WO2016050209A1 - Heterofunctionalized polyethylene glycol derivative, preparation method, and bio-related substance - Google Patents

Abstract

Disclosed are a heterofunctionalized polyethylene glycol derivative (formula I), a preparation method, and a bio-related substance modified by the derivative. The derivative has a Y-shaped structure, which is a branched central structure U_c constituted by a trivalent group U and linking groups L₁, L₂, and L₃, and is provided with two different functional groups F₁ and F₂; three PEG chains respectively have the degrees of polymerization of n₁, n₂, and n₃ and discretely have either polydispersity or monodispersity; extremities of the PEG chains respectively are connected to at least one functional group via branching groups G₁, G₂, and G₃; when g₁, g₂, and g₃ are 1, the extremities are provided with multiple active sites; the numbers of repeating units of bivalent linking groups L₄ and L₆ are p₁, p₂, and p₃; and, any one of the link groups or any linking group formed with an adjacent heteroatom group can either remain stable or be degraded. The functionalized polyethylene glycol is flexible and diverse in terms of branch structures and the lengths of branching arms, has various parameters and performance indicators that are adjustable and easy to control, and has a broad applicability.

Description

Heterofunctionalized polyethylene glycol derivative, preparation method and biological related substance thereof Technical field

The invention relates to the field of polymer synthesis, a heterofunctional polyethylene glycol derivative, a preparation method and a biological related substance thereof.

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. . Moreover, the distance between the single active group and the branching point is relatively close, and it is easily embedded by the polyethylene glycol chain, resulting in a large reaction steric hindrance when the PEGylation test is performed, and the modification efficiency is low.

Polyethylene glycol containing two different reactive groups can impart two different activities or functions to polyethylene glycol, also known as hetero-functionalization, which allows for the introduction of PEGylation of the drug. Functional groups such as targeting factors further improve the efficacy. 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 new type of heterofunctional polyethylene glycol, and to effectively combine high drug loading, effective protection of drug molecules, and high modification rate of PEGylation of drugs; The maintenance of activity, or how to achieve the release of highly active drugs, is also in need of improvement or resolution; and it is necessary to further reduce the side effects of the drug or 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 heterofunctional Y-type polyethylene glycol derivative, a preparation method, and a biologically relevant substance thereof, in order to overcome the deficiencies of the prior art.

The above object of the present invention is achieved by the following technical solutions:

A heterofunctional Y-type polyethylene glycol derivative having the general formula shown in formula (1):

Wherein n ₁ and n ₂ represent the degree of polymerization of the two PEG branching strands, each independently satisfying 2 to 2000, and n ₃ represents the degree of polymerization of the main chain PEG, which is 1 to 2000, and in the same molecule, n ₁ , n ₂ , n ₃ may be the same or different from each other; the PEG chains corresponding to n ₁ , n ₂ , and n ₃ are each independently polydisperse or monodisperse;

记为U_c；U为三价基团；Trivalent branched structure

Recorded as U _c ; U is a trivalent group;

L _1, L _2, L ₃ are the number of oxyethylene units connected to n _1, n _2, n linker polyethylene glycol units _3, are each independently present or absent and can be each other in the same molecule Same or different;

k ₁ , k ₂ , and k ₃ are each independently an integer of 1 or 2 to 250;

G ₁ , G ₂ , and G ₃ are each independently a linking group of a trivalent or higher valence state;

g ₁ , g ₂ , g ₃ are 0 or 1, and g ₁ = g ₂ ;

L ₄ and L ₆ are each independently a divalent linking group;

p ₁ , p ₂ , and p ₃ are each independently 0, 1, or 2 to 1000;

When g _i =0, k _i (i=1, 2, 3) is 1, and G _i does not exist at this time;

When g _i =1, k _i (i=1, 2, 3) is an integer of 2 to 250, in which case G _i exists, and the valence states of G ₁ , G ₂ , and G ₃ are respectively k ₁ +1, k ₂ +1, k ₃ +1;

且F₁≠F₂；其中，q、q₁各自独立地为0或1；Z₁、Z₂各自独立地为二价连接基；R₀₁为功能性基团或其被保护形式；同一分子中，F₁、F₂的Z₂、q、Z₁、q₁、R₀₁各自独立地相同或不同。Wherein F ₁ and F ₂ are each independently represented as

And F ₁ ≠F ₂ ; wherein, q, q ₁ are each independently 0 or 1; Z ₁ and Z ₂ are each independently a divalent linking group; R ₀₁ is a functional group or a protected form thereof; the same molecule In the above, Z ₂ , q, Z ₁ , q ₁ , and R _{01 of} F ₁ and F ₂ are each independently the same or different.

In the same molecule, U, L ₁ , L ₂ , L ₃ , L ₄ , L ₆ , G ₁ , G ₂ , G ₃ , Z ₁ (F ₁ ), Z ₂ (F ₁ ), Z ₁ (F ₂ ) The linker formed by any one or any of Z ₂ (F ₂ ) with an adjacent hetero atom group may be stably present or degradable.

A biologically related substance modified by a heterofunctional Y-type polyethylene glycol derivative, the general formula of which is represented by formula (6), (7) or (8):

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

其中，E₀₁为R₀₁、被保护的R₀₁、脱保护的R₀₁或被封端的R₀₁；Wherein, EF ₁ and EF ₂ are each independently expressed as

Wherein E ₀₁ is R ₀₁ , protected R ₀₁ , deprotected R ₀₁ or terminated R ₀₁ ;

Wherein n ₁ , n ₂ , n ₃ , L ₁ , L ₂ , L ₃ , U, g ₁ , g ₂ , g ₃ , k ₁ , k ₂ , k ₃ , G ₁ , G ₂ , G ₃ , L _4. The definitions of L ₆ , p ₁ , p ₂ , p ₃ , Z ₂ , q, Z ₁ , q ₁ , and R ₀₁ are the same as those of the general formula (1), and are not described herein again.

k ₁ , k ₂ , k ₃ , k ₄ , k ₅ , k ₆ are each independently an integer of 1 or 2 to 250;

G ₁ , G ₂ , G ₃ , G ₄ , G ₅ , G ₆ are each independently a linking group of a trivalent or higher valence state;

When g _i-3 =0, k _i (i=4, 5, 6) is 1, and G _i does not exist at this time;

When g _i-3 =1, k _i (i=4, 5, 6) is an integer of 2 to 250, and G _i exists, and the valence states of G ₄ , G ₅ , and G ₆ are respectively k ₄ +1. , k ₅ +1, k ₆ +1;

When g _i =0, k _i (i=1, 2, 3) is 1, and G _i does not exist at this time;

When g _i =1, k _i (i=1, 2, 3) is an integer of 2 to 250, in which case G _i exists, and the valence states of G ₁ , G ₂ , and G ₃ are respectively k ₁ +1, k ₂ +1, k ₃ +1;

Wherein D is a residue formed by reacting the modified bio-related substance with the hetero-functionalized Y-type polyethylene glycol. L is a functional group in a heterofunctional Y-type polyethylene glycol derivative or a linker formed by reacting the protected form with a biologically relevant substance;

Wherein, in the same molecule, D ₁ and D ₂ have the same Z ₂ , q, and D ₁ and D ₂ have the same or different L; in the same molecule, D of D ₁ and D ₂ are from the same biologically relevant substance, D of D ₁ and D ₃ are derived from different biologically related substances, and D of D ₂ and D ₃ are derived from different biologically related substances; wherein D ₁ and D ₂ may be residues formed by different reaction sites in the same molecule participating in the reaction. base;

In the general formula (6), D ₁ or D ₂ and D ₃ have the same or different Z ₂ , q, L;

In the general formula (7), D ₁ or D ₂ and EF ₂ have the same or different Z ₂ , q;

In the general formula (8), EF ₁ and D ₃ have the same or different Z ₂ , q;

Wherein, in the same molecule, U, L ₁ , L ₂ , L ₃ , L ₄ , L ₆ , G ₁ , G ₂ , G ₃ , G ₄ , G ₅ , G ₆ , Z ₂ (D ₁ ), Z ₂ (D ₂ ), Z ₂ (EF ₁ ), Z ₂ (D ₃ ), Z ₂ (EF ₂ ), L(D ₁ ), L(D ₂ ), L(D ₃ ), Z ₁ (EF ₁ ) The linker formed by any one or any of Z ₁ (EF ₂ ) with an adjacent hetero atom group may be stably present or degradable.

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

(1) On the basis of the conventional V-type polyethylene glycol, a third PEG chain, that is, the main chain in the present invention, is introduced between the functional group and the branching center, and the PEGylation modification is reduced. The reaction steric hindrance improves the modification efficiency. (2) The terminal functional group may be one or more, which increases the number of active groups in the polyethylene glycol, and can greatly increase the drug loading amount while improving the modification efficiency. (3) The diversity of preparation methods combined with multiple active sites allows modification of two different drug molecules or introduction of functional groups that promote drug efficacy, and can greatly enhance the drug loading while promoting drug loading. The effect of a functional group of pharmacodynamics. (4) The Y-type polyethylene glycol in the present invention can flexibly introduce a degradable group into a polyethylene glycol-modified bio-related substance in a polyethylene glycol structure and a subsequent application, allowing enzymes, light, temperature, Under acidic, alkaline, redox and other stimuli, the steric effect is weakened by the cleavage of the modified product into a low molecular weight product, or the highly active drug molecule is obtained by detachment of the modified biologically relevant substance from the polyethylene glycol; Generational dynamics or tissue distribution. (5) The heterofunctional design of the present invention allows the end of the polyethylene glycol chain of the unmodified bio-related substance to be substituted with a conventional methoxy end with a hydroxyl end, thereby reducing the immunogenicity of the modified drug. (6) The heterofunctional design of the present invention can modify two kinds of biologically related substances, so that functional molecules such as a targeting group and a fluorescent group can be introduced while modifying a drug molecule; introduction of a targeting group can improve tissue Distribution, weaken the impact on normal tissues, reduce toxic side effects; the 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.

还可以只被同一个杂原子取代，形成包括但不限于羰基、硫代羰基、亚氨基等结构的基团，如腺嘌呤、鸟嘌呤、胞嘧啶、尿嘧啶、胸腺嘧啶、N,N-二甲基鸟嘌呤、1-甲基鸟嘌呤、次黄嘌呤、1-甲基次黄嘌呤等。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, aromatic heteroalkyl, heteroarylalkyl, heteroaryl, heteroaryl, fused ring, Any one of a aryl group, a fused heterocyclic hydrocarbon group, an aromatic fused heterocycloalkyl group, a hetero fused heterocyclic hydrocarbon group 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 A propylene group, a butylene group, a pentylene group, a hexylene group, a heptylene group, an octylene group, an anthranylene group, an anthranylene group, and the like.

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

等。芳烃失去同一个芳环上的两个氢原子形成亚芳基，例如苯撑中的对苯撑

间苯撑

邻苯撑

当芳烃失去的两个氢原子一个位于芳环上，一个位于其脂肪烃基部分时，亚芳烃基，如

等。环状结构作为取代基的例子如

等。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.

支链(如

)或环状结构(如

)。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.

中，采用的

来标记二价连接基中连接其它基团位置。大多情况下，没有特别标记，如以下的苯撑结构

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 in the structural formula of some skeleton groups indicates that the skeleton is directly linked in the specified compound to the group shown in the structural formula.

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

表示任意的环状结构；

Represents an arbitrary ring structure;

表示脂肪族的环状结构，且不含任何芳环或杂芳环，也称脂肪族环；

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

表示芳香族的环状结构，至少含有一个芳环或杂芳环，也称芳香族环；

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

表示含环状单糖骨架的糖类或糖类衍生物的骨架，也称糖环；

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

表示环中含有酰胺键、酯键、酰亚胺、酸酐等化学键的环，也称缩合环；

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;

为水溶性聚合物的环状骨架，也称聚合物环；对水溶性聚合物的分子量没有特别限制。

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.

分别表示含氮原子、双键、偶氮基、三键、二硫键、共轭二烯键、酸酐、酰亚胺键、三氮唑的环状结构。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.

芳香族环

糖环

缩合环

聚合物环

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

属于脂杂环性质的环，鉴于其特殊性，有时仍将其单独作为一类列出。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:

等。

Wait.

Sugar rings, for example:

环糊精等。

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:

Examples of condensed rings are as follows:

等。

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 the structure is changed after chemical changes, but the entire linker is still only a complete linker, then the linker still falls into the category of "stably 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 speed of the degradation is not particularly limited, examples For example, it can be a rapid degradation under the action of an enzyme, or a 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.

又如赖氨酸骨架则为

这里不再逐一给出结构式。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.

又如肌氨酸(又名N-甲基甘氨酸)骨架

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 n ₁ , n ₂ , n ₃ of any one of the hetero-functionalized Y-type polyethylene glycol derivatives can be as follows: “satisfying 2 to 2000” or “for 2” The form of the integer "~2000". 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, published on Sep. 2, 2015), the disclosure of (including but not limited to aliphatic rings, aromatic rings, sugar rings, condensed rings, polymer rings, etc.), "stably stable", "degradable", "cyclic monosaccharides", "polydisperse" and "single "dispersed", 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 Partially excluding trivalent groups of heteroatoms and examples thereof, moieties other than trivalent core structures including trivalent groups of heteroatoms and examples thereof, trivalent branched structures, functional groups and protected forms thereof Examples of stable divalent linking groups, degradable divalent linking groups, degradable multivalent groups, terminally branched structures, and examples thereof (including but not limited to, cyclic structures, combs, dendrites, Hyperbranched, branched, etc.), biologically relevant substances The same may be simultaneously present in different functional group containing two or Small molecules of the same functional group, heterofunctionalized small molecules containing a trivalent core structure, terminal functionalization methods (linear functionalization and branched functionalization), and raw materials thereof. It should be noted that the preferred embodiments of the above-described structural examples are also included in the present invention.

1.1. A heterofunctional Y-type polyethylene glycol derivative having the general formula shown in formula (1):

Wherein n ₁ and n ₂ represent the degree of polymerization of the two PEG branched chains, each independently satisfying 2 to 2000, and n ₃ represents the degree of polymerization of the main chain PEG, which satisfies 1 to 2000, and in the same molecule, n ₁ , n ₂ , n ₃ may be the same or different from each other; the PEG chains corresponding to n ₁ , n ₂ , and n ₃ are each independently polydisperse or monodisperse;

记为U_c；U为所述异官能化Y型聚乙二醇衍生物的支化基团；U为三价基团；L₁、L₂、L₃分别为连接氧化乙烯基单元数为n₁、n₂、n₃的聚乙二醇单元的连接基，各自独立地存在或不存在，且在同一分子中可以彼此相同或不同；Trivalent branched structure

It is denoted as U _c ; U is a branching group of the heterofunctional Y-type polyethylene glycol derivative; U is a trivalent group; L ₁ , L ₂ and L ₃ are respectively connected to the oxyethylene unit number. The linking groups of the polyethylene glycol units of n ₁ , n ₂ , and n ₃ are each independently present or absent, and may be the same or different from each other in the same molecule;

k ₁ , k ₂ , and k ₃ are each independently an integer of 1 or 2 to 250;

G ₁ , G ₂ , and G ₃ are each independently a linking group of a trivalent or higher valence state;

g ₁ , g ₂ , g ₃ are 0 or 1, and g ₁ = g ₂ ;

L ₄ and L ₆ are each independently a divalent linking group;

p ₁ , p ₂ , and p ₃ are each independently 0, 1, or 2 to 1000;

When g _i =0, k _i (i=1, 2, 3) is 1, and G _i does not exist at this time;

When g _i =1, k _i (i=1, 2, 3) is an integer of 2 to 250, in which case G _i exists, and the valence states of G ₁ , G ₂ , and G ₃ are respectively k ₁ +1, k ₂ +1, k ₃ +1;

且F₁≠F₂；其中，q、q₁各自独立地为0或1；Z₁、Z₂各自独立地为二价连接基；R₀₁为功能性基团或其被保护形式；同一分子中，F₁、F₂的Z₂、q、Z₁、q₁、R₀₁各自独立地相同或不同，优选具有不同的R₀₁。Wherein F ₁ and F ₂ are each independently represented as

And F ₁ ≠F ₂ ; wherein, q, q ₁ are each independently 0 or 1; Z ₁ and Z ₂ are each independently a divalent linking group; R ₀₁ is a functional group or a protected form thereof; the same molecule In the above, Z ₂ , q, Z ₁ , q ₁ , and R _{01 of} F ₁ and F ₂ are each independently the same or different, and preferably have different R ₀₁ .

In the formula (1), F ₁ ≠F ₂ , which has one PEG main chain and two PEG branched chains, is named as a heterofunctional Y-type polyethylene glycol derivative.

In the same molecule, U, L ₁ , L ₂ , L ₃ , L ₄ , L ₆ , G ₁ , G ₂ , G ₃ , Z ₁ (F ₁ ), Z ₂ (F ₁ ), Z ₁ (F ₂ ) The linker formed by any one or any of Z ₂ (F ₂ ) with an adjacent hetero atom group may be stably present or degradable.

U, L ₁ , L ₂ , L ₃ , L ₄ , L ₆ , G ₁ , G ₂ , G ₃ , Z ₁ (F ₁ ), Z ₂ (F ₁ ), Z ₁ (F ₂ ), Z ₂ ( The conditions in which any one or any of F ₂ ) is bonded to an adjacent hetero atom group may be stably present or degradable without particular limitation, including but not limited to light, heat, enzyme, redox, acidity, and alkalinity. It can be stably present or degradable under physiological conditions, in vitro simulated environment, etc., preferably under the conditions of light, heat, enzyme, redox, acidity, alkaline, etc., or can be stably degraded.

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 heterofunctionalized Y-type polyethylene glycol, it has an important influence on the stability of the polymer and the releasability of the modified drug. (1) When degradation occurs between a functional group at the end of three polyethylene glycol chains and a polyethylene glycol chain, including L ₄ , L ₆ , G ₁ , G ₂ , G ₃ , Z ₁ ( At any position of F ₁ ), Z ₂ (F ₁ ), Z ₁ (F ₂ ), and Z ₂ (F ₂ ), the drug molecule and the polyethylene glycol structure are detached, and the active site of the drug molecule is exposed to the maximum extent. Especially in any of Z ₁ (F ₁ ), Z ₁ (F ₂ ), Z ₂ (F ₁ ), Z ₂ (F ₂ ), more particularly Z ₁ (F ₁ ), Z ₁ (F ₂ In any of the positions, when degradation occurs, the drug molecules can be as close as possible to the state before unmodification. (2) When degradation occurs in the middle of the Y-structure, including any of U, L ₁ , L ₂ , and L ₃ , the molecular weight of the drug-attachable polyethylene glycol is decreased, thereby reducing the wrapping of the drug. , to increase the efficacy; wherein, when degradation occurs at any of L ₁ , L ₂ , L ₃ , the drug molecule at the end of the polyethylene glycol modification may only have a linear polyethylene glycol chain, and the rest may The two branched chain ends forming the V-type polyethylene glycol carry the form of the drug molecule; and when the degradation occurs simultaneously at the L ₁ , L ₂ , and L ₃ , three linear polyethylene glycol modified drug conjugates are obtained. .

1.1.1. Degree of polymerization and dispersion of polyethylene glycol chains

In the formula (1), n ₁ and n ₂ represent the degree of polymerization of two PEG branched chains, each independently satisfying 2 to 2000, and may be the same or different from each other in the same molecule; n ₁ and n ₂ preferably satisfy 5 to 2000. More preferably, it satisfies 5 to 1000; more preferably 10 to 1000; more preferably 20 to 1000; more preferably 20 to 500; more preferably 50 to 500.

In the formula (1), n ₃ represents the degree of polymerization of the main chain PEG, and satisfies from 1 to 2,000. Preferably, it satisfies 2 to 2000 satisfaction. More preferably, it satisfies 5 to 2,000. More preferably, it is 5 to 1000. More preferably, it is 10 to 1000. More preferably, it satisfies 10 to 500. More preferably, it is 20 to 500.

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

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 .Chem. 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 heterofunctional Y-type polyethylene glycol of the formula (1) includes, but is not limited to, the following cases depending on the difference in the dispersibility of the PEG in the molecule:

(1) the PEG branching chain corresponding to the n ₁ or n ₂ is polydisperse,

The corresponding number average molecular weight 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.

(2) the PEG branching chain corresponding to n ₁ or n ₂ is monodisperse,

The n ₁ or n ₂ is preferably 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.

(3) the PEG backbone corresponding to the n ₃ is polydisperse,

The number average molecular weight thereof 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 chain corresponding to the n ₃ is monodisperse,

The n ₃ is preferably an integer of from 1 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.

(5) The PEG branching chain corresponding to n ₁ and n ₂ is polydisperse, and the PEG chain corresponding to n ₃ is monodisperse.

(6) The PEG branching chain corresponding to n ₁ and n ₂ is monodisperse, and the PEG chain corresponding to n ₃ is polydisperse.

(7) The PEG branching chain corresponding to n ₁ and n ₂ and the PEG chain corresponding to the n ₃ are all polydisperse.

(8) The PEG branching chain corresponding to n ₁ and n ₂ and the PEG chain corresponding to the n ₃ are monodisperse.

1.1.2. Branching groups U and G

U is a symmetric type or an asymmetric type.

Unless otherwise specified, for the trivalent group U, 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.

为例，其中存在两种不同类型的连接端，e1和e2。其作为三价基团U时，既可以由e1端指向主轴聚乙二醇单元，此时对应于对称型的U，也可以由任一个e2端指向主轴聚乙二醇单元，此时对应于不对称型的U。Trivalent group

As an example, there are two different types of connectors, e1 and e2. When it is a trivalent group U, it can be pointed from the e1 end to the main axis polyethylene glycol unit. In this case, it corresponds to the symmetric U, and can also be directed to the main axis polyethylene glycol unit by any e2 end. Asymmetrical U.

For the symmetrical U, when L ₁ = L ₂ , the heterofunctional Y-type polyethylene glycol derivative is specified in the present invention to have a symmetric branched structure. When L ₁ ≠ L ₂ , the heterofunctional Y-type polyethylene glycol derivative is specified to have an asymmetric branched structure.

When U is an asymmetric type, the heterofunctional Y-type polyethylene glycol derivative has an asymmetric branched structure.

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

U is selected from any of the trivalent groups in the set G ³ of the trivalent group.

Unless otherwise specified, for a k _i +1 (k _i = 2 to 250, i = 1, 2 or 3) valence group G _i , a polyethylene glycol unit may be directed to the branched chain from either of the linking ends. When marked with an asterisk *, the junction marked by an asterisk * points to the branched-chain PEG unit.

The structures of G ₁ , G ₂ , and G ₃ are not particularly limited, and each independently includes, but is not limited to, a branched, a ring-containing structure, a comb, a dendrimer, a hyperbranched, and the like. G ₁ and G ₂ preferably have the same structural type. The structure types of G ₁ and G ₃ may be the same or different.

为例，允许因重复单元数量不一致而产生的价态的不同。The same structural type, for example, is a three-branched structure, or a four-branched structure, or a comb-like structure, or a tree-like structure, or a hyperbranched structure, or a cyclic structure. . When the structure is not completely identical, the structure is mainly for comb, tree, hyperbranched, ring, etc., and the difference is in the valence state, in the comb structure.

As an example, the difference in valence states due to inconsistent number of repeating units is allowed.

In the formula (1), k ₁ , k ₂ and k ₃ represent the number of functional groups R _{01 to which} the terminal can be attached, and each independently is an integer of 1 or 2 to 250. When k _i (i=1, 2, 3), g _i =0, and G _i does not exist at this time;

When k _i (i=1, 2, 3) is an integer of 2 to 250, g _i =1, G _i exists at this time, and G _i is a linker whose valence state is k _i +1 . At this time, k _i 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 state of G _i is 3 to 251, that is, G _i is trivalent, tetravalent, pentavalent, hexavalent, seven-valent, eight-valent, nine-valent, ten-valent, eleven-valent, twelve-valent, ten Trivalent, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four , twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three or 34-251 Linker.

k ₁ , k ₂ , and k ₃ are each independently 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, it is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

(i＝1,2或3)中任一个k_i+1价基团。For any one k _i selected from 2 to 250, G _{i is} selected from the group of k _i +1 valence groups

Any one of (i = 1, 2 or 3) k _i +1 valence group.

(k＝2～250，i＝1,2或3)中的任一个k_i+1价基团的稳定性没有特别限制，可以为可稳定存在的基团或可降解的基团。所述可稳定存在的条件没有特别限制，优选在包括但不限于光、热、酶、氧化还原、酸性、碱性、生理条件、体外模拟环境等条件下可稳定存在，更优选在光、热、酶、氧化还原、酸性、碱性等条件下可稳定存在。所述可降解的条件也没有特别限制，优选在包括但不限于光、热、酶、氧化还原、酸性、碱性、生理条件、体外模拟环境等条件下可降解，更优选在光、热、酶、氧化还原、酸性、碱性等条件下可降解。set

The stability of any of the k _i +1 valence groups (k = 2 to 250, i = 1, 2 or 3) is not particularly limited, and may be a group which can be stably present 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, trivalent G _i (i = 1, 2 or 3) 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 .

也可以连接其它原子或基团，如三价碳原子核

三价硅原子核

三价磷原子核

等。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.

等。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.

也可以是多环，例如

可以是天然存在的环状结构，如来自任一环状单糖的任一个三价单环，举例如

等；也可以是经化学反应生成的环，如环肽、内酯、内酰胺、交酯等，举例如

被引出的共价单键可以直接从成环原子引出，可以通过不饱和键引出。被引出的三个共价单键，可同时从三个成环原子引出三个共价单键，如

也可以其中两个共价单键来自同一个成环原子

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 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 atoms of the ring in which M ₅ , M ₆ and M ₇ are located 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.

等。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.

为任一种脂环或脂杂环，且成环原子各自独立地为碳原子或杂原子；所述杂原子没有特别限定，包括但不限于氮原子、氧原子、硫原子、磷原子、硅原子、硼原子等。脂环的成环原子上的氢原子可以被任一取代原子或取代基取代，也可以不被取代。所述取代杂原子或取代基没有特别限制，包括但不限于术语部分列举的任一取代杂原子或任一取代基，选自卤素原子、烃基取代基、含杂原子的取代基中任一种。所述的脂环或脂杂环的定义在术语部分进行了详细定义，这里不再赘述。概况地讲，所述脂环与脂杂环包括但不限于单环、多环、螺环、桥环、稠环、碳环、杂环、脂杂环、杂单环、杂多环、杂螺环、杂桥环、杂脂环中任一种环状结构或任两种或两种以上环状类型的组合结构。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.

为任一种芳环或芳杂环，且成环原子各自独立地为碳原子或杂原子；所述杂原子没有特别限定，包括但不限于氮原子、磷原子、硅原子、硼原子等。芳环的成环原子上的氢原子可以被任一取代原子或任一取代基取代，也可以不被取代。所述取代杂原子或取代基没有特别限制，包括但不限于术语部分列举的任一取代杂原子或任一取代基，选自卤素原子、烃基取代基、含杂原子的取代基中任一种。所述取代原子优选卤素原子。所述取代基优选有助于不饱和键电子的诱导、共轭效应的基团。所述的芳环与芳杂环的定义在术语部分进行了详细定义，这里不再赘述。概况地讲，所述芳环与芳杂环：包括但不限于单环、多环、稠环、稠芳环、稠杂环、芳稠杂环、芳并杂环、苯并杂环、杂稠杂环、碳环、杂环、芳杂环、杂单环、杂多环、杂稠环、杂芳环中任一种环状结构或任两种或两种以上环状类型的组合结构。芳香族环优选上述的苯、吡啶、哒嗪、嘧啶、吡嗪、1,3,5-三嗪、四嗪(1,2,3,4-、1,2,4,5-和1,2,3,5-三种异构体)、茚、二氢化茚、吲哚、异吲哚、嘌呤、萘、二氢蒽、氧杂蒽(呫吨)、硫代呫吨、二氢菲、10,11-二氢-5H-二苯并[a,d]环庚烷、二苯并环庚烯、5-二苯并环庚烯酮、喹啉、异喹啉、芴、咔唑、亚氨基二苄、萘乙环、二苯并环辛炔、氮杂二苯并环辛炔等，任一种的被取代形式，或任一种的被杂化形式。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.

为具有环状单糖骨架的糖类或糖类衍生物的骨架。所述糖类或糖类衍生物来源为天然单糖或非天然单糖。所述环状单糖的结构为其同分异构体、手性异构体、旋光异构体、构象异构体、旋转异构体中任一种形式或任两种或两种以上的组合形式。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.

选自环状单糖或环状单糖衍生物的骨架、寡聚糖或寡聚糖衍生物的骨架、多糖或多糖衍生物骨架中任一种。

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.

其碳原子数为3、4、5、6或7，其结构为同分异构体、手性异构体、旋光异构体、构象异构体、旋转异构体中任一种形式或任两种或两种以上形式的组合形式。优选具有6个碳原子的环状单糖骨架的单糖或单糖衍生物，作为举例，包括但不限于葡萄糖、阿洛糖、阿卓糖、甘露糖、古洛糖、艾杜糖、半乳糖、塔罗糖、阿洛酮糖、果糖、山梨糖、塔格酮糖、肌醇中任一种单糖。 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.

其环状单糖骨架之间的组合方式包括但不限于线性、支化、超支化、树状、梳状、环状的方式。其单糖单元的个数为2～10。以环状方式为例，可以组合形成α-环糊精、β-环糊精、γ-环糊精中任一种环糊精或其衍生物。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.

其环状单糖骨架之间的组合方式包括但不限于线性、支化、超支化、树状、梳状、环状的方式。其单糖单元的个数为大于10。作为举例，如D-吡喃葡萄糖单元通过α-1,4糖苷键依次相连形成线性组合；上述线性结构首尾相连，则可以形成环状组合方式。又如，当至少一个D-吡喃葡萄糖单元之间通过α-1,2糖苷键、α-1,3糖苷键、α-1,4糖苷键、α-1,6糖苷键中至少两种与相连葡萄糖单元键合时，则形成支化或超支化组合方式。当所有的葡萄糖单元均通过特定的三个以上糖苷键以规则方式重复连接时，可形成梳状组合方式。具体地，作为举例，多糖或多糖衍生物可以为淀粉、几丁质、纤维素、葡聚糖中任一种。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.

为含有酰胺键、酯键、酰亚胺、酸酐等缩合形成的化学键的环。作为举例如内酯、内酰胺、环酰亚胺、环酸酐、环肽等。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.

中的任一种三价环状核结构。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 each independently more preferably 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 , aralkyloxycarbonyl, C _1-20 alkylthiocarbonyl, arylthiocarbonyl, aralkylthiocarbonyl, C _1-20 alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, C _1-20 heteroalkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, C _1-20 heteroalkylthiocarbonyl, heteroarylthiocarbonyl, heteroarylalkylthio Carbonyl, C _1-20 heteroalkylaminocarbonyl, heteroarylaminocarbonyl, heteroarylalkylaminocarbonyl, C _1-20 alkylthiocarbonyl, arylthiocarbonyl, aralkylthiocarbonyl, C _{1 -20} heteroalkylthiocarbonyl, heteroarylthiocarbonyl, heteroaralkylthiocarbonyl, C _1-20 alkoxythiocarbonyl, aryloxythiocarbonyl, aralkyloxythio Carbonyl, C _1-20 alkylthiothiocarbonyl, arylthiothio Carbonyl, aralkylthiothiocarbonyl, C _1-20 alkylaminothiocarbonyl, arylaminothiocarbonyl, aralkylaminothiocarbonyl, C _1-20 heteroalkyloxythiocarbonyl, Heteroaryloxythiocarbonyl, heteroaralkyloxythiocarbonyl, C _1-20 heteroalkylthiothiocarbonyl, heteroarylthiothiocarbonyl, heteroarylalkylthiocarbonyl a substituted form of any one of C _1-20 heteroalkylaminothiocarbonyl, heteroarylaminothiocarbonyl, heteroarylalkylaminothiocarbonyl or any of the groups.

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 A substituted form of any one or a group of 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 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. 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, a benzoyl group, a p-toluenesulfonic acid group, a methanesulfonic acid group, a methoxy group, or an ethoxy group. Alkyl, tert-butyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, methylthio, ethylthio, tert-butylthiocarbonyl, phenylthiocarbonyl, benzylthiocarbonyl, ethylamino Acyl, tert-butylaminocarbonyl, phenylaminocarbonyl, benzylaminocarbonyl, methyl, ethyl, n-propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, hydrazine Base, vinyl, propenyl, allyl, propynyl, propargyl, cyclopropyl, cyclopropenyl, phenyl, benzyl, butylphenyl, p-methylphenyl, methoxy, B Any one of an oxy group, a phenoxy group, a benzyloxy group, a methylthio group, an ethylthio group, a phenylthio group, a benzylthio group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, or the like. a group, or a substituted form of any group. 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.

包括但不限于以下结构及其被取代形式： 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.

的取代杂原子或取代基没有特别限制，包括但不限于术语部分列举的任一取代杂原子或任一取代基，选自卤素原子、烃基取代基、含杂原子的取代基中任一种。所述取代原子优选卤素原子。所述取代基优选有助于不饱和键电子的诱导、共轭效应的基团。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 Ethylthio Thiocarbonyl, tert-butylthiothiocarbonyl, phenylthiothiocarbonyl, benzylthiothiocarbonyl, methylaminothiocarbonyl, ethylaminothiocarbonyl, tert-butylaminothiocarbonyl, benzyl Aminothiocarbonyl, 2-methylsulfonylethyloxycarbonyl, C _1-10 halohydrocarbyl, trifluoroacetyl, 2-iodoethoxycarbonyl, halophenyl, halobenzyl, nitrate A substituted form of any one or a group of a benzyl group, a p-methoxybenzyl group, a trifluoromethylbenzyl group, or the like. 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 .

也可以连接其它原子或基团等。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.

等。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.

等；也可以是糖环，举例如

等；还可以为缩合环，举例如

等。 可以是天然存在的环状结构，如糖环；也可以是经化学反应生成的环，如

等。被引出的共价单键可直接从成环原子引出，也可通过不饱和键引出。任一个被引出的共价单键单独从一个成环原子引出，也可以两个共价单键同时从同一个成环原子引出。比较典型的CC₄的结构是同时从四个成环原子引出四个共价单键。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.

中任一种的四价环状核结构。CC _{4 is} selected from, but not limited to,

A tetravalent cyclic core structure of any one of them.

等。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,

又如来源于环肽的

等。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:

等。

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.

中任一种三价核结构。Taking k=2 as an example, U contains 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 A divalent linking group of a _1-6 alkylene group 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, the structure containing a C = N bond 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 hydrocarbon group, a substituted heteroaryl group, Heteroaromatic, substituted C _1-20 alkoxycarbonyl, substituted aryloxycarbonyl, substituted C _1-20 alkylthiocarbonyl, substituted arylthiocarbonyl, 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,

等。还包括但不限于专利文献CN104877127A第[0199]段公开的以下结构：

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

等。

Wait.

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

等。还包括但不限于专利文献CN104877127A第[0201]-[0202]段公开的以下结构：

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

等。上述举例为了更好地说明集合G³中三价基团的特点，并非对集合G³的范围进行限定。

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 , R ₃₇ , 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:

等。

Wait.

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

等。

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.

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.

可以看做由虚线分割的两个三价基团连接而成。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.

等。

Wait.

等。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:

等。其中，X₁的定义与上述一致。

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,

等。

Wait.

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

等。

Wait.

的同分异构结构包括但不限于D-核糖、D-阿拉伯糖、D-木糖、D-来苏糖的五价碳骨架。五价基团还包括但不限于六元环状单糖如葡萄糖、阿洛糖、阿卓糖、甘露糖、古洛糖、艾杜糖、半乳糖、塔罗糖、阿洛酮糖、果糖、山梨糖、塔格酮糖等的五价骨架结构。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,

等。还包括但不限于

来自肌醇、山梨糖醇、甘露醇、D-葡糖胺、1-巯基山梨糖醇、N-甲基-D-葡糖胺、磷酸三(2,3-二氯丙基)酯或3-磷酸D-山梨糖醇酯的脱除位于羟基、氨基或/及巯基的6个氢原子后的六价骨架结构，来自D-阿洛糖、D-阿卓糖、D-葡萄糖、D-甘露糖、D-古洛糖、D-艾杜糖、D-半乳糖、D-塔罗糖、D-阿洛酮糖的六价碳骨架等。

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,

等。

Wait.

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

等。

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 _The combination of ₁₀ k+1 groups of indirectly combined G ^k+1 and 3 to 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 3 to 150; preferably 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:

等。

Wait.

Comb combination method, for example:

等。

Wait.

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:

等。其中ng为1、2、3、4、5或6。

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

时的超支化结构：Hyperbranched combination method, for example, has the following repeating unit structure

Hyperbranched structure:

等。

Wait.

Ring combination, as for example

环糊精骨架等。

Cyclodextrin skeleton and the like.

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

Wherein n ₆ is an integer of from 2 to 150; 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.

X _{10 is} more preferably 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. 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.

为环骨架中含水溶性嵌段的环结构，价态为n₅+1，且所有的支化点均来自成环原子。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, adjacent The manner of connection between the water-soluble blocks is not particularly limited and may be directly linked or may be linked 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.

其中X₉没有特别限定，只要在阴离子聚合条件下可稳定存在即可。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.

的水溶性嵌段包括但不限于来源于以下寡聚物或聚合物的环状结构：聚乙二醇、聚乙烯醇、聚丙烯酸、聚甲基丙烯酸甲酯、聚甲基丙烯酸乙酯、聚丙烯酰胺、聚N-异丙基丙烯酰胺、聚甲基丙烯酸羟乙酯、聚羟基乙酸、聚羟基丁酸酯、聚富马酸丙二醇酯、聚乙烯吡咯烷酮、水溶性多糖、壳聚糖、葡聚糖、聚氨基酸、聚肽、羧甲基淀粉、醋酸淀粉、羟甲基纤维素、羧甲基纤维素、环糊精、环肽等。优选聚乙二醇、聚氨基酸、环糊精、聚肽、环糊精、环肽、聚羟烷基甲基丙烯酰胺、聚羟烷基甲基丙烯酸酯、聚α-羟基酸、聚磷腈、聚恶唑啉、聚N-丙烯酰吗啉等。优选聚乙二醇、取代的聚乙二醇、聚赖氨酸、聚肽、环糊精或环肽。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 groups and their protected forms R ₀₁

In the formula (1), 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 with them 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, acrylamide, acrylate, N-methyl acrylamide, methacrylate, norbornene-2-3-dicarboxyimino, maleamic acid, protected horse Imidide, 1,2,4-triazoline-3,5-dione, etc.;

Class F: cyano group, alkenyl group (including vinyl group, propenyl group, etc.), olefin group (such as allyl group), cycloalkenyl group (such as cyclooctene olefin, norbornene, etc.), alkynyl group, epoxy group, Azo group (such as linear azo compound, cyclic F10, etc.), diazo, dienyl, diolefin, tetrazolium, linear conjugated diene (such as linear butadienyl), oxidation Nitrile/cyanide, etc.;

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 , imidic acid, imidate, nitrone, hydrazine, urea, thiourea, pseudourea, isocyano, aldoxime, diazo, diazonium ion, oxidized azo, nitrile imine, N-oxidation Aldimine, tetrazole, 4-acetyl-2-methoxy-5-nitrophenoxy and its diazotized form; others may undergo a 1,3-dipolar cycloaddition functional group The group is also included in the present invention and is 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. The functional groups related to the click reaction reported in the article Adv. Funct. Mater., 2014, 24, 2572 and incorporated therein are incorporated herein by reference. CN is a precursor of its 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-rhodamine, 6-carboxy-X-rhodamine, Sulfonhodamine B, sulforhodamine G, sulforhodamine 101, rhodamine X (R101), rhodamine 101, rhodamine 110, rhodamine 123, rhodamine 700, rhodamine 800, etc., including but not It is limited to the rhodamine derivatives described in the literature "Progress in Chemistry, 2010, 22(10): 1929-1939" and its citations.

In the present invention, As a whole of a functional group or a protected form thereof. As an example,

包括但不限于活性酯中任一种的碳酸酯、乙酸酯、丙酸酯、丁酸酯、戊酸酯、己酸酯、庚酸酯、辛酸酯、壬酸酯、癸酸酯、乙二酸酯、丙二酸酯、甲基丙二酸酯、乙基丙二酸酯、丁基丙二酸酯、丁二酸酯、2-甲基丁二酸酯、2,2-二甲基丁二酸酯、2-乙基-2-甲基-丁二酸酯、2,3-二甲基丁二酸酯、戊二酸酯、2-甲基戊二酸酯、3-甲基戊二酸酯、2,2-二甲基戊二酸酯、2,3-二甲基戊二酸酯、3,3-二甲基戊二酸酯、己二酸酯、庚二酸酯、辛二酸酯、壬二酸酯、癸二酸酯、马来酸酯、富马酸酯、氨基酸酯、多肽酸酯、聚氨基酸酯等中任一种；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;

包括但不限于甲胺、乙胺、丙胺、丁胺、戊胺、己胺、庚胺、辛胺、环己胺、苯胺等一级胺失去非氨基氢原子获得的伯氨基或失去氨基氢原子获得的仲氨基，及二甲胺、二乙胺、二丙胺、二丁胺、二戊胺、二己胺、二庚胺、二辛胺、二环己胺、N-甲基苯胺、N-乙基苯胺、N-丙基苯胺、N-异丙基苯胺、N-丁基苯胺、N-环己基苯胺、氮杂环丁烷、吡咯烷、哌啶等二级胺失去非氨基氢原子获得的仲氨基。

还可以为氨基酸、氨基酸衍生物、ω-氨基羧酸(如β-丙氨酸、γ-丁氨酸、δ-戊氨酸、ε-己氨酸等)、多肽或多肽衍生物失去C-羧基或侧基羧基的羟基后形成的残基，此时R₀₁为N-氨基或侧基的氨基。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.

包括但不限于甲醛、乙醛、丙醛、丁醛、戊醛、己醛、庚醛、辛醛、壬醛、癸醛、巴豆醛、丙烯醛、异丁烯醛、2-乙基丙烯醛、一氯乙醛、碘乙醛、二氯乙醛、苯甲醛、苯乙醛、甲基苯甲醛、肉桂醛、硝基肉桂醛、溴苯甲醛、氯苯甲醛等失去一个非醛基氢原子(甲醛除外)后对应的一价功能性基团，依次对应甲醛基、乙醛基、丙醛基、丁醛基、戊醛基、己醛基、庚醛基、辛醛基、壬醛基、癸醛基、巴豆醛基、丙烯醛基、异丁烯醛基、2-乙基丙烯醛基、一氯乙醛基、碘乙醛基、二氯乙醛基、苯甲醛基、苯乙醛基、甲基苯甲醛基、肉桂醛基、硝基肉桂醛基、溴苯甲醛基、氯苯甲醛基等。如术语部分所述，当存在异构体等2种或2种以上结构形式时，可取其中任一种结构形式。作为举例，如所述丁醛包括但不限于正丁醛、异丁醛、2-甲基丙醛、2,2-二甲基乙醛。如所述戊醛包括但不限于正戊醛、2-甲基丁醛、异戊醛。如所述辛醛包括但不限于正辛醛、2-乙基己醛。如所述甲基苯甲醛包括邻甲基苯甲醛、间甲基苯甲醛、对甲基苯甲醛。如肉桂醛包括但不限于反肉桂醛。所述硝基肉桂醛包括但不限于反-2-硝基肉桂醛。如所述溴苯甲醛包括2-溴苯甲醛、3-溴苯甲醛、4-溴苯甲醛。如所述氯苯甲醛包括2-氯苯甲醛、3-氯苯甲醛、4-氯苯甲醛。如所述丙烯醛为

苯甲醛为

如所述间甲基苯甲醛为

如所述反肉桂醛，包括但不限于

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

包括但不限于甲酸、乙酸、丙酸、丁酸、戊酸、己酸、庚酸、辛酸、壬酸、癸酸、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸、油酸、花生酸、二十一烷酸、山嵛酸、异丁酸、3-甲基丁酸、丙烯酸、甲基丙烯酸、柠檬酸、乙烯基乙酸、顺芷酸、6-庚烯酸、衣康酸、香茅酸、一氯乙酸、二氯乙酸、一氟乙酸、二氟乙酸、苯甲酸、甲基苯甲酸、一氟代苯甲酸、乙氧基苯甲酸、甲氧基苯甲酸、乙基苯甲酸、乙烯基苯甲酸、丙基苯甲酸、2-异丙基苯甲酸、2-丁基苯甲酸、2-异丁基苯甲酸、氨基甲酰马来酸、N-苯基马来酸、马来酰胺酸、花生四烯酸、二十四烷酸、二十四烯酸(神经酸)、甘醇酸、乳酸、异烟酸、抗坏血酸、龙胆酸、葡萄糖酸、糖醛酸、山梨酸、N-(ω-氨基羧酸)基等一元酸失去一个非羧基氢原子后对应的一价功能性基团，以及二元酸脱除一分子羟基得到的二价功能性基团，所述二元酸包括但不限于乙二酸、丙二酸、甲基丙二酸、乙基丙二酸、丁基丙二酸、丁二酸、2-甲基丁二酸、2,2-二甲基丁二酸、2-乙基-2-甲基-丁二酸、2,3-二甲基丁二酸、戊二酸、2-甲基戊二酸、3-甲基戊二酸、2,2-二甲基戊二酸、2,3-二甲基戊二酸、3,3-二甲基戊二酸、己二酸、庚二酸、辛二酸、壬二酸、癸二酸、马来酸、富马酸、草酰乙酸、二甲基丙二酸、异丙基丙二酸、苄基丙二酸、1,1-环氧基二羧酸、1,1-环丁基二羧酸、二丁基丙二酸、乙基(1-甲基丙基)丙二酸、乙基(1-甲基丁基)丙二酸、乙基(异戊基)丙二酸、苯基丙二酸、2,2-二甲基丁二酸、2-氧代戊二酸、3-氧代戊二酸、5-降冰片烯-内-2,3-二羧酸、1,4-环己二羧酸、1,3-环己二酸、1,2-环己二酸、吡咯烷-3,4-二羧酸、樟脑酸、氯菌酸、环酸、5-甲基间苯二酸、邻苯二甲酸、4-甲基-1,2-苯二羧酸、4-氯邻苯二酸、3,4-吡啶二羧酸、2,3-吡啶二羧酸、2,4-吡啶二羧酸、3,5-吡啶二羧酸、2,6-吡啶二羧酸、2,4-二甲基吡咯-3,5-二羧酸、吡啶-2,3-二羧酸、5-甲基吡啶-2,3-二羧酸、5-乙基吡啶-2,3-二羧酸、5-甲氧基甲基-2,3-吡啶二羧酸、4,5-哒嗪二羧酸、2,3-吡嗪二羧酸、5-甲基吡嗪-2,3-二羧酸、4,5-咪唑二羧酸、2-丙基咪唑二羧酸、2-丙基咪唑二羧酸、联苯二甲酸、4,4'-二苯乙烯二羧酸、2,7-萘二羧酸、4,4'-二苯醚二甲酸、2,2'-联吡啶-5,5'-二羧酸、2,2'-联吡啶-3,3'-二羧酸、4-吡喃酮-2,6-二羧酸、邻苯二酚-O,O'-二乙酸、噻吩-2,3-二羧酸、2,5-噻吩二羧酸、2,5-二羧酸-3,4-乙撑二氧噻吩、1,3-丙酮二羧酸、亚甲基丁二酸、2-甲基-2-丁烯二酸(柠康酸和中康酸)、1,3-丁二烯-1,4-二羧酸、丁炔二酸、降冰片烯-2,3-二羧酸(双环[2.2.1]庚-5-烯-2,3-二羧酸)、双环[2.2.1]庚-2-烯-2,3-二羧酸、二甘醇酸、二硫醇二羟基乙酸、苹果酸、酒石酸、2,3-二巯基丁二酸、2,3-二溴丁二酸、吡唑解草酸、4,4'-二氯-2,2'-二羧基联苯、4,4'-二溴-2,2'-二羧基联苯、葡萄糖二酸、蔗糖酸、双羟萘酸、2-溴丁二酸、2-巯基丁二酸、1,3-金刚烷二羧酸、2,6-二甲基-1,4-二氢-3,5-吡啶二羧酸、羰基丙二酸、3-氧代戊二酸、乙氧基甲叉丙二酸、3,3'-二硫代二丙酸、5-exo-methyl-2-norbornene-5,6-endo-cis-dicarboxylicacid、乙酰基丙二酸等等。其中，作为举例，甲基苯甲酸包括邻甲基苯甲酸、间甲基苯甲酸、对甲基苯甲酸；一氟代苯甲酸包括2-氟苯甲酸、3-氟苯甲酸、4-氟苯甲酸；乙氧基苯甲酸包括邻乙氧基苯甲酸、间乙氧基苯甲酸、对乙氧基苯甲酸；甲氧基苯甲酸包括邻甲氧基苯甲酸、间甲氧基苯甲酸、对甲氧基苯甲酸；乙基苯甲酸包括邻乙基苯甲酸、间乙基苯甲酸、对乙基苯甲酸。脱除一分子羟基的二元酸的举例，如丙二酸，

对应

丁二酸对应

马来酸对应

等。

还可以为氨基酸、氨基酸衍生物、多肽或多肽衍生物失去N-氨基或侧基氨基的一个氢原子后形成的残基，此时R₀₁为C-羧基或侧基的羧基。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-pyridine Dicarboxylic 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-pyridazinedicarboxylic acid, 2,3-pyrazinedicarboxylic acid, 5-methyl Pyrazine-2,3-dicarboxylic acid, 4,5-imidazole dicarboxylic acid, 2-propylimidazole dicarboxylic acid, 2-propylimidazole dicarboxylic acid, diphenyl phthalic acid, 4,4'-diphenyl Ethylene dicarboxylic acid, 2,7-naphthalene dicarboxylic acid, 4,4'-diphenyl ether dicarboxylic acid, 2,2'-bipyridyl-5,5'-dicarboxylic acid, 2,2'-bipyridine- 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-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]g -5-ene-2,3-dicarboxylic acid), bicyclo[2.2.1]hept-2-ene-2,3-dicarboxylic acid, diglycolic acid, Mercaptan dihydroxyacetic acid, malic acid, tartaric acid, 2,3-dimercaptosuccinic acid, 2,3-dibromosuccinic acid, pyrazole oxalic acid, 4,4'-dichloro-2,2'-di Carboxybiphenyl, 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, ethoxylated fork Malonic acid, 3,3'-dithiodipropionic acid, 5-exo-methyl-2-norbornene-5, 6-endo-cis-dicarboxylic acid, acetylmalonic acid and the like. Among them, as an example, methylbenzoic acid includes o-methylbenzoic acid, m-methylbenzoic acid, p-methylbenzoic acid; monofluorobenzoic acid includes 2-fluorobenzoic acid, 3-fluorobenzoic acid, 4-fluorobenzene. Formic acid; ethoxybenzoic acid includes o-ethoxybenzoic acid, m-ethoxybenzoic acid, p-ethoxybenzoic acid; methoxybenzoic acid including o-methoxybenzoic acid, m-methoxybenzoic acid, Methoxybenzoic acid; ethyl benzoic acid includes o-ethyl benzoic acid, m-ethyl benzoic acid, 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 correspondence

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.

包括但不限于乙酰氯、乙酰溴、一氯代乙酰氯、二氯代乙酰氯、丙酰氯、丙酰溴、丁酰氯、3-环戊基丙酰氯、2-氯丙酰氯、3-氯丙酰、叔丁基乙酰氯、戊酰氯、己酰氯、庚酰氯、辛酰氯、壬酰氯、癸酰氯、月桂酰氯、肉豆蔻酰氯、棕榈酰氯、硬脂酰氯、油酰氯、山嵛酰氯、环戊烷甲酰氯、甲氧基乙酰氯、乙酰氧基乙酰氯等脱除1个氢原子获得的一价基团，以及乙二酰基、丙二酰基、甲基丙二酰基、乙基丙二酰基、丁基丙二酰基、丁二酰基、2-甲基丁二酰基、2,2-二甲基丁二酰基、2-乙基-2-甲基-丁二酰基、2,3-二甲基丁二酰基、戊二酰基、2-甲基戊二酰基、3-甲基戊二酰基、2,2-二甲基戊二酰基、2,3-二甲基戊二酰基、3,3-二甲基戊二酰基、己二酰基、庚二酰基、辛二酰基、壬二酰基、癸二酰基、马来酰基、富马酰基等二酰基与一个卤原子结合形成的酰卤基。这里二元酸的酰基指的是脱除2个羟基后的残基，如丙二酰基对应

When R01 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 acid halide group formed by combining a diacyl group such as methylglutaryl, adipoyl, pimeloyl, amlodiyl, azelane, azelayl, maleoyl or fumaryl with a halogen atom. Here, the acyl group of the dibasic acid refers to a residue obtained by removing two hydroxyl groups, such as a malonyl group.

包括但不限于乙酸酐、丙酸酐、丁酸酐、戊酸酐、己酸酐、庚酸酐、辛酸酐、壬酸酐、癸酸酐、月桂酸酐、肉豆蔻酸酐、棕榈酸酐、硬脂酸酐、山嵛酸酐、巴豆酸酐、甲基丙烯酸酐、油酸酐、亚油酸酐、亚油酸酐、氯乙酸酐、碘代乙酸酐、二氯乙酸酐、琥珀酸酐、甲基琥珀酸酐、2,2-二甲基琥珀酸酐、衣康酸酐、马来酸酐、戊二酸酐、二乙醇酸酐、苯甲酸酐、苯基琥珀酸酐、苯基马来酸酐、高酞酸酐、靛红酸酐、邻苯二甲酸酐等酸酐失去一个氢原子后对应的一价功能性基团。所述分子内酸酐还包括但不限于源于丁二酸酐、2,2-二甲基琥珀酸酐、环戊烷-1,1-二乙酸酐、1,1-环己基二乙酸酐、2-亚甲基丁二酸酐、戊二酸酐、卡龙酸酐、环丁烷-1,2-二甲酸酐、六氢邻苯二甲酸酐、甲基六氢邻苯二甲酸酐、1,2,3,6-四氢苯酐、1,2,5,6-四氢苯酐、3-甲基四氢苯二甲酸酐、甲基四氢邻苯二甲酸酐、柠康酸酐、2,3-二甲基马来酸酐、2,3-二氯马来酸酐、3,4,5,6-四氢苯酐、3-甲基邻苯二甲酸酐、4-叔丁基邻苯二甲酸酐、1,8-萘二甲酸酐、2,2'-联苯二甲酸酐、4-氟邻苯二甲酸酐、3-氟邻苯二甲酸酐、4-溴邻苯二甲酸酐、4-氯邻苯二甲酸酐、3,6-二氯邻苯二甲酸酐、3-硝基邻苯二甲酸酐、4-硝基邻苯二甲酸酐、4-溴-1,8-萘二甲酸酐、4,5-二氯-1,8-萘二甲酸酐、4-硝基-1,8-萘二甲酸酐、降冰片烯二酸酐、甲基内亚甲基四氢苯酐、去甲斑蝥素(7-氧杂二环[2.2.1]庚烷-2,3-二羧酸酐)、2,3-吡啶二羧酸酐、2,3-吡嗪二酸酐、苯并噻吨二羧酸酐等的酸酐。When R01 is an acid anhydride, it may be open-chain or may form 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'-diphenyl phthalic 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, norcantharidin (7- Oxabicyclo[2.2.1]heptane-2,3-dicarboxyl Anhydrides such as anhydrides, 2,3-pyridinedicarboxylic anhydride, 2,3-pyrazine dianhydride, benzothioxane dicarboxylic anhydride, and the like.

包括但不限于上述任一种分子内酸酐对应的酰亚胺形式，如琥珀酸酐对应的琥珀酰亚胺，马来酸酐对应的马来酰亚胺、邻苯二甲酸酐对应的邻苯二甲酰亚胺等，不再一一赘述。还包括但不限于邻磺酰苯甲酰亚胺。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.

包括但不限于来自3,4,5,6-四氢邻苯二甲酰亚胺、马来酰亚胺基乙酰基、3-马来酰亚胺基丙酰基、4-马来酰亚胺丁酰基、5-马来酰亚胺戊酰基、6-(马来酰亚胺基)己酰基、3-马来酰亚胺基苯甲酰基、4-马来酰亚胺基苯甲酰基、4-(N-马来酰亚胺基甲基)环己烷-1-甲酰基、4-(4-马来酰亚胺基苯基)丁酰基、11-(马来酰亚胺基)十一烷酸酰基、4-(4-马来酰亚胺基苯基)丁酰基、11-(马来酰亚胺基)十一烷酸酰基、N-(2-氨基乙基)马来酰亚胺、N-(4-氨基苯)马来酰亚胺、2-马来酰亚胺基乙基等的马来酰亚胺基。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.

包括但不限于甲腈、乙腈、丁腈、戊腈、己腈、庚腈、辛腈、壬腈、癸腈、十一烷基腈、烯丙基、丙烯腈、巴豆腈、甲基丙烯腈、二氯乙腈、氟乙腈、苯甲腈、苄基腈、甲基苄基腈、氯苯甲腈、甲基苯甲腈等氰基化合物失去一个氢原子后对应的一价功能性基团。 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.

包括但不限于乙炔基、丙炔基、炔丙基、环炔烃基等。When R ₀₁ is an alkynyl group,

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

包括但不限于甲醇、乙醇、丙醇、丁醇、戊醇、己醇、庚醇、辛醇、壬醇、癸醇、十一醇、十二醇、十三醇、十四醇、十五醇、十六醇、十七醇、十八醇、十八醇、油醇、苯甲醇、异丙苯醇、苯酚、甲酚、乙酚、丙酚、肉桂苯酚、萘酚、环戊醇、环己醇等一元醇失去一个非羟基氢原子后对应的一价功能性基团。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.

包括但不限于胆固醇的衍生物、胆甾醇基氢琥珀酸盐等分子修饰于PEG末端后形成的残基。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.

包括但不限于生物素-N-琥珀酰亚胺基酯、3-[3-[2-(生物素酰胺)乙基]氨基-3-氧代丙基]二硫基]丙酸琥珀酰亚胺酯、3-[[2-(生物素酰胺)乙基]二硫基]丙酸磺酸基琥珀酰亚胺酯、N-(3-叠氮丙基)生物素胺、N-生物素-3,6-二氧辛烷-1,8-二胺、N-生物素-3,6,9-三氧杂十一烷-1,11-二胺、生物素基-6-氨基喹啉、N-(6-[生物素胺]己基)-3'-(2'-吡啶二硫)丙酰胺、15-[D-(+)-生物素氨基]-4,7,10,13-四氧杂十五烷酸、3-(4-(N-生物素-6-氨基己羧基)苯基)丙酸、N-Fmoc-N'-生物素-L-赖氨酸、D-生物素酰肼、生物素-天冬氨酰-谷氨酰-缬氨酰-天冬氨醛等分子修饰于PEG末端后形成的残基。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.

包括但不限于5-羧基荧光素琥珀酰亚胺酯、6-羧基荧光素琥珀酰亚胺酯、5-氨基荧光素、6-氨基荧光素、5(6)-氨基荧光素、5-(氨基甲基)荧光素盐酸盐、6-([4,6-二氯三嗪-2-基]氨基)荧光素盐酸、5'-荧光素氨基磷酸酯、荧光素5-马来酰亚胺、荧光素6-马来酰亚胺、5-羧基荧光素、6-羧基荧光素、2,7-双(2-羧乙基)-5(6)-羧基荧光素、5-(4,6-二氯三嗪)氨基荧光素、CI 45350等分子修饰于PEG末端后形成的残基。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.

包括但不限于四甲基罗丹明、四乙基罗丹明(罗丹明B、RB200)、罗丹明3G、罗丹明6G(罗丹明590)、5-羧基-X-罗丹明、6-羧基-X-罗丹明、磺酰罗丹明B、磺酰罗丹明G、磺酰罗丹明101、罗丹明X(R101)、罗丹明101、罗丹明110、罗丹明123、罗丹明700、罗丹明800、5-羧基四甲基罗丹明、6-羧基四甲基罗丹明、5-羧基四甲基罗丹明琥珀酰亚胺酯、6-羧基四甲基罗丹明琥珀酰亚胺酯、5-羧基罗丹明6G琥珀酰亚胺酯、6-羧基罗丹明6G琥珀酰亚胺酯、四甲基罗丹明-5-马来酰亚胺、四甲基罗丹明-6-马来酰亚胺、6-羧基-X-罗丹明琥珀酰亚胺酯、四甲基罗丹明-5-异硫氰酸酯、四甲基罗丹明-6-异硫氰酸酯、四甲基罗丹明B-5-异硫氰酸酯、四甲基罗丹明B-6-异硫氰酸酯、氯化罗丹明101、磺化罗丹明B等分子修饰于PEG末端后形成的残基。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.

