl, Pramipexole, Dopamine HCl, Pergolide mesylate, PD128907 HCl), COX inhibitors (eg Celecoxib, Ibuprofen, Rofecoxib, Bufexamac, Piroxicam, Etomolac, Ketoprofen, Diclofenac Sodium, Ibuprofen Lysine, Ketorolac, Naproxen, Lornoxicam, Lumiracoxib, Asaraldehyde, Acemetacin, Tolfenamic Acid, Zaltoprofe, Valdecoxib, Phenacetin, Nimesulide, Licofelone, Nabumetone, Flunixin Meglumin, Triflusal, Ampiroxicam, MefenamicAcid), GluR inhibitors (eg LY404039, MK-801, (-)-MK 801 Maleate, CTEP, Riluzole, ADX-47273, Ifenprodil, VU 0357121, MPEP, IEM 1754dihydrobroMide, NMDA, VU 0364439, VU 0364770, VU 0361737), gamma-aminobutyric acid receptor inhibitors (eg Valproic acid sodium salt, Flumazenil, Gabapentin HCl, Etomidate, Gabapentin, (+)-Bicuculline, Nefiracetam, Niflumic acid, (R)-baclofen, Ginkgolide A), γ-secretase inhibitors, adrenergic receptor inhibitors (eg Salbutamol Sulfate, Doxazosin Mesylate, Doxazosin Mesylate, Mirabegron, Alfuzosin HCl, Carteolol HCl, Brimonidine Tartrate, Asenapine, Indacaterol Maleate Isoprenaline HCl, Formoterol Hemifumarate, Silodosin, Nebivolol, Epinephrine Bitartrate, Clonidine HCl, Oxymetazoline HCl, Phentolamine Mesylate, Propranolol HClBisoprolol fumarate, L-Adrenaline, Dexmedetomidine, Naftopidil DiHCl, Naftopidil, Maprotiline HCl, Phenylephrine HCl, Carvedilol, Metoprolol Tartrate, Terazosin HCl, Phenoxybenzamine HCl, Sotalol, Naphazoline HCl, Ritodrine HCl, Dexmedetomidine HCl, Synephrine HCl, Guanabenza Acetate, Timolol Maleate, Tizanidine HCl, Synephrine, Betaxolol HCl, Detomidine HCl, Epinephrine HCl, Medetomidine HCl, Acebutolol HCl, Scopine, DL-Adrenaline, Ivabradine HCl, Betaxolol, Cisatracurium Besylate, Adrenalone HCl , Tetrahydrozoline HCl, Tolazoline HCl, Terbutaline Sulfate), opioid receptor inhibitors (eg Loperamide HCl, Naloxone HCl, JTC-801, ADL5859 HCl, Naltrexone HCl, (+)-Matrine, Racecadotril, Trimebutine), 5-HT Receptor inhibition Agents (eg, Clozapine, Olanzapine, Ketanserin, Fluoxetine HCl, Tianeptine sodium, RS-127445, Agomelatine, Sumatriptan Succinate, Prucalopride, Dapoxetine HCl, Paroxetine, Risperidone, WAY-100635 Maleate, Aripiprazole, Naratriptan, Blonanserin, Vortioxetine, Rizatriptan Benzoate, Zolmitriptan, Fluvoxamine Maleate,Granisetron HCl,Mosapride Citrate,BRL-15572,SB269970 HCl,SB742457,PRX-08066 Maleic acid,Lorcaserin HCl,O Ndansetron HCl, Tropisetron, Lamotrigine, Eletriptan HBr, Sertraline HCl, Desvenlafaxine, Duloxetine HCl, Azasetron HCl, Escitalopram Oxalate, Ondansetron, Almotriptan Malate, Amitriptyline HCl, SB271046, LY310762 Trazodone HCl, Urapidil HCl, Atomoxetine HCl, BRL-54443, Palonosetron HCl , VUF 10166, Desvenlafaxine Succinate), P-gp inhibitors (eg Zosuquidar, Tariquidar), P2 receptor inhibitors (eg Prasugrel, Clopidogrel, MRS 2578, Ticagrelor, GW791343 HCl, Ticlopidine HCl), MT receptor inhibitors (eg Ramelteon), AChR inhibitors (eg Donepezil HCl, Tiotropium Bromide hydrate, Pancuronium dibromide Tolterodine tartrate, Fesoterodine Fumarate, (-)-Huperzine A (HupA, Oxybutynin, PNU-120596, Solifenacin succinate, Varenicline Tartrate, Galanthamine HBr, Atropine, Trospium Chloride,Rocuronium Bromide,Methscopolamine,Aclidinium Bromide,Bethanechol chloride,Scopolamine HBr,Otilonium Bromide,Biperiden HCl,Pyridostigmine Brom Ide, Irsogladine, Gallamine Triethiodide, Arecoline, 5-hydroxymethyl Tolterodine, Rivastigmine Tartrate, Neostigmine Bromide, Darifenacin HBr, Acetylcholine Chloride, Tropicamide, Orphenadrine citrate, Oxybutynin chloride, Hyoscyamine, Homatropine Methylbromide, Homatropine Bromitide, Flavoxate HCl, Diphemanil Methylsulfate, Hexamethonium Bromide, Decamethonium Bromide , Succinylcholine Chloride Dihydrate), histamine receptor inhibitors (eg Clemastine Fumarate, Loratadine, Mianserin HCl, Ranitidine, Azelastine HCl, Ebastinea, Latrepirdine, Bepotastine Besilate, Cetirizine DiHCl, Hesperetin, Chlorpheniramine Maleate, Mizolastine, Ciproxifan, Desloratadine, Nizatidine, Cimetidine, Lafutidine ,Tripelennamine HCl,FexofenadineHCl,Lidocaine,OlopatadineHCl,Brompheniramine hydrogen maleate,Ketotifen Fumarate,Cyproheptadine HCl,Azatadine dimaleate,Rupatadine Fumarate,JNJ-7777120,Hydroxyzine 2HCl,Buclizine HCl,Famotidine,Roxat Didine Acetate, Betahistine 2HCl, Pemirolast potassium, Histamine 2HCl, Levodropropizine, Cyclizine 2HCl), OX receptor inhibitors (eg Suvorexant, SB408124, Almorexant HCl), Beta Amyloid inhibitors (eg EUK 134, RO 4929097, LY 2811376);

Endocrine and hormonal inhibitors, including but not limited to androgen receptor inhibitors (eg Enzalutamide, Bicalutamide, MK-2866, ARN-509, Andarine, AZD3514, Galeterone, Flutamide, Dehydroepiandrosterone, Cyproterone Acetate), estrogen/progesterone receptor inhibitors (eg Fulvestrant, Tamoxifen Citrate, Raloxifene HCl, Erteberel, Mifepristone, Ospemifene, Toremifene Citrate, Dienogest, Bazedoxifene HCl, Gestodene, Clomifene citrate, Medroxyprogesterone acetate, Equol, Drospirenone, Hexestrol , Epiandrosterone, Estriol, Pregnenolone, Estradiol valerate, Estrone, Bazedoxifene Acetate, Altrenogest, Tamoxifen, Ethisterone, Ethynodiol diacetate, Estradiol Cypionate), Aromatase inhibitor, RAAS inhibitor (eg Candesartan, Aliskiren Hemifumarate, Losartan Potassium, Enalaprilat Dihydrate, Telmisartan, PD123319, Irbesartan, Valsartan, Perindopril Erbumine, Benazepril HCl, Olmesartan Medoxomil, Ramipril, Enalapril Maleate, Candesartan Cilexetil, Captopril, Lisinopril, Cilazapril Monohydrate, Moexipril HCl, Azilsartan Medoxomil, Quinapril HCl, Temocapril HCl, Temocapril Imidapril HCl, Fosinopril Sodium, Azilsartan Opioid receptor Agents, 5α-reductase inhibitors (e.g., Dutasteride, Finasteride), GPR inhibitors (e.g. TAK-875, GSK1292263, GW9508, AZD1981, OC000459);

Metabolic inhibitors, including but not limited to IDO inhibitors (eg NLG919), aminopeptidase inhibitors (eg Tosedost), Procollagen C Proteinase inhibitors (eg UK 383367), Phospholipase inhibitors (eg Varesladib, Darapladib), FAAH inhibitors (eg URB597, PF-3845, JNJ-1661010), Factor Xa inhibitors (eg Rivaroxaban, Apixaban, Ozagrel, Edoxaban), PDE inhibitors (eg Roflumilast, Sildenafil Citrate, Cilomilast, Tadalafil, Vardenafil HCl Trihydrate, Pimobendan, GSK256066, PF-2545920, Rolipram, Apremilast, Cilostazol, Icariin, Avanafil, S-(+)-Rolipram, Aminophylline, Anagrelide HCl, Dyphylline, Luteolin), dihydrofolate reductase inhibitors (eg Pemetrexed, Methotrexate, Pralatrexate, Pyrimethamine), Carbonic anhydrase inhibitors (such as Dorzolamide HCl, Topiramate, U-104, Tioxolone, Brinzolamide, Methazolamide), MAO inhibitors (such as Safinamide Mesylate, Rasagiline Mesylate, Tranylcypromine (2-PCPA) HCl, Moclobemide), PPAR inhibitors (eg Rosiglitazone maleate, Rosiglitazone, GW9662, T0070907, WY -14643, FH535, GSK3787 inhibitor GW0742, Ciprofibrate, Rosiglitazone HCl), CETP inhibitors (eg Anacetrapib, Torcetrapib, Evacetrapib, Dalciperib), HMG-CoA Reductase inhibitors (eg Rosuvastatin Calcium, Lovastatin, Fluvastatin Sodium, Atorvastatin Calcium, Pravastatin Sodium, Clinofibrate,), transferase, inhibitors (eg Tipifarnib, Lonafarnib, FK866A922500, Tolcapone, PF-04620110, LB42708, RG108), Ferroptosis inhibitors (eg Erastin, Ferrostatin-1), HSP inhibitors (eg HSP90 inhibitors) ), P450 inhibitors (eg Abiraterone, Abiraterone Acetate, Voriconazole, Avasimibe, Ketoconazole, Apigenin, TAK-700, Galeterone, Clarithromycin, Baicalein, Cobicistat, Naringenin, Pioglitazone HCl, Alizarin, Sodium Danshensu, PF-4981517), hydroxylase Inhibitors (eg Nepicastat (SYN-117) HCl, Isotretinoin, Mildronate, Telotristat Etiprate, (R)-Nepicastat HCl, DMOG), dehydrogenase inhibitors (eg Mycophenolate Mofetil, CPI-613, AGI-5198, MK-8245) ,Trilostane,AGI-6780PluriSIn#1,Gimer Acil);

Microbiological inhibitors, including but not limited to CCR inhibitors (eg Maraviroc), HIV protease inhibitors, reverse transcriptase Reverse Transcriptase inhibitors (eg Tenofovir, Tenofovir Disoproxil Fumarate, Emtricitabine, Adefovir Dipivoxil, Nevirapine, Rilpivirine, Didanosine, Lamivudine, Stavudine, Etravirine, Zidovudine, Zalcitabine, Abacavir sulfate, Dapivirine), HCV protease inhibitor, integrase Integrase inhibitor (eg Raltegravir, Elvitegravir, Dolutegravir, BMS-707035, MK-2048);

Epigenetic inhibitors, including but not limited to histone demethylase inhibitors (eg GSK J4 HCl, OG-L002, JIB-04, IOX1), Pim inhibitors (eg SGI-1776, SMI-4a, AZD1208, CX-6258 HCl), histone methyltransferase inhibitor (eg EPZ5676, EPZ005687, GSK343, BIX 01294, EPZ-6438, MM-102, UNC1999, EPZ004777, 3-Deazaneplanocin A, EPZ004777 HCl, SGC 0946, Entacapone), Epigenetic Reader Domain inhibitors (eg (+)-JQ1, I-BET151, PFI-1, I-BET-762, RVX-208, CPI-203, OTX015, UNC669, SGC-CBP30, UNC1215, Bromosporine) , histone acetyltransferase inhibitors (eg C646, MG149), HIF inhibitors (eg FG-4592, 2-Methoxyestradiol, IOX2, BAY 87-2243), JAK inhibitors, HDAC inhibitors (eg Vorinostat, Entinostat, Panobinostat) , Trichostatin A, Mocetinostat, TMP269, Nexturastat A, RG2833, RGFP966, Belinostat, Romidepsin, MC1568, Tubastatin A HCl, Givinostat, LAQ824, CUDC-101, Quisinostat, Pracineta, PCI-34051, Droxinostat, PCI-24781, AR-42, Rocilinostat, Valproic acid sodium Salt, CI994, CUDC-907, Tubacin, M344, Resminostat, Scriptaid, Sodium Phenylbutyrate, Tubastatin A), deacetylase inhibitors (eg SRT1720, EX 527, Resveratrol, Sirtinol), Aurora kinase inhibitors (Aurora Kinase inhibitors) ), PARP inhibitors (eg Olaparib, Veliparib, Rucaparib, Iniparib, BMN 673, 3-Aminobenzamide, ME0328, PJ34 HCl, AG-14361, INO-1001, A-966492, PJ34, UPF 1069, AZD2461), DNA methyl Transferase inhibitors (eg, Decitabine, Azacitidine, RG108, Thioguanine, Zebularine, SGI-1027, Lomeguatrib);

JAK/STAT inhibitors, including but not limited to Pim inhibitors, EGFR inhibitors, JAK inhibitors, STAT inhibitors;

DNA damage inhibitors, including but not limited to ATM/ATR inhibitor DNA-PK inhibitors (eg NU7441, NU7026, KU-0060648, PIK-75), HDAC inhibitors, deacetylase Sirtuin inhibitors, PARP inhibitors, Topoisomerase inhibitors (eg, Doxorubicin, Etoposide, Camptothecin, Topotecan HCl, Irinotecan, Voreloxin, Beta-Lapachone, Idarubicin HCl, Epirubicin HCl, Moxifloxacin HCl, Irinotecan HCl Trihydrate, SN-38, Amonafide, Genistein, Mitoxantrone, Pirarubicin, Ofloxacin, Ellagic acid, Betulinic acid, (S)-10-Hydroxycamptothecin, Flumequine, Pefloxacin Mesylate Dihydrate), telomerase inhibitors (eg BIBR 1532, Daunorubicin HCl, Costunolide), DNA/RNA Synthesis inhibitors (eg Cisplatin, Gemcitabine) HCl, Bleomycin Sulfate, Carboplatin, Oxaliplatin, CRT0044876, Triapine, Pemetrexed, Fludarabine, CX-5461, Fluorouracil Capecitabine, Fludarabine Phosphate, Cytarabine, Gemcitabine, Nelarabine, Cladribine, Raltitrexed, Clofarabine, Ifosfamide, NSC 207895, Dacarbazine, Floxu Ridine, Mercaptopurine, Flupirtine maleate, Mizoribine, Carmofur, Procarbazine HCl, Daphnetin, FT-207, Adenine, Adenine HCl, Adenine sulfate, Uridine);

NF-κB inhibitors, including but not limited to NOD1 inhibitors (eg ML130), HDAC inhibitors, NF-κB inhibitors (eg QNZ, Sodium 4-Aminosalicylate, JSH-23, Caffeic Acid Phenethyl Ester, SC75741), IκB/ IKK inhibitors (eg IKK-16, TPCA-1 IMD 0354, Bardoxolone Methyl, BAY 11-7085, BMS-345541, BX-795, SC-514);

GPCR&G Protein inhibitors, including but not limited to protease-activated receptor Protease-activated Receptor inhibitors, CGRP Receptor inhibitors (eg MK-3207 HCl), Hedgehog/Smoothened inhibitors (eg Vismodegib, Cyclopamine, LDE225, LY2940680, Purmorphamine, BMS) -833923, PF-5274857, GANT61, SANT-1), LPA Receptor inhibitors (eg Ki16425, Ki16198), PAFR inhibitors (eg Ginkgolide B), CaSR inhibitors (eg Cinacalcet HCl, NPS-2143), vascular pressurization Receptor inhibitors (eg Tolvaptan, Mozavaptan), Adenosine Receptor inhibitors (eg CGS 21680 HCl, Istradefylline), endothelin receptor inhibitors (eg Zibotentan, Bosentan Hydrate, Macitentan, Sitaxentan sodium, Bosentan), S1P Receptor inhibitors (eg Fingolimod, SKI II, PF-543), adrenergic receptor inhibitors, cannabinoid receptor inhibitors (eg Rimonabant, AM1241, AM251, Otenabant (CP-945598) HCl, GW842166X, BML-190, Org 27569) , SGLT inhibitors (eg Dapagliflozin, Canagliflozin, Empagliflozin), opioid receptor inhibitors, dopamine inhibitors, 5-HT Receptor inhibitors, M T receptor inhibitor, histamine receptor inhibitor, OX Receptor inhibitor, CXCR inhibitor (such as Plerixafor 8HCl, Plerixafor, WZ811), cAMP inhibitor (such as Forskolin, Bupivacaine HCl);

Transmembrane transporter inhibitors, including CRM1 inhibitors (eg Selinexor, KPT-185, KPT-276), CFTR inhibitors (eg Ataluren, Ivacaftor, VX-809, VX-661, CFTRinh-172, IOWH032), sodium ions Channel inhibitors (eg, Riluzole, Rufinamide, Carbamazepine, Phenytoin sodium, Amiloride HCl dihydrate, A-803467, Phenytoin, Lamotrigine, Ambroxol HCl, Ouabain, Oxcarbazepine, Propafenone HCl, Proparacaine HCl, Vinpocetine, Ibutilide Fumarate, Procaine HCl, Dibucaine HCl, Triamterene), ATPase inhibitor (eg Omecamtiv mecarbil, Oligomycin A, Brefeldin A, (-)-Blebbistatin, Sodium orthovanadate, BTB06584, Golgicide A, Milrinone, Ciclopirox ethanolamine, Esomeprazole Sodium, PF-3716556), potassium channel inhibitors (eg Amiodarone HCl, Repaglinide, TRAM-34, Nicorandil, Tolbutamide, Chlorpromazine HCl, Gliquidone, Nateglinide, TAK-438, ML133 HCl, Gliclazide, Mitiglinide Calcium), γ-amino Butyric acid receptor inhibitors, calcium channel inhibitors (eg Amlodipine Besylate, Cilnidipine, Ranolazine 2HCl, Felodipine, Isradipine, Amlodipine, Manidipine 2HCl, Manidipine, Nimodipine, Nilvadipine, Lacifipine, Clevidipine Butyrate, Benidipine HCl, Flunarizine 2HCl, Nitrindipine, Tetracaine HCl, Strontium Ranelate, Azelnidipine, Tetrandrine), proton pump inhibitors (eg Lansoprazole, Omeprazole, Esomeprazole Magnesium, Zinc Pyrithione, PF-3716556, Tenatoprazole), P-gp inhibitors;

Autophagy inhibitors such as Temozolomide, Metformin HCl, Trifluoperazine 2HCl, Divalproex Sodium, Azithromycin, Dexamethasone, Sulfacetamide Sodium;

Ubiquitin inhibitors, including but not limited to p97 inhibitors (eg NMS-873, DBeQ, MNS), E1 Activating inhibitors (eg PYR-41), proteasome inhibitors, DUB inhibitors (eg PR-619, P5091, IU1, LDN-57444, TCID, ML323, Degrasyn, P22077), E2 conjugating inhibitor (eg NSC697923), E3 Ligase inhibitor (eg (-)-Parthenolide, Nutlin-3, JNJ-26854165, Thalidomide, NSC 207895 , TAME, RITA);

Multi-target inhibitors, including but not limited to KU-60019, CUDC-101, TAK-285, WHI-P154, Chrysophanic Acid, PD168393, Butine, Sunitinib Malate, Imatinib (STI571), PP121, Sorafenib Tosylate, Imatinib Mesylate ( STI571), Ponatinib (AP24534), Axitinib, Pazopanib HCl (GW786034 HCl), Dovitinib (TKI-258, CHIR-258), Linifanib (ABT-869), Tivozanib (AV-951), Motesanib Diphosphate (AMG-706), Amuvatinib (MP-470), Dilactic Acid, MK-2461, WP1066, WHI-P154, Ponatinib, Neratinib (HKI-272), Lapatinib, TAK-285, Tyrphostin AG 879, KW-2449, Cabozantinib, R406, Amuvatinib, PF -03814735, WIKI4, AZ 3146, Fasudil, Vatalanib, MGCD-265, Golvatinib, Regorafenib, RAF265, CEP-32496, AZ 628, NVP-BHG712, AT9283, ENMD-2076, ENMD-2076, CYC116, ENMD-2076 L- (+)-Tartaric acid, PF-477736, BMY 7378, Clomipramine HCl, Latrepirdine, CUDC-907, Quercetin, BAY 11-7082;

Receptors, such as the HER2 receptor, anti-EGFR receptors (eg gefitinib, Erbitux, erlotinib, piratinib, lapatinib, carnitinib), hepatocyte growth factor receptor (HGFR, c-Met) and RON, tumor necrosis factor receptor, vascular endothelial growth factor receptor (eg Flt-1, KDR, Flt4), interleukin receptor, transferrin receptor, lipoprotein receptor, insulin-like Growth factor receptor (IGFR), lectin receptor (including asialoglycoprotein receptor and mannose receptor), scavenger receptor, folate receptor, galactose receptor (sialyl glycoprotein receptor / ASGPR) (eg BD-galactose, galactosylceramide, trigalactosylcholesterol, galactosylphosphatidylethanolamine, asialofetuin and synthetic glycoprotein), type I transmembrane tyrosine kinase growth factor (ErbB) receptor, Toll-like receptors (including TLR-1, TLR-2, TLR-3, TLR-4, TLR-5, TLR-6, TLR-7, TLR-8, and TLR-9), thin Receptor, diphtheria toxin receptor, integrin αvβ3, nucleolar protein, p32 receptor, somatostatin receptor, vasoactive intestinal peptide receptor, cholecystokinin receptor, endothelial cell selectin, etc.

Antibodies, including but not limited to the above antibodies, are not described here;

Targeted drugs including, but not limited to, tamoxifen, raloxifene, toremifene, fulvestrant, ectinib, flumatinib, faridinib, furazolinib, sip Tinidinib, sovantinib, erlotinib, erlitinib, plittinib, ibitinib, rofecoxib, sirinib, imatinib, dasatinib, nilo Dini, gefitinib, erlotinib, temsirolimus, everolimus, vandetanib, lapatinib, vorinostat, romidepsin, bexarotene, alvi Formic acid, bortezomib, pralatrexate, sorafenib, sunitinib, pazopanib, ipilimum, diltinidin 2, sunitinib, Gleevec, Iressa, Tamoxifen, tofartinib, Temsirolimus, Velcade, apatinib, motetanil, endostatin, ziv-Aflibercept, brivanib, linifanib, tivozanib, vatarani, CDP791, crizotinib, Navitoclax, cotton Phenol, Iniparib, perifosine, AN-152, vemurafenib, darafini, trimetinib, Binimetinib, Encorafenib, Palbociclib, LEE011, Salicin, Vintafolide, Ero Nie, afatinib, lapatinib, neratinib, axitinib, masatinib, Toc Vorinostat eranib, statinib, cedibutib, regisinib, simashani, ni Rotinib, punatinib, bosutinib, carbaryl, cabozantinib, ceritinib, ibrutinib, capecitabine, tegafur, competidine diphosphate, Willofini, Vismodegib, anastrozole, Arimidex, exemestane, letrozole, Dinosem, lenalidomide, pomamide, Carfilzomib, Belinostat, cabazitaxel, abiraterone acetate, 233 injection of diazonium chloride, luteinizing hormone releasing hormone, militalin, Oblimersen, Navitoclax , sectinib, Vismodegib, Marimatat, fucosyl GM1 composition, Alvocidib, havopiridol, vincristine, tipironib, depsipeptide, BSU21051, cationic porphyrin compound, UCN-01, ICR-62 , peritinib, PKI-166, carotinib, PD158780, HKI-357, ZD6126, amifostine, Ombrabulin, cobstatin, soblidotin, Denibulin, Tozasertib, decitabine, AEE788, Orantinib, SU5416, Enzastaurin, oxaliplatin, celecoxib, aspirin, obatolcax, AT-101, tamoxistat, bicepoda, rofecoxib, NS-398, SC-58125, Batimastat, pulazostat, Metastat, neovastat, BMS-275291, Lonofani, BMS-214662, SCH44342, SCH54429, L-778123, BMS-214662, BMS-185878, BMS-186511, BZA-5B, BzA-2B, 735, L-739 , L-750, L-744832, B581, Cys-4-ABA-Met, Cys-AMBAMet, FTI276 , FTI277, B956, B1096, limonene, handmycin, genistein, erbstatin, lavendustin A, herbimycin A, tyrphostin, PD169540, CL-387785, CP-358744, CGP59326, CGP59326-A, oleic acid A and B , mycomycin, florin A and its analogues, lupin derivatives, CGS27023A, squalamine, thalidomide, Cilengitide, carboxyamimidazole, suramin, IM862, DS-4152, CM- 101, novvastatin, PD98059, PD184352, diazonium tyrosine, anti-pain, MT477, benzoquinone ansamycin, geldell, neocarcin, azacitidine, aclarin A, Cholesterol derivatives thioguanine, MCC465, liver-targeted carbamazepine, liver-targeted ricin, etoposide, teniposide, poloxamer, dexamethasone, talivirin, BIBW-2992 , the above monoclonal antibody drugs, and the like.

Gene targeting molecules, such as nucleic acid aptamers, cyclins, antisense oligonucleotides (eg c-myc, c-myb, bcl-2, N-Ras, K-Ras, H-Ras, c-iun, C-fos, cdc-2 and c-mos, etc., tumor genetic engineering tumor, p53 negative regulatory molecule PACT, gene-transduced DC (such as AAV-BA46-DC), gene-transduced TIL (IL-2, TNF-α), intracellular signaling molecules and transcription factors, MDM2 oncogenes, etc.;

Viruses, such as oncolytic anti-cancer recombinant adenovirus, human T lymphocyte virus, Rous sarcoma virus, ONXY2015, herpes simplex virus type I (HSVI), serotype recombinant adenovirus (such as rAAV2, rAAV8);

Vaccines, such as tumor cell vaccines, genetically modified vaccines, dendritic cell vaccines, fusion cell vaccines, viral vaccines, protein/polypeptide vaccines, nucleic acid vaccines (eg, tumor-targeted recombinant DNA vaccines), anti-idiotype vaccines, heterologous vaccines, Recombinant human EGF-P64K vaccine, BEC-2 and BCG vaccine, fucosyl-GM 1 composition, H PV tetravalent vaccine Gar dasil, bivalent vaccine Cervarix, etc.;

Biomacromolecular targeting factors, including but not limited to proteins (eg, ligand transferrin, low density lipoprotein, hemoglobin, lectin, cytoskeletal proteins such as vimentin, heat shock proteins), low molecular weight proteins (such as lysozyme and streptavidin);

Vitamins such as folic acid and biotin.

Targets for targeting factors include, but are not limited to, CD3, CD11, CD20, CD22, CD25, CD30, CD33, CD41, CD44, CD52, CD6, CD3, CD11a, Her2, GpIIb/IIIa, RANKL, CTLA-4, CO17 -1A, IL-1β, IL-12/23, IL6, IL13, IL-17, Blys, RSV, IgE-25, integrin-α4, respiratory syncytial virus F protein, tumor necrosis factor alpha (TNFα), vascular endothelium Growth factors, epidermal growth factor receptor (EGFR), FGR3, EGFL-7, interferon alpha, and the like.

(11) vesicles, liposomes, micelles, nanocarriers for drug delivery, cells (such as myeloblasts, etc.), viruses (such as cyanobacterial cytokines), and the like, and biologically relevant substances well known to those skilled in the art. .

(12) plant or animal extract

Including but not limited to Tripterygium wilfordii extract (including but not limited to triptolide, triptolide, triptolide, beglicin, triptolide, triptolide, triptolide) Alcohol, triptolide, triptolide, tripterygium wilfordii, tripterygium wilfordii, tripterygium wilfordii, tripterygium wilfordii, triptolide, triptolide, triptolide, tripterygium, tripterygium Polysaccharide, etc., aspenwood extract (such as boxwood, including but not limited to cycloalkaline, cyclophosphannine, cyclosporine, cycloalkaline C, etc.), cantharidin extract and its derivatives (including but not limited to cantharidin, norcantharidin, methyl cantharidin, hydroxysporamine, amino acid norcanthamide, etc.; literature "Yuan Lihong. Synthesis of norcantharidin derivatives [D]. Zhongshan The cantharidin derivatives described in the University, 2005. and its citations are for reference. Incorporating the invention), flavonoids or flavonoids (such as puerarin, hydroxyisoflavone, scutellarin, scutellaria flavonoid II, scutellaria, scutellaria, 4', 5,7-trihydroxyflavone, 3', 4', 7-trihydroxyisoflavone, emodinone, emodin, 5,7,4'-trihydroxyflavone, 3,5,7-trihydroxyflavone, 4',6,7-trisone, gin Isoflavones, 4',5,7-trisgen isol-7-glycoside, etc., and Salvia miltiorrhiza extracts (such as tanshinone and its derivatives, including but not limited to tanshinone IIa, tanshinone IIb, tanshinone I, cryptotanshinone, and salvia miltiorrhiza醌A, Salvia miltiorrhiza B, Salvia miltiorrhiza B, etc.; such as salvia miltiorrhiza water-soluble extracts and their salts, including but not limited to Danshensu, protocatechuic aldehyde, rosmarinic acid, lithosperic acid, salvianolic acid A, B, C, D, E, F, G, etc., silybum extract (such as Silibinin, Silibon, Sedum, Sedum, etc.), glycyrrhetinic acid, and scutellarin , 蒺藜 extract, pollen extract (may be broken wall pollen, also can be unbroken pollen), Ginkgo biloba extract (including but not limited to flavonoids, ginkgolides, etc.) Bean leaf extract, honeysuckle extract, Schisandra chinensis extract, cucurbit plant extract (such as resveratrol, cyclopamine, etc.), Huajing crispy poison, snake venom extract (such as thrombin, defibrase, etc.) , leech extract (such as hirudin, etc.).

Most of the above extracts are also small molecule drugs.

Also included are traditional Chinese medicine extracts such as trichosanthin.

(13) In addition, the central nervous system inhibitor, the central nervous system stimulating agent, the psychotropic drug, the respiratory drug, the peripheral nervous system drug, the synaptic connection site or the neuroeffector connection disclosed in the patent CN102316902A and the literature cited therein Site-acting drugs, smooth muscle active drugs, histaminative agents, antihistamines, cardiovascular drugs, blood and hematopoietic drugs, gastrointestinal drugs, steroids, cytostatics, antitumor agents, antibiotics Infectious agents, antibiotic agents, antifungal agents, anthelmintics, antimalarials, antiprotozoal agents, antimicrobial agents, anti-inflammatory agents, immunosuppressive agents, cytokines, enzymes, imino sugars, ceramide analogs, Brain acting hormone or neurotransmitter, neuropeptide or derivative thereof, neurotrophic factor, antibody or fragment thereof, Alzheimer's disease drug or compound, nucleic acid-based compound, imaging agent, (organophosphate) antidote, etc. Bio-related substances are incorporated into the present invention as a reference. Recombinant hormonal drugs, recombinant cytokine drugs, recombinant thrombolytic drugs, human blood substitutes, therapeutic antibodies, recombinant solubles disclosed in the Biotechnology Drugs (863 Biotech Series) published in 2001 and the literature cited therein. All biologically relevant substances in the receptor and adhesion molecule drugs, antisense oligonucleotide drugs, gene drugs, genetically engineered virus vaccines, genetically engineered vaccines, genetically engineered parasitic vaccines, therapeutic vaccines are also incorporated as references. In the present invention. All of the anticancer drugs listed in the literature "Macromolecular Anticancer Therapeutics (CanCer Drug Discovery and Development)" (by L. Harivardhan Reddy and Patrick Couvreur, published year 2010) are incorporated herein by reference.

(14) Also included are phloretin, 2,4,6-trihydroxy-3,5-dimethylacetophenone and the like.

A complex of biologically relevant substances, such as lipids and other biologically relevant substances, such as combinations of fluorescent substances with other biologically relevant substances, such as combinations of targeting factors with other biologically relevant substances, such as sugars. Combinations with other biologically relevant substances also include combinations of any two or more suitable biologically relevant substances.

1.1.10. Linkage L linking biologically relevant substances to polyethylene glycol branched chains

a functional group in a polyfunctionalized H-type polyethylene glycol derivative or a covalent bond L formed by reacting a protected form thereof with a reactive group in a biologically relevant substance, the structure and biologically relevant substance and The reactive group of polyethylene glycol is related and is not particularly limited.

The reaction site in the biologically relevant substance is not particularly limited and may be a naturally occurring reaction site, or may be a modified group or a introduced reactive group. Taking a drug molecule as an example, a common naturally occurring reaction site such as an amino group, a thiol group, a carboxyl group, a disulfide bond, an N-amino group, a C-carboxy group, a hydroxyl group (containing an alcoholic hydroxyl group, a phenolic hydroxyl group, etc.), a carbonyl group, a thiol group, or the like. The literature "Journal of Controlled Release" [161 (2012): 461-472], the literature "Expert Opin Drug Deliv" [2009, 6 (1): 1-16], the literature "Pharm Sci Technol Today." [1998, 1 (8): 352-6], the reaction sites of the amino acids described in the literature "Polymers" [2012, 4(1): 561-89] are incorporated herein by reference. The non-naturally occurring group, the reaction site introduced by modification includes, but is not limited to, R ₀₁ of any of the above-mentioned class A to class H, as exemplified by, for example, an aldehyde group, an alkynyl group, an azide group or the like.

Reactive groups in the bio-related substance include, but are not limited to, any one of an amino group, a thiol group, a disulfide group, a carboxyl group, a hydroxyl group, a carbonyl group or an aldehyde group, an unsaturated bond, and a reactive group introduced. For example, biologically relevant substances containing amino groups contain active esters, active esters of formic acid, sulfonates, aldehydes, α,β-unsaturated bonds, carboxylic acid groups, epoxides, isocyanic acid, respectively. Polyethylene glycol reaction of ester and isothiocyanate gives amide group, urethane group, amino group, imino group (which can be further reduced to secondary amino group), amino group, amide group, amino alcohol, urea bond, thiourea bond a group-attached polyethylene glycol modification; the bio-related substance containing a thiol group respectively contains an active ester, an acid ester active ester, a sulfonate, a thiol group, a maleimide, an aldehyde, an α, β-unsaturated bond, Polyethylene glycol reaction of a carboxylic acid group, an iodoacetamide, or an acid anhydride to obtain a thioester group, a thiocarbonate, a thioether, a disulfide, a thioether, a thiohemiac, a thioether, a thioester, a polyethylene glycol modification in which a group such as a thioether or an imide is linked; a bio-related substance containing an unsaturated bond is reacted with a polyethylene group containing a mercapto group to obtain a polyethylene glycol modification having a sulfide group-attached; The bio-related substance containing a carboxylic acid is reacted with a polyethylene group containing a mercapto group or an amino group to obtain a polyethylene glycol modification having a group such as a thioester group or an amide group; and the bio-related substance having a hydroxyl group respectively has a carboxyl group; Polyethylene glycol of isocyanate, epoxide and chloroformyloxy A polyethylene glycol modification having a group such as an ester group, a carbamate group, an ether bond or a carbonate group; a bio-related substance containing a carbonyl group or an aldehyde group and a poly(amino) group, a hydrazide group Ethylene glycol reaction to obtain a polyethylene glycol modification linked with a group such as an imine bond, an anthracene or a hydrazide; containing an azide, an alkynyl group, an alkenyl group, a decyl group, an azide, a diene, a maleimide, Click-chemical reaction of reactive groups such as 1,2,4-triazoline-3,5-dione, dithioester, hydroxylamine, hydrazide, acrylate, allyloxy, isocyanate, tetrazolium Various linkers can be formed containing structures including, but not limited to, triazole, isoxazole, thioether bonds, and the like, as follows:

Wait. Wherein, the definitions of R ₁₃ , M ₄ , and Q ₂ are consistent with the above, and are not described herein again. The linker generated by the click reaction reported in the literature Adv. Funct. Mater., 2014, 24, 2572 and its referenced click reaction are incorporated herein by reference.

The valence state of L is not particularly limited, and may be, for example, a divalent linking group or a trivalent or higher covalent linking group. L is preferably a divalent linking group. Usually formed is a divalent linking group. a trivalent linking group, for example, formed by the reaction of a thiol group with an alkynyl group

The stability of L is not particularly limited and may be a linker which can be stably present or a linker which is degradable.

The structure of L is not particularly limited and includes, but is not limited to, a linear structure, a branched structure, or a cyclic structure.

The conditions for the stable presence are not particularly limited, and include, but are not limited to, stable in light, heat, enzyme, redox, acid, alkaline, physiological conditions, in vitro simulated environment, etc., preferably in light, heat, enzyme It can be stably present under conditions such as redox, acidity and alkalinity.

The conditions for the degradation are not particularly limited, and include, but are not limited to, degradation under conditions of light, heat, enzyme, redox, acid, alkaline, physiological conditions, in vitro simulated environment, etc., preferably in light, heat, enzyme, oxidation. It can be degraded under conditions of reduction, acidity and alkalinity.

The L is preferably a linker which is stably present under light, heat, enzyme, redox, acidic, basic, physiological conditions or an in vitro simulated environment, or is in the light, heat, enzyme, redox, acid, alkaline Degradable linkers under physiological conditions or in vitro simulated environments.

More preferably, the L is a linker which is stably present under light, heat, enzyme, redox, acidic or basic conditions, or is degradable under conditions of light, heat, enzyme, redox, acid or alkaline. Linker.

When it is a linker which can be stably present, L may contain, but is not limited to, an ether bond, a thioether bond, a urea bond, a thiourea bond, a carbamate group, a thiocarbamate group, a secondary amino group, a tertiary amino group. a linking group such as an amide group, an imide group, a thioamide group, a sulfonamide group, an enamine group, a triazole or an isoxazole.

When the position of L is degradable, the drug molecule can be dePEGylated, and the polyethylene glycol is encapsulated, so that the drug effect can be maximized.

When it is a degradable linker, L may contain, but is not limited to, any of the above-described degradable linkers, specifically including, but not limited to, disulfide bonds, vinyl ether bonds, ester groups, thioester groups, thio Ester group, dithioester group, carbonate group, thiocarbonate group, dithiocarbonate group, trithiocarbonate group, urethane group, thiocarbamate group, dithio Carbamate groups, acetals, cyclic acetals, thioacetals, azaacetals, azacyclic acetals, nitrogen thioacetals, dithioacetals, hemiacetals, thio hemiacetals, Azahemiacetal, ketal, thioketone, aza ketal, azacyclohexanone, azathioketal, imine bond, hydrazone bond, hydrazide bond, hydrazone bond, thiol ether group, half Carbazide bond, thio-semicarbazone bond, sulfhydryl group, hydrazide group, thiocarbohydrazide group, azocarbonylhydrazide group, thioazocarbonyl group, fluorenyl ester group, fluorenyl group Thioester group, carbazone, thiocarbazone, azo group, isourea group, isothiourea group, allophanate group, thiourea group, sulfhydryl group, fluorenyl group, amino group Sulfhydryl, aminoguanidino, imine Acid group, thiol thioester group, sulfonate group, sulfinate group, sulfonamide group, sulfonyl hydrazide group, sulfonylurea group, maleimide, orthoester group, phosphate group, Phosphite, phosphinate, phosphonate, phosphosilyl, silane ester, carboxamide, thioamide, sulfonamide, phosphoramide, phosphoramidite, pyrophosphoramide, cyclophosphamide, A linking group such as ifosfamide, thiophosphoramide, aconityl group, peptide bond or thioamide bond.

L preferably contains triazole, 4,5-dihydroisoxazole, ether bond, thioether group, amide bond, imide group, imine bond, secondary amino bond, tertiary amine bond, urea bond, ester group, Thioester, disulfide, thioester, dithioester, thiocarbonate, sulfonate, sulfonamide, carbamate, thiocarbamate, disulfide Any one of a carbamate group, a thiohemiacetal, a carbonate group, and the like.

In addition to the above-mentioned degradable or non-degradable linker moiety, L may further contain any of the above-mentioned divalent linkers STAG which are stably present, or a combination of two or more kinds of divalent linkers which are stably present. For example, when modifying the hydroxyl group of a drug molecule, the drug can be modified to connect one amino acid molecule (the most common glycine, or diglycine or polyglycine), and the hydroxyl group can be converted into an amino group, so that it can be used. The functional groups that react with it have a wider range of choices.

1.1.11. Reaction between polyethylene glycol derivatives and biologically relevant substances

The type of reaction between the polyfunctionalized H-type polyethylene glycol derivative and the bio-related substance is not particularly limited, and may be a fixed point modification or an indefinite point modification (also referred to as random modification). As an example, fixed-point modifications such as commercial products

Site-directed reaction between the N-amino group of methionine and the aldehyde group, and a fixed-point reaction between sulfhydryl group and maleimide, vinyl sulfone, 2-iodoacetamide, ortho-pyridine disulfide, etc. Further, for example, a fixed-point reaction between an amino group and a cyano group and an isocyanate or an isothiocyanate. By way of example, an indefinite modification such as a reaction between an amino group and an active ester, a commercial product such as

Unfixed point modification during preparation. The fixed-point modification method and the indefinite point modification method described in the literature "Pharm Sci Technol Today" [1998, 1 (8): 352-6], and the literature "Polymers" [2012, 4(1): 561-89] are used as Reference is incorporated into the present invention.

When the polyfunctionalized H-type polyethylene glycol derivative modifies a bio-related substance, one bio-related substance may be linked to one or more polyfunctionalized H-type polyethylene glycol molecules. As a reference, such as commercial products

The medium molecule polyethylene glycol reacts only with one reaction site in one drug molecule; and the commercial product

In one drug molecule, a plurality of polyethylene glycol molecules can be linked.