包括但不限于9-蒽甲醇、1-氨基蒽、2-氨基蒽、9-蒽甲醛、10-甲基蒽-9-甲醛、9-蒽甲酸、丙烯酸-9-蒽甲酯、甲基丙烯酸-9-蒽甲酯、9-蒽醛肟、9-蒽丙烯醛等分子修饰于PEG末端后形成的残基。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.

包括但不限于1-芘甲醇、7,8,9,10-四氢苯并[a]芘-7-醇、N-羟基琥珀酰亚胺酯1-芘丁酸、1-芘甲醛、1-芘丁酸、1-芘羧酸(1-芘甲酸)、1-芘乙酸、10-(1-芘)癸酸、1-芘十二酸、Fmoc-3-(1-芘基)-L-丙氨酸、叔丁基氧羰基-3-(1-芘基)-D-丙氨酸、叔丁基氧羰基-3-(1-芘基)-L-丙氨酸、1-氨基芘、1,3-二氨基芘、1,8-二氨基芘、1,6-二氨基芘、1-芘甲基胺、N-(1-芘基)马来酰亚胺等分子修饰于PEG末端后形成的残基。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.

包括但不限于咔唑、9-咔唑乙醇、2-羟基咔唑、2-(9H-咔唑基)乙基硼酸频哪醇酯、2-(9H-咔唑基)乙基硼酸二乙醇胺酯、N-氨基咔唑、9-(4-氨 基苯基)咔唑、9-咔唑乙酸等分子修饰于PEG末端后形成的残基。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.

包括但不限于4-(羟甲基)咪唑、4-羟乙基咪唑、1-(2-羟乙基)咪唑、1-甲基-2-羟甲基-1H-咪唑、1-(2-羟丙酯)咪唑、1-(β-羟乙基)-2-甲基咪唑、4-羟甲基-5-甲基-2-苯基咪唑、1-羟乙基-3-甲基咪唑、1-羟乙基-3-甲基咪唑氯盐、4-羟甲基-5-甲基咪唑、4-溴-1H-咪唑、2-溴-1H-咪唑、1-甲基-2-溴-1H-咪唑、5-氯-1-甲基咪唑、2-氨基咪唑、4-氨基咪唑、1-(3-氨基丙基)咪唑、1-甲基-4-咪唑甲酸、4-咪唑甲醛(4-甲酰基咪唑)、1-甲酰基咪唑、2-甲酰基咪唑、4-(咪唑-1-基)苯甲醛、1-甲基-2-咪唑甲醛、2-丁基-1H-咪唑-4-甲醛、5-甲基咪唑-4-甲醛、2-乙基-4-甲酰基咪唑、2-乙基-4-甲基-5-咪唑甲醛、1-苄基-1H-咪唑-5-甲醛、2-乙基-4-甲酰基咪唑、5-氨基-1H-咪唑-4-甲腈、组氨酸等分子修饰于PEG末端后形成的残基。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.

包括但不限于4-羟基吲哚、5-羟基吲哚、6-羟基吲哚、7-羟基吲哚、5-羟基-2-甲基吲哚、4-羟基-2-甲基吲哚、3-(2-甲基氨基乙基)吲哚、2-(2-氨基乙基)吲哚、3-(2-氨基乙基)-6-甲氧基吲哚、4-氨基吲哚、5-氨基吲哚、6-氨基吲哚、7-氨基吲哚、4-甲基-5-氨基吲哚、3-溴吲哚、4-溴吲哚、5-溴吲哚、6-溴吲哚、7-溴吲哚、5-溴-1-甲基-1H-吲哚、3-(2-氨基乙基)吲哚-5-醇、5-羟基吲哚-2-甲酸、6-羟基-2-吲哚甲酸、7-羟基吲哚-2-甲酸、5-溴吲哚-2-甲酸、6-溴吲哚-2-甲酸、7-溴吲哚-2-甲酸、5-溴吲哚-3-甲酸、6-溴吲哚-3-甲酸、4-溴吲哚-3-甲醛、6-溴吲哚-3-甲醛、5-溴-1H-吲哚-3-乙醇等分子修饰于PEG末端后形成的残基。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 functional groups and their protected forms 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:

等。

Wait.

等。

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 groups include, but are 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.

分别为环骨架上含有氮原子、双键、偶氮、三键、二硫键、酸酐、二烯的环状结构，包括但不限于碳环、杂环、苯并杂环、取代的碳环、取代的杂环或取代的苯并杂环等。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. And in the same molecule, R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ may be the same as each other or different

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

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 hydrocarbon group, a substituted heteroaryl group, Heteroaromatic, substituted C _1-20 alkoxycarbonyl, substituted aryloxycarbonyl, substituted C _1-20 alkylthiocarbonyl, substituted arylthiocarbonyl, 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 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 linking thio end group 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 Aminocarbonyl, C _1-20 alkylthiocarbonyl, arylthiocarbonyl, aralkylthiocarbonyl, C _1-20 heteroalkylthiocarbonyl, heteroarylthiocarbonyl, heteroarylalkylsulfide Carbonyl, C _1-20 alkoxythiocarbonyl, aryloxythiocarbonyl, aralkyl Alkylthiocarbonyl, C _1-20 alkylthiothiocarbonyl, arylthiothiocarbonyl, aralkylthiothiocarbonyl, C _1-20 alkylaminothiocarbonyl, arylaminothio 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 heterohydrocarbyl group, a substituted hydrocarbyl group or a substituted heterohydrocarbyl 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 located 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.

以D8为例，对应于

PG₈也可以为两个或三个独立的端基，相应地，D8对应于

H5对应于

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, benzyl thiomethyl sulfide, benzene Thiomethylthioether, tetrahydrothiazole sulfide, acetamidomethyl sulfide, trimethylacetamidomethyl sulfide, benzamide methyl sulfide, allyloxycarbonyl aminomethyl sulfide 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, acetyl Thiothioester, benzoyl thioester, trifluoroacetyl thioester, N-[(p-biphenyl)isopropoxycarbonyl]-N-methyl-γ-aminothiobutyrate, N-(tert-Butoxycarbonyl)-N-methyl-γ-aminothiobutyrate, 2,2,2-trichloroethoxycarbonylthiocarbonate, tert-butoxycarbonylthiocarbonate, benzyloxy Carbonylthiocarbonate, p-methoxybenzyloxycarbonylthiocarbonate, N-ethylcarbamate, N-methoxymethylcarbamate, ethyl disulfide, tert-butyl disulfide ,replaced 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.

氧基甲基醚、四氢吡喃基醚、3-溴四氢吡喃基醚、1-甲氧基环己基醚、4-甲氧基四氢吡喃环己基醚、4-甲氧基四氢噻喃基醚、S,S-二氧-4-甲氧基-四氢噻喃基醚、1-[(2-氯-4-甲基)苯基]-4-甲氧基哌啶-4-基醚、1-(2-氟苯基)-4-甲氧基哌啶-4-基醚、1,4-二噁烷-2-基醚、四氢呋喃基醚、四氢噻吩基醚、乙氧基醚、1-乙氧基乙基醚、1-(2-氯乙氧基)乙基醚、1-[2-(三甲硅基)乙氧基]乙基醚、1-甲基-1-甲基乙基醚、1-甲基-1-苄基乙基醚、1-甲基-1-苄基-2-氟乙基醚、1-甲基-1-苯氧乙基醚、2,2,2-三氯乙基醚、1,1-二甲氧基苯基-2,2,2-三氯乙基醚、1,1,1,3,3,3-六氟-2-苯基异丙基醚、2-三甲硅基乙基醚、2-(苄硫)乙基醚、2-苯硒乙基醚、叔丁基醚、烯丙基醚、炔丙基醚、对氯苯基醚、对甲氧基苯基醚、对硝基苯基醚、2,4-二硝基苯基醚、2,3,5,6-四氟-4-(三氟甲基)苯基醚、苄基醚、对甲氧基苄基醚、3,4-二甲氧基苄基醚、邻硝基苄基醚、对硝基苄基醚、对溴代苄基醚、对氯代苄基醚、2,6-二氯苄基醚、对氰基苄基醚、对苯基苄基醚、2,6-二氟苄基醚、对乙酰胺苄基醚、对叠氮基苄基醚、2-三氟甲基苄基醚、对-(甲亚磺酰基)苄基醚、2-吡啶甲基醚、4-吡啶甲基醚、3-甲基-2-吡啶甲基-N-氧化物醚、2-喹啉甲基醚、1-芘基甲基醚、二苯甲基醚、二(对硝基苯基)甲基醚、5-二苯并环庚基醚、三苯基甲基醚、α-萘基二苯甲基醚、对甲氧基苯基二苯基甲基醚、二(对硝基苯基)甲基醚、三(对甲氧基苯基)甲基醚、4-(4’-溴苯酰氧基)苯基二苯基甲基醚、4-(4’-溴苯酰氧基)苯基二苯基甲基醚、4,4’4”-三(4,5-二氯邻苯酰亚胺苯基)甲基醚、4,4’4”-三(乙酰丙酸苯基)甲基醚、4,4’4”-三(苯甲酰基苯基)甲基醚、4,4’-(二甲氧基-3”-N-咪唑甲基)三苯甲基醚、4,4’-(二甲氧基-3”-[N-(咪唑乙基)胺甲酰基]三苯甲基醚、1,1’-双(4-甲氧苯基)-1’-芘甲基醚、4-(17-四苯并[a,c,g,i]芴甲基)-4,4’-二甲氧基三苯甲基醚、9-蒽基醚、9-(9-苯基-10氧代)蒽基醚、1,3-苯并二硫杂环戊烷-2-基醚、苯并异噻唑基-S,S-二氧代醚、三甲基硅基醚、三乙基硅基醚、三异丙基硅基醚、二甲基异丙基硅基醚、二乙基异丙基硅基醚、1,1,2-三甲基丙基二甲基硅基醚、叔丁基二甲基硅基醚、叔丁基二苯基硅基醚、三苄基硅基醚、三对甲苄基硅基醚、三苯基硅基醚、二苯基甲基硅基醚、二叔丁基甲基硅基醚、三(三甲基硅基)硅基醚、2-羟基苯乙烯基-二甲基硅基醚、2-羟基苯乙烯基-二异丙基硅基醚、叔丁基甲氧基苯基硅基醚、叔丁氧基二苯基硅基醚、甲酸酯、苯甲酰甲酸酯、乙酸酯、氯乙酸酯、二氯乙酸酯、三氯乙酸酯、三氟乙酸酯、甲氧基乙酸酯、三苯甲氧基乙酸酯、酚氧乙酸酯、对氯苯氧乙酸酯、苯乙酸酯、二苯乙酸酯、尼古丁酸酯、3-苯丙酸酯、4-戊烯酸酯、4-乙酰丙酸酯、4,4-(乙二巯基)戊酸酯、5-[3-双(4-甲氧苯基)羟甲基酚基]乙酰丙酸酯、新戊酸酯、1-金刚烷甲酸酯、巴豆酸酯、4-甲氧基巴豆酸酯、苯甲酸酯、对苯基苯甲酸酯、2,4,6-三甲基苯基苯甲酸酯、烷基甲基碳酸酯、甲氧甲酯碳酸酯、9-芴甲酯碳酸酯、烷基乙酯碳酸酯、2,2,2-三氯乙酯碳酸酯、1,1-二甲基-2,2,2-三氯乙酯碳酸酯、2-(三甲硅基)乙酯碳酸酯、2-(苯磺酰基)乙酯碳酸酯、2-(三苯膦鎓)乙酯碳酸酯、异丁酯碳酸酯、乙烯酯碳酸酯、烯丙酯碳酸酯、对硝基苯基碳酸酯、对甲氧基苄酯碳酸酯、3,4-二甲氧基苄酯碳酸酯、邻硝基苄酯碳酸酯、对硝苄酯碳酸酯、2-丹酰乙基碳酸酯、2-(4-硝基苯基)乙基碳酸酯、2-(2,4-二硝基苯基)乙基碳酸酯、2-氰基-1-苯基乙基碳酸酯、S-苄基硫代酯碳酸酯、4-乙氧基-1-萘基碳酸酯、二硫代碳酸甲酯、2-碘苯甲酸酯、4-叠氮丁酸酯、4-硝基 -4-甲基戊酸酯、邻(二溴甲基)苯甲酸酯、2-甲酰基苯磺酸酯、2-(甲硫基甲氧基)乙基碳酸酯、4-(甲硫基甲氧基)丁酸酯、2-(甲硫基甲氧基甲基)苯甲酸酯、2-(氯已酰氧基甲基)苯甲酸酯、2-[2-(氯乙酰氧基)乙基]苯甲酸酯、2-[2-(苄氧基)乙基]苯甲酸酯、2-[2-(4-甲氧基苄氧基)乙基]苯甲酸酯、2,6-二氯-4-甲基苯氧乙酸酯、2,6-二氯-4-(1,1,3,3-四甲基丁基)苯氧乙酸酯、2,4-二(1,1-二甲基丙基)苯氧乙酸酯、氯代二苯基乙酸酯、异丁酸酯、丁二酸单酯、(E)-2-甲基-2-丁烯酸酯、巴豆酸酯、邻-(甲氧羰基)苯甲酸酯、苯甲酸酯、α-萘甲酸酯、硝酸酯、N,N,N’,N’-四甲基磷酰二胺、2-氯苯甲酸酯、4-溴苯甲酸酯、4-硝基苯甲酸酯、3’-5’-二甲氧基安息香碳酸酯、N-苯基氨基甲酸酯、硼酸酯、二甲基硫代膦酸酯、2,4-二硝基苯亚磺酸酯、硫酸酯、烯丙基磺酸酯、甲磺酸酯、苄基磺酸酯、对甲基磺酸酯、2-(4-硝基苯基乙基)磺酸酯。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-cyano Benzyl ether, p-phenylbenzyl ether, 2,6-difluorobenzyl ether, p-acetamide benzyl ether, p-azidobenzyl ether, 2-trifluoromethylbenzyl ether, p-(A) Sulfinyl)benzyl ether, 2-pyridylmethyl ether, 4-pyridylmethyl ether, 3-methyl-2-pyridylmethyl-N-oxide ether, 2-quinolinyl methyl ether, 1-芘Methyl ether, diphenyl methyl ether, di(p-nitrophenyl) methyl ether, 5-dibenzocycloheptyl ether, triphenyl methyl ether, α-naphthyl diphenyl methyl ether, P-methoxyphenyl diphenyl methyl ether, di(p-nitrophenyl) methyl ether, tris(p-methoxyphenyl) methyl ether, 4-(4'-bromophenyloxy) Phenyldiphenylmethyl ether, 4-(4'-bromophenoxy)phenyl diphenyl methyl ether, 4,4'4"-tris(4,5-dichlorophthalimide Phenyl)methyl ether, 4,4'4"-tris(levulinic acid phenyl)methyl ether, 4,4'4"-tris(benzoylphenyl)methyl ether, 4,4'- (Dimethoxy-3"-N-imidazolylmethyl)trityl ether, 4,4'-(dimethoxy-3"-[N-(imidazoliumethyl)amine A Acyl]trityl ether, 1,1'-bis(4-methoxyphenyl)-1'-indole methyl ether, 4-(17-tetrabenzo[a,c,g,i] armor -4,4'-dimethoxytrityl ether, 9-mercaptoether, 9-(9-phenyl-10oxo)nonyl ether, 1,3-benzodisulfide Pentan-2-yl ether, benzisothiazolyl-S,S-dioxane, trimethylsilyl ether, triethylsilyl ether, triisopropylsilyl ether, dimethylisopropyl Silyl ether, diethyl isopropyl silyl ether, 1,1,2-trimethylpropyldimethylsilyl ether, tert-butyldimethylsilyl ether, tert-butyl diphenyl silicon 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 Silyl ether, formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, Triphenylmethoxyacetate, phenolic oxyacetate, p-chlorophenoxy Acid ester, phenyl acetate, diphenyl acetate, nicotine acid ester, 3-phenylpropionate, 4-pentenoate, 4-acetylpropionate, 4,4-(ethylenedidecyl)pentanoic acid Ester, 5-[3-bis(4-methoxyphenyl)hydroxymethylphenolyl]levulinate, pivalate, 1-adamantanate, crotonate, 4-methoxy croton Acid ester, benzoate, p-phenyl benzoate, 2,4,6-trimethylphenyl benzoate, alkyl methyl carbonate, methoxy methyl carbonate, 9-armor 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-(triphenylphosphonium)ethyl carbonate, isobutyl ester carbonate, vinyl carbonate, allyl carbonate, Nitrophenyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-benzyl ester carbonate, 2-dansyl ethyl Carbonate, 2-(4-nitrophenyl)ethyl carbonate, 2-(2,4-dinitrophenyl)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-(chlorohexanoyloxy) 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-di(1,1-dimethyl Propyl phenoxyacetate, chlorodiphenylacetate, isobutyrate, succinic acid monoester, (E)-2-methyl-2-butenoate, crotonate, O-(methoxycarbonyl)benzoate, benzoate, α-naphthoate, nitrate, N,N,N',N'-tetramethylphosphoryl diamine, 2-chlorobenzate Acid ester, 4-bromobenzoate, 4-nitrobenzoate, 3'-5'-dimethoxybenzoin carbonate, N-phenylcarbamate, borate, dimethyl Thiophosphonate, 2,4- Nitrobenzene sulfinate, sulfate, allyl sulfonate, mesylate, benzyl sulfonate, p-methylsulfonate, 2-(4-nitrophenylethyl) sulfonic acid ester.

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)ethyl carbamate 2,2-bis(4'-nitrocarbamic acid) Ethyl ester, N-(2-pivaloyl)-1,1-dimethylethyl carbamic acid, 2-[(2 nitrophenyl)dithio]-1-phenyl carbamic acid Ester, 2-(N,N-dicyclohexylcarbamido)ethyl carbamate, tert-butyl carbamate, 1-adamantyl carbamate, 2-adamantyl carbamate, vinyl carbamate, amino Allyl formate, 1-isopropylallyl carbamate, cinnamyl carbamate, 4-nitrocinnamyl carbamate, 3-(3'-pyridyl) allyl carbamate, carbamate 8-quinolyl ester, N-hydroxypiperidinyl carbamate, methyl dithiocarbamate, ethyl dithiocarbamate, tert-butyl dithiocarbamate, isopropyl carbamate Alkyl dithioester, phenyl dithiocarbamate, benzyl carbamate, p-methoxybenzyl carbamate, p-nitrobenzyl carbamate, p-bromobenzyl carbamate, carbamate P-chlorobenzyl ester, 2,4-dichlorobenzyl carbamate, 4-methylsulfinyl benzyl carbamate, 9-fluorenyl methyl carbamate, amino diphenyl methyl ester, carbamate 2 -methyl sulfur Ethyl ester, 2-methylsulfonyl carbamate, 2-(p-toluenesulfonyl)carbamate, [2-(1,3-dithiohexyl)]carbamate, carbamate 4-methylthiophenyl ester, 2,4-dimethylthiophenyl carbamate, 2-phosphonium carbamic acid ethyl ester, 1-methyl-1-(triphenylphosphonium carbamic acid) Ethyl ester, 1,1-dimethyl-2-cyanoethyl carbamate, 2-dansyl ethyl carbamate, 2-(4-nitrophenyl)ethyl carbamate, 4-phenylacetyl carbamate Oxybenzyl ester, 4-azidomethoxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, methyl 5-benzoisoxazole carbamate, 2-(trifluoromethyl carbamate) Methyl ketone methyl ester, m-nitrophenyl carbamate, 3,5-dimethylbenzyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl) carbamate Ethyl ester, α-methyl nitropiperine carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, o-nitrophenyl methyl carbamate, 2-(2-nitrophenyl)ethyl carbamate, 6-nitro-3,4-dimethoxybenzyl carbamate, 4-methoxybenzoyl carbamate Ester, 3',5'-dimethoxybenzoin, uric acid tert-amyl ester, S-benzyl thiocarbamate, butynyl carbamate, p-cyanobenzyl carbamate, amino Cyclobutyl formate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropyl methyl carbamate, diisopropyl methyl carbamate, 2,2-dimethoxycarbonyl vinyl carbamate, O-(N,N'-dimethylamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furyl carbamate Ester, 2-iodoethyl carbamate, isobornyl carbamate, isonicotinoyl carbamate, p-(p-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(p-phenylazophenyl)carbamate, 1-methyl carbamate 1-phenylethyl ester, 1-methyl-1-(4'-pyridyl)ethyl carbamate, phenyl carbamate, p-phenylazobenzyl carbamate, carbamic acid 2,4,6 - Tri-tert-butylphenyl ester, 4-(trimethylammonium) carbamate Benzyl ester, 2,4,6-trimethylbenzyl carbamate, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropionamide, 4-pentyl Enamide, 2-pyridine amide, 3-pyridine amide, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, 3-o-nitrophenylpropionamide, 2 -Methyl-2-o-nitrophenoxypropanamide, 3-methyl-3-nitrobutyramide, o-nitrocinnamamide, o-nitrobenzamide, 2,2-dimethyl-3- (4-tert-butyl-2,6-dinitrophenyl)propanamide, o-(benzoyloxymethyl)benzoyl, (2-acetoxymethyl)benzoyl, 2-[(uncle Butyldiphenylsilyloxy)methyl]benzoyl, 3-(2',3',5'-trimethyl-3',6'-dioxo-1',4'-cyclohexane Alkenyl)-3,3-dimethylpropanamide; o-hydroxy-trans-cinnamamide, 2-methyl-2-o-phenylazophenoxypropionamide, 4-chlorobutyramide, acetoacetamide, 3 -p-hydroxyphenylpropionamide, (N'-dithiobenzyloxycarbonylamino)acetamide, phthalimide, tetrachlorophthalimide, 4-nitrophthalic acid Imine, dithiosuccinyl Imine, 2,3-diphenyl maleimide, 2,5-dimethylpyrrole, 2,5-bis(triisopropylsilyloxy)pyrrole, 1,1,4, 4-tetramethyldisiloxane-azacyclopentane, 1,1,3,3-tetramethyl-1,3-disilaisoindoline, 5-substituted-1,3-dimethyl -1,3,5-triazacyclopentan-2-one, 5-substituted-1,3-dibenzyl-1,3,5-triazacyclopentan-2-one, 1-substituted -3,5-dinitro-4-pyridone, 1,3,5-dioxane, methylamino, tert-butylamino, allylamino, [2-(trimethylsilane) Ethyl]methylamino, 3-acetoxypropylamino, cyanomethylamino, 1-isopropyl-4-nitro-2-oxo-3-pyrrolineamino, 2,4- Dimethoxybenzylamino, 2-azanorborneneamino, 2,4-dinitrophenylamino, quaternary ammonium, benzylamino, 4-methoxybenzylamino, 2,4-di Methoxybenzylamino, 2-hydroxybenzylamino, diphenylmethylamino, 2,4-dimethoxybenzylamino, 2-hydroxybenzylamino, diphenylmethylamino, bis (4- Methoxyphenyl)methylamino, 5-dibenzocycloheptylamino, triphenylmethylamino, (4-methoxyphenyl)diphenylmethylamino, 9 -phenylmercaptoamino, ferrocenylmethylamino, 2-pyridylmethylamine-N'-oxide, 1,1-dimethylthiomethyleneamine, benzylimine, p-methoxybenzyl Imine, diphenylmethyleneamine, [(2-pyridyl)trimethylphenyl]methyleneamine, N',N'-dimethylaminomethyleneamine, N', N'-dibenzyl Aminomethylmethyleneamine, N'-tert-butylaminomethyleneamine, isopropylenediamine, p-nitrobenzylimine, salicylaldimine, 5-chlorosalicyl imine, (5-chloro-2- Hydroxyphenyl)benzylimine, 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-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 containing Z ₁ and their protected forms

包括但不限于以下类A～类J中任一种类别中的任一种结构：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:

等。

Wait.

In the above class A to class J:

另一个为OH；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 group of any one of a group, a methylthio group, an ethylthio group, a phenylthio group, a benzylthio group, a methylamino group, an ethylamino group, a 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.

为例，则R₀₁为NH₂，q₁＝1，而前者的Z₁为亚甲基、后者的Z₁为亚乙基。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 ₁ =g ₂ =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 succinyl) Imino, -(Z ₂ ) _q -(Z ₁ ) _q1 - are 1,2-ethylene, methylene), propionaldehyde and butyraldehyde (corresponding to D5, R ₀₁ is 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 - When (Z ₁ ) _q1 - respectively methylene, 1,2-ethylene), q=0, q ₁ =1, Z ₂ are absent, have different Z ₁ , or take q=1, q ₁ =0, Z ₁ are absent and have different Z ₂ .

1.1.3.4. Heterofunctional Design - Heterofunctional Groups ("R ₀₁ Pairs")

F ₁ and F ₂ may have the same or different R ₀₁ , preferably have different R ₀₁ .

When R ₀₁ is the same, then -(Z ₂ ) _q -(Z ₁ ) _q1 - is different, and R ₀₁ is hydroxyl (H1), amino (C3), aldehyde (D5), succinimide active ester (A1 or A6) For example, the following is as follows:

等。

Wait.

When R _{01 is} different, the two R ₀₁ constituting the "R ₀₁ pair" are not particularly limited, and the two R ₀₁ are each independently selected from any one of the functional groups A to J or a protected form thereof, as long as It is allowed to exist at the same time stably. It should be noted that in the present invention, the stable existence of the functional group is different from the definition in which the linking group can be stably present. The stable presence of a functional group means a stable presence in the sense that no chemical change occurs. For example, the hydrogenation of an amino group is different from the original amino group by R ₀₁ , that is, the occurrence of aminohydrochlorination does not belong to a stable presence. Taking the R ₀₁ pair of maleimide and succinimide active ester as an example, for example:

To have the same -(Z ₂ ) _q -(Z ₁ ) _q1 - and different R ₀₁ , for example as follows:

Wherein g ₁ = g ₂ = g ₃ =0, q = 0, q ₁ =1, Z ₂ in F ₁ and F ₂ are absent, Z ₁ is all ethylene, and R _{01 in} F ₁ is R ₀₁ in the amino group (C3) and F ₂ is a fluorenyl group (C2).

To have different -(Z ₂ ) _q -(Z ₁ ) _q1 - and different R ₀₁ , for example as follows:

Wherein g ₁ = g ₂ = g ₃ =0, q = 0, q ₁ =1, Z ₂ in F ₁ and F ₂ are absent, and Z _{1 in} F ₁ is ethylene, in F ₂ Z ₁ is absent; R _{01 in} F ₁ is an aldehyde group (D5), and R _{01 in} F ₂ is an acrylate group (E2).

The heterofunctional group ("R ₀₁ pair") which may be present in the present invention includes, but is not limited to, including, but not limited to, a hydroxyl group and a protected hydroxyl group, a hydroxyl group or a protected hydroxyl group and a non-hydroxy group of the class A to class H. Reactive group (eg amino group, protected amino group, amine salt, aldehyde group, active ester group, maleimide group, carboxyl group, protected carboxyl group, alkynyl group, protected alkynyl group, azide group, An alkenyl group, an acryl group, an acrylate group, a methacrylate group, an epoxy group, an isocyanate group, etc.), a hydroxyl group or a protected hydroxyl group, and a functional group in the class I-class J or a derivative thereof (such as a target) a group, a photo-sensitive group, etc.), an active ester group and a maleimide group, an active ester group and an aldehyde group, an active ester group and an azide group, an active ester group and an alkynyl group or a protected alkynyl group , active ester groups and acrylate groups, active ester groups and methacrylate groups, active ester groups with acrylic groups, maleimide groups and azido groups, maleimido groups and alkynyl groups or protected Alkynyl, maleimide and acrylate groups, maleimide groups and methacrylate groups, maleic acid And an acrylic group, a maleimide group and a carboxyl group, a maleimide group and an amino group or a protected amino or amine salt, a maleimide group and an isocyanate group, a maleimide group and are protected Sulfhydryl, aldehyde and azide, aldehyde and acrylate, aldehyde and methacrylate, aldehyde and acrylate, aldehyde and epoxy, aldehyde and carboxyl, aldehyde and alkynyl or Protected alkynyl, azido and sulfhydryl or protected sulfhydryl, azido and amino or protected amino or amine salts, azide and acrylate groups, azido and methacrylate groups, stacks Nitrogen and acrylic, azide and carboxyl, acrylate and amino or protected amino or amine salts, acrylate and isocyanate groups, acrylate and epoxy groups, acrylate and methacrylate groups , acrylate and carboxyl groups, methacrylate groups and carboxyl groups, methacrylate groups and amino groups or protected amino or amine salts, methacrylate groups and isocyanate groups, methacrylate groups and epoxy groups, Alkynyl or protected alkynyl and amino groups or protected An amino or amine salt, an alkynyl group or a protected alkynyl group with an isocyanate group, an alkynyl group or a protected alkynyl group with an acrylate group, an alkynyl group or a protected alkynyl group with a methacrylate group, an alkynyl group or protected And alkynyl, alkynyl or protected alkynyl and epoxy, alkynyl or protected alkynyl and carboxy, protected alkynyl and azide, acrylate and isocyanate, acrylate Acrylate, acrylate and epoxy, acrylate and carboxyl, carboxyl and sulfhydryl or protected sulfhydryl, carboxy and amino or protected amino or amine salts, carboxyl and isocyanate, carboxy and epoxy, amino or A protected amino or amine salt with a thiol or protected thiol group, a targeting group and a non-hydroxyl reactive group, a photosensitive group and a non-hydroxyl reactive group, and the like.

The above active ester group may also be replaced by a similar structure of the active ester group; wherein the active ester includes, but is not limited to, any one of the succinimide active esters (such as succinimide carbonate groups) of the present invention, 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 or the like; a similar structure of the active ester group is selected from the group consisting of 2-thione-3-thiazolidinecarboxylate, 2-thioxothiazolidine-3-carboxylate, 2-thioketopyrrolidine-N- Carboxylic acid ester, 2-thioketopyrrolidine-1-carboxylate (2-thionebenzothiazole-N-formate), 2-thionebenzothiazole-N-formate, 1-oxo -3-thioxoisoindoline-N-formate or the like; the amino group includes a primary amino group and a secondary amino group. The amine salt is preferably in the form of the hydrochloride salt of an amino group such as NH ₂ HCl.

Wherein, the non-hydroxyl reactive group includes, but is not limited to, an amino group, a protected amino group, an aldehyde group, an active ester, a maleimide, a carboxyl group, a protected carboxyl group, an alkynyl group, a protected alkynyl group, an azide, An alkenyl group, an acrylic acid group, an acrylate group, a methacrylate group, an epoxy group, an isocyanate group or the like; the amino group includes a primary amino group and a secondary amino group.

1.1.4. Divalent linkage

L ₁ , L ₂ , L ₃ , L ₄ , L ₆ , Z ₁ (F ₁ ), Z ₂ (F ₁ ), Z ₁ (F ₂ ), and Z ₂ (F ₂ ) in the general formula (1) They are divalent linking groups and are independent of each other, and may be identical to each other or different in the same molecule. Wherein, Z ₁ is F ₁ or F ₂ in Z _1, Z ₂ is F ₁ or F ₂ in Z _2, denoted as _{Z 1 (F 1), Z} 1 (F 2), Z 2 (F 1 ), Z ₂ (F ₂ ).

The structures of L ₁ , L ₂ , L ₃ , L ₄ , L ₆ , Z ₁ (F ₁ ), Z ₂ (F ₁ ), Z ₁ (F ₂ ), and Z ₂ (F ₂ ) are not particularly limited, and are each independently The ground includes, but is not limited to, a linear structure, a branched structure, or a cyclic structure.

The number of non-hydrogen atoms of L ₁ , L ₂ , L ₃ , L ₄ , L ₆ , Z ₁ (F ₁ ), Z ₂ (F ₁ ), Z ₁ (F ₂ ), and Z ₂ (F ₂ ) is not particularly limited. Each of them is preferably independently from 1 to 50 non-hydrogen atoms; more preferably from 1 to 20 non-hydrogen atoms; more preferably from 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 ₁ , L ₂ , L ₃ , L ₄ , L ₆ , Z ₁ (F ₁ ), Z ₂ (F ₁ ), Z ₁ (F ₂ ), and Z ₂ (F ₂ ) each independently preferably have 1 to 50. a non-hydrogen atom; 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 the non-hydrogen atom is one, or two, or two More specifically, the non-hydrogen atom is a combination of a carbon atom and a carbon atom, a carbon atom and a hetero atom, and a hetero atom and a hetero atom.

The stability of L ₁ , L ₂ , L ₃ , L ₄ , L ₆ , Z ₁ (F ₁ ), Z ₂ (F ₁ ), Z ₁ (F ₂ ), and Z ₂ (F ₂ ) is not particularly limited, and Any divalent linking group or any divalent linking group consisting of an adjacent hetero atom group is a stable linker STAG or a degradable linker DEGG. 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.

Any of 0, ₁ , ₂ , L ₁ , L ₂ , L ₃ , L ₄ , L ₆ , Z ₁ (F ₁ ), Z ₂ (F ₁ ), Z ₁ (F ₂ ), Z ₂ (F ₂ ) 3, 4, 5, 6, 7, 8 or 9 divalent linking groups or a divalent linking group of the divalent linking group and an adjacent hetero atom group is a stable linker STAG, and the remaining divalent linkage The divalent linking group consisting of the divalent linking group and the adjacent hetero atom group is a destabilizable linking group DEGG.

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 _c (O-) ₃ of the present invention preferably does 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 heterofunctional Y-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 of L ₄ and L ₆ , and the remaining positions of the above-mentioned divalent linking groups may be stably present or degradable independently;

(4) Both L ₄ and L ₆ can be degraded, and the remaining divalent linking sites are independently stable or degradable;

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

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

(7) L ₃ or a linker formed with an adjacent hetero atom group may be degraded, and the remaining positions of the above divalent linkers may be independently present or degradable independently.

Regarding the position of degradability: (1) may be located in U, L ₁ , L ₂ , L ₃ , L ₄ , L ₆ , G ₁ , G ₂ , G ₃ , , (Z ₂ ) _q -(Z ₁ ) _q1 In any of the degradable groups, (2) may also occur at the junction of any of the above groups with an adjacent group, but does not limit the degradability of the bonding position of Z ₁ -R ₀₁ . 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 in UL _i (i=1, 2or3), L _i (i=1, 2or3)-O, O-(L ₄ ) _p1 , O-(L ₄ ) _p2 , O-(L ₆ ) _p3 , (L ₄ ) _{p1 -} G ₁ , (L ₄ ) _{p2 -} G ₂ , (L ₆ ) _{p3 -} G ₃ , G _{i -} Z ₂ (i = ₁ , 2or3), Z _{2 -} Z ₁ Debondation can occur independently of each of the attachment sites.

According to the difference in the number of degradable sites and the position of degradable sites in the heterofunctionalized Y-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 -(Z ₁ ) _q1 -, drug molecules and poly The detachment of the ethylene glycol structure maximizes the exposure of the active site of the drug molecule, and the drug molecule can be as close as possible to the state before unmodification. (2) When degradation occurs at the position of the trivalent branching center, including U, L ₁ , L ₂ , L ₃ , UL _i (i=1, 2or3), L _i (i=1, 2or3)-O In one position, the molecular weight of the drug-attachable polyethylene glycol is decreased, thereby reducing the encapsulation of the drug and increasing the efficacy.

Some typical degradation methods are as follows:

(a) g _i (i = 1, 2 or 3) = 0 or 1, and the divalent nuclear structure of the trivalent branched structure U _c degrades at the divalent junction between the PEG branching chain, at UL ₁ -O At least one position in UL ₂ -O is degradable;

(b) g _i (i=1, 2or3) = 0 or 1, and the divalent core structure of the trivalent branched structure degrades at the divalent junction between the trivalent core structure and the PEG backbone, and is degradable at the UL ₃ -O position ;

(c) g _i (i = 1, 2 or 3) = 0 or 1, the trivalent branched structure contains a cyclic trivalent core structure CC ₃ , and CC ₃ is degradable;

(d) g _i (i = 1, 2 or 3) = 0 or 1, degrading only at the position of -(Z ₂ ) _q -(Z ₁ ) _q1 -, which contains its adjacent group to the PEG side a connecting group formed;

(e) g _i (i=1, 2or3)=1, degrading only at the position between the PEG chain and the terminal branching structure, including O-(L ₄ ) _p1 and the linkage with G ₁ , O-(L ₄ ) _p2 and the linkage to G ₂ , O-(L ₆ ) _p3 and the linkage to G ₃ ;

(f) g _i (i=1, 2or3)=1, degradation occurs only in G(i=1, 2or3).

One or more types of degradation modes are allowed in the heterofunctional Y-type 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, U _c , the terminal branching structure G, or any of the divalent linking groups formed by the polyvalent group and the adjacent group.

1.1.6.1. Stable bivalent linker STAG

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 not limited to, an alkylene group, a divalent heteroalkyl group, a double bond, a triple bond, a divalent dienyl group, a divalent cycloalkyl group, a divalent cycloalkenyl group, and a divalent cycloalkenyl group. , a divalent cycloalkynyl group, an aromatic ring, an alicyclic ring, a hetero benzene ring, an arylheterocyclic ring, a hetero fused heterocyclic ring, a substituted alkylene group, a substituted heteroalkyl group, a substituted divalent heteroalkyl group, a substituted Double bond, substituted triple bond, substituted dienes, substituted divalent cycloalkyl groups, substituted divalent cycloalkenyl groups, substituted divalent cycloalkenyl groups, substituted divalent cycloalkynyl groups, substituted aromatic rings, Substituted aliphatic heterocycle, substituted heterophenyl ring, substituted arylheterocyclic ring, substituted heterofused heterocyclic ring, ether bond, thioether bond, urea bond, thiourea bond, carbamate group, thiocarbamate Acid ester group, -P(=O)-, -P(=S)-, divalent silicon group containing no active hydrogen, divalent linking group containing boron atom, secondary amino group, tertiary amino group, carbonyl group, thiocarbonyl group Any one or two or more atoms of an amino group, an amide group, a thioamide group, a sulfonamide group, an enamine group, a triazole, a 4,5-dihydroisoxazole, an amino acid and a derivative thereof A divalent group composed of a linking group.

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:

ω-氨基羧酸的骨架、含集合SG中至少一种氨基酸骨架氨基酸或氨基酸衍生物的二价连接基。所述ω-氨基羧 酸优选H₂N(CH₂)_j1COOH，其中，整数j₁选自2～20，优选2～12，更优选2～6，最优选2。-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.

的结构包括但不限于：亚甲基、

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.

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

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 _1-20 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, C _{3 . -20} 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 aliphatic acyl, heteroaryl acyl, heteroaryl Acyl, C _1-20 hydrocarbyloxyacyl, C _1-20 hydrocarbylthioacyl, C _1-20 hydrocarbylaminoacyl, C _1-20 hydrocarbyloxy, C _1-20 hydrocarbylthio, C _1-20 Any one or a group of a hydrocarbon acylamino group or the like, or a substituted form of any one of them. 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 _3-20 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 Any one or a group of an ethyl acylthio group, a phenyl acylthio group, an ethyl acylamino group, a phenyl acylamino group, a C _1-20 haloalkyl 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. 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.

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

为成环原子中含有M₁₇的环状结构，且选自C_1-20脂环、C_1-20脂杂环、C_1-20稠杂环中任一种或任一种的被取代形式。其中，取代杂原子或取代基没有特别限制，包括但不限于术语部分列举的任一取代杂原子或任一取代基，选自卤素原子、烃基取代基、含杂原子的取代基中任一种。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.

R₂₂为1,2-亚乙烯基时对应

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(R₂₀)-NH-或-NH-CH(R₂₀)-C(＝O)-；其中，R₂₀为-H、-CH₃、-CH(CH₃)₂、-CH₂-CH(CH₃)₂或-CH(CH₃)-CH₂CH₃；

-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(R₂₀)-NH-或-NH-CH(R₂₀)-C(＝O)-；其中，R₂₀为-CH₂-OH、-CH₂-OPG₄、 -CH₂-OR₃、-CH(CH₃)-OH、-CH(CH₃)-OPG₄、-CH(CH₃)-OR₃、-CH₂-SH、-CH₂-SPG₂、-CH₂-SR₃或-CH₂CH₂-S-CH₃；

-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.

括但不限于以下环状连接基：

As an example,

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

的定义与上述一致，这里不再赘述。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 Q definition, 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.

表示含三氮唑结构的杂芳环、稠杂环、取代的杂芳环或取代的稠杂环。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 examples are 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

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 not limited to, containing 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 disulfide group. Carbonate-based, trithiocarbonate, carbamate, thiocarbamate, dithiocarbamate, acetal, cyclic acetal, thioaldehyde, azaacetal , nitrogen heterocyclic acetal, nitrogen thioacetal, dithio acetal, hemiacetal, thio hemiacetal, aza hemiacetal, ketal, sulfur thione, aza ketal, nitrogen heterocycle Ketal, nitrogen thioketal, imine bond, hydrazone bond, hydrazide bond, hydrazone bond, thioxanthene group, hemocene bond, thioscarbazide bond, sulfhydryl group, hydrazide group, thiocarbon Acylhydrazide, azocarbonylhydrazide, thioazocarbonylhydrazide, fluorenylcarboxylate, mercaptothiocarbamate, carbazone, thiocarbazone, azo, isourea Base, isothiourea group, allophanate group, thiourea group, sulfhydryl group, fluorenyl group, amino fluorenyl group, amino fluorenyl group, imidic acid group, imidic acid thioester group, sulfonic acid Ester group, sulfinate group, sulfonyl hydrazide Base, sulfonylurea, maleimide, orthoester group, phosphate group, phosphite group, phosphite group, phosphonate group, phosphosilyl group, silane ester group, carbon amide, sulfur Amide, sulfonamide, polyamide, phosphoramide, phosphoramidite, pyrophosphamide, cyclophosphamide, ifosfamide, thiophosphoramide, aconityl, benzyloxycarbonyl, polypeptide fragments, nucleotides and a divalent linking group of any one of the derivative skeleton, the deoxynucleotide and its derivative skeleton, or any two or more degradable groups.

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:

此外，诸如

的连接基在生理条件下可稳定存在，但可在特殊光照条件下发生降解。普通的酯键除在酸、碱条件下可降解。而如苄氧羰基、

中的酯基，在特殊光照条件下也可发生降解(《Journal of Polymer Science:Part A:Polymer Chemistry,2008,46,6896-6906》)。-(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, phosphate group, phosphite group, phosphite group, phosphonate Base, phosphosilyl ester, silane ester group, carboxamide, thioamide, sulfonamide, polyamide, phosphoramide, phosphoramidite, pyrophosphoramide, cyclophosphamide, ifosfamide, thiophosphoramide, Aconityl, benzyloxycarbonyl, polypeptide fragments, divalent linking groups of nucleotides and derivatives thereof, divalent linking groups of deoxynucleotides and derivatives 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.

为可降解成至少两个独立的片段的环状结构。作为举例，例如交酯环、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,

其中，r3为2、3、4、5或6。R₃选为甲基、乙基或苄基。其中，M₁₅、PG₉、M₁₉、M₂₀、n₇的定义与上述一致，这里不再赘述。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)-, -O-Si(RR ₄₁ R ₄₂ )-O-, original Carbonate group, orthosilicate group, orthophosphate group, orthosulfate group, orthoester group, phosphate group, phosphite group, phosphite group, phosphonate group, phosphosilyl group, Silane ester group, carbon amide, thioamide, sulfonamide, polyamide, phosphoramide, phosphoramidite, pyrophosphoramide, cyclophosphamide, ifosfamide, thiophosphoramide, aconityl, benzyloxycarbonyl a divalent linking group of a polypeptide fragment, a nucleotide and a derivative thereof, a divalent linking group of a deoxynucleotide and a derivative thereof,

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.

)与可降解的二价连接基组合而成，举例如下：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.

)与可降解的二价连接基组成的可降解的U可举例如下：Among them, by a trivalent aromatic ring (such as

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

其中，Q、Q₂、R₁₃、R₁₄、X₁₀、M₁₉、M₂₀、M₁₅、PG₉、n₇的定义与上述一致，这里不再赘述。

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.

其中，M₁₉、M₂₀、M₁₅、PG₉、n₇的定义与上述一致，这里不再赘述。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 branching center structure U

U contains any of the following structures:

等。U进一步优选含有上述结构以选自氧基、硫基、仲氨基、二价叔氨基与羰基中1个、2个或3个相同或不同的二价连接基封端的结构；当参与构成活性阴离子聚合的引发剂分子时，进一步优选不含羰 基、仲氨基的结构。作为举例，U可选自以下任一结构：

等。当构成活性阴离子聚合的引发剂分子时，进一步优选不含羰基、仲氨基的结构。Q₅的定义与上述一致。

Wait. Further preferably, the structure further comprises a structure in which the above structure is 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; In the case of a polymerization initiator molecule, a structure containing no carbonyl group or secondary amino group is more preferable. By way of example, U can 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.

Branching group U is more preferred

U may also be selected from a trivalent skeleton structure of an amino acid or a derivative thereof, but does not participate in an initiator molecule constituting a 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 .

(记为U_c)各自独立地的包括但不限于：Specifically, the trivalent branch center structure

(Remarked as U _c ) each independently includes but is not limited to:

等。其中，Q₅为H原子、甲基、乙基或丙基；R₂₈为甲基、异丙基、异丁基。

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.

Branch center group U _c is preferred

1.1.8. Terminal branching structure G _i (i=1, 2or3) and examples thereof

The structure of G _i (i=1, 2or3) 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 or the like. G is degradable or stable.

L ₄ and L ₆ are divalent linking groups linking the PEG segment to the terminal branching structure G _i (i=1, 2or3), which may or may not be present. L ₄ and L ₆ may be stably present or degradable. L ₄ and L ₆ may be selected from any of the above STAG or DEGG.

The structural types of the terminal branching groups G _i (i=1, 2or3) 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 ends k _i (i=1, 2or3) may be unequal. For tree and ring structures, the structure is required to be completely consistent, and the corresponding k is also completely equal.

Let k be any one of k ₁ , k ₂ , and k ₃ . Let G be any one of G ₁ , G ₂ , and G ₃ .

等中任一种结构。When the terminal reaction site k=2, G is a trivalent group, including but not limited to the trivalent group, U, U _c in the above-mentioned set G ³ . (L ₄ ) _{p1 -} G ₁ , (L ₄ ) _{p2 -} G ₂ , and (L ₆ ) _{p3 -} G ₃ each independently preferably contain a structure selected from the group consisting of any of the above U, U _c ,

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 ₄ ) _{p1 -} G ₁ , (L ₄ ) _{p2 -} G ₂ , and (L ₆ ) _{p3 -} G ₃ each independently preferably contain any one of the following structures:

等。

Wait.

对于k+1价的核结构，当k≥4时，当含有k+1价核结构时，该k+1价核结构优选为环状结构。当含有两个或两个以上的L₁₀时，L₁₀可以彼此相同或不同。L₁₀的定义与上述一致。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 tree-like combined structure is preferably a trivalent G or a tetravalent G _i (i=1, 2or3).

等。其中，ng表示树状组合方式的代数。d表示树状组合方式的代数，d优选2～6代，更优选2～5代，最优选2、3或4代。其中，M₉为O、S或NX₁₀，其中X₁₀定义与上述一致。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.

等。支化或超支化组合结构与上述树状组合结构的区别在于其为多价G与其低价形式的混合式组合。所述多价G的低价形式，举例

的低价形式选自

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. The basic units of the polyvalent G constituting the comb-like combination structure include, but are not limited to, glycerin, pentaerythritol, substituted propylene oxide, a group of substituted propylene oxide and carbon dioxide, acrylates and derivatives thereof, methacrylates and derivatives thereof. a basic unit containing an acetal structure (such as (1→6) β-D-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 Things and so on. 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 set G ⁵ . The pentavalent G may include one pentavalent nuclear structure, one tetravalent nuclear structure and one trivalent nuclear structure, or three trivalent nuclear structures. (L ₄ ) _{p1 -} G ₁ , (L ₄ ) _{p2 -} G ₂ , and (L ₆ ) _{p3 -} G ₃ each independently preferably contain any one of the following structures:

3个三价G直接或间接组合而成的树枝状结构,3个三价G直接或间接组合而成的梳状结构等。其中，3个三价G直接或间接组合而成的树枝状结构的举例如上述代数d＝2的结构。3个三价基团直接组合而成的梳状结构，包括但不限于三聚赖氨酸骨架、三聚谷氨酸骨架、三聚天冬氨酸骨架、三聚甘油骨架等，如

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

3个三价基团间接组合而成的梳状结构，如由甘氨酸、丙氨酸等氨基酸作为间隔基组合在一起的三个赖氨酸等。

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.

等。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 ₄ ) _{p1 -} G ₁ , (L ₄ ) _{p2 -} G ₂ , and (L ₆ ) _{p3 -} G ₃ each independently preferably contain any one of the following structures: a comb of four trivalent Gs directly or indirectly combined Structure (for example, tetraglycerol, tetrapolylysine, tetrameric aspartic acid, tetrapolyglutamic acid, etc.),

Wait.

1.1.9. Different combinations of terminal structures of polyethylene glycol branches

1.1.9.1. When g ₁ =g ₂ =g ₃ =0, the general formula (1) is as shown in the general formula (2):

Wherein, the definitions of n ₁ , n ₂ , n ₃ , L ₁ , L ₂ , L ₃ , U, F ₁ , and F ₂ are the same as those of the general formula (1), and are not described herein again.

Any one or any of U, L ₁ , L ₂ , L ₃ , Z ₁ (F ₁ ), Z ₂ (F ₁ ), Z ₁ (F ₂ ), Z ₂ (F ₂ ) and an adjacent hetero atom group The linker formed by the group can be stably present or degradable.

1.1.9.2. When g ₁ = g ₂ =1 and g ₃ =0, the general formula (1) is as shown in the general formula (3):

Wherein, n ₁ , n ₂ , n ₃ , L ₁ , L ₂ , L ₃ , U, F ₁ , F ₂ , L ₄ , p ₁ , p ₂ , G ₁ , G ₂ are defined and the general formula (1) Consistent, no longer repeat them here. Here, k ₁ and k ₂ are each independently an integer of 2 to 250.

Any one of U, L ₁ , L ₂ , L ₃ , L ₄ , G ₁ , G ₂ , Z ₁ (F ₁ ), Z ₂ (F ₁ ), Z ₁ (F ₂ ), Z ₂ (F ₂ ) Or any of the linking groups formed with adjacent hetero atom groups may be stably present or degradable.

1.1.9.3. When g ₁ = g ₂ =0 and g ₃ =1, the general formula (1) is as shown in the general formula (4):

Wherein n ₁ , n ₂ , n ₃ , L ₁ , L ₂ , L ₃ , U, F ₁ , F ₂ , L ₆ , p ₃ , G ₃ , k _{3 have} the same meanings as in the general formula (1), here No longer.

Any one or any of U, L ₁ , L ₂ , L ₃ , L ₆ , G ₃ , Z ₁ (F ₁ ), Z ₂ (F ₁ ), Z ₁ (F ₂ ), Z ₂ (F ₂ ) The linker formed with an adjacent hetero atom group may be stably present or degradable.

1.1.9.4. When g ₁ = g ₂ = g ₃ =1, the general formula (1) is as shown in the general formula (5):

Wherein n ₁ , n ₂ , n ₃ , L ₁ , L ₂ , L ₃ , U, F ₁ , F ₂ , L ₄ , L ₆ , p ₁ , p ₂ , p ₃ , G ₁ , G ₂ , G ₃ , k ₁ , k ₂ , k ₃ are defined in accordance with the general formula (1), and are not described herein again.

U, L ₁ , L ₂ , L ₃ , L ₄ , L ₆ , G ₁ , G ₂ , G ₃ , Z ₁ (F ₁ ), Z ₂ (F ₁ ), Z ₁ (F ₂ ), Z ₂ ( The linker formed by any one or any of F ₂ ) with an adjacent hetero atom group may be stably present or degradable.

(U_c)＝

及通式(2)为例，则异官能化Y型聚乙二醇衍生物的结构分别如下所示：Take

(U _c )=

And the general formula (2) as an example, the structures of the heterofunctional Y-type polyethylene glycol derivatives are as follows:

及通式(3)为例，则异官能化Y型聚乙二醇衍生物的结构分别如下所示： Again

And the general formula (3) as an example, the structures of the heterofunctional Y-type polyethylene glycol derivatives are as follows:

In the general formulae (1) to (5), as a typical example, G ₁ = G ₂ , and G ₁ and G ₃ are each independently preferably one from the above-mentioned 1.1.8. part of the terminal branching structure, preferably three of them. A valence group, a tetravalent group, a pentavalent group, a hexavalent group, a dendritic structure.

As a typical example, G ₁ , G ₂ have a comb structure, or G ₃ has a comb structure; the comb structure includes, but is not limited to, any of the comb structures described in 1.1.9.

其中，X₁为氢原子或C_1-6烷基；R₁为C_1-6烷基；其中L₁₀的定义与上述一致，这里优选氧基。As a typical example, G ₁ and G ₂ have a hyperbranched structure, or G ₃ has a hyperbranched structure; the hyperbranched structure includes, but is not limited to, any of the above-mentioned 1.1.9. 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.

参与形成超支化结构的

的低价基团包括

举例如上述重复单元具有以下结构

时的超支化结构。By way of example, as shown in the following hyperbranched structure: the low-cost group of C participating in the formation of the hyperbranched structure is

Participate in the formation of hyperbranched structures

Low-priced groups include

For example, the repeating unit has the following structure

Hyperbranched structure.

g₁＝g₂＝1、g₃＝0、p₁＝p₂＝0及通式(3)为例，以G₁＝G₂，且 G₁＝G₂＝

或DENR(

NONE,2)，则异官能化Y型聚乙二醇衍生物的结构分别如下所示：Again

g ₁ =g ₂ =1, g ₃ =0, p ₁ =p ₂ =0 and the general formula (3) is taken as an example, with G ₁ =G ₂ and G ₁ =G ₂ =

Or DENR (

NONE, 2), the structure of the heterofunctional Y-type polyethylene glycol derivatives are as follows:

g₁＝g₂＝0、g₃＝1、p₃＝0及通式(4)为例，以

G＝DENR(

NONE,3)、

为例，则异官能化Y型聚乙二醇衍生物的结构分别如下所示：Take

g ₁ =g ₂ =0, g ₃ =1, p ₃ =0 and the general formula (4) is taken as an example to

G=DENR(

NONE, 3),

For example, the structures of the heterofunctional Y-type polyethylene glycol derivatives are as follows:

g₁＝g₂＝g₃＝1，p₁＝p₂＝1，L₄＝CONH(CH₂)₄NHCOO，G₁＝G₂＝

p₃＝2，L₆＝COCH₂NH，G₃＝DENR(

NONE,3)，M₉取O、S或NH为例，则通式(5)的结构表示如下：Again

g ₁ =g ₂ =g ₃ =1, p ₁ =p ₂ =1, L ₄ =CONH(CH ₂ ) ₄ NHCOO, G ₁ =G ₂ =

p ₃ = 2, L ₆ = COCH ₂ NH, G ₃ = DENR (

NONE, 3), M ₉ takes O, S or NH as an example, and the structure of the general formula (5) is expressed as follows:

The general formula (5) is further exemplified as follows:

1.2. The present invention also discloses a bio-related substance modified with a heterofunctional Y-type polyethylene glycol derivative. The generalized Y-type polyethylene glycol derivative modified bio-related substance has the general formula shown in formula (6), (7) or (8):

其中，E₀₁为R₀₁、被保护的R₀₁、脱保护的R₀₁或被封端的R₀₁；Wherein, EF ₁ and EF ₂ are each independently expressed as

Wherein E ₀₁ is R ₀₁ , protected R ₀₁ , deprotected R ₀₁ or terminated R ₀₁ ;

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

Wherein n ₁ , n ₂ , n ₃ , L ₁ , L ₂ , L ₃ , U, g ₁ , g ₂ , g ₃ , k ₁ , k ₂ , k ₃ , G ₁ , G ₂ , G ₃ , L _4. The definitions of L ₆ , p ₁ , p ₂ , p ₃ , Z ₂ , q, Z ₁ , q ₁ , and R ₀₁ are the same as those of the general formula (1), and are not described herein again.

Wherein k ₄ , k ₅ , k ₆ are the number of sites in the functional group or its protected form that actually react with the biologically relevant substance; wherein k ₄ , k ₅ , k ₆ are each independently 1 or an integer from 2 to 250. 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 ₄ , k ₅ , and k ₆ also represent the number of bio-related substance molecules bound in F ₁ or F ₂ . The functional group modified by the heterofunctionalized Y-type polyethylene glycol derivative or a protected form thereof may participate in all or part of the modification of a biologically relevant substance. It is preferred to participate in all modifications to biologically relevant substances. In a biologically related substance modified by a heterofunctional Y-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.

Wherein, the definitions of G ₄ , G ₅ , and G ₆ are the same as G, and each of them is independently a linking group of a trivalent or higher valence state, and the valence states thereof are k ₄ +1, k ₅ +1, and k ₆ +1;

When g _i-3 =0, k _i (i=4, 5, 6) is 1, and G _i does not exist at this time;

When g _i-3 =1, k _i (i=4, 5, 6) is an integer of 2 to 250, and G _i exists, and the valence states of G ₄ , G ₅ , and G ₆ are respectively k ₄ +1. , k ₅ +1, k ₆ +1.

Wherein D is a residue formed by reacting the modified bio-related substance with the hetero-functionalized Y-type polyethylene glycol. When there are multiple reaction sites in a biologically relevant substance, the same biologically relevant substance can be reacted with the same R ₀₁ to obtain the same or different residues. 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.

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%.

L is a linking group formed by a functional group in a heterofunctional Y-type polyethylene glycol derivative or a protected form thereof reacted with a biologically relevant substance. It can be a covalent connection or a non-covalent connection. A covalent linker is preferred; it may also be a hydrogen bond, and preferably 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. 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, and for both branched chains, it is preferred to have the same L. 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. For both branched chains, it is preferred that both L have the same stability, that is, both can be stably present or both can be degraded, and at this time, (Z ₂ ) _q -L at the end of the PEG chain also has the same stability.

Wherein, in the same molecule, D ₁ and D ₂ have the same Z ₂ , q, and D ₁ and D ₂ have the same or different L; in the same molecule, D of D ₁ and D ₂ are from the same biologically relevant substance, D of D ₁ and D ₃ are derived from different biologically related substances, and D of D ₂ and D ₃ are derived from different biologically related substances; wherein D ₁ and D ₂ may be residues formed by different reaction sites in the same molecule participating in the reaction. base;

In the general formula (6), D ₁ or D ₂ and D ₃ have the same or different Z ₂ , q, L;

In the general formula (7), D ₁ or D ₂ and EF ₂ have the same or different Z ₂ , q;

In the formula (8), EF ₁ and D ₃ have the same or different Z ₂ and q.

Wherein, in the same molecule, U, L ₁ , L ₂ , L ₃ , L ₄ , L ₆ , G ₁ , G ₂ , G ₃ , G ₄ , G ₅ , G ₆ , Z ₂ (D ₁ ), Z ₂ (D ₂ ), Z ₂ (EF ₁ ), Z ₂ (D ₃ ), Z ₂ (EF ₂ ), L(D ₁ ), L(D ₂ ), L(D ₃ ), Z ₁ (EF ₁ ) The linker formed by any one or any of Z ₁ (EF ₂ ) with an adjacent hetero atom group may be stably present or degradable.

U, L ₁ , L ₂ , L ₃ , L ₄ , L ₆ , G ₁ , G ₂ , G ₃ , G ₄ , G ₅ , G ₆ , Z ₂ (D ₁ ), Z ₂ (D ₂ ), Z ₂ (EF ₁ ), Z ₂ (D ₃ ), Z ₂ (EF ₂ ), L (D ₁ ), L (D ₂ ), L (D ₃ ), Z ₁ (EF ₁ ), Z ₁ (EF ₂ The condition in which any one or any of the linkages with adjacent hetero atom groups can be stably present or degradable is not particularly limited, and is preferably in the form of light, heat, enzyme, redox, acidity, basicity, physiological condition, in vitro It can be stably existed or degradable under simulated environment and the like, and is preferably stable or degradable under conditions of light, heat, enzyme, redox, acidity, alkalinity and the like.

In the same molecule, the structures of the branching groups G _i (i = 1 to 6) at the ends of the three PEG chains are each independently selected from, but not limited to, branched, ring-containing structures, combs, dendrimers, hyperbranched Any of the combinations.

It is preferred that the branching groups at the ends of the two branched chains in the same molecule have the same structural type, and the structural type of the branched group at the end of the main chain may be the same or different. For the general formulae (6) and (7), the G ₁ and G ₂ structural types in the same molecule are the same; and in the general formula (8), the G ₄ and G ₅ structural types in the same molecule are the same.

1.2.1. Branched structure at the end of the polyethylene glycol branching chain

以甘氨酸封端对应

又如，羟基可通过甲醇被甲基封端。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. Succinimide active ester

Glycine terminated

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

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. The definitions of F ₁ and F ₂ are identical to those of the general formula (1). When g ₁ =g ₂ =g ₃ =0, k ₁ =k ₂ =k ₃ =1, and EF ₁ is a hydroxyl group, D of D ₃ in the general formula (8) is not vitamin E.

且k₁≥k₄，且k₂≥k₅，且k₃≥k₆。其中，EF₄、EF₅、EF₆表示为

且EF₄＝EF₅，且EF₄与EF₆不同。则通式(6)、通式(7)、通式(8)的结构分别对应式(9)、式(10)、式(11)。G ₄ , G ₅ , and G ₆ are expressed as

And k ₁ ≥ k ₄ , and k ₂ ≥ k ₅ , and k ₃ ≥ k ₆ . Where EF ₄ , EF ₅ , and EF _{6 are} expressed as

And EF ₄ = EF ₅ , and EF ₄ is different from EF ₆ . The structures of the general formula (6), the general formula (7), and the general formula (8) correspond to the formula (9), the formula (10), and the formula (11), respectively.

Wherein D ₁ , D ₂ , and EF ₁ have the same Z ₂ , q, and D ₁ and D ₂ have the same D, and D ₁ and D ₂ have the same or different L; D ₃ and EF ₂ have the same Z ₂ , q.

Where k ₄ is preferably k ₄ =k ₁ , in this case corresponding to G ₄ =G ₁ ; k ₅ is preferably k ₅ =k ₂ , in this case corresponding to G ₅ =G ₂ ; k ₆ is preferably k ₆ =k ₃ , correspondingly G ₆ = G ₃ . Then, the general formula (6), the general formula (7), and the general formula (8) are preferably the general formula (12), the general formula (13), and the general formula (14):

When g ₁ =g ₂ =g ₃ =0, k ₁ =k ₂ =k ₃ =1, the structures of the general formula (6), the general formula (7), and the general formula (8) are expressed as a general formula (15, respectively). ), general formula (16), general formula (17).

及通式(15)为例，则异官能化Y型聚乙二醇衍生物的结构分别如下所示：Take

And the general formula (15) as an example, the structures of the heterofunctional Y-type polyethylene glycol derivatives are as follows:

When g ₁ = g ₂ =1, g ₃ =0, k ₃ =1, k ₁ , k ₂ , and k ₃ are integers of 2 to 250, the general formula (6), the general formula (7), and the general formula ( The structures of 8) are represented by the general formula (18), the general formula (19), and the general formula (20), respectively. Among them, k ₄ = k ₁ , G ₄ = G ₁ , k ₅ = k ₂ , and G ₅ = G _{2 are} preferable. The structural formula corresponds to the formula (18-1), the formula (19-1), and the formula (20-1), respectively. Only (18-1) are listed below.

Take (18-1) as an example:

及通式(18)为例，则异官能化Y型聚乙二醇衍生物的结构分别如下所示：Take

And the general formula (18) as an example, the structures of the heterofunctional Y-type polyethylene glycol derivatives are as follows:

或DENR(

NONE,2)，且D₁＝D₂为例，则式(18-1)的结构分别如下所示： Then p ₁ = p ₂ =0, G ₄ = G ₅ =

Or DENR (

NONE, 2), and D ₁ = D ₂ as an example, the structure of the equation (18-1) is as follows:

When g ₁ = g ₂ =0, g ₃ =1, k ₃ is an integer of 2 to 250, and k ₁ , k ₂ , and k ₃ are 1, the general formula (6), the general formula (7), and the general formula ( The structures of 8) are represented by the general formula (21), the general formula (22), and the general formula (23), respectively. Among them, k ₆ = k ₃ and G ₆ = G _{3 are} preferable.

g₁＝g₂＝0，g₃＝1，p₃＝0，G₆＝DENR(

NONE,3)、

为例，则通式(21)的结构分别如下所示：Take

g ₁ =g ₂ =0, g ₃ =1, p ₃ =0, G ₆ =DENR(

NONE, 3),

For example, the structure of the general formula (21) is as follows:

When g ₁ =g ₂ =g ₃ =1, k ₁ =k ₂ =k ₃ =1, the structures of the general formula (6), the general formula (7), and the general formula (8) are expressed as the general formula (24, respectively). ), general formula (25), general formula (26). Preferably k ₄ = k ₁ , G ₄ = G ₁ , k ₅ = k ₂ , G ₅ = G ₂ , k ₆ = k ₃ , G ₆ = G ₃ .

g₁＝g₂＝g₃＝1，p₁＝p₂＝1，L₄＝COCH₂NH，G₁＝G₂＝DENR(

NONE,2)，D₁＝D₂，p₃＝1，L₆＝CONH(CH₂)₄NHCOO，G₃＝

M₉取O、S或NH为例，则通式(24)的结构表示如下：Take

g ₁ =g ₂ =g ₃ =1, p ₁ =p ₂ =1, L ₄ =COCH ₂ NH, G ₁ =G ₂ =DENR(

NONE, 2), D ₁ = D ₂ , p ₃ =1, L ₆ = CONH(CH ₂ ) ₄ NHCOO, G ₃ =

Taking M ₉ as an example of O, S or NH, the structure of the general formula (24) is expressed as follows:

1.2.2. Biologically relevant substances

The bio-related substance modified by the hetero-functionalized Y-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 biologically relevant substance, before or after binding to the heterofunctionalized Y-type polyethylene glycol, also allows the target molecule, appendage or carrier to be bound thereto to form a modified biologically relevant substance or a complex biologically relevant substance.

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 its therapeutic field, including but not limited to the treatment of cancer, tumor, liver disease, hepatitis, diabetes, gout, rheumatism, rheumatoid, senile dementia, cardiovascular Drugs for diseases such as diseases, antiallergic drugs, anti-infective agents, antibiotic agents, antiviral agents, antifungal agents, vaccines, central nervous system inhibitors, central nervous system stimulants, psychotropic drugs, respiratory drugs, peripheral nervous system drugs, Drugs acting on synaptic junction sites or neuroeffector junction sites, smooth muscle active drugs, histaminers, antihistamines, blood and hematopoietic drugs, gastrointestinal drugs, steroids, cell growth inhibition Agent, anthelmintic, antimalarial, antiprotozoal, antimicrobial, anti-inflammatory, immunosuppressive, Alzheimer's disease drug or compound, imaging agent, antidote, anticonvulsant, muscle relaxant Medicine, anti-inflammatory drugs, appetite suppressants, migraine agents, muscle contracting drugs, antimalarials, antiemetics/emetics, tracheal dilating agents, antithrombotic drugs, antihypertensive drugs, antiarrhythmic drugs, antibiotics Oxidizers, anti-asthma drugs, diuretics, lipid regulators, antiandrogens, antiparasitic agents, anticoagulants, neoplastics, hypoglycemic agents, nutraceuticals, additives, growth supplements Agents, 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, muscles Infectious agents, 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, XIII, 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, dry Interferon-γ, interferon-ε, interferon-κ, interferon-ω, interferon-δ, interferon-τ, interferon λ, interferon α-2a, interferon α-2b, interferon β- 1a, interferon n1, interferon n3, interferon alpha 5, interferon gamma-1b, complex interferon, etc.), granulocyte colony-stimulating factor, filgrastim, macrophage colony-stimulating factor, granulocyte-macrophage Cell colony-stimulating factor, chemokine, monocyte chemoattractant protein, platelet-derived growth factor (platelet-derived growth factor), thrombopoietin, phospholipase-activating protein, insulin, proinsulin, C-peptide, glucagon, insulin-like Growth factors, insulin opsonins, glucagon-like peptides and analogues thereof (eg GLP-1, liraglutide, exenatide, exenatide, Bydureon, lixisenatide, lozenapeptide, etc.) , lectin, ricin, tumor necrosis factor (such as TNF-α), transforming growth factor (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, Cell 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, etc.

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- Glutamyl transpeptidase, mitochondrial peptidase, mitochondrial peptidase Ia, htra2 peptidase, site 1 protease, asparagine endopeptidase, cathepsin, cathepsin D, cysteine cathepsin, calcium Protease, ubiquitin isoeptidase T, caspase, glycosylphosphatidylinositol transamidase, prohormone thiol protease, γ-glutamyl hydrolase, bleomycin hydrolase, pepsin, coagulation Milk enzyme, 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, 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, blossuzumab, briakinumab, brodalumab, cantuzumab ravtansine, caplacizumab, carlumab, cd28-supermab, cuxutumumab, cladakizumab, clenoliximab, clivatuzumab tetraxetan, conatumumab, crenezumab, dacetuzumab, dalotuzumab, daratumumab, demcizumab, dupilumab, ecromeximab, Efungumab, eldelumab, elotuzumab/HuLuc63, eno kizumab, 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, lorvotuzumabmertansine, lucatumumab, mapatumumab, margetuximab, matuzumab, mavrilimumab, metelimumab, milatuzumab, mitumomab, mogamulizumab, motavizumab, moxetumomabpasudotox, 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, atumumab, atorolimumab, bectumomab, bivatuzumab mertansine, cantuzumab mertansine, cantuzumab mertansine, cedelizumab, cedelizumab, citatuzumab, bogatox, detumomab, drozitumab, duligotumab, dusigitumab, edobacomab, elsilimomab, enoticumab, erlizumab, exbivirumab, faralimomab ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, , 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, taplitumomabpaptox, technetium (99mTc) pintumomab, Technetium(99mTc)sulesomab, technetium(99mTc)votumumab, telimomab aritox, teneliximab, tovetumab, urtoxazumab, vatelizum Ab, vepalimomab, vesencumab, zolimomab aritox, bactericidal/permeability enhancing protein, antibody fragment (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, Lutotelcan, Giniconol, Difluentinkone, Cariciconol, Rubiconk, Ixitocan, Karenitecin, Jimidikekang, Gimacitan, Isatin, Affi Tetraconazole, rituxanol, cisplatin, oxaliplatin, hydroxycamptothecin (including but not limited to 10-hydroxycamptothecin, etc.), vinblastine, vincristine, ipecaine, trematocine hydrochloride, Colchicine, doxorubicin, epirubicin, pirarubicin, valrubicin, doxorubicin or doxorubicin hydrochloride, epirubicin, daunorubicin, daunorubicin, mitosis Acetin, aclaramycin, idamycin, bleomycin, pilomycin, daunorubicin, pracomycin, rapamycin, bleomycin, streptozotocin, podophyllotoxin, Actinomycin D素), maytansinoids, amikacin, mitoxantrone, all-trans retinoic acid, vindesine, vinorelbine, gemcitabine, capecitabine, cladribine, pemetrexed II Sodium, tegafur, letrozole, anastrozole, fulvestrant, goserelin, triptorelin, leuprolide, buserelin, temozolomide, cyclophosphazyl Amine, ifosfamide, gefitinib, sunitinib, erlotinib, ectinib, lapatinib, sorafenib, imatinib, dasatinib, nilotidine Nirvana, sirolimus, everolimus, guanidinium, methotrexate, 5-fluorouracil, dacarbazine, hydroxyurea, vorinostat, ixabepilone, bortezomib, cytarabine, Etoposide, azacytidine, teniposide, propranolol, procaine, tetracaine, lidocaine, valsaratin, carmustine (dichloroethyl nitrosourea) , chlorambucil, procarbazine, 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, lisinopril, levothyroxine sodium, nitrogen mustard, amphoterin, m-hydroxynorphedrine ditartrate, metoclopramide, mexiletine, mitoxantrone, nicotine , nicotinic acid nicotine salt, nilutamide, octreotide, pentastatin, pilcamycin, porphyrin, prednisone, procarbazine, prochlorperazine, ralte Thiol, streptozotocin, sirolimus, tacrolimus, tamoxifen, teniposide, tetrahydrocannabinol, thioguanine, thiotepa, dolasetron, granisetron, Formoterol, formoterol fumarate, melphalan, midazolam, alprazolam, podophylotoxins, sumatriptan, low molecular weight heparin, amifostine, carmustine, gai Statins, lomustine, tyrostin, osteoarthritis treatments (including but not limited to aspirin, salicylic acid, phenylbutazone, indomethacin, naproxen, diclofenac, meloxicam, nabidine Methotone, etodolac, sulphate Linic acid, acemetacin, diacerein, etc., amdoxovir, cyanuric blue/aminoaryl ketone, aminocaproic acid, aminophenyridinone, aminolevulinic acid, butylene glycol mesylate Diester, chloroformic acid/disodium chloroformate, L-dihydroxyphenylalanine, lovothyroxine sodium, dichloromethyldiethylamine, meta-hydroxylamine tartrate, o-p-dichlorobenzenedichloroethane , prochlorazine, ondansetron, raltitrexed, tacrolimus, tamoxifen, taniposide, tetrahydrocannabinol, fluticasone, aroyl hydrazone, sumatriptan, mecomycin, spirulina Amethyst, malt ethin, isorhamnetin, myricetin, dicyanocyanin, catechin, epicatechin, phloridzin, 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 cholesterol 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), etc.; peptides include neurotensin, cholecystokinin, vasoactive intestinal peptide, vasopressin, internal Source opioid peptides, 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, bucrine, anatazole, cyproheptadine, azastatin, Terfenadine, fexofenadine, astemizole, cetirizine, azelastine, azastatin, loratadine, desloratadine, and the like.

(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 Transporter inhibitors, autophagy inhibitors, ubiquitin inhibitors, multi-target inhibitors, receptors, antibodies, gene targeting molecules, viruses, vaccines, biomacromolecules, vitamins, targets To any of drugs and the like.

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 peptide GX1, transferrin receptor binding peptide, GE11, H24, LINGO-1 polypeptide, somatostatin analogue RC160, frog skin , gastrin-releasing peptide (GRP peptide), stimulatory peptide 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-1E-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, BAY 80-6946, YM201636, CH5132799, CAY10505, PIK-293, TG100713), mTOR inhibitors (eg CCI-779, Ridaforolimus, Rapamycin, Ivemo) Division, AZD8055, KU-0063794, XL388, PP242, INK128, Torin 1, GSK2126458, OSI-027, WYE-354, AZD2014, Torin 2, WYE-125132, Palomid 529, WYE-687, WAY-600, Chrysophanic Acid, GDC-0349), Akt inhibitors (eg A-674563, MK-2206, Perifosine, GSK690693, Ipatasertib, AZD5363, PF-04691502, AT7867, Tric Iribine, 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 (such as NU7441, NU7026, KU-0060648, PIK-75), PDK-1 inhibitors (such as OSU-03012, BX-795, BX-912, GSK2334470), S6Kinase 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, Varilitinib, Icotinib, Desmethyl Erlotinib, Tyrphostin 9, CNX-2006 , AG-18, etc., anaplastic lymphoma kinase inhibitors (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 Subreceptor 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 inhibitors such as Crenolanib/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) , Ro 31-822 0Mesylate, 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 Formulation, Abelson kinase inhibitor, 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);

Cell cycle regulatory inhibitors, including but not limited to c-Myc inhibitors (eg, 10058-F4), Wee1 inhibitors (eg, MK-1775), Rho inhibitors (eg, 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 Inhibitors (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, Mefenamic Acid), GluR inhibitors (eg LY404039, MK-801, (-)-MK 801 Maleate, CTEP, Riluzole, ADX-47273, Ifenprodil, VU 0357121, MPEP, IEM 1754 dihydrobroMide, NMDA, VU 0364439, VU 0364770, VU 036 1737), 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 HCl Bisoprolol 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 Inhibitors (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, Ondansetron 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, Bipreiden HCl, Pyridostigmine Bromide, Irsogladine, Gallamine Triethiodide, Arecoline, 5-hydroxymethyl Tolterodine, Rivastigmine Tartrate, Neostigmine Bromide, Darifenacin HBr, Acetylcholine Chloride , Tropicamide, Orphenadrine citrate, Oxybutynin chloride, Hyoscyamine, Homatropine Methylbromide, Homatropine Bromide, 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, Fexofenadine HCl, Lidocaine, Olopatadine HCl, Brompheniramine hydrogen maleate, Ketotifen Fumarate, Cyproheptadine HCl, Azatadine dimaleate, Rupatadine Fumarate, JNJ-7777120, Hydroxyzine 2HCl , Buclizine HCl, Famotidine, Roxatidine Acetate, Betahistine 2HCl, Pemirolast potassium, Histamine 2HCl, Levodropropizine, Cyclizine 2HCl), OX receptor inhibitors (eg Suvorexant, SB408124, Almorexant HCl), Beta Amyloid inhibitors (eg EUK 134, RO4929097, LY2811376);

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/progestogen Inhibitors (eg Fulvestrant, Tamoxifen Citrate, Raloxifene HCl, Erteberel, Mifepristone, Ospemifene, Toremifene Citrate, Dienogest, Bazedoxifene HCl, Gestodene, Clomifene citrate, Medroxyprogesterone acetate, Equol, Drospirenone, Hexestrol, Epiandrosterone, Estreol, 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 inhibitors, 5α reductase inhibitors (eg Dutasteride, Finasteride), GPR inhibitors (eg 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-CoAReductase 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 inhibition Agents (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, Gimerac Il);

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, PJ34HCl, AG-14361, INO-1001, A-966492, PJ34, UPF 1069, AZD2461), DNA methyltransferase 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/RNASynthesis inhibitors (eg Cisplatin, Gemcitabine HCl) ,Bleomycin Sulfate, Carboplatin, Oxaliplatin, CRT0044876, Triapine, Pemetrexed, Fludarabine, CX-5461, FluorouracilCapecitabine, Fludarabine Phosphate, Cytarabine, Gemcitabine, Nelarabine, Cladribine, Raltitrexed, Clofarabine, Ifosfamide, NSC 207895, Dacarbazine, Floxuri Dine, 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-3207HCl), Hedgehog/Smoothened inhibitors (eg Vismodegib, Cyclopamine, LDE225, LY2940680, Purmorphamine, BMS-833923, PF-5274857, GANT61, SANT-1), LPAReceptor inhibitors (eg Ki16425, Ki16198), PAFR inhibitors (eg Ginkgolide B), CaSR inhibitors (eg Cinacalcet HCl, NPS-2143), vascular boost 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), E1Activating inhibitors (eg PYR-41), proteasome inhibitors, DUB inhibitors (eg PR-619, P5091, IU1, LDN-57444, TCID, ML323, Degrasyn, P22077), E2conjugating inhibitors (eg NSC697923), E3Ligase inhibitors (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, cape Hebin, Teggio, comprilidine disodium phosphate, vemurafenib, Vismodegib, anastrozole, Arimidex, exemestane, letrozole, denosumab, lenalidomide, pomamide , Carfilzomib, Belinostat, Cabazitaxel, Abiraterone Acetate, Radium Dichloride 233 Injection, Luteinizing Hormone Releasing Hormone, Miltonin, Oblimersen, Navioklax, Secatinib, Vismodegib, Marimastat, Fucosyl GM1 Synthetic, Alvocidib, havopiridol, vincristine, tipidifoni, depsipeptide, BSU21051, cationic porphyrin compound, UCN-01, ICR-62, rititinib, PKI-166, carnitinib, PD158780, HKI-357, ZD6126, amifostine, Ombrabulin, cobstatin, soblidotin, Denibulin, Tozasertib, decitabine, AEE788, Orantinib, SU5416, Enzastaurin, oxaliplatin, celecoxib, aspirin, Obatoclax , AT-101, tamoxime, bicepod, rofecoxib, NS-398, SC-58125, Batimastat, prasostatin, metastat, neovastat, BMS-275291, Lonofani, BMS- 214662, SCH44342, SCH54429, L-778123, BMS-2 14662, 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, oxytetracycline, genistein, erbstatin, lavendustin A, herbimycin A, tyrphostin, PD169540, CL-387785, CP-358744, CGP59326, CGP59326-A, oleic acid A and B, mycobacteria , phenanthromycin A and its analogues, lupin derivatives, CGS27023A, squalamine, thalidomide, Cilengitide, carboxyamimidazole, suramin, IM862, DS-4152, CM-101, new Vastostat, PD98059, PD184352, Diazo 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, talivilin, BIBW-2992, the above list Anti-drugs, etc.

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-jun, 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]. Sun Yat-sen University, 2005." and citations The cantharidin derivatives described in the above are incorporated herein by reference), 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-glycoside, genistein, 4',5,7-trisone-7-glycoside, etc.), Salvia extract (such as tanshinone and its derivatives, including but not limited to tanshinone IIa, tanshinone IIb, tanshinone I, cryptotanshinone, salvia miltiorrhiza A, salvia miltiorrhiza B, salvia miltiorrhiza B, etc.; such as salvia miltiorrhiza water-soluble extracts and salts thereof, including but not limited to Danshensu, protocatechuic aldehyde, Rosemary acid, shikonic acid, salvianolic acid A, B, C, D, E, F, G, etc.), milk thistle extract (such as silibinin, silibinin, silibinin, water fly Suining, etc.) Glycyrrhetinic acid, sorghum lactone, alfalfa extract, pollen extract (which may be broken wall pollen or unbroken pollen), ginkgo extract (including but not limited to flavonoids, ginkgolides, etc.), Pigpea 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.

1.2.3. Attaching a linker between a biologically relevant substance and a polyethylene glycol branched chain

a covalent bond L formed by a functional group in a heterofunctional Y-type polyethylene glycol derivative or a protected form thereof and 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, a bio-related substance containing an amino group is separately polymerized with an active ester, an acid formate ester, a sulfonate, an aldehyde, an α, β-unsaturated bond, a carboxylic acid group, an epoxide, an isocyanate, an isothiocyanate. The ethylene glycol reaction gives a polyethylene glycol having a group such as an amide group, a urethane group, an amino group, an imino group (which can be further reduced to a secondary amino group), an amino group, an amide group, an amino alcohol, a urea bond, or a thiourea bond. a modification; a bio-related substance containing a thiol group respectively containing an active ester, an active ester of formic acid, a sulfonate, a thiol group, a maleimide, an aldehyde, an α,β-unsaturated bond, a carboxylic acid group, an iodoacetamide And polyethylene glycol reaction of an acid anhydride to obtain a group containing a thioester group, a thiocarbonate, a thioether, a disulfide, a thioether, a thiohemiacetal, a thioether, a thioester, a thioether, an imide, and the like. a linked polyethylene glycol modification; a bio-related substance containing an unsaturated bond is reacted with a thiol-containing polyethylene glycol to obtain a polyethylene glycol modified group having a thioether group; the biologically relevant substance containing a carboxylic acid is respectively Polyethylene glycol containing a mercapto group or an amino group to obtain a thioester group and an amide A group-attached polyethylene glycol modification; a hydroxyl-containing bio-related substance is reacted with a polyethylene glycol containing a carboxyl group, an isocyanate, an epoxide or a chloroformyloxy group to obtain an ester group or a urethane group. a polyethylene glycol modification linked with a group such as an ether bond or a carbonate group; and a biologically relevant substance containing a carbonyl group or an aldehyde group, respectively, reacted with a polyethylene glycol containing an amino group, a hydrazine or a hydrazide to obtain an imine bond, hydrazine a polyethylene glycol modification linked to a group such as a hydrazide; containing azide, alkynyl, alkenyl, decyl, azide, diene, maleimide, 1,2,4-triazoline-3 , a reactive group such as a 5-dione, a dithioester, a hydroxylamine, a hydrazide, an acrylate, an allyloxy group, an isocyanate or a tetrazole may be subjected to a click chemistry reaction to form a reaction including, but not limited to, triazole, Examples of various linking groups such as isoxazole and thioether bonds are as follows:

等。其中，R₁₃、M₄、Q₂的定义与上述一致，这里不再赘述。文献Adv.Funct.Mater.,2014,24,2572中所报道的及其引用的click反应生成的连接基作为参考均纳入本发明中。

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 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 stability of L is not particularly limited and may be a linker which can be stably present or a linker which is degradable.

The conditions for the stable presence are not particularly limited, and include, but are not limited to, stable presence under conditions of light, heat, enzymes, redox, acidity, basicity, physiological conditions, in vitro simulated environment, and the like.

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.

Preferably, the L is stable under light, heat, enzyme, redox, acidic, basic, physiological conditions or an in vitro simulated environment A linker that is present, or a linker that is degradable under light, heat, enzymes, redox, acidic, basic, 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.

1.2.4. Reaction between polyethylene glycol derivatives and biologically relevant substances

中甲硫氨酸的N-氨基与醛基之间的定点反应，又如巯基与马来酰亚胺、乙烯基砜、2-碘代乙酰胺、邻吡啶二硫醚等之间的定点反应，又如氨基与氰基与异氰酸酯、异硫氰酸酯之间的定点反应等。作为举例，不定点修饰如氨基与活性酯之间的反应，商业化产品如

制备时的不定点修饰。文献《Pharm Sci Technol Today》[1998,1(8):352-6]、文献《Polymers》[2012,4(1):561-89]中所述的定点修饰方法与不定点修饰方法均作为参考纳入本发明中。The type of reaction between the heterofunctional Y-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.

中一分子聚乙二醇仅与一个药物分子中的一个反应位点反应；而商业化产品

中，一个药物分子则可以连接多个聚乙二醇分子。When the heterofunctional Y-type polyethylene glycol derivative modifies a bio-related substance, one bio-related substance may be linked to one or more hetero-functionalized Y-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 heterofunctionalized Y-type polyethylene glycol derivative is modified with a biologically relevant substance having two or more reaction sites, the same heterofunctional Y-type polyethylene glycol derivative is modified without special explanation. Of biologically related substances, It can be reacted with any one or more of the 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, a plurality of functional groups derived from the same hetero-functionalized Y-type polyethylene glycol allow different reactions Site reaction.

When the heterogeneous Y-type polyethylene glycol derivative-modified bio-related substance has two types of bio-related substances, one of the bio-related substances is preferably a targeting factor, a dye, or a fluorescent substance.

1.3. The present invention particularly discloses a bio-related substance modified with a hydroxyl group- or a protected hydroxyl group-containing Y-type polyethylene glycol derivative, which has the general formula of formula (27), formula (28), formula (29) or formula ( 30) shown. Wherein n ₁ , n ₂ , n ₃ , L ₁ , L ₂ , L ₃ , U, g ₁ , g ₂ , g ₃ , k ₁ , k ₂ , k ₃ , k ₄ , k ₅ , k ₆ , G ₄ , G ₅ , G ₆ , L ₄ , L ₆ , p ₁ , p ₂ , p ₃ , D ₁ , D ₂ , D ₃ are defined in accordance with the general formulae (6) to (8), and the definition of PG ₄ is The above agreement is not repeated here.

Wherein, in the same molecule, U, L ₁ , L ₂ , L ₃ , L ₄ , L ₆ , G ₄ , G ₅ , G ₆ , Z ₂ (D ₁ ), Z ₂ (D ₂ ), Z ₂ (D _{3), L (D 1)} , L (D 2), L in (D ₃₎ according to any one or any of the adjacent groups form a hetero atom linker may be stable or degradable.

Where g ₁ = g ₂ =0, the structures of the equations (27) and (28) are as follows:

Wherein, when g ₁ = g ₂ =1, k ₄ and k ₅ are each independently an integer of 2 to 250, and the structures of the formulas (27) and (28) are as follows:

Where g ₃ =0, the structures of equations (29) and (30) are as follows:

Wherein, when g ₃ =1, k ₆ is an integer of 2 to 250, and the structures of the formulas (29) and (30) are as follows:

The above formula (27-1), formula (28-1), formula (27-2), formula (28-2), (29-1), formula (30-1), and formula (29-2) In the formula (30-2), n ₁ , n ₂ , n ₃ , L ₁ , L ₂ , L ₃ , U, k ₄ , k ₅ , k ₆ , G ₄ , G ₅ , G ₆ , L ₄ , The definitions of L ₆ , p ₁ , p ₂ , p ₃ , D ₁ , D ₂ , and D ₃ are the same as those of the general formulae (6) to (8), and the definition of PG ₄ is as described above. Briefly described as follows:

n ₁ and n ₂ represent the degree of polymerization of two PEG branched chains, each independently satisfying 2 to 2000, and n ₃ represents the degree of polymerization of the main chain PEG, which satisfies 1 to 2000, and in the same molecule, n ₁ , n ₂ , n ₃ may be the same or different from each other;

U is a trivalent group;

L _1, L _2, L ₃ are the number of oxyethylene units connected to n _1, n _2, n linker polyethylene glycol units _3, are each independently present or absent and can be each other in the same molecule Same or different;

Each of p ₁ , p ₂ , and p _{3 is} independently an integer of 0, 1, or 2 to 1000;

L ₄ and L ₆ are each independently a divalent linking group;

k ₄ , k ₅ , and k ₆ are each independently an integer of 1 or 2 to 250;

G ₄ , G ₅ , and G ₆ are each independently a trivalent or higher valence linking group, and the valence states of G ₄ , G ₅ , and G ₆ are respectively k ₄ +1, k ₅ +1, k ₆ +1;

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

Wherein q is 0 or 1; Z ₂ is a divalent linking group; D is a residue formed by reacting a modified bio-related substance with a hetero-functionalized Y-type polyethylene glycol; and L is a hetero-functionalized Y-type poly-B a linking group formed by reacting a functional group in a diol derivative or a protected form thereof with a biologically relevant substance;

Wherein PG ₄ is a hydroxy protecting group;

Wherein, in the same molecule, D ₁ and D ₂ have the same Z ₂ , q, and D ₁ and D ₂ have the same or different L; in the same molecule, D of D ₁ and D ₂ are from the same biologically relevant substance; Wherein D ₁ and D ₂ may be residues formed after different reaction sites in the same molecule participate in the reaction;

Wherein, in the same molecule, U, L ₁ , L ₂ , L ₃ , L ₄ , L ₆ , G ₄ , G ₅ , G ₆ , Z ₂ (D ₁ ), Z ₂ (D ₂ ), Z ₂ (D _{3), L (D 1)} , L (D 2), L in (D ₃₎ according to any one or any of the adjacent groups form a hetero atom linker may be stable or degradable.

1.4. The present invention specifically discloses a heterofunctionalized Y-type polyethylene glycol derivative modified bio-related substance having a targeting function, which is of the formula (15), formula (18), formula (21) or formula (24) is shown. Wherein U, n ₁ , n ₂ , n ₃ , L ₁ , L ₂ , L ₃ , k ₄ , k ₅ , k ₆ , G ₄ , G ₅ , G ₆ , L ₄ , L ₆ , p ₁ , p ₂ , the definitions of p ₃ , D ₁ , D ₂ , and D ₃ are the same as those of the general formulae (6) to (8), and are not described herein again. Among them, in the same molecule, D ₁ and D _{2 are} derived from the same biologically relevant substance. In the same molecule, any of D ₁ and D ₃ is a residue of a targeting factor, and the other is a residue of a different biologically relevant substance.

Wherein, the source of the targeting factor includes, but is not limited to, the class I in the above functional group and the class (10) in the above biologically relevant substance. 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 heterofunctionalized Y-type polyethylene glycol.

的典型结构及其优选方案与上述一致，这里不再赘述。among them,

The typical structure and its preferred scheme are consistent with the above, and will not be described again here.

Wherein, the typical structures of G ₄ , G ₅ , and G ₆ each independently include, but are not limited to, any of the above-mentioned 1.1.8. partial terminal branching structures, preferably a trivalent group, a tetravalent group, and a pentavalent group thereof. Group, hexavalent group, tree structure.

1.5. The present invention particularly discloses a heterofunctionalized Y-type polyethylene glycol derivative modified fluorescing bio-related substance having the general formula of formula (15), formula (18), formula (21) or formula ( 24) shown.

Wherein U, n ₁ , n ₂ , n ₃ , L ₁ , L ₂ , L ₃ , k ₄ , k ₅ , k ₆ , G ₄ , G ₅ , G ₆ , L ₄ , L ₆ , p ₁ , p ₂ , the definitions of p ₃ , D ₁ , D ₂ , and D ₃ are the same as those of the general formulae (6) to (8), and are not described herein again. Among them, in the same molecule, D ₁ and D _{2 are} derived from the same biologically relevant substance. In the same molecule, any of D ₁ and D ₃ is a residue of a fluorescent substance, and the other is a residue of a different biologically relevant substance. The fluorescent substance includes, but is not limited to, the class J in the above functional group and the class (9) among the above biologically relevant substances. The fluorescent molecule as a source may be a fluorescent molecule itself, a dimer thereof and a multimer, a subunit and a fragment thereof, a precursor, an activated state, a derivative, an isomer, a mutant, an analog, a mimetic, 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 heterofunctionalized Y-type polyethylene glycol.

G₄、G₅、G₆的典型结构及其优选方案与上述一致，这里不再赘述。among them,

The typical structures of G ₄ , G ₅ , and G ₆ and their preferred embodiments are consistent with the above, and are not described herein again.

2. Preparation method

2.1. The present invention also discloses a process for the preparation of a heterofunctional Y-type polyethylene glycol derivative. The preparation process of the heterofunctional Y-type polyethylene glycol derivative involves a hetero-functionalized Y-type intermediate compound HA having a skeleton IM; the terminal linear functionalization or terminal branching function is independently performed on both ends of the intermediate compound HA. By modification, a heterofunctional Y-type polyethylene glycol derivative having a target functional group or a protected form thereof F ₁ , F ₂ can be obtained; wherein the F _t of the terminal of the main chain polyethylene glycol is F ₂ , The F _t of the end of the branched chain polyethylene glycol is F ₁ ; and F ₁ ≠F ₂ ;

Here, the definitions of n ₁ , n ₂ , n ₃ , and U are the same as those in the general formulae (1) to (5).

The main chain end and the branch end of the compound HA are each independently a linear functionalized structure or a branched functionalized structure; when it is a linear functionalized structure, the polyethylene glycol chain end joining is only linked with one functional group or a protected form; when it is a branched functionalized structure, two or more functional groups or protected forms thereof are attached to the end of the polyethylene glycol chain;

HA is a heterofunctional compound structure, two branched end has the same functional group or a protected form F _9, and the main chain terminal functional group or a protected form different F _7; F _7, At least one of F ₉ is not a target functional group or its protected form F _t .

In the compound HA, it is preferred that any one of F ₇ and F ₉ is a target functional group or a protected form thereof F _t , a hydroxyl group or a protected hydroxyl group.

In the compound HA, the combination of F ₇ and F ₉ is preferably any one of F _t and a hydroxyl group, F _t and a hydroxy protecting group, a hydroxy protecting group and a hydroxyl group.

The process of modifying a hydroxyl or non-target functional group at the end of a polyethylene glycol chain to a target functional group or a protected form thereof is terminally functionalized and can be divided into terminal linear functionalization and terminal branch functionalization. The functional group or protected form thereof includes, but is not limited to, the functional groups listed in the classes A to J or the protected forms thereof.

The linear functionalization of the end corresponds to g _i (i = 1, 2, 3) = 0, ie the corresponding G _i is absent; the branched functionalization of the end corresponds to g _i (i = 1, 2, 3) = 1, At this time, the corresponding G _i exists, and one polyethylene glycol chain end corresponds to one functional group or its protected form R ₀₁ .

The terminal functionalization process when g _i (i=1, 2, 3) is 0 is terminal linear functionalization, in which case the corresponding G _i does not exist, the corresponding k _i =1, the functionality of the polyethylene glycol chain end The number of groups or their protected forms R ₀₁ is 1; the terminal functionalization process when g _i (i=1, 2, 3) is 1 is terminal branching functionalization, where k _i is 2 to 250 An integer, the corresponding G _i is a branched group of k _i +1 valence, and the functional group at the end of the polyethylene glycol chain or the number of protected forms R ₀₁ thereof is k _i .

When k _i =1, the terminal compound HA is subjected to terminal linear functionalization;

When k _i >1, the terminal compound HA is subjected to terminal branching functionalization;

The terminal linear functionalization is carried out at any step prior to obtaining the intermediate compound HA, at any subsequent step or at the same time as obtaining the intermediate compound;

The intermediate branched functionalized intermediate needs to have a V-shaped structure or a Y-shaped structure. The V-type structure has 2 PEG branched chains, and the intermediate positions of the two chains have a functional group or a protected form thereof; the Y-type structure has 1 polyethylene glycol backbone and 2 PEG branched chains, polyethylene glycol The end of the backbone has a functional group or a protected form thereof. The above-described terminal branching functionalization can be carried out simultaneously at the ends of the two branching ends of the V-type structure or the Y-type structure, or at the end of the main chain of the Y-type structure.

各自独立地引入到V型结构或Y型结构的聚乙二醇主链或分支链的末端。In the general formula (1), the general formula (3), the general formula (4), and the general formula (5), g _i (i = 1, 2, 3) = 1, that is, a functional group in the presence of G or Form of protection

Each is independently introduced to the end of a polyethylene glycol backbone or branched chain of a V-shaped structure or a Y-shaped structure.

Any of the linear hetero-functionalized polyethylene glycol starting materials used in the preparation of the hetero-functionalized Y-type polyethylene glycol of the present invention may be polydisperse or monodisperse. The product prepared by using a monodisperse raw material has a relatively uniform molecular weight, but the molecular weight is mostly limited based on the limitation of the preparation method. The advantage of using polydisperse starting materials is that the molecular weight has a large range of adjustment. Refer to the definitions of n ₁ , n ₂ , and n ₃ above, respectively.

2.1.1. Linear Functionalization of Polyethylene Glycol Chain Ends

The method of terminal linear functionalization is not particularly limited and is related to the type of the final functional group or its protected form. It may be a linear functionalization based on a terminal hydroxyl group of a polyethylene glycol chain, a transition to a target functional group based on a reactive group or a protected form thereof, or a combination of the two. Known techniques in the art can be employed. The parameters such as reaction temperature, reaction time, dosage and the like are well known to those skilled in the art, or can be optimized by a limited number of experiments, and are not described herein again, but mainly describe the reaction principle, reaction raw materials, reaction routes and the like.

In the following, a typical functional group in the class A to the class J or a protected form thereof is taken as an example to describe in detail the preparation method of the linear functionalization of the terminal hydroxyl group of the polyethylene glycol chain, starting from the terminal hydroxyl group of the polyethylene glycol chain. A functional group of the class A to the class J or a protected form thereof is obtained by functionalization. The reaction formula is as follows:

Wherein, the structure of PEG-OH is (CH ₂ CH ₂ O) _n CH ₂ CH ₂ OH, n is n ₁ -1, n ₂ -1 or n ₃ -1; q, Z ₂ , q ₁ , Z ₁ , The definition of R ₀₁ is consistent with the above. Wherein PEG-OH is part of a terminal hydroxyl group-containing intermediate (IF1) in the preparation of the heterofunctional Y-type polyethylene glycol; the terminal hydroxyl-containing intermediate may contain 1, 2 or 3 polyethylene The diol chain; PEG-OH can be derived from the backbone polyethylene glycol or from any polyethylene glycol branch.

By way of example, PEG-OH may be selected from (34), (45) with 1 PEG chain, or (51), (51b) with 2 polyethylene glycol chains, or with 3 polyethylene glycol chains. (25), (25b), (28), (29), (52d), (53d), (54d), (55d), (56d), (71d), etc. Alcohol chain.

In the linear functionalization method for the terminal hydroxyl group of the polyethylene glycol chain, it is preferred that q = 0, q ₁ = 1, and Z ₁ is 1,2-methylene. It is to be noted that the molar equivalent of the hydroxyl group in the default intermediate compound IF1 is 1 unless otherwise specified. When q is not 0, such as a linking group such as an amino acid or a succinyl group between PEG and R ₀₁ , the prior art which can generate Z ₂ or Z ₁ in the art (including but not limited to alkylation, condensation) may be employed. , click reaction, etc.), and prepared by reference to the linear functionalization described below.

2.1.1.1. Class A: R _{01 is} selected from the functionalization of class A

The functional group in class A is primarily an active ester or an analog of an active ester.

The corresponding active esters (A4, A6, A7, A9, A10, A16, A18) can be passed through the terminal hydroxyl intermediate in the presence of a base with the corresponding carbonate (N,N'-disuccinimidyl carbonate) , bis(p-nitrophenyl)carbonate, bis(o-nitrophenyl)carbonate, bisbenzotriazole carbonate, etc., haloformate (p-nitrophenyl chloroformate, adjacent nitrite) Phenylphenyl chloroformate, trichlorophenyl chloroformate, etc., and N,N'-carbonyldiimidazole are obtained by a condensation reaction. The corresponding substituted hydrogen atom on the ring can also be obtained in a similar manner, such as by reaction with 1,1'-carbonylbis(2-methylimidazole) to give the active ester of 2-methylimidazole. The corresponding haloformate is selected from chloro, bromo or iodo, preferably chloro. The obtained product can be purified by purification methods such as extraction, recrystallization, adsorption treatment, precipitation, precipitation, membrane dialysis or supercritical extraction.

The corresponding active esters (A1-A3, A5, A8, A11, A15, A17) can also be obtained by a condensation reaction. The terminal hydroxyl group is obtained by one or more steps to obtain a terminal carboxyl group, and then in the presence of a condensing agent, with the corresponding alcohol (N-hydroxysuccinimide, p-nitrophenol, o-nitrophenol, trichlorophenol, 1-hydroxyl) The reaction of benzotriazole or the like gives the corresponding active ester.

The analog of the active ester (A11-A14) can be passed through the terminal carboxyl group in the presence of a condensing agent with the corresponding amine (such as thiazole-2-thione, tetrahydropyrrole-2-thione, benzo[d] Thiazole-2(3H)-thione, 4-oxo-2-thiothiazolidine, etc.) are reacted to give the corresponding amide. The corresponding substituted hydrogen atom on the ring can also be obtained in a similar manner, such as by using 4-isopropyl-1,3-thiazolidine-2-thione, (R)-4-isopropylthiazole The corresponding active ester analog can be obtained by a reaction of morpholin-2-thione, 4-phenylthiazoline-2-thione or the like. The condensing agent is not particularly limited, but N,N'-dicyclohexylcarbonyldiimide (DCC), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCHCl) is preferred. ), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), benzotriazole-N,N,N' , N'-tetramethylurea hexafluorophosphate (HBTU), most preferably DCC. The solvent can be a solventless or aprotic solvent. The base includes generally an organic base, preferably triethylamine, pyridine.

2.1.1.2. Class B: R _{01 is} selected from the functionalization of class B

a. The sulfonic acid or sulfinate derivative (B1, B2) can be obtained by esterification of a terminal hydroxyl group with a sulfonyl chloride or a sulfinyl chloride containing a leaving group Y ₁ in the presence of a base.

b. Sulfone or sulfoxide derivatives (B3, B4) can be obtained by oxidation reaction through a sulfoxide intermediate or a thioether intermediate containing a leaving group Y ₁ . The definition of Y ₁ is consistent with the above. The oxidizing agent is not particularly limited as long as it is a compound or a combination of a plurality of compounds which can increase the valence of the substrate. The solvent can be a solventless or aprotic solvent.

c. The sulfone derivative (B3) can be obtained by reacting a terminal hydroxyl group with a base to deprotonate and then reacting with a vinyl sulfone.

d. The bis sulfone derivative (B5) and its variant (B6) can be prepared by the method of "Advanced Drug Delivery Reviews, 2008, 60, 3-12".

2.1.1.3. Class C: R _{01 is} selected from the functionalization of class C

The hydroxylamine compound (C1) can be obtained by reacting an excess of hydroxylamine hydrochloride under a strong base condition (e.g., diphenylmethyl potassium) through a terminal hydroxyl group.

The mercapto derivative (C2) can be obtained by reacting a terminal hydroxyl group with a thiourea, and the reaction can be carried out in a solvent or in the absence of a solvent. The solvent is not limited, and water, toluene, benzene, xylene, acetonitrile, ethyl acetate is preferred. Ethyl ether, methyl tert-butyl ether, tetrahydrofuran, chloroform, dichloromethane, dimethyl sulfoxide, dimethylformamide or dimethylacetamide, preferably water, tetrahydrofuran, dichloromethane, acetonitrile.

The mercapto derivative (C2) can also be obtained by reacting a sulfonate compound with a potassium xanthate compound and then decomposing with a primary amine. This reaction can be carried out in the absence of a solvent or a solvent, and the solvent is not limited, and an aprotic solvent is preferred.

The protected sulfur compound (C7) can be obtained by reacting the corresponding sulfur compound (C2) with a corresponding protective reagent. The preparation method is not limited, and includes, but is not limited to, the following method: a. The thioether-protected sulfide (C7) can be reacted with a corresponding leaving group-containing alkylating agent in the presence of a base of a sulfur compound. be made of. The solvent can be a solventless or aprotic solvent. b. The thioester compound (C7 & C17) can be obtained by reacting a sulfur compound with a corresponding acid halide in the presence of a base. The solvent can be a solventless or aprotic solvent.

The amine derivative (C3) can be coupled with acrylonitrile or the like under base catalysis, and then In a high pressure reactor, the cyano group is reduced under the catalysis of palladium or nickel to give the corresponding amine. This reaction can be carried out in the absence of a solvent or solvent, and the solvent is not limited, and water or 1,4-dioxane and a combination thereof are preferred. The base includes an organic base or an inorganic base, preferably an inorganic base, more preferably sodium hydroxide or potassium hydroxide.

The amine derivative (C3) can also be obtained by reacting a sulfonate compound (B1) with aqueous ammonia.

The preparation of the protected amine compound (C6, C16) can be carried out by reacting the corresponding amine (C3) with the corresponding protective reagent. The preparation method is not limited, and includes but is not limited to the following methods:

a. A carbamate compound can be obtained by reacting an amine with a corresponding haloformate in the presence of a base. The solvent can be a solventless or aprotic solvent. The base includes an organic base or an inorganic base, preferably an organic base, more preferably triethylamine or pyridine.

b. The amide compound can be obtained by reacting an amine with a corresponding acid halide in the presence of a base.

c. The alkylated amino compound can be prepared by reacting an amine with a corresponding alkylating agent having a leaving group in the presence of a base. The solvent may be a solvent-free or aprotic solvent base including an organic base or an inorganic base, preferably an organic base, more preferably triethylamine, pyridine, sodium hydrogen, DPMK, potassium hydride, sodium alkoxide.

d, another preparation method of the alkylated amine compound can be obtained by reacting an amine with a corresponding aldehyde or ketone to obtain an imine compound, and then reducing the imine (Schiff base) to the corresponding alkyl group in the presence of a reducing agent Amine compound (C6). The corresponding aldehyde or ketone is not particularly limited. The solvent may be a protic solvent or an aprotic solvent including toluene, benzene, xylene, acetonitrile, ethyl acetate, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, methanol, ethyl acetate, dimethylformamide or Dimethylacetamide, preferably tetrahydrofuran, methanol, ethyl acetate. The reducing agent is not particularly limited as long as it can reduce the Schiff base formed by the ammonia and the aldehyde or the ketone to an amino group; preferably sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, borane, diborane, diisobutylene One or a combination of alkaloaluminum, diisossonylborane, lithium borohydride, zinc borohydride, borane-pyridine, borane-methyl sulfide, borane-tetrahydrofuran, etc.; more preferably cyanoborohydride sodium.

The azide compound (C4), the halogenated compound (C5), the tetramethylpiperidinyloxy compound (C8), the dioxapiperidinyloxy compound (C9) can be passed through the sulfonate compound (B1) and the corresponding halogenated compound. The salt, 2,2,6,6-tetramethylpiperidine-nitro-hydroxy, 3,5-dioxo-1-cyclohexylamine is obtained by reaction. The bromine salt is also not limited as long as free bromide ions are formed in the solvent, and sodium bromide or potassium bromide is preferred. The azide salt is not limited as long as free azide ions are formed in the solvent, and sodium azide or potassium azide is preferred. The solvent for the reaction for preparing the azide compound (C4) is not limited, and is preferably carried out in water, ethanol, acetonitrile, dimethyl sulfoxide, dimethylformamide or dimethylacetamide solvent, preferably water and dimethylformate. Amide.

The halogenated compound (C5) can also be obtained by reacting a terminal hydroxyl group with a halogenating reagent. The halogenating agent is not particularly limited as long as it can convert a hydroxyl group to a corresponding halogen atom, preferably one of or a combination of thionyl chloride, phosphorus trichloride, phosphorus tribromide, dibromosulfoxide and the like. The solvent can be a solventless or aprotic solvent.

The ester and thioester compound (C17) can be obtained by a condensation reaction of a terminal hydroxyl group, a thiol group, a terminal carboxyl group or an acid halide, and the acid halide is preferably an acid chloride.

The thioester compound (C17) can also be obtained by a reaction between a mercapto group and an active ester. References "Journal of Controlled Release, 2014, 194: 301-309".

The carbonate or thiocarbonate compound (C18) can be obtained by a condensation reaction of a terminal hydroxyl group, a mercapto group and an oxycarbonyl chloride compound. For example, ethyl chloroformate or ethyl thiochloroformate.

The trithiocarbonate derivative (C18) may also pass through a trithioester-containing small molecule compound such as 3-(benzylthiothiocarbonylthio)propionic acid and a functionalized polyethylene glycol carrying a suitable functional group. , obtained by coupling reaction.

The haloacetamide compound (C10) can be obtained by reacting a haloacetic acid with a polyethylene glycol amine derivative (C3) under the action of a condensing agent to form an amide bond.

The lipoic acid derivative can be obtained by a condensation reaction of lipoic acid with the corresponding alcohol (H1) or amine (C3).

2.1.1.4. Class D: R _{01 is} selected from the functionalization of class D

The ester compound (D11) and the thioester compound (D13, D16, and D17) can be obtained by subjecting the terminal hydroxyl group to a protonation reaction and then undergoing a substitution reaction with the α-haloester. Examples are ethyl chloroacetate and ethyl bromoacetate.

The thioester compound (D13) can also be obtained by reacting the corresponding ester (D11) with a thiol.

The amide (D1), the hydrazide compound (D2), and the carboxylic acid compound (D4) can be passed through the ester compound (D11) and the corresponding The nucleophile is hydrolyzed or aminated. The ester compound (D11) is hydrolyzed with an alkaline solution to obtain a carboxylic acid compound (D4), which is treated with aqueous ammonia or hydrazine hydrate to obtain an amide compound (D1) and a hydrazide compound (D2), respectively.

The acid halide compound (D6) can be obtained by reacting a carboxylic acid compound (D4) with a halogenating reagent. The halogenating agent is not particularly limited as long as the hydroxyl group in the carboxylic acid can be converted into the corresponding halogen atom, preferably one of or the like of thionyl chloride, phosphorus trichloride, phosphorus tribromide or dibromosulfoxide. Its combination. The solvent can be a solventless or aprotic solvent.

The acid anhydride derivative (D11) can be obtained by reacting a carboxylic acid derivative (D4) with an acid halide, a small molecule acid anhydride, or a small molecule mixed acid anhydride. The acid halide, small molecule acid anhydride, and small molecule mixed acid anhydride reagent are not particularly limited as long as the carboxylic acid can be converted into the corresponding acid anhydride, preferably C _1-10 acid chloride, C _1-10 acid bromide, C _1-10 acid anhydride, and the like. One or a combination thereof.

The acetaldehyde derivative (D5) can be obtained by direct oxidation of a terminal hydroxyl group. The oxidizing agent is not particularly limited, and is preferably PDC, PCC, DCC + DMSO, MnO ₂ , preferably DCC + DMSO. The reaction solvent is not particularly limited, and an aprotic solvent is preferred. In addition, a weakly acidic salt should be added to the reaction, and is not particularly limited, and pyridine trifluoroacetate, triethylamine trifluoroacetate, pyridine hydrochloride, triethylamine hydrochloride, and pyridine sulfate are preferable. And triethylamine sulfate or the like, more preferably pyridine trifluoroacetate.

Propionaldehyde and other aldehyde derivatives (D5) can be deprotonated by a terminal hydroxyl group, reacted with a halogenated product to obtain an acetal intermediate (D7), and the compound (D7) is hydrolyzed under acidic conditions to obtain a corresponding aldehyde. The base to be used for protonation is not particularly limited, and is preferably sodium metal, potassium, sodium hydride, potassium hydride, sodium methoxide, potassium t-butoxide or diphenylmethyl potassium, and more preferably sodium hydride or potassium diphenylmethyl. The reaction solvent is not particularly limited, and an aprotic solvent is preferred. The acetal deprotection is carried out under acidic conditions, and the pH of the solution is preferably from 1 to 4. The acid is not particularly limited, and is preferably acetic acid, phosphoric acid, sulfuric acid, hydrochloric acid, or nitric acid, and more preferably hydrochloric acid. The reaction solvent is not particularly limited as long as it can dissolve the reactants and products, and water is preferred.

The acetal derivative (D7) can also be reacted with a corresponding alcohol by a polyethylene glycol aldehyde derivative (D5) under the catalysis of an acid to obtain an aldehyde-protected form of polyethylene glycol (D7). The acid is not particularly limited and may be a protic acid or a Lewis acid, and among them, hydrochloric acid, sulfuric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, aluminum trichloride, tin chloride or the like is preferable. Among them, a protic acid is preferred, and hydrochloric acid, sulfuric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, phosphoric acid, and nitric acid are more preferred. Preferably, the protic acid, more preferably the alcohol, is not particularly limited and may be a monohydric alcohol, a dihydric alcohol or a polyhydric alcohol, of which methanol, ethanol, propanol, butanol, pentanol, ethylene glycol, and 1,3-propanediol are preferred. 4-butanediol and the like. The solvent can be a solventless or aprotic solvent.

The isocyanate (D9) or thioisocyanate (D10) derivative can be obtained by reacting an alcohol (H1) or an amine derivative (C3) with an excess of a diisocyanate or a dithioisocyanate. The diisocyanate and the dithioisocyanate are not particularly limited, and preferably contain C _1-10 diisocyanate or C _1-10 dithioisocyanate. The solvent can be a solventless or aprotic solvent. The diisocyanate includes, but is not limited to, 1,6-hexamethylene diisocyanate, dimethylbiphenyl diisocyanate, methylene di-p-phenyl diisocyanate, p-phenylene diisocyanate, toluene-2,4-diisocyanate, 1, 5-naphthalene diisocyanate, m-xylylene diisocyanate, isophorone diisocyanate, 4,4-diisocyanate dicyclohexylmethane, bis(2-isocyanate)-5-norbornene-2,3-dimethyl Acid ester.

The square acid ester (D24) can be obtained by a reaction between an amine derivative (C3) and a squaric acid diester.

The sulfonic acid derivative (D25) can be obtained by alkylation of a haloalkylsulfonic acid (e.g., 2-bromoethylsulfonic acid) with a terminal hydroxyl group.

The oxycarbonyl chloride derivative (D29) can be obtained by reacting a terminal hydroxyl group (H1) with triphosgene under basic conditions. The base is preferably an organic base such as dimethylaminopyridine. The solvent is preferably an aprotic solvent, such as dichloromethane.

2.1.1.5. Class E: R _{01 is} selected from the functionalization of class E

The maleimide derivative (E1) can be subjected to ring-opening reaction with an amine compound (C3) with maleic anhydride to obtain an acid intermediate (E6), which is then subjected to a ring-closing condensation reaction under the catalysis of acetic anhydride or sodium acetate. The reaction solvent is not particularly limited, and an aprotic solvent is preferred. In the ring closure condensation reaction, the solvent is not limited, and the above aprotic solvent or acetic anhydride is preferred.

The maleimide derivative (E1) can also be obtained by a condensation reaction of an amine compound (C3) with an acid or an active ester containing a maleimide group (MAL). Acids containing MAL groups include, but are not limited to, 3-maleimidopropionic acid, 4-maleimidobenzoic acid, 6-maleimidocaproic acid, 11-maleimidoyl ten Alkanoic acid. Active esters containing MAL groups include, but are not limited to, maleimidoacetic acid succinimidyl ester, 3-maleimidopropionic acid hydroxysuccinimide Ester, 6-(maleimido)hexanoic acid succinimide ester, 3-maleimidobenzoic acid succinimide ester, 4-(N-maleimidomethyl) Cyclohexane-1-carboxylic acid succinimide ester, 4-(4-maleimidophenyl)butyric acid succinimide ester, 11-(maleimido)undecanoic acid Succinimide ester, N-(4-maleimidobutyryl) succinimide. Similarly, the diazamaleimide derivative (E6) can also be obtained by a condensation reaction of the amine compound (C3) with the corresponding acid or active ester.

The maleimide derivative (E1) can also be obtained by a condensation reaction of an active ester derivative (A1-A10, A15-A18) with an amine containing a MAL group. Amines containing a MAL group include, but are not limited to, N-(2-aminoethyl)maleimide, N-(4-aminophenyl)maleimide.

The maleimide protected form compound (E4) can be obtained by substituting a terminally activated alcoholic hydroxyl group with a tetrahydrofuran-protected maleimide reaction. The maleimide protected form compound (E4) of polyethylene glycol is deprotected by high temperature heating to obtain a maleimide derivative E1. Among them, the alcoholic hydroxyl activator is not particularly limited, and a combination of diisopropyl azodicarboxylate and triphenylphosphine is preferred. The reaction solvent is not particularly limited, and an aprotic solvent is preferred.

The α,β-unsaturated esters (E2, E3) can be obtained by deprotonating the terminal hydroxyl group and reacting with the corresponding halogenated product. The deprotonated base is not limited, and is preferably sodium metal, potassium, sodium hydride, potassium hydride, sodium methoxide, potassium t-butoxide or diphenylmethyl potassium, more preferably sodium hydride or potassium diphenylmethyl. The reaction solvent is not limited, and an aprotic solvent is preferred. The halogenated substance is, for example, acryloyl chloride or methacryloyl chloride.

The maleamic acid derivative (E6) can also be reacted with the corresponding dicarboxylic acid by the amine derivative (C3) in the presence of a condensing agent to give the corresponding amide derivative. The condensing agent is not particularly limited to a condensing agent, and is preferably DCC, EDC·HCl, HATU, HBTU, and most preferably DCC. The solvent can be a solventless or aprotic solvent. The base includes generally an organic base, preferably triethylamine, pyridine.

2.1.1.6. Class F: R _{01 is} selected from the functionalization of class F

The nitrile compound (F1) can be obtained by an addition reaction between a terminal hydroxyl group and acrylonitrile under basic conditions. It can also be obtained by subjecting the amine derivative (C3) to nickel or palladium-carbon catalysis, first pressurizing with ammonia, then pressurizing with hydrogen, and then dehydrogenating under high temperature conditions.

The functionalized derivatives (F2, F3, F4, F5) can be obtained by deprotonating the terminal hydroxyl group and then substituting the corresponding halogenated material. The deprotonated base is not limited, and is preferably sodium, potassium, sodium hydride, potassium hydride, sodium methoxide, potassium t-butoxide or diphenylmethyl potassium, more preferably sodium hydride or potassium diphenylmethyl. The reaction solvent is not particularly limited, and an aprotic solvent is preferred. Examples of the halogenated compound corresponding to the epoxy compound (F5) include epichlorohydrin, 2-chloromethyl-2-methyloxirane, 3-chlorophenylethylene oxide, fluorofluoropropane, and a ring. Oxybromopropane, 4-bromo-1,2-epoxybutane, 6-bromo-1,2-epoxyhexane, etc.; preferably epichlorohydrin. Examples of the halogenated product corresponding to the ethylene compound (F2) include 3-chloroethylene and 3-bromoethylene. The halogenated product corresponding to the acetylene compound is, for example, 3-bromopropyne. Examples of the halogenated product corresponding to the protected acetylene compound are, for example, 3-methylsilylbromopropyne and 3-tert-butyldimethylsilylbromopropyne.

The cyanide oxide (F11) can be obtained by oxidizing the aldehyde derivative (D5) and hydroxylamine to form hydrazine (F12). In the reaction to form a hydrazine, the solvent may be a solventless or aprotic solvent. The oxidizing agent is not particularly limited in the oxidation process, and one or a combination of N-iodosuccinimide, N-chlorosuccinimide, N-bromosuccinimide, or the like is preferable. The solvent can be a solventless or aprotic solvent.