When a polyfunctionalized H-type polyethylene glycol derivative is modified with a biologically relevant substance having two or more reaction sites, the same polyfunctionalized H-type polyethylene glycol derivative is modified without special explanation. The bio-related substance molecule may react with any one or more reaction sites of the biologically relevant substance; preferably, one bio-related substance molecule reacts with only one functional group or a protected form thereof.

When the number of bio-related substances having two or more reaction sites is two or more, the same one Functionalized H-type polyethylene glycol-derived multiple functional groups allow for reaction with different reaction sites.

When the bio-related substance is modified by the polyfunctionalized H-type polyethylene glycol derivative, when the type of the bio-related substance is two, one of the bio-related substances is preferably a targeting factor, a dye or a fluorescent substance.

1.1.12. Examples of polyfunctionalized H-type polyethylene glycol derivatives modified bio-related substances

By way of example, the bio-related substance modified by the polyfunctionalized H-type polyethylene glycol derivative of the formula (1) has the following structure:

Wherein, the definitions of U ₁ , U ₂ , n ₁ , n ₂ , n ₃ , n ₄ , m ₂ , Z ₂ , q, Z ₁ , q ₁ , E ₀₁ , L, D are consistent with the above, and are not described herein again. .

Wherein k ₁ is an integer of 1 to 4, and k ₂ = 4-k ₁ . Take

As an example, the structure of a bio-related substance modified by a polyfunctionalized H-type polyethylene glycol derivative is represented as

By way of example, the bio-related substance modified by the polyfunctionalized H-type polyethylene glycol derivative of the formula (1) has the following structure:

Wherein, the definitions of U ₁ , U ₂ , n ₁ , n ₂ , n ₃ , n ₄ , m ₂ , Z ₂ , q, Z ₁ , q ₁ , E ₀₁ , L, D, G are consistent with the above, and are not Let me repeat. Wherein k is an integer from 2 to 250; wherein k ₁ is an integer from 1 to k, and k ₂ = 4k-k ₁ . G is selected from any of the terminal branching structures of the above 1.1.8, preferably a trivalent group, a tetravalent group, a pentavalent group, a hexavalent group, or a dendritic structure.

Take

For example, when G is

The structures of the bio-related substances modified by the polyfunctionalized H-type polyethylene glycol derivatives are as follows:

Again

As an example, the structure of a bio-related substance modified by a polyfunctionalized H-type polyethylene glycol derivative is as follows:

By way of example, the bio-related substance modified by the polyfunctionalized H-type polyethylene glycol derivative of the formula (1) has the following structure:

Wherein, the definitions of U ₁ , U ₂ , n ₁ , n ₂ , n ₃ , n ₄ , m ₂ , Z ₂ , q, Z ₁ , q ₁ , E ₀₁ , L, D are consistent with the above, and are not described herein again. .

Wherein k ₅ , k ₆ , k ₇ , and k ₈ are each independently an integer of 2 to 250, and in the same molecule, k ₅ , k ₆ , k ₇ , k ₈ may be the same or different from each other; G ₅ , G ₆ The definitions of G ₇ and G ₈ are identical to those of G, and each of them is independently a linking group of a trivalent or higher valence state, and their valence states are k ₅ +1, k ₆ +1, k ₇ +1, k ₈ +1, respectively. Wherein k ₁ is an integer from 1 to k ₅ +k ₆ +k ₇ +k ₈ , and k ₁ +k ₂ =k ₅ +k ₆ +k ₇ +k ₈ .

G ₅ , G ₆ , G ₇ , G ₈ may independently be preferably a comb structure or a hyperbranched structure.

The G ₅ , G ₆ , G ₇ , G _{8 are} independently included, but not limited to, any of the comb structures of the above 1.1.8.

The G ₅ , G ₆ , G ₇ , G _{8 are} independently including, but not limited to, any of the hyperbranched structures of the above 1.1.8. As a typical example, it is preferred that any of the following structures and derived low-valent groups having a valence of more than 2 are formed by direct linkage or indirect linkage of a divalent linkage L ₁₀ :

Wherein X ₁ is a hydrogen atom or a C _1-6 alkyl group; and R ₁ is a C _1-6 alkyl group; wherein the definition of L ₁₀ is the same as defined above, and an oxy group is preferred herein.

By way of example, as shown in the following hyperbranched structure: participating in the formation of hyperbranched structures

Low price group

Participate in the formation of hyperbranched structures

Low-priced groups include

For example, the repeating unit has the following structure

Hyperbranched structure.

1.2. The present invention also discloses a bio-functional substance modified by a polyfunctionalized H-type polyethylene glycol derivative, the bio-related substance modified by the polyfunctionalized H-type polyethylene glycol derivative is a general formula (1) a stable structure formed by combining a polyfunctionalized H-type polyethylene glycol derivative with a biologically relevant substance;

Wherein, functional groups in LPEG, U ₁ , U ₂ , n ₁ , n ₂ , n ₃ , n ₄ , F ₁ , F ₂ , biologically relevant substances, polyfunctionalized H-type polyethylene glycol derivatives or The linker formed by reacting the protected form with the bio-related substance is consistent with the above definition, and the PEG chain corresponding to n ₁ , n ₂ , n ₃ , and n ₄ is polydisperse, and LPEG is monodisperse. No longer.

1.3. The present invention also specifically discloses a small molecule drug modified with a polyfunctionalized H-type polyethylene glycol derivative. The polyfunctional H-type polyethylene glycol derivative modified small molecule drug may be modified with one, two, three or four small molecule drugs. The general formula is represented by the formula (7), the formula (8), the formula (9), the formula (10) or the formula (11).

Wherein, the definitions of LPEG, n ₁ , n ₂ , n ₃ , n ₄ , m ₂ , U ₁ , U ₂ , Z ₁ , Z ₂ , q ₁ , q, L, E ₀₁ are consistent with the above, and are not described herein again. .

In the same molecule, any one or any of LPEG, U ₁ , U ₂ , U ₀₁ , U ₀₂ , L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ , Z ₁ , Z ₂ , L The linking group formed by adjacent hetero atom groups may be stably present or degradable.

Among them, SD is a residue formed by the reaction of a small molecule drug with a polyfunctionalized H-type polyethylene glycol; the SD in the same molecule is derived from the same small molecule drug, and may be a residue formed by different reaction sites participating in the reaction. . For example, for small molecule drugs with three reactive sites

A plurality of functional groups of a polyfunctionalized H-type polyethylene glycol derivative can be linked to the same or different reaction sites of a small molecule drug.

The small molecule drug is a biologically relevant substance having a molecular weight of not more than 1000 Da, or a small molecule mimetic or active fragment of any biologically relevant substance.

Take LPEG

For example, in this case, the general formula (7), the formula (8), the formula (9), the formula (10), and the formula (11) are sequentially the formula (7-1), the formula (8-1), and the formula (9-). 1), formula (10-1), and formula (11-1):

Take LPEG

As an example, the general formula (11) can also be represented by the formula (11-2).

Specifically, the above formula (11-2) is exemplified as follows:

The SD with the same label in the same molecule is derived from the same small molecule drug, and may be a residue formed by different reaction sites participating in the reaction.

The small molecule drug is a biologically relevant substance having a molecular weight of not more than 1000 Da, or a small molecule mimetic or active fragment of any biologically relevant substance.

The small molecule drug may also be any derivative, or a pharmaceutically acceptable salt of either. The derivatives include, but are not limited to, anthraquinones, nucleosides, amino acids, and polypeptide derivatives in addition to molecularly modified derivatives.

The type of the small molecule drug is not particularly limited and may be an organic, inorganic, organometallic compound, oligopeptide or polypeptide and other biologically relevant substances having a molecular weight of not more than 1000 Da. Specifically, in addition to the small molecule drug in the above class (2), a biologically relevant substance having a molecular weight of not more than 1000 Da in any of the classes (1) and (3) to (13), and A small molecule mimetic or active fragment (including variants) of any biologically relevant substance.

The molecular weight of the small molecule drug usually does not exceed 1000 Da. It can be 0-300Da, 300-350Da, 350-400Da, 400-450Da, 450-500Da, 500-550Da, 550-600Da, 600-650Da, 650-700Da, 700-750Da, 750-800Da, 800-850Da, Any molecular weight in any of 850-900Da, 900-950Da, 950-1000Da; each interval does not include a small value endpoint but includes a large value endpoint.

The manner of obtaining the small molecule drug is not particularly limited, and includes, but is not limited to, natural extracts and derivatives thereof, degradation products of natural extracts, gene recombinant products (molecular cloning products), chemical synthetic substances, and the like.

The hydrophilicity of the small molecule drug is not particularly limited, and may be hydrophilic or water-soluble, or may be hydrophobic or fat-soluble.

The small molecule drug may be a small molecule drug itself, or a dimer or a polymer thereof, a partial subunit or a fragment thereof.

The small molecule drug is selected from any one of the following: a small molecule drug itself, a precursor, an activated state, a derivative, an isomer, a mutant, an analog, a mimetic, a polymorph, or a pharmaceutically acceptable Salts, fusion proteins, chemically modified substances, genetically modified substances, etc., may also be corresponding agonists, activators, activators, inhibitors, antagonists, modulators, receptors, ligands or ligands, antibodies and Its fragments and so on. The small molecule drug also allows for the target molecule, accessory or carrier to which it binds before or after binding to the polyfunctionalized H-type polyethylene glycol.

The field of application of the small molecule drug is not particularly limited, and includes, but is not limited to, any of the above therapeutic fields of the biologically relevant substance, including, but not limited to, an anticancer drug, an antitumor drug, an anti-hepatitis drug, a diabetes drug, and an anti-infection. Medicines, antibiotics, antiviral agents, antifungal drugs, vaccines, antiregonemic drugs, anticonvulsants, muscle relaxants, anti-inflammatory drugs, appetite suppressants, migraine agents, muscle contracting drugs, rheumatoid drugs, antimalarials , anti-vomiting agent, tracheal dilator, Antithrombotic drugs, antihypertensive drugs, cardiovascular drugs, antiarrhythmic drugs, antioxidants, anti-asthma drugs, diuretics, lipid regulators, antiandrogens, antiparasitic drugs, anticoagulants, twins Agents, hypoglycemic agents, nutraceuticals and additives, growth supplements, anti-enteric agents, vaccines, antibodies, diagnostics (including but not limited to contrast agents), contrast agents, and the like. Preferred are anticancer, antitumor drug antibiotics, antiviral agents or antifungal drugs. Typical anti-cancer or anti-tumor drugs are consistent with the above.

The small molecule drug is preferably selected from the group consisting of SN38, irinotecan, resveratrol, cantharidin and its derivatives, baicalin, tripterygium wilfordii extract, flavonoid or flavonoid drug, salvia miltiorrhiza extract, milk thistle extract Any one or any derivative or a pharmaceutically acceptable salt of any one; the pharmaceutically acceptable salt, preferably a hydrochloride salt. The derivatives include, but are not limited to, anthraquinones, nucleosides, amino acids, and polypeptide derivatives in addition to molecularly modified derivatives. When the polyethylene glycol derivative is combined with a small molecule drug via an alcoholic hydroxyl group or a phenolic hydroxyl group, an amino acid derivative of a small molecule drug or an oligoethylene glycol fragment of 2 to 10 EO units is preferred, and an amino acid of a small molecule drug is more preferred. The derivative, more preferably a glycine or alanine modified product of a small molecule drug, most preferably a glycine modified product of a small molecule drug, that is, preferably contains an amino acid derivative skeleton in L, more preferably a glycine skeleton or an alanine skeleton. , most preferably glycine skeleton _{(-C (= O) -CH 2} -NH-), amino acid derivatives, small molecule drugs at this time in the reactive group converted to the corresponding amino acid in the amino group.

Taking the general formula (11) as an example, its representative structure includes but is not limited to

In the above formulas (7) to (11), the polyfunctionalized H-type polyethylene glycol derivative is not specifically limited in geometric configuration, and for example, the formula (7) can also be represented as a formula ( 7').

Specifically, when U ₁ or/and U ₂ are of an asymmetric type, the following structure is taken as an example, wherein

L ₁ and L ₃ are absent, L ₂ = L ₄ = L ₅ = L ₆ = CH ₂ ,

Can also be expressed as a structure

Another example is the following structure

Can also be expressed as

When in the general formula (7),

L ₂ and L ₃ are absent, L ₁ = L ₄ = L ₅ = L ₆ = CH ₂ , and the structure is expressed as

1.4. The present invention also specifically discloses a polyfunctionalized H-type polyethylene glycol derivative modified small molecule drug. Its general formula is as shown in formula (12).

Wherein k ₅ , k ₆ , k ₇ , and k ₈ are each independently an integer of 2 to 250, and in the same molecule, k ₅ , k ₆ , k ₇ , k ₈ may be the same or different from each other, preferably k ₅ , k ₆ , k ₇ , k ₈ are equal to each other. G ₅ , G ₆ , G ₇ , G _{8 have} the same definitions as G, and each independently is a trivalent or higher valence linkage, and their valence states are k ₅ +1, k ₆ +1, k ₇ +1, respectively. , k ₈ +1.

Wherein LPEG, n ₁ , n ₂ , n ₃ , n ₄ , m ₂ , U ₁ , U ₂ , L ₀ , g ₀ , G, k, Z ₁ , Z ₂ , q ₁ , q, E ₀₁ , L The definition of SD is consistent with the above, and will not be described here.

LPEG

For example, the general formula (12) can be expressed as the equations (12-1) and (12-2), respectively:

k ₁ is an integer greater than or equal to 1, and k ₂ is an integer greater than or equal to 0, and satisfies k ₁ + k ₂ = k ₅ + k ₆ + k ₇ + k ₈ . That is, in the small molecule drug modified with the polyfunctionalized H-type polyethylene glycol derivative, the amount of the small molecule drug that can be modified is 1 to k ₅ +k ₆ +k ₇ +k ₈ , preferably k ₅ or k ₆ Or a sum of 2 or any 3 integers of k ₇ or k ₈ or k ₅ , k ₆ , k ₇ , k ₈ or k ₅ +k ₆ +k ₇ +k ₈ , more preferably k ₅ +k ₆ + k ₇ +k ₈ . In view of the steric hindrance factor, the branching group connecting the branching center of G and SD preferably has a chain length of 5 or more non-hydrogen atoms, and more preferably has a chain length of 10 or more non-hydrogen atoms.

In the same molecule, G ₅ , G ₆ , G ₇ , G _{8 have} the same structural type, for example, the same three-branched structure, or the same four-branched structure, or the same comb-like structure, or the same tree structure. , or the same as a hyperbranched structure, or a cyclic structure; in the same molecule, preferably G ₅ , G ₆ , G ₇ , G ₈ have a completely identical structure; G ₅ , G ₆ , G ₇ , G ₈ The structure type is the same. When G ₅ = G ₆ = G ₇ = G ₈ = G, and k ₅ = k ₆ = k ₇ = k ₈ = k, the general formula (12-1) is also expressed as the general formula (13), where k is taken An integer of 2 to 250; G is a linking group of a trivalent or higher valence state, and its valence is k+1. At this time, k ₁ + k ₂ = 4k.

In the same molecule, LPEG, U ₁ , U ₂ , U ₀₁ , U ₀₂ , L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ , Z ₁ , Z ₂ , L, L ₀ , G ₅ , A linker formed by any one or any of G ₆ , G ₇ , G ₈ and an adjacent hetero atom group may be stably present or degradable.

For the general formula (13), the amount of the small molecule drug which can be modified is from 1 to 4 k; most preferably 4 k, as shown in the formula (16). When the number of small molecule drugs can be modified by k, 3k, and 4k as an example, the structures represented by the formulas (14), (15), and (16) may be used; when the number of the small molecule drug can be modified is 2k, The structure represented by the formula (17) or (18). Wherein k is an integer of 2 to 250. G is a linking group of a trivalent or higher valence state, and its valence is k+1.

Wherein, the linking group of the G trivalent or higher valence state is selected from the linking group of any one of the above-mentioned sets G ^k+1 (k≥2). G is preferably a trivalent linking group, a tetravalent linking group, a pentavalent group, a hexavalent group, a linking group of a comb structure, a linking group of a dendritic structure, a linking group of a hyperbranched structure, a linking group of a cyclic structure, Refer to the terminal branching structure of Section 1.1.8.

Taking the general formula (16), G is a trivalent group

For example, the general formula (16) can be exemplified as follows:

1.5. The present invention also specifically discloses a polyfunctionalized H-type polyethylene glycol derivative modified small molecule drug having the general formula shown in formula (19). Wherein, the definitions of LPEG, n ₁ , n ₂ , n ₃ , n ₄ , m ₂ , U ₁ , U ₂ , L ₀ , g ₀ , Z ₁ , Z ₂ , q ₁ , q, E ₀₁ , L and the above Consistent, no longer repeat them here.

Wherein g ₁ and g ₂ are each independently 0 or 1, and may be the same or different from each other in the same molecule.

Here, k ₅ , k ₆ , k ₇ , and k ₈ are each independently an integer of 1 or 2 to 250 integers.

When g ₁ =0, k ₅ =k ₆ =1. When g ₁ =1, k ₅ and k ₆ are each independently an integer of 2 to 250, and may be the same or different from each other in the same molecule. Preferably k ₅ = k ₆ .

When g ₂ =0, k ₇ = k ₈ =1. When g ₂ =1, k ₇ and k ₈ are each independently an integer of 2 to 250, and may be the same or different from each other in the same molecule. Preferably k ₇ = k ₈ .

G ₅ , G ₆ , G ₇ , G _{8 have} the same definitions as G, and each independently is a trivalent or higher valence linkage, and their valence states are k ₅ +1, k ₆ +1, k ₇ +1, respectively. , k ₈ +1.

k ₁ is an integer greater than or equal to 1, k ₂ is an integer greater than or equal to 0, and satisfies k ₁ + k ₂ = k ₅ + k ₆ + k ₇ + k ₈ ;

In the same molecule, G ₅ and G _{6 have} the same structural type, preferably G ₅ =G ₆ , in which case k ₅ =k ₆ ; G ₇ and G _{8 have} the same structural type, preferably G ₇ =G ₈ , at this time k ₇ = k ₈ . The structural types of G ₅ and G ₇ may be the same or different. Preferably, G ₅ , G ₆ , G ₇ , G ₈ have the same structural type.

In the same molecule, LPEG, U ₁ , U ₂ , U ₀₁ , U ₀₂ , L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ , Z ₁ , Z ₂ , L, L ₀ , G ₅ , A linker formed by any one or any of G ₆ , G ₇ , G ₈ and an adjacent hetero atom group may be stably present or degradable.

In the same molecule, G ₅ = G ₆ , k ₅ = k ₆ , and G ₇ = G ₈ , k ₇ = k _{8 are} preferred.

Preferably, g ₁ = g ₂ , denoted as g, and the formula is represented by the formula (19-1), wherein g is 0 or 1.

When g = 0, k ₅ = k ₆ = k ₇ = k ₈ =1, and the general formula (19-1) is expressed by the formula (19-2).

When g = 1, the formula (19-1) is represented by the formula (19-3), and preferably G ₅ , G ₆ , G ₇ , G ₈ have the same structural type.

When G ₅ , G ₆ , G ₇ , G ₈ have the same structural type in the formula (19-3), it is preferred that G ₅ = G ₆ = G ₇ = G ₈ = G, that is, k ₅ = k ₆ = k ₇ = k ₈ = k, where the general formula (19-3) is represented by the formula (19-4), k is an integer of 2 to 250; G is a trivalent or higher valence linking group, and its valence is k+1; k ₁ + k ₂ = 4k.

Among them, SD is a residue formed by reacting a small molecule drug with a polyfunctional H-type polyethylene glycol. The small molecule drug is selected from the group consisting of SN38, irinotecan, resveratrol, cantharidin and its derivatives, baicalin, tripterygium wilfordii extract, flavonoid or flavonoid drug, salvia miltiorrhiza extract, milk thistle extract Any one or any derivative or a pharmaceutically acceptable salt of any one; the pharmaceutically acceptable salt, preferably a hydrochloride salt. Such derivatives include, but are not limited to, terpenoids, nucleosides, amino acids, and polypeptide derivatives. When the polyfunctional polyethylene glycol is combined with a small molecule drug via an alcoholic hydroxyl group or a phenolic hydroxyl group, an amino acid derivative or an ω-amino acid derivative of a small molecule drug is preferred, and a glycine or alanine derivative of a small molecule drug is more preferred. The β-alanine derivative is most preferably a glycine derivative of a small molecule drug, that is, preferably contains an amino acid derivative skeleton in L, more preferably contains a glycine skeleton or an alanine skeleton, and most preferably contains a glycine skeleton (-C (= O)-CH ₂ -NH-), at which time the reactive group in the amino acid derivative of the small molecule drug is converted to the amino group in the corresponding amino acid.

Take LPEG

For example, the general formula (19-1) can be expressed as the formula (20).

Wherein, when g = 0, the formula (20) is represented by the formula (20-1).

Wherein, when G ₅ =G ₆ =G ₇ =G ₈ =G, and k ₅ =k ₆ =k ₇ =k ₈ =k, the general formula (20) is also represented by the general formula (20-2); g is 0 or 1; k is an integer of 1 or 2 to 250. When g=1, k is an integer of 2 to 250. G is a linking group of a trivalent or higher valence state, and its valence is k+1. k ₁ +k ₂ = 4k.

Wherein, when g = 1, the formula (20-2) is represented by the formula (21).

Wherein, when k=1, by way of example, the general formula (20-1) may be

As an example, when k=2, the general formula (21) may be

Where G is

G may be selected from any of the above-mentioned 1.1.8 parts of the trivalent branched structure. As an example, the structure of G may also be

Wait.

As an example, when k=3, the general formula (21) may be

Where G is

When k=4, as an example, G can be

When k=5, as an example, G can be

When k≥4, and G has a comb structure, a dendritic structure, a hyperbranched structure or a cyclic structure, taking g ₀ =0 as an example, the general formula (21) can be expressed as

Wherein, G has a comb structure, including but not limited to any of the above comb structures. When the basic unit constituting the comb structure is the same polyvalent group repeating unit, the polyvalent group repeating unit is preferably a 3- to 6-valent polyvalent group, more preferably a trivalent or tetravalent polyvalent group. . By way of example, the structure of G includes, but is not limited to, the comb structure listed in section 1.1.8.

Among them, the corresponding general formula (21) preferably has the following structure:

Wherein k ₅ , k ₆ , k ₇ , and k ₈ are each independently an integer greater than or equal to 3; preferably, k ₅ , k ₆ , k ₇ , and k ₈ are the same as each other; wherein R ₂₅ is a hydrogen atom or a methyl group.

Where G has a tree structure, by way of example, G can be DENR (

NONE, 3), DENR (

NONE, 3), DENR (

NONE, 4), DENR (

Any of -O-, 6), etc.; wherein M ₉ is O, S or NX ₁₀ , wherein X _{10 is} as defined above.

When G has a cyclic structure, G is preferably a residue after dehydroxylation of a cyclodextrin.

Wherein, when G has a hyperbranched structure, there is no particular limitation on the number of repeating units of a polyvalent group as long as the valence of G does not exceed 251. Preferably, the polyvalent group repeating unit has any of the above-described trivalent or tetravalent groups of the present invention, allowing the polyvalent group repeating units to be directly linked to each other or indirectly via the divalent linking group L ₁₀ . For example, the above polyvalent group repeating unit has the following structure

A hyperbranched structure in which the polyvalent repeating units are linked to each other by a divalent linking group L ₁₀ (L ₁₀ =oxy group).

In the small molecule drug modified by the polyfunctionalized H-type polyethylene glycol derivative represented by the formula (20-2), the amount of the small molecule drug which can be modified is 1 to 4 k. Most preferred is 4k. When the amount of the small molecule drug can be modified to be k, 3k, 4k, the structure represented by the general formulas (22), (23), and (24) can be used; when the number of the small molecule drug can be modified to be 2k, the formula can be The structure shown in (25) or (26).

When the small molecule drug of the formula (19) to the formula (26) is SN38 or a pharmaceutically acceptable salt thereof, the -L-SD preferably contains the following structure or a pharmaceutically acceptable salt thereof:

The salt is preferably a hydrochloride; in this case, L preferably contains an amino acid skeleton or an oligopeptide skeleton, and more preferably contains a glycine skeleton. Taking the general formula (20-1) as an example, the structure thereof is preferably

Where q is 0 or 1. The general formula (19) to the general formula (26) also include the general formula (19-1).

When the small molecule drug of the formula (19) to the formula (26) is irinotecan or a pharmaceutically acceptable salt thereof, the -L-SD preferably contains the following structure or a salt thereof:

The salt is preferably a hydrochloride; in this case, L preferably contains an amino acid skeleton or an oligopeptide skeleton, and more preferably contains a glycine skeleton. In the formula _(20--1) as an example, the structure is preferably

Where q is 0 or 1.

When the small molecule drug of the formula (19) to the formula (26) is resveratrol, the -L-SD preferably contains any of the following structures:

In this case, L preferably contains an amino acid skeleton or an oligopeptide skeleton, and more preferably contains a glycine skeleton.

When the small molecule drug of the formula (19) to the formula (26) is cycloalradylline D, the -L-SD preferably contains any one of the following structures or a pharmaceutically acceptable salt thereof:

The salts are preferably hydrochlorides.

When the small molecule drug of the formula (19) to the formula (26) is cycloalradylline C, the -L-SD preferably contains any of the following structures or a pharmaceutically acceptable salt thereof:

The salts are preferably hydrochlorides.

When the small molecule drug of the formula (19) to the formula (26) is cycloprostose C, the -L-SD preferably contains the following structure or a pharmaceutically acceptable salt thereof:

The salts are preferably hydrochlorides.

When the small molecule drug of the formula (19) to the formula (26) is a cantharidin extract or a derivative thereof, the -L-SD preferably contains Any of the following structures:

Wherein R ₂₅ and R ₂₆ are each independently a hydrogen atom or a methyl group.

When the small molecule drug of the formula (19) to the formula (26) is a tripterygium wilfordii extract or a derivative thereof, the -L-SD preferably contains any one of the following structures:

In this case, L preferably contains an amino acid skeleton or an oligopeptide skeleton, and more preferably contains a glycine skeleton.

When the small molecule drug of the formula (19) to the formula (26) is a flavonoid or a flavonoid drug, puerarin, hydroxyisoflavone, scutellarin, scutellaria flavone II, scutellaria, scutellaria, etc. are preferred, specifically - L-SD preferably contains any of the following structures or a pharmaceutically acceptable salt thereof:

The salt is preferably a hydrochloride; when the above terminal group is -O-, L preferably contains an amino acid skeleton or an oligopeptide skeleton, and more preferably contains a glycine skeleton.

When the small molecule drug of the formula (19) to the formula (26) is a tanshinone drug, the -L-SD preferably contains any of the following structures:

The L ₁₁ is preferably -NH-, -O-, -NH-C ₆ H ₅ -, -NH-C ₆ H ₂ (NO ₂ ) ₂ -, -NH-C(=O)-NH-, -NH -C(=O)-CH[N ⁺ (CH ₃ ) ₃ Cl]-, -C=N-NH-, -NH-C(=O)-, etc., wherein the left side points to the small molecule drug, and the right side points Polyfunctional polyethylene glycol; -L-SD, in addition to the above-mentioned moiety, preferably by methylene, 1,2-ethylene, 1,3-propylene, 1,2-propylene, The isopropylidene group, the butylene group, the pentylene group, the hexylene group, the heptylene group, and the octylene group are connected to the polyfunctional polyethylene glycol moiety, and more preferably the methylene group, the 1,2-ethylene group, and the 1,3 group. - propylene;

When the small molecule drug of the formula (19) to the formula (26) is a tanshinone drug, the small molecule drug may be linked to the polyfunctional polyethylene glycol derivative by hydrogen bonding, and L preferably contains ruthenium. A base, an amino acid backbone or an oligopeptide backbone, more preferably an arginine backbone, as follows:

When the small molecule drug of the formula (19) to the formula (26) is a milk thistle extract, it is preferably a silybin, a silybirth, a silyin, a silymarin, etc., -L- SD preferably contains any of the following structures:

1.6. The present invention also specifically discloses a bio-related substance modified with a hydroxyl group-containing or protected hydroxyl group-containing polyethylene glycol derivative, which has the general formula shown in formula (27) or formula (28). The definitions of LPEG, n ₁ , n ₂ , n ₃ , n ₄ , U ₁ , U ₂ , Z ₂ , q , L, and PG ₄ are the same as described above, and the definition of BD is consistent with D, and will not be described herein. The BD in the same molecule is derived from the same biologically relevant substance, and may be a residue formed by different reaction sites participating in the reaction.

In the same molecule, any one or any of LPEG, U ₁ , U ₂ , U ₀₁ , U ₀₂ , L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ , Z ₂ , L The linker formed by the atomic group can be stably present or degradable.

1.7. The present invention also specifically discloses a bio-related substance modified with a hydroxyl group- or protected hydroxyl group-containing polyethylene glycol derivative, which has the general formula shown in formula (29) or formula (30). Wherein LPEG, n ₁ , n ₂ , n ₃ , n ₄ , U ₁ , U ₂ , Z ₂ , q, L, PG ₄ , L ₀ , g ₀ , G ₅ , G ₆ , k ₅ , k ₆ , The definition of BD is consistent with the above, and will be described again. Wherein k ₅ and k ₆ are each independently an integer of from 2 to 250, and in the same molecule, k ₅ and k ₆ may be the same or different from each other; G ₅ and G _{6 have} the same meaning as G, and each independently is trivalent. The valence states of the higher or higher valence states are k ₅ +1 and k ₆ +1, respectively; in the same molecule, the structural types of G ₅ and G ₆ are the same.

Among them, LPEG is preferably

The definitions of m ₁ , m ₂ , and W ₀ are consistent with the above, and are not described herein again.

In the same molecule, LPEG, U ₁ , U ₂ , U ₀₁ , U ₀₂ , L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ , Z ₂ , L, L ₀ , G ₅ , G ₆ Any one or any of the linking groups formed with adjacent hetero atom groups may be stably present or degradable.

1.8. The present invention also specifically discloses a polyfunctionalized H-type polyethylene glycol derivative modified bio-related substance having a targeting function, which has the general formula of formula (31), formula (32), formula (33) or Formula (34). Wherein, the definitions of LPEG, n ₁ , n ₂ , n ₃ , n ₄ , U ₁ , U ₂ , Z ₂ , q, L, PG ₄ , L ₀ , g ₀ , BD are consistent with the above, L _t0 , g _t The definitions of Z _t and q _t are consistent with L ₀ , g ₀ , Z ₂ , and q, respectively, and are not described herein again. Among them, TD is a residue formed by reacting a targeting molecule with a polyfunctionalized H-type polyethylene glycol. L _t is a functional group in the H-type polyethylene glycol derivative or a linker formed by reacting the protected form with a targeting molecule. In the same molecule, L _t0 , L ₀ may be the same or different from each other, g _t , g ₀ may be the same or different from each other, Z _t , Z ₂ may be the same or different from each other, and q _t , q may be the same or different from each other, L _t , L may be the same or different from each other.

Wherein k ₅ , k ₆ , k ₃ , and k ₄ are each independently an integer of 2 to 250, and in the same molecule, k ₅ , k ₆ , k ₃ , and k ₄ may be the same or different from each other, and preferably k ₅ =k ₆ and k ₃ = k ₄ .

Wherein, G ₅ , G ₆ , G ₃ , G _{4 have} the same definitions as G, and each independently is a trivalent or higher valence linking group, and their valence states are k ₅ +1, k ₆ +1, k _{3 , respectively.} +1, k ₄ +1.

In the same molecule, G ₅ and G _{6 have} the same structural type, and G ₃ and G ₄ have the same structural type, for example, the same three-branched structure, or the same four-branched structure, or the same comb-like structure, or the same a dendritic structure, or a hyperbranched structure, or a cyclic structure; in the same molecule, preferably G ₅ and G ₆ have completely identical structures; in the same molecule, preferably G _t3 and G _t4 have completely identical Structure; the structure type is the same, and G ₅ and G _{6 are} different, or G ₃ and G _{4 are} different, mainly for comb, tree, hyperbranched, ring and other special structures, the difference is in the valence state, in the shape of a comb structure

For example, G ₅ , G ₆ (or G ₃ , G ₄ ) allow different valence states due to inconsistent number of repeating units.

In the same molecule, LPEG, U ₁ , U ₂ , U ₀₁ , U ₀₂ , L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ , Z ₂ , Z _t , L, L _t , L ₀ , A linker formed by any one or any of L _t0 , G ₃ , G ₄ , G ₅ , G ₆ and an adjacent hetero atom group may be stably present or degradable.

Wherein, the source of TD includes, but is not limited to, class I in the above functional group and class (10) among the above biologically relevant substances. The target molecule as a source may be the targeting molecule itself, or a dimer, a polymer, a subunit or a fragment thereof, a precursor, an activated state, a derivative, an isomer, a mutant, an analog, a simulation , polymorphs, pharmaceutically acceptable salts, fusion proteins, chemically modified substances, genetically modified substances, etc., may also be corresponding agonists, activators, activators, modulators, receptors, ligands Or ligands, antibodies and fragments thereof. The targeting molecule also allows for the target molecule, accessory or carrier to which it binds before or after binding to the polyfunctionalized H-type polyethylene glycol.

Taking the general formula (33) as an example, the structure of a bio-related substance having a targeting function modified by a polyfunctionalized H-type polyethylene glycol derivative can be expressed as follows:

Wherein, the structures of G ₅ and G ₆ are preferably a trivalent group, a tetravalent group, a pentavalent group, a hexavalent group, a comb structure, a dendritic structure, a hyperbranched structure, etc. as exemplified in the general formula (21). Ring structure, etc.

1.9. The present invention also specifically discloses a polyfunctionalized H-type polyethylene glycol derivative modified fluorescing bio-related substance having the general formula of formula (35), formula (36), formula (37) or formula (38) is shown. Wherein, the definitions of LPEG, n ₁ , n ₂ , n ₃ , n ₄ , U ₁ , U ₂ , Z ₂ , q, L, PG ₄ , L ₀ , g ₀ , BD are consistent with the above, L _t0 , g _t The definitions of Z _t and q _t are consistent with L ₀ , g ₀ , Z ₂ , and q, respectively, and are not described herein again. Among them, FD is a residue formed by reacting a fluorescent substance with a polyfunctionalized H-type polyethylene glycol. L _t is a linking group formed by a functional group in the H-type polyethylene glycol derivative or a protected form thereof and a fluorescent substance. In the same molecule, L _t0 , L ₀ may be the same or different from each other, g _t , g ₀ may be the same or different from each other, Z _t , Z ₂ may be the same or different from each other, and q _t , q may be the same or different from each other, L _t , L may be the same or different from each other.

Wherein k ₅ , k ₆ , k ₃ , and k ₄ are each independently an integer of 2 to 250, and in the same molecule, k ₅ , k ₆ , k ₃ , and k ₄ may be the same or different from each other, and preferably k ₅ =k ₆ and k ₃ = k ₄ .

Wherein, the definitions of G ₅ , G ₆ , G ₃ , and G ₄ are each independently identical to G, and each independently is a linking group of a trivalent or higher valence state, and their valence states are k ₅ +1, k ₆ +1, respectively. , k ₃ +1, k ₄ +1.

In the same molecule, G ₅ and G _{6 have} the same structural type, and G ₃ and G ₄ have the same structural type, for example, the same three-branched structure, or the same four-branched structure, or the same comb-like structure, or the same a dendritic structure, or a hyperbranched structure, or a cyclic structure; in the same molecule, preferably G ₅ and G ₆ have completely identical structures; in the same molecule, preferably G ₃ and G ₄ have completely identical Structure; the structure type is the same, and G ₅ and G _{6 are} different, or G ₃ and G _{4 are} different, mainly for comb, tree, hyperbranched, ring and other special structures, the difference is in the valence state, in the shape of a comb structure

For example, G ₅ , G ₆ (or G ₃ , G ₄ ) allow different valence states due to inconsistent number of repeating units.

Wherein, the source of FD includes, but is not limited to, the class J in the above functional group and the class (9) in the above biologically relevant substance. The fluorescent molecule as a source may be selected from any one of the following: a fluorescent molecule itself, a dimer and a multimer, a subunit and a fragment thereof, a precursor, an activated state, a derivative, an isomer, a mutant, an analog , mimics, polymorphs, fusion proteins, chemically modified substances, genetically recombinant substances, and the like. The fluorescent molecule also allows for the target molecule, accessory or carrier to which it binds before or after binding to the polyfunctionalized H-type polyethylene glycol.

Taking the general formula (33) as an example, the structure of the fluorogenic bio-related substance modified by the polyfunctionalized H-type polyethylene glycol derivative can be expressed as follows:

Wherein, the structures of G ₅ and G ₆ are preferably the terminal branching structures exemplified above in the general formula (21), and examples thereof include a trivalent group, a tetravalent group, a pentavalent group, a hexavalent group, a comb structure, Tree structure, hyperbranched structure, ring structure, and the like.

The polyfunctionalized H-type polyethylene glycol derivative of the present invention and its preparation method are further described below in conjunction with some specific embodiments. The specific embodiments are intended to describe the invention in further detail, without limiting the scope of the invention.

Example 1: Preparation of a polyfunctionalized H-type polyethylene glycol succinimide active ester derivative modified interferon alpha-2a (amide linkage)

In a dry and clean 50 mL round bottom flask, 645 mg (about 2 times molar ratio) of polyfunctionalized H-type polyethylene glycol succinimide active ester derivative (A1-1, molecular weight about 26 kDa) was added, and nitrogen was added to PBS. The pH of the buffer was adjusted to pH=8.0, 7.5 mL of interferon α-2a (NH ₂ -IFN) in PBS buffered saline was added, the reaction was shaken at 25 ° C for 4 hours, and the reaction was shaken at 4 ° C for 12 hours. The reaction was stopped by adding 1.5 ml of glycine solution. The concentration of interferon α-2a was diluted to 0.5 mg/mL with a PBS buffered saline solution of pH=8.0, and purified by agarose gel exchange resin, and the single-modified and double-modified fractions were separately collected and concentrated by ultrafiltration. The MALDI-TOF-MS test showed that the single modified product (1 molecule of interferon combined with 1 molecule of H-type polyethylene glycol) and the double-modified product (2 molecules of interferon combined with 1 molecule of H-type polyethylene glycol) have molecular weights of approximately 45 kDa, respectively. 64KDa; GPC characterization of the single modified product showed no free PEG molecule; the purity of the single modified product was determined by SDS-PAGE electrophoresis, and the purity of the modified polyethylene glycol product was above 96%.

Among them, the structure of the polyfunctionalized H-type polyethylene glycol succinimide active ester derivative A1-1 having the general formula (2) is as follows:

Wherein, the structural parameter of the compound A1-1 is

(U ₁ , U _{2 are} symmetrical,

L ₁ = L ₂ = L ₃ = L ₄ = CH ₂ , L ₅ , L ₆ are absent), F ₁ = F ₂ = CH ₂ CONHS (g = 0, k = 1, q = 0, q ₁ =1 , Z ₁ =CH ₂ CO, R ₀₁ =NHS), j=0. The designed total molecular weight is about 26 kDa, wherein the four branched chains have a molecular weight of about 4 x 5000 = 20000 Da, i.e., n ₁ ≈n ₂ ≈n ₃ ≈n ₄ ≈ 114, and the molecular weight of the main chain is about 5000 Da, m ₂ ≈ 114.

The structure of the obtained pegylated interferon monomer product and the dimerization product corresponds to the general formulae (2) to (4) as follows:

Where j=0, g=0, k=1, q=0, q ₁ =1, Z ₁ =CH ₂ , L=-CH ₂ CONH-, D=IFN, R ₀₁ in EF ₁ and EF ₂ Capped with glycine.

Example 2: Preparation of a recombinant human granulocyte colony-stimulating factor (rhG-CSF) modified with a polyfunctionalized H-type polyethylene glycol aldehyde derivative (secondary amine linkage)

600 mg (about 1.5 times molar ratio) of polyfunctionalized H-type polyethylene glycol aldehyde derivative (D5-1, molecular weight about 20 kDa) was added to a dry clean 50 mL round bottom flask, nitrogen-protected, and pH was added to PBS buffer. Adjust the value to pH=5.0, add 7.6mL rhG-CSF in PBS buffer salt solution, react at room temperature for 4 hours, add sodium cyanoborohydride, react at room temperature for about 24h, quench with saturated ammonium chloride solution, dilute with water to protein The concentration is about 0.1 mg/mL. The pH was adjusted to about 5.0 with dilute hydrochloric acid, and subjected to Resource S ion exchange column chromatography, and eluted with a gradient of 0-0.5 mol/L NaCl solution (containing 20 mmol/L NaAc, pH 5.0) to collect single-modification and double-modification. The polyethylene glycol modified component was concentrated by Sephadex G25 desalting chromatography and ultrafiltration. The MALDI-TOF-MS test showed that the molecular weight of the single modified product (1 molecule of rhG-CSF combined with 1 molecule of H-type polyethylene glycol) and the double modified product (2 molecules of rhG-CSF combined with 1 molecule of H-type polyethylene glycol) were respectively It is 39kDa, 58kDa; the GPC characterization of the single modified product shows that there is no free PEG molecule; the purity of the single modified product is determined by SDS-PAGE electrophoresis, and the purity of the modified polyethylene glycol product is above 96%.

Among them, the structure of the polyfunctionalized H-type polyethylene glycol aldehyde derivative D5-1 having the general formula (2) is as follows:

Wherein, the structural parameter of the compound D5-1 is

(U ₁ , U _{2 are} asymmetrical,

L ₁ , L ₃ are absent, L ₂ = L ₄ = CH ₂ , L ₅ = L ₆ = CH ₂ ), F ₁ = F ₂ = CH ₂ CH ₂ CHO (g = 0, k = 1, q = 0) , q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =CHO), j=0. The designed total molecular weight is about 20kDa, wherein the molecular weight of the four branched chains is about 4×4750=19000Da, that is, n ₁ ≈n ₂ ≈n ₃ ≈n ₄ ≈108, the main chain polyethylene glycol has monodispersity, EO unit The number m ₂ = 24.