2.1.1.7. Class G: R _{01 is} selected from the functionalization of class G

The cycloalkyne compound (G1-G3, G19-G22), the cyclic diolefin compound (G12, G9), and the furan compound (G5) can pass through an alcohol, a carboxylic acid, an amine, an amide, a methyl ester derivative having a corresponding ring structure. It is obtained by a condensation reaction with a corresponding reactive group to form a linking group including, but not limited to, an ester bond, an amide bond, a urethane bond, a carbonate bond, a hydrazide bond or the like. Examples of raw materials are as follows:

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2.1.1.8. Class H: R _{01 is} selected from the functionalization of class H

The product obtained after the polymerization of ethylene oxide is a mixture of an alcohol and an oxygen anion, which is protonated to obtain a polyethylene glycol chain having a terminal hydroxyl group.

The alcohol derivative (H1) having a hydroxyl group at the end can also be obtained by modifying a non-hydroxyl reactive group, for example, an ethylene carbonate reacts with a secondary amine to form an alcohol having a structure of -NH-CH(=O)CH ₂ CH ₂ OH. .

The alcohol derivative (H1) having a hydroxyl group at the end can also be obtained by subjecting the amine derivative (C3) to diazotization with nitrite and hydrolyzing under low temperature acidic conditions. The acid is not particularly limited and may be a protic acid or a Lewis acid. Among them, a protic acid is preferred, and hydrochloric acid, sulfuric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, phosphoric acid, and nitric acid are more preferred. The low temperature is preferably about 0 °C.

The protected hydroxyl group (H2) can be obtained by reacting a terminal hydroxyl group with a protective agent. The general protective agent is not particularly limited, and a halogenated silane, a carboxylic acid, an acid chloride, an acid anhydride, a halogenated hydrocarbon, a sulfonyl chloride, an alkenyl ether, a carbonyl group, etc. are preferable. .

A. Generally, the terminal hydroxyl group is reacted with a halosilane, an acid chloride, an acid anhydride, a sulfonyl chloride or a halogenated hydrocarbon in the presence of a neutral or a base to give a protected form (H2). The solvent can be a solventless or aprotic solvent. The base includes an organic base or an inorganic base, preferably an organic base, more preferably triethylamine or pyridine. The protected form OPG _{4 of} the ether structure is consistent with the above.

B. The terminal hydroxyl group is reacted with a carboxylic acid in the presence of a base and a condensing agent to obtain (H2), and the reaction conditions are similar to the method for preparing an active ester when R _{01 is} selected from the group A.

C. The terminal hydroxyl group is subjected to an addition reaction with an alkenyl ether in the presence of an acid to obtain (H2), and the alkenyl ether is not particularly limited, and among them, ethyl vinyl ether or tetrahydropyran is preferable. Among them, the acid is not particularly limited and may be a protic acid or a Lewis acid. The solvent can be a solventless or aprotic solvent.

D, terminal hydroxyl group and tert-butyldimethylchlorosilane, vinyl ethyl ether, dihydropyran, benzyl bromide, di-tert-butyl dicarbonate can be respectively a silicon group, a vinyl ether group, a dihydropyranyl group, Benzyl, Boc protected hydroxyl.

The terminally protected bishydroxy (H3) may be employed including, but not limited to, the literature "Macromol. Biosci. 2011, 11, 1570-1578", and the literature "J. Am. Chem. Soc., Vol. 123, No. 25, 2001. The method of getting it.

Photoreactive groups (H6) and (H7) which can be converted to the enol hydroxyl group can be prepared by the method of US Pat. No. 14,021,040.

2.1.1.9. Class I: R _{01 is} selected from the functionalization of a group I group

The PEGylated folic acid (I1) can be obtained by a condensation reaction of a carboxyl group in folic acid with a polyethylene glycol alcohol or an alcohol derivative (H1) or an amine derivative (C4), wherein the condensing agent is not particularly limited, but Preferred DCC, EDCHCl, HATU, HBTU, most preferably DCC. While the molar ratio of the folic acid of the general condensing agent is from 1 to 20 times, preferably from 5 to 10 times, a suitable catalyst such as 4-dimethylaminopyridine can be added to this reaction. The solvent can be a solventless or aprotic solvent. The base includes generally an organic base, preferably triethylamine, pyridine.

The PEGylated cholesterol (I2) can be carried out by a polyethylene glycol terminal hydroxyl group and a carboxylic acid (D4), an acid halide (D6), a sulfonyl chloride (D27), an isocyanate (D9), an isothiocyanate (D10), or the like. The condensation reaction is obtained. Pegylated cholesterol can also be obtained by a coupling reaction of a derivative of cholesterol with a suitable group. Taking cholesteryl hydrosuccinate as an example, it can be obtained by a condensation reaction with a terminal hydroxyl group of polyethylene glycol.

The PEGylated biotin (I3) can be obtained by a condensation reaction of a carboxyl group in biotin with polyethylene glycol or an alcohol derivative (H1) or an amine derivative (C3). The reaction conditions are in agreement with the above reaction between a carboxyl group and a hydroxyl group. Biotin derivatives such as D-desulfurized biotin and 2-iminobiotin can also be obtained by condensation reaction of a carboxyl group with polyethylene glycol or an alcohol derivative (H1) or an amine derivative (C3).

The PEGylated biotin (I3) can also be obtained by including, but not limited to, the biotin derivative disclosed above in the present invention and an amine derivative (C3) selected from polyethylene glycol, polyethylene glycol, and an alkyne derivative ( A suitable polyethylene glycol or a derivative thereof of the group consisting of F3, G1-G3, G19-G22), a carboxylic acid derivative (D4), an acid halide derivative (D6), an aldehyde derivative (D5), or the like is coupled The reaction was obtained. Among them, the amine derivative and the alcohol derivative of biotin can also be alkylated with the corresponding polyethylene glycol sulfonate or polyethylene glycol halide.

2.1.1.10. Class J: R _{01 is} selected from the functionalization of a J-like group

Fluorescein and its derivatives (including but not limited to J1, J3), rhodamine and its derivatives (including but not limited to J2), purines and their derivatives (J4), purines and their derivatives (J5) , coumarin and its derivatives (including but not limited to J6), fluorescent yellow 3G and its derivatives (including but not limited to J7), carbazole and its derivatives (J8), imidazole and its derivatives (J9), Rhodium and its derivatives (J10), which can be used as active succinimide esters (A1, A6), carboxyl groups (D4), primary amino groups (C3), secondary amino groups (C14), sulfhydryl groups or substituted hydrazines. Base (C12, such as N-aminocarbazole), cyano (F1), maleimide unsaturated bond (E1), maleimide group (D35), aldehyde group (D5), acrylate group (E2), a methacrylate group (E3), a thiol group (F12), a hydroxyl group (H1) and a functionalized polyethylene glycol are coupled to each other to obtain a polyethylene glycol-modified bio-related substance. The coupling reaction includes, but is not limited to, the coupling reaction described above. Among them, the raw materials of the (J1-J10) class include, but are not limited to, the above-mentioned fluorescent reagents of the present invention.

2.1.1.11. Transition of a reactive group to a functional group of interest or its protected form

This can be done in any of the following ways:

Method 1: Direct modification, based on direct modification of a reactive group, to obtain a target functional group or a protected form thereof. By way of example, a transition of a carboxy group to an acid halide, a hydrazide, an ester, a thioester, a dithioester, such as a transition of a hydroxyl group, a decyl group, an alkynyl group, an amino group, a carboxyl group, etc. to a corresponding protected structure, and the like. Further, for example, the modification of an acid anhydride to a hydroxyl group, an amino group, or the like.

Mode 2: a coupling reaction between two reactive groups, starting from a reactive group containing one reactive group and a functional group of interest or a protected form thereof, through one of the reactive groups The reaction between the group and the reactive group at the end of the polyethylene glycol chain introduces the target functional group or its protected form. The reaction mode and method between the two reactive groups are not particularly limited, and the reaction conditions are related to the type of divalent linking group formed by the reaction, and the prior art can be employed. Such as alkylation, alkenyl addition reaction, alkynyl addition reaction, Schiff base reaction combined reduction reaction, condensation reaction and the like. Among them, the alkylation reaction is preferably a reaction based on alkylation of a hydroxyl group, a mercapto group or an amino group, which in turn corresponds to formation of an ether bond, a thioether bond, a secondary amino group or a tertiary amino group. The condensation reaction includes, but is not limited to, a condensation reaction which produces an ester group, a thioester group, an amide group, an imine bond, a hydrazone bond, a carbamate group or the like. Another example is a group containing an azide, an alkynyl group, an alkenyl group, a trithioester group, a decyl group, a dienyl group, a furyl group, a 12,4,5-tetraazinyl group, a cyanate group, and the like, or a functional group thereof or The protected form of the heterofunctionalizing reagent is used as a starting material to introduce a target functional group or a protected form thereof by a click reaction. The reaction between two reactive groups is accompanied by the formation of a new bond, and the typical representative of the newly formed divalent linking group is an amide bond, a urethane bond, an ester group, a secondary amine bond, a thioether bond, a triazole group. Wait.

Mode 3: The target functional group or its protected form is obtained by a combination of direct modification and coupling reaction.

2.1.2. Branching Functionalization of Polyethylene Glycol Chain Ends

Branched functionalization refers to the introduction of a branched group linking functional group or a protected form thereof at the end of a polyethylene glycol chain. At this time, the number of functional groups at the end of the corresponding polyethylene glycol chain or the protected form thereof is greater than 1. The end of the polyethylene glycol chain introduced into the branching group may be a hydroxyl group or a linearly functionalized reactive group.

2.1.2.1. End branching functionalization method

Wherein, when p _i (i=1, 2, 3) is 0 or 1, the functionalization modification process of the branched terminal includes introduction of a branching group, introduction of a functional group or a protected form thereof . There are no special restrictions on the succession of these two links. At this point, the implementation of the terminal branching functionalization includes, but is not limited to, the following: (1) the functionalized branching group directly reacts with the terminal hydroxyl group of the polyethylene glycol chain; (2) the main chain polyethylene glycol The terminal hydroxyl group is functionalized and then reacted with the functionalized branching group; (3) the branching group is introduced first, and the branching group is functionalized. Wherein, the introduction of a branching group may or may not form a linking group L ₄ or L ₆ . Taking the terminal hydroxyl group of polyethylene glycol as an example: when the branching group is linked by an alkylation reaction, the branching group reagent loses the leaving group, and the hydroxyl group loses the hydrogen atom, which can be regarded as the formation of no linker; For example, when the terminal hydroxyl group of the polyethylene glycol reacts with a group such as an isocyanate or a carboxyl group, the entire group of the formed bond NHCOO, COO, or the like, or a part of the group NHCO, CO, or the like is contained in L ₄ or L ₆ ; Further, a succinic acid functionalized polyethylene glycol terminal is reacted with a branching reagent to form a succinyl group in the linking group. The above-described method of functionalizing the branching group is not particularly limited, and includes a hydroxyl group-based functional modification, and also includes conversion to a new functional group based on a non-hydroxy functional group or a protected form thereof.

When p _i (i=1, 2, 3) is greater than 1, the branched functionalization modification of the terminal includes the introduction of a linker, the introduction of a branching group, the introduction of a target functional group or a protected form thereof. Link. The linker is not particularly limited, and may, for example, include a repeating fragment of an amino acid, a polypeptide or the like. Starting from the terminal hydroxyl group of the polyethylene glycol or the terminal functional group, the order of the above three steps and the combination thereof are not particularly limited. The terminal branching functionalization of the main chain polyethylene glycol is exemplified, including but not limited to the following four modes: (1) one-time introduction of a linking group, a branching group, and a functional group or a protected form thereof; 2) first introducing a linking group, then introducing a branching group and a target functional group or a protected form thereof; (3) introducing a linking group first, then introducing a branching group, and then introducing a target functional group or Protected form; (4) first introducing a linking group and a branching group, and then introducing a target functional group or a protected form thereof.

The method of introducing the above-mentioned branching group is not particularly limited, and the prior art in the chemical field may be employed as long as a covalent linkage bond can be formed, including but not limited to the target functional group of the above reactive group or Various coupling reactions when the form of protection is changed. By way of example, the literature is "Macromolecules 2013, 46, 3280-3287", the literature "Macromol. Chem. Phys. 2014, 215, 566-571", the literature "Macromolecules, 2012, 45, 3039-3046", the literature "Polym. Chem." , 2012, 3, 1714-1721, US 5, 811, 510, US 7,790, 150, US 7,838, 619, etc., in the preparation of a comb structure, such as the document "Journal of Polymer Science, Part A: Polymer Chemistry, 2013, 51, 995-1019" Hyperbranched structure in the literature "Macromol.Biosci.2011, 11, 1553-1562", the literature "Macromol.Rapid Commun.2010, 31,1811-1815", "Langmuir 2010,26(11),8875-8881" The preparation is as described in the literature "Nanoscale Research Letters, 2014, 9:247", the literature "J. Movellan et al. Biomaterials 35 (2014) 7940-7950", and the literature "Chem. Soc. Rev., 2011, 40, 2673". -2703", the literature "Macromolecules, Vol.33, No.12, 2000", the literature "Chem.Soc. Rev., 2011, 40, 2673-2703", the literature "Biomacromolecules 2012, 13, 4089-4097", etc. Preparation of tree structure and so on.

The functionalization method of the terminal of the branching group is not particularly limited and includes, but is not limited to, the linear functionalization method described above.

2.1.2.2. End-branched functionalized raw materials

)、含1个环氧基的磺酸酯、含1个环氧基的卤代物、含一个环氧基和1个其它反应性基团的化合物构成的组。还包括伯胺与2分子丙烯酸酯进行Michael加成反应的组合。还可以采用硫辛酸封端后，对双硫键进行还原而开环，得到末端两个巯基。When terminal difunctionalization is carried out, it is preferred from the above heterofunctionalized small molecule htriSM containing a trivalent core structure, an aldehyde having one epoxy group, and an alcohol having one epoxy group (eg

a group consisting of a sulfonate containing one epoxy group, a halogenated product containing one epoxy group, a compound containing one epoxy group and one other reactive group. Also included is a combination of a primary amine with a two molecule acrylate for a Michael addition reaction. It is also possible to use a lipoic acid to terminate the disulfide bond to reduce the ring opening to obtain two terminal thiol groups.

Wherein, the htriSM contains two different functional groups, one of which is one and the other of which is two. The heterofunctional groups which may be present at the same time include, but are not limited to, those listed in section 1.1.4. above.

The htriSM includes, but is not limited to, an alcohol, a thiol, a primary amine, a secondary amine, a sulfonate or a halogenated product having two exposed hydroxyl groups or two protected hydroxyl groups (also as triethanolamine p-toluenesulfonate, monothioglycolic acid) Glyceride, 3,4-dihydroxy-2'-chloroacetophenone and the protected form of the above-mentioned htriSM hydroxy group), containing two thiol groups or two protected thiol alcohols, thiols, primary amines, secondary amines, sulfonates An acid ester or a halogenated product (also as a protected form of dimercaptopropanol and its sulfhydryl group) containing two primary amino groups, two secondary amino groups, two protected primary amino groups or two protected secondary amino groups, a thiol, A primary amine, a secondary amine, a sulfonate or a halogenate, and the like, including but not limited to any of the htriSMs used in the polymerization process of 2.1. above. Among them, an alcohol containing two primary amines is, for example, 1,3-diamino-2-propanol.

The htriSM further includes, but is not limited to, a primary amine having 2 hydroxyl groups, an aldehyde containing 2 protected hydroxyl groups, an aldehyde having 1 epoxy group, a primary amine having 1 epoxy group, and 2 primary amino groups. The secondary amine, the sulfonic acid containing two hydroxyl groups, the carboxylic acid containing two hydroxyl groups, the azide compound containing two hydroxyl groups, and the above-mentioned hydroxyl group are protected forms. The primary amine containing two hydroxyl groups includes, but is not limited to, 2-amino-1,3-propanediol, 2-amino-2-methyl-1,3-propanediol, N,N-bis(2-hydroxyethyl) Ethylenediamine, 3-amino-1,2-propanediol, 2-amino-1-[4-(methylthio)phenyl]-1,3-propanediol, 2-amino-1-phenyl-1,3 - propylene glycol, 2-(3,4-dihydroxyphenyl)ethylamine, 2-amino-1,3-benzenediol, and the like. The secondary amine containing two primary amino groups includes, but is not limited to, diethylenetriamine, N-(3-aminopropyl)-1,4-butanediamine, 3,3'-diaminodipropylamine, N-(2-Aminoethyl)-1,3-propanediamine, 3,6-diaminocarbazole, and the like. The sulfonic acid containing two hydroxyl groups includes, but is not limited to, 6,7-dihydroxynaphthalene-2-sulfonic acid, 1,4-dihydroxyindole-2-sulfonic acid. The hydroxy group-containing carboxylic acid (dihydroxy monocarboxylic acid) includes, but is not limited to, 2,3-dihydroxypropionic acid, 2,2-dimethylolpropionic acid, 2,4-dihydroxy-3,3 - dimethylbutyric acid, N,N-dihydroxyethylglycine, 2,3-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid, 2,5-dihydroxybenzoic acid, 2,6-dihydroxyl Benzoic acid, 3,4-dihydroxybenzoic acid, 3,5-dihydroxybenzoic acid, 3,4-dihydroxyphenylacetic acid, 3,5-dihydroxyphenylacetic acid, 3,4-dihydroxycinnamic acid, 2, 6-Dihydroxypyridine-4-carboxylic acid, 4,8-dihydroxyquinoline-2-carboxylic acid. The azide compound containing two hydroxyl groups includes, but is not limited to, 3-azido-2,3-dideoxy-1-O-(tert-butyldimethylsilyl)-β-D-arab-six Pyranose, 2,2-dimethylolpropionic acid azidohexyl ester. Wherein, two hydroxyl groups are protected, taking bishydroxyl protection as an example, such as

等，及上述任一种的数量为2的官能团被保护的形式。The htriSM also includes, but is not limited to, 3-allyloxy-1,2-propanediol, 5-norbornene-2,3-dicarboxylic acid, 1-propynyl glyceryl ether, 2,6-dihydroxyl 3-cyano-4-methylpyridine, 1,3-dibromo-2-propanol, 2,3-dibromo-1-propanol, 1,4-dibromo-2-butanol, 1, 4-Diazido-2-butanol, 1,3-dichloropropanol, 4,4'-dichlorodibenzyl alcohol, 2-bromomalonaldehyde, 2-hydroxyhexanedialdehyde, 2-(4 -chlorophenyl)malonaldehyde, 2-(3-hydroxycarbonyl-6-pyridyl)malonaldehyde, 7-amino-1,3-naphthalene disulfonic acid, 4-chloro-1,2-phenylenediamine , 4-bromo-o-phenylenediamine, 6,8-dimercaptooctanoic acid, 4-chloro-1,3-benzenedithiol, 2,6-di(p-azidobenzylidene)-4-carboxycyclohexane Ketone, hydroxy dicarboxylic acid (including but not limited to propanol diacid, L-malic acid, D-malic acid, citramalic acid, 3-hydroxyglutaric acid), amino dicarboxylic acid (including but not limited to 2 -aminomalonic acid, diethyl 2-aminomalonate, 3-aminoglutaric acid), mercapto dicarboxylic acid (including but not limited to mercapto succinic acid), 4-chlorophthalic acid, 2- Bromosuccinic acid, methylene succinic acid, 4-amino-2-(2-aminoethylamino)butyric acid, two amino-protected 4-amino-2-(2-aminoethylamino) ) butyric acid, glyceryl dimethacrylate, 2,2-bis(allyloxymethyl)-1-butanol,

And the like, and the functional group of the number 2 of any of the above is protected.

The htriSM also includes, but is not limited to, lysine, two amino-protected lysine, glutamic acid, and aspartic acid.

Since both hydrogens in the primary amine can be substituted to form a trivalent N-branch center, hetero-functionalized small molecules containing one primary amino group and another reactive group can also be used as the htriSM. For example, diglycolamine, 2-(2-aminoethenyl)ethanol, 1-amino-2-propanol, 4-hydroxyphenethylamine, mercaptoethylamine, N-methyl-1,3-propane Amine, N-ethyl-1,3-propanediamine, N-isopropyl-1,3-propanediamine.

For terminal trifunctionalization, including but not limited to the use of a tetrafunctional small molecule htetraSM comprising three hydroxyl groups and another reactive group, including but not limited to: N-trishydroxymethylmethyl-2-amino Sulfonic acid, trishydroxymethylmethylaminopropanesulfonic acid, methyl-6-O-p-toluenesulfonyl-α-D-glucoside, 2-(bromomethyl)-2-(hydroxymethyl)-1 , 3-propanediol, tris, 3-amino-1,3,4-octadecanol, 3-aminopropylsilane triol, 4-(2-amino-1-hydroxyethyl) -1,2-benzenediol, 4-[(2-isopropylamino-1-hydroxy)ethyl]-1,2-benzenediol, 3,4-dihydroxy-α-((methylamino)- Benzyl alcohol, 2,5-anhydro-1-azide-1-deoxy-D-glucitol, 2,3,4-trihydroxybutanal (L-erythrose, D-erythrose, L- (+)-threose, D-(+)-threose), 2,3,4-trihydroxybenzaldehyde, 3,4,5-trihydroxybenzaldehyde, tris(hydroxymethyl)methylglycine, 2 , 3,4-trihydroxybutyric acid (including but not limited to erythric acid, threonic acid), 2,4,6-trihydroxybenzoic acid, shikimic acid, 3,4,5-trihydroxybenzoic acid, 2, 3,4-trihydroxybenzoic acid, arsenic acid, 1,4,7-tri-tert-butoxycarbonyl-1,4,7,10-tetraazacyclododecane, three uncle Butyloxycarbonyl spermine, 1,4,7-tri-tert-butoxycarbonyl-1,4,7,10-tetraazacyclododecane, and the like, and a hydroxy group of any of the above is protected. It may also be selected from the group consisting of citric acid, abietic acid, N-hydroxyethylethylenediaminetriacetic acid, pentaerythritol triacrylate, aminomethane tripropionic acid, aminomethane tripropionate tri-tert-butyl ester, and the like. Also included are terminal branching reactions based on alkenyl, trichlorosilane and allylmagnesium chloride, and reference is made to the document "Macromolecules, Vol. 33, No. 12, 2000" to form a tetravalent silicon-based branching center. Also included are terminal branching reactions based on alkenyl, trichlorosilane and allyl alcohol to form tetravalent siloxane branching centers. It may also include trifunctionalized small molecules such as 1,4,7-tris(tert-butoxycarbonylmethyl)-1,4,7,10-azacyclotetradecane (NOTA), such as three Functionalized small molecules require an excess.

When terminal tetrafunctionalization is carried out, the starting material may be selected from the group consisting of pentafunctional xylitol, 1,5-anhydroglucitol, bis(2-hydroxyethyl)amino(trimethylol)methane, and miglitol. , D-(+)- talose, arbutin, diethylenetriamine pentaacetic acid, and the like. However, heteropentafunctional small molecules containing two functional groups are preferred. Including but not limited to 1,2,5,6-diisopropylidene-α-D-isofuranosyl, 2,3,5,6-di-O with four protected hydroxyl groups and one reactive group -cyclohexylene-α-D-mannose, 2-azido-1,3-bis[(2,2-dimethyl-1,3-dioxan-5-yl)oxopropane, etc. . Also included are, but are not limited to, molecules containing two epoxy groups and one reactive group. It is also preferred to have two functional groups, one of which is 4, another quantity of 1, a pentafunctionalized small molecule hpentSM: 2-(2-hydroxyethylamino)-2-hydroxymethyl-1,3-propanediol , 2-hydroxymethylpiperidine-3,4,5-triol, 6-amino-4-(hydroxymethyl)-4-cyclohexyl-[4H,5H]-1,2,3-triol, Fenoterol, benserazide, 1-azido-1-deoxy-β-D-galactopyranoside, 2-azidoethyl-β-D-glucopyranoside, 2,3,4, 5-tetrahydroxypentanal (including but not limited to ribose, arabinose, xylose, lyxose), 2,3,4,5-tetrahydroxyvaleric acid (including but not limited to ribonic acid, arabinic acid, woody A functional group having a number of 4 in which any of the above is protected by acid, lysine, diethylenetriamine, N-(3-aminopropyl)-1,4-butanediamine, and the like.

When performing terminal penthouse functionalization, the starting material preferably contains two functional groups, one of which is 5, and another quantity of 1 is a hexafunctionalized small molecule hexaSM, including but not limited to: sorbitol, mannitol, D-tower Rotitol, D-glucosamine, 1-mercaptosorbitol, N-methyl-D-glucosamine, 2,3,4,5,6-pentahydroxyhexanal (including but not limited to β-D -alose, D-aldose, D-anhydrous glucose, D-(+)-mannose, L(-)-mannose, D-gulose, idose, D-galactose, L -(-)- talose, D-(+)-talose, 2,3,4,5,6-pentahydroxyhexanoic acid (including but not limited to aralonic acid, albinoic acid, Portuguese a functional group having a number of 5 of any of the above, such as sugar acid, mannonic acid, gulonic acid, iduronic acid, galactonic acid, tartaric acid, D-sorbitol-3-phosphate, etc. The form of protection.

环氧 氯丙烷、氨基被保护的赖氨酸、谷氨酸、天冬氨酸、N,N-二羟乙基甘氨酸及其羟基被保护形式、二羟基一元羧酸及其羟基被保护形式、羟基二元羧酸及其羟基被保护形式、氨基二元羧酸及其氨基被保护形势、巯基二元羧酸及其巯基被保护形式、甘油醛及其羟基被保护形式、甲基-6-O-对甲苯磺酰基-α-D-葡萄糖苷、3-氨丙基硅烷三醇、2,3,4-三羟基丁醛、2,3,4-三羟基丁酸、柠檬酸、N-羟乙基乙二胺三乙酸、

2-叠氮基-1,3-双[(2,2-二甲基-1,3-二恶烷-5-基)氧代]丙烷等。其中，二羟基一元羧酸优选2,2-二羟甲基丙酸。羟基二元羧酸优选苹果酸、3-羟基戊二酸。The starting material for preparing the dendritic structure may be selected from the group consisting of, but not limited to, htriSM, htetraSM, hpentSM, hexaSM, a heterofunctional molecule containing one epoxy group and another reactive group, and two acetylenes. Combination of htriSM, diallyl (meth) silane, acrylate and diamine with a protected or ethynyl group and another reactive group (repeated Michael addition reaction of primary amine with 2 molecules of acrylate, Combination of amidation of ester groups), propargyl glycidyl ether with mercaptoethylamine, mercaptoethylamine hydrochloride or amino-protected mercaptoethylamine (repeating the addition reaction of primary amino groups with epoxy groups, alkynyl groups) Reaction with two thiol groups, diallylmethylsilane, and the like. Specific examples

Epichlorohydrin, amino protected lysine, glutamic acid, aspartic acid, N,N-dihydroxyethylglycine and its hydroxy protected form, dihydroxy monocarboxylic acid and its hydroxy group protected form, The hydroxy dicarboxylic acid and its hydroxyl group are protected, the amino dicarboxylic acid and its amino group are protected, the mercapto dicarboxylic acid and its mercapto group are protected, the glyceraldehyde and its hydroxyl group are protected, methyl-6- O-p-toluenesulfonyl-α-D-glucoside, 3-aminopropylsilane triol, 2,3,4-trihydroxybutanal, 2,3,4-trihydroxybutyric acid, citric acid, N- Hydroxyethylethylenediaminetriacetic acid,

2-azido-1,3-bis[(2,2-dimethyl-1,3-dioxan-5-yl)oxopropane and the like. Among them, the dihydroxy monocarboxylic acid is preferably 2,2-dimethylolpropionic acid. The hydroxy dicarboxylic acid is preferably malic acid or 3-hydroxyglutaric acid.

(3-乙基-3-氧杂丁环甲醇)、

丙烯酸酯与二元胺的组合等。Monomers for preparing hyperbranched structures include, but are not limited to, the monomers disclosed in the journal Journal of Polymer Science, Part A: Polymer Chemistry, 2013, 51, 995-1019, for example: glycidol,

(3-ethyl-3-oxabutanemethanol),

A combination of an acrylate and a diamine, and the like.

(Z₁、q₁、R₀₁的定义与上述一致，优选被保护形式，优选形式之一为被保护的羟基OPG₄，如1-乙氧基乙基-2,3-环氧丙醚、苄基缩水甘油醚、叔丁基缩水甘油醚、烯丙基缩水甘油醚、炔丙基缩水甘油醚、甲基丙烯酸缩水甘油酯、

)、

(举例如甲基丙烯酸叠氮丙酯)、二氧化碳与

的组合(如《Macromolecules 2013,46,3280-3287》，又如二氧化碳与选自

炔丙基缩水甘油醚等中任一种而形成的组合)、二异氰酸酯与含1个反应性基团或其被保护形式的二元醇的组合、

与二元胺的组合(形成悬挂多个巯基的梳状物，Macromol.Rapid Commun.2014,35,1986-1993)、D-吡喃葡萄糖单元(形成缩醛化聚糖结构，举例如聚(1→6)己糖、2,1-聚果糖，具体如US5,811,510,US7,790,150,US7,838,619中所记载的葡聚糖及其氧化结构、多聚果糖结构)、赖氨酸、天冬氨酸、谷氨酸等。其它的三元醇、含一个被保护羟基的三元醇、四元醇、含2个被保护羟基的四元醇、含2个裸露羟基且其它羟基被保护的多元醇均可作为制备梳状结构的原料。此外，梳状结构还可为非重复的结构，举例如由其它氨基酸(如甘氨酸)作为间隔基团，连接2个以上的选自赖氨酸、天冬氨酸、谷氨酸的任1种或1种以上的氨基酸而形成多肽结构。此外，包括但不限于上述的2,3,4,5-四羟基戊醛、2,3,4,5-四羟基戊酸、2,3,4,5,6-五羟基己醛、2,3,4,5,6-五羟基己酸、D-萄糖胺、1-巯基山梨糖醇、N-甲基-D-葡糖胺、D-山梨糖醇-3-磷酸酯等可以直接作为制备梳状支化末端的原料。 Monomers for preparing a comb structure having repeating units, including but not limited to: 2-position hydroxyl protected glycerol (forming polyglycerol structure), two hydroxyl protected pentaerythritol (such as monobenzaldehyde pentacene tetraol, Forming polypentaerythritol),

(Z ₁ , q ₁ , R ₀₁ are as defined above, preferably in protected form, one of which is protected hydroxy OPG ₄ , such as 1-ethoxyethyl-2,3-epoxypropyl ether, Benzyl glycidyl ether, tert-butyl glycidyl ether, allyl glycidyl ether, propargyl glycidyl ether, glycidyl methacrylate,

),

(for example, azidopropyl methacrylate), carbon dioxide and

Combination (such as "Macromolecules 2013, 46, 3280-3287", as well as carbon dioxide and selected

a combination of a propargyl glycidyl ether or the like, a combination of a diisocyanate and a diol having one reactive group or a protected form thereof,

Combination with a diamine (forming a comb that suspends multiple sulfhydryl groups, Macromol. Rapid Commun. 2014, 35, 1986-1993), D-glucopyranose unit (forming an acetalized glycan structure, such as poly( 1→6) hexose, 2,1-polyfructose, specifically glucan and its oxidized structure, polyfructose structure, lysine, day as described in US Pat. No. 5,811,510, US 7,790,150, US 7,838,619 Aspartic acid, glutamic acid, etc. Other triols, triols containing a protected hydroxyl group, tetrahydric alcohols, tetraols containing 2 protected hydroxyl groups, polyols containing 2 exposed hydroxyl groups and other hydroxyl groups can be used as preparation combs The raw material of the structure. Further, the comb structure may also be a non-repetitive structure, for example, by using another amino acid (such as glycine) as a spacer group, and connecting two or more kinds selected from lysine, aspartic acid, and glutamic acid. Or one or more amino acids to form a polypeptide structure. In addition, including but not limited to 2,3,4,5-tetrahydroxypentanal, 2,3,4,5-tetrahydroxypentanoic acid, 2,3,4,5,6-pentahydroxyhexanal, 2 , 3,4,5,6-pentahydroxyhexanoic acid, D-glucosamine, 1-mercaptosorbitol, N-methyl-D-glucosamine, D-sorbitol-3-phosphate, etc. Directly used as a raw material for the preparation of comb-branched ends.

Starting materials for preparing the cyclic structure include, but are not limited to, 2,5-anhydro-1-azide-1-deoxy-D-glucitol, 1,4,7-tri-tert-butoxycarbonyl-1,4,7,10. - tetraazacyclododecane, 2-hydroxymethylpiperidine-3,4,5-triol, 6-amino-4-(hydroxymethyl)-4-cyclohexyl-[4H,5H]-1 , 2,3-triol, 1-azido-1-deoxy-β-D-galactopyranoside, 2-azidoethyl-β-D-glucopyranoside, propargyl-α-D - pyranomannosides, propargyl-α-L-pyranoside, propargyl-β-D-lactoside, monofunctional cyclodextrins (eg mono-6-O-(azido) -β-cyclodextrin, mono-6-O-(p-toluenesulfonyl)-γ-cyclodextrin, mono-2-O-(p-toluenesulfonyl)-γ-cyclodextrin, mono-6-O -(p-toluenesulfonyl)-β-cyclodextrin, mono-2-O-(p-toluenesulfonyl)-α-cyclodextrin).

2.1.3. Coupling reaction process

The selection range of the coupling reaction described in the method is not particularly limited as long as two identical or different reactive groups are reacted to form a covalent linking group. The reaction conditions are related to the type of covalent linker formed by the reaction, and the prior art can be employed. Including, but not limited to, reactions in which any of the reactive groups described in the above-described class A-class H can occur to form a covalent linker. Also included are the types of reactions already mentioned above. The valence state of the covalent linking group may be divalent or trivalent, and the divalent is dominant.

The coupling reaction can form stable groups and can also form degradable groups.

In summary,

For example, an amino group is reacted with an active ester, an acid ester active ester, a sulfonate, an aldehyde, an α, β-unsaturated bond, a carboxylic acid group, an epoxide, an isocyanate or an isothiocyanate to obtain an amide group or a urethane group. a divalent linking group such as an amino group, an imido group (which can be further reduced to a secondary amino group), an amino group, an amide group, an amino alcohol, a urea bond, or a thiourea bond; and the thiol group respectively contains an active ester, an active ester of formic acid, a sulfonate, Mercapto, maleimide, aldehyde, α,β-unsaturated bond, carboxylic acid group, iodoacetamide, anhydride to react to obtain thioester group, thiocarbonate, thioether, disulfide, thioether, a divalent linking group such as a thio-hemiacetal, a thioether, a thioester, a thioether or an imide; an unsaturated bond reacting with a thiol group to obtain a thioether group; and a carboxyl group or an acid halide reacting with a thiol group or an amino group to obtain a thioester group, a group such as an amide group; a hydroxyl group reacts with a carboxyl group, an isocyanate, an epoxide or a chloroformyloxy group to obtain a divalent linking group such as an ester group, a urethane group, an ether bond or a carbonate group; a carbonyl group or an aldehyde group and an amino group; , hydrazine, hydrazide reaction to obtain divalent linkages such as imine bond, hydrazine, hydrazide; azide Alkynyl, alkenyl, decyl, azide, diene, maleimide, 1,2,4-triazoline-3,5-dione, dithioester, hydroxylamine, hydrazide, acrylate, A reactive chemical reaction of a reactive group such as allyloxy, isocyanate or tetrazole can form various divalent linking groups including structures including, but not limited to, triazole, isoxazole, thioether bonds and the like. 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. Specifically, for example, azide-alkynyl cycloaddition reaction, Diels-Alder addition reaction, reaction of producing hydrazine or hydrazide, thiol-vinyl addition reaction, mercapto-alkynyl addition reaction, mercapto-isocyanate reaction, 1 , 3-dipolar cycloaddition reaction, and the like. Also included, but not limited to, the cycloaddition reaction, the Diels-Alder addition reaction, the 1,3-dipolar cycloaddition reaction, and the like which may occur in the above-mentioned G. The primary amine reacts with one molecule of a sulfonate, a halogenated substance, an epoxide, and an α,β-unsaturated bond to obtain a divalent secondary amino group, and when reacted with two molecules, a trivalent tertiary amino group can be formed. Further, as a reaction between a B5 or B6 type functional group and a disulfide bond, a trivalent linking group can be formed.

Typical representatives of the resulting divalent linking group are an amide bond, a urethane bond, an ester group, a secondary amine bond, a thioether bond, a triazole group, and the like. When an amide bond (-CONH-) or an imide (-CON(-) ₂ ) is formed, the synthesis can be carried out by including, but not limited to, the following: (1) by a condensation reaction between an amino group and a carboxyl group; 2) by a reaction between an amino group and a carboxylic acid derivative; (3) by an amidation reaction of a substrate amine with an acid halide, preferably the acid halide is an acid chloride. When a urethane bond (-OCONH-) is formed, it can be obtained by a condensation reaction between a terminal amino group and a terminal activated carbonate; wherein the reactive formate can be a derivative which can react with an amino group to obtain a urethane bond, including Not limited to succinimide carbonate (SC), p-nitrophenol carbonate (p-NPC), 2,4,6-trichlorophenol carbonate, imidazole carbonate, N-hydroxybenzotriazole carbonate Preferred are succinimide carbonate (SC), o-nitrophenol carbonate (o-NPC) and the like; the urethane bond can also be obtained by reacting a hydroxyl group with an isocyanate. When a thio or dithiocarbamate linkage is formed, it can be obtained by reacting a terminal amino group with a terminal thiooxycarbonyl chloride, a hydroxyl group or a mercapto group with an isothiocyanate, or a reaction of a mercapto group with an isocyanate. When an ester bond (-OCO-) is formed, it can be obtained by a condensation reaction of a terminal hydroxyl group with a terminal carboxyl group or an acid halide, which is preferably an acid chloride. When a secondary amine bond (-CH ₂ NHCH ₂ -) is formed, it can be obtained by condensation or reduction between an aldehyde group and an amino group, or can be obtained by an alkylation reaction between a primary amine and a sulfonate or a halogenated product. . When a thioether bond (>CHS-) is formed, it can be obtained by an addition reaction between a terminal thiol group and a maleimide or other reactive group containing an unsaturated bond ("Angew.Chem.Int.Ed. , 2010, 49, 3415-3417,) can also be obtained by alkylation reaction between a terminal sulfhydryl group and a sulfonate or a halogenated product. When a triazole group is formed, it can be obtained by performing a click reaction between an alkynyl group and an azide. When 4,5-dihydroisoxazole is formed, it can be obtained by a 1,3-dipolar cycloaddition reaction between a cyanide oxide and an alkynyl group.

A typical reaction to form a stable divalent linking group is an alkylation type including, but not limited to, a reaction of a hydroxyl group, a mercapto group or an amino group with an alkylation of a sulfonate or a halide, which in turn corresponds to an ether bond, a thioether bond, Formation of a secondary or tertiary amino group.

In this method, some small molecules (biSM) containing two identical or different functional groups are also allowed as raw materials, as a connecting arm between tetraSM and htriSM, or as a connecting arm between htriSM and PEG branching chain or main chain, or in LPEG. A connecting arm between the PEG block and the PEG block. A heterofunctionalized biSM (biheteroSM) is preferred. Typically, such as an amino acid or a derivative thereof, and preferably a neutral amino acid such as glycine, alanine or β-alanine or a derivative thereof. Examples of biheteroSM include, but are not limited to, 2-mercaptoethanol, aminoethylethanolamine, 2-(2-aminoethoxy)ethanol, 2-(2-aminoethylhydrinyl)ethanol, 1-amino-2-propanol Alcohol, 4-hydroxyphenethylamine, 2-azidoethanol, 2-(2-(2-azidoethoxy)ethoxy)ethanol, hydroxycitronellal diethyl acetal, hydroxycarboxylic acid, Aralkyl and aryl substituted hydroxycarboxylic acids, N-hydroxymaleimide, N-(2-hydroxyethyl)maleimide, 3-hydroxybutyronitrile, 4-hydroxy-1-naphthalene sulfonate Acid, 8-hydroxyquinoline-5-sulfonic acid, 2-(p-toluenesulfonyl)ethanol, 1-phenyl-1,2-ethane-2-p-toluenesulfonate, 2-amino-1- Naphthalenesulfonic acid, 8-naphthylamine-1-sulfonic acid, 4-amino-1-naphthalenesulfonic acid, 5-amino-1-naphthalenesulfonic acid, 2-(methylsulfonyl)ethylsuccinimidyl carbonate , 2-chloroethyl p-toluenesulfonate, 3-(2-pyridinedithio)propionic acid N-hydroxysuccinimide ester, 4-toluenesulfonylacetonitrile, 2-(thiophen-2-yl)B 4-methylbenzenesulfonate, mercaptoethylamine, mercaptoethylamine hydrochloride, mercaptoacetic acid, 2-mercaptopropionic acid, 2-aminoethanethiol, 2-azidoethylamine, O-(2- Aminoethyl)-O'-(2-azidoethyl)pentaethylene glycol, 1 -azido-2-(2-(2-chloroethoxy)ethoxy)ethanol, 4-bromobenzenesulfonyl chloride, 3-chloropropanesulfonyl chloride, 3-chloropropionyl chloride, 4-chloromethyl Benzoyl chloride, 4-bromobutyryl chloride, iodoacetic acid, 3-chloropropyl isocyanate, 3-chloro-4-methylphenyl isocyanate, 3-bromophenyl isocyanate, 4-cyanyl cyanate, 3 -Cyanophenyl isocyanate, 2-cyanophenyl isocyanate, Boc-piperazine-2-carboxylic acid, 3,4-morpholinedicarboxylic acid 4-tert-butyl ester, 2,4-morpholinedicarboxylic acid 4-tert Butyl ester, N-benzyl maleic acid, 4-carboxybenzenesulfonyl azide, α-azidoisobutyric acid, p-azidobenzoic acid, N-succinimide 4-azide-2,3,5, 6-tetrafluorobenzoic acid, 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-azidobutanoic acid, acrolein diethyl acetal, bromoacetaldehyde diethyl acetal, 3-bromopropanal dimethyl acetal; 2-bromobenzaldehyde diethyl acetal, 3-(2,2-diethoxy)propyne (propargyl acetaldehyde acetal), 3 -trimethylsilynal aldehyde acetal, maleimidoacetic acid succinimide ester, 3-maleimidopropionic acid hydroxysuccinimide ester, 6-(maleimide Acetyl succinimide ester, 3-maleimidobenzene Acid succinimide ester, 4-(N-maleimidomethyl)cyclohexane-1-carboxylic acid succinimide ester, 4-(4-maleimidophenyl) Acid succinimide ester, 11-(maleimido)undecanoic acid succinimide ester, N-(4-maleimidobutyryl)succinimide, 3-maleyl Iminopropionic acid, 4-maleimidobenzoic acid, 6-maleimidocaproic acid, 11-maleamidodecanoic acid, N-(2-aminoethyl)male Imide, N-(4-aminophenyl)maleimide, 4-pentynoic acid-N-succinimide ester, propargyl chloroformic acid, 2-butyn-1-yl chloroformate , 3-butyn-1-yl chloroformate, 4-ethynylaniline, 2-ethynylaniline, 4-ethynylbenzaldehyde, 4-[(trimethylsilyl)ethynyl]benzaldehyde, 2 -[(Trimethylsilyl)ethynylbenzaldehyde, 3-cyano-2-hydroxypyridine, 3-hydroxybenzonitrile, N-2-cyanoethylsuccinimide, cyanomethylbenzenesulfonic acid Ester, cyanomethyl p-toluenesulfonate, o-cyanobenzyl chloride, m-cyanobenzyl chloride, p-cyanobenzyl chloride, 2-chloro-3-cyanopyridine, p-iodobenzonitrile, 4'-amino 4-cyanobiphenyl, 2-amino-5-methylbenzonitrile, 1-a 4-cyano-5-amino-1,2-pyrazole, 2-amino-5-trifluoromethylbenzonitrile, 2-amino-2-cyanoacetamide, cyanoacetic acid, p-cyanobenzoic acid , m-cyanobenzoic acid, o-cyanobenzoic acid, 1-cyanocyclopropane-1-carboxylic acid, methyl 4-cyanobenzoate, 4-cyanobenzoyl chloride, 4-cyanobenzaldehyde, cyanide Ethyl acetal dimethyl acetal, allyl nitrile, 5-norbornene-2-methanol, 5-norbornene-2-carboxamide, 2-cyano-5-norbornene, 5-norbornene 2-methylamine, allyl chloride, propargyl chloroformate, allyl chloroformate, 2-hydroxyethyl methacrylate (HEMA), etc., and a form in which any one of the above compounds is protected . Among them, the hydroxycarboxylic acid is typically a 2-hydroxycarboxylic acid and a 3-hydroxycarboxylic acid. Taking 2-hydroxycarboxylic acid as an example, including but not limited to 2-hydroxypropionic acid, 2-hydroxybutyric acid, 2-hydroxyvaleric acid, 2-hydroxyhexanoic acid, 2-hydroxyheptanoic acid, 2-hydroxyoctanoic acid, 2- Hydroxydecanoic acid, 2-hydroxydecanoic acid, 2-hydroxyundecanoic acid, 2-hydroxylauric acid, 2-hydroxy myristic acid, 2-hydroxypalmitic acid, 2-hydroxystearic acid, 2-hydroxyoleic acid, 2-hydroxy-oleic acid, 2-hydroxylinolenic acid, 2-hydroxyarachiic acid, 2-hydroxyarachidonic acid, 2-hydroxyoctadecanoic acid, 2-hydroxy behenic acid, 2-hydroxy-22 Alkenoic acid, 2-hydroxytetracosanoic acid, 2-hydroxytetracosenoic acid, 2-hydroxylevousic acid, 2-hydroxyoctadecanoic acid, 2-hydroxyoctadecanoic acid, 2-hydroxyl The lacquer wax is preferably a C _3-20 2-hydroxycarboxylic acid, more preferably a C _3-10 2-hydroxycarboxylic acid, preferably a C _3-6 2-hydroxycarboxylic acid. Wherein the aralkyl and aryl substituted 2-hydroxycarboxylic acids include, but are not limited to, mandelic acid, 2,2-diphenyl-2-hydroxyacetic acid, 3-phenyl-2-hydroxypropionic acid, 2-phenyl -2-methyl-2-hydroxyacetic acid. 3-Hydroxycarboxylic acids include, but are not limited to, salicylic acid, 2-phenyl-3-hydroxypropionic acid. Further, the raw material of the hydroxycarboxylic acid may also be a salt or a lactone thereof.

The trivalent linking group is reacted between an alkynyl group and a fluorenyl group, and the reaction conditions can be carried out by a conventionally known technique, for example, the reference "Macromolecules, 2010, 43, 4937-4942" and its cited documents, "Angew. Chem. Int. Ed., 2010, 49, 3415-3417 and its citations, the literature "Chem. Commun., 2011, 47, 11086-11088" and its cited documents and the like.

2.1.4. Preparation of linear polyethylene glycol intermediates

Monodisperse linear polyethylene glycol intermediates involved in any of the routes, routes or methods of the present invention, including monodisperse linear polyethylene glycols and difunctional or heterofunctionalized derivatives thereof, for monodisperse preparation The preparation method of the polyethylene glycol chain refers to the literature "J. Org. Chem. 2006, 71, 9884-9886" and its cited documents, the literature "Angew. Chem. 2009, 121, 1274-1278" and its cited documents, literature "Expert Rev. Mol. Diagn. 2013, 13(4), 315-319" and references cited therein.

The structure, molecular weight and molecular weight distribution of key intermediates and products are characterized by characterization methods including, but not limited to, nuclear magnetic, electrophoresis, ultraviolet-visible spectrophotometer, FTIR, AFM, GPC, HPLC, MALDI-TOF. For monodisperse eight-arm polyethylene glycol derivatives, the molecular weight is preferably confirmed by MALDI-TOF.

2.1.5. Purification of intermediates and products

The intermediate or product prepared in the present invention can be purified by a purification method including, but not limited to, extraction, recrystallization, adsorption treatment, precipitation, precipitation, membrane dialysis or supercritical extraction.

2.2. The heterofunctionalized Y-type polyethylene glycol derivative is prepared by any of the following routes, and the intermediates of the V-type structure or the Y-type structure involved are hetero-functionalized structures.

2.2.1. Route 1, the route of the first chain after the main chain, the steps of the route one are as follows:

Step i, generation of a linear polyethylene glycol spindle: preparing a linear spindle end to be protected hydroxyl group, and the branching group is linked to two exposed hydroxyl intermediates IM1, and IM1 is not unstable under anionic polymerization conditions Non-hydroxyl group;

Step ii, the formation of two polyethylene glycol branched chains: starting from the intermediate IM1, the ethylene oxide polymerization is initiated by two bare hydroxyl groups of the branched group to form two polyethylene glycol branches having hydroxyl groups at the ends. a chain, a heterofunctional Y-type polyethylene glycol forming a structure of the formula (IM2);

Step iii, functionalization of the ends of the branched chain: starting from the compound (IM2), functionalizing the two branched chain ends to further obtain a functional group of the branched chain at the end of the branched chain or a heterofunctionalized form of the protected form R ₀₁ Y-type polyethylene glycol derivative; when terminal linear functionalization is carried out, a structure represented by formula (31) is obtained; when terminal branching functionalization is carried out, a structure represented by formula (32) is obtained; And F ₁ in (32) is not a hydrogen atom and does not contain a hydroxyl group.

Step iv, deprotection of the protected hydroxyl group at the end of the main chain: removal of the hydroxy protecting group PG ₄ at the end of the main chain polyethylene glycol, to obtain a naked hydroxyl group and a branch at the end of the main chain represented by the formula (IM3) or the formula (IM4) a heterofunctionalized Y-type polyethylene glycol having a terminal functional group or a protected form thereof;

Step v, functionalization of the end of the main chain: linear functionalization or branching functional modification of the terminal hydroxyl group of the main chain, resulting in heterofunctionalization of the main functional group or the branched chain end having the desired functional group or its protected form Y-type polyethylene glycol. Starting from the heterofunctional Y-type polyethylene glycol derivative represented by the formula (IM3) and the formula (IM4), further linear functionalization or terminal branching functionalization can be carried out, and the formula (2) and the formula (3) can be obtained. a heterofunctional Y-type polyethylene glycol derivative represented by formula (4) or formula (5); wherein, F ₁ ≠F ₂ , corresponding to formula (2), formula (3), and formula ( 4), general formula (5).

In Scheme 1, the product of the formula (2) is prepared as follows, wherein the intermediate (31) and the intermediate (IM3) are also heterofunctional Y-type polyethylene glycols.

In Scheme 1, the product of the formula (3) is prepared as follows, wherein the intermediate (32) and the intermediate (IM4) are also heterofunctional Y-type polyethylene glycols.

In the first route, the product of the formula (4) is prepared as follows:

In the first route, the product of the formula (5) is prepared as follows:

2.2.1.1. The implementation of the step i in the step i is a protected hydroxyl group, and one end is a trivalent branching group U containing two naked hydroxyl groups, including but not limited to the following six ways:

Mode 1: starting from a small molecule initiator IN1 having a bare hydroxyl group and two protected hydroxyl groups OPG ₇ , initiate polymerization of ethylene oxide to form an intermediate (34) containing a polyethylene glycol backbone; The hydroxyl group at the end of the spindle polyethylene glycol is protected to form a protected terminal OPG ₄ to obtain an intermediate (35); the ends of the branched chain are deprotected to form two exposed hydroxyl groups to obtain an intermediate IM1.

Among them, PG ₄ and PG ₇ are different hydroxy protecting groups, can exist at the same time, and can be deprotected under different conditions. For example, a combination of 1-ethoxyethoxy and tert-butyldimethylsilyl (TBS) obtained from vinyl ethyl ether (EE).

等。By way of example, the structure of initiator IN1 includes, but is not limited to:

Wait.

Mode 2: starting from a protected hydroxyl group OPG ₄ , a linear polyethylene glycol (36) containing a functional group or its protected form F ₄ at one end, and a functional group containing two protected hydroxyl groups OPG ₇ a group or a small molecule compound (37) thereof protected form F ₃ , which reacts between F ₄ and F ₃ to form a divalent linking group L ₃ to obtain a polyethylene glycol chain and a branching group U Linking group L ₃ to obtain intermediate (35); deprotecting two protected hydroxyl groups OPG ₇ of the branching group to obtain intermediate IM1;

If the reaction process for the formation of the linker L ₃ is not interfered by the naked hydroxyl group, a small molecule compound (38) containing two naked hydroxyl groups and one functional group or its protected form F ₃ may be used instead of (37), linear polymerization. Ethylene glycol (36) is reacted to form intermediate IM1;

Wherein the reaction between the compound (36) and the branching agent includes, but is not limited to, an alkylation, an alkenyl addition reaction, a Schiff base reaction, a reduction reaction, and the like; wherein the alkylation reaction is preferably based on a hydroxyl group, a thiol group or The reaction of alkylation of an amino group, which in turn corresponds to the formation of an ether bond, a thioether bond, a secondary amino group or a tertiary amino group;

Wherein the alkenyl addition reaction includes, but is not limited to, a click reaction between a maleimide and a sulfhydryl reagent; the Schiff base reaction is combined with a reduction reaction, including formation of an imine bond or an imine bond containing C=N. The two processes of reduction to form a secondary amine bond.

By way of example, as the oxygen anion intermediate (100) of polyethylene glycol, two bare hydroxyl groups linked by a branching group U can be introduced in the following two ways. The negative ion intermediate (100) can be obtained by deprotonation of a hydroxyl group.

Mode 1: The oxygen anion intermediate (100) of polyethylene glycol is alkylated with a leaving group-containing compound (101) such as an alkyl halide or an alkyl sulfonate.

Among them, PG ₇ is a hydroxy protecting group, and may be, for example, a silyl ether, a benzyl group, an acetal, a ketal or a tert-butyl group. LG ₁ is a leaving group including, but not limited to, chlorine, bromine, iodine, mesylate, p-toluenesulfonate, 2,2,2-trifluoroacetate sulfonate, preferably iodine.

In general, the terminal group-containing compound (101) such as an alkyl halide or an alkyl sulfonate is used in an amount of 5 to 20 mole equivalents, preferably 8 to 15 times, based on the initiator. If the amount of the capping reagent is less than 5 times the molar equivalent of the initiator, resulting in incomplete capping, the terminal oxygen anion will participate in the subsequent polymerization reaction, thereby obtaining an impurity having a molecular weight larger than the target molecular weight, resulting in a broad molecular weight distribution and containing a plurality of reactive functional groups. When the drug is modified, it may result in a decrease or complete loss of drug activity. When the amount of the capping reagent is more than 20 times the molar equivalent of the initiator, the excess reagent brings trouble to the purification, and may be mixed into the subsequent step, causing a side reaction. The temperature of the capping reaction is not particularly limited, and it is preferably carried out at 25 to 50 °C.

Mode 2: adding an activator to the polyethylene glycol anion intermediate (100) to obtain a corresponding polyethylene glycol sulfonate, and then undergoing a substitution reaction with a deprotonated alcohol (such as 102) to obtain a compound (103). Commonly used activators are methanesulfonyl chloride, p-toluenesulfonic acid, 2,2,2-trifluoroacetic acid sulfonyl chloride.

Among them, PG ₇ is a hydroxy protecting group, and may be, for example, a silyl ether, a benzyl group, an acetal, a ketal or a tert-butyl group.

(丙酮缩甘油)、

其中，EE为1-乙氧基乙氧基，TBS为叔丁基二甲基硅基。上述化合物(101)也可以通过(102)进行制备。Among them, the compound (102) is a modified form in which any two hydroxyl groups in the triol are protected and the other hydroxyl group is exposed. The triol molecules include, but are not limited to, glycerol, 2-hydroxymethyl-2-methyl-1,3-propanediol, 1,1,1-trimethylolpropane, 2-hydroxymethyl-1 , 3-butanediol, 1,2,4-butanetriol, 1,2,3-butanetriol, 2-benzyloxy-1,3,4-butanetriol, 1,2,5-pentyl Triol, 3-methyl-1,3,5-pentanetriol, 1,2,3-hexanetriol, 1,2,6-hexanetriol, 1,2,7-heptanetriol, 1, 2,8-octanetriol, 1,2,9-nonanetriol, 1,2,10-nonanetriol, 1,3,5-cyclohexanetriol, mesitylene glycol, 2-hydroxy-5 - M-m-phenylenediethanol, 1,2,3-benzenetriol, 1,3,5-benzenetriol, 1,2,4-benzenetriol, dimethyl pyrogallol, and the like. The triol may be in the form of an isomer of either a cis structure or a trans structure. For example, the 1,2,4-butanetriol may be (S)-1,2,4-butanetriol, (R)-1. , a trihydric alcohol such as 2,4-butanetriol. The triol may also be in the form of an ether formed with a glycol based on any of the above triols, for example, 1,2-propanediol 1,2,6-hexanetriol triether. The trihydric alcohol also allows the presence of a hydroxyl group in the form of a hemiacetal such as benzaldehyde glycerol acetal or phenylacetaldehyde-1,2,3-propanetriol cyclic acetal. By way of example, the structure of compound (102) is as

(acetone glycerol),

Wherein EE is 1-ethoxyethoxy and TBS is tert-butyldimethylsilyl. The above compound (101) can also be produced by (102).

The above two methods can achieve complete capping. Since the first method can be carried out in the same reaction vessel as the polymerization reaction, the production process is relatively simple, and the preferred method mode (1).

The above product can be purified by purification methods such as extraction, recrystallization, adsorption treatment, precipitation, precipitation, membrane dialysis or supercritical extraction to obtain an intermediate compound (103).

Mode 3: starting from a protected hydroxyl group OPG ₄ , a linear polyethylene glycol (36) having a functional group or its protected form F ₄ at one end, and a functional group or protected form thereof F ₃ The branching reagent F ₃ -U reacts to form a divalent linking group L ₃ , introduces a branching group to obtain an intermediate represented by (46), and then chemically modifies the branched group to introduce two naked hydroxyl groups. IM1.

Mode 4: Starting from a linear polyethylene glycol (39) having a protected hydroxyl group OPG ₄ and a glycidyl ether group at one end, ring opening to obtain an intermediate IM1 having two exposed hydroxyl groups; at this time, branching of IM1 The group is the center of the carbon atom. The conditions under which the epoxy group is opened are basic conditions. The base includes an organic base (such as triethylamine, pyridine, 4-dimethylaminopyridine, imidazole or diisopropylethylamine) or an inorganic base (such as sodium carbonate, sodium hydroxide, sodium hydrogencarbonate, sodium acetate, carbonic acid). Potassium or potassium hydroxide), preferably an inorganic base. The solvent used is preferably an aqueous solvent. Starting from the polyethylene glycol hydroxyl group, a glycidyl ether group is attached via a terminal linear functional modification, and then two naked hydroxyl groups are obtained by ring opening under basic conditions.

Mode 5: Starting from a linear polyethylene glycol (40) having a protected hydroxyl group at one end and an azide group at one end, and performing a click reaction with a reagent (41) having a hydroxyl group at one end and a hydroxyl group at one end, thereby obtaining two naked hydroxyl groups. Intermediate (42) (IM1); at this point the branched group of IM1 is the center of the carbon atom. Wherein L ₁₂ is a divalent linking group which is stably present under anionic polymerization conditions.

Alternatively, a reagent (43) having a thiol group at one end and a protected hydroxyl group at one end is reacted with a linear polyethylene glycol (40) to obtain an intermediate (44) in which a branched center is bonded to a protected hydroxyl group; Deprotection of the two protected hydroxyl groups affords intermediate (42) (IM1).

The alkynyl group here is a precursor of the branching group U.

Method 6: starting from a small molecule initiator IN2 having a bare hydroxyl group and a precursor of a branching group U or U, initiating polymerization of ethylene oxide to form an intermediate (45) containing a polyethylene glycol spindle; The hydroxyl group at the end of the spindle polyethylene glycol is protected with a hydroxy protecting group to form a protected terminal OPG ₄ to obtain an intermediate (46); the branching group U is modified to introduce two naked hydroxyl groups to obtain an intermediate. IM1.

The linear polyethylene glycol intermediates 36, 39, and 40 corresponding to the above aspects 2 to 5 may be polydisperse or monodisperse.

2.2.1.2. Route 1 The preparation of the ethylene oxide polymerization initiated by the exposed hydroxyl group comprises the following two steps: A, deprotonation of the exposed hydroxyl group to form an oxygen anion; B, initiate polymerization of ethylene oxide. These two steps can be carried out in a solvent or without a solvent, and the solvent is not particularly limited, but an aprotic solvent such as toluene, benzene, xylene, acetonitrile, ethyl acetate, tetrahydrofuran, chloroform, dichloromethane, or the like is preferable. Methyl sulfoxide, dimethylformamide or dimethylacetamide, more preferably toluene or tetrahydrofuran. The resulting polyethylene glycol chain is polydisperse.

When preparing the polyethylene glycol branching chain, the amount of ethylene oxide charged is consistent with the definition of the degree of polymerization of the corresponding polyethylene glycol segment. According to the definition of n ₁ and n ₂ , a polyethylene glycol branched chain is formed by adding 2 to 2000 times the molar amount of ethylene oxide. It is preferably 5 to 2000 times the molar amount; more preferably 5 to 1000 times the molar amount; more preferably 10 to 1000 times the molar amount; more preferably 20 to 1000 times the molar amount; more preferably 20 to 500 times the molar amount; more preferably 50 to 500 times. Molar amount. According to the definition of n ₃ , 1 to 2000 times the molar amount of ethylene oxide is added when the polyethylene glycol backbone is formed. It is preferably 2 to 2000 by mole amount; more preferably 5 to 2000 times mole amount; more preferably 5 to 1000 times mole amount; more preferably 10 to 1000 times mole amount; more preferably 10 to 500 times mole amount; more preferably 20 to 500 times A molar amount; more preferably 20 to 500 times the molar amount.

Step A: Deprotonation of bare hydroxyl groups

The deprotonation of the exposed hydroxyl group forms an oxygen anion, acts as an initiator for initiating the polymerization of ethylene oxide, and forms a co-initiator system with the base.

The deprotonation of the naked hydroxyl group is carried out under basic conditions. The base used for deprotonation is not particularly limited, but is preferably sodium metal, potassium, sodium hydride, potassium hydride, sodium methoxide, potassium methoxide, lithium naphthalate, n-butyllithium, t-butyllithium, potassium t-butoxide or diphenyl. The methyl group potassium is more preferably sodium, potassium or diphenylmethyl potassium, and most preferably potassium diphenylmethyl. The amount of the catalyst used is from 5 to 80 mol%. If the amount of the catalyst is less than 5 mol%, the polymerization rate is slow and the cumulative heat is increased, resulting in the formation of by-products, such as elimination of terminal hydroxyl groups to form vinyl ether compounds. When the reaction is carried out in the absence of a solvent, the amount of the catalyst exceeding 50 mol% causes an increase in the viscosity of the reaction solution or precipitation of solids, resulting in an unbalanced reaction and difficulty in purification. When toluene or tetrahydrofuran is used as a solvent, the problem that the viscosity of the reaction liquid increases or solid precipitation can be solved, and the amount of the catalyst can be correspondingly increased to 80 mol%.

Deprotonation is generally carried out at 10 to 5 ° C, preferably 25 to 50 ° C. When the temperature is less than 10 ° C, the deprotonation is incomplete, and the base participates in the anionic polymerization as a nucleophilic reagent, thereby obtaining a low molecular weight impurity having a target polymer chain of 0.5 times the target molecular weight. Such impurities may react with biologically relevant substances and alter their physical properties. When the temperature is higher than 50 ° C, partial deprotection of the protecting group is caused, and high molecular weight impurities having a target molecular weight higher than the target polymer chain are obtained. When the drug is modified in a state containing such an impurity, the pharmaceutical preparation is inevitably uneven, the quality is unstable, and the modification of the high-purity drug cannot be satisfied.

The protonation time is preferably 10 minutes to 24 hours, and the control of the time varies depending on the base. In general, strong bases with weak basicity or relatively low solubility in organic solvents (eg sodium methoxide, potassium methoxide, sodium hydride, potassium hydride, etc.) require longer deprotonation times, typically from 1 hour to 24 hours. a base which is strong in alkali and has good solubility in an organic solvent (for example, potassium diphenylmethyl, n-butyllithium, t-butyllithium, etc.) can be sufficiently miscible with the initiator even in the absence of a solvent. The rate of deprotonation is fast, generally from 10 minutes to 24 hours, preferably from 20 minutes to 1 hour. When the deprotonation time is short and the deprotonation is incomplete, the base participates in the anionic polymerization as a nucleophilic reagent to obtain a low molecular weight impurity having a molecular weight of 0.5 times the target polymer chain target; and when the deprotonation time is more than 24 hours, the protection is caused. The partial decomposing of the base deprotects to obtain high molecular weight impurities higher than the target molecular weight, and cannot satisfy the modification of the high purity drug.

When potassium methoxide, potassium t-butoxide or sodium methoxide is used as the catalyst, potassium methoxide is preferably used in an amount of 5 to 80 mol%, carried out at 25 to 80 ° C, preferably 50 to 60 ° C, and in addition, it should be reduced. Operate under pressure to promote proton exchange. Since potassium methoxide, potassium t-butoxide or sodium methoxide itself is polymerized under polymerization conditions, it also polymerizes with ethylene oxide to obtain an etherified polyethylene glycol having a molecular weight of the target polymer chain of 0.5 times the target molecular weight, which interferes with subsequent reactions. A by-product is produced.

Therefore, such a reaction requires removal of the lower alcohol at a higher temperature (preferably 50 to 60 ° C) while ensuring complete protonation.

Step B: Initiating polymerization of ethylene oxide

The amount of ethylene oxide is determined by the molecular weight of the polyethylene glycol chain and is metered in ethylene oxide.

The polymerization is carried out under conditions of an aprotic solvent, preferably at 50 to 70 °C. When the temperature is lower than 50 ° C, as the polymerization progresses, the molecular weight gradually increases, the viscosity of the reaction liquid increases or solid precipitates, resulting in uneven reaction system, and the obtained target product is widely distributed, and is not suitable for use in high-purity drugs. When the temperature is higher than 70 ° C, the reaction system is prone to explosion or prone to side reactions, such as elimination of terminal alcohol to obtain vinyl ether.

When solvent-free conditions are employed, it is preferred to carry out the polymerization at 50 to 130 ° C, more preferably at 80 to 110 ° C. When the temperature is lower than 50 ° C, the polymerization rate is low, and the cumulative heat is increased to lower the quality of the target product; moreover, when the temperature is higher than 130 ° C, side reactions such as terminal alcohol elimination tend to occur to obtain a vinyl ether. Similarly, as the polymerization proceeds, the molecular weight gradually increases, the viscosity of the reaction liquid increases or solidifies, making the reaction uneven, and the obtained target product is widely distributed, and is generally preferably carried out under an aprotic solvent, preferably a tetrahydrofuran solvent. Or toluene.

The polymerization product obtained after the step B is a mixture of an alcohol and an oxygen anion. When the polymerization is carried out to a certain extent, a proton source is added. A hydroxy-terminated intermediate compound having a specific degree of polymerization can be obtained. The proton source is required to provide active hydrogen, such as methanol, ethanol, water, acetic acid.

2.2.1.3. In step iii and step v, the preparation method of linear functionalization refers to 2.1.1., and the method of branching functionalization refers to 2.1.2., and details are not described herein again.

When p _i (i=1, 2, 3) is 0 or 1, the branching functionalization is carried out by branching functionalization of the terminal polyethylene glycol terminal of the formula (4) and forming the linking group L ₆ as an example. The three implementations are as follows:

Wherein F ₆ and F ₇ are each a functional group or a protected form thereof. For the reaction between two functional groups or their protected forms (which may be hydroxyl groups), refer to 2.1.3. and 2.1.4. When one of them is protected, it can be deprotected and then reacted. .

When p _i (i = 1, 2, 3) is greater than 1, the branching functionalization of the terminal polyethylene glycol of the formula (4) is taken as an example, as follows:

Wherein F ₄ , F ₅ and F ₇ are all functional groups or protected forms thereof. For the reaction between two functional groups or their protected forms (which may be hydroxyl groups), refer to 2.1.3. and 2.1.4. When one of them is protected, it can be deprotected and then reacted. .

2.2.1.4. In step iv, the deprotection of the protected hydroxyl group is related to the type of hydroxyl protecting group. The type of the hydroxy protecting group is not particularly limited, and the benzyl group, the silyl ether, the acetal, and the tert-butyl group are used to protect the terminal hydroxyl group. The corresponding deprotection methods are as follows:

A: Deprotection of benzyl group

Benzyl deprotection can be achieved by hydrogenation of a hydrogenation reducing agent and a hydrogen donor. The water content in this reaction system should be less than 1% for the reaction to proceed smoothly. When the water content in the system is greater than 1%, the breakage of the polyethylene glycol chain occurs. The production of low molecular weight polyethylene glycol with hydroxyl groups will participate in subsequent polymerization or functional group modification, introduce impurities into the target product, and even react with biologically relevant substances, changing the properties of the preparation.

The hydrogenation reduction catalyst is not limited, and is preferably palladium and nickel, but does not limit the carrier, but is preferably alumina or carbon, more preferably carbon. The palladium is used in an amount of from 1 to 100% by weight of the protected hydroxy compound, preferably from 1 to 20% by weight of the protected hydroxy compound. When the amount of palladium is less than 1% by weight, the rate of deprotection and the conversion rate are lowered, and the undeprotected portion cannot undergo subsequent polymerization or functional grouping, resulting in a low functional group ratio of the final product. However, when the amount of palladium is more than 100% by weight, it tends to cause breakage of the polyethylene glycol chain.

The reaction solvent is not particularly limited as long as the starting material and the product are both solvent, but methanol, ethanol, ethyl acetate, tetrahydrofuran, acetic acid is preferred; methanol is more preferred. The hydrogen donor is not particularly limited, but hydrogen, cyclohexene, 2-propanol, ammonium formate or the like is preferable. The reaction temperature is preferably from 25 to 40 °C. When the temperature is higher than 40 ° C, the chain scission of the polyethylene glycol chain is liable to occur. The reaction time is not particularly limited, and the reaction time is negatively correlated with the amount of the catalyst, preferably 1 to 5 hours. When the reaction time is less than 1 hour, the conversion rate is low, and when the reaction time is more than 5 hours, polyethylene glycol is easily generated. Broken chain of chains.

B: Deprotection of acetal and ketal

The acetal or ketal compound used for such hydroxy protection is preferably ethyl vinyl ether, tetrahydropyran, acetone, 2,2-dimethoxypropane, benzaldehyde or the like. The deprotection of such acetals and ketals is achieved under acidic conditions, and the pH of the solution is preferably from 0 to 4. When the pH value is greater than 4, the acidity is too weak to completely remove the protecting group; when the pH value is less than 0, the acidity is too strong, and the chain scission of the polyethylene glycol chain is liable to occur. The acid is not particularly limited, but is preferably acetic acid, phosphoric acid, sulfuric acid, hydrochloric acid or nitric acid, and more preferably hydrochloric acid. The reaction solvent is not particularly limited as long as it can dissolve the reactants and products, and water is preferred. The reaction temperature is preferably 0 to 30 °C. When the temperature is lower than 0 ° C, the reaction rate is slow, and the protecting group cannot be completely removed; when the temperature is high at 30 ° C, under the acidic condition, the chain scission of the polyethylene glycol chain is liable to occur.

C: Deprotection of silyl ether

Compounds useful for such hydroxy protection include trimethylsilyl ether, triethylsilyl ether, dimethyl tert-butylsiloxane, tert-butyldiphenylsilyl ether, and the like. The deprotection of such a silyl ether is carried out by a fluorine-containing ion compound, preferably tetrabutylammonium fluoride, tetraethylammonium fluoride, hydrofluoric acid, potassium fluoride, more preferably tetrabutylammonium fluoride or potassium fluoride. . The fluorine-containing reagent is used in an amount of 5 to 20 times, preferably 8 to 15 times, the molar equivalent of the protected hydroxyl group. If the fluorine is used in an amount less than 5 times the molar equivalent of the protected hydroxyl group, the deprotection may be incomplete; The amount of the protective reagent is greater than 20 times the molar equivalent of the protected hydroxyl group, and the excess reagent or compound causes trouble for purification and may be mixed into subsequent steps to cause side reactions. The reaction solvent is not particularly limited as long as it can dissolve the reactants and the product, and is preferably an aprotic solvent, more preferably tetrahydrofuran or dichloromethane. The reaction temperature is preferably 0 to 30 ° C. When the temperature is lower than 0 ° C, the reaction rate is slow, and the protecting group cannot be completely removed.

D: deprotection of tert-butyl

The deprotection of the tert-butyl group is carried out under acidic conditions, and the pH of the solution is preferably from 0 to 4. When the pH value is greater than 4, the acidity is too weak to completely remove the protecting group; when the pH value is less than 0, the acidity is too strong, and the chain scission of the polyethylene glycol chain is liable to occur. The acid is not particularly limited, but is preferably acetic acid, phosphoric acid, sulfuric acid, hydrochloric acid or nitric acid, and more preferably hydrochloric acid. The reaction solvent is not particularly limited as long as it can dissolve the reactants and products, and water is preferred. The reaction temperature is preferably 0 to 30 °C. When the temperature is lower than 0 ° C, the reaction rate is slow, and the protecting group cannot be completely removed; when the temperature is high at 30 ° C, under the acidic condition, the chain scission of the polyethylene glycol chain is liable to occur.

The above steps can be purified by purification methods such as extraction, recrystallization, adsorption treatment, precipitation, reverse precipitation, membrane dialysis or supercritical extraction, and the compound having a naked hydroxyl group after removing the hydroxy protecting group.

2.2.2. Route 2, the route of the main chain after the branch, the steps of the route 2 are as follows:

Step i, Generation of a linear polyethylene glycol spindle: preparation of a linear spindle end containing a functional group or its protected form F ₇ , and a branching group linking two exposed hydroxyl intermediates IM1b, and IM1b is not contained in An unstable non-hydroxyl group under anionic polymerization conditions;

Step ii, the formation of two polyethylene glycol branched chains: starting from the intermediate IM1b, two bare hydroxyl groups linked by a branching group initiate the polymerization of ethylene oxide to form two polyethylene glycols having hydroxyl groups at the ends. Branching the chain to form a heterofunctional Y-type polyethylene glycol having the formula (IM2b);

Step iii, terminal functionalization modification: functionally modifying the main chain polyethylene glycol or branched polyethylene glycol terminal of the Y-form intermediate obtained in step ii, respectively, to obtain a functionalized group having a target or Protected form of the heterofunctionalized Y-type polyethylene glycol (2), (3), (4) or (5); the functionalized modification is a linear functional modification or a branched functionalization modification;

When F ₇ is a target functional group or a protected form thereof, linear functionalization is carried out starting from the terminal hydroxyl group of the polyethylene glycol branched chain of the compound (IM2b) to obtain a heterofunctional Y represented by the formula (2). The polyethylene glycol of the type or the branched functionalization modification gives the heterofunctional Y-type polyethylene glycol represented by the formula (3).

2.2.2.1. Referring to Route 1, the steps i of Route 2 include, but are not limited to, the following six implementations:

Method 1: Starting from a small molecule initiator IN1 having a bare hydroxyl group and two protected hydroxyl groups OPG ₇ , the polymerization of ethylene oxide is initiated to form an intermediate (34) containing a polyethylene glycol spindle; linearization of the terminal hydroxyl group The functionalization modification introduces F ₂ to give the intermediate (35b); the ends of the branched chain are deprotected to form two exposed hydroxyl groups to give the intermediate IM1b. The initiators include, but are not limited to, the initiators described in 2.2.1.1., which are defined hereinafter and will not be described again.

Embodiment 2: one end is a functional group or a protected form F _7, containing functional end group or a protected form F isobutyl functionalized linear polyethylene glycol (36b) ₄ starting with two are comprising Protecting the hydroxyl group OPG ₇ and a functional group or a small molecule compound (37) thereof in a protected form F ₃ , and reacting one or more steps to obtain an intermediate (35b) linking the branch group via a linker L ₃ ; Deprotection of the two protected hydroxyl groups OPG _{7 of the} branching center gives the intermediate IM1b. The compound (37) includes, but is not limited to, a leaving group-containing compound (101) such as an alkyl halide or an alkylsulfonate described in 2.2.1.1. and a deprotonated alcohol (102), which are defined hereinafter. Will not repeat them.

If the process of generating the linker L ₃ is not interfered by the naked hydroxyl group, a small molecule compound (38) containing two naked hydroxyl groups and one functional group or its protected form F ₃ may be used instead of (37), linear polyethylene. The diol (36b) is reacted to form the intermediate IM1b.

Mode 3: starting from linear polyethylene glycol (36b), reacting with the branching agent F ₃ -U to form a divalent linking group L ₃ , introducing a branching group to obtain an intermediate represented by (46b), and then branching The group is chemically modified to introduce two exposed hydroxyl groups to give IM1b.

Embodiment 4: From one end a functional group or a protected form F _7, one end of the linear polyethylene glycol with an epoxy group (39b) depart, ring opening to give an intermediate having two IM1b exposed hydroxyl groups; in this case The branching group of IM1b is the center of a carbon atom.

Mode 5: Starting from a linear polyethylene glycol (40b) having a functional group or a protected form thereof F ₇ and an azide group at one end, and a click reaction with a reagent (41) having a hydroxyl group at one end and a hydroxyl group at one end. An intermediate (42b) (IM1b) having two naked hydroxyl groups is obtained; at this time, the branched group of IM1b is the center of the carbon atom.

Alternatively, a reagent (43) having a thiol group at one end and a protected hydroxyl group at one end is reacted with a linear polyethylene glycol (40b) to obtain an intermediate (44b) having two protected hydroxyl groups in the branch center; Deprotection of one protected hydroxy group affords intermediate (42b) (IM1b).

Embodiment 6: Initiator IN2 from a small molecule having a hydroxyl group exposed initiate polymerization of ethylene oxide to produce a polyethylene glycol-containing intermediate spindle (45); of the terminal hydroxyl functional linear modification is introduced in the F _7, Intermediate (46b) is obtained; the branching group U is modified to introduce two exposed hydroxyl groups to give the intermediate IM1b.

The corresponding linear polyethylene glycol intermediates 36b, 39b, and 40b in the second to fifth modes of the second route may be polydisperse or monodisperse.

2.2.2.2. The preparation of the Y-form intermediate IM2b in step ii comprises three steps: deprotonation of the exposed hydroxyl group, initiation of polymerization of ethylene oxide, addition of a proton source to obtain terminal hydroxyl groups. The reaction conditions are referred to step b (2.2.1.2.) in the above route 1, and will not be described herein. After 2 to 2000 times the molar amount of ethylene oxide is polymerized with the compound containing two naked hydroxyl groups (IM1b), a protonating agent is added to form a polydisperse polyethylene glycol intermediate (IM2b). Refer to 2.2.1.2., which is not repeated here.

2.2.2.3. Terminal functionalization

The preparation method of linear functionalization refers to 2.1.1., and the method of branching functionalization refers to 2.1.2., and details are not described herein again.

2.2.3. Route 3, the route of the main chain after the first branch, the steps of the third route are as follows:

In step i, a V-type intermediate having two polyethylene glycol branched chains is formed by initiating polymerization of ethylene oxide, and contains a branching group U.

Wherein, the branching group U may be bonded to the protected hydroxyl group OPG ₄ or a functional group which is stable under anionic polymerization conditions or its protected form F ₁₀ , or UF ₁₀ together constitutes a functional group or a protected form thereof; F _{10 is} not a hydroxy protecting group PG ₄ . The UF ₁₀ as a whole may be, for example, a secondary amino group, in which case F ₁₀ corresponds to an active hydrogen atom.

Wherein, the polyethylene glycol branch end may be in a linear functionalized form (only one R ₀₁ is attached) or a branched functionalized form (connecting two or more R ₀₁ ); linear functionalization or branching The functional group of the functionalized end or its protected form is F ₉ , F ₉ may be the same or different from the target functional group or its protected form F ₁ , and F ₉ may also be a hydroxy protecting group PG ₇ ; It is also required that F ₉ is a functional group which is stable under anionic polymerization conditions or a protected form thereof.

The V-type intermediate has any one of (52), (53), (54), (55), (56), (52b), (53b), (54b), (55b), (56b) Structure

This can be achieved in either of two ways:

The end of the branching group is a mode of protecting the hydroxy PG ₄ : starting from a small molecule initiator IN3 having two exposed hydroxyl groups and a protected hydroxyl group, the polymerization of ethylene oxide is initiated to form two intermediates containing terminal hydroxyl groups ( 51);

Intermediate (51) can give intermediate (52) protected hydroxy, may be modified by the end of the linear functionalized to give a target or a functional group of intermediate (53) F ₁ is the protected form, may be functionalized with terminal linear Modification to give intermediate (54) having a non-target functional group or its protected form F ₉ which can be modified by terminal branching to give an intermediate having the desired functional group or its protected form (F ₁ ) 55, it may be terminally branched functional modification give intermediate 56 having a non-target functional group or a protected form of F _9. When F ₉ =F ₁ , the structure of (54) is consistent with (53), the structure of (56) is consistent with (55); when F ₉ = PG ₇ , the structure of (54) is consistent with (52).

Mode 2 in which the end of the branching group is F ₁₀ : Ethylene oxide is initiated from a functional group having a stable anionic polymerization condition or its protected form F ₁₀ and a small molecular initiator IN4 having two exposed hydroxyl groups. Polymerization to form two terminal hydroxyl group-containing intermediates (51b), which can be obtained by the method of the first method, respectively, with the protected hydroxyl group OPG ₇ , linear functionalized target functional group or its protected form F ₁ , linear functional a non-target functional group or a protected form thereof F ₉ , a branched functionalized functional group or a protected form thereof F ₁ , a branched functionalized non-target functional group or a protected form thereof F ₉ corresponds to the intermediates (52b), (53b), (54b), (55b), and (56b) in this order. When F ₉ = F ₁ , the structure of (54b) is identical to (53b), and the structure of (56b) is identical to (55b); when F ₉ = PG ₇ , the structure of (54b) is identical to (52b).

Step ii, preparation of an intermediate having a naked hydroxyl group in the branching group: functionalizing the branching group U of the V-form intermediate obtained in step i to obtain a V-type intermediate (52c) in which a U is attached to a bare hydroxyl group. ), (53c), (54c), (55c), (56c).

Obtaining a naked hydroxyl group by deprotecting a protected hydroxyl group of a branching group of (52), (53), (54), (55) or (56), or by pairing (52b), (53b), (54b) The branching group of (55b) or (56b) is chemically modified to form a divalent linking group L ₃ to introduce a naked hydroxyl group; the intermediates (52c), (53c), (54c), (55c) shown below are obtained. ), (56c). When F ₉ = F ₁ , the structure of (54c) is identical to (53c), and the structure of (56c) is identical to (55c); when F ₉ = PG ₇ , the structure of (54c) is identical to (52c).

Step iii, the formation of a linear polyethylene glycol spindle: starting from the bare hydroxyl group of the branched group U of the V-type intermediate obtained in the step ii, initiating polymerization of ethylene oxide to form a hydroxyl terminated linear polyethylene glycol spindle The Y-form intermediate (52d), (53d), (54d), (55d) or (56d) is obtained.

The resulting substances based on (52c), (53c), (54c), (55c), (56c) correspond to (52d), (53d), (54d), (55d), (56d), respectively; (52d) (53d), (54d), (55d), and (56d) are all heterofunctional Y-type polyethylene glycols. When F ₉ = F ₁ , the structure of (54d) is identical to (53d), and the structure of (56d) is identical to (55d); when F ₉ = PG ₇ , the structure of (54d) is identical to (52d).

Step iv, each independently functionalizing the main chain polyethylene glycol or branched polyethylene glycol terminal of the Y-form intermediate obtained in the step iii to obtain a heterofunctional group having a target functionalized group or a protected form thereof Y-type polyethylene glycol (2), (3), (4) or (5); the functionalization modification is a linear functional modification or a branched functionalization modification.

Functionalization of the ends of linear polyethylene glycol spindles or/and polyethylene glycol branched chains may involve, but is not limited to, (4e), (5e), (54e), (56e), (57), (58) The intermediate shown. When F ₉ = F ₁ , the structures of (4e), (5e), (54e), and (56e) are identical to (4), (5), (2), and (3), respectively.

As a summary, the preparation methods in Route 3 include, but are not limited to, the following synthetic routes.

(1) Starting from initiator IN3:

(2) Starting from initiator IN4:

2.2.4. Route 4, Branch 1 - Branch 2 - Main Chain Method

Step i: by initiating the polymerization of ethylene oxide or by reacting with a heterofunctionalized linear polyethylene glycol, two polyethylene glycol branched chains are successively introduced to respectively form divalent linking groups L ₁ and L ₂ to obtain a branch. V-form intermediate of group U.

Wherein, the branching group may be bonded to the protected hydroxyl group OPG ₄ or other functional group or its protected form F ₁₀ , or UF ₁₀ together to form a functional group or a protected form thereof; OPG ₄ corresponds to the intermediate (52) , (53), (54), (55) or (56); F ₁₀ corresponds to the intermediate (52b), (53b), (54b), (55b) or (56b).

Wherein, the polyethylene glycol branch end may be in a linear functionalized form (only one R ₀₁ is attached) or a branched functionalized form (connecting two or more R ₀₁ ); linear functionalization or branching functionalization of the terminal functional group or a protected form, is a functional group or a protected form F _9, F ₉ and the target or the functional groups F ₁ are the same or different protected form, F ₉ may also be a hydroxy protecting group PG ₇ .

Step ii: preparation of Y-form intermediate; Y-form intermediate may be (52d), (53d), (54d), (55d) or (56d); or may be IM7 or IM8; wherein F ₇ and target function The sexual group or its protected form F ₂ may be the same or different and F ₇ may also be a hydroxy protecting group. F ₇ and F ₉ in the same molecule are different; any one of F ₇ and F ₉ is allowed to be a hydroxy protecting group.

Implemented in one of the following ways:

Deprotecting the hydroxy protecting group PG ₄ from the branched group U of the V-form intermediate (52), (53), (54), (55) or (56) or chemically modifying it to introduce a bare hydroxyl group to initiate the epoxy B Alkyne polymerization, obtaining Y-type polyethylene glycol intermediate (52d), (53d), (54d), (55d) or (56d) with a linear spindle end hydroxyl group;

Or containing functional group or a protected form of intermediate F V type (52b) ₁₀ of, (53b), (54b) , (55b) or (56b), by containing a functional group or a protected form F reaction between iso-functional linear polyethylene glycol ₇ generates divalent linking group L _3, to give intermediate Y-polyethylene glycol or IM8 IM7, which spindle end is a linear functional group or which is Protection form F ₇ ;

Or chemically modifying the branching group U of the V-type polyethylene glycol intermediate (52b), (53b), (54b), (55b) or (56b) to form a divalent linking group L ₃ and introducing a new The functional group or its protected form is then reacted with a heterofunctionalized linear polyethylene glycol to give the Y-type polyethylene glycol intermediate IM7 or IM8.

Step iii: functionally modifying the main chain polyethylene glycol or branched polyethylene glycol terminal of the Y-form intermediate obtained in the step ii, respectively, to obtain a heterofunctional group having a target functionalized group or a protected form thereof. Y-type polyethylene glycol (2), (3), (4) or (5); the functionalization modification is a linear functional modification or a branched functionalization modification.

The linear polyethylene glycol intermediate used in Scheme 4 may be polydisperse or monodisperse.

By way of example, including but not limited to the following implementations:

2.2.4.1. Mode 1, a branched small molecule compound containing a protected hydroxyl group (59) and a heterofunctionalized linear polyethylene glycol containing two different functional groups or protected forms thereof F ₉ , F ₁₁ ( 60), the reaction between the branched groups U and F ₁₁ forms a divalent linking group L ₁ , and the first branched chain is introduced to form a compound represented by the formula (61); and the functional group or protected _{form. 9} F, ₁₂ F iso-functionalized linear polyethylene glycol (60b) reaction, the reaction between the _U-12 and F generate divalent linking group L _2, introduced into the second branched, to give (54) as The compound shown; referring to step ii, step iii and step iv of Scheme 3, the heterofunctional Y-type polyethylene glycol represented by (2), (3), (4) or (5) is obtained. Wherein F ₉ is a group which is stable under anionic polymerization conditions; F ₉ and the functional group of the branched polyethylene glycol terminal or the protected form F _{1 thereof} may be the same or different; F ₉ may be a hydroxy protecting group . F ₁₁ and F ₁₂ may be the same or different.

2.2.4.2. Mode 2, a functional group or a protected reagent of the protected form F ₁₀ (62) and a heterofunctionalization comprising two different functional groups or protected forms thereof F ₉ , F ₁₁ a linear polyethylene glycol (60), which reacts between the branched groups U and F ₁₁ to form a divalent linking group L ₁ , and introduces the first branched chain to form a compound represented by the formula (63); _{9. The} two functional groups of F ₁₂ or their protected forms of the heterofunctionalized linear polyethylene glycol (60b) react to form a divalent linking group L ₂ , and the second branched chain is introduced to obtain the compound represented by (54b). Referring to step ii, step iii and step iv of Scheme 3, a heterofunctional Y-type polyethylene glycol represented by (2), (3), (4) or (5) is obtained. The F ₉ may be the same or different from the target functional group of the branched polyethylene glycol terminal or its protected form F ₁ ; F ₉ may be a hydroxy protecting group.

2.2.4.3. Mode 3, referring to Mode 2 (2.2.4.2.) of this Route 4, the compound shown by 54b is obtained, and the functional group containing the target or its protected form F ₂ , and another functional group are obtained. Or a heterofunctionalized linear polyethylene glycol (64) protected by the protected form F _{4 to} form a divalent linking group L ₃ to give a Y-type polyethylene glycol as shown in (54e), linearly functionalizing the ends of the branched chain The functionalized or branched functionalized, respectively obtained the heterofunctionalized Y-type polyethylene glycol represented by (2), (3). Wherein F ₉ is a functional group which may exist simultaneously with F ₂ or a protected form thereof. The F ₉ may be the same or different from the target functional group of the branched polyethylene glycol terminal or its protected form F ₁ ; F ₉ may be a hydroxy protecting group.

2.2.4.4. Mode 4, referring to Mode 2 (2.2.4.2.) of this Route 4, the compound shown by 54b is obtained, which differs from the two functional groups or their protected forms F ₇ and F ₄ . Functionalized linear polyethylene glycol (64b), which reacts between the branched groups U and F ₄ to form a divalent linking group L ₃ to give a heterofunctional Y-type polyethylene glycol as shown by IM7, each independently Linear or functionalized functionalization of the polyethylene glycol end and the branched polyethylene glycol end of the main chain to obtain the heterofunctional Y represented by (2), (3), (4) or (5), respectively. Polyethylene glycol. In IM7, F ₉ is a functional group which can coexist with F ₇ or a protected form thereof, and F ₇ ≠F ₉ ; F ₇ and F ₉ each independently allow the target function of the branched polyethylene glycol terminal Any one of the functional groups or protected forms thereof, F ₇ or F ₉ , is allowed to be a hydroxy protecting group; when F ₇ or F ₉ is the target functional group at the end of the polyethylene glycol chain or a protected form thereof, Chemical modification of the end of the polyethylene glycol chain can be omitted.

2.2.4.5. Mode 5, a heterofunctionalized linear polyethylene glycol comprising a branched small molecule compound (59) containing a protected hydroxyl group and a protected hydroxyl group OPG ₇ , and a functional group or a protected form thereof F ₁₁ a reaction between a branched group and F ₁₁ to form a divalent linking group L ₁ , introducing a first branched chain to obtain a structure represented by the formula (66); and a functional group or a protected form thereof F ₁₁ and a hetero-functionalized linear polyethylene glycol (65b) protected by a hydroxyl group are reacted to form a divalent linking group L ₂ , and a second branched chain is introduced to obtain the structure shown in (52); referring to step ii in Scheme 3 In step iii and step iv, a heterofunctional Y-type polyethylene glycol represented by (2), (3), (4) or (5) is obtained.

2.2.4.6. Method 6, starting from a branching reagent (67) with a bare hydroxyl group, initiates the polymerization of ethylene oxide to form an intermediate (69) with a hydroxyl group at the end of the polyethylene glycol chain; Linear functionalization modification is introduced to introduce a functional group or its protected form F ₉ to obtain an intermediate represented by formula (63); and a linear polyethylene glycol (60b) terminated by F _{9 is} coupled to form a divalent linking group. L ₂ , an intermediate having two branched chains represented by formula (54b) is obtained, and a heterofunctionalized linear polyethylene glycol (64b) having a functional group or a protected form thereof F ₇ is coupled to form a divalent group Linking group L ₃ to obtain Y-type polyethylene glycol represented by IM7; respectively, linearly functionalizing or branching functionalizing the terminal of the main chain polyethylene glycol terminal and the branched chain polyethylene glycol, respectively (2 The heterofunctional Y-type polyethylene glycol shown in (3), (4) or (5). F ₉ and F _{7 in} IM7 coincide with mode 4 of route 4.

The corresponding linear polyethylene glycol intermediates (60), (60b), (64) or (64b) in the first to sixth modes of the route 4 may be polydisperse or monodisperse.

2.2.5. Route 5, main chain - branch 1 - branch 2 method.

Step i: by the reaction between two heterofunctionalized linear polyethylene glycols, a divalent linking group L ₁ or L _{3 is formed} , which gives two functional groups at both ends or their protected forms F ₇ , F iso-functionalized polyethylene glycol intermediate ₉ IM5, two linear polyethylene glycol via chain or branched groups U U F ₁₀ is connected unsubstituted. F ₁₀ is a functional group or a protected form thereof, or UF ₁₀ together constitutes a functional group or a protected form thereof.

Step ii: linking the heterofunctionalized linear polyethylene glycol (60) having a functional group or its protected form F ₉ to the branched group of the polyethylene glycol intermediate IM5 obtained in the step i by a reaction At U, a divalent linking group L _{2 is formed} to obtain a heterofunctional Y-form intermediate represented by IM7.

Step iii: functionally modifying the main chain polyethylene glycol or branched polyethylene glycol terminal of the Y-form intermediate obtained in the step ii, respectively, to obtain a heterofunctional group having a target functionalized group or a protected form thereof. Y-type polyethylene glycol (2), (3), (4) or (5); the functionalization modification is a linear functional modification or a branched functionalization modification.

F ₉ and F _{7 in} IM7 coincide with mode 4 of route 4.

The linear polyethylene glycol intermediate used in Scheme 5 may be polydisperse or monodisperse.

Route 5 can be achieved in any of the following ways.

2.2.5.1. 1, or a functional group is a functional group having a linear or a protected form are F ₉ F ₇ protected form polyethylene and linear polyethylene glycol (46c) branching groups, and Ethylene glycol (60) is reacted to form a divalent linking group L ₁ to obtain an intermediate (77) having a main chain polyethylene glycol and a branched polyethylene glycol; and further having a functional group or The linear polyethylene glycol (60b) protected by the form F ₉ is grafted to form a divalent linking group L ₂ , and a second polyethylene glycol branched chain is introduced to obtain a heterofunctional Y-shaped poly(B) represented by the formula IM7. a diol; each independently linearly functionalizing or branching functionalizing the polyethylene glycol terminal and the branched polyethylene glycol terminal to obtain (2), (3), (4) or (5) The heterofunctionalized Y-type polyethylene glycol is shown. F ₉ and F _{7 in} IM7 coincide with mode 4 of route 4.

2.2.5.2. Mode 2, a linear polyethylene glycol 64b having a functional group or its protected form F ₇ , and a linear polyethylene having a functional group or its protected form F ₉ and a branched group U The diol (63) is coupled to form a divalent linking group L ₃ to obtain an intermediate (77) having a main chain polyethylene glycol and a branched polyethylene glycol; and referring to Route 5, Mode 1 (2.2.5.1) .), obtaining a heterofunctional Y-type polyethylene glycol represented by (2), (3), (4) or (5).

The corresponding linear polyethylene glycol intermediates 60, 60b, and 64b in the first to second modes of the fifth route may be polydisperse or monodisperse.

2.2.6. Route 6: Branch-Bearing, Polymerization-Coupling,

Step i: starting from a functional group having a stable anionic polymerization condition or its protected form F ₁₀ and a small molecular initiator IN4 of two naked hydroxyl groups, the polymerization of ethylene oxide is initiated, and the ends of the two branched chains are obtained. Hydroxy V-form intermediate (51b).

Step ii: linearly functionalizing the terminal hydroxyl group of the branched polyethylene glycol of the V-form intermediate obtained in the step ii to introduce a functional group or a protected form thereof F ₉ to obtain a V-form intermediate (54b).

Step iii, the V-form intermediate obtained in step i and the hetero-functionalized linear polyethylene glycol (64b) having two functional groups or protected forms thereof F ₄ , F ₇ , between F ₁₀ and F ₄ The reaction produces a divalent linking group L ₃ to give a heterofunctional Y-type polyethylene glycol intermediate as shown by IM7. F ₉ and F _{7 in} IM7 are consistent with mode 4 (2.2.4.4.) of route 4.

Step iv: linearly functionalizing or branching functionalizing the main chain polyethylene glycol terminal and the branched polyethylene glycol terminal, respectively, to obtain (2), (3), (4) or (5) respectively The heterofunctionalized Y-type polyethylene glycol is shown.

The corresponding linear polyethylene glycol intermediate (64b) in Route 6 may be polydisperse or monodisperse.

2.2.7. Route 7: Branch Chain - Main Chain Method, Coupling - Aggregation,

Step i: a branching agent (59) having a protected hydroxyl group OPG ₄ , a branching group U, and a heterofunctionalized linear polyethylene glycol having two functional groups or a protected form thereof F ₉ (60) Coupling to form divalent linking groups L ₁ and L ₂ yields a V-form intermediate (71) in which two PEG branching ends are F ₉ and the branched group U is linked to OPG ₄ .

It should be noted that the two n ₁ in (71) do not mean that the number of oxyethylene units of the corresponding polyethylene glycol chain is strictly equal in value, but means that the source is the same, and thus is numerically close. When the source is a monodisperse compound, it is allowed to be strictly equal in value.

Step ii: The hydroxy protecting group PG _{4 is} removed from the branched hydroxy group of the branched group of the V-form intermediate (71) obtained in the step i to obtain a V-form intermediate (71c) having a bare hydroxyl group.

Step iii, the naked hydroxyl group of the V-form intermediate (71c) obtained in the step ii is initiated to polymerize ethylene oxide to obtain a Y-type intermediate in which the terminal polyethylene glycol terminal is a hydroxyl group and the branched polyethylene glycol terminal is F ₉ . Body IM6 (71d).

Step iv: linearly functionalizing or branching functionalizing the main chain polyethylene glycol terminal and the branched polyethylene glycol terminal, respectively, to obtain (73), (74), (75) or (76) respectively The heterofunctionalized Y-type polyethylene glycol is shown.

Wherein F _{9 is} allowed to be the target functional group of the branched polyethylene glycol terminal or a protected form thereof; F _{9 is} allowed to be a hydroxy protecting group; and when F ₉ is the target functional group at the end of the polyethylene glycol chain When the group or its protected form, the chemical modification of the end of the polyethylene glycol chain can be omitted.

The corresponding linear polyethylene glycol intermediate (60) in Scheme 7 may be polydisperse or monodisperse.

2.2.8. Route 8: Branch Chain - Main Chain Method, Even Law

Step i: a branching agent (59b) having two different functional groups or protected forms thereof F ₁₀ and F ₁₃ , a branching group U, and two molecules having a functional group or a protected form thereof F ₉ Coupling of the heterofunctionalized linear polyethylene glycol (60) to form the divalent linking groups L ₁ and L ₂ , resulting in a V-shaped intermediate with two PEG branching ends ending at F ₉ and a branched group U linking F ₁₀ body (71b); wherein F _9, F ₁₀ different functional groups or protected forms; F _10, F ₁₃ is different from the functional group or a protected form.

It should be noted that the two n ₁ in (71b) do not mean that the number of oxyethylene units of the corresponding polyethylene glycol chain is strictly equal in value, but means that the source is the same, and thus is numerically close. When the source is a monodisperse compound, it is allowed to be strictly equal in value.

Step ii: Form V obtained from step i (71b) and heterofunctionalized linear polyethylene glycol (64b) having two functional groups or protected forms thereof F ₄ , F ₇ , through F ₁₀ and F ₄ The reaction between the two forms a divalent linking group L ₃ to give a heterofunctional Y-type polyethylene glycol intermediate represented by IM9. The definitions of F ₉ and F ₇ in IM7 are consistent with the way 4 (2.2.4.4.) of Route 4.

Step iv: linearly functionalizing or branching functionalizing the main chain polyethylene glycol terminal and the branched polyethylene glycol terminal, respectively, to obtain (2), (3), (4) or (5) respectively The heterofunctionalized Y-type polyethylene glycol is shown.

The corresponding linear polyethylene glycol intermediates (60) and (64b) in Route 8 may be polydisperse or monodisperse.

2.2.9. Route IX, main chain-branch method,

Step i: having a functional group or a protected form F linear polyethylene glycol (64b) ₇ of the reaction, reaction with a functional group or a protected form of small molecule compounds (62) F ₃ divalent The linker L ₃ gives a polyethylene glycol intermediate (46c) having a functional group or a protected form F ₇ and a branched group U. (46c) may contain two functional groups which are reacted to form a divalent linking group or a protected form thereof F ₁₀ , or may contain a functional group which is reacted to obtain a three-branched structure or is protected Form F ₁₀ (such as alkynyl).

Step ii: The polyethylene glycol intermediate (46c) obtained in step i is coupled with two molecules of linear polyethylene glycol (60) having a functional group or its protected form F _{9 to} form a divalent linking group L ₁ And L ₂ to obtain a heterofunctional Y-type polyethylene glycol intermediate represented by IM9.

It should be noted that the two n _{1 in} IM9 do not mean that the number of oxyethylene units of the corresponding polyethylene glycol chain is strictly equal in value, but means that the source is the same, and thus is numerically close. When the source is a monodisperse compound, it is allowed to be strictly equal in value.

Step iii: linearly functionalizing or branching functionalizing the main chain polyethylene glycol terminal and the branched polyethylene glycol terminal, respectively, to obtain (73), (74), (75) or (76) respectively The heterofunctionalized Y-type polyethylene glycol is shown.

Among them, F ₉ and F _{7 in} IM9 are consistent with IM3 in Mode 4 (2.2.4.4.) of Route 4.

Taking the target functional group of the terminal of polyethylene glycol as the main chain of F ₇ or its protected form, F ₉ as the target functional group of the branched polyethylene glycol terminal or a protected form thereof, as an example, The preparation process can be simplified as follows:

Taking F ₇ as the target functional group of the polyethylene glycol terminal of the main chain or a protected form thereof, and F _{9 is} not a target functional group of the branched polyethylene glycol terminal or a protected form thereof, The preparation process of the method can be simplified as follows:

The corresponding linear polyethylene glycol intermediates 36b, 60, 60b, and 64b in the first to second modes of the route 9 may be polydisperse or monodisperse.

2.2.10. Reaction between two functional groups or their protected forms

The reaction between the above two functional groups of the present invention or a protected form thereof is not particularly limited. By way of example, a reaction between a hydroxyl group, F ₃ , F ₄ , F ₅ , F ₆ , F ₇ , F ₉ , F ₁₀ , F ₁₁ and the same or different functional groups or protected forms thereof. The reaction conditions are related to the type of divalent linking group formed by the reaction, and the prior art can be employed. Typical representatives of newly formed divalent linking groups are amide bonds, urethane bonds, ester groups, secondary amine bonds, thioether bonds, triazole groups, and the like. Refer to 2.1.3., and I will not repeat them here.

2.3. Specifically, the present invention also discloses a process for the preparation of several heterofunctional Y-type polyethylene glycol derivatives.

2.3.1. Main chain-branch method

2.3.1.1. Main chain-branched method, obtaining polyethylene glycol spindle by polymerization method

a) a co-initiation system consisting of a small molecule initiator (IN1) containing 1 naked hydroxyl group and 2 protected hydroxyl groups OPG ₇ and a base, deprotonating the bare hydroxyl group, then initiating polymerization of ethylene oxide to form polyethylene a linear spindle of the diol, an oxygen anion intermediate is obtained, and a proton source is added to obtain an intermediate (34) having a linear main chain terminal hydroxyl group and a branching group linking the two protected hydroxyl groups OPG ₇ ;

b) linearly functionalizing the polyethylene glycol terminal hydroxyl group of the linear spindle of the intermediate (34) obtained in the step a) to obtain an intermediate (35b) having a functional group or a protected form thereof F ₇ ; ₇ stable under anionic polymerization conditions;

c) removing the two hydroxy protecting groups PG ₇ from the intermediate (35b) obtained in step b) to obtain an intermediate IM1b having two naked hydroxyl groups;

d) The intermediate IM1b obtained in step c) is combined with a base to form a co-initiation system. After deprotonation of the two exposed hydroxyl groups, polymerization of ethylene oxide is initiated to form two polyethylene glycol branched chains to obtain an oxygen anion intermediate. Adding a proton source to obtain a Y-type polyethylene glycol intermediate (IM2b) having a hydroxyl group at the end of the branch chain;

e) linearly functionalizing the terminal hydroxyl group of the branched chain of the Y-form obtained in step d) to obtain Y-type polyethylene glycol (105) or branching functionalization to obtain Y-type polyethylene glycol (106);

f) linearly functionalizing the terminal polyethylene glycol end of the Y-form intermediate (105) obtained in the step e) to obtain the structure represented by the formula (2), or performing branching functionalization to obtain the formula (4) Structure;

Or linearly functionalizing the main chain polyethylene glycol terminal of the Y-form intermediate (106) obtained in the step e) to obtain the structure represented by the formula (3), or performing branching functionalization to obtain the formula (5) structure;

Wherein U, L ₁ , L ₂ , L ₃ , n ₁ , n ₂ , n ₃ , F ₁ , k ₁ , k ₂ , G ₁ , G ₂ , p ₁ , p ₂ , L ₄ , and formula (2) The definitions of the general formula (3), the general formula (4), and the general formula (5) are the same as those described above, and are not described herein again. PG ₇ is a hydroxy protecting group, preferably a silyl ether, a benzyl group, an acetal, a ketal or a tert-butyl group. F ₁ is a target functional group or a protected form thereof; F ₇ is stably present under anionic polymerization conditions, and F _{7 is} not equal to any of F ₁ , a hydrogen atom, a hydroxyl group-containing functional group, and OPG ₇ . F ₇ may be the same or different from the target functional group or its protected form. The PEG chains corresponding to n ₁ , n ₂ , and n ₃ are polydisperse.

等。参照2.2.1.1.。Step a) After deprotonation, 1 to 2000 times the molar amount of ethylene oxide is added to initiate polymerization of ethylene oxide to form a polydisperse polyethylene glycol spindle to obtain an intermediate (34). The structure of the initiator IN1 includes but is not limited to:

Wait. Refer to 2.2.1.1.

Step b) Linear functionalization of the end of the polyethylene glycol spindle. Refer to 2.1.1.

Step c) Removal of the hydroxy protecting group of intermediate (35b), see 2.2.1.4.

Step d) After deprotonation, 2 to 2000 times the molar amount of ethylene oxide is added to initiate polymerization of ethylene oxide to form a polydisperse polyethylene glycol branched chain to obtain a Y-form intermediate (IM2b). Refer to 2.2.1.2.

Steps e), f) Linear functionalization of the ends of the polyethylene glycol chain. Refer to 2.1.1. or perform branching functionalization with reference to 2.1.2.

When F ₇ is a hydroxy protecting group PG ₄ different from PG ₇ , the corresponding preparation process is as shown in the following formula.

Wherein, according to the above reaction steps a) to d), intermediates represented by (34), (35), IM1, and IM2 are respectively obtained;

Linearly functionalizing the terminal hydroxyl group of the branched chain of the Y-form obtained in step d) to obtain Y-type polyethylene glycol (31) or branched functionalized to obtain Y-type polyethylene glycol (32);

Step f: removal of the hydroxy protecting group PG ₄ to obtain a hydroxyl group Y intermediate IM3 (corresponding to 31) and IM4 (corresponding to 32) at the end of the main chain; and then linearly functionalizing the terminal polyethylene glycol end of IM3 a structure represented by formula (2), or branched functionalization to obtain a structure represented by formula (4);

Alternatively, linearly functionalizing the terminal polyethylene glycol end of IM4 to obtain a structure represented by formula (3) or branching functionalization to obtain a structure represented by formula (5).

The preparation process is as follows:

2.3.1.2. Using a heterofunctionalized linear polyethylene glycol as the polyethylene glycol spindle

a) using a heterofunctionalized linear polyethylene glycol (36b) as a starting material, and alkylating with a small molecular branching compound (37) to form a divalent linking group L ₃ to obtain an intermediate having two protected hydroxyl groups. (35b); wherein, F ₇ and F ₄ are different functional groups or protected forms thereof;

b), c), d), e) repeat steps c), d), e), f) in 2.3.1.1;

Wherein, step e): linearly functionalizing the terminal polyethylene glycol end of the Y-form intermediate (105) obtained in the step d) to obtain a structure represented by the formula (2), or performing branching functionalization to obtain a formula ( 4) the structure shown;

Or linearly functionalizing the main chain polyethylene glycol terminal of the Y-form intermediate (106) obtained in the step d) to obtain the structure represented by the formula (3), or performing branching functionalization to obtain the formula (5) structure;

Wherein U, L ₁ , L ₂ , L ₃ , n ₁ , n ₂ , n ₃ , F ₁ , k ₁ , k ₂ , G ₁ , G ₂ , p ₁ , p ₂ , L ₄ , and formula (2) The definitions of the general formula (3), the general formula (4), and the general formula (5) are the same as those described above, and are not described herein again. PG ₇ hydroxy protecting group, preferably silyl ether, benzyl, acetal, ketal or tert-butyl. F ₁ is a target functional group or a protected form thereof; F ₇ is stably present under anionic polymerization conditions, and F _{7 is} not equal to F ₄ , F ₁ , a hydrogen atom, a hydroxyl group-containing functional group, or any of OPG ₇ F _{3 is} not equal to OPG ₇ ; the PEG chain corresponding to n ₁ , n ₂ has polydispersity; the corresponding PEG chain of n ₃ may be polydisperse or monodisperse. F ₇ may be the same or different from the target functional group F ₂ .

The alkylation reaction of the step a) to form the divalent linking group L ₃ includes, but is not limited to, an alkylation reaction involving a hydroxyl group, a mercapto group or an amino group. The preparation conditions can be referred to in 2.1.4., and are not described herein again. Typical alkylation reactions such as alkylation between substrate alcohols, substrate thiols, substrate amines and sulfonates or halides, as well as alkylation between substrate amines and aldehyde derivatives Reaction, etc.

The linear polyethylene glycol derivative (36b) may be polydisperse or monodisperse, so the linear major axis of the resulting heterofunctional Y-type polyethylene glycol (n ₃ corresponds to the PEG chain) may be polydisperse. It can also be monodisperse.

Step b) Removal of the hydroxy protecting group is referred to 2.2.1.4.

Step c) Deprotonation to initiate polymerization of ethylene oxide to form a polydisperse polyethylene glycol branch, see 2.2.1.2.

Step d), step e) Polyethylene glycol chain end linear functionalization Refer to 2.1.1., for branching functionalization reference 2.1.2.

For example, when the small molecule branching compound (37) is an amine derivative (107) having two protected hydroxyl groups, the heterofunctionalized linear polyethylene glycol (36b) is preferably a heterofunctionalized polyethylene glycol polyethylene. An alcohol sulfonate or a halide, at which point alkylation of step a) yields an intermediate (108) having two protected hydroxyl groups. According to the above steps b), c), d), and e), the hetero-functionalization of the branch center of the nitrogen atom represented by the general formula (2), (3), (4) or (5) wherein U is a nitrogen atom is obtained. Y-type polyethylene glycol.

The preparation process is as follows:

Wherein PG _{4 is} selected from the group consisting of a silyl ether, a benzyl group, an acetal, a ketal or a tert-butyl group.

The alkylation reaction conditions of the substrate of the above step a), which are amine derivatives, refer to 2.1.4.2., and are not described herein again.

2.3.1.3. Asymmetric glycerol branching groups

Step a) Deprotonation (K, THF) of the heterofunctionalized linear polyethylene glycol (111) containing a functional group or its protected form F ₇ at the other end to give an oxygen anion intermediate, and a chloromethyl group Alkylation of ethylene oxide to obtain an intermediate having a glycidyl ether group represented by (39b);

Step b) under basic conditions, the epoxy group in the intermediate (39b) obtained in step a) undergoes a ring opening reaction to obtain an intermediate (112) having two naked hydroxyl groups;

的结构为

其中U为

L₁不存在，L₂＝CH₂，L₃＝CH₂。c) The intermediate (112) obtained in the step b) is combined with a base to form a co-initiation system. After deprotonation of the two exposed hydroxyl groups, polymerization of ethylene oxide is initiated to form two polyethylene glycol branched chains to obtain an oxygen anion. An intermediate, a proton source is added to obtain a Y-type polyethylene glycol intermediate (113) having a hydroxyl group at the end of the branch chain; wherein the branch group is

Structure

Where U is

L ₁ is absent, L ₂ = CH ₂ , L ₃ = CH ₂ .

d) linearly functionalizing the terminal hydroxyl group of the branched chain of the Y-form obtained in step c) to obtain Y-type polyethylene glycol (114) or branching functionalization to obtain Y-type polyethylene glycol (115);

e) linearly functionalizing the terminal polyethylene glycol end of the Y-form intermediate (114) obtained in the step d) to obtain the structure represented by the formula (2), or performing branching functionalization to obtain the formula (4) Structure;

Or linearly functionalizing the main chain polyethylene glycol terminal of the Y-form intermediate (115) obtained in the step d) to obtain the structure represented by the formula (3), or performing branching functionalization to obtain the formula (5) structure;

L₁不存在，L₂＝CH₂，L₃＝CH₂；The structure of the branching group in the formulas (2), (3), (4), (5) satisfies U=

L ₁ is absent, L ₂ =CH ₂ , L ₃ =CH ₂ ;

L₁不存在，L₂＝CH₂，L₃＝CH₂；F₁为目标功能性基团或其被保护形式，且F₇不等于缩水甘油醚基、F₁、氢原子、含羟基的功能性基团、OPG₇中任一种。其中，n₁、n₂对应的聚乙二醇链具有多分散性；n₃对应的聚乙二醇链可以为多分散性或单分散性。Wherein n ₁ , n ₂ , n ₃ , F ₁ , k ₁ , k ₂ , G ₁ , G ₂ , p ₁ , p ₂ , L ₄ , formula (2), formula (3), formula ( 4), the definition of the general formula (5) is consistent with the above, and U=

L ₁ is absent, L ₂ =CH ₂ , L ₃ =CH ₂ ; F ₁ is a target functional group or a protected form thereof, and F _{7 is} not equal to a glycidyl ether group, F ₁ , a hydrogen atom, or a hydroxyl group-containing Any of the functional groups and OPG ₇ . Wherein, the polyethylene glycol chains corresponding to n ₁ and n ₂ have polydispersity; and the polyethylene glycol chains corresponding to n ₃ may be polydisperse or monodisperse.

Step a) blocking the glycidyl ether of the terminal hydroxyl group of the polyethylene glycol, which is an alkylation reaction between the terminal hydroxyl group of the polyethylene glycol and the acid chloride ethylene oxide, refer to 2.1.4.1. Linear polyethylene glycol (111) may be polydisperse or monodisperse;

Step b) ring opening reaction of epoxy group under basic conditions, refer to 2.2.1.1.

Step c) initiating polymerization of ethylene oxide to prepare a polydisperse polyethylene glycol chain, see 2.2.1.2.

The linear functionalization of the polyethylene glycol chain ends of step d) and step f) is referred to in 2.1.1., and the branched functionalization is referred to in 2.1.2.

L₁不存在，L₂＝CH₂，L₃＝CH₂。其中，(111b)可以为多分散性或单分散性。When F ₇ is a hydroxy protecting group, a silyl ether, a benzyl group, an acetal, a ketal or a tert-butyl group is preferred. At this time, the reaction raw material (111) is a heterofunctionalized linear polyethylene glycol (111b) having one end of the hydroxyl group and a protected hydroxyl group at one end, and (39) and (112b) are obtained through steps a), b), and c), respectively. The intermediate represented by (113b); the Y-form intermediate represented by (114b) or (115b) is obtained by the step d); the hydroxy protecting group PG _{4 of the} main chain polyethylene glycol is removed by the step e), Obtaining a Y-form intermediate (114c) or (115c) having a hydroxyl group at the end of the main chain; linearly functionalizing the terminal polyethylene glycol end of (114c) via step f) to obtain a structure represented by the formula (2), or Branching functionalization gives the structure shown in formula (4); or linearly functionalizing the terminal polyethylene glycol terminal of (115c) via step f) to obtain the structure represented by formula (3), or branching Functionalization gives a structure represented by formula (5); wherein the structure of the branch group in the formulas (2), (3), (4), (5) satisfies U=

L ₁ is absent, L ₂ = CH ₂ , L ₃ = CH ₂ . Among them, (111b) may be polydisperse or monodisperse.

L₁不存在，L₂＝CH₂，L₃＝CH₂；PG₄羟基保护基， 优选硅醚、苄基、缩醛、缩酮或叔丁基；F₁为目标功能性基团或其被保护形式，且F₁不等于OPG₄。其中，n₁、n₂对应的PEG链具有多分散性；n₃对应的聚乙二醇链可以为多分散性或单分散性。Wherein n ₁ , n ₂ , n ₃ , F ₁ , k ₁ , k ₂ , G ₁ , G ₂ , p ₁ , p ₂ , L ₄ , formula (2), formula (3), formula ( 4), the definition of the general formula (5) is consistent with the above, and U=

L ₁ is absent, L ₂ =CH ₂ , L ₃ =CH ₂ ; PG ₄ hydroxy protecting group, preferably silyl ether, benzyl, acetal, ketal or tert-butyl; F ₁ is a target functional group or Protected form, and F _{1 is} not equal to OPG ₄ . Wherein, the PEG chains corresponding to n ₁ and n ₂ have polydispersity; the polyethylene glycol chains corresponding to n ₃ may be polydisperse or monodisperse.

2.3.2. Branch Chain-Main Chain Polymerization

Wherein U, L ₁ , L ₂ , L ₃ , n ₁ , n ₂ , n ₃ , k ₁ , k ₂ , G ₁ , G ₂ , p ₁ , p ₂ , L ₄ , formula (2), pass The definitions of formula (3), formula (4), and formula (5) are consistent with the above; PG ₄ is a hydroxy protecting group, preferably a silyl ether, a benzyl group, an acetal, a ketal or a t-butyl group; F _{9 is} not OPG ₄ and is stably present under anionic polymerization conditions; F ₉ may be the same or different from the target functional group or its protected form F ₁ . The PEG chains corresponding to n ₁ , n ₂ , and n ₃ are polydisperse;

a) a co-initiation system consisting of a small molecule initiator (IN3) containing two exposed hydroxyl groups and one protected hydroxyl group OPG ₄ , and deprotonating the bare hydroxyl group to initiate polymerization of ethylene oxide to form two a polyethylene glycol branched chain, an oxygen anion intermediate is obtained, and two branched chain ends obtained by adding a proton source are terminated by a hydroxyl group, and a branched group is bonded to a V-type intermediate (51) which is protected by a hydroxyl group OPG ₄ ;

b) linearly functionalizing the branch end of the V-form intermediate (51) obtained in the step a to obtain a V-form intermediate represented by (54), or performing the main chain end of the V-form intermediate (51) Branching functionalization modification to give a V-form intermediate as shown in (56); wherein the functional group or its protected form F ₉ is stably present under anionic polymerization conditions;

c) the V-form intermediate (54) or (56) obtained in step b, the hydroxy-protecting group PG ₄ linked to the branch group is removed, to obtain a V-form intermediate (54c) or (56c) having one naked hydroxyl group. ;

d) The intermediate (54c) or (56c) obtained in step c) is combined with a base to form a co-initiation system for the naked hydroxyl group. After protonation, the polymerization of ethylene oxide is initiated to form a linear polyethylene glycol spindle to obtain an oxygen anion intermediate, and a proton source is added to obtain a Y-type polyethylene glycol intermediate (54d) or (56d) having a hydroxyl group at the end of the main chain. ;

e) linearly functionalizing the ends of the main chain polyethylene glycol of the Y-form intermediate (54d) obtained in the step d) and the branched polyethylene glycol to obtain the formulas (2), (3), (4) Or a heterofunctional Y-type polyethylene glycol as shown in (5);

Or functionally modifying the main chain polyethylene glycol terminal and the branch chain end of the Y-form intermediate (56c) obtained in the step d) independently to obtain the heterofunctional Y-type poly group represented by (3) or (5). Ethylene glycol; wherein a linear functional modification or a branched functionalization modification is performed on the end of the main chain, and a linear functional modification is performed on the end of the branched chain.

Bn为苄基。Step a) 2 to 2000 times the molar amount of ethylene oxide. Initiating the polymerization of ethylene oxide to form a polydisperse polyethylene glycol branched chain, refer to 2.2.1.2. wherein the small molecule initiator IN3 contains a protected hydroxyl group and two exposed hydroxyl groups, for example, the structure includes But not limited to:

Bn is a benzyl group.