The monomeric product and the dimerization product structure of the obtained PEGylated recombinant human granulocyte colony-stimulating factor correspond to the general formula (2 to 4), wherein j=0, g=0, k=1, q=0, q ₁ =1, Z ₁ =CH ₂ , L=-CH ₂ CH ₂ CH ₂ NH-, D=rhG-CSF, and EF ₁ and EF ₂ are both -CH ₂ CH ₂ CHO.

The structure of the monomeric product is as follows:

The structure of the dimerization product is as follows:

Example 3: Preparation of polyfunctionalized H-type polyethylene glycol maleimide derivative modified exenatide (thioether linkage)

In a dry clean 100 mL round bottom flask, 4.3 mL of exenatide mutant (Exanatide-Cys introduced a cysteine at the C-terminus of the inactive region) in PBS buffered saline was added, and the pH was adjusted to pH=7.2, adding 46.3 mg (about 1.1 times molar ratio) of polyfunctionalized H-type polyethylene glycol maleimide derivative (E1-1, molecular weight about 42 kDa), reacting at 4 ° C for 24 h, adding cysteine The solution was diluted at room temperature for 2 h and diluted with distilled water. It was selected from MacroCap SP (GE) ion exchange column for purification by transfer chromatography. The column was first equilibrated with 20 mM NaAc buffer pH 4.0, and then eluted with a gradient of 20 M mM buffer containing pH 1 of 1 M NaCl. The single-molecule exenatide, the bimolecular exenatide, the three-molecule exenatide, and the polyethylene glycol modification component of the four-molecule exenatide were concentrated by Sephadex G25 desalting chromatography and ultrafiltration. Different components were subjected to SDS-PAGE electrophoresis and high performance liquid chromatography. The result shows that single molecule Essex The polyethylene glycol modified products of the peptide, the bimolecular exenatide, the three-molecule exenatide, and the four-molecule exenatide have molecular weights of about 46 kDa, 51 kDa, 55 kDa, and 59 kDa, respectively, and the purity is 96% or more.

Wherein, the structural parameter of the compound E1-1 is

(U ₁ , U _{2 are} symmetrical,

L ₁ = L ₂ = L ₃ = L ₄ = CH ₂ CH ₂ , L ₅ = L ₆ = CH ₂ CH ₂ ),

(g=0, k=1, q=1,

q ₁ =1,

), j=0. The designed total molecular weight is about 42 kDa, wherein the four branched chains have a molecular weight of about 4 x 10000 = 40,000 Da, i.e., n ₁ ≈n ₂ ≈n ₃ ≈n ₄ ≈ 227, and the molecular weight of the main chain is about 1000 Da, m ₂ ≈23.

The structure of the obtained PEGylated exenatide product corresponds to the general formula (2-6), wherein j=0, g=0, k=1, q=0, q ₁ =1,

D=Exanatide-Cys, EF ₁ and EF ₂ are

Example 4: Preparation of a small molecule drug SN38 modified with a polyfunctionalized H-type polyethylene glycol carboxylic acid derivative (amide linkage)

Step a, Preparation of TBDPS-(10)-(7-ethyl-10-hydroxycamptothecin) (Compound 2): To a dry clean 250 mL round bottom flask was charged 1.96 g (5.0 mmol, 1 eq.) 7- 100 mL of anhydrous dichloromethane (DCM) suspension of ethyl-10-hydroxycamptothecin (SN38, compound 1), followed by 30 mmol (6 equivalents) of triethylamine and 30 mmol (6 equivalents) of t-butyl diphenyl The chlorosilane (TBDPSCl) was heated to reflux overnight, and then washed successively with a 0.2N HCl solution (50 mL×3), a saturated NaHCO ₃ solution (100 mL), and a 20 mM NaCl solution (100 mL). The organic phase was dried over MgSO _4, filtered, evaporated in vacuo, and the residue was dissolved in anhydrous dichloromethane was added hexane to precipitate, the precipitate was collected, dissolved in methylene chloride is repeated, the step of removing excess hexane precipitated TBDPSC1. Filtration and drying in vacuo gave Compound 2. The structure was determined by NMR.

Step b, preparation of TBDPS-(10)-(7-ethyl-10-hydroxycamptothecin)-(20)-glycine-Boc (compound 3, TBDPS-SN38-Gly-Boc): under ice water bath conditions, To a dry clean 250 mL round bottom flask was added 2.52 g (4 mmol, 1 eq.) of compound 2 and 1.05 g (6 mmol, 1.5 eq.) of N-(tert-butoxycarbonyl)aminoacetic acid (Boc-glycine, Boc-Gly) in 100 mL. Anhydrous DCM solution was added 6 mmol (1.5 eq.) of dichloroethane (EDC), 244 mg (2 mmol, 0.5 eq.) of 4-dimethylaminopyridine (DMAP). The reaction was stirred for 2 hours under ice-water bath conditions, and HPLC showed that the peak of compound 2 completely disappeared. The washing was carried out with a saturated NaHCO ₃ solution (50 mL×3), ultrapure water (50 mL), 0.1 N HCl solution (50 mL×2), and 20 mM NaCl solution (100 mL). _Organic phase was dried over MgS04, filtered, concentrated by evaporation in vacuo, to give compound 3, without further purification, it was used directly in the next reaction. The structure was determined by NMR.

Step c, Preparation of TBDPS-(10)-(7-ethyl-10-hydroxycamptothecin)-(20)-Gly-HCl (Compound 4): To a dry clean 100 mL round bottom flask was added 2.36 g ( 3 mmol) Compound 3, 10 mL of anhydrous dioxane, 10 mL of 4N HCl in dioxane, stirred and mixed, and reacted at room temperature for about 1.5 h. At this time, HPLC detection showed that the peak of Compound 3 completely disappeared. Precipitation with 50mL ether, filtered, the precipitate was collected, redissolved in 50mL DCM, to the _solution with saturated NaHCO HCl pH2.5 was washed, organic phase was dried over MgSO _4, filtered, concentrated by evaporation in vacuo. The concentrated product was dissolved in 5 mL of DCM, which was crystallised from diethyl ether. The precipitate was collected, and the residue was evaporated, and then evaporated to ethyl ether. The structure was determined by NMR.

Step d, Preparation of polyfunctionalized H-type polyethylene glycol modified Gly-SN38-TBDPS (H-PEG-Gly-SN38-TBDPS, compound 5): 1.5 g (0.05) was added to a dry clean 100 mL round bottom flask. Methanol, 1 equivalent of active site) 15 mL of polyfunctionalized H-type polyethylene glycol carboxylic acid (Compound D4-1, 30 kDa) in anhydrous DCM, 290 mg (0.4 mmol, 2 eq.) of compound 4, 244 mg (2 mmol) 10 equivalents of DMAP, 10 equivalents of 50% ethyl acetate solution. The mixture was stirred at room temperature, and the residue was evaporated. The structure was determined by NMR.

Step e, Preparation of polyfunctionalized H-type polyethylene glycol modified Gly-SN38 (H-PEG-Gly-SN38, compound 6): 980 mg (0.03 mmol) of compound 5 was added to a dry clean 100 mL round bottom flask. 0.48 mmol of tetrabutylammonium fluoride, 15 mL of tetrahydrofuran / 0.05 N hydrochloric acid solution (1:1 v/v), and stirred and mixed. At room temperature for 4h, extracted twice with dichloromethane and the combined organic phases were dried over MgSO _4, filtered, concentrated by evaporation in vacuo. The residue was dissolved in dimethylformamide, precipitated with isopropanol, filtered, and precipitated with isopropanol. The solvent was dissolved and precipitated. The residue was dissolved in dichloromethane and precipitated with diethyl ether. Drying under vacuum at 37 ° C for 16 h gave compound 6. The structure was determined by NMR. And high performance liquid chromatography, SDS-PAGE electrophoresis test, molecular weight of about 31kDa, purity of more than 95%.

The synthetic route of the above steps a-e has the following reaction formula:

Wherein, in the compound 6, L is CH ₂ CH ₂ CONH, and D is SN38-Gly.

Wherein, the structural parameter of the compound D4-1 is

F ₁ = F ₂ = CH ₂ CH ₂ COOH (g = 0, k = 1, q = 0, q ₁ = 1, Z ₁ = CH ₂ CH ₂ , R ₀₁ = COOH), j = 0. The designed total molecular weight is about 30 kDa, wherein the four branched chains have a molecular weight of about 4 x 6000 = 24000 Da, i.e., n ₁ ≈n ₂ ≈n ₃ ≈n ₄ ≈ 136, and the molecular weight of the main chain is about 6000 Da, m ₂ ≈ 136.

Example 5: Preparation of a small molecule drug SN38 modified with a polyfunctionalized H-type polyethylene glycol carboxylic acid derivative (amide linkage)

Step a, preparation of tert-butoxycarbonyl-(10)-(7-ethyl-10-hydroxycamptothecin) (Compound 7, Boc-SN38): to a dry and clean 250 mL round bottom under room temperature and nitrogen protection conditions A suspension of 1.96 g (5.0 mmol, 1 equivalent) of 7-ethyl-10-hydroxycamptothecin (SN38, compound 1) in anhydrous dichloromethane (DCM) was added to the flask, followed by the addition of 1.64 g (1.5 equivalents). Di-tert-butyl dicarbonate (Boc2O) and 15 mL of anhydrous pyridine were stirred at room temperature overnight, filtered over celite, and then with 0.5N HCl solution (100 mL×3), sat. NaHCO ₃ (100 mL) ) Washing is carried out. _Organic phase was dried over MgS04, filtered, evaporated in vacuo, and dried in vacuo to give compound 7. The structure was determined by NMR.

Step b, Preparation of tert-butoxycarbonyl-(10)-(7-ethyl-10-hydroxycamptothecin)-(20)-alanine-Bsmoc (Compound 8, Boc-SN38-Ala-Bsmoc): To a dry clean 100 mL round bottom flask was added 1.97 g (4 mmol, 1 equivalent) of compound 7, 1.87 g (6 mmol, 1.5 equivalents) of N-Bsmoc-L-alanine (Bsmoc-Ala) in 20 mL of ice-bath. Anhydrous dichloromethane solution was added, and 6.4 mmol (1.6 equivalents) of dichloroethane and 195 mg (1.6 mmol, 0.4 equivalents) of 4-dimethylaminopyridine were added. After stirring for 1 h under nitrogen atmosphere and ice water bath, the mixture was returned to room temperature, and the peak of compound 7 was completely disappeared by HPLC. The washing was carried out in 1% NaHCO ₃ solution (50 mL × 3), ultrapure water (50 mL), and 0.1 N HCl solution (50 mL × 2). _Organic phase was dried over MgS04, filtered, evaporated under reduced pressure, and dried in vacuo under 4 ℃, to give compound 8. The structure was determined by NMR.

Step c, Preparation of tert-butoxycarbonyl-(10)-(7-ethyl-10-hydroxycamptothecin)-(20)-alanine hydrochloride (Boc-SN38-Ala.HCl compound 9): 2. To a dry clean 500 mL round bottom flask was added 2.36 g (3 mmol) of compound 8, 4 mmol of 4-piperidin piperidine 150 mL of anhydrous dichloromethane, stirred and mixed, and reacted at room temperature for about 5 h, at which time HPLC showed compound 8. The peak disappeared completely. Carried out with 0.1N HCl solution (50mL × 2), dried the organic phase over MgSO _4, filtered, concentrated by evaporation in vacuo, Purity by HPLC 94%. The mixture was triturated with anhydrous diethyl ether (15 mL×3), ethyl acetate (15 mL×4), purified by dichloroethane and purified by diethyl ether, filtered, and concentrated in vacuo to give compound 9 which was purified by HPLC. It is 98%. The structure was determined by NMR.

Step d, Preparation of polyfunctionalized H-type polyethylene glycol modified Ala-SN38-Boc (H-PEG-Ala-SN38-Boc, compound 10): 1.5 g (0.05) was added to a dry clean 250 mL round bottom flask. Methanol, 1 equivalent of active site) 100 mL of a polyfunctionalized H-type polyethylene glycol carboxylic acid (compound D4-2, 30 kDa) in anhydrous dichloromethane, 120 mg (0.2 mmol, 0.5 eq.) of compound 9, ice water bath After cooling, 1 mmol of anhydrous dichloroethane and 48.8 mg (0.4 mmol) of 4-dimethylaminopyridine were added. Under nitrogen protection and ice water bath conditions, the reaction was stirred for 1 h, the reaction was terminated by the addition of alanine, allowed to stand at room temperature for 16 h, and distilled under reduced pressure. The residue was dissolved in anhydrous methylene chloride, and then filtered and evaporated. Recrystallization from a mixed solution of dimethylformamide/isopropanol. The specific step is to lower the solid product solution in a mixed solution of dimethylformamide/isopropanol (1:4 v/v) at 65 ° C, slowly. Cool to room temperature (about 3 h). Filtration and washing of the solid phase with anhydrous diethyl ether (100 mL x 3). The filter cake was dried under vacuum at 37 ° C to give the product 10. The structure was determined by NMR.

Step e, Preparation of polyfunctionalized H-type polyethylene glycol modified Ala-SN38 (H-PEG-Ala-SN38, compound 11): Adding 30% trifluoroacetic acid to a dry clean 100 mL round bottom flask A water dichloromethane solution, 933 mg of Compound 10, was stirred and mixed, and reacted at room temperature for 3 hours, and the peak of Compound 10 disappeared by HPLC. Really at 37 ° C The solvent was removed by evaporation, and the obtained material was crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Filter and wash the solid phase with anhydrous ether. The filter cake was dried under vacuum at 37 ° C to give the product 11. The structure was determined by NMR. And high performance liquid chromatography test, the main product molecular weight is about 31kDa.

The synthetic route of the above steps a-e has the following reaction formula:

Among them, the mixture of k ₁ of 3, 4, and 5 is 90% by mass or more, and the product of k ₁ = 4 is about 45% by mass. Wherein L is CH ₂ CH ₂ CONH and D is SN38-Ala.

Wherein, the structural parameter of the compound D4-2 is

F ₁ =F ₂ , g=1, k=2, g ₀ =0,

q=1,

q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =COOH, j=0. The designed total molecular weight is about 30 kDa, wherein the four branched chains have a molecular weight of about 4 x 5000 = 20,000 Da, i.e., n ₁ ≈n ₂ ≈n ₃ ≈n ₄ ≈ 114, and the molecular weight of the main chain is about 8750 Da, m ₂ ≈ 199.

Example 6: Preparation of a small molecule drug SN38 modified with a polyfunctionalized H-type polyethylene glycol carboxylic acid derivative (amide linkage)

The synthetic route of step a-e has the following reaction formula:

Wherein, in the compound 13, L is CH ₂ CH ₂ CONH, and D is SN38-Ala.

Steps a to c: Steps a to c of Example 5 were repeated.

Step d, Preparation of polyfunctionalized H-type polyethylene glycol modified Ala-SN38-Boc (H-PEG-Ala-SN38-Boc, compound 12): 1.5 g (0.05) was added to a dry clean 250 mL round bottom flask. Methanol, 1 equivalent of active site) 100 mL of polyfunctionalized H-type polyethylene glycol carboxylic acid (Compound D4-2, 30 kDa) in anhydrous dichloromethane, 480 mg (0.8 mmol, 2 equivalents) of compound 9, ice bath After cooling, 4 mmol (10 equivalents) of anhydrous dichloroethane and 488 mg (4 mmol, 10 equivalents) of 4-dimethylaminopyridine were added. Under nitrogen protection and ice water bath conditions, the reaction was stirred for 1 h, allowed to stand at room temperature for 16 h, and distilled under reduced pressure. The residue was dissolved in anhydrous methylene chloride, and then filtered and evaporated. Recrystallization from a mixed solution of dimethylformamide/isopropanol. The specific step is to lower the solid product solution in a mixed solution of dimethylformamide/isopropanol (1:4 v/v) at 65 ° C, slowly. Cool to room temperature (about 3 h). Filtration, solid phase with anhydrous ether Wash (100 mL x 3). The filter cake was dried under vacuum at 37 ° C to give the product 12. The structure was determined by NMR.

Step e, Preparation of polyfunctionalized H-type polyethylene glycol modified Ala-SN38 (H-PEG-Ala-SN38, compound 13): Adding 30% trifluoroacetic acid to a dry clean 100 mL round bottom flask A solution of water dichloromethane, 966 mg of Compound 12, was stirred and mixed, and reacted at room temperature for 3 h, and the peak of Compound 12 disappeared by HPLC. The solvent was evaporated under vacuum at 37 ° C, and the obtained material was dissolved in methylene chloride, and precipitated with anhydrous diethyl ether. The precipitate was collected and recrystallized from dimethylformamide / isopropyl alcohol. Filter and wash the solid phase with anhydrous ether. The filter cake was dried under vacuum at 37 ° C to give the product 13. The structure was determined by NMR. The product was tested by high performance liquid chromatography and the molecular weight of the product was about 31 kDa.

Example 7: Preparation of a small molecule drug SN38 modified with a polyfunctionalized H-type polyethylene glycol carboxylic acid derivative (amide linkage)

In step a, step a of step 5 is repeated.

Step b, Preparation of tert-butoxycarbonyl-(10)-(7-ethyl-10-hydroxycamptothecin)-(20)-methionine-Bsmoc (Compound 14, Boc-SN38-Met-Bsmoc) : In a dry water 100 mL round bottom flask, 1.97 g (4 mmol, 1 equivalent) of compound 7, 2.23 g (6 mmol, 1.5 equivalents) of N-Bsmoc-L-methionine (Bsmoc-Met) was added under ice-water bath. A solution of 20 mL of anhydrous dichloromethane was added 6.4 mmol (1.6 eq.) of dichloroethane, 195 mg (1.6 mmol, 0.4 eq.) of 4-dimethylaminopyridine. After stirring for 1 h under nitrogen atmosphere and ice water bath, the mixture was returned to room temperature, and the peak of compound 7 was completely disappeared by HPLC. The washing was carried out in 1% NaHCO ₃ solution (50 mL × 3), ultrapure water (50 mL), and 0.1 N HCl solution (50 mL × 2). _Organic phase was dried over MgS04, filtered, evaporated under reduced pressure, and dried in vacuo under 4 ℃, to give compound 14. The structure was determined by NMR.

Step c, Preparation of tert-butoxycarbonyl-(10)-(7-ethyl-10-hydroxycamptothecin)-(20)-methionine hydrochloride (Boc-SN38-Met·HCl compound 15) Adding 2.54 g (3 mmol) of compound 14, 4 mmol of 4-piperidine piperidine 150 mL of anhydrous dichloromethane to a dry clean 500 mL round bottom flask, stirring and mixing, and reacting at room temperature for about 5 h, at which time HPLC detection showed The peak of Compound 14 completely disappeared. Carried out with 0.1N HCl solution (50mL × 2), dried the organic phase over MgSO _4, filtered, concentrated by evaporation in vacuo, Purity by HPLC 94%. It was triturated with anhydrous diethyl ether (15 mL×3), ethyl acetate (15 mL×4), purified by dichloroethane and diethyl ether precipitation, filtered and evaporated in vacuo to give compound 15 which was determined by NMR. The purity was 98% as determined by HPLC.

Step d, Preparation of polyfunctionalized H-type polyethylene glycol modified Met-SN38-Boc (H-PEG-Met-SN38-Boc, compound 16): 1.5 g (0.05) was added to a dry clean 250 mL round bottom flask. Methanol, 1 equivalent of active site) 100 mL of a polyfunctionalized H-type polyethylene glycol carboxylic acid (compound D4-3, 11 kDa) in anhydrous dichloromethane, 793 mg (1.2 mmol, 2 eq.) of compound 15 in ice bath After cooling, 6 mmol of anhydrous dichloroethane and 733 mg (6 mmol, 10 equivalents) of 4-dimethylaminopyridine were added. Under nitrogen protection and ice water bath conditions, the reaction was stirred for 1.5 h, allowed to stand at room temperature for 16 h, and distilled under reduced pressure. The residue was dissolved in anhydrous methylene chloride, and then filtered and evaporated. Recrystallization from a mixed solution of dimethylformamide/isopropanol. The specific step is to lower the solid product solution in a mixed solution of dimethylformamide/isopropanol (1:4 v/v) at 65 ° C, slowly. Cool to room temperature (about 3 h). Filtration and washing of the solid phase with anhydrous diethyl ether (100 mL x 3). The filter cake was dried under vacuum at 37 ° C to give compound 16. The structure was determined by NMR.

Step e, Preparation of polyfunctionalized H-type polyethylene glycol modified Met-SN38 (H-PEG-Met-SN38, compound 17): Adding 30% trifluoroacetic acid to a dry clean 100 mL round bottom flask A solution of water methylene chloride and 418 mg of Compound 16 were stirred and mixed, and reacted at room temperature for 3 hours, and the peak of Compound 16 disappeared by HPLC. The solvent was evaporated under vacuum at 37 ° C, and the obtained material was dissolved in methylene chloride, and precipitated with anhydrous diethyl ether. The precipitate was collected and recrystallized from dimethylformamide / isopropyl alcohol. Filter and wash the solid phase with anhydrous ether. The filter cake was dried under vacuum at 37 ° C to give the product 17. The structure was determined by NMR. The product was tested by high performance liquid chromatography and the molecular weight of the product was about 13.0 kDa.

The synthetic route of the above steps a-e has the following reaction formula:

Wherein, in the compound 17, L is CH ₂ CONH, and D is SN38-Met.

Wherein, the structural parameter of the compound D4-3 is

F ₁ =F ₂ , g=1, k=3, g ₀ =0,

q = 0, q ₁ = 1, Z ₁ = CH ₂ , R ₀₁ = COOH, j = 0. The designed total molecular weight is about 11kDa, wherein the molecular weight of the four branched chains is about 4×2000=8000Da, that is, n ₁ ≈n ₂ ≈n ₃ ≈n ₄ ≈45, and the main chain polyethylene glycol is monodisperse, EO unit The number m ₂ = 44.

Example 8: Preparation of a small molecule drug SN38 modified with a polyfunctionalized H-type polyethylene glycol carboxylic acid derivative (amide linkage)

In step a, step a of step 5 is repeated.

Step b, Preparation of tert-butoxycarbonyl-(10)-(7-ethyl-10-hydroxycamptothecin)-(20)-sarcosine-Boc (Compound 18, Boc-SN38-Sar-Boc): To a dry clean 100 mL round bottom flask was added 1.97 g (4 mmol, 1 equivalent) of compound 7, 2.84 g (6 mmol, 1.5 eq.) of N-tert-butoxycarbonyl-L-sarcosine (Boc-Sar) in 25 mL anhydrous. The methylene chloride solution was cooled to 0 ° C, and 2 mmol (0.5 eq.) of dichloroethane and 733 mg (6 mmol, 1.5 eq.) of 4-dimethylaminopyridine were added under ice water bath. After stirring for 2 h under nitrogen atmosphere and ice water bath, the mixture was returned to room temperature, and the peak of compound 7 was completely disappeared by HPLC. The washing was carried out in a 0.5% NaHCO ₃ solution (60 mL × 3), ultrapure water (60 mL), and a 0.1 N HCl solution (60 mL × 2). _Organic phase was dried over MgS04, filtered, evaporated in vacuo and the solvent was removed in vacuo and dried under 4 ℃, to give compound 18. The structure was determined by NMR.

Step c, Preparation of 7-ethyl-10-hydroxycamptothecin-(20)-sarcosine trifluoroacetate (Boc-SN38-Sar·TFA, compound 19): dry clean 100 mL round bottom flask 1.99 g (3 mmol) of compound 18, 4 mL of trifluoroacetic acid, and 16 mL of anhydrous dichloromethane were added thereto, and the mixture was stirred and stirred, and reacted at room temperature for about 1 hour. At this time, HPLC detection showed that the peak of Compound 18 completely disappeared. Toluene was added and evaporated at 30 °C. It was dissolved in 10 mL of chloroform and precipitated with anhydrous diethyl ether. Filtration, collection of the precipitate, and drying gave Compound 19. The structure was determined by NMR.

Step d, Preparation of TBDMS-(10)-(7-ethyl-10-hydroxycamptothecin)-(20)-sarcosine hydrochloride (TBDMS-SN38-Sar·HCl, compound 20): drying A clean 500 mL round bottom flask was charged with 1.65 g (3 mmol) of a solution of compound 19 in dimethylformamide (25 mL). 15 mmol (5 equivalents) of triethylamine and 1.81 g of t-butyldimethylsilyl chloride (TBDMS, 12 mmol, 4 eq.) were added, and the mixture was reacted at room temperature for about 1 hour, at which time HPLC analysis showed that the peak of compound 19 was completely disappeared. This was washed with a 0.5% NaHCO ₃ solution (50 mL × 3), ultrapure water (50 mL), and a 0.1N HCl saturated NaCl solution (50 mL × 2). The organic phase was dried over MgSO _4, filtered, concentrated by evaporation in vacuo. It was dissolved in anhydrous dichloromethane and precipitated with anhydrous diethyl ether. The mixture was filtered twice, and the precipitate was collected and dried in vacuo to give compound 20. The structure was determined by NMR.

Step e, Preparation of polyfunctionalized H-type polyethylene glycol modified Sar-SN38-Boc (H-PEG-Sar-SN38-TBDMS, compound 21): 2.47 g (0.1) was added to a dry clean 250 mL round bottom flask. Methanol, 1 equivalent of active site) 80 mL of polyfunctionalized H-type polyethylene glycol carboxylic acid (Compound D4-4, 25 kDa) in anhydrous dichloromethane, 599 mg (1 mmol, 2.5 eq.) of dimethyl 20 mL of the formamide solution was cooled to 0 ° C in an ice bath, and 2 mmol of anhydrous dichloroethane (5 equivalents) and 147 mg (1.2 mmol, 3 equivalents) of 4-dimethylaminopyridine were added. Slowly return to room temperature, stir the reaction for 16 h and concentrate in vacuo. The residue was dissolved in a minimum of anhydrous methylene chloride, anhydrous diethyl ether was added, filtered in vacuo, and re-precipitated with acetonitrile/isopropanol (1:20 v/v), isopropanol, anhydrous The ether was washed, filtered, and the precipitate was collected and dried to give Compound 21. The structure was determined by NMR.

Step f, Preparation of polyfunctionalized H-type polyethylene glycol-modified Ala-SN38 (H-PEG-Sar-SN38, compound 22): a 50% aqueous solution of trifluoroacetic acid was added to a dry clean 500 mL round bottom flask. 200 mL and 800 mg of Compound 21 were stirred and mixed, and reacted at room temperature for 12 hours, diluted with ultrapure water, and extracted with anhydrous dichloromethane (250 mL × 3). The organic phases were combined and washed with ultrapure water (100 mL x 2). The organic phase was dried over MgSO _4, filtered, concentrated by evaporation in vacuo. Dissolved in 100 mL of dimethylformamide, slightly heated, and slowly added to 400 mL of dimethylformamide to coprecipitate. After filtration, the mixture was washed with a mixture of dimethylformamide / isopropyl alcohol (1:4 v / v) and anhydrous diethyl ether, and the solid was dissolved in anhydrous dichloromethane and precipitated with diethyl ether. Product 22 was obtained. The structure was determined by NMR. The product was tested by high performance liquid chromatography and the molecular weight of the product was about 26 kDa.

The synthetic route of the above steps a-f is as follows:

Wherein, in the compound 22, L is CH ₂ CH ₂ CONH, and D is SN38-Sar.

Wherein, the structural parameter of the compound D4-4 is

(U ₁ , U _{2 are} asymmetrical,

L ₁ = L ₃ = CH ₂ CH ₂ , L ₂ = L ₄ = CH ₂ CH ₂ , L ₅ , L ₆ are absent), F ₁ = F ₂ = CH ₂ CH ₂ COOH (g = 0, k = 1 , q=0, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =COOH), j=0. . The designed total molecular weight is about 25 kDa, wherein the four branched chains are monodisperse, the number of EO units is n ₁ = n ₂ = n ₃ = n ₄ = 22, and the molecular weight of the main chain is about 20,000 Da, m ₂ ≈ 455.

Example 9: Preparation of a small molecule drug SN38 modified with a polyfunctionalized H-type polyethylene glycol carboxylic acid derivative (amide linkage)

In steps a-e, steps a-e of step 8 are repeated.

Step f, Preparation of polyfunctionalized H-type polyethylene glycol modified Ala-SN38 (H-PEG-Sar-SN38, compound 23): 800 mg of compound 21 was added to a dry clean 50 mL round bottom flask, and 10 mL of 1 N HCl was added. The mixture was dissolved, stirred and mixed, and reacted at room temperature for 1 h. The peak of Compound 21 disappeared by HPLC. Extraction was carried out with anhydrous dichloromethane (50 mL x 3). The organic phase was dried over MgSO _4, filtered, concentrated by evaporation in vacuo. The resultant was dissolved in 10 mL of dimethylformamide, slightly heated, and immediately added 40 mL of isopropyl alcohol to precipitate. After filtration, the precipitate was collected and dried under vacuum at 37 °C. Product 23 was obtained. The structure was determined by NMR. The product was tested by high performance liquid chromatography and the molecular weight of the product was about 26 kDa.

The synthetic route reaction formula of the above steps a-f is the same as in the eighth embodiment. Among them, in compound 23, L is CONH, and D is SN38-Sar.

Example 10: Preparation of a polyfunctionalized H-type polyethylene glycol succinimide active ester derivative modified small molecule drug irinotecan (urethane linkage, ie urethane linkage)

Step a: Preparation of irinotecan-glycine-Boc (Compound 25, IRES-Gly-Boc): 294 mg of irinotecan (compound 24, 0.5 mmol, 1 equivalent), 175 mg were added sequentially to a dry clean 100 mL round bottom flask. Boc-glycine (1 mmol, 2 equivalents), 61.1 mg of 4-dimethylaminopyridine (0.5 mmol, 1 equivalent), and 40 mL of anhydrous dichloromethane were stirred and dissolved. 6 mL of a solution of dicyclohexylcarbodiimide (DCC, 1 mmol, 2 equivalents) in anhydrous dichloromethane was added and stirred and mixed. The reaction was stirred at room temperature for 16 h. The core was filtered to remove solid impurities, and the organic phase was washed successively with 20 mL of 0.1 N HCl solution and 20 mL of ultrapure water in a separating funnel. Dried over Na ₂ SO _4, solvent was removed by rotary evaporation, and dried in vacuo. Compound 25 was obtained. The structure was determined by ¹ H NMR. The molecular weight was determined by high performance liquid chromatography to be 744 Da.

Step b: Preparation of irinotecan-glycine (Compound 26, IRES-Gly): 298 mg of compound 25 (0.4 mmol, 1 eq.), 10 mL of anhydrous dichloromethane were added to a dry clean 50 mL round bottom flask, and dissolved. 2 mmol of trifluoroacetic acid (5 equivalents) was added and stirred and mixed. The reaction was stirred at room temperature for 1 h, and the solvent was removed by rotary evaporation. The crude product was dissolved in a minimum of methanol, taken up in 25 mL of dry diethyl ether and sp. Compound 26 was obtained. The structure was determined by ¹ H NMR test. The purity was 97% by high performance liquid chromatography.

Step c: Preparation of polyfunctionalized H-type polyethylene glycol modified glycine-irinotecan (H-PEG-Gly-IRES, compound 27): Add compound 26 (4 mmol, 5) to a dry clean 50 mL round bottom flask. Equivalent), 8.14 g of polyfunctionalized H-type polyethylene glycol succinimide carbonate (compound A6-1, 40 kDa, 0.2 mmol, 1 equivalent active site), 244 mg 4-dimethylaminopyridine (2 mmol, 2.5 equivalents, 60 mL of anhydrous dichloromethane, stirred and dissolved. 1.15 g DCC (5.6 mmol, 7 equivalents) was added and stirred and mixed. The reaction was carried out for 12 h at room temperature. The sand core was filtered to remove impurities, and the solvent was removed by rotary evaporation, and 200 mL of isopropanol was added thereto, followed by precipitation under ice water bath. Filter and vacuum dry. Product 27 was obtained. The structure was determined by ¹ H NMR test. High performance liquid chromatography was performed with a molecular weight of approximately 43 kDa. The SDS-PAGE electrophoresis test was carried out, and the purity was 95% or more.

The synthetic route of the above steps a-c is as follows:

The results for product 27 are shown below, wherein L is OCONH and D is IRES-Gly.

Wherein, the structural parameter of the compound A6-1 is

F ₁ = F ₂ = CH ₂ CH ₂ OCONHS (g = 0, k = 1, q = 1, Z ₂ = CH ₂ CH ₂ , q ₁ =1, Z ₁ = -OC(=O)-, R ₀₁ =NHS), j=0. The designed total molecular weight is about 40 kDa, wherein the four branched chains have a molecular weight of about 4 x 8000 = 32,000 Da, i.e., n ₁ ≈n ₂ ≈n ₃ ≈n ₄ ≈ 182, and the molecular weight of the main chain is about 8000 Da, m ₂ ≈ 182.

Example 11: Preparation of a polyfunctionalized H-type polyethylene glycol succinimide active ester derivative modified small molecule drug irinotecan (amide linkage)

Wherein, the structural parameter of the compound A1-2 is

F ₁ =F ₂ =CH ₂ CH ₂ CONHS(g=0,k=1,q=0,q ₁ =1,Z ₁ =-CH ₂ CH ₂ C(=O)-, R ₀₁ =NHS), j=0. The designed total molecular weight is about 26 kDa, wherein the four branched chains have a molecular weight of about 4 x 5000 = 20000 Da, i.e., n ₁ ≈n ₂ ≈n ₃ ≈n ₄ ≈ 114, and the molecular weight of the main chain is about 5000 Da, m ₂ ≈ 114.

Step a: Preparation of 2-(2-t-Boc-aminoethoxy)ethanol (Compound 28): 21.5 g (0.2 mol) of 2-(2-aminoethoxy) were added sequentially to a dry clean 500 mL round bottom flask. Ethyl alcohol, 25.2 g (0.3 mol) of NaHCO ₃ , 150 mL of dichloromethane and 150 mL of ultrapure water, stirred for 15 min, added 43.6 g (0.2 mol) of 2-tert-butyl dicarbonate, stirred and mixed, at room temperature The reaction was carried out for 10 h, and then dried over anhydrous methylene chloride (100 mL×3). The organic phases were combined, dried over Na ₂ SO ₄ evaporated to dryness in vacuo. Compound 28 was obtained. The structure was determined by NMR test.

Step b: Preparation of 2-(2-t-Boc-aminoethoxy)ethoxycarbonyl-irinotecan (Compound 29): To a dry clean 1000 mL round bottom flask was added 10.25 g (50 mmol) of compound 28 in order. 12.2 g (100 mmol) of 4-dimethylaminopyridine and 200 mL of anhydrous dichloromethane were dissolved by stirring. While stirring, 18 mmol of triphosgene was added and stirring was continued for 20 min. 200 mL of a solution of irinotecan (5.87 g, 10 mmol) and DMAP (12.2 g, 100 mmol) in dichloromethane was added. Stir and mix. The reaction was carried out for 2 h at room temperature and washed with a pH 3.2 HCl solution (200 mL×3). The organic phases were combined, dried over Na ₂ SO _4, concentrated by evaporation in vacuo. Compound 29 was obtained. The structure was determined by NMR test.

Step c: Preparation of 2-(2-aminoethoxy)ethoxycarbonyl-irinotecan trifluoroacetate (Compound 30): sequentially added to a dry clean 200 mL round bottom flask, 4.9 g (6 mmol) Compound 29, 60 mL of anhydrous dichloromethane was stirred and dissolved, and 20 mL of trifluoroacetic acid was added at room temperature, and the reaction was stirred for 2 h. Solvent removal by vacuum distillation, residue with anhydrous B The ether was precipitated, filtered, and the precipitate was collected and dried to give Compound 30. The structure was determined by NMR test.

Step d: Preparation of polyfunctionalized H-type polyethylene glycol-modified 2-(2-aminoethoxy)ethoxycarbonyl-irinotecan (H-PEG-IRES, compound 31): 500 mL to dry clean In a round bottom flask, 12 mL of a solution of compound 30 (1.96 g, 2.4 mmol, 1.2 eq.) in dimethylformamide was added, 0.6 mL of triethylamine was added and mixed, and polyfunctional H-type polyethylene glycol succinimide was added. 200 mL of a solution of propionate (Compound A1-2, 26 kDa, 12.8 g, 0.5 mmol, 1 equivalent of active site) in dichloromethane, stirred and mixed, and reacted at room temperature for 12 h. Precipitation was carried out with anhydrous diethyl ether, recrystallized from isopropyl alcohol, filtered and dried. The structure was determined by NMR test and high performance liquid chromatography test. According to the HPLC test results, the molecular weight was about 26 kDa and the purity was about 94%.

The synthetic route of the above steps a-d is as follows:

Wherein L is CH ₂ CH ₂ CONH and D is 2-(2-aminoethoxy)ethoxycarbonyl-irinotecan.

Example 12: Preparation of a polyfunctionalized H-type polyethylene glycol carboxylic acid derivative modified small molecule drug irinotecan (amide linkage)

Step a: Preparation of irinotecan-glycine hydrochloride (Compound 32, IRES-Gly.HCl): To a dry clean 100 mL round bottom flask was charged 2.23 g (3 mmol) of irinotecan-glycine-Boc (Compound 25, IRES-Gly-Boc), 10 mL of anhydrous dioxane, 10 mL of 4N HCl in dioxane solution, stirred and stirred, and reacted at room temperature for about 1.5 h. At this time, HPLC detection showed that the peak of Compound 25 completely disappeared. Precipitation with 50mL ether, filtered, the precipitate was collected, redissolved in 50mL DCM, to the _solution with saturated NaHCO HCl pH2.5 was washed, organic phase was dried over MgSO _4, filtered, concentrated by evaporation in vacuo. The concentrated product was dissolved in 5 mL of DCM eluting with dry diethyl ether. The structure was determined by NMR.

Step b: Preparation of polyfunctionalized H-type polyethylene glycol modified glycine-irinotecan (H-PEG-Gly-IRES, compound 33): 2 g (0.05 mmol, 1) was added to a dry clean 100 mL round bottom flask. Equivalent active site) 20 mL of polyfunctionalized H-type polyethylene glycol carboxylic acid (Compound D4-5, 40 kDa) in anhydrous DCM, 272 mg (0.4 mmol, 2 eq.) of compound 32, 244 mg (2 mmol, 10 eq. DMAP, 10 equivalents of 50% ethyl acetate solution. The mixture was stirred at room temperature, and the residue was evaporated, evaporated, evaporated, evaporated. The resultant was dissolved in dichloromethane and precipitated with anhydrous diethyl ether filtered and dried in vacuo at 37 ° C. Compound 33 was obtained. The structure was determined by NMR. It was tested by high performance liquid chromatography and SDS-PAGE electrophoresis with a molecular weight of about 42 kDa and a purity of more than 95%.

Wherein, the structural parameter of the compound D4-5 is

F ₁ = F ₂ = CH ₂ COOH (g = 0, k = 1, q = 0, q ₁ = 1, Z ₁ = CH ₂ , R ₀₁ = COOH), j = 0. The designed total molecular weight is about 40 kDa, wherein the four branched chains have a molecular weight of about 4 x 8000 = 32,000 Da, i.e., n ₁ ≈n ₂ ≈n ₃ ≈n ₄ ≈ 182, and the molecular weight of the main chain is about 8000 Da, m ₂ ≈ 182.

Wherein L is CH ₂ CONH and D is IRES-Gly.

Further, H-type polyethylene glycol-modified irinotecan (33b) was prepared by the same method using tetracarboxylic H-type polyethylene glycol having the structure D4-1 as a raw material. Its designed total molecular weight is about 20kDa, and the molecular weight of the four branched chains is about 4×4750=19000Da, that is, n ₁ ≈n ₂ ≈n ₃ ≈n ₄ ≈108, the main chain polyethylene glycol has monodispersity, EO The number of cells is m ₂ =24.

Example 13: Preparation of a polyfunctionalized H-type polyethylene glycol carboxylic acid derivative modified small molecule drug irinotecan (amide linkage)

Step a: Repeat step a of implementation 12.

Step b: Preparation of polyfunctionalized H-type polyethylene glycol modified glycine-irinotecan (H-PEG-Gly-IRES, compound 34): To a dry clean 100 mL round bottom flask was added 1 g (0.05 mmol, 1 equivalent of active site) of polyfunctionalized H-type polyethylene glycol carboxylic acid (Compound D4-6, 20 kDa) in anhydrous DCM 20 mL 408 mg (0.6 mmol, 3 equivalents) of compound 32, 244 mg (2 mmol, 10 equivalents) of DMAP, and 10 equivalents of 50% ethyl acetate solution were added in that order. The mixture was stirred at room temperature, EtOAc (EtOAc m. The resultant was dissolved in dichloromethane and precipitated with anhydrous diethyl ether filtered and dried in vacuo at 37 ° C. Compound 34 was obtained. The structure was determined by NMR. It was tested by high performance liquid chromatography and SDS-PAGE. The molecular weight was about 23 kDa and the purity was more than 95%.

Wherein, the structural parameter of the compound D4-6 is

(U ₁ , U _{2 are} symmetrical,

L ₁ = L ₃ = CH ₂ , L ₂ = L ₄ = CH ₂ , L ₅ = L ₆ = CH ₂ ), F ₁ = F ₂ = CH ₂ COOH (g = 0, k = 1, q = 0, q ₁ =1, Z ₁ =CH ₂ , R ₀₁ =COOH), j=0. The designed total molecular weight is about 20 kDa, wherein the four branched chains have a molecular weight of about 4 x 3000 = 12000 Da, i.e., n ₁ ≈n ₂ ≈n ₃ ≈n ₄ ≈68, and the molecular weight of the main chain is about 8000 Da, m ₂ ≈ 182.

The structure of Compound 34 is shown below, wherein L is CH ₂ CONH and D is IRES-Gly.