Step b) Linear functionalization of the polyethylene glycol terminal hydroxyl group Refer to 2.1.1., for branching functionalization reference 2.1.2.

Step c) removal of the hydroxy protecting group PG ₄ , refer to 2.2.1.4.

Step d) 1 to 2000 times the molar amount of ethylene oxide. The polyethylene glycol backbone which initiates the polymerization of ethylene oxide to form polydispersity, refer to 2.2.1.2.

Step e) Perform linear or modified functionalization of the polyethylene glycol chain ends, see 2.1.1. and 2.1.2.

2.3.3. Branch 1 - Branch 2 - Main Chain Method

2.3.3.1. Coupling-coupling-even law

a) a heterofunctionalized linear polyethylene glycol containing a functional group or its protected form F _{10 and} a branching agent (62) with two different functional groups or protected forms thereof F ₉ , F ₁₁ (60), reacting between the branched groups U and F ₁₁ to form a divalent linking group L ₁ , introducing a first branched chain to form an intermediate represented by the formula (63);

b) the intermediate compound (63) obtained in the step a) and the heterofunctionalized linear polyethylene glycol (60b) containing two functional groups F ₉ and F ₁₂ or a protected form thereof, a branched group a reaction between U and F ₁₂ to form a divalent linking group L ₂ and a second branched chain to give an intermediate represented by (54b);

c) step b) to give intermediate (54b), containing two different functional groups, or a protected form F isobutyl functionalized linear polyethylene glycol (64b) _7, F _4, dried and F ₁₀ a reaction between F ₄ to form a divalent linking group L ₃ to obtain a heterofunctional Y-type polyethylene glycol intermediate represented by IM7;

d) independently linearly functionalizing or branching functionalizing the polyethylene glycol end and the branched polyethylene glycol end of the main chain, respectively, as shown in (2), (3), (4) or (5) Heterofunctionalized Y-type polyethylene glycol.

Wherein, the definitions of U, L ₁ , L ₂ , L ₃ , n ₁ , n ₂ , n ₃ , formula (2), formula (3), formula (4), and formula (5) are consistent with the above ; F ₄ , F ₇ , F ₉ , F ₁₀ , F ₁₁ , F ₁₂ are all functional groups or protected forms thereof; and two functional groups present in the same molecule or their protected forms are different . (F ₁₁ , F ₉ ), (F ₁₀ , F ₉ ), (F ₁₂ , F ₉ ), (F ₇ , F ₄ ), (F ₇ , F ₉ ) are all heterofunctionalized pairs. Wherein, n ₁ , n ₂ , and n ₃ each independently may be polydisperse or monodisperse. Any of F ₇ and F ₉ may be a target functional group or a protected form thereof.

The reactions between the two functional groups of L ₁ , L ₂ , L ₃ or their protected forms in step a), step b), step c) are independently referenced to 2.1.3. and 2.1.4. When one of them is in a protected form, it can be deprotected before reacting. I won't go into details here. The reaction materials (60), (60b), and (64b) are each independently polydisperse or monodisperse.

When UF ₁₀ is a primary amine (-NH ₂ ), the synthesis steps are as follows:

a) having a functional group or a protected form F ₉ heterologous functional linear amine derivative of polyethylene glycol (116) having a functional group or are different linear polyethylene functionalized protected form F ₉ II The alkylation reaction of the sulfonate, halogenated or aldehyde derivative (60b) of the alcohol forms a V-type secondary amine intermediate (117);

b) the V-type secondary amine intermediate (117) obtained in step a) is reacted with a heterofunctionalized linear polyethylene glycol active derivative (64b) containing a functional group or its protected form F ₁₂ , F ₉ Base or amidation reaction to obtain a Y-type polyethylene glycol intermediate (118) of a nitrogen atom branching center;

c) independently linearly functionalizing or branching functionalizing the polyethylene glycol terminal and the branched polyethylene glycol terminal of the main chain, respectively, as shown in (2), (3), (4) or (5) The heterofunctionalized Y-type polyethylene glycol of the nitrogen atom branching center.

Wherein, definitions of L ₁ , L ₂ , L ₃ , n ₁ , n ₂ , n ₃ , formula (2), formula (3), formula (4), and formula (5) are consistent with the above; U Is a nitrogen atom N; F ₄ , F ₇ , F ₉ , F ₁₁ , F ₁₂ are all functional groups or protected forms thereof; and two functional groups present in the same molecule or protected forms thereof different. (F ₁₁ , F ₉ ), ((F ₁₂ , F ₉ ), (F ₇ , F ₄ ), (F ₇ , F ₉ ) are all heterofunctionalized pairs, wherein n ₁ , n ₂ , n ₃ correspond The PEG chains may each independently be polydisperse or monodisperse. Any of F ₇ and F ₉ may be a target functional group or a protected form thereof.

The reaction materials (116), (60b), and (64b) may be polydisperse or monodisperse.

Step a) Alkylation of a primary amine to form a V-form compound (117), which can be achieved by Mode A or Mode B as follows:

A. The alkylation of the polyethylene glycol amine derivative (116) with the polyethylene glycol sulfonate or halogenated product (60b); see 2.1.4.2.

B. The alkylation reaction of the polyethylene glycol amine derivative (116) with the polyethylene glycol aldehyde derivative (60b); refer to 2.1.4.3.

Step b) Alkylation or amidation of a secondary amine to form a Y-type compound of a branch center of a nitrogen atom (118)

If it is necessary to introduce two chains into the primary amine, the primary amine can only be introduced through the alkylation reaction, and the second branch can be introduced through the alkylation process and acylation. The method was introduced.

The alkylation method is referred to 2.1.4.2. or 2.1.4.3. An example of the structure of the Y compound (118) is as follows:

For the amidation method, refer to 2.1.3.1. The branched group U of the Y-type compound (118) contains an imide bond, (118) The structure is as shown in (120), and is specifically shown, for example, in (121).

2.3.3.2. Coupling-coupling-polymerization

a) a branched small molecule compound (59) containing a protected hydroxyl group OPG ₄ and a heterofunctionalized linear polyethylene glycol (60) containing two different functional groups or protected forms thereof F ₉ , F ₁₁ , Directly reacting the branched group U with F ₁₁ to form a divalent linking group L ₁ , and introducing the first branched chain to form a compound represented by the formula (61);

b) (61) obtained in step a) and a heterofunctionalized linear polyethylene glycol (60b) containing a functional group or a protected form thereof F ₉ , via F ₉ and F ₁₂ functional groups or The reaction between the protected forms forms a divalent linking group L ₂ and introduces a second branched chain to form a V-form intermediate as shown in (54);

c) the V-form intermediate (54) or (56) obtained in step b, the hydroxy-protecting group PG ₄ linked to the branch group is removed, to obtain a V-form intermediate (54c) or (56c) having one naked hydroxyl group. ;

d) The intermediate (54c) or (56c) obtained in the step c) is combined with a base to form a co-initiation system, and after deprotonation of the exposed hydroxyl group, polymerization of ethylene oxide is initiated to form a linear polyethylene glycol spindle to obtain oxygen. Anion intermediate, adding a proton source to obtain a Y-type polyethylene glycol intermediate (54d) or (56d) having a hydroxyl group at the end of the main chain;

e) linearly functionalizing the ends of the main chain polyethylene glycol of the Y-form intermediate (54d) obtained in the step d) and the branched polyethylene glycol to obtain the formulas (2), (3), (4) Or a heterofunctional Y-type polyethylene glycol as shown in (5);

Or functionally modifying the main chain polyethylene glycol terminal and the branch chain end of the Y-form intermediate (56c) obtained in the step d) independently to obtain the heterofunctional Y-type poly group represented by (3) or (5). Ethylene glycol; wherein a linear functional modification or a branched functionalization modification is performed on the end of the main chain, and a linear functional modification is performed on the end of the branched chain.

Wherein, the definitions of U, L ₁ , L ₂ , L ₃ , n ₁ , n ₂ , n ₃ , formula (2), formula (3), formula (4), and formula (5) are consistent with the above PG ₄ is a hydroxy protecting group, preferably a silyl ether, a benzyl group, an acetal, a ketal or a tert-butyl group; F ₉ , F ₁₁ , F ₁₂ are all functional groups or protected forms thereof; F ₉ is an anionic polymerization It is stable under the conditions; two functional groups present in the same molecule or their protected forms are different. (F ₁₁ , F ₉ ), (OPG ₄ , F ₉ ), (F ₁₂ , F ₉ ), (OH, F ₉ ) are all heterofunctionalized pairs. Wherein, n _1, n ₂ corresponding to the PEG chain may be independently polydispersity, it may be a monodisperse; n ₃ corresponding to a PEG chain having a polydispersity; F ₉ and the target functional group or a protected form F ₁ may be the same or different.

The reactions between the two functional groups of L ₁ and L ₂ in step a), step b) or their protected forms are each independently referenced to 2.1.3. and 2.1.4., when one of them is When the form is protected, it can be deprotected before reacting. I won't go into details here. The reaction materials (60) and (60b) are each independently polydisperse or monodisperse.

Steps c), d), e) refer to steps c), d), e) of 2.3.2. and are not described here.

2.3.3.3. Aggregation-coupling-even law

a) a small molecule initiator (67) having a functional group or a protected form thereof, F ₁₀ and a hydroxyl group, and a base-constituting co-initiation system, after deprotonating the exposed hydroxyl group, initiating polymerization of ethylene oxide to form a poly The ethylene glycol chain is obtained as an oxygen anion intermediate, and a proton source is added to obtain an intermediate (69) having a hydroxyl group at the end of the PEG chain; F ₁₀ is a functional group which is stable under anionic polymerization conditions or a protected form thereof;

b) linearly functionalizing the terminal hydroxyl group of the polyethylene glycol chain of the intermediate (69) obtained in the step a), and capping with a functional group or its protected form F _{9 to} obtain an intermediate (63);

c) the intermediate compound (63) obtained in the step b) and the heterofunctionalized linear polyethylene glycol (60b) containing two functional groups F ₉ and F ₁₂ or a protected form thereof, a branched group a reaction between U and F ₁₂ to form a divalent linking group L ₂ and a second branched chain to give a compound represented by (54b);

d) step c) to give the intermediate (54b), containing two different functional groups, or a protected form F _7, iso-functionalized linear polyethylene glycol (64b) F _4, dried and F ₁₀ a reaction between F ₄ to form a divalent linking group L ₃ to obtain a heterofunctional Y-type polyethylene glycol represented by IM7;

e) linearly functionalizing or branching functionalizing the main chain polyethylene glycol terminal and the branched polyethylene glycol terminal independently, respectively, as shown in (2), (3), (4) or (5) Heterofunctionalized Y-type polyethylene glycol.

Wherein, the definitions of U, L ₁ , L ₂ , L ₃ , n ₁ , n ₂ , n ₃ , formula (2), formula (3), formula (4), and formula (5) are consistent with the above ; F ₄ , F ₇ , F ₁₀ , F ₉ , F ₁₂ are all functional groups or protected forms thereof; F ₁₀ is stably present under anionic polymerization conditions; two functional groups present in the same molecule; Or it is protected in different forms. (F ₁₀ , hydroxy), (F ₁₀ , F ₉ ), (F ₁₂ , F ₉ ), (F ₇ , F ₄ ), (F ₇ , F ₉ ) are all heterofunctionalized pairs. Wherein, the PEG chain corresponding to n ₁ has polydispersity, and the n ₂ and n ₃ corresponding PEG chains may independently be polydisperse or monodisperse. Any of F ₇ and F ₉ may be a target functional group or a protected form thereof.

Step a) 2 to 2000 times the molar amount of ethylene oxide. Initiating polymerization of ethylene oxide to form a polydisperse polyethylene glycol chain, refer to 2.2.1.2.; F ₁₀ in reagent (67) is preferably a protected form of the functional group, or preferably under anionic polymerization conditions. Stable functional group. By way of example, it may be in the form of a protected amino group, a protected thiol group, a protected alkynyl group, a protected maleimide, a protected carboxyl group, and the like.

The process of linearly functionalizing the terminal hydroxyl group of the polyethylene glycol in step b) is referred to in 2.1.1. and will not be repeated here.

The reaction between the two functional groups of the step c) and the step d) for generating the divalent linking group L ₁ , L ₂ or the protected form thereof is independently referred to 2.1.3. and 2.1.4. When it is protected, it can be deprotected and then reacted. I won't go into details here. Among them, the heterofunctionalized linear polyethylene glycols (60b) and (64b) as raw materials are each independently polydisperse or monodisperse. At the same time, step b) and step c) of 2.3.3.1.

Step e) Step d) of 2.3.3.1.

Taking F ₁₀ in the reagent (67) as the protected amino NHPG ₅ as an example, the structure is as shown in (122).

a) using one end of the hydroxyl group as the protected amino NHPG ₅ small molecule initiator (122) as a raw material, repeat the above step a) to obtain the intermediate (123);

b) linearly functionalizing the terminal hydroxyl group of the polyethylene glycol chain of the intermediate (123) obtained in the step a), and capping with a functional group or its protected form F _{9 to} obtain an intermediate (124);

c) deprotecting the protected amino group NHPG ₅ from the intermediate (124) obtained in step b) to obtain a primary amine intermediate (116) of polyethylene glycol;

d), e), f) repeat the steps in 2.3.3.1. respectively to obtain a heterofunctional Y-form represented by (2), (3), (4) or (5) and having a branching center of a nitrogen atom Polyethylene glycol.

The synthesis steps are as follows:

Wherein, definitions of L ₁ , L ₂ , L ₃ , n ₁ , n ₂ , n ₃ , formula (2), formula (3), formula (4), and formula (5) are consistent with the above; U Is a nitrogen atom N; wherein PG ₅ is an amino protecting group; F ₄ , F ₇ , F ₉ , F ₁₂ are all functional groups or protected forms thereof; and two functionalities present in the same molecule The group or its protected form is different. (NHPG ₅ , F ₉ ), (NH ₂ , F ₉ ), (F ₁₂ , F ₉ ), (F ₇ , F ₄ ), (F ₇ , F ₉ ) are all heterofunctionalized pairs. Wherein, the PEG chain corresponding to n ₁ has polydispersity; and the n ₂ and n ₃ corresponding PEG chains are each independently polydisperse or monodisperse. Any of F ₇ and F ₉ may be a target functional group or a protected form thereof.

其中，NHPG₅为氨基被保护后的结构，优选为氨基甲酸酯、酰胺、酰亚胺、N-烷基胺、N-芳基胺、亚胺、烯胺、咪唑、吡咯或吲哚。Step a) 2 to 2000 times the molar amount of ethylene oxide. A polyethylene glycol intermediate (123) which initiates polymerization of ethylene oxide to form polydispersity. Structure in reagent (122), by way of example, including but not limited to

Among them, NHPG ₅ is a structure in which an amino group is protected, and is preferably a carbamate, an amide, an imide, an N-alkylamine, an N-arylamine, an imine, an enamine, an imidazole, a pyrrole or a hydrazine.

The process of linearly functionalizing the terminal hydroxyl group of the polyethylene glycol in step b) is referred to in 2.1.1. and will not be repeated here.

The reaction between the two functional groups of the step c) and the step d) for generating the divalent linking group L ₁ , L ₂ or the protected form thereof is independently referred to 2.1.3. and 2.1.4. When it is protected, it can be deprotected and then reacted. I won't go into details here. Among them, the heterofunctionalized linear polyethylene glycols (60b) and (64b) as raw materials are each independently polydisperse or monodisperse. Refer to step b) and step c) of 2.3.3.1.

Step e) based on the alkylation or amidation reaction of the secondary amine, refer to step d) of 2.3.3.1.

Step f) Linear functionalization or branching functional modification of the polyethylene glycol chain ends is referred to in 2.1.1. and 2.1.2.

2.3.4. Main chain / branch 1 - branch 2

a) using two heterofunctionalized linear polyethylene glycols as starting materials to form a divalent linking group L ₁ or L ₃ to obtain a heterofunctional polyethylene glycol intermediate IM5 having two polyethylene glycol blocks; polyethylene glycol segment spindle end to a functional group or a protected form terminated F _7; polyethylene glycol as an end of one of the branched segment to a functional group or a protected form capped F ₉ a junction of two polyethylene glycol chains having a branching group U, U linked to a functional group or a protected form thereof F ₁₀ , or UF ₁₀ together forming a functional group or a protected form thereof;

When the divalent linking group L ₁ is formed, U is located at the end of the main chain polyethylene glycol raw material; the structures of the raw materials of the main chain polyethylene glycol and the branched polyethylene glycol are as shown in (46c) and (60), respectively;

When the divalent linking group L ₃ is formed, U is located at the end of the branched polyethylene glycol raw material; the structures of the raw materials of the main chain polyethylene glycol and the branched polyethylene glycol are as shown in (64b) and (63), respectively;

b) intermediate IM5 obtained in step a), and a heterofunctionalized linear polyethylene glycol (60b) containing two functional groups F ₉ and F ₁₂ or a protected form thereof, between F ₁₀ and F ₁₂ Reaction to form a divalent linking group L ₂ to obtain a Y-form intermediate IM7;

c) independently linearly functionalizing or branching functionalizing the main chain polyethylene glycol terminal and the branched polyethylene glycol terminal to obtain the results shown in (2), (3), (4) or (5) Heterofunctionalized Y-type polyethylene glycol.

2.3.4.1. Taking (46c) and (60) as raw materials for the preparation of IM5 as an example, the process for preparing heterofunctional Y-type polyethylene glycol is as follows:

The reactions between the two functional groups of the divalent linking groups L ₁ , L ₂ or the protected forms thereof in step a) and step b) are independently referenced to 2.1.3. and 2.1.4. One of the protected forms can be deprotected before reacting. I won't go into details here. Among them, the heterofunctionalized linear polyethylene glycols (46c), (60b), and (64b) as raw materials are each independently polydisperse or monodisperse.

Step b) Linear functionalization of the end of the polyethylene glycol chain. Refer to 2.1.1. for branching functionalization. Refer to 2.1.2.

Wherein, the definitions of U, L ₁ , L ₂ , L ₃ , n ₁ , n ₂ , n ₃ , formula (2), formula (3), formula (4), and formula (5) are consistent with the above ; F ₇ , F ₉ , F ₁₀ , F ₁₁ , and F ₁₂ are all functional groups or protected forms thereof; two functional groups present in the same molecule or their protected forms are different. (F ₇ , F ₁₀ ), (F ₁₁ , F ₉ ), (F ₇ , F ₉ ), (F ₁₂ , F ₉ ) are all heterofunctionalized pairs. Wherein, n ₁ , n ₂ , and n ₃ each independently may be polydisperse or monodisperse. Any of F ₇ and F ₉ may be a target functional group or a protected form thereof.

Taking UF ₁₀ as NH ₂ as an example, the structure of the main chain polyethylene glycol raw material (46c) is as shown in (125).

a) having a functional group or a protected form F iso-functionalized polyethylene glycol amine derivative ₇ (125) having a functional group or a functional heterologous F is a protected form of a linear polyethylene glycol ₉ The sulfonate, halogenated or aldehyde derivative (60) undergoes an alkylation reaction to form a secondary amine intermediate (126);

b) alkylation of the secondary amine intermediate (126) obtained in step a) with a heterofunctionalized linear polyethylene glycol reactive derivative (60b) containing a functional group or its protected form F ₁₂ , F ₉ Or amidation reaction to obtain a Y-type polyethylene glycol intermediate (118) of a nitrogen atom branching center;

c) independently linearly functionalizing or branching functionalizing the polyethylene glycol terminal and the branched polyethylene glycol terminal of the main chain, respectively, as shown in (2), (3), (4) or (5) The heterofunctionalized Y-type polyethylene glycol of the nitrogen atom branching center.

Wherein, definitions of L ₁ , L ₂ , L ₃ , n ₁ , n ₂ , n ₃ , formula (2), formula (3), formula (4), and formula (5) are consistent with the above; U Is a nitrogen atom N; F ₇ , F ₉ , F ₁₁ , F ₁₂ are all functional groups or protected forms thereof; and two functional groups present in the same molecule or protected forms thereof are different. (F ₇ , NH ₂ ), (F ₁₁ , F ₉ ), (F ₇ , F ₉ ), (F ₁₂ , F ₉ ) are all heterofunctionalized pairs. Wherein, n ₁ , n ₂ , and n ₃ each independently may be polydisperse or monodisperse. Any of F ₇ and F ₉ may be a target functional group or a protected form thereof.

Step a) Alkylation of a primary amine to form a secondary amine intermediate compound (126), which can be achieved by Mode A or Mode B as follows:

A. The alkylation of the polyethylene glycol amine derivative (125) with the polyethylene glycol sulfonate or halogenated product (60); see 2.1.4.2.

B. The alkylation reaction of the polyethylene glycol amine derivative (125) with the polyethylene glycol aldehyde derivative (60); refer to 2.1.4.3.

Step b) Alkylation or amidation of the secondary amine (126) to form a Y-type compound (118) of the branch center of the nitrogen atom, see 2.1.3.1.

When a second branch is introduced by an alkylation method, by way of example, the structure of (118) can be as shown in (127):

When the second branch is introduced by the amidation method, by way of example, the structure of (118) can be as shown in (128):

2.3.5. Branch-Bearing Method, Coupling-Polymerization

a) a small initiator (IN4) having two protected hydroxyl groups and a base co-initiation system, after deprotonating two exposed hydroxyl groups, initiating polymerization of ethylene oxide to form a polyethylene glycol branching chain, Obtaining an oxygen anion intermediate, adding a proton source to obtain a V-type intermediate (51b) having a hydroxyl group terminal at the PEG chain; F ₁₀ or UF ₁₀ is a functional group stable under anionic polymerization conditions or a protected form thereof;

b) linearly functionalizing the terminal hydroxyl group of the PEG branch chain of the V-form intermediate (51b) to obtain the V-form intermediate represented by (54b), or performing branching functionalization to obtain V as shown in (56b) Type intermediate

c) a V-form intermediate (54b) or (56b) obtained in step b), and a heterofunctionalized linear polyethylene glycol (64b) containing two different functional groups or protected forms thereof F ₇ , F ₄ a reaction between F ₁₀ and F ₄ to form a divalent linking group L ₃ to give a hetero-functionalized Y-type polyethylene glycol intermediate IM7 or (IM8);

e) linearly functionalizing or branching functionalization of the main chain polyethylene glycol terminal and the branched polyethylene glycol terminal of IM7, respectively, to obtain (2), (3), (4) or (5) a heterofunctionalized Y-type polyethylene glycol as shown;

Or independently functionalize the functionalization or branching functionalization of the main chain polyethylene glycol terminal and the branched polyethylene glycol terminal of IM8, respectively, to obtain the heterofunctional Y-type poly group represented by (3) or (5), respectively. Ethylene glycol.

Wherein U, L ₁ , L ₂ , L ₃ , n ₁ , n ₂ , n ₃ , k ₁ , k ₂ , G ₁ , G ₂ , p ₁ , p ₂ , L ₄ , formula (2), pass The definitions of formula (3), formula (4), and formula (5) are consistent with the above; F ₄ , F ₇ , F ₉ , and F ₁₀ are all functional groups or protected forms thereof; F ₁₀ or UF ₁₀ A functional group that is stable under anionic polymerization conditions or a protected form thereof; two functional groups present in the same molecule or a protected form thereof. (F ₁₀ , OH), (F ₁₀ , F ₉ ), (F ₇ , F ₉ ) are all heterofunctionalized pairs. Wherein, the PEG chain corresponding to n ₁ and n ₂ has polydispersity; the PEG chain corresponding to n ₃ may be polydisperse or monodisperse; any one of F ₇ and F ₉ may be a target functional group. Or its protected form.

Step a) 2 to 2000 times the molar amount of ethylene oxide. The polyethylene glycol branched chain which initiates the polymerization of ethylene oxide to form polydispersity is referred to 2.2.1.2.

Step b) Linear functionalization of the terminal hydroxyl groups of the polyethylene glycol branching chain, see 2.1.1.

Step c) The reaction between the two functional groups or their protected forms to form the divalent linking group L ₃ , refer to 2.1.3. and 2.1.4., when one of them is protected, it can be carried out first Deprotection and then reacting. I won't go into details here. Among them, the heterofunctionalized linear polyethylene glycol (64b) as a raw material is polydisperse or monodisperse.

Step d) Linear functionalization of the end of the polyethylene glycol chain Refer to 2.1.1., for branching functionalization reference 2.1.2.

Wherein L ₁ , L ₂ , L ₃ , n ₁ , n ₂ , n ₃ , k ₁ , k ₂ , G ₁ , G ₂ , p ₁ , p ₂ , L ₄ , formula (2), formula ( 3), the definitions of the general formula (4) and the general formula (5) are consistent with the above; U is a nitrogen atom N; wherein PG ₅ is an amino protecting group; and F ₄ , F ₇ and F ₉ are functional groups. Or a protected form thereof; two functional groups present in the same molecule or in a protected form. (NPG ₅ , F ₉ ), (F ₇ , F ₉ ) are all heterofunctionalized pairs. Wherein, the PEG chain corresponding to n ₁ and n ₂ has polydispersity; the PEG chain corresponding to n ₃ may be polydisperse or monodisperse; any one of F ₇ and F ₉ may be a target functional group. Or its protected form.

Taking UF ₁₀ as the protected amino NPG ₅ as an example, the structure of the small molecule initiator IN4 is as shown in (129), and the corresponding reaction process is as follows. The intermediates represented by (130), (131) or (130), and (132) are obtained by the above steps a) and b), respectively.

c) removing the amino protecting group PG ₅ at the branched group from the V-form intermediate (131) or (132) obtained in the step b) to obtain a V-type polyethylene glycol amine derivative (117) or (133) ;

d) a V-form intermediate (117) or (133) obtained in step c), and a heterofunctionalized linear polyethylene glycol containing two different functional groups or protected forms thereof F ₇ , F ₄ ( 64b), a reaction between F ₁₀ and F ₄ to form a divalent linking group L ₃ to obtain a heterofunctional Y-type polyethylene glycol intermediate (118) or (134);

e) linearly functionalizing or branching functionalizing the (PEG) main chain polyethylene glycol terminal and the branched polyethylene glycol terminal, respectively, to obtain (2), (3), (4) or 5) a heterofunctionalized Y-type polyethylene glycol of the nitrogen atom branching center shown;

Or linearly functionalizing or branching functionalizing the main chain polyethylene glycol terminal and the branched polyethylene glycol terminal of (134), respectively, to obtain the nitrogen atom branching represented by (3) or (5), respectively. Central heterofunctional Y-type polyethylene glycol.

Step a) 2 to 2000 times the molar amount of ethylene oxide. The polyethylene glycol branched chain which initiates the polymerization of ethylene oxide to form polydispersity is referred to 2.2.1.2. The NHPG ₅ in the small molecule initiator IN4 is a structure in which an amino group is protected, and is preferably a carbamate, an amide, an imide, an N-alkylamine, an N-arylamine, an imine, an enamine, or an imidazole. Pyrrole or hydrazine.

Step b) Linear functionalization of the terminal hydroxyl groups of the polyethylene glycol branching chain, see 2.1.1.

Step c) Removal of the amino protecting group, see 2.2.1.4.

Step d) The reaction between the two functional groups or their protected forms to form the divalent linking group L ₃ , refer to 2.1.3. and 2.1.4., when one of them is protected, it may be carried out first Deprotection and then reacting. I won't go into details here. Among them, the heterofunctionalized linear polyethylene glycol (64b) as a raw material is polydisperse or monodisperse.

Step e) Linear functionalization of the end of the polyethylene glycol chain. Refer to 2.1.1. for branching functionalization. Refer to 2.1.2.

2.3.6. Branch Chain-Main Chain, Coupling-Polymerization

a) a small molecule compound (59c) having one protected hydroxyl OPG ₄ and two functional groups or a protected form thereof F ₁₃ and two molecules having a functional group or a protected form thereof F ₁₁ , F ₉ The functionalized linear polyethylene glycol (60) reacts to form a divalent linking group L ₁ , L ₂ through the reaction between F ₁₃ and F _{11 to} obtain a V-form intermediate (71);

b) removing the hydroxy protecting group PG ₄ from the V-form intermediate (71) to obtain a V-form intermediate (71c) having a bare hydroxyl group;

c) Step a) to obtain a V-form intermediate (71c) and a base co-initiation system, after deprotonating the exposed hydroxyl group, initiate polymerization of ethylene oxide to form a polyethylene glycol main chain, and obtain an oxygen anion intermediate a heterofunctional Y-type polyethylene glycol intermediate IM6 having a hydroxyl group terminal at the end of the PEG chain; F ₉ is a functional group stable under anionic polymerization conditions or a protected form thereof;

d) independently linearly functionalizing or branching functionalizing the terminal polyethylene glycol terminal hydroxyl group and the branched polyethylene glycol terminal, respectively, to obtain (73), (74), (75) or (76) The heterofunctionalized Y-type polyethylene glycol is shown.

The synthetic route reaction is as follows:

Wherein, the definitions of U, L ₁ , L ₂ , L ₃ , n ₁ , n ₂ , n ₃ , (73), (74), (75), (76) are consistent with the above; PG ₄ is a hydroxy protecting group, Preferred are silyl ether, benzyl, acetal, ketal or tert-butyl; F ₉ , F ₁₁ and F ₁₃ are all functional groups or protected forms thereof; F ₉ is a functional group which is stable under anionic polymerization conditions. a group or a protected form thereof; two functional groups present in the same molecule or in a protected form. (OPG ₄ , F ₁₃ ), (F ₁₁ , F ₉ ), (OPG ₄ , F ₉ ), (OH, F ₉ ) are all heterofunctionalized pairs. Wherein, the PEG branch chains corresponding to n ₁ and n ₂ are both polydisperse (n ₁ ≈n ₂ ) or the same monodispersity (n ₁ =n ₂ ); the PEG chain corresponding to n _{3 is} polydisperse; ₉ may be the same or different from the target functional group or its protected form F ₁ .

等。Step a) The reaction between the two functional groups or their protected forms F ₁₃ and F _{9 to} form the divalent linking groups L ₁ , L ₂ , refer to 2.1.3. and 2.1.4. In the protected form, it can be deprotected before reacting. I won't go into details here. Among them, the heterofunctionalized linear polyethylene glycol (60) as a raw material is polydisperse or monodisperse. The structure of IN4 is exemplified by but not limited to

Wait.

Step b) For the removal of the hydroxy protecting group for the intermediate (71), refer to 2.2.1.4.

Step a) 1 to 2000 times the molar amount of ethylene oxide. The polyethylene glycol backbone chain which initiates the polymerization of ethylene oxide to form polydispersity is referred to 2.2.1.2.

Step d) Linear functionalization of the end of the polyethylene glycol chain Refer to 2.1.1., for branching functionalization reference 2.1.2.

2.3.7. Branch-chain, coupling-even law

a) a small molecule compound (59b) having a functional group or a protected form thereof F ₁₀ or UF ₁₀ and 2 functional groups or a protected form thereof F ₁₃ and 2 molecules having a functional group or The heterofunctionalized linear polyethylene glycol (60) of the protected forms F ₁₁ and F ₉ is reacted to form a divalent linking group L ₁ and L ₂ by the reaction between F ₁₃ and F _{11 to} obtain a V-form intermediate (71b). ;

b) to step a) of the V-shaped intermediate (71b), containing two different functional groups, or a protected form F isobutyl functionalized linear polyethylene glycol (64b) _7, F _4, dried a reaction between F ₁₀ and F ₄ to form a divalent linking group L ₃ to obtain a heterofunctional Y-type polyethylene glycol intermediate IM9 of a nitrogen atomic branching center;

c) linearly functionalizing or branching functionalization of the main chain polyethylene glycol terminal and the branched polyethylene glycol terminal of IM9, respectively, to obtain (73), (74), (75) or (76) a heterofunctionalized Y-type polyethylene glycol as shown;

Wherein, the definitions of U, L ₁ , L ₂ , L ₃ , n ₁ , n ₂ , n ₃ , (73), (74), (75), (76) are consistent with the above; F ₄ , F ₇ , F _9. F ₁₀ , F ₁₁ and F ₁₃ are all functional groups or protected forms thereof; two functional groups present in the same molecule or their protected forms are different. (F ₁₀ , F ₁₃ ), (F ₁₁ , F ₉ ), (F ₁₀ , F ₉ ), (F ₇ , F ₄ ), (F ₇ , F ₉ ) are all heterofunctionalized pairs. Wherein, the PEG branch chains corresponding to n ₁ and n ₂ are polydisperse (n ₁ ≈n ₂ ) or are monodisperse (n ₁ =n ₂ ); the PEG chain corresponding to n ₃ is polydisperse or single Dispersibility; any of F ₇ and F ₉ may be a target functional group or a protected form thereof.

等；其中PG₅为氨基保护基，NPG₅为氨基被保护后的结构，优选为氨基甲酸酯、酰胺、酰亚胺、N-烷基胺、N-芳基胺、亚胺、烯胺、咪唑、吡咯或吲哚；PG₄为羟基保护基，优选硅醚、苄基、缩醛、缩酮或叔丁基。Step a) The reaction between the two functional groups or their protected forms F ₁₃ and F _{9 to} form the divalent linking groups L ₁ , L ₂ , refer to 2.1.3. and 2.1.4. In the protected form, it can be deprotected before reacting. I won't go into details here. Among them, the heterofunctionalized linear polyethylene glycol (60) as a raw material is polydisperse or monodisperse. By way of example, the structure of (59b) includes but is not limited to

And the like; wherein PG ₅ is an amino protecting group, and NPG ₅ is a structure in which an amino group is protected, preferably a carbamate, an amide, an imide, an N-alkylamine, an N-arylamine, an imine, an enamine , imidazole, pyrrole or hydrazine; PG ₄ is a hydroxy protecting group, preferably a silyl ether, a benzyl group, an acetal, a ketal or a tert-butyl group.

Step b) a reaction between two functional groups or their protected forms (F ₁₃ , F ₁₁ ), (F ₁₀ , F ₄ ) to form a divalent linking group L ₁ , L ₂ or L ₃ , with reference to 2.1 .3. and 2.1.4. When one of them is protected, it can be deprotected before reacting. I won't go into details here. Among them, the heterofunctionalized linear polyethylene glycols (60) and (64b) as raw materials are each independently polydisperse or monodisperse.

Step c) Linear functionalization of the end of the polyethylene glycol chain. Refer to 2.1.1. for branching functionalization. Refer to 2.1.2.

2.3.8. Main chain coupling branch method

a) containing two different functional groups, or a protected form F _7, F ₄ iso-functionalized linear polyethylene glycol (64b), and a functional group or a protected form F ₃ (1 th) , F ₁₃ (two) small molecule compound (62) reacts, and a reaction between F ₄ and F ₃ forms a divalent linking group L ₃ to obtain a polyethylene glycol intermediate (46c) having the structure shown by (46c). );

b) the polyethylene glycol intermediate (46c) obtained in step a) is reacted with two molecules of a heterofunctionalized linear polyethylene glycol (60) having a functional group or a protected form thereof F ₁₁ , F ₉ , via U The reaction between F ₁₁ forms a divalent linking group L ₁ , L ₂ to obtain a Y-form intermediate IM9;

c) linearly functionalizing or branching functionalization of the main chain polyethylene glycol terminal and the branched polyethylene glycol terminal of IM9, respectively, to obtain (73), (74), (75) or (76) a heterofunctionalized Y-type polyethylene glycol as shown;

Wherein, the definitions of U, L ₁ , L ₂ , L ₃ , n ₁ , n ₂ , n ₃ , (73), (74), (75), (76) are consistent with the above; F ₃ , F ₄ , F _7. F ₉ , F ₁₁ and F ₁₃ are all functional groups or protected forms thereof; two functional groups present in the same molecule or protected forms thereof are different. (F ₇ , F ₄ ), (F ₃ , F ₁₃ ), (F ₇ , F ₁₃ ), (F ₁₁ , F ₉ ), ((F ₇ , F ₉ ) are all heterofunctionalized pairs. Among them, n ₁ , n ₂ corresponding PEG branch chain is polydisperse (n ₁ ≈n ₂ ) or the same monodispersity (n ₁ = n ₂ ); n ₃ corresponding PEG chain is polydisperse or monodisperse; Any of F ₇ and F ₉ may be a target functional group or a protected form thereof.

等。其中PG₅为氨基保护基，NPG₅为氨基被保护后的结构，优选为氨基甲酸酯、酰胺、酰亚胺、N-烷基胺、N-芳基胺、亚胺、烯胺、咪唑、吡咯或吲哚；PG₄为羟基保护基，优选硅醚、苄基、缩醛、缩酮或叔丁基。Step a), step b) formation of a divalent linking group L ₃ , L ₁ or L ₂ between two functional groups or their protected forms (F ₄ , F ₃ ), (F ₁₃ , F ₁₁ ) For the reaction, refer to 2.1.3. and 2.1.4. When one of them is in the protected form, it can be deprotected and then reacted. I won't go into details here. Among them, the heterofunctionalized linear polyethylene glycols (60) and (64b) as raw materials are each independently polydisperse or monodisperse. (62) may contain two reactive groups, by way of example, the structure including but not limited to

Wait. Wherein PG ₅ is an amino protecting group, and NPG ₅ is a structure in which an amino group is protected, preferably a carbamate, an amide, an imide, an N-alkylamine, an N-arylamine, an imine, an enamine, or an imidazole. , pyrrole or hydrazine; PG ₄ is a hydroxy protecting group, preferably a silyl ether, a benzyl group, an acetal, a ketal or a tert-butyl group.

此时步骤a)、b)的反应式如下所示，依次得到(135)所示的异官能化线性聚乙二醇炔基衍生物、(136)所示的V型中间体。 In addition, (62) may also contain only one reactive group, as long as step a) can be carried out to form a trivalent branching group U, such as a molecule of polyethylene glycol alkynyl derivative and two molecules a polyethylene glycol thiol derivative capable of forming a trivalent branched group by a click reaction between an alkynyl group and a fluorenyl group

At this time, the reaction formulas of the steps a) and b) are as follows, and the heterofunctionalized linear polyethylene glycol alkynyl derivative represented by (135) and the V-type intermediate represented by (136) are sequentially obtained.

Step c) Linear functionalization of the end of the polyethylene glycol chain. Refer to 2.1.1. for branching functionalization. Refer to 2.1.2.

The above provides a relatively classic reference preparation method, and of course, there may be other preparation methods in the art, which will not be repeated here. Those skilled in the art can select a suitable method as needed.

2.4. Preparation of Bio-related Substances Modified by Heterofunctional Y-Type Polyethylene Glycol Derivatives

The bio-related substance modified by the heterofunctional Y-type polyethylene glycol derivative disclosed by the invention is prepared by reacting a hetero-functionalized Y-type polyethylene glycol derivative represented by the general formula (1) with a corresponding biologically relevant substance. . The preparation method, route, process, conditions and the like are not particularly limited and can be used as known in the art.

The heterofunctionalized Y-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:

(1) Preparation of intermediate H1-H2-1

为

(U为对称类型；U＝

L₁、L₂、L₃不存在)，g₁＝g₂＝g₃＝0,k₁＝k₂＝k₃＝1,F₁＝CH₂CH₂OPG₄(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂CH₂,R₀₁＝OPG₄,PG₄＝TBS),F₂＝CH₂CH₂OH(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂CH₂,R₀₁＝OH)。设计总分子量约为20kDa，其中主链分子量约为10000Da，即n₃≈227,分支链分子量约为5000Da，n₁≈n₂≈114。among them,

for

(U is a symmetric type; U=

L ₁ , L ₂ , L ₃ are absent), g ₁ = g ₂ = g ₃ =0, k ₁ = k ₂ = k ₃ =1, F ₁ = CH ₂ CH ₂ OPG ₄ (q = 0, Z ₂ None, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =OPG ₄ , PG ₄ =TBS), F ₂ =CH ₂ CH ₂ OH (q=0, Z ₂ is absent, q ₁ =1 , Z ₁ =CH ₂ CH ₂ , R ₀₁ =OH). The designed total molecular weight is about 20 kDa, wherein the main chain molecular weight is about 10,000 Da, i.e., n ₃ ≈ 227, and the branched chain molecular weight is about 5000 Da, n ₁ ≈ n ₂ ≈ 114.

a, into a water-free oxygen-free closed reaction vessel, followed by the addition of tetrahydrofuran (125 mL), EE-protected ethylene glycol 137 (2.5 mmol) and diphenylmethyl potassium (2.0 mmol);

b, adding a calculated amount of ethylene oxide (58mL, 1140mmol), gradually heating to a temperature of 60 ° C, the reaction for 48 hours;

c, adding an excess of potassium diphenylmethyl (20 mmol), then adding excess TBSCl (100 mmol), the reaction temperature is 30 ° C, the reaction time is 12 hours; the reaction kettle is opened, the solvent is concentrated, anhydrous ether at 0 ° C Precipitating, filtering, drying, that is, a V-type polyethylene glycol intermediate 138 protected by hydroxysilicon ether at both ends;

The hydrogen spectrum data of the intermediate 138 described in this example is as follows:

¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ), 1.22 (-OCH ₂ CH ₃ ), 1.36 (-OCH(O) CH ₃ ), 3.40-3.80 (-CH ₂ CH ₂ O-, -OCH ₂ CH ₂ OSi-, OCH ₂ CH ₃ , -OCH(CH ₂ O-) ₂ ), 3.80-4.00 (-OCH ₂ CH ₂ OSi -), 4.75 (-OCHCH ₃ (OCH ₂ )); M _n ≈ 10 kDa, PDI = 1.02.

d. Add the V-type polyethylene glycol 138 prepared in the above step to a dry and clean container, dissolve it with methanol, add 1M hydrochloric acid to pH=3.5, and after reacting for 4 hours, obtain a hydroxyl-formed V-shaped poly. Ethylene glycol intermediate 139.

The hydrogen spectrum data of the intermediate 139 in this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ), 3.40-3.80 (-CH ₂ CH ₂ O-, -OCH ₂ CH ₂ OSi-, -OCH(CH ₂ O-) ₂ ), 3.80-4.00 (-OCH ₂ CH ₂ OSi-, -OCH(CH ₂ O-) ₂ ) .

e, repeat steps (a), (b), according to the metering change of the amount of feed and the amount of ethylene oxide to carry out the reaction, and finally add an excess of proton source (methanol), and concentrate, precipitate, filter, and dry to obtain a compound H1-H2-1.

The hydrogen spectrum data of the Y-form intermediate H1-H2-1 in this example are as follows:

¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ), 3.40-3.80 (-CH ₂ CH ₂ O-, -OCH ₂ CH ₂ OSi-, -OCH(CH ₂ O-) ₂ ), 3.80-4.00 (-OCH ₂ CH ₂ OSi-); M _n ≈ 20 kDa, PDI=1.03.

(2) Synthesis of succinimide carbonate ester A6-H2-1

为

g₁＝g₂＝g₃＝0,k₁＝k₂＝k₃＝1,F₁＝F₁＝CH₂CH₂OPG₄,F₂＝CH₂CH₂OCONHS(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂CH₂,R₀₁＝OCONHS)。设计总分子量约为20kDa，其中主链分子量约为10000Da，即n₃≈227,分支链分子量约为5000Da，n₁≈n₂≈114。among them,

for

g ₁ =g ₂ =g ₃ =0,k ₁ =k ₂ =k ₃ =1, F ₁ =F ₁ =CH ₂ CH ₂ OPG ₄ ,F ₂ =CH ₂ CH ₂ OCONHS(q=0,Z ₂ Not present, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =OCONHS). The designed total molecular weight is about 20 kDa, wherein the main chain molecular weight is about 10,000 Da, i.e., n ₃ ≈ 227, and the branched chain molecular weight is about 5000 Da, n ₁ ≈ n ₂ ≈ 114.

In a dry clean 1 L round bottom flask, 40 g of the branched polyethylene glycol (H1-H2-1, azeotropic removal of water via toluene) prepared in Example 1, 500 mL of acetonitrile, 40 mL of triethylamine and 10 g of N were added. The N'-disuccinimidyl carbonate was reacted at room temperature for 24 hours, concentrated, and recrystallized from isopropanol to give the active compound (A6-H2-1) as a white solid.

The hydrogen spectrum data of succinimide carbonate ester A6-H2-1 is as follows:

¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ), 2.70-2.85 (-(O=)CCH ₂ CH ₂ C (= O)-, 3.40-3.80 (-CH ₂ CH ₂ O-, -OCH(CH ₂ O-) ₂ , -OCH ₂ CH ₂ OSi-), 3.80-4.00 (-OCH ₂ CH ₂ OSi-), 4.23 _{4.43 (-CH 2 OCO -);} M n ≈20kDa, PDI = 1.03.

(3) Synthesis of carboxylic acid derivative D4-H2-1

为

g₁＝g₂＝g₃＝0,k₁＝k₂＝k₃＝1,F₁＝CH₂CH₂OPG₄(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂CH₂,R₀₁＝OPG₄,PG₄＝TBS),F₂＝

(q＝1,Z₂＝CO,q₁＝1,Z₁＝CH₂CH₂,R₀₁＝COOH)。设计总分子量约为20kDa，其中主链分子量约为10000Da，即n₃≈227,分支链分子量约为5000Da，n₁≈n₂≈114。among them,

for

g ₁ =g ₂ =g ₃ =0,k ₁ =k ₂ =k ₃ =1, F ₁ =CH ₂ CH ₂ OPG ₄ (q=0, Z ₂ is absent, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =OPG ₄ , PG ₄ =TBS), F ₂ =

(q=1, Z ₂ =CO, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =COOH). The designed total molecular weight is about 20 kDa, wherein the main chain molecular weight is about 10,000 Da, i.e., n ₃ ≈ 227, and the branched chain molecular weight is about 5000 Da, n ₁ ≈ n ₂ ≈ 114.

In a dry clean 1 L round bottom flask, the Y-form polyethylene glycol intermediate H1-H2-1 (2.5 mmol) prepared above was added to toluene (500 ml), and then excess succinic anhydride (50 mmol) was added, and the reaction temperature was 50. °C, the reaction time was 12 hours; the reaction kettle was opened, the solvent was concentrated, and then precipitated in anhydrous diethyl ether at 0 ° C, filtered, and dried to obtain a Y-type polyethylene glycol D4-H2-1 having a carboxyl group at the end of the main chain.

The hydrogen spectrum data of D4-H2-1 in this example is as follows:

¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ), 2.40-2.70 (-OCOCH ₂ CH ₂ COO-), 3.40-3.80 (-CH ₂ CH ₂ O-, -OCH ₂ CH ₂ OSi-, -OCH(CH ₂ O-) ₂ ), 3.80-4.00 (-OCH ₂ CH ₂ OSi-), 4.10-4.30 (-COOCH ₂ -) .

(4) Synthesis of succinimide active ester A1-H2-1

为

g₁＝g₂＝g₃＝0,k₁＝k₂＝k₃＝1,F₁＝CCH₂CH₂OPG₄(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂CH₂,R₀₁＝OPG₄,PG₄＝TBS),F₂＝OCCH₂CHCONHS(q＝1,Z₂＝CO,q₁＝1,Z₁＝CH₂CH₂,R₀₁＝CONHS)。设计总分子量约为20kDa，其中主链分子量约为10000Da，即n₃≈227,分支链分子量约为5000Da，n₁≈n₂≈114。among them,

for

g ₁ =g ₂ =g ₃ =0,k ₁ =k ₂ =k ₃ =1, F ₁ =CCH ₂ CH ₂ OPG ₄ (q=0, Z ₂ is absent, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =OPG ₄ , PG ₄ =TBS), F ₂ =OCCH ₂ CHCONHS (q=1, Z ₂ =CO, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =CONHS) . The designed total molecular weight is about 20 kDa, wherein the main chain molecular weight is about 10,000 Da, i.e., n ₃ ≈ 227, and the branched chain molecular weight is about 5000 Da, n ₁ ≈ n ₂ ≈ 114.

In a dry clean 1 L round bottom flask, 40 g of the branched polyethylene glycol acetic acid derivative (D4-H2-1) obtained in Example 1, 20 mL of triethylamine and 10 g of the compound N-hydroxysuccinimide succinate were added. Nitrogen protection, adding solvent dichloromethane (500 mL), stirring until dissolved, and adding 20 g of dicyclohexane carbodiimide (DCC) in dichloromethane, reacting at room temperature for 24 hours, filtering to remove insoluble matter, concentration Recrystallization from isopropanol gave the active ester (A1-H2-1) as a white solid.

The hydrogen spectrum data of the succinimide active esters A1-H2-1 are as follows:

¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ), 2.40-2.85 (-(O=)CCH ₂ CH ₂ C (= O)-), 3.40-3.80 (-CH ₂ CH ₂ O-, -OCH ₂ CH ₂ OSi-, -OCH(CH ₂ O-) ₂ ), 3.80-4.00 (-OCH ₂ CH ₂ OSi-), 4.15 (-CH ₂ OCO-); M _n ≈ 20 kDa, PDI=1.03.

(5) Synthesis of propionic acid derivative D4-H2-2

为

g₁＝g₂＝g₃＝0,k₁＝k₂＝k₃＝1,F₁＝CH₂CH₂OTBS(q＝0,Z₂不存在,q₁＝1Z₁＝CH₂CH₂,R₀₁＝OTBS),F₂CH₂CH₂COOH(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂CH₂,R₀₁＝COOH)。设计总分子量约为20kDa，其中主链分子量约为10000Da，即n₃≈227,分支链分子量约为5000Da，n₁≈n₂≈114。among them,

for

g ₁ =g ₂ =g ₃ =0, k ₁ =k ₂ =k ₃ =1, F ₁ =CH ₂ CH ₂ OTBS (q=0, Z ₂ is absent, q ₁ =1Z ₁ =CH ₂ CH ₂ , R ₀₁ = OTBS), F ₂ CH ₂ CH ₂ COOH (q=0, Z ₂ is absent, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =COOH). The designed total molecular weight is about 20 kDa, wherein the main chain molecular weight is about 10,000 Da, i.e., n ₃ ≈ 227, and the branched chain molecular weight is about 5000 Da, n ₁ ≈ n ₂ ≈ 114.

A: 80 mmol KOH was added to a dry and clean 1 L round bottom flask, 400 mL of water was added, and 40 g of the branched polyethylene glycol (H1-H2-1, toluene azeotropic water removal) prepared in Example 1 was slowly added dropwise in an ice bath. After stirring at room temperature for 3 hours, 40 mmol of acrylamide was added, and the reaction was carried out for 24 hours at room temperature. After quenching with a small amount of concentrated hydrochloric acid, the mixture was concentrated, then added to 400 mL of dichloromethane solution, washed with saturated brine (3*100 mL), and dried. Concentration and recrystallization gave a white branched polyethylene glycol ester intermediate (D4-H2-2).

The hydrogen spectrum data of the intermediate D4-H2-2 is as follows:

¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ), 2.40-2.60 (-CH ₂ CH ₂ COOH), 3.40-3.80 ( _{-CH 2 CH 2 O -, -} OCH 2 CH 2 OSi -, - CH 2 CH 2 COOH, -OCH (CH 2 O-) 2), 3.80-4.00 (-OCH 2 CH 2 OSi -); M n ≈ 20kDa, PDI=1.03.

(6) Synthesis of active esters A1-H2-1

为

(U为对称类型；U＝

L₁、L₂、L₃不存在)，g₁＝g₂＝g₃＝0,k₁＝k₂＝k₃＝1,F₁＝CH₂CH₂OTBS(q＝0,Z₂不存在,q₁＝1Z₁＝CH₂CH₂,R₀₁＝OTBS),F₂＝CH₂CH₂CONHS(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂CH₂,R₀₁＝CONHS)。设计总分子量约为20kDa，其中主链分子量约为10000Da，即n₃≈227,分支链分子量约为5000Da，n₁≈n₂≈114。among them,

for

(U is a symmetric type; U=

L ₁ , L ₂ , L ₃ are absent), g ₁ = g ₂ = g ₃ =0, k ₁ = k ₂ = k ₃ =1, F ₁ = CH ₂ CH ₂ OTBS (q = 0, Z _{2 is} not Exist, q ₁ =1Z ₁ =CH ₂ CH ₂ , R ₀₁ =OTBS), F ₂ =CH ₂ CH ₂ CONHS (q=0, Z ₂ is absent, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =CONHS). The designed total molecular weight is about 20 kDa, wherein the main chain molecular weight is about 10,000 Da, i.e., n ₃ ≈ 227, and the branched chain molecular weight is about 5000 Da, n ₁ ≈ n ₂ ≈ 114.

In a dry clean 1 L round bottom flask, 40 g of the branched polyethylene glycol propionic acid derivative (D4-H2-2) obtained in Example 1, 20 mL of triethylamine and 10 g of N-hydroxysuccinimide were added, and nitrogen protection was carried out. Add solvent dichloromethane (500 mL), stir until dissolved, add 20 g of dicyclohexane carbodiimide (DCC) in dichloromethane, react at room temperature for 24 hours, remove insolubles by filtration, concentrate, isopropyl The alcohol was recrystallized to give the active solid (A1-H2-2) as a white solid.

The hydrogen spectrum data of the active esters A1-H2-2 are as follows:

¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ), 2.40-2.60 (-CH ₂ CH ₂ COO-), 2.70-2.85 (-(O=)CCH ₂ CH ₂ C(=O)-), 3.40-3.80 (-CH ₂ CH ₂ O-, -OCH ₂ CH ₂ OSi-, -CH ₂ CH ₂ COO-, -OCH(CH ₂ O-) ₂ ), 3.80-4.00 (-OCH ₂ CH ₂ OSi-); M _n ≈ 20 kDa, PDI=1.03.

(7) Synthesis of p-nitrophenyl carbonate compound A7-H2-1

为

g₁＝g₂＝g₃＝0,k₁＝k₂＝k₃＝1,F₁＝CH₂CH₂OPG₄,PG₄＝TBS,F₂＝

(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂CH₂,R₀₁＝NPC)。设计总分子量约为20kDa，其中主链分子量约为10000Da，即n₃≈227,分支链分子量约为5000Da，n₁≈n₂≈114。among them,

for

g ₁ = g ₂ = g ₃ =0, k ₁ = k ₂ = k ₃ =1, F ₁ = CH ₂ CH ₂ OPG ₄ , PG ₄ = TBS, F ₂ =

(q=0, Z ₂ is absent, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =NPC). The designed total molecular weight is about 20 kDa, wherein the main chain molecular weight is about 10,000 Da, i.e., n ₃ ≈ 227, and the branched chain molecular weight is about 5000 Da, n ₁ ≈ n ₂ ≈ 114.

In a 1 L round bottom flask equipped with a condenser, 40 g of the branched polyethylene glycol (H1-H2-1, azeotropically removed with toluene) obtained in Example 1, 500 mL of toluene, 40 mL of triethylamine and 10 g were placed. The p-nitrophenyl chloroformate was reacted at 80 ° C for 24 hours, filtered, concentrated, and recrystallized from isopropanol to give p-nitrophenyl carbonate compound (A7-H2-1).

The hydrogen spectrum data of p-nitrophenyl carbonate compound A7-H2-1 are as follows:

¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ), 3.40-3.80 (-CH ₂ CH ₂ O-, -OCH ₂ CH ₂ OSi-, -OCH(CH ₂ O-) ₂ ), 3.80-4.00 (-OCH ₂ CH ₂ OSi-), 4.20 (-OCH ₂ CH ₂ OC(=O)-), 7.40 (-C ₆ H ₄ NO ₂ ), 8.28 (-C ₆ H ₄ NO ₂ ); M _n ≈ 20 kDa, PDI=1.03.

(8) Synthesis of A11-H2-1

为

(U为对称类型；U＝

L₁、L₂、L₃不存在)，g₁＝g₂＝g₃＝0,k₁＝k₂＝k₃＝1,F₁＝CH₂CH₂OPG₄,PG₄＝TBS,F₂＝

(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂CH₂,R₀₁＝

)。设计总分子量约为20kDa，其中主链分子量约为10000Da，即n₃≈227,分支链分子量约为5000Da，n₁≈n₂≈114。among them,

for

(U is a symmetric type; U=

L ₁ , L ₂ , L ₃ are absent), g ₁ = g ₂ = g ₃ =0, k ₁ = k ₂ = k ₃ =1, F ₁ = CH ₂ CH ₂ OPG ₄ , PG ₄ = TBS, F ₂ =

(q=0, Z ₂ does not exist, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =

). The designed total molecular weight is about 20 kDa, wherein the main chain molecular weight is about 10,000 Da, i.e., n ₃ ≈ 227, and the branched chain molecular weight is about 5000 Da, n ₁ ≈ n ₂ ≈ 114.

In a dry clean 1 L round bottom flask, 40 g of branched polyethylene glycol propionic acid derivative (D4-H2-2), 20 mL of triethylamine and 4.8 g of thiazole-2-thione were added, protected with nitrogen, and solvent dichloride was added. Methane (500 mL), stirred until dissolved, and then added 15.2 g of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and 5.4 A solution of 1-hydroxybenzotriazole (HOBT) in dichloromethane, reacted at room temperature for 24 hours, filtered to remove insolubles, concentrated, and recrystallized from isopropyl alcohol to give the active compound as a white solid (A11-H2-1) .

The hydrogen spectrum data of the active ester A11-H2-1 are as follows:

¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ), 2.30-2.50 (-CH ₂ CH ₂ CON-), 3.05-3.25 (SCH ₂ CH ₂ N), 3.40-3.80 (-CH ₂ CH ₂ O-, -OCH ₂ CH ₂ OSi-, -CH ₂ CH ₂ CON-, -OCH(CH ₂ O-) ₂ ), 3.80-4.00 (-OCH ₂ CH ₂ OSi-, SCH ₂ CH ₂ N); M _n ≈ 20 kDa, PDI=1.03.

(9) Synthesis of sulfone B3-H2-1

为

g₁＝g₂＝g₃＝0,k₁＝k₂＝k₃＝1,F₁＝CH₂CH₂OPG₄,PG₄＝TBS,F₂＝

(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂CH₂,R₀₁为S(＝O)₂CH＝CH₂)。设计总分子量约为20kDa，其中主链分子量约为10000Da，即n₃≈227,分支链分子量约为5000Da，n₁≈n₂≈114。among them,

for

g ₁ = g ₂ = g ₃ =0, k ₁ = k ₂ = k ₃ =1, F ₁ = CH ₂ CH ₂ OPG ₄ , PG ₄ = TBS, F ₂ =

(q=0, Z ₂ is absent, q ₁ =1, Z ₁ =CH ₂ CH ₂ , and R ₀₁ is S(=O) ₂ CH=CH ₂ ). The designed total molecular weight is about 20 kDa, wherein the main chain molecular weight is about 10,000 Da, i.e., n ₃ ≈ 227, and the branched chain molecular weight is about 5000 Da, n ₁ ≈ n ₂ ≈ 114.

Add 0.32g of sodium hydride (60% by weight in oil) to a dry clean 1L round bottom flask, protect with nitrogen, add 400 mL of anhydrous tetrahydrofuran, and slowly add 30 g of the branched polyethylene obtained in Example 1 under ice bath. A solution of alcohol (H1-H2-1, azeotropic removal of toluene) in tetrahydrofuran was stirred at room temperature for 3 hours, then 1 g of divinyl sulfone was added and reacted at room temperature for 24 h. After quenching with a small amount of saturated ammonium chloride solution, After concentration, it was added to a solution of 400 mL of dichloromethane, washed with saturated brine (3*100 mL), dried, concentrated, and recrystallized to give white-branched polyglycol sulfone derivative (B3-H2-1).

The hydrogen spectrum data of the polyethylene glycol sulfone derivative B3-H2-1 is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ), 3.40-3.80 (-CH ₂ CH ₂ O-, -OCH ₂ CH ₂ OSi-, -SO ₂ CH ₂ CH ₂ O-, -OCH(CH ₂ O-) ₂ ), 3.80-4.00 (-OCH ₂ CH ₂ OSi-), 6.19-6.81 (-SO ₂ CH=CH ₂ ); M _n ≈ 20 kDa, PDI=1.03.

(10) Synthesis of acetal derivative D7-H2-1

为

g₁＝g₂＝g₃＝0,k₁＝k₂＝k₃＝1,F₁＝CH₂CH₂OPG₄,PG₄＝TBS,F₂＝

(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂CH₂,R₀₁＝

)。设计总分子量约为20kDa，其中主链分子量约为10000Da，即n₃≈227,分支链分子量约为5000Da，n₁≈n₂≈114。among them,

for

g ₁ = g ₂ = g ₃ =0, k ₁ = k ₂ = k ₃ =1, F ₁ = CH ₂ CH ₂ OPG ₄ , PG ₄ = TBS, F ₂ =

(q=0, Z ₂ does not exist, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =

). The designed total molecular weight is about 20 kDa, wherein the main chain molecular weight is about 10,000 Da, i.e., n ₃ ≈ 227, and the branched chain molecular weight is about 5000 Da, n ₁ ≈ n ₂ ≈ 114.

In a dry and clean 1 L round bottom flask, 40 g of the branched polyethylene glycol (H1-H2-1) and 5 g of sodium hydroxide prepared in Example 1 were successively added, and nitrogen was added. After adding 400 mL of toluene, 2 mL of 2-mL was added dropwise. (2-Bromoethyl)-1,3-dioxane, after heating to reflux for 24 h, 400 mL of deionized water was added, the layers were separated, and the aqueous phase was extracted with dichloromethane (3*200 mL). The mixture was washed with saturated brine (3*100 mL), dried, concentrated, and then recrystallized to give white-branched polyethylene glycol acetal intermediate (D7-H2-1).

The hydrogen spectrum data of the polyethylene glycol acetal intermediate D7-H2-1 is as follows:

¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ), 1.91 (-OCH ₂ CH ₂ CHO(O)-), 3.40- 3.80 (-CH ₂ CH ₂ O-, -OCH ₂ CH ₂ OSi-, -OCH ₂ CH ₂ CHO(O)-, -OCH(CH ₂ O-) ₂ ), 3.80-4.00 (-OCH ₂ CH ₂ OSi -), 4.89 (-OCH ₂ CH ₂ CHO(O)-); M _n ≈ 20 kDa, PDI = 1.03.

(11) Preparation of A1-H1-1

为

g₁＝g₂＝g₃＝0,k₁＝k₂＝k₃＝1,F₁＝CH₂CH₂OH(q＝0,Z₂不存在,q₁＝1Z₁＝CH₂CH₂,R₀₁＝OH),F₂＝CH₂CH₂CONHS(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂CH₂,R₀₁＝CONHS)。设计总分子量约为20kDa，其中主链分子量约为10000Da，即n₃≈227,分支链分子量约为5000Da，n₁≈n₂≈114。among them,

for

g ₁ =g ₂ =g ₃ =0, k ₁ =k ₂ =k ₃ =1, F ₁ =CH ₂ CH ₂ OH (q=0, Z ₂ is absent, q ₁ =1Z ₁ =CH ₂ CH ₂ , R ₀₁ = OH), F ₂ = CH ₂ CH ₂ CONHS (q = 0, Z ₂ is absent, q ₁ =1, Z ₁ = CH ₂ CH ₂ , R ₀₁ = CONHS). The designed total molecular weight is about 20 kDa, wherein the main chain molecular weight is about 10,000 Da, i.e., n ₃ ≈ 227, and the branched chain molecular weight is about 5000 Da, n ₁ ≈ n ₂ ≈ 114.

Add A1-H2-2 to a dry and clean container, dissolve it in tetrahydrofuran, add tetra-tert-butylammonium fluoride (TBAF), react overnight, concentrate, wash, recrystallize, and dry to obtain a bare polymer at both ends. Ethylene glycol intermediates A1-H1-1.

The hydrogen spectrum data of the active esters A1-H1-1 are as follows:

¹ H NMR (CDCl ₃ ) δ (ppm): 2.40-2.60 (-CH ₂ CH ₂ COO-), 2.70-2.85 (-(O=)CCH ₂ CH ₂ C(=O)-), 3.40-3.80 ( -CH ₂ CH ₂ O-, -CH ₂ CH ₂ COO-, -OCH(CH ₂ O-) ₂ ); M _n ≈ 20 kDa, PDI=1.03.

(12) Synthesis of amide derivative D1-H2-1

为

g₁＝g₂＝g₃＝0,k₁＝k₂＝k₃＝1,F₁＝CH₂CH₂OPG₄,PG₄＝TBS,F₂＝CH₂CONH₂(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂,R₀₁＝CONH₂)。设计总分子量约为20kDa，其中主链分子量约为10000Da，即n₃≈227,分支链分子量约为5000Da，n₁≈n₂≈114。among them,

for

g ₁ =g ₂ =g ₃ =0,k ₁ =k ₂ =k ₃ =1, F ₁ =CH ₂ CH ₂ OPG ₄ ,PG ₄ =TBS,F ₂ =CH ₂ CONH ₂ (q=0,Z ₂ does not exist, q ₁ =1, Z ₁ =CH ₂ , R ₀₁ =CONH ₂ ). The designed total molecular weight is about 20 kDa, wherein the main chain molecular weight is about 10,000 Da, i.e., n ₃ ≈ 227, and the branched chain molecular weight is about 5000 Da, n ₁ ≈ n ₂ ≈ 114.

A: 0.32 g of sodium hydride (60% by weight in oil) was added to a dry clean 1 L round bottom flask, protected with nitrogen, 400 mL of anhydrous tetrahydrofuran was added, and 40 g of the branched polypolymer obtained in Example 1 was slowly added dropwise in an ice bath. Ethylene glycol (H1-H2-1, toluene azeotropic removal of water) in tetrahydrofuran, stirred at room temperature for 3 hours, added 2.2 mL of ethyl bromoacetate, reacted at room temperature for 24 h, quenched with a small amount of saturated ammonium chloride solution After the reaction, the mixture was concentrated, and then added to a solution of methylene chloride (3,100 mL), which was washed with saturated brine (3*100mL), dried, concentrated, and recrystallized to give white-branched polyethylene glycol ester intermediate (D11-H2-1).

The hydrogen spectrum data of the intermediate D11-H2-1 are as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ), 1.31 (-C(=O)OCH ₂ CH ₃ ), 3.40-3.80 (-CH ₂ CH ₂ O-, -OCH ₂ CH ₂ OSi-, -OCH ₂ CH _{3 ,} -OCH(CH ₂ O-) ₂ ), 3.80-4.00 (-OCH ₂ CH ₂ OSi-), 4.53 (-OCH ₂ C(=O)O-); M _n ≈ 20 kDa, PDI=1.03.

B: After adding 40 g of the branched polyethylene glycol ester intermediate (D11-H2-1) obtained in the step A to a dry and clean 500 mL autoclave, add 200 mL of 34% ammonia water and stir until completely dissolved at 80 ° C. After the reaction for 24 hours, 200 mL of deionized water was added, and the mixture was extracted with dichloromethane (3*100 mL). The organic phase was combined, washed with brine, dried, filtered, concentrated, and recrystallized to give white amide compound (D1-H2- 1).

The hydrogen spectrum data of the amide compound D1-H2-1 are as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ), 3.40-3.80 (-CH ₂ CH ₂ O-, -OCH ₂ CH ₂ OSi-, -OCH(CH ₂ O-) ₂ ), 3.80-4.00 (-OCH ₂ CH ₂ OSi-), 4.30 (-OCH ₂ CONH ₂ ); M _n ≈ 20kDa, PDI=1.03.

(13) Synthesis of hydrazide derivative D2-H2-1

为

g₁＝g₂＝g₃＝0,k₁＝k₂＝k₃＝1,F₁＝CH₂CH₂OPG₄,PG₄＝TBS,F₂＝

(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂,R₀₁＝CONHNH₂)。设计总分子量约为kDa，其中主链分子量约为10000Da，即n₃≈227,分支链分子量约为5000Da，n₁≈n₂≈114。among them,

for

g ₁ = g ₂ = g ₃ =0, k ₁ = k ₂ = k ₃ =1, F ₁ = CH ₂ CH ₂ OPG ₄ , PG ₄ = TBS, F ₂ =

(q=0, Z ₂ does not exist, q ₁ =1, Z ₁ =CH ₂ , R ₀₁ =CONHNH ₂ ). The designed total molecular weight is about kDa, wherein the main chain has a molecular weight of about 10,000 Da, i.e., n ₃ ≈ 227, and the branched chain has a molecular weight of about 5000 Da, n ₁ ≈n ₂ ≈ 114.

Add 40 g of the branched polyethylene glycol ester intermediate (D11-H2-1) to a dry clean 500 mL round bottom flask, add 200 mL of 80% hydrazine hydrate, stir until completely dissolved, and react at room temperature for 24 hours. After that, 200 mL of deionized water was added, and the mixture was extracted with dichloromethane (3*100 mL), and the organic phase was combined, washed with brine, dried, filtered, concentrated, and recrystallized to give the hydrazide compound (D2-H2-1).

The hydrogen spectrum data of the hydrazide compound D2-H2-1 is as follows:

¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ), 2.21 (-OCH ₂ CONH ₂ NH ₂ ), 3.40-3.80 (- _{CH 2 CH 2 O -, -} OCH 2 CH 2 OSi -, - OCH (CH 2 O-) 2), 3.80-4.00 (-OCH 2 CH 2 OSi -), 4.26 (-OCH 2 CONHNH 2), 7.52 ( -CH ₂ CONH ₂ NH ₂ ); M _n ≈ 20 kDa, PDI=1.03.

Example 2:

(1) Synthesis of intermediate H2-H1-1

为

(U为对称类型；U＝

L₁＝L₂＝CH₂,L₃不存在)，g₁＝g₂＝g₃＝0,k₁＝k₂＝k₃＝1,F₁＝CH₂CH₂OH(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂CH₂,R₀₁＝OH),F₂＝CH₂CH₂OPG₄(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂CH₂,R₀₁＝OPG₄,PG₄＝

＝EE)。设计总分子量约为40kDa，其中主链分子量约为20000Da，即n₃≈455,分支链分子量约为10000Da，n₁≈n₂≈227。among them,

for

(U is a symmetric type; U=

L ₁ = L ₂ = CH ₂ , L ₃ is absent), g ₁ = g ₂ = g ₃ =0, k ₁ = k ₂ = k ₃ =1, F ₁ = CH ₂ CH ₂ OH (q = 0, Z ₂ is absent, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =OH), F ₂ =CH ₂ CH ₂ OPG ₄ (q=0, Z ₂ is absent, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =OPG ₄ , PG ₄ =

=EE). The designed total molecular weight is about 40 kDa, wherein the main chain molecular weight is about 20,000 Da, i.e., n ₃ ≈ 455, and the branched chain molecular weight is about 10,000 Da, n ₁ ≈ n ₂ ≈ 227.

a, into a water-free and oxygen-free closed reaction vessel, followed by the addition of tetrahydrofuran (125 mL), EE-protected ethylene glycol 140 (2.5 mmol) and diphenylmethyl potassium (2.0 mmol);

b, adding a calculated amount of ethylene oxide (25mL, 495mmol), gradually heating to a temperature of 60 ° C, the reaction for 48 hours;

c. Add excess potassium diphenylmethyl (20 mmol), then add excess compound 142 (50 mmol), the reaction temperature is 30 ° C, the reaction time is 12 hours; the reaction kettle is opened, the solvent is concentrated, and the temperature is 0 ° C Precipitated in ether Filtration, drying, that is, the hydroxy-silicon ether protected at both ends, a Y-type polyethylene glycol intermediate 143 protected by a hydroxyl group EE;

The hydrogen spectrum data of the intermediate 143 described in this example is as follows:

¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ), 1.22 (-OCH ₂ CH ₃ ), 1.36 (-OCH(O) CH ₃ ), 2.90-3.00 (-OCH(CH ₂ O-) ₂ ), 3.40-3.80 (-CH ₂ CH ₂ O-, OCH ₂ CH ₃ ), 3.90-4.00 (-OCH(CH ₂ O-) ₂ ), 4.75 (-OCHCH ₃ (OCH ₂ )); M _n ≈ 20000, PDI=1.03.

d. Add the intermediate 143 prepared in the above step to a dry and clean container, dissolve it with tetrahydrofuran, add tetra-tert-butylammonium fluoride (TBAF), react overnight, concentrate, precipitate, filter, and dry to obtain A polyethylene glycol intermediate 144 with a hydroxyl group exposed at both ends.

The hydrogen spectrum data of the intermediate 144 in this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 1.22 (-OCH ₂ CH ₃ ), 1.36 (-OCH(O)CH ₃ ), 2.90-3.00 (- OCH(CH ₂ O-) ₂ ), 3.40-3.80 (-CH ₂ CH ₂ O-, OCH ₂ CH ₃ , -OCH(CH ₂ O-) ₂ ), 4.75 (-OCHCH ₃ (OCH ₂ )); M _n ≈20000, PDI=1.03.

e, repeat steps (a), (b), according to the metering change of the amount of feed and the amount of ethylene oxide to carry out the reaction, and finally add an excess of proton source DPMK, then add TBSCl, concentrated, precipitated, filtered, recrystallized Dry to give the compound H2-H2-1.

The hydrogen spectrum data of the compound H2-H2-1 is as follows:

¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ), 1.22 (-OCH ₂ CH ₃ ), 1.36 (-OCH(O) CH ₃ ), 3.40-3.80 (-CH ₂ CH ₂ O-, -OCH ₂ CH ₂ OSi-, OCH ₂ CH ₃ , -OCH(CH ₂ O-) ₂ ), 3.80-4.00 (-OCH ₂ CH ₂ OSi _{-), 4.75 (-OCHCH 3 (} OCH 2)); M n ≈40000, PDI = 1.04.

f. Add the Y-type polyethylene glycol H2-H2-1 obtained in the above step to a dry and clean container, dissolve it with tetrahydrofuran, add tetra-tert-butylammonium fluoride (TBAF), and react overnight to concentrate. Precipitation, filtration, and drying gave the hydroxy exposed intermediate (H2-H1-1).

The hydrogen spectrum data of the intermediate H2-H1-1 in this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 1.22 (-OCH ₂ CH ₃ ), 1.36 (-OCH(O)CH ₃ ), 3.40 -3.80 (-CH ₂ CH ₂ O-, OCH ₂ CH ₃ , -OCH(CH ₂ O-) ₂ ), 4.75 (-OCHCH ₃ (OCH ₂ )); M _n ≈40000, PDI=1.04.

(2) Preparation of sulfonate derivative H2-B1-1

为

g₁＝g₂＝g₃＝0,k₁＝k₂＝k₃＝1,F₁＝CH₂CH₂OTs(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂CH₂,R₀₁＝OTs),F₂＝CH₂CH₂OPG₄,PG₄＝EE。设计总分子量约为40kDa，其中主链分子量约为20000Da，即n₃≈455,分支链分子量约为10000Da，n₁≈n₂≈227。among them,

for

g ₁ =g ₂ =g ₃ =0, k ₁ =k ₂ =k ₃ =1, F ₁ =CH ₂ CH ₂ OTs (q=0, Z ₂ is absent, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ = OTs), F ₂ = CH ₂ CH ₂ OPG ₄ , PG ₄ = EE. The designed total molecular weight is about 40 kDa, wherein the main chain molecular weight is about 20,000 Da, i.e., n ₃ ≈ 455, and the branched chain molecular weight is about 10,000 Da, n ₁ ≈ n ₂ ≈ 227.

A: 40 g of the branched polyethylene glycol (H2-H1-1) prepared in Example 2 (1) was added to a dry clean 1 L round bottom flask, and nitrogen-protected, 500 mL of anhydrous oxygen-free dichloromethane was added. 40 mL of pyridine and 10 g of p-toluenesulfonyl chloride were reacted at room temperature for 24 hours, then neutralized to pH <7 by adding 1 mol/L hydrochloric acid, and the aqueous phase was washed with dichloromethane (3*50 mL), and the organic phase was combined with saturated brine. It was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated, and recrystallized to give the sulfonic acid ester (H2-B1-1).

The hydrogen spectrum data of the sulfonate H2-B1-1 is as follows: The hydrogen spectrum data of the compound 131 (H2-B1-1) described in this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 1.22 (-OCH ₂ CH ₃ ), 1.36 (-OCH(O)CH ₃ ), 2.35 (CH ₃ C ₆ H ₄ SO ₂ -), 3.40-3.80 (-CH ₂ CH ₂ O-, OCH ₂ CH ₃ , -OCH (CH _{2 )} O-) ₂ ), 4.20 (-OCH ₂ CH ₂ OSO ₂ -), 4.75 (-OCHCH ₃ (OCH ₂ )), 7.30 (CH ₃ C ₆ H ₄ SO ₂ -), 7.80 (CH ₃ C ₆ H ₄ SO ₂ -); M _n ≈40000, PDI=1.04.

(3) Preparation of amine derivative H2-C3-1

为

g₁＝g₂＝g₃＝0,k₁＝k₂＝k₃＝1,F₁＝CH₂CH₂NH₂(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂CH₂,R₀₁＝NH₂),F₂＝CH₂CH₂OPG₄,PG₄＝EE。设计总分子量约为40kDa，其中主链分子量约为20000Da，即n₃≈455,分支链分子量约为10000Da，n₁≈n₂≈227。among them,

for

g ₁ =g ₂ =g ₃ =0,k ₁ =k ₂ =k ₃ =1, F ₁ =CH ₂ CH ₂ NH ₂ (q=0, Z ₂ is absent, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =NH ₂ ), F ₂ =CH ₂ CH ₂ OPG ₄ , PG ₄ =EE. The designed total molecular weight is about 40 kDa, wherein the main chain molecular weight is about 20,000 Da, i.e., n ₃ ≈ 455, and the branched chain molecular weight is about 10,000 Da, n ₁ ≈ n ₂ ≈ 227.

In a dry clean 2L round bottom flask, 40 g of the branched polyethylene glycol sulfonate (H2-B1-1) prepared in Example 2 (2) was added, and then 1600 mL of an aqueous ammonia solution (mass fraction of 40%) was added and stirred. After complete reaction at room temperature, the reaction mixture was diluted with methylene chloride (3*400 mL). 1).

The hydrogen spectrum data of H2-C3-1 in this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 1.22 (-OCH ₂ CH ₃ ), 1.36 (-OCH(O)CH ₃ ), 2.70-2.85 (-CH ₂ CH ₂ NH ₂ ), 3.40-3.80 (-CH ₂ CH ₂ O-, OCH ₂ CH ₃ , -OCH(CH ₂ O-) ₂ , -OCH ₂ CH ₂ NH ₂ ), 4.75 (-OCHCH ₃ (OCH ₂ )); M _n ≈40000, PDI=1.04.

(4) Preparation of maleimide derivative H2-E1-1

为

g₁＝g₂＝g₃＝0,k₁＝k₂＝k₃＝1,F₁＝

(q＝1,Z₂＝CH₂CH₂,q₁＝1,Z₁＝NHCOCH₂CH₂,R₀₁＝

),F₂＝CH₂CH₂OPG₄,PG₄＝EE。设计总分子量约为40kDa，其中主链分子量约为20000Da，即n₃≈455,分支链分子量约为10000Da，n₁≈n₂≈227。among them,

for

g ₁ =g ₂ =g ₃ =0, k ₁ =k ₂ =k ₃ =1, F ₁ =

(q=1, Z ₂ =CH ₂ CH ₂ , q ₁ =1, Z ₁ =NHCOCH ₂ CH ₂ , R ₀₁ =

), F ₂ = CH ₂ CH ₂ OPG ₄ , PG ₄ = EE. The designed total molecular weight is about 40 kDa, wherein the main chain molecular weight is about 20,000 Da, i.e., n ₃ ≈ 455, and the branched chain molecular weight is about 10,000 Da, n ₁ ≈ n ₂ ≈ 227.

In a dry clean 1 L round bottom flask, 40 g of the branched polyethylene glycol amine derivative prepared by the above step (H2-C3-1, azeotropic removal of water via toluene) and 20 g of β-maleimidopropionic acid were added. After nitrogen protection, add solvent dichloromethane (600 mL), stir until dissolved, then add 40 mL of triethylamine and 40 g of dicyclohexanecarbodiimide (DCC) in sequence, react at room temperature for 24 hours, and remove insoluble matter by filtration. Concentration and recrystallization from isopropanol gave a white maleimide derivative (H2-E1-1).

The hydrogen spectrum data of H2-E1-1 in this example are as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 1.22 (-OCH ₂ CH ₃ ), 1.36 (-OCH(O)CH ₃ ), 2.70-2.80 (-NHC(=O)CH ₂ CH ₂ -), 3.40-3.80 (-CH ₂ CH ₂ O-, OCH ₂ CH ₃ , -OCH(CH ₂ O-) ₂ ), 3.92 (-NHCOCH ₂ CH ₂ N -), 4.75 (-OCHCH ₃ (OCH ₂ )), 6.81 (-CH=CH-); M _n ≈40000, PDI=1.04.

Preparation of Maleimide Derivative H1-E1-1

为

g₁＝g₂＝g₃＝0,k₁＝k₂＝k₃＝1,F₁＝

F₂＝CH₂CH₂OH。设计总分子量约为40kDa，其中主链分子量约为20000Da，即n₃≈455,分支链分子量约为10000Da，n₁≈n₂≈227。among them,

for

g ₁ =g ₂ =g ₃ =0, k ₁ =k ₂ =k ₃ =1, F ₁ =

F ₂ =CH ₂ CH ₂ OH. The designed total molecular weight is about 40 kDa, wherein the main chain molecular weight is about 20,000 Da, i.e., n ₃ ≈ 455, and the branched chain molecular weight is about 10,000 Da, n ₁ ≈ n ₂ ≈ 227.

The intermediate H2-E1-1 obtained in the above step was added to a dry clean container, dissolved in 1 M HCl, stirred at room temperature overnight, concentrated, precipitated, filtered, recrystallized and dried to give a hydroxy exposed intermediate H1. -E1-1.

The hydrogen spectrum data of the intermediates H1-E1-1 in this example are as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 2.70-2.80 (-NHC(=O)CH ₂ CH ₂ -), 3.40-3.80 ( -CH ₂ CH ₂ O-, -OCH(CH ₂ O-) ₂ ), 3.92 (-NHCOCH ₂ CH ₂ N-), 6.81 (-CH=CH-); M _n ≈40000, PDI=1.04.

(5) Preparation of active ester derivative H2-A6-1

Synthesis of succinimide carbonate derivative H2-A6-1

为

g₁＝g₂＝g₃＝0,k₁＝k₂＝k₃＝1,F₁＝

(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂CH₂,R₀₁＝OCONHS),F₂＝CH₂CH₂PG₄,PG₄＝EE。设计总分子量约为40kDa，其中主链分子量约为20000Da，即n₃≈455,分支链分子量约为10000Da，n₁≈n₂≈227。among them,

for

g ₁ =g ₂ =g ₃ =0, k ₁ =k ₂ =k ₃ =1, F ₁ =

(q=0, Z ₂ is absent, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =OCONHS), F ₂ =CH ₂ CH ₂ PG ₄ , PG ₄ =EE. The designed total molecular weight is about 40 kDa, wherein the main chain molecular weight is about 20,000 Da, i.e., n ₃ ≈ 455, and the branched chain molecular weight is about 10,000 Da, n ₁ ≈ n ₂ ≈ 227.

In a dry clean 1 L round bottom flask, 40 g of the branched polyethylene glycol (H2-H1-1, azeotropically removed by toluene) obtained in Example 2, 500 mL of acetonitrile, 80 mL of triethylamine and 20 g of N were added. N'-disuccinimidyl carbonate was reacted at room temperature for 24 hours, concentrated, and recrystallized from isopropanol to give the active compound (H2-A6-1) as a white solid.

The hydrogen spectrum data of the active ester H2-A6-1 are as follows:

¹ H NMR (CDCl ₃ ) δ (ppm): 1.22 (-OCH ₂ CH ₃ ), 1.36 (-OCH(O)CH ₃ ), 2.70-2.85 (-(O=)CCH ₂ CH ₂ C (=O) -, 3.40-3.80 (-CH ₂ CH ₂ O-, OCH ₂ CH ₃ , -OCH(CH ₂ O-) ₂ ), 4.15 (-CH ₂ OCO-), 4.75 (-OCHCH ₃ (OCH ₂ )); M _n ≈ 40kDa, PDI=1.04.

(6) Preparation of succinimide carbonate derivative H1-A6-1

为

g₁＝g₂＝g₃＝0,k₁＝k₂＝k₃＝1,F₁＝

(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂CH₂,R₀₁＝OCONHS),F₂＝CH₂CH₂PG₄,PG₄＝EE。设计总分子量约为40kDa，其中主链分子量约为20000Da，即n₃≈455,分支链分子量约为10000Da，n₁≈n₂≈227。among them,

for

g ₁ =g ₂ =g ₃ =0, k ₁ =k ₂ =k ₃ =1, F ₁ =

(q=0, Z ₂ is absent, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =OCONHS), F ₂ =CH ₂ CH ₂ PG ₄ , PG ₄ =EE. The designed total molecular weight is about 40 kDa, wherein the main chain molecular weight is about 20,000 Da, i.e., n ₃ ≈ 455, and the branched chain molecular weight is about 10,000 Da, n ₁ ≈ n ₂ ≈ 227.

Add compound H2-A6-1 to a dry and clean container, dissolve it with methanol, add 1M hydrochloric acid to pH=3.5, react for 4 hours, concentrate, precipitate, filter, recrystallize and dry to obtain 1 hydroxyl exposed Y-type polyethylene glycol intermediate H1-A6-1.

The hydrogen spectrum data of the active esters H1-A6-1 are as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 2.70-2.85 (-(O=)CCH ₂ CH ₂ C(=O)-, 3.40-3.80 (- CH ₂ CH ₂ O-, -OCH(CH ₂ O-) ₂ ), 4.15 (-CH ₂ OCO-).

(7) Preparation of cyano derivative H2-F1-1

为

g₁＝g₂＝g₃＝0,k₁＝k₂＝k₃＝1,F₁＝CH₂CH₂CN(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂CH₂,R₀₁＝CN),F₂＝CH₂CH₂PG₄,PG₄＝EE。设计总分子量约为40kDa，其中主链分子量约为20000Da，即n₃≈455,分支链分子量约为10000Da，n₁≈n₂≈227。among them,

for

g ₁ =g ₂ =g ₃ =0, k ₁ =k ₂ =k ₃ =1, F ₁ =CH ₂ CH ₂ CN(q=0, Z ₂ is absent, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =CN), F ₂ =CH ₂ CH ₂ PG ₄ , PG ₄ =EE. The designed total molecular weight is about 40 kDa, wherein the main chain molecular weight is about 20,000 Da, i.e., n ₃ ≈ 455, and the branched chain molecular weight is about 10,000 Da, n ₁ ≈ n ₂ ≈ 227.

In a dry clean 1 L round bottom flask, 40 g of the branched polyethylene glycol (H2-H1-1) obtained in Example 1 was added, and then nitrogen-protected, 500 mL of 1,4-dioxane was added, and stirred until dissolved. Under ice bath, add 20 g of 50% potassium hydroxide solution, add acrylonitrile dropwise, react at room temperature for 24 hours, neutralize with 1 mol/L hydrochloric acid to pH=7, and concentrate to remove 1,4-dioxane. Hexacyclohexane, dissolved in 400 mL of deionized water, washed with dichloromethane (3*200 mL), combined organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, -1).

The hydrogen spectrum data for the intermediate H2-F1-1 are as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 1.22 (-OCH ₂ CH ₃ ), 1.36 (-OCH(O)CH ₃ ), 2.60 (-CH _{2 )} CH ₂ CN), 3.40-3.80 (-CH ₂ CH ₂ O-, OCH ₂ CH ₃ , -OCH(CHO-) ₂ , -OCH ₂ CH ₂ CN), 4.75 (-OCHCH ₃ (OCH ₂ )); M _n ≈40000, PDI=1.04.

Example 3: Preparation of asymmetrically branched Y-form intermediate H1-H2-2

为

(U为不对称类型；U＝

L₁、L₂、L₃不存在；或U＝

L₁不存在,L₂＝CH₂,L₃＝CH₂)，g₁＝g₂＝g₃＝0,k₁＝k₂＝k₃＝1,F₁＝CH₂CH₂OPG₄(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂CH₂,R₀₁＝OPG₄,PG₄＝

),F₂＝CH₂CH₂OH(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂CH₂,R₀₁＝OH)。设计总分子量约为25kDa，其中主链分子量约为5000Da，即n₃≈114分支链分子量约为10000Da，n₁≈n₂≈227。among them,

for

(U is an asymmetrical type; U=

L ₁ , L ₂ , L ₃ do not exist; or U=

L ₁ is absent, L ₂ =CH ₂ , L ₃ =CH ₂ ), g ₁ =g ₂ =g ₃ =0, k ₁ =k ₂ =k ₃ =1, F ₁ =CH ₂ CH ₂ OPG ₄ ( q=0, Z ₂ does not exist, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =OPG ₄ , PG ₄ =

), F ₂ =CH ₂ CH ₂ OH (q=0, Z ₂ is absent, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =OH). The designed total molecular weight is about 25 kDa, wherein the main chain molecular weight is about 5000 Da, that is, the molecular weight of the n ₃ ≈ 114 branched chain is about 10,000 Da, n ₁ ≈ n ₂ ≈ 227.

a, into a water-free and oxygen-free closed reaction vessel, followed by the addition of tetrahydrofuran (125 mL), small molecule initiator 145 (2.5 mmol) and diphenylmethyl potassium (2.0 mmol);

b, adding a calculated amount of ethylene oxide (50mL, 990mmol), gradually heating to a temperature of 60 ° C, the reaction for 48 hours;

c, adding an excess of proton source (such as methanol) to obtain a hydroxyl group-containing V-type polyethylene glycol, after purification, adding excess dihydropyran (100 mmol), p-toluenesulfonic acid, 30 ° C in dichloromethane reaction 12 The reaction vessel is opened, washed with water, dried, and the solvent is concentrated, precipitated in anhydrous ether at 0 ° C, filtered, and dried to obtain a hydroxypyran-protected V-type polyethylene glycol intermediate 147 at both ends;

Intermediate 147 (ppm) as described in this example: 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ), 1.50-1.90 (-OCH ₂ CH ₂ CH ₂ CH ₂ CH-), 3.15-3.35 (-CH ₂ CHCH ₂ OSi-), 3.40-3.80 (-CH ₂ CH ₂ O-, -OCH ₂ CH ₂ CH ₂ CH ₂ CH-, -CH ₂ CHCH ₂ OSi-), 3.70-4.10 ( -CH ₂ CHCH ₂ OSi-), 4.80-5.00 (-OCH(O)CH ₂ ); M _n ≈ 20 kDa, PDI=1.03.

d. Add the V-type polyethylene glycol 147 prepared in the above step to a dry and clean container, dissolve it with tetrahydrofuran, add tetra-tert-butylammonium fluoride (TBAF), react overnight, concentrate, precipitate, and filter. Drying gave 1 hydroxy-exposed V-type polyethylene glycol intermediate 148.

The hydrogen spectrum data for the intermediate 148 described in this example are as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 1.50-1.90 (-OCH ₂ CH ₂ CH ₂ CH ₂ CH-), 3.15-3.35 (-CH ₂ CHCH ₂ OH), 3.40-3.90 (-CH ₂ CH ₂ O-, -CH ₂ CHCH ₂ -OH, -OCH ₂ CH ₂ CH ₂ CH ₂ CH-, -CH ₂ CHCH ₂ OH), 4.80-5.00 (-OCH (O)CH ₂ ); M _n ≈20 kDa, PDI=1.03.

e, repeat steps (a), (b), according to the metering change of the amount of feed and the amount of ethylene oxide to carry out the reaction, adding excess proton source methanol, concentrated, precipitated, filtered, recrystallized, dried to give compound H1 -H2-2

The hydrogen spectrum data of the intermediate H1-H2-2 in this example are as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 1.50-1.90 (-OCH ₂ CH ₂ CH ₂ CH ₂ CH-), 3.40-3.80 ( -CH ₂ CH ₂ O-, -OCH ₂ CH ₂ CH ₂ CH ₂ CH-, -OCH(CH ₂ O-) ₂ ), 4.80-5.00 (-OCH(O)CH ₂ ); M _n ≈25kDa, PDI =1.03.

(2) Preparation of asymmetrically branched Y-form intermediate 153 (H2-H1-7)

为

g₁＝g₂＝g₃＝0,k₁＝k₂＝k₃＝1,F₂＝CH₂CH₂OPG₄,PG₄＝TBS,F₁＝CH₂CH₂OH。设计总分子量约为22kDa，其中主链聚乙二醇为单分散性，EO单元数为n₃＝44，分支链分子量约为10000Da，n₁≈n₂≈227。among them,

for

g ₁ = g ₂ = g ₃ =0, k ₁ = k ₂ = k ₃ =1, F ₂ = CH ₂ CH ₂ OPG ₄ , PG ₄ = TBS, F ₁ = CH ₂ CH ₂ OH. The designed total molecular weight is about 22 kDa, wherein the main chain polyethylene glycol is monodisperse, the number of EO units is n ₃ = 44, and the molecular weight of the branched chain is about 10000 Da, n ₁ ≈ n ₂ ≈ 227.

a: In a water-free and oxygen-free closed reaction vessel, tetrahydrofuran (125 mL), TBS mono-protected monodisperse linear polyethylene glycol 149 (2.5 mmol) and diphenylmethyl potassium (5 mmol) were added in sequence; chlorine was added. Substituted propylene oxide (18mmol), the reaction temperature was 50 ° C, the reaction was carried out for 12 hours, the reaction was quenched by adding a small amount of saturated ammonium chloride solution; the solvent was concentrated, precipitated in anhydrous ether at 0 ° C, filtered and dried to obtain a poly Ethylene glycol intermediate 151; Polyethylene glycol intermediate 151 was added to a 20% aqueous potassium hydroxide solution for hydrolysis, filtered, recrystallized and dried to give an epoxy ring-opened polyethylene glycol intermediate 152.

Nuclear magnetic resonance spectrum data of Intermediate 152 ¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ), 3.40-3.80 (-CH ₂ CH _{2 O -, - OCH (CH} 2 O-) 2, -OCH 2 CH 2 OSi -), 3.80-4.00 (-OCH 2 CH 2 OSi-).

b: In a water-free and oxygen-free closed reaction vessel, tetrahydrofuran (125 mL), polyethylene glycol 152 (2.5 mmol) and diphenylmethyl potassium (2.0 mmol) were added in sequence; a calculated amount of ethylene oxide was added ( 1140 mmol), gradually heated to a temperature of 60 ° C, and reacted for 48 hours; finally, an excess of proton source methanol was added, concentrated, precipitated, filtered, recrystallized and dried to give compound 153 (H2-H1-7).

The hydrogen spectrum data of the intermediate 153 in this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ), 3.40-3.80 _{(-CH 2 CH 2 O -,} - OCH (CH 2 O -, - OCH 2 CH 2 OSi -), 3.80-4.00 (-OCH 2 CH 2 OSi -); M n ≈22kDa, PDI = 1.02.

Example 4: Preparation of intermediate H2-H1-2

为

(U为对称类型；U＝

L₁＝L₂＝CH₂CH₂,L₃＝CH₂CH₂)，g₁＝g₂＝g₃＝0,k₁＝k₂＝k₃＝1,F₁＝CH₂CH₂OH(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂CH₂,R₀₁＝OH),F₂＝CH₂CH₂PG₄,PG₄＝EE。设计总分子量约为32kDa，其中主链分子量约为2000Da，即n₃≈45,分支链分子量约为15000Da，n₁≈n₂≈341。among them,

for

(U is a symmetric type; U=

L ₁ = L ₂ = CH ₂ CH ₂ , L ₃ = CH ₂ CH ₂ ), g ₁ = g ₂ = g ₃ =0, k ₁ = k ₂ = k ₃ =1, F ₁ = CH ₂ CH ₂ OH (q=0, Z ₂ is absent, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =OH), F ₂ =CH ₂ CH ₂ PG ₄ , PG ₄ =EE. The designed total molecular weight is about 32 kDa, wherein the main chain molecular weight is about 2000 Da, i.e., n ₃ ≈ 45, and the branched chain molecular weight is about 15,000 Da, n ₁ ≈n ₂ ≈ 341.

a, into a water-free and oxygen-free closed reaction vessel, followed by the addition of tetrahydrofuran (125 mL), EE-protected ethylene glycol 140 (2.5 mmol) and diphenylmethyl potassium (2.0 mmol);

b, adding a calculated amount of ethylene oxide (25mL, 495mmol), gradually heating to a temperature of 60 ° C, the reaction for 48 hours;

c, an excess of potassium diphenylmethyl (20 mmol) was added, then an excess of compound 154 (50 mmol) was added, the reaction temperature was 30 ° C, and the reaction time was 12 hours; the reaction vessel was opened, the solvent was concentrated, and the mixture was dried at 0 ° C. Precipitating in diethyl ether, filtering, drying, to obtain PEG-protected at both ends, PEG-protected polyethylene glycol intermediate 155;

The hydrogen spectrum data of the intermediate 155 in this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ), 1.22 (- OCH ₂ CH ₃ ), 1.36 (-OCH(O)CH ₃ ), 2.70-2.80 (-NCH ₂ CH ₂ O-), 3.30-3.90 (-CH ₂ CH ₂ O-, -NCH ₂ CH ₂ O- , OCH ₂ CH ₃ ), 4.75 (-OCHCH ₃ (OCH ₂ )); M _n ≈ 30 kDa, PDI=1.03.

d. Add the intermediate 155 prepared in the step c to a dry and clean container, dissolve it in tetrahydrofuran, add tetra-tert-butylammonium fluoride (TBAF), react overnight, concentrate, precipitate, filter and dry to obtain a hydroxyl group. Exposed Y-type polyethylene glycol intermediate 156.

The hydrogen spectrum data of the intermediate 156 in this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 1.22 (-OCH ₂ CH ₃ ), 1.36 (-OCH(O)CH ₃ ), 2.45-2.65 ( -NCH ₂ CH ₂ O-), 3.30-3.90 (-CH ₂ CH ₂ O-, -NCH ₂ CH ₂ O-, OCH ₂ CH ₃ ), 4.75 (-OCHCH ₃ (OCH ₂ )); M _n ≈32kDa , PDI=1.04.

e, repeat steps (a), (b), according to the metering change of the amount of feed and the amount of ethylene oxide to carry out the reaction, and finally add an excess of proton source DPMK, then add TBSCl, concentrated, precipitated, filtered, recrystallized Dry to give the compound H2-H2-2.

The hydrogen spectrum data of the intermediate H2-H2-2 described in this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ) , 1.22 (-OCH ₂ CH ₃ ), 1.36 (-OCH(O)CH ₃ ), 2.70-2.80 (-NCH ₂ CH ₂ O-), 3.40-3.80 (-CH ₂ CH ₂ O-, -OCH ₂ CH ₂ OSi-, -NCH ₂ CH ₂ O-, OCH ₂ CH ₃ , -OCH(CH ₂ O-) ₂ ), 3.80-4.00 (-OCH ₂ CH ₂ OSi-), 4.75 (-OCHCH ₃ (OCH ₂₎ )); M _n ≈ 32000, PDI=1.04.

f. Add the polyethylene glycol H2-H2-2 obtained in the above step to a dry and clean container, dissolve it with tetrahydrofuran, add tetra-tert-butylammonium fluoride (TBAF), react overnight, concentrate, and precipitate. Filtration, recrystallization, and drying gave Intermediate H2-H1-2.

The hydrogen spectrum data of the intermediate H2-H1-2 in this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 1.22 (-OCH ₂ CH ₃ ), 1.36 (-OCH(O)CH ₃ ), 2.70 -2.80 (-NCH ₂ CH ₂ O-), 3.40-3.80 (-CH ₂ CH ₂ O-, -NCH ₂ CH ₂ O-, OCH ₂ CH ₃ , -OCH(CH ₂ O-) ₂ ), 4.75 ( -OCHCH ₃ (OCH ₂ )); M _n ≈ 32000, PDI=1.04.

Example 5: Preparation of main chain (succinimide carbonate)-branched chain (bismaleimide)-Y type polyethylene glycol derivative (A6-E1-1)

为

g₁＝g₂＝g₃＝0,k₁＝k₂＝k₃＝1,F₁＝

(q＝1, Z₂＝

q₁＝1,Z₁＝

R₀₁＝

),F₂＝CH₂CH₂OCONHS(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂CH₂,R₀₁＝OCONHS)。设计总分子量约为20kDa，其中主链分子量约为1000Da，即n₃≈23,分支链分子量约为9500Da，n₁≈n₂≈216。among them,

for

g ₁ =g ₂ =g ₃ =0, k ₁ =k ₂ =k ₃ =1, F ₁ =

(q=1, Z ₂ =

q ₁ =1, Z ₁ =

R ₀₁ =

), F ₂ =CH ₂ CH ₂ OCONHS (q=0, Z ₂ is absent, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =OCONHS). The designed total molecular weight is about 20 kDa, wherein the main chain molecular weight is about 1000 Da, i.e., n ₃ ≈23, and the molecular weight of the branched chain is about 9,500 Da, n ₁ ≈n ₂ ≈ 216.

Step a: The preparation method of H2-H1-1 in Example 2 is used to prepare a hydroxyl intermediate having the same structure and a total molecular weight of about 20 kDa (9500*2+1000, n ₁ ≈n ₂ ≈216, n ₃ ≈23). H2-H1-3. Among them, PG ₄ is EE.

The hydrogen spectrum data of the intermediate H2-H1-3 described in this example are as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 1.22 (-OCH ₂ CH ₃ ), 1.36 (-OCH(O)CH ₃ ), 3.40- 3.80 (-CH ₂ CH ₂ O-, OCH ₂ CH ₃ , -OCH(CH ₂ O-) ₂ ), 4.75 (-OCHCH ₃ (OCH ₂ )); M _n ≈ 20000, PDI=1.03.

Step b: using the preparation method of H2-B1-1 in Example 2, using H2-H1-3 as a raw material to prepare a sulfonate derivative H2-B1-2, the total molecular weight is about 20 kDa (9500*2+1000) .

The hydrogen spectrum data of the sulfonate H2-B1-2 is as follows: The hydrogen spectrum data of H2-B1-2 in this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 1.22 (-OCH ₂ CH ₃ ), 1.36(-OCH(O)CH ₃ ), 2.35 (CH ₃ C ₆ H ₄ SO ₂ -), 3.40-3.80 (-CH ₂ CH ₂ O-, OCH ₂ CH ₃ , -OCH(CH ₂ O-) ₂ ), 4.20 (-OCH ₂ CH ₂ OSO ₂ -), 4.75 (-OCHCH ₃ (OCH ₂ )), 7.30 (CH ₃ C ₆ H ₄ SO ₂ -), 7.80 (CH ₃ C ₆ H ₄ SO ₂ -) ;M _n ≈20000, PDI=1.03.

Step c: Using the preparation method of H2-C3-1 in Example 2, using H2-B1-2 as a raw material, preparing a polyethylene glycol amine derivative H2-C3-2, the total molecular weight is about 20 kDa (9500*2+). 1000).

The hydrogen spectrum data of the intermediate H2-C3-2 in this example are as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 1.22 (-OCH ₂ CH ₃ ), 1.36 (-OCH(O)CH ₃ ), 2.70 -2.85 (-CH ₂ CH ₂ NH ₂ ), 3.40-3.80 (-CH ₂ CH ₂ O-, OCH ₂ CH ₃ , -OCH(CH ₂ O-) ₂ , -OCH ₂ CH ₂ NH ₂ ), 4.75 ( _{-OCHCH 3 (OCH 2));} M n ≈20000, PDI = 1.03.

Step d: Using the preparation method of H2-E1-1 in Example 2, using H2-C3-2 as a raw material, preparing a polyethylene glycol maleimide derivative H2-E1-2 with a total molecular weight of about 20 kDa ( 9500*2+1000).

The hydrogen spectrum data of H2-E1-2 in this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 1.22 (-OCH ₂ CH ₃ ), 1.36 (-OCH(O)CH ₃ ), 2.70-2.80 (-NHC(=O)CH ₂ CH ₂ -), 3.40-3.80 (-CH ₂ CH ₂ O-, OCH ₂ CH ₃ , -OCH(CH ₂ O-) ₂ ), 3.92 (-NHCOCH ₂ CH ₂ N -), 4.75 (-OCHCH ₃ (OCH ₂ )), 6.81 (-CH=CH-); M _n ≈ 20000, PDI = 1.03.

Step e: Using the preparation method of H1-E1-1 in Example 2, using H2-E1-2 as a raw material, preparing polyethylene glycol maleimide derivative H1-E1-2, the total molecular weight is about 20 kDa ( 9500*2+1000).

The hydrogen spectrum data of the intermediates H1-E1-2 described in this example are as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 2.70-2.80 (-NHC(=O)CH ₂ CH ₂ -), 3.40-3.80 ( -CH ₂ CH ₂ O-, -OCH(CH ₂ O-) ₂ ), 3.92 (-NHCOCH ₂ CH ₂ N-), 6.81 (-CH=CH-); M _n ≈ 20000, PDI=1.03.

Step f: In a dry clean 1 L round bottom flask, add H2-E1-2 (azeotropic removal of water via toluene), 500 mL of acetonitrile, 40 mL of triethylamine and 10 g of N,N'-disuccinimide. The base carbonate was reacted at room temperature for 24 hours, concentrated, and recrystallized from isopropanol to give the active compound (A6-E1-1) as a white solid.

The hydrogen spectrum data of the active ester A6-E1-1 are as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 2.70-2.85 (-(O=)CCH ₂ CH ₂ C(=O)-, -NHC(=O CH ₂ CH ₂ -), 3.40-3.80 (-CH ₂ CH ₂ O-, -OCH(CH ₂ O-) ₂ ), 3.92 (-NHCOCH ₂ CH ₂ N-), 6.81 (-CH=CH-) ;M _n ≈20000, PDI=1.03.

Example 6

Preparation of main chain (maleimide)-branched chain (disuccinimidyl acetate)-Y type polyethylene glycol derivative (E1-A1-1)

为

g₁＝g₂＝g₃＝0,k₁＝k₂＝k₃＝1,F₁＝CH₂CONHS(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂,R₀₁＝CONHS),F₂＝

(q＝1,Z₂＝

q₁＝1,Z₁＝

R₀₁＝

)。设计总分子量约为20kDa，其中主链分子量约为4000Da，即n₃≈91，分支链分子量约为8000Da，n₁≈n₂≈182。among them,

for

g ₁ =g ₂ =g ₃ =0,k ₁ =k ₂ =k ₃ =1, F ₁ =CH ₂ CONHS(q=0, Z ₂ is absent, q ₁ =1, Z ₁ =CH ₂ ,R ₀₁ =CONHS), F ₂ =

(q=1, Z ₂ =

q ₁ =1, Z ₁ =

R ₀₁ =

). The designed total molecular weight is about 20 kDa, wherein the main chain molecular weight is about 4000 Da, i.e., n ₃ ≈91, and the branched chain molecular weight is about 8000 Da, n ₁ ≈n ₂ ≈ 182.

In step a, using the preparation method of H1-H2-2 in Example 3, the feed ratio was changed to obtain an intermediate H1-H2-4 having the same structure and a total molecular weight of about 20 kDa (8000*2+4000).

The hydrogen spectrum data of the intermediates H1-H2-4 in this example are as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 1.50-1.90 (-OCH ₂ CH ₂ CH ₂ CH ₂ CH-), 3.40-3.80 ( -CH ₂ CH ₂ O-, -OCH(CH ₂ O-) ₂ -OCH ₂ CH ₂ CH ₂ CH ₂ CH-), 4.80-5.00 (-OCH(O)CH ₂ ); M _n ≈20kDa, PDI= 1.03.

Step b: Compound H1-H2-4 (2 mmol) was dissolved in 500 mL of THF, excess potassium diphenylmethyl (20 mmol) was added, then excess TBSCl (50 mmol) was added, the reaction temperature was 30 ° C, and the reaction time was 12 hours. The reaction vessel is opened, the solvent is concentrated, and precipitated in anhydrous ether at 0 ° C, filtered, and dried to obtain a single-end hydroxysilicone-protected Y-type polyethylene glycol intermediate H2-H2-3;

The hydrogen spectrum data of the intermediate H2-H2-3 described in this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ) , 1.50-1.90 (-OCH ₂ CH ₂ CH ₂ CH ₂ CH-), 3.40-3.80 (-CH ₂ CH ₂ O-, -OCH ₂ CH ₂ OSi-, -OCH(CH ₂ O-) _2, -OCH ₂ CH ₂ CH ₂ CH ₂ CH-), 3.80-4.00 (-OCH ₂ CH ₂ OSi-), 4.80-5.00 (-OCH(O)CH ₂ ); M _n ≈ 20 kDa, PDI=1.03.

Step c: adding Y-type polyethylene glycol H2-H2-3 prepared in the above step to a dry and clean container, dissolving in methanol, adding 1 M hydrochloric acid to pH=3.0, reacting for 4 hours, concentrating, and precipitating. Filtration, recrystallization, and drying gave Y-type polyethylene glycol intermediate H2-H1-4.

The hydrogen spectrum data of the intermediate H2-H1-4 described in this example are as follows:

¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ), 3.40-3.80 (-CH ₂ CH ₂ O-, -OCH ₂ CH ₂ OSi-, -OCH(CH ₂ O-) ₂ ), 3.80-4.00 (-OCH ₂ CH ₂ OSi-); M _n ≈ 20 kDa, PDI=1.03.

Step d: Dissolve the Y-type polyethylene glycol H2-H1-4 (2.5 mmol) obtained in the above step in 500 mL of water, add an excess of potassium hydroxide (20 mmol), and then add excess sodium bromoacetate (50 mmol), the reaction temperature. The reaction time was 12 hours at 30 ° C; the reaction vessel was opened, and the pH was adjusted to pH = 1 with 3M hydrochloric acid under ice-cooling, and the mixture was stirred at room temperature for 30 hr. Precipitated in anhydrous diethyl ether at 0 ° C, filtered and dried to give Y-type polyethylene glycol (H2-D4-1).

The hydrogen spectrum data of the intermediate H2-D4-1 is as follows:

¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ), 2.40-2.60 (-CH ₂ CH ₂ COOH), 3.30-3.70 ( -OCH(CH ₂ -) ₂ ), 3.40-3.80 (-CH ₂ CH ₂ O-, -OCH ₂ CH ₂ OSi-, -CH ₂ CH ₂ COOH, -OCH(CH ₂ O-) ₂ ), 3.80- _{4.00 (-OCH 2 CH 2 OSi -} ); M n ≈20kDa, PDI = 1.03.

Step e: 40 g of the branched polyethylene glycol acetic acid derivative (H2-D4-1) obtained in the above step, 40 mL of triethylamine and 10 g of N-hydroxysuccinimide, nitrogen were added to a dry clean 1 L round bottom flask. Protect, add solvent dichloromethane (500mL), stir until dissolved, add 40g of dicyclohexane carbodiimide (DCC) in dichloromethane, react at room temperature for 24 hours, filter to remove insoluble matter, concentrate, different The propanol was recrystallized to give the active solid (H2-A1-1) as a white solid.

The hydrogen spectrum data of the active ester H2-A1-1 is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ), 2.40-2.60 (-CH ₂ CH ₂ COO-), 2.70-2.85 (-(O=)CCH ₂ CH ₂ C(=O)-), 3.40-3.80 (-CH ₂ CH ₂ O-, -OCH(CH ₂ O- ₂ , -OCH ₂ CH ₂ OSi- _, -CH ₂ CH ₂ COO-), 3.80-4.00 (-OCH ₂ CH ₂ OSi-); M _n ≈ 20 kDa, PDI=1.03.

Step f: adding Y-type polyethylene glycol H2-A1-1 obtained in the above step to a dry and clean container, dissolving in tetrahydrofuran, adding tetra-tert-butylammonium fluoride (TBAF), and reacting overnight, concentrated , precipitation, filtration, recrystallization, and drying to give the hydroxy exposed intermediate H1-A1-1.

The hydrogen spectrum data of the active ester H1-A1-1 are as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 2.40-2.60 (-CH ₂ CH ₂ COO-), 2.70-2.85 (-(O=) CCH ₂ CH ₂ C(=O)-), 3.40-3.80 (-CH ₂ CH ₂ O-, -OCH(CH ₂ O-) ₂ , -CH ₂ CH ₂ COO-); M _n ≈ 20 kDa, PDI=1.03.

Step g: the monohydroxyl-exposed Y-type polyethylene glycol intermediate H1-A1-1 obtained in the above step is used as a raw material, and the amino group modification method of the example H2-C3-1 is used to obtain the corresponding Y-type polyethylene II. Alcoholamine derivative C3-A1-1.

The hydrogen spectrum data of the active ester C3-A1-1 are as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 2.40-2.60 (-CH ₂ CH ₂ COO-), 2.70-2.85 (-(O=)CCH ₂ CH ₂ C(=O)-, -CH ₂ CH ₂ NH ₂ ), 3.40-3.80 (-CH ₂ CH ₂ O-, -OCH(CH ₂ O-) ₂ , -CH ₂ CH ₂ COO-, OCH ₂ CH ₂ NH ₂ ); M _n ≈ 20 kDa, PDI=1.03.

Step h: In a dry clean 1 L round bottom flask, 40 g of the branched polyethylene glycol amine derivative C3-A1-1 prepared by the above step, azeotropic removal of water via toluene) and 10 g of β-maleimide were added. Propionic acid (157), nitrogen protection, adding solvent dichloromethane (600 mL), stirring until dissolved, then adding 40 mL of triethylamine, 40 g of dicyclohexanecarbodiimide (DCC), and reacting at room temperature for 24 hours. Insoluble matter was removed by filtration, concentrated, and recrystallized from isopropanol to obtain a white maleimide derivative. (E1-A1-1).

The hydrogen spectrum data of the main chain (maleimide)-branched chain (disuccinimidyl acetate)-Y type polyethylene glycol derivative (E1-A1-1) are as follows: ¹ H NMR (CDCl _{3 )} δ (ppm): 2.40-2.60 (-CH ₂ CH ₂ COO-), 2.70-2.85 (-(O=)CCH ₂ CH ₂ C(=O)-, -NHC(=O)CH ₂ CH ₂ - , -CH ₂ CH ₂ NH ₂ ), 3.40-3.80 (-CH ₂ CH ₂ O-, -OCH(CH ₂ O-) ₂ , -CH ₂ CH ₂ COO-, -OCH ₂ CH ₂ NH ₂ ), 3.92 (-NHCOCH ₂ CH ₂ N-), 6.81 (-CH=CH-); M _n ≈ 20 kDa, PDI=1.03.

Example 7 Preparation of Heterofunctionalized Y-Type Polyethylene Glycol C6-A6-1

为

(U为对称类型；U＝

L₁＝L₂＝CH₂CH₂,L₃＝CH₂CH₂)，g₁＝g₂＝g₃＝0,k₁＝k₂＝k₃＝1,F₁＝CH₂CH₂OCONHS(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂CH₂,R₀₁＝CONHS),F₂＝CH₂CH₂NPG₅(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂CH₂,R₀₁＝NPG₅＝N(Bn)₂)。设计总分子量约为25kDa，其中主链分子量约为3000Da，即n₃≈68,分支链分子量约为11000Da，n₁≈n₂≈250。among them,

for

(U is a symmetric type; U=

L ₁ = L ₂ = CH ₂ CH ₂ , L ₃ = CH ₂ CH ₂ ), g ₁ = g ₂ = g ₃ =0, k ₁ = k ₂ = k ₃ =1, F ₁ = CH ₂ CH ₂ OCONHS (q=0, Z ₂ is absent, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =CONHS), F ₂ =CH ₂ CH ₂ NPG ₅ (q=0, Z ₂ is absent, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =NPG ₅ =N(Bn) ₂ ). The designed total molecular weight is about 25 kDa, wherein the main chain molecular weight is about 3000 Da, i.e., n ₃ ≈68, and the branched chain molecular weight is about 11,000 Da, n ₁ ≈n ₂ ≈250.

Step A: Using the preparation method of Example 4, changing the feed ratio, the same structure as H2-H2-2 was prepared, and the molecular weight was about 25 kDa (11000*2+3000, n ₁ ≈n ₂ ≈250, n ₃ ≈68). Protected intermediate H2-H2-4.

The hydrogen spectrum data of the intermediate H2-H2-4 described in this example are as follows:

¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ), 1.22 (-OCH ₂ CH ₃ ), 1.36 (-OCH(O) CH ₃ ),, 2.70-2.80 (-NCH ₂ CH ₂ O-), 3.40-3.80 (-CH ₂ CH ₂ O-, -OCH ₂ CH ₂ OSi-, NCH ₂ CH ₂ O-, OCH ₂ CH ₃ , -OCH(CH ₂ O-) ₂ ), 3.80-4.00 (-OCH ₂ CH ₂ OSi-), 4.75 (-OCHCH ₃ (OCH ₂ )); M _n ≈ 25000, PDI=1.03.

Step B: Compound H2-H2-4 was added to a dry clean container, dissolved in methanol, and 1 M hydrochloric acid was added until pH = 3.5. After reacting for 4 hours, Y-type polyethylene glycol intermediate H1-H2-5 was obtained.

The hydrogen spectrum data of the intermediate H1-H2-5 in this example are as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ) , 2.70-2.80(-NCH ₂ CH ₂ O-), 3.40-3.80 (-CH ₂ CH ₂ O-, -OCH ₂ CH ₂ OSi-, -NCH ₂ CH ₂ O-, -OCH(CH ₂ O- ₂ ), 3.80-4.00 (-OCH ₂ CH ₂ OSi-).

Step C: The Y-type polyethylene glycol intermediate H1-H2-5 obtained in the above step is used as a raw material, and the corresponding Y-type polyethylene glycol amine derivative C3- is obtained by the amino modification method of the example H2-C3-1. H2-1.

The hydrogen spectrum data of the intermediate C3-H2-1 described in this example are as follows:

¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ), 2.70-2.85 (-NCH ₂ CH ₂ O-, -CH ₂ CH ₂ NH ₂ ), 3.40-3.80 (-CH ₂ CH ₂ O-, -OCH ₂ CH ₂ OSi-, -NCH ₂ CH ₂ O-, -OCH ₂ CH ₂ NH ₂ , -OCH(CH ₂ O-) ₂ ), 3.80-4.00 (-OCH ₂ CH ₂ OSi-).

Step D: In a dry clean 1 L round bottom flask, 25.6 g of the branched polyethylene glycol amine derivative prepared by the above step (C3-H2-1, azeotropic removal of water via toluene), nitrogen protection, and solvent water were added. (600 mL), stirring to dissolve, and then adding benzyl bromide (40 mmol) and potassium carbonate (20 mmol), and reacting at room temperature for 24 hours, then removing insolubles by filtration, dichloromethane (3*200 mL), and dried, concentrated. The isopropyl alcohol was recrystallized to obtain a white maleimide derivative (C6-H2-1).

The hydrogen spectrum data of the intermediate C6-H2-1 described in this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ) , 2.40-2.85 (-NCH ₂ CH ₂ O-), 3.40-3.80 (-CH ₂ CH ₂ O-, -OCH ₂ CH ₂ OSi-, -NCH ₂ CH ₂ O-, PhCH ₂ -), 3.80- 4.00 (-OCH ₂ CH ₂ OSi-), 6.90-7.30 (Ph-H).

Step E: adding Y-type polyethylene glycol C6-H2-1 prepared in the above step to a dry and clean container, dissolving in tetrahydrofuran, adding tetra-tert-butylammonium fluoride (TBAF), and reacting overnight to obtain Two hydroxyl-naked Y-type polyethylene glycol intermediates C6-H1-1.

The hydrogen spectrum data of the intermediate C6-H1-1 described in this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 2.40-2.80 (-NCH ₂ CH ₂ O-), 3.40-3.80 (-CH ₂ CH ₂ O-, -NCH ₂ CH ₂ O-, PhCH ₂ -), 6.90-7.30 (Ph-H).

Step F: In a dry clean 1 L round bottom flask, 40 g of the branched polyethylene glycol (C6-H1-1, azeotropic removal of water via toluene), 500 mL of acetonitrile, 80 mL of triethylamine and 20 g of N were obtained. N'-disuccinimidyl carbonate was reacted at room temperature for 24 hours, concentrated, and recrystallized from isopropanol to give the title compound (C6-A6-1) as a white solid.

The hydrogen spectrum data of the intermediate C6-A6-1 described in this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 2.40-2.85 (-NCH ₂ CH ₂ O-), 2.70-2.85 (-(O= _{) CCH 2 CH 2 C (=} O) -, 3.40-3.80 (-CH 2 CH 2 O -, - NCH 2 CH 2 O-, PhCH 2 -), 4.15 (-CH 2 OCO -), 6.90-7.30 ( Ph-H); M _n ≈ 25000, PDI=1.03.