Example 14: Preparation of polyfunctionalized H-type polyethylene glycol modified resveratrol (urethane linkage)

To a 50 mL dry clean round bottom flask was added 9.6 g (0.2 mmol, 1 equivalent of active site) of a polyfunctionalized H-type polyethylene glycol amine (Compound C3-1) in dichloromethane, and 30 μL of triethylamine was added. Stir. In a dry clean 100 mL round bottom flask, solid triphos was dissolved in 25 mL of dichloromethane, and stirred to dissolve. The dichloromethane/triethylamine solution of compound C3-1 was added to a solution of triphosgene in dichloromethane and stirred for 10 min. The reaction was heated to reflux for 2 h and cooled to room temperature. Compound D9-1 was obtained, and the structure was determined by NMR test.

The mixture was slowly added to a solution of resveratrol (1.82 g, 8 mmol, 10 eq.) in dichloromethane (25 mL, for 4-6 h). Recrystallization, filtration, dichloroethane dissolution, anhydrous diethyl ether precipitation, repeated dissolution, precipitation step 2 times, filtration, vacuum drying. Product 35 was obtained and the structure was determined by NMR.

Wherein, the structural parameter of the compound C3-1 is that U ₁ and U _{2 are} symmetric,

F ₁ = F ₂ = CH ₂ CH ₂ NH ₂ (g = 0, k = 1, q = 0, q ₁ = 1, Z ₁ = CH ₂ CH ₂ , R ₀₁ = NH ₂ ), j = 0. The designed total molecular weight is about 52kDa, wherein the molecular weight of the four branched chains is about 4×12000=48000Da, that is, n ₁ ≈n ₂ ≈n ₃ ≈n ₄ ≈273, the main chain polyethylene glycol has monodispersity, EO unit The number m ₂ = 65.

Wherein, the structural parameters of the compound D9-1 are U ₁ , U ₂ , L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ , j, n ₁ , n ₂ , n ₃ , n ₄ , m ₂ , G is consistent with compound C3-1. F ₁ = F ₂ = CH ₂ CH ₂ NCO (g = 0, k = 1, q = 0, q ₁ = 1, Z ₁ = CH ₂ CH ₂ , R ₀₁ = NCO), and the designed total molecular weight is about 52 kDa.

Where product 35 is a mixture as shown below:

Wherein L is CH ₂ NHCOO and D is RES.

Example 15: Preparation of polyfunctionalized H-type polyethylene glycol modified cyclic evergreen boxin D (ester linkage)

Step a: Preparation of N,N'-di-tert-butoxycarbonyl-cycloalkaneine D (Compound 37): To a 100 mL dry clean round bottom flask was charged 1.21 g of cycloalkaline D (3 mmol), 1 mL. Trifluoroethylamine, 12 mL of anhydrous dichloromethane, and stirred and mixed. Under ice water bath conditions, 12 mL of a solution of 1.64 g (7.5 mmol) of di-tert-butyl dicarbonate (Boc 2 O) in dichloromethane was added dropwise, and the addition was completed in about 15 minutes. The ice bath was removed, and the mixture was naturally returned to room temperature, and reacted for 4 hours under stirring. Concentration under reduced pressure, precipitation with isopropyl alcohol, filtration, washed twice with isopropyl alcohol and dried in vacuo to give compound 37. The structure was determined by NMR.

Step b: Preparation of polyfunctionalized H-type polyethylene glycol-modified N,N'-di-tert-butoxy-cyclic evergreen boxin D (Compound 38): Add more to 100 mL of dry clean round bottom flask Functionalized H-type polyethylene glycol carboxylic acid derivative (compound D4-7, molecular weight 40 kDa, 2 g, 0.05 mmol 1 equivalent active site), 241 mg of compound 37 (0.4 mmol, 2 equivalents) obtained in step a, 48.9 mg ( 0.4mmol, 2 equivalents) 4-dimethylaminopyridine (DMAP), add 20mL anhydrous dichloromethane, dissolve, add 206mg (1mmol, 5 equivalents) DCC, stir and mix, react at room temperature 12h. The sand core was filtered to remove solid impurities, concentrated by evaporation, and precipitated with a mixed solution of isopropanol/anhydrous ether (1:6 v/v), filtered, washed and dried in vacuo to give compound 38. The structure was determined by NMR. It was tested by high performance liquid chromatography with a molecular weight of approximately 42 kDa.

Step c: Preparation of polyfunctionalized H-type polyethylene glycol-modified cyclic evergreen boxin D (Compound 39): To a 50 mL dry clean round bottom flask was charged 847 mg of compound 38 (0.02 mmol), 5 mL of chloroform, and stirred. Dissolve, add 1.5 mL of trifluoroacetic acid, stir and mix, and react at room temperature for 3 h. The solution was changed from colorless to light green, concentrated under reduced pressure and purified using diethyl ether. The structure was determined by NMR. It was tested by high performance liquid chromatography with a molecular weight of approximately 41 kDa and a purity of 96%.

The reaction formula of the above steps a-c is as follows:

Wherein L is CH ₂ COO and D is CVBD.

Wherein, the structural parameter of the compound D4-7 is

(U ₁ , U _{2 are} symmetrical,

L ₁ = L ₃ = CH ₂ CH ₂ CH ₂ , L ₂ = L ₄ = CH ₂ CH ₂ CH ₂ , L ₅ = L ₆ = CH ₂ CH ₂ CH ₂ ), F ₁ = F ₂ =

(g=0, k=1, q=1, Z ₂ =-CH ₂ CH ₂ C(=O)NH-, q ₁ =1, Z ₁ =-CH ₂ -, R ₀₁ =COOH),j= 0. The designed total molecular weight is about 40 kDa, wherein the four branched chains have a molecular weight of about 4 x 8000 = 32,000 Da, i.e., n ₁ ≈n ₂ ≈n ₃ ≈n ₄ ≈ 182, and the molecular weight of the main chain is about 7100 Da, m ₂ ≈ 161.

Example 16: Preparation of a polyfunctionalized H-type polyethylene glycol modified cyclic evergreen boxin D (amide linkage)

To a 100 mL dry clean round bottom flask was added 806 mg of cyclochloroxanthine (Compound 36, 2 mmol, 5 equivalents), 488 mg (4 mmol, 10 equivalents) of 4-dimethylaminopyridine, 20 mL of anhydrous under nitrogen. Dichloromethane was stirred and mixed, and 412 mg (2 mmol, 5 equivalents) of DCC was added and mixed. Under nitrogen protection, 30 mL of polyfunctionalized H-type polyethylene glycol carboxylic acid derivative (Compound D4-7, molecular weight 40 kDa, 4 g, 0.1 mmol, 1 equivalent active site) of anhydrous dichloromethane was slowly added in batches. Into the mixture (about 12 h), stir for 1 h. The solvent was removed by rotary evaporation, 1,4-dioxane was added, and solid impurities were removed by filtration. The filtrate was concentrated by rotary evaporation and the residue was crystallised eluted with EtOAc. The structure was determined by NMR test. It was tested by high performance liquid chromatography and SDS-PAGE. The molecular weight was about 41 kDa and the purity was about 95%.

Product 40 is a mixture of the structures shown below,

Wherein L is CH ₂ CONH and D is CVBD.

Example 17: Preparation of polyfunctionalized H-type polyethylene glycol modified cyclic evergreen boxin D (amide linkage)

Step a: Step a of Example 15 is repeated.

Step b: Preparation of N,N'-di-tert-butoxy-cyclic evergreenwood D-glycine-Boc (Compound 41): Add 3 g of N,N'-di-tert-butyl to 100 mL of dry clean round bottom flask Oxylyl-ring evergreen boxwood D (compound 37, 5 mmol), 1.4 g Boc-glycine (8 mmol), 611 mg 4-dimethylaminopyridine, 30 mL anhydrous dichloromethane, stirred to dissolve, and added 1.65 g (8 mmol) DCC, stirred, and reacted at room temperature for 15 h. The precipitate was removed by filtration, and the organic phase was washed twice with 0.5M EtOAc EtOAc. The structure was determined by NMR test.

Step c: Preparation of glycine-cyclic evergreen boxin D ester (Compound 42, CVBD-Gly-NH ₂ ): Compound 41 obtained in Step a was dissolved in 12 mL of dichloromethane, 8 mL of trifluoroacetic acid was added, and the reaction was stirred for 1 h. The organic layer was concentrated under reduced pressure. EtOAc was evaporated. The structure was determined by NMR test.

Step d: Preparation of a polyfunctionalized H-type polyethylene glycol modified glycine-cyclic evergreen boxin D ester (Compound 43): 4 g of a polyfunctionalized H-type polyethylene glycol was added to a 100 mL dry clean round bottom flask. a carboxylic acid derivative (compound D4-8, molecular weight 40 kDa, 0.1 mmol, 1 equivalent active site), 552 mg of compound 42 (1.2 mmol, 3 eq.) prepared in step c, 98 mg of 4-dimethylaminopyridine (0.8 mmol, 2 equivalents), a mixed solution of 15 mL of anhydrous dichloromethane and 3 mL of dimethylformamide was added, and the mixture was mixed. 123.6 mg (0.6 mmol, 1.5 equivalents) of DCC was added, stirred and mixed, and reacted at room temperature for 12 hours. Filtration, concentration by evaporation, precipitation with a mixed solution of isopropanol / anhydrous diethyl ether (1:6 v / v), filtered, washed and dried in vacuo to afford compound 43. The structure was determined by NMR. It was tested by high performance liquid chromatography with a molecular weight of approximately 42 kDa.

Wherein, the structural parameter of the compound D4-8 is

(U ₁ , U _{2 are} symmetrical,

L ₁ = L ₃ = CH ₂ CH ₂ CH ₂ , L ₂ = L ₄ = CH ₂ CH ₂ CH ₂ , L ₅ = L ₆ = CH ₂ CH ₂ CH ₂ ), F ₁ = F ₂ = CH ₂ CH ₂ COOH (g = 0, k = 1, q = 0, q ₁ = 1, Z ₁ = CH ₂ CH ₂ , R ₀₁ = COOH), j = 0. The designed total molecular weight is about 40 kDa, wherein the four branched chains have a molecular weight of about 4 x 8000 = 32,000 Da, i.e., n ₁ ≈n ₂ ≈n ₃ ≈n ₄ ≈ 182, and the molecular weight of the main chain is about 7100 Da, m ₂ ≈ 161.

The reaction formula of the above steps a-d is as follows:

Wherein L is CH ₂ CH ₂ CONH and D is CVBD-Gly.

Example 18: Preparation of polyfunctionalized H-type polyethylene glycol-modified cyclic evergreen boxin D (amide linkage)

A polyfunctionalized H-type polyethylene glycol-modified glycine-cyclic evergreen boxin D ester (Compound 44) was prepared by the method of Example 17 using the compound D4-9 in place of the compound D4-8. The structure was determined by NMR. It was tested by high performance liquid chromatography with a molecular weight of approximately 27 kDa.

Wherein, the structural parameter of the compound D4-9 is

(g=1, k=2, g ₀ =0,

q=0, q ₁ =1,

R ₀₁ =COOH), W ₀₁ =W ₀₂ =

The asterisks of U ₁ and U ₂ point to the polyethylene glycol backbone, the asterisks in G and Z ₁ point to the polyethylene glycol branching chain, and the asterisks in W ₀₁ and W ₀₂ point to the polyethylene glycol where m ₃ is located. Block. The designed total molecular weight is about 24kDa, wherein the molecular weight of the four branched chains is about 4×3000=12000Da, that is, n ₁ ≈n ₂ ≈n ₃ ≈n ₄ ≈68, and the molecular weights of the three PEG blocks of the main chain are 2000Da. 6000Da, 2000Da, corresponding to m ₁ =44, m ₃ ≈136, m ₂ =44, wherein the middle block is polydisperse, and the terminal blocks are monodisperse.

The structure of the obtained product polyfunctionalized H-type polyethylene glycol-modified glycine-cyclic evergreen boxwood D ester (Compound 44) is shown below, wherein L is

D is CVBD-Gly.

Example 19: Preparation of polyfunctionalized H-type polyethylene glycol modified cyclic evergreen boxin C (amide linkage)

Step ac: using N-c-cyanate C (Compound 45) as a raw material, and referring to Step ac of Example 17, respectively, N-tert-butoxycarbonyl-cycloalkaneline C (Compound 46), N-tert-butoxy acyl - evergreen boxwood base ring C- -Boc glycine (compound 47), glycine - evergreen boxwood base ring C ester (compound _{48, NH 2 -Gly-CVBC)} .

Step d: Preparation of a polyfunctionalized H-type polyethylene glycol modified glycine-cyclic evergreen carboxine base C ester (product 49, H-PEG-Gly-CVBC): 1.2 g was added to a 100 mL dry clean round bottom flask Polyfunctional H-type polyethylene glycol carboxylic acid derivative (compound D4-10, molecular weight 60 kDa, 0.02 mmol, 1 equivalent active site), 883 mg of compound 48 prepared in step c (1.92 mmol, 3 equivalents), 156 mg 4- Dimethylaminopyridine (1.28 mmol, 2 equivalents), adding a mixed solution of 15 mL of anhydrous dichloromethane and 3 mL of dimethylformamide, and mixing, adding 198 mg (0.96 mmol, 1.5 equivalents) of DCC, stirring and mixing, room temperature The reaction was carried out for 12 h under the conditions, and the reaction was terminated by the addition of glycine. Filtration, concentration by evaporation, precipitation with a mixed solution of isopropanol / anhydrous diethyl ether (1:6 v / v), filtered, washed and dried in vacuo to give product 49. The structure was determined by NMR and was a mixture of the structure 49 (k ₁ = 28 to 32) in the following reaction formula, wherein the compound 50 accounted for 70%. The different components were collected by ion exchange column method, the structure was determined by NMR, and subjected to high performance liquid chromatography, and the molecular weight of Compound 50 was about 62 kDa.

The reaction formula of the above steps a-d is as follows:

In compound 49, wherein L is COCH ₂ CH ₂ CONH, D is CVBC-Gly, and R ₀₁ in EF ₁ and EF ₂ is capped with glycine.

In compound 50, L is -CH ₂ CONH- and D is CVBC-Gly.

Wherein, the structural parameter of the compound D4-10 is

(U ₁ , U _{2 are} asymmetrical,

L ₁ = L ₃ = CH ₂ CH ₂ , L ₂ = L ₄ = -C(=O)CH ₂ -, L ₅ = L ₆ = CH ₂ CH ₂ ), F ₁ = F ₂ =

(g=1, k=8, g ₀ =1,

q=0, q ₁ =1, Z ₁ = -C(=O)CH ₂ CH ₂ -, R ₀₁ =COOH), j=0. The designed total molecular weight is about 60 kDa, wherein the molecular weight of the four branched chains is about 4 x 12000 = 48000 Da, i.e., n ₁ ≈n ₂ ≈n ₃ ≈n ₄ ≈ 273, and the molecular weight of the main chain is about 7600 Da, m ₂ ≈ 172.

Example 20: Preparation of a polyfunctionalized H-type polyethylene glycol modified cyclopentanyl C (amide linkage)

Preparation of polyfunctionalized H-type polyethylene glycol modified cyclopentanyl C (H-PEG-CPBC, compound 52): To a dry clean 50 mL round bottom flask was added 1.6 g of cyclopentanylline C (Compound 51, 4 mmol, 5 equivalents, 8.16 g of polyfunctionalized H-type polyethylene glycol succinimide succinate (compound A1-3, 41 kDa, 0.2 mmol, 1 equivalent active site), 98 mg 4-dimethylaminopyridine (2 mmol, 2.5 equivalents), 60 mL of anhydrous dichloromethane, stirred and dissolved. 989 mg of DCC (4.8 mmol, 6 equivalents) was added and stirred and mixed. The reaction was carried out for 12 h at room temperature. The sand core was filtered to remove impurities, and the solvent was removed by rotary evaporation, and 200 mL of isopropanol was added thereto, followed by precipitation under ice water bath. Filter and vacuum dry. Product 52 was obtained. The structure was determined by ¹ H NMR test. High performance liquid chromatography was performed with a molecular weight of approximately 42 kDa. SDS-PAGE electrophoresis was performed with a purity of 96%.

Wherein, the structural parameter of the compound A1-3 is

(U ₁ , U _{2 are} symmetrical,

L ₁ = L ₂ = L ₃ = L ₄ = CH ₂ , L ₅ , L ₆ are absent), F ₁ = F ₂ = COCH ₂ CH ₂ CONHS (g = 0, k = 1, q = 0, q ₁ =1, Z ₁ =COCH ₂ CH ₂ CO, R ₀₁ =NHS), j=0. The total molecular weight of the designed PEG block is about 40 kDa, wherein the molecular weight of the four branched chains is about 4×7500=30000Da, that is, n ₁ ≈n ₂ ≈n ₃ ≈n ₄ ≈170, and the molecular weight of the main chain is about 10000 Da, m _{2 .} ≈227.

Wherein the structures of the compound 51 and the product 52 are as follows, wherein, in the product 52, L is COCH ₂ CH ₂ CONH, and D is CPBC.

Example 21: Preparation of polyfunctionalized H-type polyethylene glycol modified hydroxyethyl norcanthamide (ester linkage)

Example 21-1: To a dry clean 50 mL round bottom flask was charged 4 g of a polyfunctionalized H-type polyethylene glycol carboxylic acid derivative (Compound D4-11, molecular weight 80 kDa, 0.05 mmol, 1 equivalent active site), 1 g Hydroxyethyl norcanthamide (Compound 51, 4.8 mmol, 3 equivalents), 586 mg 4-dimethylaminopyridine (DMAP, 4.8 mmol, 3 equivalents), 20 mL of anhydrous dichloromethane, stirred and mixed, and added 989 mg ( 4.8 mmol, 3 equivalents of DCC, stir and mix. The reaction was stirred for 12 h under nitrogen atmosphere and room temperature. The solid impurities were removed by filtration, rotary evaporated, and the residue was precipitated with isopropyl alcohol, filtered, and the precipitate was collected and dried in vacuo to give compound 53 (H-PEG-HENC). The structure was determined by ¹ H NMR test. Among them, the product carboxyl value was determined to confirm the presence of unreacted carboxyl groups.

Example 21-2: Compound 54 was prepared by the same preparation method and feed ratio, substituting D4-13 for D4-11. The amount of unreacted carboxyl groups in compound 54 was significantly lower than that of compound 53 after testing.

Wherein, the structural parameter of the compound D4-11 is

(U ₁ , U _{2 are} symmetrical,

L ₅ , L ₆ does not exist), F ₁ = F ₂ = G(CH ₂ COOH) ₈ , g = 1, k = 8, G = DENR (

NONE, 3), g ₀ =0, q=0, q ₁ =1, Z ₁ =CH ₂ , R ₀₁ =COOH, j=0. The designed total molecular weight is about 80 kDa, wherein the four branched chains have a molecular weight of about 4 x 16000 = 64000 Da, i.e., n ₁ ≈n ₂ ≈n ₃ ≈n ₄ ≈ 364, and the molecular weight of the main chain is about 16,000 Da, m ₂ ≈ 364.

Wherein, the structural parameter of the compound D4-13 is that U ₁ , U ₂ , j are consistent with D4-11, F ₁ = F ₂ = G(CH ₂ COOH) ₈ , g = 1, k = 8, G = DENR (

NONE, 3), g ₀ =0, q=1, Z ₂ =CH ₂ CO, q ₁ =1, Z ₁ =(NHCH ₂ CO) ₅ NHCH ₂ , R ₀₁ =COOH. The designed total molecular weight is about 95 kDa, wherein the four branched chains have a molecular weight of about 4 x 16000 = 64000 Da, i.e., n ₁ ≈n ₂ ≈n ₃ ≈n ₄ ≈ 364, and the molecular weight of the main chain is about 5000 Da, m ₂ ≈ 114.

Among them, taking the compound D4-11 as an example, the above reaction process is as follows:

Wherein, in product 53, L is CH ₂ COO, D is HENC, and k ₁ is about 16-24. In product 54, L contains 6 glycine units, L is (NHCH ₂ CO) ₆ O, D is HENC, and k ₁ is about 28-32.

Example 22: Preparation of polyfunctionalized H-type polyethylene glycol modified hydroxysporamine (ester linkage)

Example 22-1: A polyfunctionalized H-type polyethylene glycol carboxylic acid derivative (Compound D4-12, molecular weight 25 kDa, 0.05 mmol, 1 equivalent active site), 1 g hydroxyl group was added to a dry clean 50 mL round bottom flask. Cantharidin (4.8 mmol, 3 equivalents), 586 mg of 4-dimethylaminopyridine (DMAP, 4.8 mmol, 3 equivalents), 20 mL of anhydrous dichloromethane, stirred and mixed, and added 659 mg (3.2 mmol, 2 equivalents) of DCC. Stir and mix. The reaction was stirred for 12 h under nitrogen atmosphere and room temperature. The solid impurities were removed by filtration, rotary evaporated, and the residue was crystallised from isopropyl alcohol, filtered, and the precipitate was collected and dried in vacuo to afford compound 55 (H- PEG-HCN). The structure was determined by ¹ H NMR test. Among them, the product carboxyl value was determined to confirm the presence of unreacted carboxyl groups.

Wherein, the structural parameter of the compound D4-12 is

F ₁ = F ₂ = G(CH ₂ COOH) ₈ , g = 1, k = 8, G is the same as in Example 21, G = DENR (

NONE, 3), g ₀ =0, q=0, q ₁ =1, Z ₁ =CH ₂ , R ₀₁ =COOH, j=0. The designed total molecular weight is about 25 kDa, wherein the molecular weights of the four branched chains are about 3500 Da, 3500 Da, 4500 Da, 4500 Da, that is, n ₁ ≈n ₂ ≈ 80, n ₃ ≈n ₄ ≈ 102, and the molecular weight of the main chain is about 5000 Da. m ₂ ≈ 114.

Among them, the above reaction process is as follows:

In the product 55, L is CH ₂ COO, D is HNC, and k ₁ is about 16-20.

Example 22-2: Compound 57 was prepared by the same preparation method using Compound 56 instead of Hydroxyphylline. The amount of unreacted carboxyl groups in compound 58 was significantly lower than that of compound 55 by testing.

Wherein, in product 57, Z ₂ is CH ₂ , L is COCH ₂ CH ₂ NHCOCH ₂ CH ₂ CO, D is HENC, and k ₁ is about 28-32.

Example 23: Preparation of polyfunctionalized H-type polyethylene glycol modified cantharidin (imide bond linkage)

To a 50 mL dry clean round bottom flask was added polyfunctional H-type polyethylene glycol amine (compound C3-2, molecular weight 31 kDa, 0.02 mmol, 1 equivalent active site), 376 mg cantharidin (1.92 mmol, 3 equivalents) 235 mg of 4-dimethylaminopyridine (1.92 mmol, 3 equivalents), adding a mixed solution of 10 mL of anhydrous dichloromethane and 2 mL of dimethylformamide, and mixing, adding 198 mg (0.96 mmol, 1.5 equivalents) of DCC, stirring Mix and react at room temperature for 12 h, and add glycine to terminate the reaction. Filtration, concentration by evaporation, precipitation with a mixed solution of isopropanol / anhydrous diethyl ether (1:6 v / v), filtered, washed and dried in vacuo to give product 58. The structure was determined by NMR.

Wherein, the structural parameter of the compound C3-2 is

F ₁ =F ₂ =G(CH ₂ CH ₂ NH ₂ ) ₈ , g=1, k=8, G is the same as in Example 21, G=DENR (

NONE, 3), g ₀ =0, q=0, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =NH ₂ , j=0. Design of the total molecular weight of about 31kDa, wherein the molecular weight are approximately four branched 3500Da, 4400Da, 3500Da, 4400Da, i.e., _{n 1 ≈80, n 2 ≈80,} n 3 ≈100, n 4 ≈100, the molecular weight of the main chain It is about 12000 Da, m ₂ ≈ 272.

Wherein, the above reaction process is as follows, and the structure shown in the formula 58 is the main component of the product 57:

Where L is

LD is

Example 24: Preparation of polyfunctionalized H-type polyethylene glycol modified glycine dipeptide norcanthamide (triazole linker)

Wherein, the structural parameter of the compound C4-1 is

F ₁ =F ₂ =G(CH ₂ CH ₂ N ₃ ) ₂₅ (g=1, k=25, g ₀ =0, q=0, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ = N ₃ ), j=0. The designed total molecular weight is about 40 kDa, wherein the four branched chains have a molecular weight of about 4 x 5000 = 20000 Da, i.e., n ₁ ≈n ₂ ≈n ₃ ≈n ₄ ≈ 114, and the molecular weight of the main chain is about 5000 Da, m ₂ ≈ 114.

Step a, Preparation of a cycloalkyne-modified glycine dipeptide norcanthamide compound 60: To a dry clean 100 mL round bottom flask was added 1.34 g of compound 58 (5 mmol, 1 equivalent), 1.42 g of glycine dipeptide norcanthamide ( 10 mmol, 2 eq.), 1.22 g of 4-dimethylaminopyridine (DMAP, 10 mmol, 2 eq.), 40 mL of anhydrous dichloromethane, stirred and stirred, and then added 2.06 g (10 mmol, 2 equivalents) of DCC, and stirred and mixed. The reaction was stirred for 12 h under nitrogen atmosphere and room temperature. The solid impurities were removed by filtration, rotary evaporated, and the residue was crystallised from isopropyl alcohol, filtered and dried in vacuo to give compound 60. The structure was determined by ¹ H NMR test.

Step b, Preparation of polyfunctionalized H-type polyethylene glycol modified glycine dipeptide norcanthamide (H-PEG-Gly-Gly-NCN, compound 61): 2.35 g was added to a dry clean 100 mL round bottom flask Compound 60 (6 mmol, 1.2 eq.) in dichloromethane (24 mL), 1.98 g of polyfunctional H-type polyethylene glycol azide derivative (Compound 4-1, molecular weight 40 kDa, 0.05 mmol, 1 equivalent active site) Chloromethane (20 mL) was stirred for 15 min, and solid impurities were removed by filtration, and then evaporated, and the residue was precipitated with isopropyl alcohol, filtered and dried in vacuo to give Compound 61. The structure was determined by ¹ H NMR test. The yield was about 98%. GPC and high performance liquid chromatography tests were carried out with a molecular weight of approximately 78 kDa.

Wherein, the reaction formula of the above steps a-b is as follows:

Where L is

D is NCN-Gly-Gly.

Example 25: Preparation of a polyfunctionalized H-type polyethylene glycol modified triptolide (urethane linkage)

A polyfunctionalized H-type polyethylene glycol isocyanate derivative (Compound D9) was prepared by the preparation method of Example 14 using a polyfunctionalized H-type polyethylene glycol amine derivative (compound C3-3, molecular weight 40 kDa) as a raw material. -2), polyfunctionalized H-type polyethylene glycol modified triptolide (compound 62, H-PEG-TP), and isolated and purified. The structure was determined by NMR test. GPC and high performance liquid chromatography tests were carried out with a molecular weight of approximately 87 kDa.

Wherein * indicates a polyethylene glycol branching chain, and *a indicates a connecting repeating unit

or

*b indicates connection

Wherein, the structural parameter of the compound C3-3 is

F ₁ =F ₂ =G(CH ₂ CH ₂ NH ₂ ) ₄₁ (g=1, k=31, g0=0, G is a hyperbranched structure, q=0, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =NH ₂ ), j=0. The designed total molecular weight is about 40 kDa, wherein the molecular weight of the four branched chains is about 4×4000=16000 Da, that is, n ₁ ≈n ₂ ≈n ₃ ≈n ₄ ≈91, and the molecular weight of the main chain is about 4000 Da, m ₂ ≈91.

Wherein, the structural parameters of the compound D9-2 are U ₁ , U ₂ , L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ , j, n ₁ , n ₂ , n ₃ , n ₄ , m ₂ , G is consistent with compound C3-2. F ₁ =F ₂ =CH ₂ CH ₂ NCO (g=1, k=31, g ₀ =0, q=0, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =NCO), total design The molecular weight is about 42 kDa.

The structure of the compound 62 is as follows, wherein L is CH ₂ CH ₂ NHCOO, D is TP, and k ₁ is about 50 to 70.

Example 26: Preparation of polyfunctionalized H-type polyethylene glycol modified triptolide (carbonate linkage)

Step a, Preparation of Polyfunctional Polyglycolyl Chloride Derivative (Compound D6-1): Add 3 g of polyfunctional H-type polyethylene glycol (Compound H1) to a dry clean 100 mL round bottom flask under nitrogen atmosphere. -1, molecular weight 30 kDa, 0.1 mmol, 1 equivalent of active site), 475 mg of solid phosgene (1.6 mmol, 4 equivalents), dissolved in 40 mL of acetonitrile, 1.2 mL of anhydrous pyridine was added dropwise, stirring was continued for 3 h. Excess solvent was removed by rotary evaporation, then precipitated with anhydrous diethyl ether. Compound D6-1 was obtained. The structure was confirmed by NMR.

Step b, preparation of polyfunctional polyethylene glycol derivative modified triptolide (compound 63): under the protection of nitrogen, the compound D6-1 prepared in step a is dissolved in 15 mL of dichloromethane, and 288 mg of thunder is added. Canola (0.8 mmol, 2 equivalents), 489 mg 4-dimethylaminopyridine (4 mmol, 10 equivalents). Stirring was continued for 5 h. The solid impurities were removed by filtration, and the excess solvent was removed by rotary evaporation. The residue was precipitated from a mixed solution of isopropyl alcohol / anhydrous diethyl ether (1:2 v / v), filtered, and the precipitate was collected, washed, and dried in vacuo to give compound 63. The structure was determined by NMR. It was tested by high performance liquid chromatography with a molecular weight of approximately 32 kDa.

Wherein, the structural parameter of the compound H1-1 is

F ₁ =F ₂ =H (g=0, g ₀ =0, q=0, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =OH), j=0. The designed total molecular weight is about 30 kDa, wherein the four branched chains have a molecular weight of about 4 x 5000 = 20000 Da, i.e., n ₁ ≈n ₂ ≈n ₃ ≈n ₄ ≈ 114, and the molecular weight of the main chain is about 10,000 Da, m ₂ ≈ 227.

Wherein, the structural parameters of the compound D6-1 are U ₁ , U ₂ , L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ , j, n ₁ , n ₂ , n ₃ , n ₄ , m ₂ , G is consistent with compound H1-1. F ₁ =F ₂ =CH ₂ CH ₂ OC(=O)Cl(g=0,q=0,q ₁ =1,Z ₁ =CH ₂ CH ₂ ,R ₀₁ =OC(=O)Cl), design The total molecular weight is about 30 kDa.

Wherein the structure of the compound 63 is

Wherein L is CH ₂ CH ₂ OC(=O)O and D is TP. TP-O is identical to Example 25.

Example 27: Preparation of polyfunctionalized H-type polyethylene glycol modified xanthine (amide linkage)

Wherein, the structural parameter of the compound C3-4 is

F ₁ =F ₂ =G(CH ₂ CH ₂ NH2) ₁₅ (g=1, k=15,

g ₀ =1, L ₀ = CH ₂ CH ₂ , q=0, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =NH ₂ ), j=0. The designed total molecular weight is about 35 kDa, wherein the four branched chains have a molecular weight of about 4 x 5000 = 20000 Da, i.e., n ₁ ≈n ₂ ≈n ₃ ≈n ₄ ≈ 114, and the molecular weight of the main chain is about 5000 Da, m ₂ ≈ 114.

Preparation of polyfunctionalized H-type polyethylene glycol modified xanthine (product 65, H-PEG-BCN): 696 mg of polyfunctionalized H-type polyethylene glycol amine derivative (compound) was added to a 100 mL dry clean round bottom flask. C3-4, molecular weight 35 kDa, 0.02 mmol, 1 equivalent active site), 1.1 g xanthine (compound 64, 2.4 mmol, 2 equivalents), 293 mg 4-dimethylaminopyridine (2.4 mmol, 2 equivalents), added to 20 mL of no A mixed solution of water dichloromethane and 4 mL of dimethylformamide was mixed, and 494 mg (2.4 mmol, 2 equivalents) of DCC was added, stirred and mixed, and reacted at room temperature for 12 hours. Filtration, concentration by evaporation, precipitation with a mixed solution of isopropanol / anhydrous diethyl ether (1: 6 v / v), filtered, washed and dried in vacuo to give product 65. The structure was determined by NMR. It was tested by high performance liquid chromatography with a molecular weight of approximately 70 kDa.

Wherein, the structure of the main component in the product 65 is

Wherein L is CH ₂ CH ₂ NHCO and D is BCN.

Example 28: Preparation of polyfunctionalized H-type polyethylene glycol modified tanshinone IIa (imine bond linkage)

Preparation of polyfunctionalized H-type polyethylene glycol modified tanshinone IIa (Compound 67): To a 100 mL dry clean round bottom flask was added 2.55 g of a polyfunctionalized H-type polyethylene glycol amine derivative (Compound C3-5, Molecular weight 25 kDa, 0.1 mmol, 1 equivalent of active site), 118 mg of tanshinone IIa (Compound 66, 0.4 mmol, 1 equivalent), 20 mL of anhydrous methanol was added, 0.1 mL of trifluoroacetic acid was added, and the reaction was heated under reflux for 2 h in the dark. Excess solvent was removed by rotary evaporation, the residue was precipitated with isopropyl alcohol, and the precipitate was collected and dried in vacuo. Purified using an ion exchange resin. Dry in vacuum. Product 67 was obtained. The structure was determined by NMR. It was tested by high performance liquid chromatography with a molecular weight of approximately 27 kDa.

Wherein, the structure of the main component in the product 67 is

Among them, L contains an imine bond.

Wherein, the structural parameter of the compound C3-5 is

F ₁ =F ₂ =CH ₂ CH ₂ NH ₂ (g=0, k=1, q=0, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =NH ₂ ), j=1,

The designed total molecular weight is about 25 kDa, wherein the molecular weight of the four branched chains is about 4×5000=20000 Da, that is, n ₁ ≈n ₂ ≈n ₃ ≈n ₄ ≈ 114, and the molecular weights of the two PEGs of the main chain are about 2000 Da, respectively. 3000Da, m ₁ ≈ 45, m ₂ ≈ 68.

Example 29: Preparation of polyfunctionalized H-type polyethylene glycol modified tanshinone IIa (腙 bond linkage)

Preparation of polyfunctionalized H-type polyethylene glycol modified tanshinone IIa (Compound 68): To a 100 mL dry clean round bottom flask was added 3.05 g of a polyfunctionalized H-type polyethylene glycol hydrazide derivative (Compound D2-1). , molecular weight 30kDa, 0.1mmol, 1 equivalent active site), 118mg tanshinone IIa (compound 66, 0.4mmol, 1 equivalent), added 40mL anhydrous methanol, added 0.15mL trifluoroacetic acid, heated under reflux conditions for 2h . Excess solvent was removed by rotary evaporation, the residue was precipitated with isopropyl alcohol, and the precipitate was collected and dried in vacuo. Purified using an ion exchange resin. Dry in vacuum. Product 68 was obtained. The structure was determined by NMR. It was tested by high performance liquid chromatography with a molecular weight of approximately 32 kDa.

Wherein, the structural parameter of the compound D2-1 is

F ₁ = F ₂ = CH ₂ CONH ₂ NH ₂ (g = 0, k = 1, q = 0, q ₁ = 1, Z ₁ = CH ₂ , R ₀₁ = CONH ₂ NH ₂ ), j = 0. The designed total molecular weight is about 30 kDa, wherein the four branched chains have a molecular weight of about 4 x 6000 = 24000 Da, i.e., n ₁ ≈n ₂ ≈n ₃ ≈n ₄ ≈ 136, and the molecular weight of the main chain is about 6000 Da, m ₂ ≈ 136.

Wherein, the structure of the main component of the product 68 is

Among them, L contains a 腙 bond.

Example 30: Preparation of polyfunctionalized H-type polyethylene glycol modified tanshinone IIa (hydrogen bonding)

Wherein, the structural parameter of the compound D21-1 is

(g=0, k=1, q=1, Z ₂ =CH ₂ CO, q ₁ =1,

R ₀₁ =NHC(=NH)NH ₂ ), j=0. The designed total molecular weight is about 31 kDa, wherein the four branched chains have a molecular weight of about 4 x 6000 = 24000 Da, i.e., n ₁ ≈n ₂ ≈n ₃ ≈n ₄ ≈ 136, and the molecular weight of the main chain is about 6000 Da, m ₂ ≈ 136.

Preparation of polyfunctionalized H-type polyethylene glycol modified tanshinone IIa (Compound 69): To a 100 mL dry clean round bottom flask, 3.1 g of polyfunctionalized H-type polyethylene glycol fluorenyl derivative was added under nitrogen atmosphere. (Compound D2-1, molecular weight 31kDa, 0.1mmol, 1 equivalent active site), 118mg tanshinone IIa (Compound 66, 0.4mmol, 1 equivalent), add 50mL of anhydrous acetonitrile, add 0.65mL of anhydrous pyridine, stir and mix, After reacting overnight, the residue was precipitated with anhydrous diethyl ether. The precipitate was collected, isolated, purified and dried. Product 69 was obtained. The structure was determined by NMR.

Wherein the structure of the product 69 is

Wherein L contains a hydrogen bond.

Example 31: Preparation of polyfunctionalized H-type polyethylene glycol modified tanshinone IIb (ester linkage)

Under a nitrogen atmosphere, 3.3 g of a polyfunctionalized H-type polyethylene glycol carboxyl derivative (compound D4-14, molecular weight 33 kDa, 0.1 mmol, 1 equivalent active site), 184 mg of tanshinone was added to a 100 mL dry clean round bottom flask. IIb (Compound 66b, 0.6 mmol, 1.5 eq.), 108 mg of hydroxybenzotriazole (0.8 mmol, 2 eq.), 98 mg of 4-dimethylaminopyridine (0.8 mmol, 2 eq.). Stir to dissolve. Add 165 mg (0.8 mmol, 2 equivalents) of DCC and mix. The reaction was stirred overnight under nitrogen atmosphere. Concentration by evaporation, the residue was dissolved in EtOAc EtOAc EtOAc. The structure was determined by NMR.

Wherein, the structural parameter of the compound D4-14 is

(g=0, k=1, q=1, Z ₂ =CH ₂ CH ₂ NH, q ₁ =1, Z ₁ =COCH ₂ CH ₂ , R ₀₁ =COOH), j=0. The designed total molecular weight is about 33 kDa, wherein the four branched chains have a molecular weight of about 4 x 6000 = 24000 Da, i.e., n ₁ ≈n ₂ ≈n ₃ ≈n ₄ ≈ 136, and the molecular weight of the main chain is about 8000 Da, m ₂ ≈ 182.

Wherein, the structure of the product 70 is

Wherein L is C(=O)CH ₂ CH ₂ C(=O)O, and D is TIIb.

Example 32: Preparation of polyfunctionalized H-type polyethylene glycol modified 6-thioguanine (thioether linkage)

Under a nitrogen atmosphere, add 30 mL of 6-thioguanine (147 mg, 0.88) to a dry clean 100 mL round bottom flask. Mmol, 1.1 equivalents) of PBS buffered saline (containing 100 mM NaCl and 5 mM ethylenediaminetetraacetic acid), pH adjusted to pH=8.0, plus 20 mL of polyfunctionalized H-type polyethylene glycol maleimide derivative (B2-1 or F3-1, an ultrapure aqueous solution having a molecular weight of about 25 kDa, 5 g, 0.2 mmol, 1 equivalent of active site), the pH was adjusted to pH = 8.5, and reacted at room temperature for 24 hours. The reaction was terminated by adding dilute hydrochloric acid to pH. Precipitation and centrifugation were carried out at 39 °C. The mixture was washed with a pH 8.5100 mM borate buffer at room temperature and precipitated at 39 °C. Filtration, the precipitate was collected, washed with dry diethyl ether and dried in vacuo to afford product 71. The structure was determined by NMR.

Wherein, the structural parameter of the compound B2-1 or F3-1 is

(U ₁ , U _{2 are} symmetrical,

L ₅ , L ₆ are absent), F ₁ = F ₂ = CH ₂ CH ₂ S(=O) ₂ CH=CH ₂ (g=0, k=1, q=0, q ₁ =1, Z ₁ = CH ₂ CH ₂ , R ₀₁ =S(=O) ₂ CH=CH ₂ ), j=1, W ₀ =-CH ₂ CH ₂ S-SCH ₂ CH ₂ -. The designed total molecular weight is about 25 kDa, wherein the molecular weight of the four branched chains is about 4×5000=20000 Da, that is, n ₁ ≈n ₂ ≈n ₃ ≈n ₄ ≈ 114, and the molecular weights of the two PEGs of the main chain are about 2000 Da, respectively. 2000Da, m ₁ ≈ 45, m ₂ ≈ 45.

Wherein, the structure of the product 71 is

Where L is

Example 33: Preparation of polyfunctionalized H-type polyethylene glycol modified cholesterol (ester linkage)

Step a, Preparation of di-tert-butoxycarbonyloxy-H-polyethylene glycol-dicholesterol ester (Compound 73): Under a nitrogen atmosphere, 2.1 g of di-tert-butoxycarbonyl was added to a 200 mL dry clean round bottom flask. oxy-H-type polyethylene glycol-dicarboxyl (compound H1/D4-1, molecular weight 20 benzotriazole (0.4 mmol, 2 equivalents), 49 mg 4-dimethylaminopyridine (0.4 mmol, 2 equivalents), Add 50 mL of anhydrous dichloromethane, stir to dissolve. Add 82 mg (0.4 mmol, 2 equivalents) of DCC, mix. Under nitrogen protection, stir the reaction overnight. Evaporate and concentrate, residue solution 20 mL 1,4-dioxane The precipitate was removed by filtration, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated

Step b, Preparation of dihydroxy-H-type polyethylene glycol-dicholesterol ester (Compound 74): To a 50 mL dry clean round bottom flask was charged 1.1 g of di-tert-butoxycarbonyloxy-H-polyethylene glycol- A solution of dicholesterol ester (Compound 73) and 30% trifluoroacetic acid in anhydrous dichloromethane (15 mL) was stirred and mixed, and reacted at room temperature for 3 hours, and the peak of Compound 73 was confirmed by HPLC. The solvent was removed by evaporation under vacuum at 37 ° C, and the obtained material was dissolved in methylene chloride, and precipitated with diethyl ether, filtered, and recrystallized from dimethylformamide / isopropyl alcohol. Filter and wash the solid phase with anhydrous ether. The filter cake was dried under vacuum at 37 ° C to give the product 74. The structure was determined by NMR.

Wherein, the reaction formula of step ab is as follows:

Wherein D ₁ = D ₂ , wherein, g=0, k=1, q=0, q ₁ =1, L is CH ₂ CH ₂ CO, and D is CHL. EF _{2 is} not equal to F ₂ , EF ₂ =CH ₂ CH ₂ OH, and is a deprotected form of F ₂ .

Wherein, the structural parameter of the compound H1/D4-1 is

(U ₁ , U _{2 are} symmetrical,

L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ are absent), F ₁ =CH ₂ CH ₂ COOH (g=0, k=1, q=0, q ₁ =1, Z ₁ = CH ₂ CH ₂ , R ₀₁ =COOH), F ₂ =CH ₂ CH ₂ OPG ₄ (g=0, k=1, q=0, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =OPG ₄ , PG ₄ = Boc), j = 0. The designed total molecular weight is about 20kDa, wherein the molecular weights of the four branched chains are about 4000Da, 4000Da, 4000Da, 4000Da, ie, n ₁ ≈91, n ₂ ≈91, n ₃ ≈91, n ₄ ≈91, the molecular weight of the main chain. It is about 4000 Da, m ₂ ≈91. PG ₄ can also be

A hydroxy protecting group such as tert-butyldiphenylsilyl or tert-butyldimethylsilyl.

Example 34: Preparation of polyfunctionalized H-type polyethylene glycol modified irinotecan with targeting function (amide linkage)

Step a: Using the step a of the production method in Example 12, irinotecan-glycine hydrochloride (Compound 32, IRES-Gly.HCl) was prepared.

Step b, Preparation of H-type polyethylene glycol modified glycine-irinotecan with protected amino group (PG5N-H-PEG-Gly-IRES, compound 75): Step b using the preparation method of Example 12 To a dry clean 100 mL round bottom flask, add 3 g (0.1 mmol, 1 equivalent of active site) of 20 mL of a polyfunctionalized H-type polyethylene glycol carboxylic acid (compound C6/D4-1, 30 kDa) in anhydrous DCM. 272 mg of irinotecan-glycine hydrochloride (Compound 32, 0.4 mmol, 2 equivalents), 244 mg (2 mmol, 10 equivalents) of DMAP, and 10 equivalents of a 50% ethyl acetate solution were added in that order. After stirring overnight at room temperature, the residue was evaporated to dryness eluting with methylene chloride, eluting with diethyl ether, filtered, and the precipitate was collected and recrystallized from dimethylformamide / isopropyl alcohol. The resultant was dissolved in dichloromethane and precipitated with anhydrous diethyl ether filtered and dried in vacuo at 37 ° C. Compound 75 was obtained. The structure was determined by NMR.

Step c, Preparation of H-type polyethylene glycol modified glycine-irinotecan with naked amino group (NH ₂ -H-PEG-Gly-IRES, compound 76): Refer to step c in Example 17, and obtain step b Compound 75 was dissolved in 24 mL of dichloromethane, 16 mL of trifluoroacetic acid was added, the reaction was stirred for 1 h, concentrated under reduced pressure, and the mixture was evaporated to diethyl ether. The supernatant was evaporated, and then filtered, filtered, and washed with diethyl ether. The vacuum was driven away to obtain compound 76. The structure was determined by NMR test. It was tested by high performance liquid chromatography with a molecular weight of approximately 31 kDa.

Step d, Preparation of difolate-H-polyethylene glycol-bis(glycine-irinotecan) (Compound 77): To a 100 mL dry clean round bottom flask was added 1.55 g of compound 76 (0.05 mmol) according to Example 27. ), 52.7 mg of folic acid (0.12 mmol, 1.2 equivalents), 18.3 mg of 4-dimethylaminopyridine (0.15 mmol, 1.5 equivalents), and a mixture of 20 mL of anhydrous dichloromethane and 4 mL of dimethylformamide was added and mixed. 41.2 mg (0.2 mmol, 2 equivalents) of DCC was added, stirred and mixed, and reacted at room temperature for 12 h. Filtration, concentration by evaporation, precipitation with a mixed solution of isopropanol / anhydrous diethyl ether (1:6 v / v), filtered, washed and dried in vacuo to give product 77. The structure was determined by NMR. It was tested by high performance liquid chromatography with a molecular weight of approximately 32 kDa.

The reaction of the above step ad is as follows, wherein the L in both D ₁ and D ₂ (D ₂ may also be F ₂ , belonging to the class I1) contains an amide bond:

Wherein, the structural parameter of the compound C6/D4-1 is

(U ₁ symmetry,

L ₁ =CH ₂ , L ₂ =CH ₂ , L ₅ does not exist),

(U _{2 is} asymmetrical,

L ₃ =(CH ₂ ) ₄ NHCOCH ₂ , L ₄ =NHCOCH ₂ , L ₆ =SCH ₂ CH ₂ ), F ₁ =CH ₂ CH ₂ COOH (g=0, k=1, q=0, q ₁ = 1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =COOH), F ₂ =CH ₂ CH ₂ NPG ₅ (g=0, k=1, q=0, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =NPG ₅ , NPG ₅ is NHBoc, PG ₅ =Boc), j=0. The designed total molecular weight is about 30 kDa, wherein the four branched chains have molecular weights of about 8,500 Da, 8,500 Da, 1400 Da, and 1400 Da, respectively, ie, n ₁ ≈ 193, n ₂ ≈ 193, n ₃ = 32, n ₄ = 32, wherein the protected amino group The two branched chains are monodisperse, and the molecular weight of the main chain is about 9000 Da, m ₂ ≈ 205.

Example 35: Preparation of polyfunctionalized H-type polyethylene glycol modified irinotecan with targeting function (amide linkage)

Preparation of the difolate-H type polyethylene glycol-bis(glycine-irinotecan) by the preparation method of Example 34 and substituting the compound C6/D4-2 having the following structure for the compound C6/D4-1 78).

Wherein, the structural parameter of the compound C6/D4-2 is

(U ₁ symmetry,

L ₁ =CH ₂ , L ₂ =CH ₂ , L ₅ does not exist),

(U _{2 is} asymmetrical,

L ₃ =(CH ₂ ) ₂ CONHCH ₂ CH ₂ , L ₄ =CONHCH ₂ CH ₂ , L ₆ =NHCOCH ₂ CH ₂ ), F ₁ =G(COCH ₂ CH ₂ CONHCH ₂ COOH) ₈ [g=1,k =8, G=DENR(

NONE,3),q=1,Z ₂ =COCH ₂ CH ₂ CO,q ₁ =1,Z ₁ =NHCH ₂ ,R ₀₁ =COOH],F ₂ =CH ₂ CH ₂ NPG ₅ (g=0,k =1, q=0, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =NPG ₅ , NPG ₅ is NHFmoc, PG ₅ =Fmoc), j=0. The designed total molecular weight is about 26 kDa, wherein the molecular weights of the four branched chains are about 10000 Da, 10000 Da, 700 Da, 700 Da, respectively, ie, n ₁ ≈ 227, n ₂ ≈ 227, n ₃ = 16, n ₄ = 16, wherein the folic acid is modified. The two branched chains are monodisperse, the main chain polyethylene glycol has monodispersity, and the number of EO units is m ₂ = 9.

Example 36: Preparation of a polyfunctionalized H-type polyethylene glycol modified irinotecan having a fluorophore (amide linkage)

Using the preparation method of Example 34, and replacing the compound C6/D4-1 with the compound C6/D4-3 having the following structure, and replacing the compound folic acid molecule with Rhodamine B (Compound 79) to prepare the dihodamine BH type polyethylene glycol. Preparation of di-(glycine-irinotecan) (product 80).

Wherein, the structural parameter of the compound C6/D4-3 is

F ₁ =CH ₂ CH ₂ COOH (g=0, k=1, q=0, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =COOH), F ₂ =CH ₂ CH ₂ NHCOCH ₂ NPG ₅ (g=0, k=1, q=0, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =NPG ₅ , NPG ₅ is NHFmoc, PG ₅ =Fmoc), j=1,

The designed total molecular weight is about 20kDa, wherein the four branched chains have molecular weights of about 8000 Da, 8000 Da, 500 Da, and 500 Da, respectively, ie, n ₁ ≈ 182, n ₂ ≈ 182, n ₃ = 12, and n ₄ = 12, wherein they are protected. The two glycine chains terminated by glycine are monodisperse. Both PEG blocks in the main chain are monodisperse, and the number of EO units is m ₁ =16 and m ₂ =32, respectively.

The structure of product 80 is as follows:

Example 37: Pharmacokinetics and Tissue Distribution Experiment of Polyethylene Glycol Modified Interferon α-2a

(1) Preparation and purification of polyfunctionalized H-type polyethylene glycol modified interferon alpha-2a (H-PEG-IFN)

The polyfunctionalized H-type polyethylene glycol-modified interferon alpha-2a (compound 81, compound 82) in the following table was prepared by the method of Example 1, and the polyfunctionalized H-type polyethylene glycol was modified to modify a single interferon. The product of the α-2a molecule. At the same time, preparation of linear polyethylene glycol modified interferon α-2a (compound 83, compound 84), two-arm polyethylene glycol modified interferon α-2a (compound 85, compound 86), four-arm polyethylene glycol The modified interferon alpha-2a (compound 87, compound 88) was used as a control. The molecular weight and other parameters are shown in Table 1.

Table I

(2) Pharmacokinetic study

Male mice weighing about 30 g were selected as the study subjects, and the blood concentration of interferon modified by polyethylene glycol modified by ELISA double antibody sandwich method was studied in mice. In the above Table 1, each group of 6 mice was administered by tail vein injection at a dose of 150 μg/kg interferon, respectively before administration and 10 min, 30 min, 1 h, 2 h, 6 h, 12 h, 24 h, 36 h. After 48h, 72h, 120h, 100 μL of blood was taken from the middle eye of the mouse eyelid. The blood sample was coagulated at 4 ° C and centrifuged at low temperature. The serum was separated and stored at -20 ° C until use. After the blood was thawed at room temperature, the blood concentration was measured by ELISA double antibody sandwich method, and the curve was fitted by software and the half-life t _{1/2 was} calculated as shown in Table 2. The half-life of interferon modified by H-type polyethylene glycol was significantly longer than that of linear polyethylene glycol and two-arm polyethylene glycol, and the modified product of four-arm polyethylene glycol was also prolonged. .

Table II

(3) Tissue distribution test

Male mice weighing about 30 g were selected as the study subjects. Each group of 6 mice in Table 1 was administered by tail vein injection at a dose of 150 μg/kg interferon for 10 min, 30 min, 1 h, 2 h, 6 h. After 12h, the mice were sacrificed after 24 hours, and the tissues from heart, lung, liver, spleen, stomach, kidney and bladder were sampled, centrifuged and stored at -20 °C until use. After taking out and returning to room temperature, a tissue homogenate was prepared and stored at -20 ° C until use. After the extraction was taken out, the supernatant of each tissue was centrifuged, and the concentration of the drug in the tissue was measured by ELISA double antibody sandwich method using a standard curve as a reference. The results showed that the interferon modified by H-type polyethylene glycol and four-arm polyethylene glycol was in the spleen, lung, liver, bladder and stomach compared with the modified product of linear polyethylene glycol and two-arm polyethylene glycol. The distribution is improved (H-type polyethylene glycol is slightly higher than the four-armed polyethylene glycol), and the distribution in the heart and kidney is significantly decreased, which reflects the decrease in cardiotoxicity and the weakening of renal exclusion, and the extended half-life described above. Consistent.

Example 38: Pharmacokinetics and Tissue Distribution Experiment of Polyethylene Glycol Modified Recombinant Human Granulocyte Colony Stimulating Factor (rhG-CSF)

(1) Preparation and purification of polyfunctionalized H-type polyethylene glycol modified G-CSF (H-PEG-rhG-CSF)

The polyfunctionalized H-type polyethylene glycol-modified G-CSF (Compound 89, Compound 90) in the following table was prepared by the method of Example 2, and the polyfunctionalized H-type polyethylene glycol was collected to modify a single G-CSF molecule. Product. At the same time, linear polyethylene glycol modified G-CSF (Compound 91, Compound 92), two-arm polyethylene glycol modified G-CSF (Compound 93, Compound 94), four-arm polyethylene glycol modified G- were prepared. CSF (Compound 95, Compound 96) was used as a control. The molecular weight and other parameters are shown in Table 3.

Table 3

(2) Pharmacokinetic study

SD rats weighing about 250 g were used as subjects, and the concentration of PEG-rhG-CSF in rat plasma was determined by enzyme-linked immunosorbent assay (ELISA). Each group of 6 SD rats in Table 3 was administered subcutaneously at a dose of 100 μg/kg G-CSF, before administration and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 respectively. Blood was taken after 48 and 60 hours, and the plasma was separated by centrifugation and stored at -20 ° C until use. After the extraction was removed, the concentration of PEG-rhG-CSF was determined by ELISA, and the pharmacokinetic parameters were calculated using a non-compartmental model. The half-life t _1/2 results are shown in Table 4. The modification of rhG-CSF with the H-type polyethylene glycol of the present invention can significantly prolong the residence time of the drug in the blood.

Table 4

(3) Tissue distribution test

SD rats weighing about 250 g were used as subjects, and the distribution of tissues was examined by [125I] labeled tracer combined with size exclusion chromatography. Each group of 6 SD rats in Table 3 was administered subcutaneously at a dose of 100 μg/kg G-CSF, and was sacrificed before administration and after 2, 4, 8, 12, 24, 48 and 60 hours of administration. Rats were sampled from serum, heart, liver, spleen, lung, kidney, bone, muscle, fat, brain, lymph nodes, small intestine, gonads, etc. and made into tissue or body fluid, homogenized, added TCA precipitated protein, determined Total gamma radioactivity of each tissue. The results showed that after PEG modification, it was mainly distributed in the vascular bed and excretory system, followed by blood flow-rich tissues. Compared with the modified products of linear polyethylene glycol and two-arm polyethylene glycol, the distribution of G-CSF modified by H-type polyethylene glycol and four-arm polyethylene glycol was significantly reduced in bone marrow and kidney. The H-type polyethylene glycol modified G-CSF is slightly higher than the four-arm polyethylene glycol modified G-CSF.

Example 39: Polyethylene glycol modified irinotecan drug

(1) Preparation of polyethylene glycol modified irinotecan drug molecule

Using H-type polyethylene glycol represented by A6-1, D4-2, D4-12, C6/D4-1, and C6/D4-2 as raw materials, Example 10, Example 5, and Example 22 were respectively used. The H-type polyethylene glycol-modified irinotecan was prepared in the same manner as in Example 34 and Example 35, and corresponded to Compound 27, Compound 97, Compound 98, Compound 77, and Compound 78, respectively. Wherein, the end of each branch of A6-1 is bound to one drug D4-12; the end of each branch of D4-12 is connected by a dendritic structure (which may also be a branched, comb, or ring structure) Irinotecan molecules up to 8 molecules, H-type polyethylene glycol shown by D4-12 can bind up to 32 irinotecan molecules; C6/D4-1, C6/D4-2 contain targeting A group (folate molecule), wherein C6/D4-1 can bind up to 4 irinotecan molecules, and C6/D4-2 can bind up to 32 irinotecan molecules through a dendritic structure.

Simultaneous preparation of linear polyethylene glycol modified single molecule irinotecan (compound 99), linear polyethylene glycol modified bimolecular irinotecan (compound 100), two-arm polyethylene glycol modified single molecule Polyethylene glycol (Compound 101), four-arm polyethylene glycol modified four molecules of irinotecan (Compound 102).

Table 5

The molecular weight and other parameters are shown in Table 5.

(2) Cytotoxicity test

6 kinds of cells including COLO205 human colon cancer cells, human colon adenocarcinoma cells HT29 cells, human lung adenocarcinoma cells A549 cells, pancreatic cancer cells MiaPaCa-2 cells, human ovarian cancer cells A2780 cells, and human ovarian adenocarcinoma cells OVCAR-3 The cells were seeded in a 12-well plate at a seeding density of 10,000 cells/well, and the same irinotecan concentration was added to the nine PEGylated irinotecan drugs shown in Table 5 for culture.

For each cell cytotoxicity test, 4 sample points were used for each set of experiments, and a blank control group without drug application was added. The cells were cultured in a 4% CO ₂ cell culture incubator at 37 ° C. After 72 h of inoculation, the cytotoxicity test was carried out by MTT staining, and incubation was carried out for 4 h in pH 7.4 PBS buffer containing 0.5 mg/mL of MTT. The purple crystals were dissolved in DMSO, and the absorbance at 490 nm was measured with a microplate reader. The results showed that PEGylated irinotecan corresponding to S5, S6, S7, S8, S9, SL5, SL6, SV5 and SF5 significantly inhibited cell proliferation in six cells. The inhibitory effects of S5, S6, S7, S8, S9, SF5, and SL6 were significantly higher than those of SL5 and SV5. The inhibitory effect on tumor/cancer cells from S10 to S7>S7>S6>S9>S5>SF5>S8>SL6>SL5>SV5. S9 is slightly higher than S7, and S5 is slightly higher than SF5.

(3) Anti-tumor effect

Using the animal transplant tumor test method, H ₂₂ mouse hepatoma cells were inoculated into the right side of the mouse to form a solid tumor, and the tail vein injection was administered 2 days and 7 days after the inoculation, respectively. medicine. Two weeks after the inoculation, the mice were sacrificed by cervical dislocation, the tumor was removed, and weighed. The results showed that PEGylated irinotecan corresponding to S5, S6, S7, S8, S9, SL5, SL6, SV5 and SF5 had obvious antitumor effect on the six cells compared with the blank control. The tumor inhibition rates of S5, S6, S7, S8, S9, SF5, and SL6 were significantly higher than those of SL5 and SV5. The tumor inhibition rate from high to low is S7>S9>S6>S9>S8>S5>SF5>SL6>SL5>SV5. The positive effects of the experimental group with targeting groups were enhanced compared to the cytotoxicity experiments.

The above is only the embodiment of the present invention, and is not intended to limit the scope of the invention, and the equivalent structure or equivalent process transformation made by using the content of the specification of the present invention, or directly or indirectly applied in other related technical fields, The same is included in the scope of patent protection of the present invention.

Claims (98)

1. A bio-related substance modified with a polyfunctional polyethylene glycol derivative, characterized in that the bio-related substance modified by the polyfunctional polyethylene glycol derivative is polyfunctionalized as represented by the general formula (1) a stable structure formed by combining a H-type polyethylene glycol derivative with a biologically relevant substance;

   

   The H-type structure is composed of a linear PEG spindle and four PEG branch chains, and the total number of oxidized vinyl units of the linear PEG spindle and the four PEG branch chains does not exceed 5000;

   Among them, LPEG is a linear spindle structure; LPEG is a monoblock, diblock, triblock or block fragment of 1-150 composed of polyethylene glycol or polyethylene glycol; the number of oxyethylene units in LPEG is satisfied. An integer from 2 to 2000;

   n ₁ , n ₂ , n ₃ , and n ₄ are respectively the degree of polymerization of four PEG branched chains, each independently satisfying 2 to 2000, and may be the same or different from each other in the same molecule;

   LPEG and four PEG branching chains corresponding to n ₁ , n ₂ , n ₃ , n ₄ are each independently polydisperse or monodisperse;

   U ₁ and U ₂ are each a trivalent branched group linking LPEG and two PEG branching chains;

   The structure of U ₁ is

   

   The structure of U ₂ is

   

   U ₀₁ and U ₀₂ are each independently a trivalent group; L ₁ , L ₂ , L ₃ and L ₄ are polyethylene glycols each having an alkyl group number of n ₁ , n ₂ , n ₃ , and n ₄ . The linking group of the unit, L ₅ , L ₆ is a linking group connecting the linear spindle polyethylene glycol unit, and L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ are each independently present or absent, and The same molecule may be the same or different from each other;

   F ₁ and F ₂ contain a functional group or a protected form thereof, which may be the same or different from each other in the same molecule, and their structures are independently represented as

   

   among them,

   

   a linker for linking a polyethylene glycol unit; k is an integer of 1 or 2 to 250; g is 0 or 1; G is a linker of a trivalent or higher valence state; when g=0, k=1; g= 1, k is an integer of 2 to 250, and the valence state of G is k+1; L ₀ is a divalent linking group; g ₀ is 0, 1 or 2 to 1000; q and q ₁ are each independently 0 or 1 ; Z ₁ , Z ₂ are each independently a divalent linking group; R ₀₁ is a functional group or a protected form thereof; in the same molecule, k, G, g, L ₀ , g _{0 of} F ₁ and F ₂ , Z ₂ , q, Z ₁ , q ₁ , R ₀₁ are each independently the same or different;

   In the same molecule, LPEG, U ₁ , U ₂ , U ₀₁ , U ₀₂ , L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ , L ₀ (F ₁ ), G(F ₁ ), Z Any one or any of ₁ (F ₁ ), Z ₂ (F ₁ ), L ₀ (F ₂ ), G(F ₂ ), Z ₁ (F ₂ ), Z ₂ (F ₂ ) and adjacent heteroatoms The linking group formed by the group may be stably present or degradable;

   The bio-related substance modified by the polyfunctionalized H-type polyethylene glycol derivative contains at least one bio-related substance molecule; the type of the bio-related substance to be combined is one or two; the polyfunctionalized H-type The manner in which the polyethylene glycol derivative binds to the bio-related substance is a covalently linked or non-covalently linked mode; any of the functionalized groups of the polyfunctionalized H-type polyethylene glycol derivative or protected The manner in which the functional group is combined with the biologically relevant substance is independently stable or degradable;

   When F ₁ or F _{2 is} combined with a biologically relevant substance, they are each independently expressed as

   

   They may be the same or different from each other in the same molecule;

   Wherein D is a residue formed by reacting a modified bio-related substance with a polyfunctionalized H-type polyethylene glycol; wherein L is a functional group in the polyfunctionalized H-type polyethylene glycol derivative or a linker formed by reacting a protected form with a biologically relevant substance; any one of L may be stably present or degradable independently, and a linker of L and an adjacent hetero atom group may be stably present or degradable; wherein, E ₀₁ R ₀₁ , protected R ₀₁ or blocked R ₀₁ ; wherein k ₀ is the number of sites in the F ₁ or F ₂ that react with the biologically relevant substance; k ₀ is 1 to k.
2. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein the functional group modified by the polyfunctional polyethylene glycol derivative or the protected form thereof may be all or Partially involved in the modification of biologically relevant substances; functional groups or protected functional groups that are not bound to biologically relevant substances may retain the structural form before the reaction, or may form a deprotected functional group, or Capped with non-biologically related substances; F ₁ modified bio-related substances may be the same or different from F ₂ modified bio-related substances.
3. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein the degradable condition is light, heat, enzyme, redox, acidity, alkalinity, physiological condition, Any of the conditions in an in vitro simulated environment; preferably in any of light, heat, enzyme, redox, acidic or basic conditions.
4. The multi-functionalized polyethylene glycol derivative-modified bio-related substance according to claim 1, wherein the total number of oxidized vinyl units of the linear PEG main axis and the four PEG branched chains does not exceed 2,500.
5. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein the number of oxyethylene units in the LPEG is an integer of from 5 to 1,000; preferably an integer of from 10 to 1,000; An integer of 20 to 500 is preferred.
6. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein each of n ₁ , n ₂ , n ₃ and n ₄ independently satisfies 5 to 1000; preferably 10 to 10 More preferably, it is 20 to 500.
7. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein the LPEG is polydisperse.
8. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 7, wherein the LPEG has a number average molecular weight of about 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3350, 3500, 4000, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, 10000, 11000, 12000, 13000, 14000, 15000, 16000, 17000, 18000, 19000, 20000, 25000, 30000, 35000, 40000, 50000 or 60000, the unit is Da; preferably the corresponding number average molecular weight is about 1000, 1500, 2000, 2500, 3000, 3350, 3500, 4000, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, 10000, 11000, 12000, 13000, 14000, 15000, 16000, 17000, 18000, 19000 or 20000Da.
9. The bio-related substance modified with the polyfunctional polyethylene glycol derivative according to claim 1, wherein the LPEG is monodisperse.
10. A bio-related substance modified with a polyfunctional polyethylene glycol derivative according to claim 9, characterized in that

    The LPEG has 1 PEG block, and the number of EO units of LPEG is selected from an integer of 2 to 70; more preferably an integer of 3 to 70; more preferably an integer of 5 to 70; more preferably an integer of 5 to 50;

    Or the LPEG has 2 PEG blocks, and the total number of EO units of LPEG is selected from an integer of 2 to 140; more preferably an integer of 3 to 140; more preferably an integer of 5 to 140; more preferably an integer of 5 to 70; An integer of 5 to 50 is preferred;

    Or the LPEG has 3 PEG blocks, and the total number of EO units of LPEG is selected from an integer of 3 to 210; more preferably an integer of 5 to 210; more preferably an integer of 5 to 150; more preferably an integer of 5 to 100; An integer of 5 to 70 is preferred; an integer of 5 to 50 is more preferred;

    Or the LPEG has 4 or more PEG blocks, and the total number of EO units of the LPEG is selected from an integer of 4 to 500; more preferably an integer of 5 to 500; more preferably an integer of 5 to 250; more preferably 5 to 200 An integer of 5 to 100; more preferably an integer of 5 to 50.
11. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein the PEG chain corresponding to n ₁ , n ₂ , n ₃ or n ₄ is polydisperse.
12. The polyfunctional polyethylene glycol derivative according to claim 11, wherein the number average molecular weight of the PEG chain corresponding to n ₁ , n ₂ , n ₃ or n ₄ is about 500, 600, 700, 800, 900, 1000, 1500, 2000. , 2500, 3000, 3350, 3500, 4000, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, 10000, 11000, 12000, 13000, 14000, 15000, 16000, 17000, 18000, 19000 , 20000, 25000, 30000, 35000, 40000, 50000 or 60000, the unit is Da; preferably the corresponding number average molecular weight is about 1000, 1500, 2000, 2500, 3000, 3350, 3500, 4000, 5000, 5500, 6000, 6500 , 7000, 7500, 8000, 8500, 9000, 9500, 10000, 11000, 12000, 13000, 14000, 15000, 16000, 17000, 18000, 19000 or 20000Da.
13. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein the PEG chain corresponding to n ₁ , n ₂ , n ₃ or n ₄ is monodisperse.
14. The polyfunctional polyethylene glycol derivative according to claim 13, wherein said n ₁ , n ₂ , n ₃ or n _{4 is} selected from an integer of from 2 to 70; more preferably an integer of from 3 to 70; An integer of 5 to 70 is preferable; an integer of 5 to 50 is more preferable.
15. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein the PEG chain corresponding to n ₁ , n ₂ , n ₃ , and n ₄ is polydisperse, and LPEG is monodisperse.
16. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein any two of the PEG branched chains corresponding to n ₁ , n ₂ , n ₃ , and n ₄ are polydisperse Sex, the other two are monodisperse. LPEG is polydisperse or monodisperse.
17. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein the PEG branching chain corresponding to n ₁ , n ₂ , n ₃ , and n ₄ is monodisperse, and LPEG is polydisperse.
18. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein the PEG branching chain and the LPEG corresponding to the n ₁ , n ₂ , n ₃ and n ₄ are polydisperse .
19. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein the PEG branching chain and the LPEG corresponding to the n ₁ , n ₂ , n ₃ and n ₄ are monodisperse. .
20. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein the bio-related substance modified by the polyfunctional polyethylene glycol derivative has the formula (2) and the formula (3) a general structure represented by formula (4), formula (5) or formula (6);

    

    

    Wherein D ₁ , D ₂ , D ₃ , and D ₄ are each independently represented as

    

    They may be the same or different from each other in the same molecule;

    Wherein, EF ₁ and EF ₂ are each independently expressed as

    

    And may be the same or different from each other in the same molecule;

    In the same molecule, D ₁ , D ₂ , and EF ₁ are on the right side, and D ₃ , D ₄ , and EF ₂ are on the left side; wherein, i, g, L ₀ , g ₀ , Z ₂ , q, Z _{1 on the same side} , q ₁ , E _{01 are the} same, and D is from the same biologically relevant substance, k, k ₀ , G, L in the same side may be the same or different; wherein, the opposite side k, G, g, L ₀ , g ₀ Z ₂ , q, Z ₁ , q ₁ , E ₀₁ may each independently be the same or different; D on the opposite side is derived from the same or different biologically relevant substances.
21. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein the LPEG is

    

    

    Wherein, W ₀ , W ₀₁ , and W ₀₂ are each independently a linking group having 1 to 100 atoms; W ₀ , W ₀₁ , and W ₀₂ are each independently stable or degradable; m ₁ , m ₂ , m ₃ each independently satisfy 0 to 2000, may be the same or different from each other in the same molecule; and the PEG blocks corresponding to m ₁ , m ₂ , and m ₃ are each independently polydisperse or monodisperse; j is 1 or 2 An integer of ~100.
22. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 21, wherein the degradation property is selected from any of the following cases:

    (a) g = 0 or 1, and degrading at the divalent junction between the trivalent core structure of the trivalent branched structure and the PEG branching chain, wherein U ₁ (O-) _{3 is} in U ₀₁ -L ₁ At least one of -O, U ₀₁ -L ₂ -O is degradable, and U ₂ (O-) ₃ is degradable at least one position of U ₀₂ -L ₃ -O in U ₀₂ -L ₄ -O;

    (b) g = 0 or 1, and degradation occurs at the divalent junction between the trivalent core structure of the trivalent branched structure and the PEG backbone, wherein U ₁ (O-) _{3 is} in U ₀₁ -L ₅ The -O position is degradable and U ₂ (O-) ₃ is degradable at the U ₀₂ -L ₆ -O position;

    (c) g = 0 or 1, the trivalent branched structure contains a cyclic trivalent core structure CC ₃ , and CC ₃ is degradable;

    (d) g = 0 or 1, degradation occurs in LPEG, where m ₁ × j ≠ 0 or m ₁ + m ₃ ≠ 0, when m ₁ × j ≠ 0, degradable at -OW ₀ O- position When m ₁ +m ₃ ≠0, at least one of -OW ₀₁ O-, -OW ₀₂ O- is degradable;

    (e) g = 0 or 1, degrading only at the position of -(Z ₂ ) _q -L-, the position comprising a linker formed with an adjacent group on the PEG side;

    (f) g = 1, only the (L ₀₎ of the position of _g0 degradation, comprising (L ₀₎ within _g0, O- (L _{0) g0} is connected, (L _{0) g0} -G connection;

    (g) g = 1, degradation occurs only in G.
23. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 21, wherein the polyfunctional polyethylene glycol derivative-modified bio-related substance has a general formula represented by the formula (6) -2) or formula (6-3);

    

    Wherein D ₁ , D ₂ , D ₃ , and D ₄ are each independently represented as

    

    They may be the same or different from each other in the same molecule.
24. A bio-related substance modified with a polyfunctional polyethylene glycol derivative according to claim 21, wherein said LPEG is

    

    
25. The polyfunctional polyethylene glycol derivative-modified bio-related substance according to claim 24, wherein the polyfunctional polyethylene glycol derivative-modified bio-related substance has a general formula represented by the formula (6) -4), general formula (6-4b), formula (6-5), formula (6-5b), formula (6-6) or formula (6-3);

    

    

    Wherein D ₁ , D ₂ , D ₃ , and D ₄ are each independently represented as

    

    They may be the same or different from each other in the same molecule;

    The W0 in the formula (6) preferably has 1 to 50 non-hydrogen atoms; more preferably 1 to 20 non-hydrogen atoms; more preferably 1 to 10 non-hydrogen atoms.
26. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein the U ₀₁ and U ₀₂ are each independently a symmetric type or an asymmetric type;

    When U ₀₁ and U ₀₂ are of a symmetric type, in the same molecule, U ₁ and U ₂ are each independently a symmetric type or an asymmetric type;

    When U ₀₁ and U ₀₂ are of an asymmetric type, U ₁ and U ₂ are asymmetric types;

    The structures of U ₀₁ and U ₀₂ are each independently a branched structure or a cyclic structure.
27. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein each of U ₀₁ and U ₀₂ independently contains a trivalent atomic core CM ₃ , a trivalent unsaturated bond core CB ₃ , and a trivalent ring. Any of the trivalent core structures in the nucleus CC ₃ ;

    The CM _{3 is} selected from

    

    Any of them;

    The CB _{3 is} selected from

    

    Any of them;

    The ring structure of CC ₃ is selected from

    

    Wherein R ₁ is a hydrogen atom or a group selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, fluorene , undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosane a benzyl group, a substituted C _1-20 alkyl group, a substituted aromatic hydrocarbon group, a substituted C _1-20 open chain heteroalkyl group, a substituted heteroaryl hydrocarbon group; and R ₁ is preferably a hydrogen atom, a methyl group, an ethyl group, or a positive Propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, decyl, C _1-10 halohydrocarbyl, haloacetyl or alkoxy substituted C _1-10 fat a hydrocarbon group; R _{1 is} most preferably a hydrogen atom, a methyl group or an ethyl group;

    Wherein R _{37 is} selected from a C _1-20 hydrocarbyl group, more preferably a C _1-20 alkyl group, most preferably a methyl group;

    Wherein M ₅ , M ₆ , M ₇ and M ₂₃ are ring-forming atoms, each independently selected from any one of a carbon atom, a nitrogen atom, a phosphorus atom and a silicon atom; M ₅ , M ₆ , M ₇ , M ₂₃ The cyclic structure is 3 to 50 membered rings, preferably 3 to 32 members, more preferably 3 to 18 members, more preferably 5 to 18 members; and the cyclic structure is selected from any one of the following groups. a substituted form, or a hybrid form of any of: cyclohexane, furanose ring, pyranose ring, benzene, tetrahydrofuran, pyrrolidine, thiazolidine, cyclohexane, cyclohexene, tetrahydrogen Pyran, piperidine, 1,4-dioxane, pyridine, pyridazine, pyrimidine, pyrazine, 1,3,5-triazine, 1,4,7-triazacyclononane, cyclic tripeptide , hydrazine, hydrazine, hydrazine, isoindole, hydrazine, naphthalene, dihydroanthracene, xanthene, thioxanthene, dihydrophenanthrene, 10,11-dihydro-5H-dibenzo[a, d] cycloheptane, dibenzocycloheptene, 5-dibenzocycloheptenone, quinoline, isoquinoline, indole, oxazole, iminodibenzyl, naphthyl ring, dibenzocyclooctyne Azadibenzocyclooctene.
28. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein each of U ₀₁ and U ₀₂ independently contains any of the following structures:

    

    

    Wherein Q ₅ is a H atom, a methyl group, an ethyl group or a propyl group; when Q ₅ is on the ring, it may be one or more; when more than one, it may be the same structure or two or A combination of two or more different structures.
29. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 28, wherein each of U ₀₁ and U ₀₂ independently contains one of an oxy group, a thio group, a secondary amino group, a divalent tertiary amino group and a carbonyl group. , 2 or 3 identical or different divalent linking groups are capped; when participating in an initiator molecule constituting living anionic polymerization, no carbonyl or secondary amino groups are present.
30. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 29, wherein each of U ₀₁ and U _{02 is} independently selected from any one of the following structures:

    

    

    

    

    The structure which does not contain a carbonyl group and a secondary amino group when constituting the initiator molecule of a living anionic polymerization.
31. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein each of U ₀₁ and U _{02 is} independently a trivalent skeleton structure of an amino acid or a derivative thereof, but does not participate in the formation of living anionic polymerization. An initiator molecule; wherein the amino acid is _L -form or _D -form; and the amino acid or derivative thereof is derived from any one of the following: serine, threonine, cysteine, tyrosine, hydroxyproline, Aspartic acid, glutamic acid, asparagine, glutamine, lysine, arginine, citrulline, histidine, tryptophan.
32. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein each of U ₁ and U _{2 is} independently selected from any one of the following structures:

    

    

    

    

    

    Wherein Q ₅ is a H atom, a methyl group, an ethyl group or a propyl group; and R ₂₈ is a methyl group, an isopropyl group or an isobutyl group.
33. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 32, wherein the U ₁ and U ₂ each independently satisfy one of the following conditions:

    (1) U ₁ (O-) ₃ and U ₂ (O-) ₃ can be stably present;

    (2) U ₁ (O-) ₃ and U ₂ (O-) ₃ can be degraded;

    (3) U ₁ (O-) ₃ can be stably present, and U ₂ (O-) ₃ can be degraded;

    (4) U ₁ (O-) ₃ is degradable, and U ₂ (O-) ₃ is stable.
34. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein the g is 1, the structure of the G is branched, containing a ring structure, a comb, or a tree Any of the hyperbranched.
35. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein the g=1, G is stably present or degradable.
36. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to any one of claims 1, 26 to 33, wherein g = 1, and when k = 2, G is trivalent a group; (L ₀ ) _g0 -G contains any structure selected from the group consisting of U ₀₁ , U ₀₂ , U ₁ , U ₂ ,

    

    

    When k=3, G is a tetravalent group; tetravalent G contains one atom CM ₄ , an unsaturated bond CB ₄ , a tetravalent nuclear structure of a cyclic structure CC ₄ , or contains two trivalent core structures ; L ₀ -G contains any of the following structures:

    

    

    

    Wherein X _{1 is} selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, tert-butyl, pentyl, hexyl, allyl, benzyl, trityl, phenyl, benzyl, nitrobenzyl Any one of a p-methoxybenzyl group and a trifluoromethylbenzyl group;

    When k≥3, that is, when the valence state of G≥4, the G+1 valence G contains 1 k+1 valence core structure, or 2~k-1 3~k valence low valence groups The direct linkage is combined or indirectly combined by one or more divalent spacers L ₁₀ ; the 3 to k valence group may be the same or different, and the valence states may be the same or different; The nuclear structure of k+1 valence, when k≥4 and containing a k+1 valence core structure, the k+1 valence core structure is preferably a ring structure; when two or more L ₁₀ are contained, L ₁₀ may The same or different from each other; the k+1 (k≥4) valence G directly or indirectly combined, the combination manner is selected from the group consisting of a comb combination method, a tree combination method, a branch combination method, and a hyperbranched combination Any of the combination methods of the release and the ring.
37. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 36, wherein the k+1 (k≥4) valence G, which is directly or indirectly combined,

    Wherein, the tree-shaped combined structure is selected from any one of the following:

    

    

    

    Wherein d represents an algebra of a tree-like combination, selected from 2, 3, 4, 5 or 6; wherein ng represents an algebra of a tree-like combination;

    Wherein, the basic unit of the multivalent G constituting the branched or hyperbranched combination structure is selected from the group consisting of trivalent G and tetravalent G, and is a mixed combination of the multivalent G and its low-cost form;

    Wherein, the basic unit of the polyvalent G constituting the comb-shaped combined structure is trivalent G, tetravalent G or pentavalent G; and the comb-like combination structure is composed of any basic unit selected from the group consisting of polyglycerol and polypentaerythritol. , substituted propylene oxide, substituted propylene oxide and carbon dioxide groups, acrylates and their derivatives, methacrylates and their derivatives, basic units containing acetal structures (eg (1→6)β-D A glucopyranoside, a hydroxyl or sulfur-containing amino acid and a derivative thereof, an acidic amino acid and a derivative thereof, a basic amino acid and a derivative thereof, or a D-glucopyranose unit through a β-1,6 glycosidic bond, Any one of the α-1,6 glycosidic bond, β-1,4 glycosidic bond, α-1,4 glycosidic bond, β-1,3 glycosidic bond, α-1,3 glycosidic bond is formed end to end. An acetalized dextran, and an oxidized form of the above multimer;

    Wherein the multivalent G of the cyclic combination is selected from the group consisting of a residue of a cyclic peptide or a derivative thereof, a residue of a cyclic monosaccharide or a derivative thereof, a residue of a cyclic polysaccharide or a derivative thereof, 1, 4, Skeleton of 7-tri-tert-butoxycarbonyl-1,4,7,10-tetraazacyclododecane, skeleton of 2-hydroxymethylpiperidine-3,4,5-triol, 6-amino-4 - Skeleton of (hydroxymethyl)-4-cyclohexyl-[4H,5H]-1,2,3-triol.
38. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein said g = 1; said L ₀ is stably present, and L _{0 is} selected from any one of the following two types; Class: (1) an oligopeptide or polypeptide comprising N- and C-terminal ends of a plurality of amino acids, which may be the same or different, but excluding polypeptide fragments which are degradable by in vivo biological enzymes; (2) L ₀ Containing -(L ₁₁ O) _nj -, -(OL ₁₁ ) _nj -, -(R ₂₉ O) _nj -, -(OR ₂₉ ) _nj -, -(CH ₂ CH ₂ O) _nj -, -(OCH ₂ Any one of CH ₂ ) _nj - wherein R _{29 is} selected from a C _3-20 alkylene group and has a linear, branched or cyclic structure; wherein L ₁₁ is a C _1-20 subunit which is stably present a hydrocarbyl group or a C _1-20 substituted alkylene group; having a linear structure, a branched structure or a cyclic structure; wherein the integer nj is a monodisperse structure having a repeating unit number selected from 2 to 20.
39. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein the k is selected from the group consisting of 1 to 100, specifically selected from 1, 2, 3, 4, 5, 6, and 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 to 100; preferably 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 or 33-64; more preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 13, 14, 15, 16, 17, 18, 19 or 20.
40. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein the R _{01 is} selected from the group consisting of: a reactive group, a variant of a reactive group, and a therapeutic targeting property. Functional group, fluorescent functional group; wherein the variant comprises a precursor of a reactive group, an active form thereof as a precursor, a substituted active form, a protected form, deprotection Any one of the forms; wherein the precursor of the reactive group is subjected to oxidation, reduction, hydration, dehydration, electron rearrangement, structural rearrangement, salt complexation and decomplexation, ionization, protonation At least one process of deprotonation can be converted into a structure of the reactive group; wherein the variant of the reactive group refers to oxidation, reduction, hydration, dehydration, and electron rearrangement of a reactive group. , structural rearrangement, salt complexation and decomplexation, ionization, protonation, deprotonation, substitution, deprotection, at least one of the processes still active, or protected inactive form.
41. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein the R _{01 is} selected from the group consisting of the following functional groups of the class A to the class H, and the class (AH)' Any of the functional groups in the group consisting of:

    Class A: a similar structure of an active ester group or an active ester group; wherein the active ester comprises: a succinimide active ester, a sodium nitrate Active benzene ester, o-nitrobenzene active ester, benzotriazole active ester, 1,3,5-trichlorobenzene active ester, 1,3,5-trifluorobenzene active ester, pentafluorobenzene active ester, imidazole An active ester; wherein the similar structure of the active ester group comprises: 2-thione-3-thiazolidinecarboxylate (tetrahydrothiazole-2-thione-N-formate), 2-thioxothiazolidine- 3-carboxylate, 2-thioketopyrrolidine-N-carboxylate, 2-thioketopyrrolidine-N-formate, 2-thionebenzothiazole-N-formate, 1-oxo -3-thiooxoisoporphyrin-N-formate;

    Class B: sulfonate, sulfinate, sulfone, sulfoxide, 1,3-disulfonyl-2-propylcarbonylphenyl, sulfone methacryloyl;

    Class C: hydroxylamine, mercapto, amino, azide, halogenated hydrocarbon, haloacetamide, tetramethylpiperidinyloxy, dioxapiperidinyloxy, ammonium salt, guanidine, disulfide compound; Primary or secondary amino group;

    Class D: amide, hydrazide, carboxamide, carboxyl, aldehyde, glyoxal, acid halide, acetal, hemiacetal, hydrated aldehyde, ketal, hemi-ketal, hemi-ketal, ketal, hydration Ketones, orthoesters, cyanates, isocyanates, esters, siloxanes, silicates, silyls, thioesters, thioesters, dithioesters, trithiocarbonates, thio-half-condensation Aldehyde, monothiohydrate, dithiohydrate, disulfide, mercaptan hydrate, thioketone, thioacetal, thioketone hydrate, keto mercaptan, hemi-ketal, dihydrooxazole, Isothiocyanate, mercapto, ureido, thiourea, sulfhydryl, anhydride, squaric acid, square acid ester;

    Class E: maleimide, acrylamide, acrylate, methacrylamide, methacrylate, norbornene-2-3-dicarboxyimino, maleamic acid, 1,2,4- Triazoline-3,5-dione;

    Class F: cyano group, alkenyl group, alkene group, cycloalkenyl group, alkynyl group, epoxy group, azo group, diazo group, diolefin group, diolefin group;

    Class G: cycloalkyne, cyclodiene, furan, 1,2,4,5-tetrazinyl;

    Class H: hydroxyl group, protected hydroxyl group, siloxy group, protected bishydroxy group, trihydroxy silicon group, protected trihydroxysilyl group; wherein hydroxyl group includes alcoholic hydroxyl group, phenolic hydroxyl group, enol hydroxyl group, semi-condensed Aldehyde hydroxyl group;

    Class (AH)': imide, sulfonyl hydrazide, hydrazine, imine, enamine, acetyleneamine, xanthate, perthiocarbonate, tetrathiodiester, sulfonate, sulfenate, Hydroxamic acid, thiohydroxamic acid, xanthogen, sulfonyl chloride, ortho acid, cyanate, thiocyanate, thiocarboxylic acid (monothiocarboxylic acid (thiocarbonyl or thiol) , dithiocarboxylic acid), mercapto and its protonated form, semi-squaric acid, hemi-squarate, N-carbamoyl-3-imidazole or N-carbamoyl-3-methylimidazolium iodide, Imino, imidate, nitrone, hydrazine, urea, thiourea, pseudourea, isocyano, aldoxime, diazo, diazonium ion, oxidized azo, nitrile imine, N-oxyaldehyde The imine, tetrazolium, 4-acetyl-2-methoxy-5-nitrophenoxy group and its diazotized form can undergo a 1,3-dipolar cycloaddition reaction functional group.
42. A bio-related substance modified with a polyfunctional polyethylene glycol derivative according to claim 1, wherein

    The R _{01 is} selected from any one of the following classes I to J, or a derivative thereof:

    Class I: a targeting group and a pharmaceutically acceptable salt thereof;

    Class J: a fluorescent group, including fluorescein, rhodamine, hydrazine, hydrazine, coumarin, fluorescein 3G, carbazole, imidazole, anthraquinone, anthraquinone violet, and any of them functional derivative.
43. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to any one of claims 41 to 42, wherein when R ₀₁ is an active ester,

    

    a carbonate, acetate, propionate, butyrate, valerate, hexanoate, heptanoate, octanoate, phthalate, phthalate, oxalic acid of any of the active esters Ester, malonate, methylmalonate, ethylmalonate, butyl malonate, succinate, 2-methylsuccinate, 2,2-dimethylbutyl Diester, 2-ethyl-2-methyl-succinate, 2,3-dimethylsuccinate, glutarate, 2-methylglutarate, 3-methylpentyl Diester, 2,2-dimethylglutarate, 2,3-dimethylglutarate, 3,3-dimethylglutarate, adipate, pimelate, Any of a suberate, a sebacate, a sebacate, a maleate, a fumarate, an amino acid ester, a polypeptide acid ester, or a polyamino acid ester;

    When R ₀₁ is an amino group,

    

    A primary amino group obtained by losing a non-amino hydrogen atom to a primary amine of methylamine, ethylamine, propylamine, butylamine, pentylamine, hexylamine, heptylamine, octylamine, cyclohexylamine or aniline or losing an amino hydrogen atom The secondary amino group obtained is either dimethylamine, diethylamine, dipropylamine, dibutylamine, diamylamine, dihexylamine, diheptylamine, dioctylamine, dicyclohexylamine, N-methylaniline, N 2-ethylaniline, N-propylaniline, N-isopropylaniline, N-butylaniline, N-cyclohexylaniline, azetidine, pyrrolidine, piperidine a secondary amino group obtained by an amino hydrogen atom, or a residue formed by losing an amino acid, an amino acid derivative, an ω-aminocarboxylic acid, a polypeptide or a polypeptide derivative to a hydroxyl group of a C-carboxy group or a pendant carboxyl group;

    When R ₀₁ is an aldehyde group,

    

    Is a formaldehyde group, an acetaldehyde group, a propionaldehyde group, a butyraldehyde group, a valeraldehyde group, a hexanal group, a heptaldehyde group, an octanal group, a furfural group, a furfural group, a crotonaldehyde group, an acrolein group, an isobutenyl group, and a 2- Ethyl acrolein, monochloroacetaldehyde, iodoacetaldehyde, dichloroacetaldehyde, benzaldehyde, phenylacetaldehyde, methyl benzaldehyde, cinnamaldehyde, nitrocinnamaldehyde, bromobenzene Any one of a formaldehyde group and a chlorobenzaldehyde group;

    When R ₀₁ is a carboxyl group,

    

    Formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, heptanoic acid, caprylic acid, capric acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, arachidic acid, twenty Monoalkanic acid, behenic acid, isobutyric acid, 3-methylbutyric acid, acrylic acid, methacrylic acid, citric acid, vinyl acetic acid, cis citric acid, 6-heptenoic acid, itaconic acid, citronellic acid, Monochloroacetic acid, dichloroacetic acid, monofluoroacetic acid, difluoroacetic acid, benzoic acid, methylbenzoic acid, monofluorobenzoic acid, ethoxybenzoic acid, methoxybenzoic acid, ethylbenzoic acid, vinylbenzene Formic acid, propyl benzoic acid, 2-isopropylbenzoic acid, 2-butyl benzoic acid, 2-isobutyl benzoic acid, carbamoyl maleic acid, N-phenyl maleic acid, maleamic acid, Arachidonic acid, tetracosanoic acid, tetracosic acid (neric acid), glycolic acid, lactic acid, isonicotinic acid, ascorbic acid, gentisic acid, gluconic acid, uronic acid, sorbic acid, N-( a monovalent functional group in which a monobasic acid of a ω-aminocarboxylic acid group loses a non-carboxyl hydrogen atom, or is oxalic acid, malonic acid, methylmalonic acid, ethyl Diacid, butylmalonic acid, succinic acid, 2-methylsuccinic acid, 2,2-dimethylsuccinic acid, 2-ethyl-2-methyl-succinic acid, 2,3- Dimethyl succinic acid, glutaric acid, 2-methylglutaric acid, 3-methylglutaric acid, 2,2-dimethylglutaric acid, 2,3-dimethylglutaric acid, 3 , 3-dimethylglutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, maleic acid, fumaric acid, oxaloacetic acid, dimethylmalonic acid, different Propyl malonic acid, benzylmalonic acid, 1,1-epoxydicarboxylic acid, 1,1-cyclobutyldicarboxylic acid, dibutylmalonic acid, ethyl (1-methylpropyl) Malonic acid, ethyl (1-methylbutyl)malonic acid, ethyl (isopentyl)malonic acid, phenylmalonic acid, 2,2-dimethylsuccinic acid, 2-oxygen Y-glutaric acid, 3-oxoglutaric acid, 5-norbornene-endo-2,3-dicarboxylic acid, 1,4-cyclohexanedicarboxylic acid, 1,3-cyclohexanedicarboxylic acid, 1, 2-cycloadipate, pyrrolidine-3,4-dicarboxylic acid, camphoric acid, chloric acid, cyclic acid, 5-methylisophthalic acid, phthalic acid, 4-methyl-1,2 - benzenedicarboxylic acid, 4-chlorophthalic acid, 3,4-pyridinedicarboxylic acid, 2,3-pyridinedicarboxylic acid, 2,4-pyridinedicarboxylic acid, 3,5-pyridinedi Carboxylic acid, 2,6-pyridinedicarboxylic acid, 2,4-dimethylpyrrole-3,5-dicarboxylic acid, pyridine-2,3-dicarboxylic acid, 5-methylpyridine-2,3-di Carboxylic acid, 5-ethylpyridine-2,3-dicarboxylic acid, 5-methoxymethyl-2,3-pyridinedicarboxylic acid, 4,5-pyridazine dicarboxylic acid, 2,3-pyrazine Dicarboxylic acid, 5-methylpyrazine-2,3-dicarboxylic acid, 4,5-imidazole dicarboxylic acid, 2-propylimidazolium dicarboxylic acid, 2-propylimidazoledicarboxylic acid, diphenyl phthalic acid 4,4'-stilbene dicarboxylic acid, 2,7-naphthalene dicarboxylic acid, 4,4'-diphenyl ether dicarboxylic acid, 2,2'-bipyridyl-5,5'-dicarboxylic acid, 2,2'-bipyridyl-3,3'-dicarboxylic acid, 4-pyrone-2,6-dicarboxylic acid, catechol-O, O'-diacetic acid, thiophene-2,3- Dicarboxylic acid, 2,5-thiophene dicarboxylic acid, 2,5-dicarboxylic acid-3,4-ethylenedioxythiophene, 1,3-acetone dicarboxylic acid, methylene succinic acid, 2-methyl Base-2-butenedioic acid (citraconic acid and mesaconic acid), 1,3-butadiene-1,4-dicarboxylic acid, butynedioic acid, norbornene-2,3-dicarboxylic acid (bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid), bicyclo[2.2.1]hept-2-ene-2,3-dicarboxylic acid, diglycolic acid, dithiol Dihydroxyacetic acid, malic acid, tartaric acid, 2,3-dimercaptosuccinic acid, 2,3-dibromosuccinic acid, pyridyl Oxalic acid, 4,4'-dichloro-2,2'-dicarboxybiphenyl, 4,4'-dibromo-2,2'-dicarboxybiphenyl, gluconic acid, sucrose, pamoate , 2-bromosuccinic acid, 2-mercaptosuccinic acid, 1,3-adamantane dicarboxylic acid, 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid, carbonyl Malonic acid, 3-oxoglutaric acid, ethoxymethanemalonic acid, 3,3'-dithiodipropionic acid, 5-exo-methyl-2-norbornene-5,6-endo-cis a divalent functional group obtained by removing one molecule of a hydroxyl group from any of dicarboxylic acid and acetylmalonic acid, or losing an N-amino group or a pendant amino group for an amino acid, an amino acid derivative, a polypeptide or a polypeptide derivative. a residue formed after a hydrogen atom;

    When R ₀₁ is an acid halide,

    

    Is acetyl chloride, acetyl bromide, monochloroacetyl chloride, dichloroacetyl chloride, propionyl chloride, propionyl bromide, butyryl chloride, 3-cyclopentylpropionyl chloride, 2-chloropropionyl chloride, 3-chloropropionyl, uncle Butylacetyl chloride, valeryl chloride, hexanoyl chloride, heptanoyl chloride, octanoyl chloride, decanoyl chloride, decanoyl chloride, lauroyl chloride, myristoyl chloride, palmitoyl chloride, stearoyl chloride, oleoyl chloride, behenyl chloride, cyclopentanecarbonyl chloride, a monovalent group obtained by removing one hydrogen atom from any one of methoxyacetyl chloride and acetoxyacetyl chloride, or oxalyl, malonyl, methylmalonyl or ethylpropane Acyl, butyl malonyl, succinyl, 2-methylsuccinyl, 2,2-dimethylsuccinyl, 2-ethyl-2-methyl-succinyl, 2,3-di Methylsuccinyl, glutaryl, 2-methylglutaryl, 3-methylglutaryl, 2,2-dimethylglutaryl, 2,3-dimethylglutaryl, 3, An acyl group formed by combining a diacyl group of 3-dimethylglutaryl group, adipoyl group, pimeloyl group, suberyl group, sebacyl group, sebacyl group, maleoyl group or fumaryl group with a halogen atom halogen base;

    When R ₀₁ is an acid anhydride,

    

    It is acetic anhydride, propionic anhydride, butyric anhydride, valeric anhydride, hexanoic anhydride, heptanoic anhydride, octanoic anhydride, phthalic anhydride, phthalic anhydride, lauric anhydride, myristic acid anhydride, palmitic anhydride, stearic anhydride, behenic anhydride, crotonic anhydride, Acrylic anhydride, oleic anhydride, linoleic anhydride, linoleic anhydride, chloroacetic anhydride, iodoacetic anhydride, dichloroacetic anhydride, succinic anhydride, methyl succinic anhydride, 2,2-dimethyl succinic anhydride, itaconic anhydride , maleic anhydride, glutaric anhydride, diethanol anhydride, benzoic anhydride, phenyl succinic anhydride, phenyl maleic anhydride, phthalic anhydride, isatoic anhydride, phthalic anhydride, succinic anhydride, 2,2- Dimethyl succinic anhydride, cyclopentane-1,1-diacetic anhydride, 1,1-cyclohexyl diacetic anhydride, 2-methylene succinic anhydride, glutaric anhydride, caroic anhydride, cyclobutane-1 , 2-Dicarboxylic anhydride, hexahydrophthalic anhydride, methylhexahydrophthalic anhydride, 1,2,3,6-tetrahydrophthalic anhydride, 1,2,5,6-tetrahydrophthalic anhydride, 3 -methyltetrahydrophthalic anhydride, methyltetrahydrophthalic anhydride, citraconic anhydride, 2,3-dimethylmaleic anhydride, 2,3-dichloromaleic anhydride, 3,4,5 ,6-tetrahydrophthalic anhydride, 3-methylphthalic anhydride, 4-tert-butylphthalic anhydride, 1,8-naphthalic anhydride, 2,2'-diphthalic anhydride, 4-fluorophthalic anhydride, 3- Fluorophthalic anhydride, 4-bromophthalic anhydride, 4-chlorophthalic anhydride, 3,6-dichlorophthalic anhydride, 3-nitrophthalic anhydride, 4-nitrate Phthalic anhydride, 4-bromo-1,8-naphthalic anhydride, 4,5-dichloro-1,8-naphthalic anhydride, 4-nitro-1,8-naphthalic anhydride, Norbornene dianhydride, methyl endomethylene tetrahydrophthalic anhydride, norcantharidin (7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic anhydride), 2,3-pyridine a monovalent functional group corresponding to any one of a carboxylic anhydride, a 2,3-pyrazine dianhydride, and a benzothioxane dicarboxylic anhydride;

    When R ₀₁ is an intramolecular carbon imide,

    

    An imide form corresponding to any one of the intramolecular acid anhydrides;

    When R ₀₁ is a maleimide group,

    

    Is derived from 3,4,5,6-tetrahydrophthalimide, maleimidoacetyl, 3-maleimidopropionyl, 4-maleimidobutyryl, 5-maleimidopentanoyl, 6-(maleimido)hexanoyl, 3-maleimidobenzoyl, 4-maleimidobenzoyl, 4-( N-maleimidomethyl)cyclohexane-1-formyl, 4-(4-maleimidophenyl)butanoyl, 11-(maleimido)undecane Acid acyl, 4-(4-maleimidophenyl)butanoyl, 11-(maleimido)undecanoyl acyl, N-(2-aminoethyl)maleimide a maleimide group of any one of N-(4-aminophenyl)maleimide and 2-maleimidoethyl;

    When R ₀₁ is a cyano group, it is carbonitrile, acetonitrile, butyronitrile, valeronitrile, hexanenitrile, heptonitrile, octonitrile, phthalonitrile, phthalonitrile, undecylnitrile, allyl, acrylonitrile, croton After the cyano compound of nitrile, methacrylonitrile, dichloroacetonitrile, fluoroacetonitrile, benzonitrile, benzyl nitrile, methylbenzyl nitrile, chlorobenzonitrile or methyl benzonitrile loses a hydrogen atom Corresponding monovalent functional group;

    When R ₀₁ is an alkynyl group,

    

    Is any one of an ethynyl group, a propynyl group, a propargyl group, and a cycloalkynyl group;

    When R ₀₁ is a hydroxyl group,

    

    It is methanol, ethanol, propanol, butanol, pentanol, hexanol, heptanol, octanol, decyl alcohol, decyl alcohol, undecyl alcohol, dodecanol, tridecyl alcohol, tetradecanol, pentadecyl alcohol, ten Hexaol, heptadecyl alcohol, stearyl alcohol, stearyl alcohol, oleyl alcohol, benzyl alcohol, cumene alcohol, phenol, cresol, phenol, propanol, cinnamyl phenol, naphthol, cyclopentanol, cyclohexanol a monovalent functional group corresponding to any one of the monohydric alcohols after losing a non-hydroxyl hydrogen atom;

    When R ₀₁ is cholesterol or a derivative thereof,

    

    a derivative selected from the group consisting of cholesterol, a residue of cholesterol-based hydrosuccinate;

    When R ₀₁ is biotin or a derivative thereof,

    

    Selected from biotin-N-succinimidyl ester, 3-[3-[2-(biotinamide)ethyl]amino-3-oxopropyl]dithio]propionic acid succinimide ester , 3-[[2-(biotinamide)ethyl]dithio]propionic acid sulfosuccinimide, N-(3-azidopropyl) biotinamine, N-biotin-3 ,6-dioxooctane-1,8-diamine, N-biotin-3,6,9-trioxadecane-1,11-diamine, biotinyl-6-aminoquinoline, N-(6-[biotinamine]hexyl)-3'-(2'-pyridinedithio)propanamide, 15-[D-(+)-biotinamino]-4,7,10,13-tetra Oxapentadecanoic acid, 3-(4-(N-biotin-6-aminohexylcarboxy)phenyl)propionic acid, N-Fmoc-N'-biotin-L-lysine, D-biotin a residue of any one of hydrazide, biotin-aspartyl-glutamyl-prolyl-aspartic acid;

    When R ₀₁ is fluorescein or a derivative thereof,

    

    Selected from 5-carboxyfluorescein succinimide ester, 6-carboxyfluorescein succinimide ester, 5-aminofluorescein, 6-aminofluorescein, 5(6)-aminofluorescein, 5-(aminocarba Fluorescein hydrochloride, 6-([4,6-dichlorotriazin-2-yl]amino)fluorescein hydrochloride, 5'-fluorescein phosphoramidate, fluorescein 5-maleimide, Fluorescein 6-maleimide, 5-carboxyfluorescein, 6-carboxyfluorescein, 2,7-bis(2-carboxyethyl)-5(6)-carboxyfluorescein, 5-(4,6 a residue of any one of -dichlorotriazine)aminofluorescein and CI 45350;

    When R ₀₁ is rhodamine or a derivative thereof,

    

    From tetramethylrhodamine, tetraethylrhodamine (rhodamine B, RB200), rhodamine 3G, rhodamine 6G (rhodamine 590), 5-carboxy-X-rhodamine, 6-carboxy-X-rhodan Ming, sulforhodamine B, sulforhodamine G, sulforhodamine 101, rhodamine X (R101), rhodamine 101, rhodamine 110, rhodamine 123, rhodamine 700, rhodamine 800, 5-carboxyl Tetramethylrhodamine, 6-carboxytetramethylrhodamine, 5-carboxytetramethylrhodamine succinimide ester, 6-carboxytetramethylrhodamine succinimide ester, 5-carboxyrhodamine 6G amber Imidate ester, 6-carboxyrhodamine 6G succinimide ester, tetramethylrhodamine-5-maleimide, tetramethylrhodamine-6-maleimide, 6-carboxy-X - Rhodamine succinimide ester, tetramethylrhodamine-5-isothiocyanate, tetramethylrhodamine-6-isothiocyanate, tetramethylrhodamine B-5-isothiocyanate a residue of any one of an ester, tetramethylrhodamine B-6-isothiocyanate, rhodamine 101 chloride, and sulfonated rhodamine B;

    When R ₀₁ is hydrazine or a derivative thereof,

    

    Selected from 9-oxime methanol, 1-aminoindole, 2-aminoindole, 9-nonanoxine, 10-methylindole-9-formaldehyde, 9-anthracenecarboxylic acid, 9-fluorene methyl acrylate, methacrylic acid-9 a residue of any one of methyl hydrazine, 9-nonanal oxime, and 9-fluorene acrolein;

    When R ₀₁ is hydrazine or a derivative thereof,

    

    Selected from 1-indole methanol, 7,8,9,10-tetrahydrobenzo[a]indol-7-ol, N-hydroxysuccinimide ester 1-indolebutyric acid, 1-indolyl formaldehyde, 1-indole Butyric acid, 1-indole carboxylic acid (1-indolecarboxylic acid), 1-indole acetic acid, 10-(1-indole) decanoic acid, 1-decanoic acid, Fmoc-3-(1-indenyl)-L- Alanine, tert-butyloxycarbonyl-3-(1-indolyl)-D-alanine, tert-butyloxycarbonyl-3-(1-indolyl)-L-alanine, 1-aminoindole Any one of 1,3-diaminopurine, 1,8-diaminopurine, 1,6-diaminopurine, 1-indolylmethylamine, and N-(1-indenyl)maleimide Residues;

    When Suos R ₀₁ is an oxazolium or a derivative thereof,

    

    Including but not limited to carbazole, 9-oxazole ethanol, 2-hydroxycarbazole, 2-(9H-carbazolyl)ethylboronic acid pinacol ester, 2-(9H-carbazolyl)ethylboronic acid diethanolamine a residue formed by modifying any one of ester, N-aminocarbazole, 9-(4-aminophenyl)oxazole, and 9-carbazole acetic acid at the end of PEG;

    When R ₀₁ is imidazole or a derivative thereof,

    

    Selected from 4-(hydroxymethyl)imidazole, 4-hydroxyethylimidazole, 1-(2-hydroxyethyl)imidazole, 1-methyl-2-hydroxymethyl-1H-imidazole, 1-(2-hydroxyl Propyl ester)imidazole, 1-(β-hydroxyethyl)-2-methylimidazole, 4-hydroxymethyl-5-methyl-2-phenylimidazole, 1-hydroxyethyl-3-methylimidazole, 1-hydroxyethyl-3-methylimidazolium chloride, 4-hydroxymethyl-5-methylimidazole, 4-bromo-1H-imidazole, 2-bromo-1H-imidazole, 1-methyl-2-bromo -1H-imidazole, 5-chloro-1-methylimidazole, 2-aminoimidazole, 4-aminoimidazole, 1-(3-aminopropyl)imidazole, 1-methyl-4-imidazolium, 4-imidazolecarboxaldehyde (4-formyl imidazole), 1-formyl imidazole, 2-formyl imidazole, 4-(imidazol-1-yl)benzaldehyde, 1-methyl-2-imidazolecarboxaldehyde, 2-butyl-1H-imidazole 4-carbaldehyde, 5-methylimidazole-4-carbaldehyde, 2-ethyl-4-formylimidazole, 2-ethyl-4-methyl-5-imidazolecarboxaldehyde, 1-benzyl-1H-imidazole- a residue of any one of 5-formaldehyde, 2-ethyl-4-formyl imidazole, 5-amino-1H-imidazole-4-carbonitrile, and histidine;

    When R ₀₁ is hydrazine or a derivative thereof,

    

    Selected from 4-hydroxyindole, 5-hydroxyindole, 6-hydroxyindole, 7-hydroxyindole, 5-hydroxy-2-methylindole, 4-hydroxy-2-methylindole, 3- (2-methylaminoethyl) hydrazine, 2-(2-aminoethyl) hydrazine, 3-(2-aminoethyl)-6-methoxy hydrazine, 4-amino hydrazine, 5- Aminoguanidine, 6-aminopurine, 7-aminopurine, 4-methyl-5-aminopurine, 3-bromoindole, 4-bromoindole, 5-bromoindole, 6-bromoindole , 7-bromoindole, 5-bromo-1-methyl-1H-indole, 3-(2-aminoethyl)indol-5-ol, 5-hydroxyindole-2-carboxylic acid, 6-hydroxyl -2-indolecarboxylic acid, 7-hydroxyindole-2-carboxylic acid, 5-bromoindole-2-carboxylic acid, 6-bromoindole-2-carboxylic acid, 7-bromoindole-2-carboxylic acid, 5-bromine Indole-3-carboxylic acid, 6-bromoindole-3-carboxylic acid, 4-bromoindole-3-carbaldehyde, 6-bromoindole-3-carbaldehyde, 5-bromo-1H-indole-3-ethanol Any of the residues.
44. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein the R _{01 is} selected from the group consisting of functional groups of the following classes A to J, and changes of the classes A to H Form, functional derivative of class I-class J:

    

    

    

    

    In the above class A to class J:

    _E02 and _E03 correspond to a carbonyl group and the other to OH;

    Y ₁ is a leaving group to which a sulfonyl group, a sulfinyl group, an oxysulfonyl group or an oxysulfinyl group is bonded; wherein Y _{1 is} selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, butyl, Pentyl, hexyl, heptyl, octyl, decyl, decyl, vinyl, phenyl, benzyl, p-methylphenyl, 4-(trifluoromethoxy)phenyl, trifluoromethyl, 2 Any of 2,2-trifluoroethyl;

    W is F, Cl, Br or I;

    W ₂ is F, Cl, Br or I;

    among them,

    

    a cyclic structure containing a nitrogen atom, a nitrogen argon ion, a double bond, an azo, a triple bond, a disulfide bond, an acid anhydride, or a diene, respectively, wherein the cyclic structure is selected from the group consisting of a carbocyclic ring, a heterocyclic ring, and a benzo a heterocyclic ring, a substituted carbocyclic ring, a substituted heterocyclic ring or a substituted benzoheterocyclic ring;

    Wherein M is a carbon atom, a nitrogen atom, a phosphorus atom or a silicon atom;

    Wherein M ₅ is a ring-forming atom selected from any one of a carbon atom, a nitrogen atom, a phosphorus atom and a silicon atom; and the ring structure in which M ₅ is is a 3- to 50-membered ring, preferably a 3- to 32-membered ring, more preferably a 3 to 18 membered ring, more preferably a 5 to 18 membered ring; the cyclic structure is selected from any one of the following groups, a substituted form of any one, or a hybridized form of any of: cyclohexane, Furanose ring, pyranose ring, benzene, tetrahydrofuran, pyrrolidine, thiazolidine, cyclohexane, cyclohexene, tetrahydropyran, piperidine, 1,4-dioxane, pyridine, pyridazine, pyrimidine , pyrazine, 1,3,5-triazine, 1,4,7-triazacyclononane, cyclic tripeptide, hydrazine, indane, hydrazine, isoindole, indole, naphthalene, indoline , xanthene, thioxanthene, dihydrophenanthrene, 10,11-dihydro-5H-dibenzo[a,d]cycloheptane, dibenzocycloheptene, 5-dibenzocycloheptene Ketone, quinoline, isoquinoline, anthracene, oxazole, iminodibenzyl, naphthylethene, dibenzocyclooctyne, azadibenzocyclooctyne;

    Wherein M ₈ is a carbon atom, a nitrogen atom, a phosphorus atom or a silicon atom located on the ring; the ring number of the ring in which M ₈ is 4 to 32;

    Wherein M ₁₉ , M ₂₀ , and M ₂₁ are each independently an oxygen atom or a sulfur atom, and may be the same or different from each other in the same molecule;

    Wherein M ₂₂ is a carbon atom, a nitrogen atom, a phosphorus atom or a silicon atom on the alicyclic or aliphatic heterocyclic ring; and the ring in the ring of M ₂₂ has 4, 5, 6, 7, or 8;

    Wherein R ₂ is a terminal group or a divalent linkage to which an oxygen or sulfur atom is bonded; and R _{2 is} selected from a hydrogen atom, any one of R ₂₁ or R ₃ or a group;

    Wherein R ₂₁ is a divalent linking group and participates in ring formation; and R _{21 is} selected from the group consisting of methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, aa Base, fluorenylene, 1,2-phenylene, benzylidene, C _{1-20 oxaalkylene} , C _1-20 thiaalkylene, C _1-20 azaalkylene, aza a substituted group of any one of the aromatic hydrocarbon groups, any one of the groups, a combination of any two or two or more of the same or different groups or a substituted form thereof

    Wherein R ₃ is a terminal group which is bonded to an oxy group or a thio group, and is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, fluorenyl a substituted form of any one or any of benzyl or allyl;

    Wherein R ₄ is -(R ₄ )C=N ⁺ =N ^— a hydrogen atom, a substituted atom or a substituent on C in the structure, selected from a hydrogen atom, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, Any of butyl, pentyl, hexyl, heptyl, octyl, decyl, decyl, allyl, propenyl, vinyl, phenyl, methylphenyl, butylphenyl, benzyl Or group;

    Wherein R ₈ , R ₉ , R ₁₀ , R ₁₁ and R ₁₂ are each independently a hydrogen atom, a substituted atom or a substituent on a double bond (-C=C-), and in the same molecule, R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ may be the same as or different from each other; R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ are each independently selected from the group consisting of: a hydrogen atom, a fluorine atom, a methyl group; , R ₈ is a methyl group;

    Wherein R ₂₄ is a terminal group attached to a disulfide bond, and is selected from the group consisting of: a C _1-20 alkyl group, an aryl group, an aromatic hydrocarbon group, and a hybrid phenyl group;

    Wherein R ₂₇ is a substituent attached to the azo, and is selected from the group consisting of: a phenyl group, a substituted phenyl group or a hybrid phenyl group;

    Wherein R ₃₀ is a hydrocarbon group selected from the group consisting of: a C _1-20 alkyl group, a benzyl group, and a benzyl group in which a hydrogen atom of a benzene ring is substituted with a C _1-20 hydrocarbon group;

    Wherein X ₅ is a terminal group attached to a thio group, and is selected from the group consisting of a fluorenyl protecting group and a group LG ₂ ; wherein LG _{2 is} selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, t-butyl, and pentyl. , hexyl, heptyl, octyl, decyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, Octadecyl, nonadecyl, eicosyl, allyl, benzyl, trityl, phenyl, benzyl, methylbenzyl, nitrobenzyl, tert-butylthio, benzyl Thiothio, 2-pyridylthio, acetyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, methylthiocarbonyl, Ethylthiocarbonyl, tert-butylthiocarbonyl, phenylthiocarbonyl, benzylthiocarbonyl, 2-pyridylcarbonyl, methylaminocarbonyl, ethylaminocarbonyl, tert-butylaminocarbonyl, benzylaminocarbonyl, B Thiocarbonyl, phenylmethylthiocarbonyl, methoxythiocarbonyl, ethoxythiocarbonyl, tert-butyloxythiocarbonyl, phenoxythiocarbonyl, benzyloxythiocarbonyl, A Sulfur Thiocarbonyl, ethylthiocarbonylthio, tert-butylthiothiocarbonyl, phenylthiothiocarbonyl, benzylthiothiocarbonyl, methylaminothiocarbonyl, ethylaminothiocarbonyl, tert-butyl Any one of a base aminothiocarbonyl group, a benzylaminothiocarbonyl group, a C _1-10 halogenated hydrocarbon group, a trifluoroacetyl group, a halogenated phenyl group, a halogenated benzyl group, a nitrophenyl group, or a nitrobenzyl group a substituted form of a group or a group; wherein the substituted atom or substituent is a fluorine atom, an alkoxy group or a nitro group;

    Wherein X ₆ is a terminal group attached to an oxygen atom in the ester group, and is selected from a hydroxy protecting group or a group LG ₄ ; LG _{4 is} selected from a C _1-20 alkyl group, an aryl group, an aralkyl group, and a C _1-20 hetero group. Alkyl, heteroaryl, heteroarylalkyl, C _1-20 alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, C _1-20 heteroalkylcarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl, C _1-20 alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, C _1-20 alkylthiocarbonyl, arylthiocarbonyl, aralkylthiocarbonyl, C _1-20 alkylamino Carbonyl, arylaminocarbonyl, aralkylaminocarbonyl, C _1-20 heteroalkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, C _1-20 heteroalkylthiocarbonyl, Heteroarylthiocarbonyl, heteroaralkylthiocarbonyl, C _1-20 heteroalkylaminocarbonyl, heteroarylaminocarbonyl, heteroarylalkylaminocarbonyl, C _1-20 alkylthiocarbonyl, aryl thiocarbonyl group, an aralkyl group thiocarbonyl, C _1-20 heteroalkyl thiocarbonyl group, thiocarbonyl group heteroaryl, heteroaralkyl thiocarbonyl, C _1-20 alkoxy-thiocarbonyl group, an aryl group thiocarbonyl group, thiocarbonyl group, an aralkyl group, C _1-20 Thiocarbonyl thio, thiocarbonyl arylthio, aralkylthio thiocarbonyl, C _1-20 alkylamino thiocarbonyl group, thiocarbonyl group arylamino, aralkylamino thiocarbonyl, C _1-20 heteroalkyloxythiocarbonyl, heteroaryloxythiocarbonyl, heteroaralkyloxythiocarbonyl, C _1-20 heteroalkylthiothiocarbonyl, heteroarylthiosulfur Any one of a carbonyl group, a heteroarylalkylthiocarbonyl group, a C _1-20 heteroalkylaminothiocarbonyl group, a heteroarylaminothiocarbonyl group, a heteroarylalkylaminothiocarbonyl group, or any a substituted form of a group; wherein the substituted atom or substituent is a fluorine atom, an alkoxy group or a nitro group;

    Wherein X ₁₁ is a terminal group to which a carbonyl group or a thiocarbonyl group is bonded, and is selected from a C _1-20 alkyl group;

    Wherein X ₁₂ is a terminal group to which a carbonate group or a thiocarbonate group is bonded, and is selected from a C _1-20 hydrocarbon group;

    Wherein Q is an atom or a substituent which contributes to the induction and conjugation effect of electrons of unsaturated bonds; when Q is on the ring, it may be one or more; when it is plural, it may be the same structure, or a group of two or more different structures When it is a substituent, Q has a linear structure, a branched structure containing a pendant group or a cyclic structure;

    Wherein Q ₃ is a H atom or a group contributing to the induction and conjugation effect of an unsaturated bond electron, and is selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, an ethyl group, and a n-propyl group. Base, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, decyl, vinyl, propenyl, allyl, propynyl, propargyl, cyclopropyl, cyclopropene Base, phenyl, benzyl, butylphenyl, p-methylphenyl, p-nitrophenyl, o-nitrophenyl, p-methoxyphenyl, azaphenyl, methoxy, ethoxy Any one or a group of phenoxy, benzyloxy, methylthio, ethylthio, phenylthio, benzylthio, trifluoromethyl, 2,2,2-trifluoroethyl, or a substituted form of any one of the groups;

    Wherein Q ₅ is a H atom, a methyl group, an ethyl group or a propyl group; when Q ₅ is on the ring, it may be one or more; when more than one, it may be the same structure or two or a combination of two or more different structures;

    Wherein Q ₆ is a hydrogen atom or a methyl group; Q ₇ is a hydrogen atom, a methyl group, a phenyl group or a substituted phenyl group; in the same molecule, Q ₆ and Q ₇ may be the same or different;

    Wherein Q ₈ is a substituted atom or a substituent on the imidazole group, and is selected from any one of a H atom, a methyl group, an ethyl group, a propyl group, a butyl group, and a phenyl group; and when Q ₈ may be one or more; When it is greater than one, it may be the same structure, or a combination of two or more different structures;

    Wherein Q ₁₁ is a substituent on the nitrogen atom of the tetrazole, and is selected from any one of a phenyl group, a substituted phenyl group, and an azaphenyl group;

    Wherein PG ₂ is a thiol protecting group, and the protected fluorenyl group is represented by SPG ₂ and is selected from the group consisting of thioether, disulfide, silyl sulfide, and thioester;

    Wherein PG ₃ is an alkynyl protecting group selected from a silicon group;

    Wherein PG ₄ is a hydroxy protecting group, and the protected hydroxy group is represented by OPG ₄ and is selected from any one of an ether, a silyl ether, an ester, a carbonate, and a sulfonate;

    Wherein PG ₅ is an amino protecting group and the protected amino group is represented by NPG ₅ and is selected from the group consisting of carbamates, amides, imides, N-alkylamines, N-arylamines, imines, enamines, imidazoles Any of pyrrole and pyrene;

    Wherein PG ₆ is a bishydroxy protecting group, and PG ₆ and two oxygen atoms constitute a five-membered or six-membered ring acetal structure; PG ₆ is a methylene group or a substituted methylene group; wherein PG ₆ is substituted The substituent is a hydrocarbyl substituent or a hetero atom-containing substituent selected from the group consisting of methylene, 1-methylmethylene, 1,1-dimethylmethylene, 1,1-cyclopentylene, 1 , 1-cyclohexylene group, 1-phenylmethylene group, 3,4-dimethylphenylmethylene group;

    Among them, PG ₈ is a protective group of orthocarbonic acid or ortho silicic acid.
45. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein the L ₀ , L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ , W ₀ , W ₀₁ , W ₀₂ , Z ₁ , and Z ₂ are all divalent linking groups, and are each independently, and may be the same or different in the same molecule; each independently is a linear structure, a branched structure, or a cyclic structure. Each independently has 1 to 50 non-hydrogen atoms; wherein, the non-hydrogen atom is C, O, S, N, P, Si or B; when the number of non-hydrogen atoms is greater than 1, the type of non-hydrogen atom is 1 Species, or two or more, non-hydrogen atoms are a combination of a carbon atom and a carbon atom, a carbon atom and a hetero atom, a hetero atom and a hetero atom;

    Any one of L ₀ , L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ , W ₀ , W ₀₁ , W ₀₂ , Z ₁ , Z ₂ , or any adjacent hetero atom group The divalent linking groups constituting each are independently a linker STAG or a degradable linker DEGG which is stably present.
46. A bio-related substance modified with a polyfunctional polyethylene glycol derivative according to claim 45, wherein

    The STAG can be stably present under any conditions of light, heat, enzyme, redox, acid, alkaline, physiological conditions and in vitro simulated environment, preferably under any conditions of light, heat, enzyme, redox, acidity and alkalinity. Can be stable.
47. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 45, wherein the STAG is selected from the group consisting of an alkylene group, a divalent heteroalkyl group, a double bond, a triple bond, and a divalent diene. , divalent cycloalkyl, divalent cycloalkenyl, divalent cycloalkenyl, divalent cycloalkynyl, aromatic, heterocyclic, heterocyclic, heterocyclic, heterocyclic, substituted Alkyl, substituted heteroalkyl, substituted divalent heteroalkyl, substituted double bond, substituted triple bond, substituted dienes, substituted divalent cycloalkyl, substituted divalent cycloalkenyl, substituted Divalent cycloalkenyl group, substituted divalent cycloalkynyl group, substituted aromatic ring, substituted aliphatic heterocyclic ring, substituted hetero benzene ring, substituted aryl heterocyclic ring, substituted hetero fused heterocyclic ring, ether bond, thioether Key, urea bond, Thiourea bond, carbamate group, thiocarbamate group, -P(=O)-, -P(=S)-, divalent silicon group containing no active hydrogen, bivalent containing boron atom Linker, secondary amino group, tertiary amino group, carbonyl group, thiocarbonyl group, amide group, thioamido group, sulfonamide group, enamine group, triazole, 4,5-dihydroisoxazole, amino acid and derivatives thereof A stable divalent linking group composed of any one of two kinds or a combination of two or more kinds of divalent linking groups in the skeleton.
48. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 45, wherein the STAG is any one of the following structures or a combination of two or more kinds of structures: -L ₁₁ - , -(R ₅ ) _r1 -C(R ₈ )=C(R ₉ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -C≡C-(R ₆ ) _r2 -, -(R ₅ ) _R1 - C(R ₈ )=C(R ₉ )-C(R ₁₀ )=C(R ₁₁ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -O-(R ₆ ) _r2 -,- (R ₅ ) _r1 -S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₁₈ )-C(=O)-N(R ₁₉ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₁₈ )-C(=S)-N(R ₁₉ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-C(=O)-O- (R ₆ ) _r2 -, -(R ₅ ) _r1 -OC(=O)-N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-C(=S )-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -OC(=S)-N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )- C(=O)-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -SC(=O)-N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N( R ₇ )-C(=S)-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -SC(=S)-N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _R1 -N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -C(=O)-(R ₆ ) _r2 -, -(R ₅ ) _r1 -C(=S)-(R ₆ ) _r2 -, -(R ₅ ) _r1 -P(=O)-(R ₆ ) _r2 -, -(R ₅ ) _r1 -(R ₃₈ )P (=O)-(R ₆ ) _r2 -, -(R ₅ ) _r1 -(R ₃₈ O)P(=O)-(R ₆ ) _r2 -, -(R ₅ ) _r1 -P(=S)- (R ₆ ) _r2 -, -(R ₅ ) _r1 -(R ₃₈ )P(=S)-(R ₆ ) _r2 -, -(R ₅ ) _r1 -(R ₃₈ O)P(=S)-( R ₆ ) _r2 -, -(R ₅ ) _r1 -C(=O)N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )C(=O)-( R ₆ ) _r2 -, -(R ₅ ) _r1 -CH ₂ N(R ₇ )CH ₂ -(R ₆ ) _r2 -, -(R ₅ ) _r1 -NHCH ₂ -(R ₆ ) _r2 -, -(R ₅ ) _r1 -CH ₂ NH-(R ₆ ) _r2 -, -(R ₅ ) _r1 -CH ₂ -N(R ₇ )-CH ₂ -(R ₆ ) _r2 -, -(R ₅ ) _r1 -C( R ₈ )=C(R ₉ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -C≡C-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )C(= O)CH ₂ -S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -S-CH ₂ C(=O)N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 - S(=O) ₂ -(R ₆ ) _r2 -, -(R ₅ ) _r1 -S(=O)-(R ₆ ) _r2 -, -(R ₅ ) _r1 -(R ₈ )C=C(NR ₇ R ₃₉ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -(NR ₇ R ₃₉ )C=C(R ₈ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -M ₁₇ ( R ₂₂ )-(R ₆ ) _r2 -,

    

    a skeleton of the ω-aminocarboxylic acid, a divalent linking group derived from an amino acid skeleton or a skeleton of an amino acid derivative;

    Wherein r1 and r2 are each independently 0 or 1;

    Wherein R ₅ and R ₆ may be stably present, each independently selected from a C _1-20 alkylene group and a C _1-20 substituted alkylene group; and in the same molecule, R ₅ and R ₆ may be the same as each other or different. ; R ₅ and R ₆ are each independently a linear structure, a branched structure or a cyclic structure; and R ₅ and R ₆ are each independently selected from the group consisting of methylene, 1,1-ethylene, 1,2-Asia. Ethyl, 1,3-propylene, 1,2-propylene, isopropylidene, butylene, pentylene, hexylene, heptylene, octylene, fluorenylene, fluorenylene, Y-undecylene, dodecylene, tridecylene, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, y-10 Any of the alkylene, decylene, cyclopropylene, cyclohexylene, cyclooctylene, cyclodecyl, p-phenylene, o-phenylene, m-phenylene, and benzylidene groups. Or a substituted form of any one, or a combination of any two or more alkylene groups or substituted alkylene groups;

    Wherein L ₁₁ is a C _1-20 alkylene group or a C _1-20 substituted alkylene group which may be stably present; having a linear structure, a branched structure or a cyclic structure;

    Wherein R ₇ , R ₁₈ and R ₁₉ are each independently a hydrogen atom, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, a t-butyl group, a pentyl group, a hexyl group, an allyl group or a benzyl group. , trityl, phenyl, benzyl, nitrobenzyl, p-methoxybenzyl or trifluoromethylbenzyl;

    Wherein R ₈ , R ₉ , R ₁₀ and R ₁₁ are each independently a hydrogen atom or a methyl group;

    Wherein R ₃₈ is a C _1-20 hydrocarbon group;

    Wherein R ₃₉ is a hydrogen atom or a substituent to which a nitrogen atom is bonded, and is selected from the group consisting of a hydrogen atom, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, an n-butyl group, and a benzyl group;

    Wherein -M ₁₇ (R ₂₂ )- is a 1,1-cyclic divalent linking group having a ring atomic number of 3, 4, 5, 6, 7, or 8;

    Wherein M ₁₇ is a carbon atom, a phosphorus atom or a silicon atom located on the ring;

    Wherein R ₂₂ is a divalent linking group and participates in ring formation; R _{22 has} a carbon number of 1 to 20; R ₂₂ has a linear structure, a branched structure containing a side group or a cyclic structure; R ₂₂ may Containing a hetero atom or a hetero atom; R _{22 is} selected from the group consisting of methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, fluorenylene, arylene decyl group, C _1-20 bivalent oxa-alkyl, C _1-20 divalent sulfur hetero alkyl, C _1-20 divalent diaza group, a divalent aromatic hydrocarbon group diaza any one group, any A substituted form of a group, a combination of any two or more than two identical or different groups or groups substituted forms.
49. A bio-related substance modified with a polyfunctional polyethylene glycol derivative according to claim 48, wherein said R ₇ , R ₁₈ , R ₁₉ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₃₉ All are H atoms.
50. A bio-related substance modified with a polyfunctional polyethylene glycol derivative according to claim 45, wherein

    The DEGG is degradable under any conditions of light, heat, enzyme, redox, acid, alkaline, physiological conditions, and in vitro simulated environment; preferably in any condition of light, heat, enzyme, redox, acidity, or alkaline It can be degraded.
51. A bio-related substance modified with a polyfunctional polyethylene glycol derivative according to claim 45, wherein

    The DEGG contains a disulfide bond, a vinyl ether bond, an ester group, a thioester group, a thioester group, a dithioester group, a carbonate group, a thiocarbonate group, a dithiocarbonate group, a trithio group. Carbonate group, carbamate group, thiocarbamate group, dithiocarbamate group, acetal, cyclic acetal, sulfur reduction, azaacetal, azacyclic acetal, nitrogen Thia acetal, dithio acetal, hemiacetal, thio hemiacetal, aza hemiacetal, ketal, sulfur thione, aza ketal, aziridine ketal, nitrogen thioketal , imine bond, hydrazone bond, hydrazide bond, hydrazone bond, thioxanthene group, carbaryl bond, thioscarbazide bond, sulfhydryl group, hydrazide group, thiocarbohydrazide group, azocarbonyl group Sulfhydryl, thioazocarbonyl hydrazide, carbazate, mercapto thioformate, carbazone, thiocarbazone, azo, isourea, isothiourea, urea Carbamate group, thiourea group, sulfhydryl group, fluorenyl group, amino fluorenyl group, amino fluorenyl group, imidic acid group, imidate thioester group, sulfonate group, sulfinate group , sulfonyl hydrazide, sulfonylurea, maleimide, original Acid ester group, phosphate group, phosphite group, phosphite group, phosphonate group, phosphosilyl group, silane ester group, carbon amide, thioamide, sulfonamide group, polyamide, phosphoramide, sub Phosphoramide, pyrophosphamide, cyclophosphamide, ifosfamide, thiophosphoramide, aconityl, benzyloxycarbonyl, polypeptide fragments, nucleotides and their derivative backbones, deoxynucleotides and their derivative skeletons Any one of a divalent linking group, any two or a combination of two or more divalent linking groups.
52. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 45, wherein the DEGG contains any one of the following structures or a combination of two or more kinds of structures: - (R) ₅ ) _r1 -SS-(R ₆ ) _r2 -, -(R ₅ ) _r1 -C(R ₈ )=C(R ₉ )-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -OC( R ₉ )=C(R ₈ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -C(=O)-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -C(=O )-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -C(=O)-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -SC(=O)-(R ₆ ) _R2 -, -(R ₅ ) _r1 -C(=S)-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -OC(=S)-(R ₆ ) _r2 -, -(R ₅ ) _R1 -C(=S)-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -SC(=S)-(R ₆ ) _r2 -, -(R ₅ ) _r1 -OC(=O)- O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -SC(=O)-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -OC(=S)-O-(R ₆ ) _R2 -, -(R ₅ ) _r1 -OC(=O)-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -SC(=S)-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -OC(=S)-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -SC(=O)-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -SC( =S)-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-C(=O)-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -OC( =O)-N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )- C(=S)-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -OC(=S)-N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N( R ₇ )-C(=O)-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -SC(=O)-N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _R1 -N(R ₇ )-C(=S)-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -SC(=S)-N(R ₇ )-(R ₆ ) _r2 -,- (R ₅ ) _r1 -CH(OR ₃ )-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -O-CH(OR ₃ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 - CH(OR ₃ )-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -S-CH(OR ₃ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -CH(SR ₃ )- O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -O-CH(SR ₃ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -CH(SR ₃ )-S-(R ₆ ) _R2 -, -(R ₅ ) _r1 -S-CH(SR ₃ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -CH(OR ₃ )-N(R ₇ )-(R ₆ ) _r2 - , -(R ₅ ) _r1 -N(R ₇ )-CH(OR ₃ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -CH(NR ₁₈ R ₁₉ )-O-(R ₆ ) _r2 - , -(R ₅ ) _r1 -O-CH(NR ₁₈ R ₁₉ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -CH(NR ₁₈ R ₁₉ )-N(R ₇ )-(R ₆ ) _R2 -, -(R ₅ ) _r1 -N(R ₇ )-CH(NR ₁₈ R ₁₉ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -(R ₁₈ R ₁₉ N)C(SR ₃ ) -(R ₆ ) _r2 -, -(R ₅ ) _r1 -CH(SR ₃ )-N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-CH(SR _{3) - (R 6) r2} -, - (R 5) r1 -CH (NR 18 R 19) -S- (R 6) r2 - _{- (R 5) r1 -S-} CH (NR 18 R 19) - (R 6) r2 -, - (R 5) r1 -CH (OH) -O- (R 6) r2 -, - (R 5) _R1 -O-CH(OH)-(R ₆ ) _r2 -, -(R ₅ ) _r1 -CH(OH)-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -S-CH(OH) -(R ₆ ) _r2 -, -(R ₅ ) _r1 -CH(OH)-N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-CH(OH) -(R ₆ ) _r2 -, -(R ₅ ) _r1 -CR ₁₃ (OR ₃ )-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -O-CR ₁₃ (OR ₃ )-(R _{6 R2} -, -(R ₅ ) _r1 -CR ₁₃ (OR ₃ )-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -S-CR ₁₃ (OR ₃ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -CR ₁₃ (SR ₃ )-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -O-CR ₁₃ (SR ₃ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -CR ₁₃ (SR ₃ )-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -S-CR ₁₃ (SR ₃ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -CR ₁₃ (OR ₃ )-N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-CR ₁₃ (OR ₃ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -CR ₁₃ (NR ₁₈ R ₁₉ )-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -O-CR ₁₃ (NR ₁₈ R ₁₉ )-(R ₆ ) _r2 -, -(R _{5 R1} -CR ₁₃ (NR ₁₈ R ₁₉ ))-N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-CR ₁₃ (NR ₁₈ R ₁₉ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -CR ₁₃ (SR ₃ )-N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-CR ₁₃ (SR ₃ ) - (R _{6) r2} - _{- (R 5) r1 -CR 13} (NR 18 R 19) -S- (R 6) r2 -, - (R 5) r1 -S-CR 13 (NR 18 R 19) - (R 6) r2 -, -(R ₅ ) _r1 -CR ₁₃ (OH)-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -O-CR ₁₃ (OH)-(R ₆ ) _r2 -, -(R ₅ ) _r1 -CR ₁₃ (OH)-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -S-CR ₁₃ (OH)-(R ₆ ) _r2 -, -(R ₅ ) _r1 -CR ₁₃ (OH) -N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-CR ₁₃ (OH)-(R ₆ ) _r2 -, -(R ₅ ) _r1 -(R ₁₅ C=N-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N=C(R ₁₅ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -(R ₁₅ )C=NN(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-N=C(R ₁₅ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -(R ₁₅ )C =NN(R ₇ )-C(=O)-(R ₆ ) _r2 -, -(R ₅ ) _r1 -C(=O)-N(R ₇ )-N=C(R ₁₅ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -(R ₁₅ )C=NO-(R ₆ ) _r2 -, -(R ₅ ) _r1 -ON=C(R ₁₅ )-(R ₆ ) _r2 -, -( R ₅ ) _r1 -(R ₁₅ )C=NS-(R ₆ ) _r2 -, -(R ₅ ) _r1 -SN=C(R ₁₅ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N (R ₇ )-C(=O)-N(R ₁₈ )-N=C-(R ₆ ) _r2 -, -(R ₅ ) _r1 -C=NN(R ₁₈ )-C(=O)-N (R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-C(=S)-N(R ₁₈ )-N=C-(R ₆ ) _r2 -, -( R ₅ ) _r1 -C=NN(R ₁₈ )-C(=S)-N(R ₇ )-(R _{6 R2} -, -(R ₅ ) _r1 -N(R ₇ )-N(R ₁₈ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-N(R ₁₈ )-C (=O)-(R ₆ ) _r2 -, -(R ₅ ) _r1 -C(=O)-N(R ₁₈ )-N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-N(R ₁₈ )-C(=S)-(R ₆ ) _r2 -, -(R ₅ ) _r1 -C(=S)-N(R ₁₈ )-N(R ₇ ) -(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-N(R ₁₈ )-C(=O)-N=N-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N=NC(=O)-N(R ₁₈ )-N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-N(R ₁₈ )-C(= S)-N=N-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N=NC(=S)-N(R ₁₈ )-N(R ₇ )-(R ₆ ) _r2 -, -( R ₅ ) _r1 -N(R ₁₈ )-N(R ₇ )-C(=O)-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -OC(=O)-N(R ₇ ) -N(R ₁₈ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₁₈ )-N(R ₇ )-C(=S)-O-(R ₆ ) _r2 -, -( R ₅ ) _r1 -OC(=S)-N(R ₇ )-N(R ₁₈ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₁₈ )-N(R ₇ )-C (=O)-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -SC(=O)-N(R ₇ )-N(R ₁₈ )-(R ₆ ) _r2 -, -(R _{5 R1} - N(R ₁₈ )-N(R ₇ )-C(=S)-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -SC(=S)-N(R ₇ )-N (R ₁₈ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-N(R ₁₈ )-C(=O)-N(R ₁₉ )-N(R ₂₃ )-( R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-N(R ₁₈ )- C(=S)-N(R ₁₉ )-N(R ₂₃ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N=N-(R ₆ ) _r2 -, -(R ₅ ) _r1 - OC(=NR ₁₈ )-N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-C(=NR ₁₈ )-O-(R ₆ ) _r2 -,- (R ₅ ) _r1 -OC(=NH ₂ ⁺ )-N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-C(=NH ₂ ⁺ )-O- (R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-C(=NR ₁₈ )-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -SC(=NR ₁₈ )- N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-C(=NH ₂ ⁺ )-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 - SC(=NH ₂ ⁺ )-N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₁₈ )-C(=O)-N(R ₇ )-C(=O )-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -OC(=O)-N(R ₇ )-C(=O)-N(R ₁₈ )-(R ₆ ) _r2 -,- (R ₅ ) _r1 -N(R ₁₈ )-C(=S)-N(R ₇ )-C(=O)-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -OC(=O )-N(R ₇ )-C(=S)-N(R ₁₈ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₁₈ )-C(=NR ₇ )-N(R ₁₉ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₁₈ )-C(=NH ₂ ⁺ )-N(R ₁₉ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -C(=NR ₇ )-N(R ₁₉ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₁₉ )-C(=NR ₇ )-(R ₆ ) _r2 -, -( R ₅ ) _r1 -N(R ₁₈ )-C(=NH ₂ ⁺ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -C(=NH ₂ ⁺ )-N(R ₁₈ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₂₃ )-N(R ₁₈ )-C(=NR ₇ )-N(R ₁₉ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₁₉ )-C(=NR ₇ )-N(R ₁₈ )-N(R ₂₃ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-N(R ₁₈ )-C(=NH ₂ ⁺ )-N(R ₁₉ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₁₉ )-C(=NH ₂ ⁺ )-N(R ₁₈ )- N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -C(=NR ₇ )-N(R ₁₈ )-N(R ₁₉ )-(R ₆ ) _r2 -, -(R _{5 R1} - N(R ₁₉ )-N(R ₁₈ )-C(=NR ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₁₉ )-N(R ₁₈ )-C( =NH ₂ ⁺ )-, -(R ₅ ) _r1 -C(=NH ₂ ⁺ )-N(R ₁₈ )-N(R ₁₉ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -C( =NR ₇ )-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -OC(=NR ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -OC(=NH ₂ ⁺ )- (R ₆ ) _r2 -, -(R ₅ ) _r1 -C(=NH ₂ ⁺ )-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -C(=NR ₇ )-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -SC(=NR ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -SC(=NH ₂ ⁺ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -C(=NH ₂ ⁺ )-S-(R ₆ ) _r2 -, -(R ₅ ) _r1 -S(=O) ₂ -O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -OS(=O) ₂ -(R ₆ ) _r2 -, -(R ₅ ) _r1 -S(=O)-O-(R ₆ ) _r2 -, -(R ₅ ) _r1 -OS(=O)- (R ₆ ) _r2 -, -(R ₅ ) _r1 -S(=O) ₂ -N(R ₇ )-(R _{6 R2} -, -(R ₅ ) _r1 -N(R ₇ )-S(=O) ₂ -(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₁₉ )-S(=O) ₂ -N(R ₁₈ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -S(=O) ₂ -N(R ₁₈ )-N(R ₁₉ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 - N(R ₁₉ )-N(R ₁₈ )-S(=O) ₂ -(R ₆ ) _r2 -, -(R ₅ ) _r1 -S(=O) ₂ -N(R ₁₈ )- C(=O)-N(R ₇ )-(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-C(=O)-N(R ₁₈ )-S(=O) ₂ -(R ₆ ) _r2 -, -(R ₅ ) _r1 -N(R ₇ )-(CH ₂ ) _r3 -OC(=O)-, -(R ₅ ) _r1 -N(R ₇ )-(CH _{2 ) r3 -OC (= O) -} (R 6) r2 -, - (R 5) r1 -O-Si (R 41 R 42) -O- (R 6) r2 -, orthoester group, a phosphate group , phosphite, phosphite, phosphonate, phosphosilyl, silane ester, carboxamide, thioamide, sulfonamide, polyamide, phosphoramide, phosphoramidite, pyrophosphamide, Divalent linkage of cyclophosphamide, ifosfamide, thiophosphoramide, aconityl, benzyloxycarbonyl, polypeptide fragments, divalent linking groups of nucleotides and derivatives thereof, deoxynucleotides and their derivatives base,

    

    

    Wherein r1 and r2 are each independently 0 or 1;

    Wherein r3 is 2, 3, 4, 5 or 6;

    Wherein n ₇ is the number of double bonds, and is selected from a natural number of 0 or 1-10;

    Wherein R ₃ is methyl, ethyl or benzyl;

    Wherein R ₅ and R ₆ are each independently a C _1-20 alkylene group or a C _1-20 substituted alkylene group which may be stably present; and in the same molecule, R ₅ and R ₆ may be the same as or different from each other; R ₅ and R ₆ are each independently a linear structure, a branched structure or a cyclic structure; and R ₅ and R ₆ are each independently selected from the group consisting of methylene, 1,1-ethylene and 1,2-Asian Base, 1,3-propylene, 1,2-propylene, isopropylidene, butylene, pentylene, hexylene, heptylene, octylene, fluorenylene, fluorenylene, arylene Undecyl, dodecylene, tridecylene, tetradecylene, pentadecyl, hexadecyl, heptadecyl, octadecyl, sub-19 Any alkylene group, alkylene group, cyclopropylene group, cyclohexylene group, cyclooctylene group, cyclodecylene group, p-phenylene, o-phenylene, m-phenylene or benzylidene group, Or a substituted form of any one, or a combination of any two or more alkylene groups or substituted alkylene groups;

    Wherein R ₇ = R ₁₈ = R ₁₉ = R ₂₃ is a hydrogen atom or a methyl group;

    Wherein R ₈ = R ₉ is a hydrogen atom or a methyl group;

    Wherein R ₁₃ is a hydrogen atom, a hetero atom or a substituent on the secondary or tertiary carbon, and is selected from the group consisting of: a hydrogen atom, a fluorine atom, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a butyl group, a phenyl group, a substituted form of any one or a group of benzyl, butylphenyl, p-methylphenyl, trifluoromethyl, 2,2,2-trifluoroethyl, or a group of any of the groups;

    Wherein R ₁₅ is a hydrogen atom or a methyl group;

    Wherein R ₄₁ and R ₄₂ are each independently selected from C _1-20 alkyl, phenyl, benzyl, C _1-20 alkyl substituted phenyl, C _1-20 alkyl substituted benzyl, C _1- Any of ₂₀ alkoxy groups;

    among them,

    

    a ring structure that is degradable into at least two separate segments;

    Wherein, M ₅ and M ₆ are ring-forming atoms, each independently selected from any one of a carbon atom, a nitrogen atom, a phosphorus atom and a silicon atom; and the ring structure in which M ₅ and M ₆ are located is a ring of 3 to 50 members; The cyclic structure is selected from any one of the following groups, a substituted form of any one, or a hybridized form of any one of: cyclohexane, furanose ring, pyranose ring, benzene, tetrahydrofuran, pyrrole Alkane, thiazolidine, cyclohexane, cyclohexene, tetrahydropyran, piperidine, 1,4-dioxane, pyridine, pyridazine, pyrimidine, pyrazine, 1,3,5-triazine, 1 , 4,7-triazacyclononane, cyclic tripeptide, hydrazine, indane, hydrazine, isoindole, hydrazine, naphthalene, dihydroanthracene, xanthene, thioxanthene, dihydrophenanthrene, 10,11-dihydro-5H-dibenzo[a,d]cycloheptane, dibenzocycloheptene, 5-dibenzocycloheptenone, quinoline, isoquinoline, indole, carbazole, Iminodibenzyl, naphthyl ring, dibenzocyclooctyne, azadibenzocyclooctyne;

    Wherein M ₁₅ is a hetero atom selected from an oxygen atom, a sulfur atom, a nitrogen atom; PG ₉ is a protecting group corresponding to M ₁₅ ; when M ₁₅ is O, PG ₉ corresponds to a hydroxy protecting group PG ₄ , when M ₁₅ When S is S, PG ₉ corresponds to the thiol protecting group PG ₂ , and when M ₁₅ is N, PG ₉ corresponds to the amino protecting group PG ₅ ;

    Wherein M ₁₉ and M ₂₀ are each independently an oxygen atom or a sulfur atom;

    Wherein Q is an atom or a substituent which contributes to the induction and conjugation effect of electrons of unsaturated bonds; when Q is on the ring, it may be one or more; when it is plural, it may be the same structure, or It is a combination of two or more different structures; when it is a substituent, Q has a linear structure, a branched structure containing a side group, or a cyclic structure.
53. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 52, wherein the DEGG contains any one of the following structures or a combination of two or more kinds of structures: -SS-, -CH=CH-O-, -O-CH=CH-, -C(=O)-O-, -OC(=O)-, -C(=O)-O-CH ₂ -, -CH ₂ -OC(=O)-, -C(=O)-O-CH ₂ -, -CH ₂ -OC(=O)-, -C(=O)-O-CH ₂ -OC(=O)- , -C(=O)-O-CH ₂ -NH-C(=O)-, -OC(=O)-R ₅ -C(=O)-O-, -C(=O)-S- , -SC(=O)-, -C(=S)-O-, -OC(=S)-, -C(=S)-S-, -SC(=S)-, -OC(=O )-O-, -SC(=O)-O-, -OC(=S)-O-, -OC(=O)-S-, -SC(=S)-O-, -OC(=S )-S-, -SC(=O)-S-, -SC(=S)-S-, -NH-C(=O)-O-, -OC(=O)-NH-, -NH- C(=S)-O-, -OC(=S)-NH-, -NH-C(=O)-S-, -SC(=O)-NH-, -NH-C(=S)- S-, -SC(=S)-NH-, -CH(OR ₃ )-O-, -O-CH(OR ₃ )-, -CH(OR ₃ )-S-, -S-CH(OR ₃ )-, -CH(SR ₃ )-O-, -O-CH(SR ₃ )-, -CH(SR ₃ )-S-, -S-CH(SR ₃ )-, -CH(OR ₃ )- NH-, -NH-CH(OR ₃ )-, -CH(NPG ₅ )-O-, -O-CH(NH ₂ )-, -CH(NH ₂ )-NH-, -NH-CH(NH ₂ )-, -(NH ₂ )C(SR ₃ )-,- CH(SR ₃ )-NH-, -NH-CH(SR ₃ )-, -CH(NH ₂ )-S-, -S-CH(NH ₂ )-, -CH(OH)-NH-, -NH -CH(OH)-, -CH(OR ₃ )-O-, -O-CH(OR ₃ )-, -CH(OR ₃ )-S-, -S-CH(OR ₃ )-, -CH( SR ₃ )-O-, -O-CH(SR ₃ )-, -CH(SR ₃ )-S-, -S-CH(SR ₃ )-, -CH(OR ₃ )-NH-, -NH- CH(OR ₃ )-, -CH(NH ₂ )-O-, -O-CH(NH ₂ )-, -CH(NH ₂ )-NH-, -NH-CH(NH ₂ )-, -CH( SR ₃ )-NH-, -NH-CH(SR ₃ )-, -CH(NH ₂ )-S-, -S-CH(NH ₂ )-, -CH(OH)-O-, -O-CH (OH)-, -CH(OH)-S-, -S-CH(OH)-, -CH(OH)-NH-, -NH-CH(OH)-, -HC=N-, -N= CH-, -HC=N-NH-, -NH-N=CH-, -HC=N-NH-C(=O)-, -C(=O)-NH-N=CH-, -HC= NO-, -ON=CH-, -HC=NS-, -SN=CH-, -NH-C(=O)-NH-N=CH-, -HC=N-NH-C(=O)- NH-, -NH-C(=S)-NH-N=CH-, -HC=N-NH-C(=S)-NH-, -NH-NH-, -NH-NH-C(=O )-, -C(=O)-NH-NH-, -NH-NH-C(=S)-, -C(=S)-NH-NH-, -NH-NH-C(=O)- N=N-, -N=NC(=O)-NH-NH-, -NH-NH-C(=S)-N=N-, -N=NC(=S)-NH-NH-,- NH-NH-C(=O)-O-, -OC(=O)-NH-NH-, -NH-NH-C(=S)-O-, -OC(=S)-NH-NH- , -NH-NH-C(=O)-S-, -SC(=O)-NH-NH- -NH-NH-C(=S)-S-, -SC(=S)-NH-NH-, -NH-NH-C(=O)-NH-NH-, -NH-NH-C(= S)-NH-NH-, -N=N-, -OC(=NH)-NH-, -NH-C(=NH)-O-, -OC(=NH ₂ ⁺ )-NH-, -NH -C(=NH ₂ ⁺ )-O-, -NH-C(=NH)-S-, -SC(=NH)-NH-, -NH-C(=NH ₂ ⁺ )-S-, -SC (=NH ₂ ⁺ )-NH-, -NH-C(=O)-NH-C(=O)-O-, -OC(=O)-NH-C(=O)-NH-, -NH -C(=S)-NH-C(=O)-O-, -OC(=O)-NH-C(=S)-NH-, -NH-C(=NH-NH-, -NH- C(=NH ₂ ⁺ )-NH--NH-C(=O)-NH-C(=O)-O-, -OC(=O)-NH-C(=O)-NH-, -NH -C(=S)-NH-C(=O)-O-, -OC(=O)-NH-C(=S)-NH-, -NH-C(=NH)-NH-, -NH -C(=NH ₂ ⁺ )-NH-, -C(=NH)-NH-, -NH-C(=NH)-, -NH-C(=NH ₂ ⁺ )-, -C(=NH ₂ ⁺ )-NH-, -NH-NH-C(=NH)-NH-, -NH-C(=NH)-NH-NH-, -NH-NH-C(=NH ₂ ⁺ )-NH-, -NH-C(=NH ₂ ⁺ )-NH-NH-, -C(=NH)-NH-NH-, -NH-NH-C(=NH)-, -NH-NH-C(=NH ₂ ⁺ )-, -C(=NH ₂ ⁺ )-NH-NH-, -C(=NH)-O-, -OC(=NH)-, -OC(=NH ₂ ⁺ )-, -C(= NH ₂ ⁺ )-O-, -C(=NH)-S-, -SC(=NH)-, -SC(=NH ₂ ⁺ )-, -C(=NH ₂ ⁺ )-S-, -S (=O) ₂ -O-, -OS(=O) ₂ -, -S(=O)-O- , -OS(=O)-, -S(=O) ₂ -NH-, -NH-S(=O) ₂ -, -NH-S(=O) ₂ -NH-, -S(=O) ₂ -NH-NH-, -NH-NH-S(=O) ₂ -, -S(=O) ₂ -NH-C(=O)-NH-, -NH-C(=O)-NH- S(=O) ₂ -, -NH-(CH ₂ ) _r3 -OC(=O)-, -N(CH ₃ )-(CH ₂ ) _r3 -OC(=O)-, -O-Si(R ₄₁ R ₄₂ )-O-, orthocarbonate group, orthosilicate group, orthophosphate group, orthosulfonate group, orthoester group, phosphate group, phosphite group, phosphite group, phosphine Acid ester group, phosphosilyl ester group, silane ester group, carbon amide, thioamide, sulfonamide group, polyamide, phosphoramide, phosphoramidite, pyrophosphoramide, cyclophosphamide, ifosfamide, thiophosphorus Amide, aconityl, benzyloxycarbonyl, polypeptide fragments, divalent linking groups of nucleotides and derivatives thereof, divalent linking groups of deoxynucleotides and derivatives thereof,

    

    

    Wherein R ₃ is a methyl group, an ethyl group or a benzyl group.
54. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein the biologically relevant substance is a drug, a protein, a polypeptide, an oligopeptide, a protein mimetic, a fragment and the like, and an enzyme. , antigens, antibodies and fragments thereof, receptors, small molecule drugs, nucleosides, nucleotides, oligonucleotides, antisense oligonucleotides, polynucleotides, nucleic acids, aptamers, polysaccharides, proteoglycans, sugars Proteins, steroids, terpenoids, lipids, hormones, vitamins, vesicles, liposomes, phospholipids, glycolipids, dyes, fluorescent substances, targeting factors, cytokines, neurotransmitters, extracellular matrix substances, plants Or any of animal extracts, viruses, vaccines, cells, vesicles, and micelles.
55. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein the biologically relevant substance is selected from any one of the following: a biologically relevant substance itself, a dimer or a multimer. , a partial subunit or fragment, a precursor, an activated state, a derivative, an isomer, a mutant, an analog, a mimetic, a polymorph, a pharmaceutically acceptable salt, a fusion protein, a chemically modified substance, Any one of the recombinant substances, and any of the agonists, activators, activators, inhibitors, antagonists, modulators, receptors, ligands or ligands, antibodies and fragments thereof, enzymes or enzymes Substrate.
56. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein the biologically relevant substance is a biologically related substance, a modified biologically relevant substance, or a composite biologically relevant substance; The bio-related substance is allowed to have a target molecule, an appendage or a carrier with which it binds before or after binding to the octagonal polyethylene glycol derivative to form a modified bio-related substance or a complex bio-related substance.
57. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein the bio-related substance is used as a medicine, and is selected from the group consisting of: treating cancer, tumor, liver disease, hepatitis, Diabetes, gout, rheumatism, rheumatoid, senile dementia, drugs for any of cardiovascular diseases, anti-allergic drugs, anti-infectives, antibiotics, antivirals, antifungals, vaccines, central nervous system inhibitors, Central nervous system stimulants, psychotropic drugs, respiratory drugs, peripheral nervous system drugs, drugs acting at synaptic junction sites or neuroeffector junction sites, smooth muscle active drugs, histaminers, antihistamines, Blood and hematopoietic drugs, gastrointestinal drugs, steroids, cytostatics, anthelmintics, antimalarials, antiprotozoal agents, antimicrobials, anti-inflammatory agents, immunosuppressive agents, Alzheimer's disease Drugs or compounds, imaging agents, antidote, anticonvulsants, muscle relaxants, anti-inflammatory drugs, appetite suppressants, migraine agents, muscle contractions Medicine, antimalarial, anti-vomiting agent / antiemetic, tracheal dilator, antithrombotic, antihypertensive, antiarrhythmic, antioxidant, antiasthmatic, diuretic, lipid regulator, antiandrogen Medicine, anti-parasitic drugs, anticoagulants, antibiotics, hypoglycemic agents, nutraceuticals, additives, growth supplements, anti-inflammatory drugs, Vaccines, antibodies, diagnostics, contrast agents, hypnotics, sedatives, psychostimulants, tranquilizers, anti-Parkinson's drugs, analgesics, anti-anxiety drugs, muscle infection agents, and hearing disease preparations; among them, anti-cancer or anti-tumor The drug is used to treat any of the following diseases: breast cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, gastrointestinal cancer, intestinal cancer, metastatic colorectal cancer, rectal cancer, colon cancer, colorectal cancer, stomach cancer , squamous cell carcinoma, laryngeal cancer, esophageal cancer, esophageal cancer, malignant tumor, lung cancer, small unit lung cancer (small cell lung cancer), non-small cell lung cancer, liver cancer, thyroid cancer, kidney cancer, cholangiocarcinoma, brain cancer, skin cancer , pancreatic cancer, prostate cancer, bladder cancer, testicular cancer, nasopharyngeal carcinoma, head and neck cancer, gallbladder and cholangiocarcinoma, retinal cancer, renal cell carcinoma, gallbladder adenocarcinoma, multidrug resistant cancer, melanoma, lymphoma , non-Hodgkin's lymphoma, adenoma, leukemia, chronic lymphocytic leukemia, multiple myeloma, brain tumor, Wilms' tumor, liposarcoma, endometrial sarcoma, rhabdomyosarcoma, neuroblastoma and AI Any of the DS-related cancers, either primary or secondary, cancerous, sarcoma or carcinosarcoma.
58. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein the L is a divalent linking group or a trivalent linking group; and the structure of L is a linear structure or a branched structure. Or contain any of the cyclic structures.
59. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein the L contains any of the following stable linking groups: an ether bond, a thioether bond, a urea bond, Thiourea bond, carbamate group, thiocarbamate group, secondary amino group, tertiary amino group, amide group, imide group, thioamide group, sulfonamide group, enamine group, triazole, different Oxazole, or any of the following degradable linkages: disulfide, vinyl ether, ester, thioester, thioester, dithioester, carbonate, thiocarbonate , dithiocarbonate group, trithiocarbonate group, carbamate group, thiocarbamate group, dithiocarbamate group, acetal, cyclic acetal, sulfur reduction, nitrogen a acetal, a nitrogen heterocyclic acetal, a nitrogen thioacetal, a dithio acetal, a hemiacetal, a thio hemiacetal, an aza hemiacetal, a ketal, a thioketone, an aza ketal, Azacyclohexanone, nitrogen thioketal, imine bond, hydrazone bond, hydrazide bond, hydrazone bond, thioxanthene group, hemocene bond, thioscarbazide bond, thiol group, acyl group Base, thiocarbohydrazide, azocarbonylhydrazide, thioazocarbonylcarbonyl, carbazate, thiol thioate, carbazone, thiocarbazone, couple Nitrogen, isoureido, isothiourea, allophanate, thioureido, sulfhydryl, fluorenyl, aminoguanidino, aminoguanidino, imidate, sulfite Ester group, sulfonate group, sulfinate group, sulfonamide group, sulfonyl hydrazide group, sulfonylurea group, maleimide, orthoester group, phosphate group, phosphite group, hypophosphorous acid Ester, phosphonate, phosphosilyl, silane ester, carboxamide, thioamide, sulfonamide, phosphoramide, phosphoramidite, pyrophosphoramide, cyclophosphamide, ifosfamide, thio Phosphoramide, aconityl, peptide bonds and thioamide bonds.
60. The bio-related substance modified with the polyfunctional polyethylene glycol derivative according to claim 59, wherein the L contains triazole, 4,5-dihydroisoxazole, an ether bond, a thioether group, Amide bond, imide group, imine bond, secondary amino bond, tertiary amine bond, urea bond, ester group, thioester group, disulfide group, thioester group, dithioester group, thiocarbonate group Any one of a sulfonate group, a sulfonamide group, a urethane group, a thiourethane group, a dithiocarbamate group, a thioheptal, and a carbonate group.
61. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein the bio-related substance in the bio-related substance modified by the polyfunctional polyethylene glycol derivative is 2 And one of the biologically relevant substances is a targeting factor, a dye or a fluorescent substance.
62. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein the bio-related substance modified by the polyfunctional polyethylene glycol derivative has the following structure:

    

    Wherein k ₁ is an integer of 1 to 4, and k ₂ = 4-k ₁ .
63. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein the bio-related substance modified by the polyfunctional polyethylene glycol derivative has the following structure:

    

    Wherein k is an integer of 2 to 250; wherein k ₁ is an integer of 1 to k, and k ₂ = 4k - k ₁ ; wherein G is a branched structure or a tree structure.
64. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein the bio-related substance modified by the polyfunctional polyethylene glycol derivative has the following structure:

    

    Wherein k ₅ , k ₆ , k ₇ , and k ₈ are each independently an integer of 2 to 250, and in the same molecule, k ₅ , k ₆ , k ₇ , k ₈ may be the same or different from each other; G ₅ , G ₆ , G ₇ and G ₈ are each independently a linking group of a trivalent or higher valence state, and their valence states are k ₅ +1, k ₆ +1, k ₇ +1, k ₈ +1; wherein k ₁ is An integer from 1 to k ₅ +k ₆ +k ₇ +k ₈ , and k ₁ +k ₂ =k ₅ +k ₆ +k ₇ +k ₈ ; G ₅ , G ₆ , G ₇ , G _{8 are} independently Comb structure or hyperbranched structure.
65. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 1, wherein the PEG chain corresponding to n ₁ , n ₂ , n ₃ , and n ₄ is polydisperse, and LPEG is a single Dispersibility.
66. A small molecule drug modified with a polyfunctional polyethylene glycol derivative, characterized in that the polyfunctional polyethylene glycol derivative modified small molecule drug has the formulas of formula (7) and formula (8) , formula (9), formula (10) or formula (11);

    

    Wherein, LPEG is a linear spindle structure; LPEG is a monoblock, diblock, triblock or block fragment of 1-150 composed of polyethylene glycol or polyethylene glycol; the number of oxyethylene units in LPEG is An integer from 2 to 2000; the sum of the number of oxyethylene units of the linear PEG spindle and the four PEG branch chains does not exceed 5000;

    n ₁ , n ₂ , n ₃ , and n ₄ are respectively polymerization degrees of four PEG branching strands, each independently satisfying 2 to 2000, and may be the same or different from each other in the same molecule; LPEG and n ₁ , n ₂ , n ₃ The four PEG branching chains corresponding to n ₄ are each independently polydisperse or monodisperse;

    The structure of U ₁ is

    

    The structure of U ₂ is

    

    U ₀₁ and U ₀₂ are each independently a trivalent group; L ₁ , L ₂ , L ₃ and L ₄ are polyethylene glycols each having an alkyl group number of n ₁ , n ₂ , n ₃ , and n ₄ . The linking group of the unit, L ₅ , L ₆ is a linking group connecting the linear spindle polyethylene glycol unit, and L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ are each independently present or absent, and The same molecule may be the same or different from each other;

    q, q ₁ are each independently 0 or 1;

    Z ₁ and Z ₂ are each independently a divalent linking group;

    SD is a residue formed by reacting a small molecule drug with a polyfunctionalized H-type polyethylene glycol;

    The small molecule drug is a biologically related substance having a molecular weight of not more than 1000 Da, or a small molecule mimetic or active fragment of any biologically relevant substance;

    L is a functional group in the polyfunctionalized H-type polyethylene glycol derivative or a linker formed by reacting the protected form with a small molecule drug;

    E ₀₁ is R ₀₁ , protected R ₀₁ or blocked R ₀₁ ; wherein R ₀₁ is a functional group or a protected form thereof;

    In the same molecule, any one or any of LPEG, U ₁ , U ₂ , U ₀₁ , U ₀₂ , L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ , Z ₁ , Z ₂ , L The linking group formed by adjacent hetero atom groups may be stably present or degradable.
67. A small molecule drug modified with a polyfunctional polyethylene glycol derivative according to claim 66, wherein said LPEG is

    

    

    Wherein, W ₀ , W ₀₁ , and W ₀₂ are each independently a linking group having 1 to 100 atoms; W ₀ , W ₀₁ , and W ₀₂ are each independently stable or degradable; m ₁ , m ₂ , m ₃ each independently satisfy 0 to 2000, and may be identical or different from each other in the same molecule; and the PEG blocks corresponding to m ₁ , m ₂ , and m ₃ are each independently polydisperse or monodisperse.
68. A small molecule drug modified with a polyfunctional polyethylene glycol derivative according to claim 66, wherein said small molecule drug is selected from the group consisting of a biologically relevant substance having a molecular weight of not more than 1000 Da and a small amount of any biologically relevant substance. a molecular mimetic or active fragment; the small molecule drug being selected from any of the small molecule drugs, or a derivative of either, or a pharmaceutically acceptable salt of either.
69. A small molecule drug modified with a polyfunctional polyethylene glycol derivative according to claim 66, wherein the molecular weight of said small molecule drug is selected from any of the following molecular weights: 0 to 300 Da, 300 to 350 Da, 350 ~ 400Da, 400 ~ 450Da, 450 ~ 500Da, 500 ~ 550Da, 550 ~ 600Da, 600 ~ 650Da, 650 ~ 700Da, 700 ~ 750Da, 750 ~ 800Da, 800 ~ 850Da, 850 ~ 900Da, 900 ~ 950Da, 950 ~ 1000Da.
70. A small molecule drug modified with a polyfunctional polyethylene glycol derivative according to claim 66, wherein said small molecule drug is a flavonoid, a terpenoid, a carotenoid, a saponin, a steroid, a steroid, Any of lanthanum, cerium, fluoranthene, coumarin, alkaloid, porphyrin, polyphenol, macrolide, monolactam, phenylpropanol, anthracycline, aminoglycoside .
71. The polyfunctional polyethylene glycol derivative-modified small molecule drug according to claim 66, wherein the small molecule drug is selected from any one of the following categories:

    Class I: anti-cancer or anti-tumor drugs, including: taxanes, paclitaxel and its derivatives, docetaxel, docetaxel, Camptothecin and its derivatives, irinotecan, SN38, topotecan, topotecan hydrochloride, topotecan, beloitkon, esabutine, lutetotecan, genicomone, difluoro Tecolan, cariciconol, rubatecan, ezetidine, Karenitecin, jigitotecan, gimacitan, isaticom, aficicon, letoticon, cisplatin, oxali Platinum, hydroxycamptothecin, vinblastine, vincristine, ipecaine, ipecaine hydrochloride, colchicine, doxorubicin, epirubicin, pirarubicin, valrubicin, doxorubicin Or doxorubicin hydrochloride, epirubicin, daunorubicin, daunorubicin, mitomycin, aclaramicin, idamycin, bleomycin, pilomycin, daunorubicin , serotonin, rapamycin, bleomycin, streptozotocin, podophyllotoxin, actinomycin D (dactinomycin), maytansinoids, amikacin, mitoxantrone, All-trans retinoic acid, vindesine, vinorelbine, gemcitabine, capecitabine, cladribine, pemetrexed disodium, teggio, letrozole, anastrozole, fulvestrant, Goserelin, triptorelin , leuprolide, buserelin, temozolomide, cyclophosphamide, ifosfamide, gefitinib, sunitinib, erlotinib, ectinib, lapatinib, sorafi Nim, imatinib, dasatinib, nilotinib, sirolimus, everolimus, guanidinium, methotrexate, 5-fluorouracil, dacarbazine, hydroxyurea, vorinostat , Ixabepilone, bortezomib, cytarabine, etoposide, azacytidine, teniposide, propranolol, procaine, tetracaine, lidocaine, 蓓saro Butane, carmustine (dichloroethyl nitrosourea), chlorambucil, procarbazine, thiotepa, topotecan, erlotinib, plitidepsin, ramustine and gin Isoflavones;

    Class II: antibiotics, antiviral agents, antifungal drugs, including: macrolides, defensins, polymyxin E methanesulfonic acid, polymyxin, polymyxin B, capreomycin, bacitracin , gramicidin, amphotericin B, aminoglycoside antibiotics, gentamicin, paramecium, tobramycin, kanamycin, amikacin, neomycin, streptavidin , nystatin, echinomycin, carbenicillin, penicillin, penicillin-sensitive agent, penicillin G, penicillin V, penicillin enzyme resistance, penem, amoxicillin, vancomycin, daptomycin, Anthracycline, chloramphenicol, cyclic erythromycin, flavomycin, oleandomycin, oleandomycin, clarithromycin, dafaxin, erythromycin, dirithromycin, erythromycin , erythromycin, azithromycin, fluoroerythromycin, josamycin, spiramycin, medimycin, dexamethasone, leucomycin, miokamycin, rotamycin, doxy Cyclin, swinolide A, teicoplanin, lanpranin, mazinine, statin, polymyxin E methanesulfonic acid, fluorocytosine, micon , econazole, fluconazole, itraconazole, ketoconazole, voriconazole, fluconazole, clotrimazole, bifonazole, netilmicin, amikacin, caspofungin, Mika Fenjing, terbinafine, fluoroquinolone, lomefloxacin, norfloxacin, ciprofloxacin, enoxacin, ofloxacin, levofloxacin, troxafloxacin, alafloxacin, moxifloxacin , norfloxacin, gepafloxacin, gatifloxacin, sparfloxacin, temafloxacin, pefloxacin, amloxacin, fleroxacin, tolfloxacin, prulifloxacin, y Loxafloxacin, pazufloxacin, clinfloxacin, sitafloxacin, idarubicin, tosufloxacin, iloxacin, teicoplanin, rampolanin, daptomycin, colitimethate, nucleoside resistance Poison, ribavirin, anti-monospora penicillin, ticarcillin, azlocillin, mezlocillin, piperacillin, gram (negative) negative microbial active agent, ampicillin, hetacillin, grappi Xilin, amoxicillin, cephalosporin, monolactam, aztreonam, carbapenem, imipenem, pentamidine isethionate, imipenoid , melopenem, pentamidine, thiourea, salbutamol sulphate, lidocaine, osinalin sulphate, beclomethasone, beclomethasone dipropionate, m-hydroxyisoproterenol sulfate, dipropylene Acid spirulina, triamcinolone acetoacetate, butadipine, budesonide acetonide, fluticasone, fluticasone propionate, ipratropium bromide, flunisolide, sodium cromoglycate, ergotamine tartrate, spray Bismuth, pentamidine isethionate and chlorogenic acid;

    Class III, including: cytochalasin B, aminotoluic acid, sodium urate, aminoglutethimide, aminolevulinic acid, aminosalicylic acid, pamidronic acid, amsacrine, anagrelide, ana Toxazole, levamisole, busulfan, cabergoline, liulin, carboplatin, cilastatin sodium, disodium clodronate, amiodarone, ondansetron, deacetyl cyproterone Ketone, megestrol acetate, testosterone, estramustine, exemestane, fluoromethylol testosterone, diethylstilbestrol, fexofenadine, fludarabine, hydrocortisone, 16α-methyl Hydrocortisone, fluticasone, deferoxamine, flutamide, betaxalamine, thalidomide, L-dopa, leucovorin, lisinopril, levothyroxine sodium, nitrogen mustard, Angong lutein, m-hydroxynorphedrine ditartrate, metoclopramide, mexiletine, mitoxantrone, nicotine, nicotinate tartrate, nilutamide, octreotide, pentastatin, pilcamycin, guanidine Benz, prednisone, procarbazine, prochlorperazine, raltitrexe, streptozotocin, sirolimus, tacrolimus, tamoxifen, teniposide, tetrahydrogen Heparin, thioguanine, thiotepa, dolasetron, granisetron, formoterol, formoterol fumarate, melphalan, midazolam, alprazolam, podophylotoxins, sulphate Martriptan, low molecular weight liver , amitoxine, carmustine, gemcitastatin, lomustine, taifustin, osteoarthritis treatment, amdoxovir, cyanide blue/aminoaryl ketone, aminocaproic acid, amino Phenethidin, aminolevulinic acid, butanediol diester, chloroformic acid/disodium chloromethylphosphate, L-dihydroxyphenylalanine, lovothyroxine sodium, dichloromethyldiethyl Amine, m-hydroxylamine tartrate, o-p-dichlorophenyldichloroethane, prochlorazine, ondansetron, raltitrexed, tacrolimus, tamoxifen, taniposide, tetrahydrocannabinol, fluticasone, aromatic Acyl hydrazine, sumatriptan, mecomycin, spirulina, malt ethin, isorhamnetin, myricetin, dicyanoprenaline, catechin, epicatechin, phloridin , acarbose, salmeterol, salmeterol, naloxone, opioids, phenytoin, cinacalcet and diphenhydramine.
72. The polyfunctional polyethylene glycol derivative-modified small molecule drug according to claim 66, wherein the small molecule drug is selected from the group consisting of SN38, irinotecan, resveratrol, cantharidin and derivatives thereof, Any of the boxwood, Tripterygium wilfordii extract, flavonoid or flavonoid drug, Salvia miltiorrhiza extract, Milk Thistle extract, or any derivative thereof, or a pharmaceutically acceptable salt thereof.
73. A small molecule drug modified with a polyfunctional polyethylene glycol derivative, characterized in that the polyfunctional polyethylene glycol derivative modified small molecule drug has the general formula shown in formula (12);

    

    Wherein, LPEG is a linear spindle structure; LPEG is a monoblock, diblock, triblock or block fragment of 1-150 composed of polyethylene glycol or polyethylene glycol; the number of oxyethylene units in LPEG is An integer from 2 to 2000; the sum of the number of oxyethylene units of the linear PEG spindle and the four PEG branch chains does not exceed 5000;

    n ₁ , n ₂ , n ₃ , and n ₄ are respectively polymerization degrees of four PEG branching strands, each independently satisfying 2 to 2000, and may be the same or different from each other in the same molecule; LPEG and n ₁ , n ₂ , n ₃ The four PEG branching chains corresponding to n ₄ are each independently polydisperse or monodisperse;

    The structure of U ₁ is

    

    The structure of U ₂ is

    

    U ₀₁ and U ₀₂ are each independently a trivalent group; L ₁ , L ₂ , L ₃ and L ₄ are polyethylene glycols each having an alkyl group number of n ₁ , n ₂ , n ₃ , and n ₄ . The linking group of the unit, L ₅ , L ₆ is a linking group connecting the linear spindle polyethylene glycol unit, and L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ are each independently present or absent, and The same molecule may be the same or different from each other;

    q, q ₁ are each independently 0 or 1;

    Z ₁ and Z ₂ are each independently a divalent linking group;

    SD is a residue formed by reacting a small molecule drug with a polyfunctionalized H-type polyethylene glycol;

    The small molecule drug is a biologically related substance having a molecular weight of not more than 1000 Da, or a small molecule mimetic or active fragment of any biologically relevant substance;

    L is a functional group in the polyfunctionalized H-type polyethylene glycol derivative or a linker formed by reacting the protected form with a small molecule drug;

    E ₀₁ is R ₀₁ , protected R ₀₁ or blocked R ₀₁ ; wherein R ₀₁ is a functional group or a protected form thereof;

    L ₀ is a divalent linking group; g ₀ is 0, 1 or 2 to 1000;

    k ₅ , k ₆ , k ₇ , k ₈ are each independently an integer of 2 to 250, and in the same molecule, k ₅ , k ₆ , k ₇ , k ₈ may be the same or different from each other; G ₅ , G ₆ , G ₇ and G ₈ are each independently a linking group of a trivalent or higher valence state, and their valence states are k ₅ +1, k ₆ +1, k ₇ +1, k ₈ +1;

    k ₁ is an integer greater than or equal to 1, k ₂ is an integer greater than or equal to 0, and satisfies k ₁ + k ₂ = k ₅ + k ₆ + k ₇ + k ₈ ;

    In the same molecule, G ₅ , G ₆ , G ₇ , G _{8 have} the same structural type;

    In the same molecule, LPEG, U ₁ , U ₂ , U ₀₁ , U ₀₂ , L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ , Z ₁ , Z ₂ , L, L ₀ , G ₅ , A linker formed by any one or any of G ₆ , G ₇ , G ₈ and an adjacent hetero atom group may be stably present or degradable.
74. A polyfunctional polyethylene glycol derivative-modified small molecule drug according to claim 73, wherein said LPEG is

    

    

    Wherein, W ₀ , W ₀₁ , and W ₀₂ are each independently a linking group having 1 to 100 atoms; W ₀ , W ₀₁ , and W ₀₂ are each independently stable or degradable; m ₁ , m ₂ , m ₃ each independently satisfy 0 to 2000, and may be identical or different from each other in the same molecule; and the PEG blocks corresponding to m ₁ , m ₂ , and m ₃ are each independently polydisperse or monodisperse.
75. A polyfunctional polyethylene glycol derivative-modified small molecule drug according to claim 73, wherein said G ₅ = G ₆ = G ₇ = G ₈ = G, and k ₅ = k ₆ = k ₇ = k ₈ = k; the general formula of the polyfunctional polyethylene glycol derivative modified small molecule drug is expressed as formula (13);

    

    Wherein k is an integer from 2 to 250; G is a linking group of a trivalent or higher valence state, the valence of which is k+1; k ₁ + k ₂ = 4k.
76. The polyfunctional polyethylene glycol derivative-modified small molecule drug according to claim 73, wherein the polyfunctional polyethylene glycol derivative-modified small molecule drug has a general formula represented by the formula (16) ;

    

    Wherein k is an integer from 2 to 250; G is a trivalent or higher valence linkage having a valence of k+1; and said G is selected from the group consisting of a trivalent linking group, a tetravalent linking group, a pentavalent group, Any of a hexavalent group, a linking group of a comb structure, a linking group of a dendritic structure, a linking group of a hyperbranched structure, and a linking group of a cyclic structure.
77. A polyfunctional polyethylene glycol derivative modified small molecule drug, characterized in that the polyfunctional polyethylene glycol derivative modified small molecule drug has the general formula shown in formula (19);

    

    Among them, LPEG is a linear spindle structure; LPEG is a monoblock, diblock, triblock or block fragment of 1-150 composed of polyethylene glycol or polyethylene glycol; the number of oxyethylene units in LPEG is satisfied. An integer from 2 to 2000; the sum of the number of oxyethylene units of the linear PEG spindle and the four PEG branch chains does not exceed 5000;

    n ₁ , n ₂ , n ₃ , and n ₄ are respectively polymerization degrees of four PEG branching strands, each independently satisfying 2 to 2000, and may be the same or different from each other in the same molecule; LPEG and n ₁ , n ₂ , n ₃ The four PEG branching chains corresponding to n ₄ are each independently polydisperse or monodisperse;

    The structure of U ₁ is

    

    The structure of U ₂ is

    

    U ₀₁ and U ₀₂ are each independently a trivalent group; L ₁ , L ₂ , L ₃ and L ₄ are polyethylene glycols each having an alkyl group number of n ₁ , n ₂ , n ₃ , and n ₄ . The linking group of the unit, L ₅ , L ₆ is a linking group connecting the linear spindle polyethylene glycol unit, and L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ are each independently present or absent, and The same molecule may be the same or different from each other;

    q, q ₁ are each independently 0 or 1;

    Z ₁ and Z ₂ are each independently a divalent linking group;

    SD is a residue formed by reacting a small molecule drug with a polyfunctionalized H-type polyethylene glycol;

    The small molecule drug is selected from the group consisting of SN38, irinotecan, resveratrol, cantharidin and its derivatives, baicalin, tripterygium wilfordii extract, flavonoid or flavonoid drug, salvia miltiorrhiza extract, milk thistle extract Any one or any derivative or pharmaceutically acceptable salt of any one;

    L is a functional group in the polyfunctionalized H-type polyethylene glycol derivative or a linker formed by reacting the protected form with a small molecule drug;

    E ₀₁ is R ₀₁ , protected R ₀₁ or blocked R ₀₁ ; wherein R ₀₁ is a functional group or a protected form thereof;

    g ₁ , g ₂ are each independently 0 or 1;

    k ₅ , k ₆ , k ₇ , k ₈ are each independently an integer of from 2 to 250, and in the same molecule, k ₅ , k ₆ , k ₇ , k ₈ may be the same or different from each other;

    When g ₁ =0, k ₅ =k ₆ =1;

    When g ₁ =1, k ₅ and k ₆ are each independently an integer of 2 to 250, and may be the same or different from each other in the same molecule;

    When g ₂ =0, k ₇ =k ₈ =1;

    When g ₂ =1, k ₇ and k ₈ are each independently an integer of 2 to 250, and may be the same or different from each other in the same molecule;

    L ₀ is a divalent linking group; g ₀ is 0, 1 or 2 to 1000;

    G ₅ , G ₆ , G ₇ , G ₈ are each independently a linking group of a trivalent or higher valence state, and their valence states are k ₅ +1, k ₆ +1, k ₇ +1, k ₈ +1; In the same molecule, the structural types of G ₅ and G ₆ are the same, and the structural types of G ₇ and G ₈ are the same; the structural types of G ₅ and G ₇ may be the same or different;

    k ₁ is an integer greater than or equal to 1, k ₂ is an integer greater than or equal to 0, and satisfies k ₁ + k ₂ = k ₅ + k ₆ + k ₇ + k ₈ ;

    In the same molecule, LPEG, U ₁ , U ₂ , U ₀₁ , U ₀₂ , L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ , Z ₁ , Z ₂ , L, L ₀ , G ₅ , A linker formed by any one or any of G ₆ , G ₇ , G ₈ and an adjacent hetero atom group may be stably present or degradable.
78. A polyfunctional polyethylene glycol derivative-modified small molecule drug according to claim 77, wherein said LPEG is

    

    

    Wherein, W ₀ , W ₀₁ , and W ₀₂ are each independently a linking group having 1 to 100 atoms; W ₀ , W ₀₁ , and W ₀₂ are each independently stable or degradable; m ₁ , m ₂ , m ₃ each independently satisfy 0 to 2000, and may be identical or different from each other in the same molecule; and the PEG blocks corresponding to m ₁ , m ₂ , and m ₃ are each independently polydisperse or monodisperse.
79. A polyfunctional polyethylene glycol derivative-modified small molecule drug according to claim 77, wherein said G ₅ = G ₆ , k ₅ = k ₆ , and G ₇ = G ₈ , k ₇ = k ₈ .
80. The polyfunctional polyethylene glycol derivative-modified small molecule drug according to claim 77, wherein said g ₁ = g ₂ = g; said polyfunctional polyethylene glycol derivative modified small molecule The formula of the drug is as shown in formula (19-1); wherein g is 0 or 1;

    

    Wherein, when g=0, the formula (19-1) is represented by the formula (19-2);

    

    Wherein, when g = 1, the formula (19-1) is represented by the formula (19-3).

    
81. The polyfunctional polyethylene glycol derivative-modified small molecule drug according to claim 80, wherein in the formula (19-3), G ₅ = G ₆ = G ₇ = G ₈ = G, k ₅ =k ₆ =k ₇ =k ₈ =k, the structure is expressed by the formula (19-4); wherein k is an integer of 2 to 250; G is a linking group of a trivalent or higher valence state, and its valence state is k+1; k ₁ + k ₂ = 4k.

    
82. A polyfunctional polyethylene glycol derivative-modified small molecule drug according to claim 80, wherein said L =

    

    Formula (19-1) can be represented by formula (20);

    

    Wherein m ₂ is the degree of polymerization of the PEG block, and satisfies 2 to 1000; preferably 5 to 1000;

    Wherein, when g=0, the formula (20) is represented by the formula (20-1);

    

    Wherein, when G ₅ =G ₆ =G ₇ =G ₈ =G, and k ₅ =k ₆ =k ₇ =k ₈ =k, the general formula (20) is also represented by the general formula (20-2); g is 0 or 1; k is an integer of 1 or 2 to 250; when g=1, k is an integer of 2 to 250; G is a linking group of a trivalent or higher valence state, and its valence is k+1; ₁ + k ₂ = 4k;

    

    Wherein, when g = 1, the formula (20-2) is represented by the formula (21).

    
83. The polyfunctional polyethylene glycol derivative-modified small molecule drug according to claim 77, wherein the small molecule drug is SN38 or a pharmaceutically acceptable salt thereof.
84. The polyfunctional polyethylene glycol derivative-modified small molecule drug according to claim 83, wherein the -L-SD contains the following structure or a pharmaceutically acceptable salt thereof:

    
85. A small molecule drug modified with a polyfunctional polyethylene glycol derivative according to claim 77, wherein the small molecule drug is irinotecan or a pharmaceutically acceptable salt thereof.
86. The polyfunctional polyethylene glycol derivative-modified small molecule drug according to claim 85, wherein the -L-SD contains the following structure or a pharmaceutically acceptable salt thereof.

    
87. The polyfunctional polyethylene glycol derivative modified small molecule drug according to claim 77, wherein the small molecule drug is resveratrol, cycloalkaline D, and ring green boxin C. Cyclogenic carnosine C, cantharidin extract or its derivative, flavonoid or flavonoid drug, tanshinone or silymarin extract.
88. The polyfunctional polyethylene glycol derivative modified small molecule drug according to claim 77, wherein the small molecule drug is puerarin, hydroxyisoflavone, scutellarin, scutellaria flavone II, xanthine or jaundice .
89. A bio-related substance modified with a hydroxyl group-containing or protected hydroxyl group-containing polyethylene glycol derivative, characterized in that the hydroxyl-containing polyethylene glycol derivative modified bio-related substance has the general formula of formula (27) or Formula (28);

    

    Wherein, LPEG is a linear spindle structure; LPEG is a monoblock, diblock, triblock or block fragment of 1-150 composed of polyethylene glycol or polyethylene glycol; the number of oxyethylene units in LPEG is An integer from 2 to 2000; the sum of the number of oxyethylene units of the linear PEG spindle and the four PEG branch chains does not exceed 5000;

    n ₁ , n ₂ , n ₃ , and n ₄ are respectively polymerization degrees of four PEG branching strands, each independently satisfying 2 to 2000, and may be the same or different from each other in the same molecule; LPEG and n ₁ , n ₂ , n ₃ The four PEG branching chains corresponding to n ₄ are each independently polydisperse or monodisperse;

    The structure of U ₁ is

    

    The structure of U ₂ is

    

    U ₀₁ and U ₀₂ are each independently a trivalent group; L ₁ , L ₂ , L ₃ and L ₄ are polyethylene glycols each having an alkyl group number of n ₁ , n ₂ , n ₃ , and n ₄ . The linking group of the unit, L ₅ , L ₆ is a linking group connecting the linear spindle polyethylene glycol unit, and L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ are each independently present or absent, and The same molecule may be the same or different from each other;

    q is 0 or 1; Z ₂ is a divalent linking group;

    BD is a residue formed by reacting a biologically relevant substance with H-type polyethylene glycol; L is a functional group in the H-type polyethylene glycol derivative or a linker formed by reacting the protected form with a biologically relevant substance ;

    In the same molecule, any one or any of LPEG, U ₁ , U ₂ , U ₀₁ , U ₀₂ , L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ , Z ₂ , L The linking group formed by the atomic group may be stably present or degradable;

    PG ₄ is a hydroxy protecting group; OPG ₄ is a protected hydroxy group.
90. A bio-related substance modified with a hydroxyl group-containing or protected hydroxyl group-containing polyethylene glycol derivative, characterized in that the hydroxyl group-containing polyethylene glycol derivative modified bio-related substance has the general formula of formula (29) or Formula (30);

    

    Wherein, LPEG is a linear spindle structure; LPEG is a monoblock, diblock, triblock or block fragment of 1-150 composed of polyethylene glycol or polyethylene glycol; the number of oxyethylene units in LPEG is An integer from 2 to 2000; the sum of the number of oxyethylene units of the linear PEG spindle and the four PEG branch chains does not exceed 5000;

    n ₁ , n ₂ , n ₃ , and n ₄ are respectively polymerization degrees of four PEG branching strands, each independently satisfying 2 to 2000, and may be the same or different from each other in the same molecule; LPEG and n ₁ , n ₂ , n ₃ The four PEG branching chains corresponding to n ₄ are each independently polydisperse or monodisperse;

    The structure of U ₁ is

    

    The structure of U ₂ is

    

    U ₀₁ and U ₀₂ are each independently a trivalent group; L ₁ , L ₂ , L ₃ and L ₄ are polyethylene glycols each having an alkyl group number of n ₁ , n ₂ , n ₃ , and n ₄ . The linking group of the unit, L ₅ , L ₆ is a linking group connecting the linear spindle polyethylene glycol unit, and L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ are each independently present or absent, and The same molecule may be the same or different from each other;

    q is 0 or 1; Z ₂ is a divalent linking group;

    BD is a residue formed by reacting a biologically relevant substance with H-type polyethylene glycol;

    L is a functional group in the H-type polyethylene glycol derivative or a linker formed by reacting the protected form with a biologically relevant substance;

    L ₀ is a divalent linking group; g ₀ is 0, 1 or 2 to 1000;

    k ₅ and k ₆ are each independently an integer of from 2 to 250, and in the same molecule, k ₅ and k ₆ may be the same or different from each other;

    G ₅ and G ₆ are each independently a linking group of a trivalent or higher valence state, and their valence states are k ₅ +1 and k ₆ +1, respectively;

    1 In the same molecule, G ₅ and G _{6 have} the same structural type;

    In the same molecule, LPEG, U ₁ , U ₂ , U ₀₁ , U ₀₂ , L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ , Z ₂ , L, L ₀ , G ₅ , G ₆ Any one or any of the linking groups formed with adjacent hetero atom groups may be stably present or degradable.
91. A bio-related substance modified by a polyfunctional polyethylene glycol derivative, characterized in that the bio-related substance modified by the polyfunctional polyethylene glycol derivative has a targeting function, and the general formula is as shown in formula (31) , the formula (32), the formula (33) or the formula (34);

    

    Wherein, LPEG is a linear spindle structure; LPEG is a monoblock, diblock, triblock or block fragment of 1-150 composed of polyethylene glycol or polyethylene glycol; the number of oxyethylene units in LPEG is An integer from 2 to 2000; the sum of the number of oxyethylene units of the linear PEG spindle and the four PEG branch chains does not exceed 5000;

    n ₁ , n ₂ , n ₃ , and n ₄ are respectively polymerization degrees of four PEG branching strands, each independently satisfying 2 to 2000, and may be the same or different from each other in the same molecule; LPEG and n ₁ , n ₂ , n ₃ The four PEG branching chains corresponding to n ₄ are each independently polydisperse or monodisperse;

    The structure of U ₁ is

    

    The structure of U ₂ is

    

    U ₀₁ and U ₀₂ are each independently a trivalent group; L ₁ , L ₂ , L ₃ and L ₄ are polyethylene glycols each having an alkyl group number of n ₁ , n ₂ , n ₃ , and n ₄ . The linking group of the unit, L ₅ , L ₆ is a linking group connecting the linear spindle polyethylene glycol unit, and L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ are each independently present or absent, and The same molecule may be the same or different from each other;

    q, q _t are each independently 0 or 1, and may be the same or different from each other in the same molecule;

    Z ₂ and Z _t are each independently a divalent linking group, and may be the same or different from each other in the same molecule;

    BD is a residue formed by the reaction of biologically relevant substances with H-type polyethylene glycol; TD is a targeting molecule and polyfunctionalized H a residue formed after the reaction of the polyethylene glycol;

    L and L _t are respectively a functional group in the H-type polyethylene glycol derivative or a linker formed by reacting the protected form with a biologically relevant substance or a targeting molecule;

    L ₀ and L _t0 are each independently a divalent linking group, and may be the same or different from each other in the same molecule;

    g ₀ , g _t are 0, 1 or 2 to 1000, and may be the same or different from each other in the same molecule;

    k ₃ , k ₄ , k ₅ , and k ₆ are each independently an integer of from 2 to 250, and in the same molecule, k ₃ , k ₄ , k ₅ , and k ₆ may be the same or different from each other;

    G ₃ , G ₄ , G ₅ , G ₆ are each independently a linking group of a trivalent or higher valence state, and their valence states are k ₃ +1, k ₄ +1, k ₅ +1, k ₆ +1; In the same molecule, G ₅ and G _{6 have} the same structural type, and G ₃ and G _{4 have} the same structural type;

    In the same molecule, LPEG, U ₁ , U ₂ , U ₀₁ , U ₀₂ , L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ , Z ₂ , Z _t , L, L _t , L ₀ , A linker formed by any one or any of L _t0 , G ₃ , G ₄ , G ₅ , G ₆ and an adjacent hetero atom group may be stably present or degradable.
92. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 91, wherein the targeting factor is selected from the group consisting of a polypeptide ligand, a small molecule ligand, and the like which is recognized by a cell surface receptor. Ligand and ligand variants, tumor angiogenesis targeting ligands, tumor cell apoptosis targeting ligands, disease cell cycle targeting ligands, disease receptor targeting ligands, kinase inhibitors or proteasome inhibitors, PI3K/Akt/mTOR inhibitors, angiogenesis inhibitors, cytoskeletal signaling inhibitors, stem cell and Wnt gene inhibitors, protease inhibitors, protein tyrosine kinase inhibitors, apoptosis inhibitors, MAPK inhibitors, cell cycle Regulatory inhibitors, TGF-beta/Smad inhibitors, neuronal signaling inhibitors, endocrine and hormone inhibitors, metabolic inhibitors, microbial inhibitors, epigenetic inhibitors, JAK/STAT inhibitors, DNA damage inhibitors, NF-κB inhibitors, GPCR & G Protein inhibitors, transmembrane transporter inhibitors, autophagy inhibitors, ubiquitin Ubiquitin inhibitors, multi-target inhibitors, receptors, antibodies, genes Targeting molecules, viruses, vaccines, biomacromolecular targeting factors, vitamins, targeted drugs;

    The targeting molecule is selected from any one of the following: a targeting molecule itself, a dimer or a multimer, a partial subunit or fragment, a precursor, an activated state, a derivative, an isomer, a mutant, an analog , a mimetic, a polymorph, a pharmaceutically acceptable salt, a fusion protein, a chemically modified substance, a recombinant substance, and an agonist, activator, activator, inhibitor of any one , antagonists, modulators, receptors, ligands or ligands, antibodies and fragments thereof, substrates for enzymes or enzymes.
93. The polyfunctional polyethylene glycol derivative-modified bio-related substance according to claim 91, wherein the target of the targeting factor is selected from the group consisting of CD3, CD11, CD20, CD22, CD25, CD30, CD33, CD41 , CD44, CD52, CD6, CD3, CD11a, Her2, GpIIb/IIIa, RANKL, CTLA-4, CO17-1A, IL-1β, IL-12/23, IL6, IL13, IL-17, Blys, RSV, IgE -25, integrin-α4, respiratory syncytial virus F protein, tumor necrosis factor alpha (TNFα), vascular endothelial growth factor, epidermal growth factor receptor (EGFR), FGR3, EGFL-7, interferon alpha .
94. The polyfunctional polyethylene glycol derivative-modified bio-related substance according to claim 91, wherein the targeted drug is selected from the group consisting of tamoxifen, raloxifene, toremifene, and fulvic Group, ectatinib, flumatinib, faritinib, furazolinib, sirbitinib, sovanidinib, erlotinib, erlitinib, plittinib, eptidini Nie, rofecoxib, sidini, imatinib, dasatinib, nilotinib, gefitinib, erlotinib, temsirolimus, everolimus, van der ta Nipa, lapatinib, vorinostat, romidepsin, bexarotene, aliviric acid, bortezomib, pralatrexate, sorafenib, sunitinib, pazopanib, Iplimma, Dini interleukin 2, sunitinib, Gleevec, Iressa, tamoxifen, tofacitinib, Temsirolimus, Velcade, apatinib, motetanil, endostatin, ziv -Aflibercept, brivanib, linifanib, tivozanib, vatarani, CDP791, crizotinib, Navitoclax, gossypol, Iniparib, perifosine, AN-152, vemurafenib, dalafini, ko Tinini, Binimetinib, Encorafenib, Palbociclib, LEE011, Salicin, Vintafolide, Erlotinib, Alfatinib, Lapatinib, Lanatinib, Axitinib, Marsetinib, Toc Vorinostat eranib , toltinib, cedibutib, reguginib, simasani, nilotinib, punatinib, bosutinib, carbaryl, cabotinib, ceritinib, yi Lutinib, capecitabine, tegafur, comprilidine disodium phosphate, vemurafenib, Vismodegib, anastrozole, Arimidex, exemestane, letrozole, denosumab, lenalidomide , Pomamide, Carfilzomib, Belinostat, Cabazitaxel, Abiraterone Acetate, Dichloro Radium 233 injection, luteinizing hormone releasing hormone, midazoline, Oblimersen, Navitoclax, sectinib, Vismodegib, Marimastat, fucosyl GM1 composition, Alvocidib, havopiridol, vincristine, tipidifoni, Depsipeptide, BSU21051, cationic porphyrin compound, UCN-01, ICR-62, piratinib, PKI-166, carotinib, PD158780, HKI-357, ZD6126, amifostine, Ombrabulin, Cobb Statins, soblidotin, denibulin, Tozasertib, decitabine, AEE788, Orantinib, SU5416, Enzastaurin, oxaliplatin, celecoxib, aspirin, obatolcax, AT-101, tamoxifen, bicepoda, ro Non-Coxicam, NS-398, SC-58125, Batimastat, Promstat, metastat, neovastat, BMS-275291, Lonofani, BMS-214662, SCH44342, SCH54429, L-778123, BMS-214662, BMS- 185878, BMS-186511, BZA-5B, BzA-2B, 735, L-739, L-750, L-744832, B581, Cys-4-ABA-Met, Cys-AMBAMet, FTI276, FTI277, B956, B1096, Limonene, chiralin, genistein, erbstatin, lavendustin A, herbimycin A, tyr Phostin, PD169540, CL-387785, CP-358744, CGP59326, CGP59326-A, oleic acid A and B, mycomycin, marinin A and its analogues, lupin derivatives, CGS27023A, squalamine , Thalidomide, Cilengitide, Carboxylimidazole, Suramin, IM862, DS-4152, CM-101, Xinvastatin, PD98059, PD184352, Diazo tyrosine, Anti-pain, MT477, Benzopyrene Neomycin, geldellin, neocarcin, azacitidine, aclarin A, cholesterol derivative thioguanine, MCC465, liver-targeted carbamazepine, liver-targeted ricin, etopo Glycosides, teniposide, poloxamer, dexamethasone, talivirin, BIBW-2992, tumor necrosis factor alpha antibody, GRO-beta antibody, anti-CMV antibody, anti-CD3 monoclonal antibody, anti-human interleukin-8 Monoclonal Antibody, Anti-Tac Monoclonal Antibody, Respiratory Polysaccharide Virus Antibody, Abciximab, Rituximab, Trastuzumab, Teimomozumab, Tosimizumab, Alemtuzumab, Gitutobe Monoclonal antibody, cetuximab, bevacizumab, adalimumab, golimumab, basiliximab, infliximab, panitumumab, olva Anti-Dalibizumab, Ussuzumab, Nimotuzumab, Iodine [131I] rituximab, belimumab, ranibizumab, inotuzumab, obinutuzumab, ustekinumab, cetuximab, pertuzumab, nimotuzumab, edrecolomab, omalizumab, Ipilimumab, etanercept, certolizumab, tocilizumab, natalizumab, palivizumab, muromonab-CD3, siplizumab, eculizumab, canakinumab, afelimomab, mitumomab, olizumab, nofetumomab, arcitumomab, capromab, denosumab, efalizumab, afuutuzumab, ramucirumab, raxibacumab, siltuximab, fanolesomab, vedolizumab, Dorlimomab aritox, imciromab penetetate, alefacept, abatacept, belatacept, aflibercept, Zinapax, abagovomab, abx-il8, actoxumab, adecatumumab, alirocumab, anifrolumab, anrukinzumab, anti-LAG-3, apolizumab, bapineuzumab, bavituximab, benralizumab, bertilimumab, bezlotoxumab, Bispecific antibody MDX-447, blinatumomab, blosozumab, briakinumab, brodalumab, cantuzumab ravtansine, caplacizumab, carlumab, cd28-supermab, cixu Tumumab, clazakizumab, clenoliximab, clivatuzumab tetraxetan, conatumumab, crenezumab, dacetuzumab, dalotuzumab, daratumumab, demcizumab, dupilumab, ecromeximab, efungumab, eldelumab, elotuzumab/HuLuc63, enokizumab, ensituximab, epratuzumab, ertumaxomab, etaracizumab/etaratuzumab, etrolizumab, evolocumab, farletuzumab , fezakinumab, ficlatuzumab, figitumumab, flanvotumab, fontolizumab, fresolimumab, galiximab, ganitumab, gantenerumab, gavilimomab, girentuximab, glembatumumab vedotin, gomiliximab/lumiliximab, guselkumab, ibalizumab/Hu5A8, icrucumab, inclacumab, intetumumab, iratumumab, labetuzumab, lampalizumab, lebrikizumab, Lebrikizumab, lerdelimumab, lexatumumab, lirilumab, lorvotuzumab mertansine, lucatumumab, mapatumumab, margetuximab, matuzumab, mavrilimumab, metelimumab, milatuzumab, mitumumab, mogamulizumab, motavizumab, moxetumomab pasudotox, MSB0010718C, namilumab, naptumomab estafenatox, narnatumab, necitumu Mab, nesvacumab, nivolumab, ocaratuzumab, ocrelizumab, olaratumab, olokizumab, onartuzumab, oregovomab, otelixizumab, otlertuzumab, ozanezumab, pagibaximab, pascolizumab, pateclizumab, patritumab, pembrolizumab (lambrolizumab), pemtumomab, pexelizumab, pidilizumab, ponezumab, PRO 140, quilizumab, Racotumomab, reslizumab, rilotumumab, romosozumab, rontalizumab, ruplizumab, sarilumab, secukinumab, sevirumab, sibrotuzumab, sifalimumab, simtuzumab, sirukumab, solanezumab, stamulumab, tabalumab, tanezumab, tefibazumab, tenatumomab, teplizumab, teprotumumab, tigatuzumab, tildrakizumab, toralizumab, tralokinumab, tregalizumab, tremelimumab, tucotuzumab celmoleukin, tuvirumab, ublituximab, urelumab, vantictumab, visilizumab, volociximab , zalutumumab, zanolimumab, dorlimomab aritox, aducanumab, alacizumab pegol, anatumomab mafenatox, aselizumab, aselizumab, atinumab, atorolimumab, bectumomab, bivatuzumab mertansine, cantuzumabmertansine, cantuzumab mertansine, cedelizumab, cedelizumab, citatuzumab, bogatox, detumomab, drozitumab, duligotumab, dusigitumab, Edobacomab, elsilimomab, enoticumab, erlizumab, exbivirumab, faralimomab, fasinumab, felvizumab, foravirumab, fulranumab, futuximab, imgatuzumab, indatuximab ravtansine, indium (111in) altumomab pentetate, indium (111in) biciromab, indium (111In) biciromab, indium (111In) Igovomab, Indium(111In))satumomab pendetide, inolimomab, iodine(125I)CC49, itolizumab, keliximab, keliximab, lemalesomab, libivirumab, liligizumab, maslimomab, minretumomab, morolimumab, nacolomab tafenatox, nebacumab, nerelimomab, odulimomab, ontuxizumab, oportuzumab monatox, orticumab, Oxelumab, ozoralizumab, panobacumab, parsatuzumab, perakizumab, placulumab, priliximab (CMT 412), pritumumab, radretumab, rafivirumab, regavirumab, robatumumab, rovelizumab/leukarrest/Hu23F2G, samalizumab, solitomab, suvizumab, tacatuzumab tetraxetan, tadocizumab, talizumab/TNX-901 , taplitumomab paptox, technetium (99mTc) pintumomab, technetium (99mTc) sulesomab, technetium (99mTc) votumumab, telimomab aritox, teneliximab, tovetumab, urtoxazumab, vatelizumab, vepalimomab, vesencumab, zolimomab aritox.
95. A bio-related substance modified by a polyfunctional polyethylene glycol derivative, characterized in that the bio-related substance modified by the polyfunctional polyethylene glycol derivative has a fluorescent property, and the general formula is as in the formula (35), Formula (36), formula (37) or formula (38);

    

    Wherein, LPEG is a linear spindle structure; LPEG is a monoblock, diblock, triblock or block fragment of 1-150 composed of polyethylene glycol or polyethylene glycol; the number of oxyethylene units in LPEG is An integer from 2 to 2000; the sum of the number of oxyethylene units of the linear PEG spindle and the four PEG branch chains does not exceed 5000;

    n ₁ , n ₂ , n ₃ , and n ₄ are respectively polymerization degrees of four PEG branching strands, each independently satisfying 2 to 2000, and may be the same or different from each other in the same molecule; LPEG and n ₁ , n ₂ , n ₃ The four PEG branching chains corresponding to n ₄ are each independently polydisperse or monodisperse;

    The structure of U ₁ is

    

    U ₂ knot

    Constructed as

    

    U ₀₁ and U ₀₂ are each independently a trivalent group; L ₁ , L ₂ , L ₃ and L ₄ are polyethylene glycols each having an alkyl group number of n ₁ , n ₂ , n ₃ , and n ₄ . The linking group of the unit, L ₅ , L ₆ is a linking group connecting the linear spindle polyethylene glycol unit, and L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ are each independently present or absent, and The same molecule may be the same or different from each other;

    q, q _t are each independently 0 or 1, and may be the same or different from each other in the same molecule;

    Z ₂ and Z _t are each independently a divalent linking group, and may be the same or different from each other in the same molecule;

    BD is a residue formed by reacting a biologically relevant substance with H-type polyethylene glycol; FD is a residue formed by reacting a fluorescent substance with a polyfunctionalized H-type polyethylene glycol;

    L and L _t are respectively a functional group in the H-type polyethylene glycol derivative or a linker formed by reacting the protected form with a biologically relevant substance or a fluorescent substance;

    L ₀ and L _t0 are each independently a divalent linking group, and may be the same or different from each other in the same molecule;

    g ₀ , g _t are 0, 1 or 2 to 1000, and may be the same or different from each other in the same molecule;

    k ₃ , k ₄ , k ₅ , and k ₆ are each independently an integer of from 2 to 250, and in the same molecule, k ₃ , k ₄ , k ₅ , and k ₆ may be the same or different from each other;

    G ₃ , G ₄ , G ₅ , G ₆ are each independently a linking group of a trivalent or higher valence state, and their valence states are k ₃ +1, k ₄ +1, k ₅ +1, k ₆ +1; In the same molecule, G ₅ and G _{6 have} the same structural type, and G ₃ and G _{4 have} the same structural type;

    In the same molecule, LPEG, U ₁ , U ₂ , U ₀₁ , U ₀₂ , L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ , Z ₂ , Z _t , L, L _t , L ₀ , A linker formed by any one or any of L _t0 , G ₃ , G ₄ , G ₅ , G ₆ and an adjacent hetero atom group may be stably present or degradable.
96. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 95, wherein the G is a trivalent linking group, a tetravalent linking group, a pentavalent group, a hexavalent group, and a comb Any of a linking group of a structural structure, a linking group of a dendritic structure, a linking group of a hyperbranched structure, and a linking group of a cyclic structure.
97. The bio-related substance having a fluorescing property modified according to claim 95, wherein the fluorescent substance is selected from the group consisting of a fluorescent protein, a rhodamine, a phalloidin and a derivative thereof , rhodamine, cyanine dye, acridine, phycoerythrin, phycocyanin, methyl green, alizarin red, aniline blue, pyronine, fluorescein, hematoxylin, eosin, neutral red , Basic Fuchsin, Alexa Fluor Series, Oregon Green Series, BODIPY Series, Cy3, Cy3.5, Cy5, Cy5.5, Cy7, Cy7.5, Hex, PerCP, DAPI, Hoechst Series, Cascade Blue, Astrazon Series, SYTO series, stilbene, naphthalimide, coumarin, anthraquinone, phenanthridine, porphyrin, anthraquinone derivative, chromomycin A, ethidium bromide .
98. The bio-related substance modified by the polyfunctional polyethylene glycol derivative according to claim 95, wherein the fluorescent substance is selected from any one of the following: a fluorescent substance itself, a dimer or a polymer, and a part. Subunit or fragment, precursor, activated state, derivative, isomer, mutant, analog, mimetic, polymorph, pharmaceutically acceptable salt, fusion protein, chemically modified substance, genetic recombination Any of the substances.