Example 8 Preparation of Heterofunctionalized Y-Type Polyethylene Glycol C3-D4-1 Branched at the End of a Branch Chain

为

g₁＝g₂＝1,p₁＝p₂＝0,G₁＝G₂＝

k₁＝k₂＝2,F₁＝COCH₂CH₂COOH(q＝1,Z₂＝

q₁＝1,Z₁＝CH₂CH₂,R₀₁＝COOH),g₃＝0,k₃＝1,F₂＝CH₂CH₂NH₂(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂CH₂,R₀₁＝NH₂)。设计总分子量约为25kDa，其中主链分子量约为20000Da，即n₃≈455,分支链分子量约为2000Da，n₁≈n₂≈45。among them,

for

g ₁ =g ₂ =1, p ₁ =p ₂ =0, G ₁ =G ₂ =

k ₁ =k ₂ =2, F ₁ =COCH ₂ CH ₂ COOH(q=1, Z ₂ =

q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =COOH), g ₃ =0, k ₃ =1, F ₂ =CH ₂ CH ₂ NH ₂ (q=0, Z ₂ is absent, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =NH ₂ ). The designed total molecular weight is about 25 kDa, wherein the main chain molecular weight is about 20,000 Da, i.e., n ₃ ≈ 455, and the branched chain molecular weight is about 2000 Da, n ₁ ≈ n ₂ ≈ 45.

Preparation of heterofunctional Y-type polyethylene glycol C6-D4-1 branched at the end of branched chain

Wherein, in C6-D4-1, U, L ₁ , L ₂ , L ₃ , g ₁ , g ₂ , p ₁ , p ₂ , G ₁ , G ₂ , k ₁ , k ₂ , F ₁ , g ₃ , The definitions of k ₃ , n ₁ , n ₂ , and n ₃ are consistent with C3-D4-1, and F ₂ is CH ₂ CH ₂ NPG ₅ (q=0, Z ₂ is absent, q ₁ =1, Z ₁ is CH ₂ CH ₂ , R ₀₁ is NPG ₅ , specifically NHBoc, and PG ₅ is tert-butyloxycarbonyl). The total molecular weight of the design is approximately 25 kDa.

Step A: Using the preparation method of H1-H2-1 in Example 1, the feed ratio was changed, and the preparation was the same as that of H1-H2-1, and the designed molecular weight was about 24 kDa (2000*2+20000, n ₁ ≈n ₂ ≈45). , n ₃ ≈ 455) of the intermediate H1-H2-6.

The hydrogen spectrum data of the intermediates H1-H2-6 described in this example are as follows:

¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ), 3.40-3.80 (-CH ₂ CH ₂ O-, -OCH ₂ CH _{2 OSi -, - OCH (CH} 2 O) 2 -), 3.80-4.00 (-OCH 2 CH 2 OSi -); M n ≈24kDa, PDI = 1.03.

Step B: using the amino modification method of H2-C3-1 in Example 2, preparing a polyethylene glycol amine derivative intermediate having the same structure as H1-H2-1 and having a total molecular weight of about 24 kDa (2000*2+20000). C3-H2-1.

The hydrogen spectrum data of the intermediate in this example to C3-H2-1 is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ), 2.70-2.85 (-CH ₂ CH ₂ NH ₂ ), 3.40-3.80 (-CH ₂ CH ₂ O-, -OCH ₂ CH ₂ OSi-, -OCH(CH ₂ O-) ₂ , -OCH ₂ CH ₂ NH ₂ ), 3.80-4.00 (-OCH ₂ CH ₂ OSi-); M _n ≈ 24000, PDI=1.03.

Step C: Add 40 g of the above-prepared branched polyethylene glycol ethylamine (C3-H2-1) to a dry clean 1 L round bottom flask, add 500 mL of dichloromethane solution, and add di-tert-butyl dicarbonate (10). g), after reacting at room temperature overnight, add satiety And sodium bicarbonate solution, using dichloromethane (3 × 200 mL), the organic phase was combined, washed with brine, dried, filtered, concentrated, and recrystallized to give white-t-butyloxycarbonyl-protected amine derivative (C6-H2) -2).

The hydrogen spectrum data of the tert-butoxycarbonyl protected amine derivative C6-H2-2 is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC (CH ₃ ) ₃ ), 1.38 (-C(CH ₃ ) ₃ ), 2.70-3.15 (-CH ₂ CH ₂ NH), 3.40-3.80 (-CH ₂ CH ₂ O-, -OCH(CH ₂ O-) ₂ , -OCH ₂ CH ₂ NH), 3.80-4.00 (-OCH ₂ CH ₂ OSi-)-OCH ₂ CH ₂ OSi-; M _n ≈ 24000, PDI=1.03.

Step D: adding Y-type polyethylene glycol C6-H2-2 obtained in the above step to a dry and clean container, dissolving in tetrahydrofuran, adding tetra-tert-butylammonium fluoride (TBAF), and reacting overnight to obtain Two bare hydroxyl-terminated polyethylene glycol intermediates C6-H1-2.

The hydrogen spectrum data of the tert-butoxycarbonyl protected amine derivative C6-H1-2 is as follows:

¹ H NMR (CDCl ₃ ) δ (ppm): 1.38 (-C(CH ₃ ) ₃ ), 2.70-3.15 (-CH ₂ CH ₂ NH), 3.40-3.80 (-CH ₂ CH ₂ O-, -OCH ( CH ₂ O-) ₂ , -OCH ₂ CH ₂ NH); M _n ≈ 24000, PDI=1.03.

E: To a Y-type polyethylene glycol C6-H1-2 (2.5 mmol) was added an excess of potassium diphenylmethyl (20 mmol), then an excess of compound 142 (50 mmol) was added, the reaction temperature was 30 ° C, and the reaction time was 12 After the reaction vessel was opened, the solvent was concentrated, and then precipitated in anhydrous diethyl ether (0 °C), filtered, and dried to obtain a hydroxy hydroxy ether-protected Y-type polyethylene glycol intermediate H2-H2-5. Repeating step D can obtain Y-type polyethylene glycol 158 containing 4 terminal hydroxyl groups exposed;

The hydrogen spectrum data of the tert-butoxycarbonyl protected amine derivative 158 is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 1.38 (-C(CH ₃ ) ₃ ), 2.70-3.15 (-CH ₂ CH ₂ NH), 2.90-3.00 (-OCH(CH ₂ OSi-) ₂ ), 3.40-3.80 (-CH ₂ CH ₂ O-, -OCH(CH ₂ O-) ₂ , -OCH ₂ CH ₂ NH), 3.90 -4.00 (-OCH(CH ₂ OSi-) ₂ ); M _n ≈ 25000, PDI=1.03.

F: Toluene (500 ml) was added to Y-type polyethylene glycol 158 (2.5 mmol), then excess succinic anhydride (200 mmol) was added, the reaction temperature was 50 ° C, and the reaction time was 12 hours; the reaction kettle was opened, and the solvent was concentrated. Precipitated in anhydrous diethyl ether at 0 ° C, filtered and dried to give a terminal carboxyl group Y-type polyethylene glycol intermediate C6-D4-1.

The hydrogen spectrum data of the tert-butoxycarbonyl protected amine derivative C6-D4-1 is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 1.38 (-C(CH ₃ ) ₃ ), 2.40-2.70 ( -OCOCH ₂ CH ₂ COO-), 2.70-3.15 (-CH ₂ CH ₂ NH), 3.40-3.80 (-CH ₂ CH ₂ O-, -OCH(CH ₂ O-) ₂ , -OCH ₂ CH ₂ NH) , 3.90-4.30 (-OCH(CH ₂ OCO-) ₂ ); M _n ≈ 25000, PDI=1.03.

G: In the dry clean container, add the amine-protected intermediate C6-D4-1 at the end of the main chain, dissolve in dichloromethane, add TFA to 0.1M, and adjust the pH to neutral after 4 hours of reaction. The amine-exposed intermediate C3-D4-1 can be obtained by extraction and precipitation.

The hydrogen spectrum data of the Y-type polyethylene glycol C3-D4-1 is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 2.70-2.85 (-CH ₂ CH ₂ NH ₂ ), 3.40-3.80 (-CH ₂ CH ₂ O-, -OCH(CH ₂ O-) ₂ , -OCH ₂ CH ₂ NH ₂ ), 3.90-4.30 (-OCH(CH ₂ OCO-) ₂ ); M _n ≈ 25000, PDI=1.03.

Example 9 Preparation of Heterofunctionalized Y-Type Polyethylene Glycol H1-D4-1 with Branch Chain End Branching

为

(U为对称类型，U＝

L₁＝L₂＝CH₂,L₃＝CH₂CH₂)，g₁＝g₂＝1,p₁＝p₂＝0,G₁＝G₂＝

k₁＝k₂＝3,F₁＝CH₂COOH(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂,R₀₁＝COOH),g₃＝0,k₃＝1,F₂＝CH₂CH₂OH(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂CH₂,R₀₁＝OH)。设计总分子量约为20kDa，其中主链分子量约为14000Da，即n₃≈318,分支链分子量约为3000Da，n₁≈n₂≈68。among them,

for

(U is a symmetric type, U=

L ₁ = L ₂ = CH ₂ , L ₃ = CH ₂ CH ₂ ), g ₁ = g ₂ =1, p ₁ = p ₂ =0, G ₁ = G ₂ =

k ₁ =k ₂ =3, F ₁ =CH ₂ COOH (q=0, Z ₂ is absent, q ₁ =1, Z ₁ =CH ₂ , R ₀₁ =COOH), g ₃ =0, k ₃ =1 , F ₂ =CH ₂ CH ₂ OH (q=0, Z ₂ is absent, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =OH). The designed total molecular weight is about 20 kDa, wherein the main chain molecular weight is about 14000 Da, that is, n ₃ ≈ 318, and the branched chain molecular weight is about 3000 Da, n ₁ ≈n ₂ ≈ 68.

a, into a water-free and oxygen-free closed reaction vessel, followed by the addition of tetrahydrofuran (125 mL), EE-protected ethylene glycol 140 (2.5 mmol) and diphenylmethyl potassium (2.0 mmol);

b, adding a calculated amount of ethylene oxide (25mL, 495mmol), gradually heating to a temperature of 60 ° C, the reaction for 48 hours;

c, adding an excess of potassium diphenylmethyl (20 mmol), then adding an excess of compound 159 (50 mmol), the reaction temperature is 30 ° C, the reaction time is 12 hours; the reaction kettle is opened, the solvent is concentrated, anhydrous at 0 ° C Precipitating in diethyl ether, filtering, drying, to obtain PEG-protected at both ends, a polyethylene glycol intermediate 160 protected by hydroxyl EE;

The hydrogen spectrum data of the intermediate 160 described in this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ), 1.05-1.45 (-OCH ₂ CH ₃ , -CCH ₂ CH ₂ -, -CCH ₃ , -OCH(O)CH ₃ ), 3.40-3.80 (-CH ₂ CH ₂ O-, -CCH ₂ CH ₂ -, -CCH ₂ O -, OCH ₂ CH ₃ ), 4.75 (-OCHCH ₃ (OCH ₂ )); M _n ≈ 14000, PDI=1.03.

d. Add the polyethylene glycol prepared in the above step to a dry and clean container, dissolve it in tetrahydrofuran, add tetra-tert-butylammonium fluoride (TBAF), react overnight, concentrate, precipitate, filter and dry. Intermediate 161. The above product is reacted with reference to (a), (b) reaction amount and reaction step, and finally an excess proton source (such as methanol) is added, concentrated, precipitated, filtered, and dried to obtain a compound (H2-H1-5). .

The hydrogen spectrum data of the intermediate (H2-H1-5) described in this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 1.05-1.45 (-OCH ₂ CH ₃ , -CCH ₂ CH ₂ -, -CCH ₃ , -OCH(O)CH ₃ ), 3.20-3.40 (-CCH ₂ O-), 3.40-3.80 (-CH ₂ CH ₂ O-, -CCH ₂ CH ₂ -, OCH ₂ CH ₃ ), 4.75 (- OCHCH ₃ (OCH ₂ )); M _n ≈ 20000, PDI=1.03.

E: To the Y-type polyethylene glycol H2-H1-5 (2.5 mmol) was added an excess of potassium diphenylmethyl (20 mmol), then an excess of compound 162 (50 mmol) was added, the reaction temperature was 30 ° C, and the reaction time was 12 After the reaction vessel was opened, the solvent was concentrated, and then precipitated in anhydrous diethyl ether at 0 ° C, filtered, and dried to obtain a terminal hydroxysilyl ether-protected Y-type polyethylene glycol intermediate 163. The obtained Y-type polyethylene glycol 163 is added to a dry and clean container, dissolved in tetrahydrofuran, and tetra-tert-butylammonium fluoride (TBAF) is added. After reacting overnight, it is concentrated, precipitated, filtered, recrystallized, and dried. Intermediate 164 was obtained.

The hydrogen spectrum data of the intermediate 164 in this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 1.05-1.45 (-OCH ₂ CH ₃ , -CCH ₂ CH ₂ -, -CCH ₃ , -OCH (O CH ₃ ), 3.20-3.40 (-CCH ₂ O-), 3.40-3.80 (-CH ₂ CH ₂ O-, -CCH ₂ CH ₂ -, -CCH ₂ OH, OCH ₂ CH ₃ ), 4.75 (-OCHCH) ₃ (OCH ₂ )).

F: The Y-type polyethylene glycol 164 (2.5 mmol) obtained in the above step was dissolved in 500 mL of water, excess potassium hydroxide (20 mmol) was added, and then excess sodium bromoacetate (50 mmol) was added, and the reaction temperature was 30 ° C, and the reaction was carried out. The reaction time was 12 hours; the reaction vessel was opened, the pH was adjusted to pH = 1 with 3M hydrochloric acid, and the reaction temperature was 30 ° C. After stirring for 1 hour, it was extracted with dichloromethane and concentrated. The precipitate was precipitated in anhydrous diethyl ether at 0 ° C, filtered, recrystallized and dried to give the Y-type polyethylene glycol intermediate (H1-D4-1).

The hydrogen spectrum data of the intermediate (H1-D4-1) described in this example are as follows:

¹ H NMR (CDCl ₃ ) δ (ppm): 1.05-1.45 (-CCH ₂ CH ₂ -, -CCH ₃ ), 3.20-3.40 (-CCH ₂ O-), 3.40-3.80 (-CH ₂ CH ₂ O- , -CCH ₂ CH ₂ -), 4.35 (-OCH ₂ C(=O)O-).

Example 10 Preparation of Dicarboxypolyethylene Glycolamine Derivative C3-D4-3 and Its Protected Form C6-D4-3

Dicarboxypolyethylene glycol amine derivative C3-D4-3

为

(U为不对称类型，U＝

L₁＝L₂＝CH₂CH₂,L₃不存在)，g₁＝g₂＝0,G₁、G₂不存在,k₁＝k₂＝1,F₁＝CH₂CH₂COOH(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂CH₂,R₀₁＝COOH),g₃＝1,p₃＝0,k₃＝2,G₃＝

F₂＝NH₂(q＝0,Z₂不存在,q₁＝0,Z₁不存在,R₀₁＝NH₂)。设计总分子量约为32kDa，其中主链分子量约为30000Da，即n₃≈682,聚乙二醇分支链具有固定分子量，EO单元数为n₁＝n₂＝22。In C3-D4-3,

for

(U is an asymmetrical type, U=

L ₁ = L ₂ = CH ₂ CH ₂ , L ₃ is absent), g ₁ = g ₂ =0, G ₁ , G ₂ are absent, k ₁ = k ₂ =1, F ₁ = CH ₂ CH ₂ COOH ( q=0, Z ₂ is absent, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =COOH), g ₃ =1, p ₃ =0, k ₃ =2, G ₃ =

F ₂ =NH ₂ (q=0, Z ₂ is absent, q ₁ =0, Z ₁ is absent, R ₀₁ =NH ₂ ). The designed total molecular weight is about 32 kDa, wherein the main chain molecular weight is about 30,000 Da, i.e., n ₃ ≈ 682, the polyethylene glycol branched chain has a fixed molecular weight, and the number of EO units is n ₁ = n ₂ = 22.

Protected form of dicarboxypolyethylene glycol amine C6-D4-3

Wherein, in C6-D4-3, U, L ₁ , L ₂ , L ₃ , g ₁ , g ₂ , k ₁ , k ₂ , F ₁ , g ₃ , p ₃ , G ₃ , k ₃ , n ₁ , n ₂ , n ₃ are defined as C3-D4-4, F ₂ is CH ₂ CH ₂ NPG ₅ (q=0, Z ₂ is absent, q ₁ =1, Z ₁ is CH ₂ CH ₂ , R ₀₁ is NPG ₅ , specifically NHBoc, PG ₅ is tert-butyloxycarbonyl). The total molecular weight of the design is approximately 32 kDa.

A: In a dry crystallized 1 L round bottom flask, 0.3 g of sodium hydride (60% by weight in mineral oil) was added, protected with nitrogen, 400 mL of anhydrous tetrahydrofuran was added, and linear polyethylene glycol 165 was slowly added dropwise (number average A tetrahydrofuran solution with a molecular weight of 30 kDa and azeotropic removal of toluene. After stirring at room temperature for 3 h, TBS-protected bromopropyne (5 mL) was added and allowed to react at room temperature for 24 h, quenched with a small amount of saturated ammonium chloride solution, dried and concentrated. Recrystallization gave the protected form intermediate (166) of the polyethylene glycol alkyne as a white solid.

The obtained intermediate was dissolved in tetrahydrofuran, tetra-tert-butylammonium fluoride (TBAF) was added, and the reaction was allowed to stand overnight, concentrated, precipitated, filtered, recrystallized and dried to give a one-protected polyethylene glycol alkyne derivative 167. .

The hydrogen spectrum data of the intermediate 167 described in this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 1.22 (-OCH ₂ CH ₃ ), 1.36 (-OCH(O)CH ₃ ), 2.40-2.60 (HC ≡CCH ₂ O-), 3.40-3.80 (-CH ₂ CH ₂ O-, OCH ₂ CH ₃ ), 4.05-4.25 (HC≡CCH ₂ O-), 4.75 (-OCHCH ₃ (OCH ₂ )); M _n ≈30000, PDI=1.03.

B. In a dry and clean 1L round bottom flask, add 10 g of polyethylene glycol thiol with polyethylene glycol alkyne intermediate (167, toluene azeotropic water removal), 20 g of monodisperse 22 EO units (the other end) The hydroxyl group protected by TBS is dissolved in 500 mL of water, protected by nitrogen, stirred until dissolved, and reacted for 24 hours under ultraviolet light. The insoluble matter is removed by filtration, concentrated, recrystallized from isopropanol, and finally dialyzed to obtain a sulfur-containing bond group. Y-type polyethylene glycol compound white solid (H2-H2-6).

The hydrogen spectrum data of the intermediate (H2-H2-6) described in this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ), 1.22 (-OCH ₂ CH ₃ ), 1.36 (-OCH(O)CH ₃ ), 2.50-3.00 (-SCH ₂ CH ₂ -, OCH ₂ CHCH ₂ S), 3.00-3.20 (OCH ₂ CHCH ₂ S ), 3.40-3.90 (-CH ₂ CH ₂ O-, -OCH ₂ CH ₂ OSi-, OCH ₂ CHCH ₂ S, -SCH ₂ CH ₂ -, OCH ₂ CH ₃ ), 3.80-4.00 (-OCH ₂ CH _{2 ) OSi -), 4.75 (-OCHCH 3} (OCH 2)); M n ≈32000, PDI = 1.03.

C: The compound (H2-H2-6) was dissolved in methanol in a dry and clean container, and 1 M hydrochloric acid was added to pH=3.5. After reacting for 4 hours, it was concentrated, precipitated, filtered, recrystallized and dried to obtain a Y-polymer. Ethylene glycol intermediate (H1-H2-7)

The hydrogen spectrum data of the intermediate (H1-H2-7) described in this example is as follows:

¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ), 3.00-3.20 (OCH ₂ CHCH ₂ S), 2.50-3.00 (- SCH ₂ CH ₂ -, OCH ₂ CHCH ₂ S), 3.40-3.90 (-CH ₂ CH ₂ O-, -OCH ₂ CH ₂ OSi-OCH ₂ CHCH ₂ S, -SCH ₂ CH ₂ -), 3.80-4.00 ( -OCH ₂ CH ₂ OSi-).

D: In a dry and clean 1L round bottom flask, add 30g of amino acid with polyethylene glycol intermediate (H1-H2-7, toluene azeotropic water removal), 10mL of triethylamine and 20mol Boc protection, nitrogen protection, add The solvent dichloromethane (600 mL) was stirred until dissolved, and then 20 g of dicyclohexanecarbodiimide (DCC) was added. After reacting for 24 hours at room temperature, the insoluble matter was removed by filtration, concentrated, and recrystallized from isopropanol to obtain a Y-form. Polyethylene glycol compound white solid (C6-H2-3).

The hydrogen spectrum data of the intermediate C6-H2-3 described in this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ) _{, 1.20-1.60 (-NCH 2 CH 2 CH} 2 CH 2 CHCOO -, - OC (CH 3) 3), 1.80-2.00 (-NCH 2 CH 2 CH 2 CH 2 CHCOO -), 2.50-3.20 (-SCH 2 CH ₂ -, OCH ₂ CHCH ₂ S, -NCH ₂ CH ₂ CH ₂ CH ₂ CHCOO-, OCH ₂ CHCH ₂ S), 3.40-3.90 (-CH ₂ CH ₂ O-, -OCH ₂ CH ₂ OSi-,- COOCH ₂ CH ₂ O-, OCH ₂ CHCH ₂ S, -SCH ₂ CH ₂ -), 3.80-4.00 (-OCH ₂ CH ₂ OSi-), 4.15-4.50 (-NCH ₂ CH ₂ CH ₂ CH ₂ CHCOO-, -COOCH ₂ CH ₂ O-).

E: Polyethylene glycol C6-H2-3 prepared in the previous step, dissolved in tetrahydrofuran, added with tetra-tert-butylammonium fluoride (TBAF), reacted overnight, concentrated, precipitated, filtered and dried to obtain a bare hydroxyl group. Intermediate 169. Referring to the preparation method of D4-H2-2 in Example 1, propionic acid derivatization was carried out on the end of the branched chain to obtain a polyethylene glycol derivative C6-D4-3 having a carboxyl group at one end and a carboxyl group at one end. The polyethylene glycol derivative C6-D4-3 was continued. Dissolved in dichloromethane, TFA was added to 0.1 M, and after reacting for 4 hours, the pH was adjusted to neutrality, and the amine-exposed intermediate C3-D4-3 was obtained by extraction and precipitation.

The hydrogen spectrum data of the intermediate C3-D4-3 described in this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 1.20-1.60 (-NCH ₂ CH ₂ CH ₂ CH ₂ CHCOO-), 1.80-2.00 ( -NCH ₂ CH ₂ CH ₂ CH ₂ CHCOO-), 2.40-2.75 (-CH ₂ CH ₂ COOH, -NCH ₂ CH ₂ CH ₂ CH ₂ CHCOO-, OCH ₂ CHCH ₂ S), 2.50-3.00 (-SCH ₂ CH ₂ -, OCH ₂ CHCH ₂ S), 3.40-3.90 (-CH ₂ CH ₂ O-, -COOCH ₂ CH ₂ O-, -CH ₂ CH ₂ COOH, -NCH ₂ CH ₂ CH ₂ CH ₂ CHCOO-, OCH ₂ CHCH ₂ S, -SCH ₂ CH ₂ -), 4.15-4.35 (-COOCH ₂ CH ₂ O-).

Example 11 Preparation of Heterofunctionalized Y-Type Polyethylene Glycol D4-D9-1

L₁＝L₂＝

L₃＝

g₁＝g₂＝0,G₁、G₂不存在,k₁＝k₂＝1,F₁＝CONH(CH₂)₄NCO(q＝1,Z₂＝CONH,q₁＝1,Z₁＝CH₂CH₂CH₂CH₂,R₀₁＝NCO),g₃＝1,p₃＝1,L₃＝CH₂CO,k₃＝2,G₃＝

F₂＝COOH(q＝0,Z₂不存在,q₁＝0,Z₁不存在,R₀₁＝COOH)。设计总分子量约为21kDa，其中主链分子量约为12000Da，即n₃≈273,分支链分子量约为4000Da，n₁≈n₂≈91。Where U is a symmetric type, U=

L ₁ =L ₂ =

L ₃ =

g ₁ =g ₂ =0, G ₁ , G ₂ are absent, k ₁ =k ₂ =1, F ₁ =CONH(CH ₂ ) ₄ NCO(q=1, Z ₂ =CONH,q ₁ =1,Z ₁ = CH ₂ CH ₂ CH ₂ CH ₂ , R ₀₁ = NCO), g ₃ =1, p ₃ =1, L ₃ = CH ₂ CO, k ₃ = 2, G ₃ =

F ₂ =COOH (q=0, Z ₂ is absent, q ₁ =0, Z ₁ is absent, R ₀₁ =COOH). The designed total molecular weight is about 21 kDa, wherein the main chain molecular weight is about 12000 Da, that is, n ₃ ≈ 273, and the branched chain molecular weight is about 4000 Da, n ₁ ≈n ₂ ≈91.

A. After adding the amine intermediate 170 (2.0 mmol), dichloromethane (250 mL) and triethylamine (10 mmol) in an anhydrous and oxygen-free round bottom flask, the polyethylene glycol chloride derivative 171 was slowly added dropwise. (5 mmol, molecular weight about 4000, PDI=1.03) in dichloromethane (50 mL), and then reacted at 25 ° C for 24 h, washed with water, dried, concentrated, and purified by anion exchange resin to afford intermediate 172.

The hydrogen spectrum data of Compound 172 is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ), 1.22 (-OCH ₂ CH ₃ ) , 1.36 (-OCH(O)CH ₃ ), 3.40-3.80 (-CH ₂ CH ₂ O-, -OCH ₂ CH ₂ OSi-, OCH ₂ CH ₃ ), 3.80-4.30 (-OCH ₂ CH ₂ OSi-, OCH ₂ CHPh, -NC(=O)CH ₂ -O-), 4.75 (-OCHCH ₃ (OCH ₂ )), 7.6-8.00 (Ph-H).

B: The intermediate 172 obtained in the above step was added to a dry and clean vessel, dissolved in tetrahydrofuran, and tetra-tert-butylammonium fluoride (TBAF) was added. After reacting overnight, concentrated, precipitated, filtered, and dried to obtain Y. Type polyethylene glycol intermediate 173.

The hydrogen spectrum data of Compound 173 is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 1.22 (-OCH ₂ CH ₃ ), 1.36 (-OCH(O)CH ₃ ), 3.40-3.80 (-CH ₂ CH ₂ O -, OCH ₂ CH ₃ ), 3.90-4.30 (OCH ₂ CHPh), 4.32 (-NC(=O)CH ₂ -O-), 4.75 (-OCHCH ₃ (OCH ₂ )), 7.6-8.00 (Ph-H ).

Add 10 g of Y-type polyethylene glycol (173) to a dry clean 1 L round bottom flask, add 200 mL of anhydrous dichloromethane solution, stir until dissolved, and add 5 mL of triethylamine and 4 g of compound 174 in sequence, and react at room temperature. After a few hours, it was concentrated and diethyl ether was crystallised to afford white crystals.

The hydrogen spectrum data of the intermediate 175 in this example is as follows: The hydrogen spectrum data of the compound 175 is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 1.22 (-OCH ₂ CH ₃ ), 1.32-1.55 (-CH ₂ CH ₂ CH ₂ CH ₂ -, -OCH(O)CH ₃ ), 2.70-3.15 (NCOCH ₂ CH ₂ CH ₂ -, -OCONHCH ₂ -), 3.40-3.80 (-CH ₂ CH ₂ O-, OCH ₂ CH ₃ ), 3.90-4.30 (OCH ₂ CHPh), 4.32 (-NC(=O)CH ₂ -O-), 4.75 (-OCHCH ₃ (OCH ₂ )), 7.6-8.00 (Ph-H).

C: Add the V-type polyethylene glycol 175 prepared in the above step to a dry and clean container, dissolve it with methanol, add 1 M hydrochloric acid to pH=3.5, and after reacting for 4 hours, obtain a hydroxyl-formed V-shaped poly. Ethylene glycol intermediate 176.

D: A dry clean 1 L round bottom flask was charged with 10 g of a polyethylene glycol intermediate having a carboxyl group (177, azeotropic removal of toluene), 5 mL of triethylamine and 10 g of a V-type polyethylene glycol intermediate 176 at one end hydroxyl group. , nitrogen protection, adding solvent dichloromethane (200 mL), stirring until dissolved, and then adding 5 g of dicyclohexane carbodiimide (DCC), reacting at room temperature for 24 hours, filtering to remove insoluble matter, concentration, isopropanol weight Crystallization, and finally dialysis gave a Fmoc-containing Y-type polyethylene glycol compound white solid 178.

The hydrogen spectrum data of Compound 178 is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.98 (-SiC(CH ₃ ) ₃ ), 1.32-1.55 (-CH ₂ CH ₂ CH ₂ CH ₂ -), 2.70-3.15 (NCOCH ₂ CH ₂ CH ₂ -, -OCONHCH ₂ -), 3.40-3.80 (-CH ₂ CH ₂ O-, -OCH ₂ CH ₂ OSi-), 3.80-4.00 (-OCH ₂ CH ₂ OSi-), 3.90-4.30 (OCH ₂ CHPh), 4.32 (-NC(=O)CH ₂ -O-), 7.6-8.00 (Ph-H).

Example 12 Preparation of Heterofunctionalized Y-Type Polyethylene Glycol D5-H1-1

为

(U为对称类型，U＝

L₁＝L₂＝CH₂,L₃＝CH₂)，g₁＝g₂＝0,k₁＝k₂＝1,F₁＝CH₂CH₂OH(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂CH₂,R₀₁＝OH),g₃＝0,k₃＝1,F₂＝CH₂CH₂CHO(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂CH₂,R₀₁＝CHO)。设计总分子量约为20kDa，其中主链分子量约为8000Da，即n₃≈182,分支链分子量约为6000Da，n₁≈n₂≈136。 Among them, in D5-H1-1,

for

(U is a symmetric type, U=

L ₁ = L ₂ = CH ₂ , L ₃ = CH ₂ ), g ₁ = g ₂ =0, k ₁ = k ₂ =1, F ₁ = CH ₂ CH ₂ OH (q = 0, Z ₂ is absent, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =OH), g ₃ =0, k ₃ =1, F ₂ =CH ₂ CH ₂ CHO (q=0, Z ₂ is absent, q ₁ = 1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =CHO). The designed total molecular weight is about 20 kDa, wherein the main chain molecular weight is about 8000 Da, i.e., n ₃ ≈ 182, and the branched chain molecular weight is about 6000 Da, n ₁ ≈n ₂ ≈ 136.

a, into a water-free and oxygen-free closed reaction vessel, followed by the addition of tetrahydrofuran (125 mL), EE-protected ethylene glycol 140 (2.5 mmol) and diphenylmethyl potassium (2.0 mmol);

b, adding a calculated amount of ethylene oxide (25mL, 495mmol), gradually heating to a temperature of 60 ° C, the reaction for 48 hours;

c. Add excess potassium diphenylmethyl (20 mmol), then add excess compound 179 (50 mmol), the reaction temperature is 30 ° C, the reaction time is 12 hours; the reaction kettle is opened, the solvent is concentrated, and the temperature is 0 ° C. Precipitating in diethyl ether, filtering, drying, to obtain a polyethylene glycol intermediate 180 protected by hydroxyl hydroxy ether at both ends, one end hydroxyl EE protection;

The hydrogen spectrum data of the intermediate 180 described in this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.90-1.10 (-SiC(CH ₃ ) ₃ , -CCH ₂ CH ₃ ), 1.05-1.45 (-OCH ₂ CH ₃ , -CCH ₂ CH ₃ , -OCH(O)CH ₃ ), 3.20-3.40 (-CCH ₂ O-), 3.40-3.80 (-CH ₂ CH ₂ O-, -CCH ₂ OSi-, OCH ₂ CH ₃ ), 4.75 (-OCHCH ₃ (OCH ₂ )); M _n ≈ 8000, PDI=1.02.

d. Add the polyethylene glycol 180 obtained in the above step to a dry and clean container, dissolve it with tetrahydrofuran, add tetra-tert-butylammonium fluoride (TBAF), react overnight, concentrate, precipitate, filter, and dry. The hydroxy exposed intermediate 181 was obtained.

e. Repeat steps (a) and (b), and carry out the reaction according to the metering change amount and the amount of ethylene oxide charged, and finally add excess proton source methanol to obtain compound H2-H1-6.

The hydrogen spectrum data of the intermediate H2-H1-6 described in this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 0.90-1.10 (-CCH ₂ CH ₃ ), 1.05-1.45 (-OCH ₂ CH ₃ , -CCH ₂ CH ₃ , -OCH(O)CH ₃ ), 3.20-3.40 (-CCH ₂ O-), 3.40-3.80 (-CH ₂ CH ₂ O-, OCH ₂ CH ₃ ), 4.75 (-OCHCH ₃ ( OCH ₂ )); M _n ≈ 20000, PDI=1.03.

f, the compound H2-H1-6 (2mmol) was dissolved in 500mL of THF, an excess of potassium diphenylmethyl (20mmol) was added, then an excess of TBSCl (50mmol) was added, the reaction temperature was 30 ° C, the reaction time was 12 hours; The reaction kettle was opened, the solvent was concentrated, and then precipitated in anhydrous diethyl ether (EtOAc), filtered, and dried to give the y y y y The compound H2-H2-7 was added to a dry and clean container, dissolved in methanol, and 1 M hydrochloric acid was added until pH=3.5. After reacting for 4 hours, concentrated, filtered and dried to obtain Y-type polyethylene glycol intermediate H1-H2. -8.

The NMR data of the intermediates H1-H2-8 in this example are as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-Si(CH ₃ ) ₂ ), 0.90-1.10 (-SiC (CH _{3 ) 3} , -CCH ₂ CH ₃ ), 1.05-1.45 (-OCH ₂ CH ₃ , -CCH ₂ CH ₃ , -OCH(O)CH ₃ ), 3.20-3.40 (-CCH ₂ O-), 3.40-3.80 ( -CH ₂ CH ₂ O-, -OCH ₂ CH ₂ OSi-, OCH ₂ CH ₃ ), 3.80-4.00 (-OCH ₂ CH ₂ OSi-), 4.75 (-OCHCH ₃ (OCH ₂ )); M _n ≈ 20000 , PDI=1.03.

g. The H1-H2-8 obtained in the step f was modified according to the synthesis method for preparing D7-H2-1 in Example 1 to obtain a Y-type polyethylene glycol acetal intermediate D7-H2-2.

h. Dissolve D7-H2-2 in tetrahydrofuran, add tetra-tert-butylammonium fluoride (TBAF), and react overnight, concentrate, wash, recrystallize and dry. Add to a dry and clean 1L round bottom flask, add 400 mL of deionized water, stir until completely dissolved, adjust the pH to 1.0 with 1 mol/L HCl in an ice bath, react for 4 hours at room temperature, and use dichloro Methane (3*200 mL) was extracted, and the organic phase was combined, washed with brine, dried, filtered, concentrated, and recrystallized to give white polyethylene aldehyde derivative (D5-H1-1).

The nuclear magnetic resonance spectrum data of the intermediate D5-H1-1 described in this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 0.90-1.10 (-CCH ₂ CH ₃ ), 1.05-1.45 (-OCH ₂ CH ₃ , -CCH ₂ CH ₃ , -OCH(O)CH ₃ ), 1.91 (-OCH ₂ CH ₂ CHO), 3.20-3.40 (-CCH ₂ O-), 3.40-3.80 (-CH ₂ CH ₂ O-,- OCH ₂ CH ₂ CHO, OCH ₂ CH ₃ ), 4.75 (-OCHCH ₃ (OCH ₂ )), 9.75 (-OCH ₂ CH ₂ CHO); M _n ≈ 20000, PDI=1.03.

Example 13 Preparation of Heterofunctional Y-Form Derivative D5-E2-1

为

(对称类型，U＝

L₁＝L₂＝CH₂CH₂CH₂,L₃＝CH₂CH₂CH₂)，g₁＝g₂＝0,k₁＝k₂＝1,F₁为COCH＝CH₂(q＝0,Z₂不存在,q₁＝0,Z₁不存在,R₀₁为COCH＝CH₂),g₃＝0,k₃＝1,F₂＝CH₂CH₂CH₂CHO(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂CH₂CH₂,R₀₁＝CHO)。设计总分子量约为40kDa，其中主链分子量约为16000Da，即n₃≈364,分支链分子量约为12000Da，n₁≈n₂≈273。 among them,

for

(symmetric type, U=

L ₁ = L ₂ = CH ₂ CH ₂ CH ₂ , L ₃ = CH ₂ CH ₂ CH ₂ ), g ₁ = g ₂ =0, k ₁ = k ₂ =1, F ₁ is COCH=CH ₂ (q= 0, Z ₂ does not exist, q ₁ =0, Z ₁ does not exist, R ₀₁ is COCH=CH ₂ ), g ₃ =0, k ₃ =1, F ₂ = CH ₂ CH ₂ CH ₂ CHO (q=0 Z ₂ is absent, q ₁ =1, Z ₁ =CH ₂ CH ₂ CH ₂ , R ₀₁ =CHO). The designed total molecular weight is about 40 kDa, wherein the main chain molecular weight is about 16000 Da, i.e., n ₃ ≈ 364, and the branched chain molecular weight is about 12,000 Da, n ₁ ≈n ₂ ≈ 273.

a, in a water-free and oxygen-free closed reactor, adding tetrahydrofuran (125 mL), acetal-protected butanol 140e (2.5 mmol) and diphenylmethyl potassium (2.0 mmol); adding the calculated amount of epoxy B The alkane is gradually heated to a temperature of 60 ° C and reacted for 48 hours;

b. Add excess potassium diphenylmethyl (20 mmol), then add excess compound 142e (50 mmol), the reaction temperature is 30 ° C, the reaction time is 12 hours; the reaction kettle is opened, the solvent is concentrated, and the temperature is 0 ° C. Precipitate in diethyl ether, filter and dry to give polyethylene glycol intermediate 182. The structure was determined by ¹ H NMR. M _n ≈ 16000 Da, PDI=1.03.

c. Add the polyethylene glycol 182 prepared in the above step to a dry and clean container, dissolve it with tetrahydrofuran, add tetra-tert-butylammonium fluoride (TBAF), react overnight, concentrate, precipitate, filter, and dry. The hydroxy exposed intermediate 183 was obtained.

d, repeating step (a), according to the metering change of the amount of feed and the amount of ethylene oxide to carry out the reaction, and finally adding an excess of triethylamine and acryloyl chloride (10mL), reaction at room temperature for 5 hours, concentrated, purified Y-type polyethylene glycol D7-E2-1 as a white solid. The structure was determined by ¹ H NMR. M _n ≈40000, PDI=1.06.

e. In the method of performing propionaldehyde modification in Example 12, selective dealdehyde group protection affords the product D5-E2-1.

The hydrogen spectrum data of the derivative D5-E2-1 described in this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 0.21 (-SiCH ₃ ), 0.62 (-SiCH ₂ CH ₂ CH ₂ -), 1.51- 1.72 (-SiCH ₂ CH ₂ CH ₂ O-), 1.88 (-OCH ₂ CH ₂ CH ₂ CHO), 2.43 (-OCH ₂ CH ₂ CH ₂ CHO) 3.40-4.01 (-CH ₂ CH ₂ O-, -OCH ₂ CH ₂ CH ₂ CHO, -SiCH ₂ CH ₂ CH ₂ O-), 4.25 (-OCH ₂ CH ₂ OCO-), 5.59-6.05 (-CH=CH ₂ ). M _n ≈40000, PDI=1.06.

Example 14 Preparation of branched-chain end-branched Y-type polyethylene glycol derivative F3-F5-1

为

g₁＝g₂＝1,k₁＝k₂＝8,p₁＝p₂＝0,G₁＝G₂＝DENR(

NONE,3),F₁为

(q＝0,Z₂不存在,q₁＝0,Z₁不存在,R₀₁为COCH＝CH₂),g₃＝0,k₃＝1,F₂为CH₂C≡CH(q＝0,Z₂不存在,q₁＝1,Z₁为CH₂,R₀₁为C≡CH)。设计总分子量约为52kDa，其中主链分子量约为10000Da，即n₃≈227,分支链分子量约为20000Da，n₁≈n₂≈455。Among them, in F3-F5-1,

for

g ₁ =g ₂ =1, k ₁ =k ₂ =8, p ₁ =p ₂ =0, G ₁ =G ₂ =DENR(

NONE, 3), F ₁ is

(q=0, Z ₂ does not exist, q ₁ =0, Z ₁ does not exist, R ₀₁ is COCH=CH ₂ ), g ₃ =0, k ₃ =1, F ₂ is CH ₂ C≡CH (q= 0, Z ₂ does not exist, q ₁ =1, Z ₁ is CH ₂ , and R ₀₁ is C≡CH). The designed total molecular weight is about 52 kDa, wherein the main chain molecular weight is about 10,000 Da, i.e., n ₃ ≈ 227, and the molecular weight of the branched chain is about 20,000 Da, n ₁ ≈ n ₂ ≈ 455.

为

g₁＝g₂＝1,k₁＝k₂＝8,p₁＝p₂＝0,G₁＝G₂＝DENR(

NONE,3),F₁为

(q＝0,Z₂不存在,q₁＝0,Z₁不存在,R₀₁为COCH＝CH₂),g₃＝0,k₃＝1,F₂为CH₂C≡CPG₃(q＝0,Z₂不存在,q₁＝1,Z₁为CH₂,R₀₁为C≡CPG₃,PG₃为叔丁基二甲基硅基TBS)。设计总分子量约为52kDa，其中主链分子量约为10000Da，即n₃≈227,分支链分子量约为20000Da，n₁≈n₂≈455。Among them, in F4-F5-1,

for

g ₁ =g ₂ =1, k ₁ =k ₂ =8, p ₁ =p ₂ =0, G ₁ =G ₂ =DENR(

NONE, 3), F ₁ is

(q=0, Z ₂ is absent, q ₁ =0, Z ₁ is absent, R ₀₁ is COCH=CH ₂ ), g ₃ =0, k ₃ =1, F ₂ is CH ₂ C≡CPG ₃ (q =0, Z ₂ is absent, q ₁ =1, Z ₁ is CH ₂ , R ₀₁ is C≡CPG ₃ , and PG ₃ is tert-butyldimethylsilyl TBS). The designed total molecular weight is about 52 kDa, wherein the main chain molecular weight is about 10,000 Da, i.e., n ₃ ≈ 227, and the molecular weight of the branched chain is about 20,000 Da, n ₁ ≈ n ₂ ≈ 455.

A. Using the preparation method of Example 2, the amount of ethylene oxide charged was changed according to the metering, and the terminal hydroxyl group of the branched chain was protected with vinyl ether to obtain a Y-type polyethylene glycol intermediate H2-H1-8 (n ₃ ≈ 227, n ₁ ≈ n ₂ ≈ 455). The structure was determined by ¹ H NMR. M _n ≈50000, PDI=1.05.

B, adding an excess of potassium diphenylmethyl (80 mmol) to the polyethylene glycol intermediate H2-H1-8, and then adding an excess of compound 142 (200 mmol), the reaction temperature is 30 ° C, the reaction time is 12 hours; The reaction kettle was opened, the solvent was concentrated, and then precipitated in anhydrous ethyl ether (EtOAc), filtered, and dried to afford the hydroxy hydroxy ether ether-protected Y-type polyethylene glycol intermediate 184. The structure was confirmed by 1H NMR. M _n ≈50000, PDI=1.05.

C. Add the intermediate prepared in the above step to a dry and clean container, dissolve it in tetrahydrofuran, add tetra-tert-butylammonium fluoride (TBAF), and react overnight to obtain a hydroxyl-naked Y-type polyethylene glycol intermediate. 185.

D. Repeat steps B and C twice, precipitate, filter, and dry to obtain a TBS-protected dendritic Y-type polyethylene glycol intermediate 186. The structure was determined by ¹ H NMR. M _n ≈50000, PDI=1.05.

E. The Y-type polyethylene glycol intermediate 186 is dissolved in tetrahydrofuran, and tetra-tert-butylammonium fluoride (TBAF) is added. After reacting overnight, the precipitate is precipitated, filtered, and dried to obtain a hydroxyl group-exposed Y-type polyethylene glycol intermediate. 187.

F. Under anhydrous and anaerobic conditions, tetrahydrofuran (125 mL), Y-type polyethylene glycol intermediate 187 and diphenylmethyl potassium (5 mmol) were added in sequence, and chloropropylene oxide (18 mmol) was added at 50 ° C. 12 hours, a small amount of saturated ammonium chloride solution was added to quench the reaction; the solvent was concentrated, precipitated 0 ℃ anhydrous ether, filtered and dried, to give an intermediate polyethylene glycol _{188; M n ≈52000, PDI =} 1.05.

G, Y-type polyethylene glycol 188 is dissolved in methanol, 1M hydrochloric acid is added to pH=3.5, after reacting for 4 hours, concentrated, precipitated, filtered, recrystallized, dried, Y-type polyethylene glycol intermediate H1-F5 -1. The structure was determined by ¹ H NMR. M _n ≈ 52000, PDI = 1.05.

H. Using the method of Example 10, the Y-type polyethylene glycol intermediate H1-F5-1 was modified with TBS-protected bromopropyne to obtain Y-type polyethylene glycol represented by F4-F5-1. The alkynyl protecting group TBS was removed by the method of Step E to obtain a Y-type polyethylene glycol represented by F3-F5-1.

The hydrogen spectrum data of Y-type polyethylene glycol F4-F5-1 in this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 0.10 (-SiCH ₃ ), 0.98 (-SiC(CH ₃ ) ₃ ) , 2.38-2.86 (-OCHCH ₂ O-), 3.38-3.67 (-OCH ₂ CH ₂ O-, OCH ₂ CHO-, -OCH ₂ CH(O)CH ₂ O-), 4.15 (CH≡CCH ₂ O- ). M _n = 52000, PDI = 1.05.

The hydrogen spectrum data of the Y-type polyethylene glycol F3-F5-1 in this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 2.39-2.87 (-OCHCH ₂ O-), 3.32-3.67 (CH≡ CCH ₂ O-, -OCH ₂ CH ₂ O-, OCH ₂ CHO-, -OCH ₂ CH(O)CH ₂ O-), 4.15 (CH≡CCH ₂ O-). M _n ≈ 52000, PDI = 1.05.

Example 15 Preparation of a Heterofunctionalized Y-Type Polyethylene Glycol Thiol Derivative

在室温下反应24小时后，浓缩后，加入400mL二氯甲烷后，过滤除去不溶物，用饱和食盐水洗涤(3*100mL)，干燥，浓缩，异丙醇重结晶，得到白色或淡黄色固体中间体。氮气保护下，向中间体中加入200mL四氢呋喃、搅拌至完全溶解，加入10mL正丙胺，在室温下反应24小时后，浓缩，除氧的异丙醇重结晶，得到白色或淡黄色固体的硫基衍生物(C2-H2-1)。结构以¹H NMR测试确定。M_n≈20000,PDI＝1.03。The Y-type polyethylene glycol intermediate H1-H2-1 prepared in Example 1 was added to a dry clean 1 L round bottom flask, protected with nitrogen, 400 mL of tetrahydrofuran, 16 mL of DMF was added, stirred until completely dissolved, and 10 g of ethyl xanthogen was added. Potassium acid

After reacting for 24 hours at room temperature, after concentration, 400 mL of dichloromethane was added, and the insoluble material was filtered, washed with saturated brine (3*100 mL), dried, concentrated, and then recrystallized from isopropyl alcohol to give white or pale yellow solid. Intermediate. Under nitrogen protection, 200 mL of tetrahydrofuran was added to the intermediate, stirred until completely dissolved, and 10 mL of n-propylamine was added thereto. After reacting at room temperature for 24 hours, it was concentrated, and the oxygen-depleted isopropanol was recrystallized to obtain a sulfur group of white or pale yellow solid. Derivative (C2-H2-1). The structure was determined by ¹ H NMR test. M _n ≈ 20000, PDI=1.03.

The hydrogen spectrum data of the Y-type polyethylene glycol C2-H2-1 in this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 0.98 (-SiCH ₃ ), 1.38 (-SiC(CH ₃ ) ₃ ) , 1.6 (-SH), 2.85 (-OCH ₂ CH ₂ SH), 3.40-3.96 (-OCH ₂ CH ₂ O-, -OCH ₂ CH ₂ S-, -OCH(CH ₂ O) ₂ -).

Add the Y-type polyethylene glycol thio derivative C2-H2-1 obtained in the above step to a dry and clean container, dissolve it in tetrahydrofuran, and add tetra-tert-butylammonium fluoride (TBAF). After reacting overnight, Y-type polyethylene glycol C2-H1-1 was obtained. The structure was determined by ¹ H NMR test. M _n ≈ 20000, PDI=1.03.

The hydrogen spectrum data of the Y-type polyethylene glycol C2-H1-1 in this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 1.6 (-SH), 2.85 (-OCH ₂ CH ₂ SH), 3.40 -3.80 (-OCH ₂ CH ₂ O-, -OCH ₂ CH ₂ S-, -OCH(CH ₂ O) ₂ -). M _n ≈ 20000, PDI=1.03.

Example 16 Preparation of Heterofunctionalized Y-Type Polyethylene Glycol C2-C6-1

为

(对称类型，U＝

L₁＝CH₂CH₂,L₂＝CH₂CH₂,L₃＝COCH₂)，g₁＝g₂＝1,k₁＝k₂＝8,p₁＝p₂＝0,G₁＝G₂＝DENR(

NONE,3),F₁为Boc,g₃＝0,k₃＝1,F₂为CH₂CH₂SH(q＝0,Z₂不存在,q₁＝1,Z₁为CH₂CH₂,R₀₁为SH)。设计总分子量约为54kDa，其中主链分子量约为14000Da，即n₃≈318,分支链分子量约为18000Da，n₁≈n₂≈409。among them,

for

(symmetric type, U=

L ₁ =CH ₂ CH ₂ , L ₂ =CH ₂ CH ₂ , L ₃ =COCH ₂ ), g ₁ =g ₂ =1, k ₁ =k ₂ =8, p ₁ =p ₂ =0, G ₁ = G ₂ =DENR(

NONE, 3), F ₁ is Boc, g ₃ =0, k ₃ =1, F ₂ is CH ₂ CH ₂ SH (q=0, Z ₂ is absent, q ₁ =1, Z ₁ is CH ₂ CH ₂ , R ₀₁ is SH). The designed total molecular weight is about 54 kDa, wherein the main chain molecular weight is about 14000 Da, i.e., n ₃ ≈ 318, and the branched chain molecular weight is about 18,000 Da, n ₁ ≈n ₂ ≈ 409.

a. In a waterless and oxygen-free round bottom flask, after adding secondary amine 189 (7.5 mmol), dichloromethane (250 mL) and triethylamine (10 mmol), the other end of the EE-protected polyethylene glycol was slowly added dropwise. The acid chloride derivative 190 (2.5 mmol, molecular weight: about 14,000, PDI = 1.03) in dichloromethane (50 mL) was reacted at 25 ° C for 24 h, washed with water, dried, concentrated, and diethyl ether. The structure was determined by ¹ H NMR. M _n ≈ 14000, PDI=1.02.

b. In an anhydrous and oxygen-free round bottom flask, intermediate 191 (2.0 mmol), methanol (250 mL) and 10% Pd/C (10 g) were added successively, and then protected with nitrogen. After hydrogenolysis overnight at room temperature, heat was applied. The ethanol was filtered, washed, concentrated and diethyl ether afforded 129. The structure was determined by ¹ H NMR. M _n =14000, PDI=1.02.

c. In a water-free and oxygen-free closed reaction vessel, tetrahydrofuran (250 mL), intermediate 192 and diphenylmethyl potassium (4.0 mmol) were added in sequence; a calculated amount of ethylene oxide was added, and the temperature was gradually raised to 60. °C, reaction for 48 hours; add excess potassium diphenylmethyl (40 mmol), then add excess TBSCl, the reaction temperature is 30 ° C, the reaction time is 12 hours; the reaction kettle is opened, the solvent is concentrated, anhydrous at 0 ° C Precipitate in diethyl ether, filter and dry to give the main Y-type polyethylene glycol intermediate 193. The structure was determined by ¹ H NMR. M _n ≈50000, PDI=1.05.

d. Add the intermediate 193 prepared in the above step to a dry and clean container, dissolve it with tetrahydrofuran, add tetra-tert-butylammonium fluoride (TBAF), and react overnight to obtain a hydroxyl group-exposed Y-type polyethylene glycol. Body 194 (H2-H1-9).

e. Under a nitrogen-protected condition, add polyethylene glycol intermediate 194, dendrimer 195 (2 equivalents), hydroxybenzotriazole (2 equivalents), 4-dimethylaminopyridine to a dry clean round bottom flask. (2 equivalents), anhydrous dichloromethane was added and stirred to dissolve. Add (2 equivalents) of DCC and mix. The reaction was stirred overnight under nitrogen atmosphere. Concentration by evaporation, precipitation with isopropanol, filtration, and the precipitate was collected, washed with anhydrous diethyl ether and dried in vacuo to give &lt The structure was determined by ¹ H NMR. M _n ≈ 54000, PDI = 1.05.

f. Add the intermediate 196 obtained in the step f to a dry clean container, dissolve with 1 M HCl, stir at room temperature overnight, concentrate, precipitate, filter, recrystallize and dry to obtain a hydroxy-exposed Y-type polyethylene glycol. Intermediate H1-C6-1. The structure was determined by ¹ H NMR test. M _n = 64000, PDI = 1.05.

g. The thiol modification of the end of the main chain was carried out by the method of Example 15 to obtain a Y-type polyethylene glycol represented by C2-C6-1. M _n = 54000, PDI ≈ 1.05.

The hydrogen spectrum data of Y-type polyethylene glycol C2-C6-1 in this example is as follows:

¹ H NMR (CDCl ₃ ) δ (ppm): 1.38 (NCOOC(CH ₃ ) ₃ ), 1.60 (-SH), 1.79 (-CHCH ₂ CH ₂ NCO), 2.43 (-NCOCH (CH ₂ CH ₂ ) ₂ ) , 2.85 (-SCH ₂ CH ₂ -), 3.25-3.80 (-OCH ₂ CH ₂ O-, -NCOCH(CH ₂ O) ₂ -, -OCH ₂ CH(O)CH ₂ O-), 4.15 (-OCH ₂ CH ₂ OCO-), 4.24 - 4.26 (-OCH ₂ CO-, OCOCH ₂ N-).

Example 17 Preparation of a comb-branched Y-polyethylene glycol derivative

Preparation of terminal comb-branched Y polyethylene glycol derivative C7-C4-1

为

(对称类型，U＝

L₁＝L₂＝

L₃不存在)，g₁＝g₂＝1,k₁≈k₂≈25,p₁＝p₂＝0,G₁＝G₂＝

F₁为CH₂CH₂N₃(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂CH₂,R₀₁为N₃),g₃＝0,k₃＝1,F₂为CH₂CH₂SH(q＝1,Z₂为CH₂CH₂NH,q₁＝1,Z₁为COCH₂CH₂,R₀₁为

)。设计总分子量约为64kDa，其中主链分子量约为6000Da，即n₃≈136,分支链分子量约为25000Da，n₁≈n₂≈568。among them,

for

(symmetric type, U=

L ₁ =L ₂ =

L ₃ does not exist), g ₁ =g ₂ =1, k ₁ ≈k ₂ ≈25, p ₁ =p ₂ =0, G ₁ =G ₂ =

F ₁ is CH ₂ CH ₂ N ₃ (q=0, Z ₂ is absent, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ is N ₃ ), g ₃ =0, k ₃ =1, F ₂ is CH ₂ CH ₂ SH (q=1, Z ₂ is CH ₂ CH ₂ NH, q ₁ =1, Z ₁ is COCH ₂ CH ₂ , R ₀₁ is

). The designed total molecular weight is about 64 kDa, wherein the main chain molecular weight is about 6000 Da, i.e., n ₃ ≈ 136, and the branched chain molecular weight is about 25,000 Da, n ₁ ≈n ₂ ≈ 568.

A: Using the amino group modification method of H2-C3-1 in Example 2, a linear polyethylene glycol amine 251 having a protected hydroxyl group at the other end was prepared. Add 40g of polyethylene glycolamine (251) to a dry clean 1L round bottom flask, protect with nitrogen, add 400mL of anhydrous tetrahydrofuran, stir until completely dissolved, and slowly add small molecule active ester (3-(2) under ice bath. -pyridine dithio)propionic acid N-hydroxysuccinimide ester, 252,10 equivalents, and then reacted at room temperature overnight, added saturated ammonium chloride solution, concentrated, dissolved in 400 mL of water, and washed with dichloromethane ( 3*150 mL), the combined organic phases, washed with brine, dried, evaporated The structure was determined by ¹ H NMR test. M _n ≈ 6000, PDI=1.02.

B: To a solution of the intermediate 253 in tetrahydrofuran, an excess of tetra-tert-butylammonium fluoride was added and reacted overnight; an excess of potassium diphenylmethyl (20 mmol) was added, and then an excess of small molecule branched compound 254 was added, the reaction temperature The reaction was carried out at 30 ° C for 12 hours, the solvent was concentrated, and then crystallised from ethyl ether. The intermediate 255 was dissolved in dichloromethane, trifluoroacetic acid (5 eq.) was added, and the mixture was stirred and stirred, and the mixture was stirred at room temperature for 1 hr, solvent was removed, and the mixture was filtered and dried in vacuo to afford Intermediate Compound 256. The structure was determined by ¹ H NMR test.

C: The methylene chloride solution of the intermediate 256 was slowly added to the polyethylene glycol isocyanate 257 (M _n = 25000, PDI = 1.03) having a TBS-protected hydroxyl group at the other end, and the reaction was stirred at room temperature for 1 hour, methanol was added, and recrystallization was carried out. It was filtered and dried to obtain a Y-type polyethylene glycol represented by C7-H2-1. The structure was determined by ¹ H NMR. M _n ≈ 56000, PDI = 1.05.

D: To a solution of the intermediate C7-H2-1 in tetrahydrofuran, tetra-tert-butylammonium fluoride (TBAF) was added, and after reacting overnight, concentrated, filtered, filtered and dried to give a Y-type polyethylene glycol intermediate C7-H1- 1. The structure was determined by ¹ H NMR. E: To a solution of the intermediate C7-H1-1 in tetrahydrofuran, an excess of potassium diphenylmethyl (20 mmol) was added, and then an excess of small molecular branching compound 258 (k ₁ ≈k ₂ ≈ 25) was added, and the reaction temperature was The reaction was carried out for 12 hours at 30 ° C, the solvent was concentrated, and the residue was crystallised from ethyl ether (ethyl ether), filtered, recrystallized, filtered, and dried to give a hetero-functional Y-type polyethylene glycol derivative as shown by C7-C4-1. The structure was determined by ¹ H NMR. M _n ≈ 64000, PDI = 1.05.

The hydrogen spectrum data of the Y-type polyethylene glycol C7-C4-1 in this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): ¹ H NMR (CDCl ₃ ) δ (ppm): 1.66-1.70 (- _{CHCH 2 CH 2 N -, -} CH 2 N 3), 2.48 (-NCOCH 2 CH 2 S -), 2.65-2.85 (-SSCH 2 CH 2 -, - CHCH 2 CH 2 NCON -), 3.30 (-OCH 3 ), 3.35-3.67 (-OCH ₂ CH ₂ O-, -OCH ₂ CHO-).

Preparation of terminal comb-branched Y polyethylene glycol derivative G2-H1-1

为

g₁＝g₂＝1,k₁＝k₂＝15,p₁＝p₂＝0,G₁＝G₂＝

F₁为OH(q＝0,Z₂不存在,q₁＝1,Z₁＝CH₂CH₂,R₀₁为NH₂),g₃＝0,k₃＝1,F₂为

(q＝1,Z₂为CH₂,q₁＝1,Z₁为COO,R₀₁为

)。设计总分子量约为54kDa，其中主链分子量约为40000Da，即n₃≈909,分支链分子量约为5000Da，n₁≈n₂≈114。among them,

for

g ₁ =g ₂ =1, k ₁ =k ₂ =15, p ₁ =p ₂ =0, G ₁ =G ₂ =

F ₁ is OH (q=0, Z ₂ is absent, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ is NH ₂ ), g ₃ =0, k ₃ =1, F ₂ is

(q=1, Z ₂ is CH ₂ , q ₁ =1, Z ₁ is COO, R ₀₁ is

). The designed total molecular weight is about 54 kDa, wherein the main chain molecular weight is about 40,000 Da, i.e., n ₃ ≈ 909, and the branched chain molecular weight is about 5000 Da, n ₁ ≈n ₂ ≈ 114.

A: Using the preparation method of Example 2, the molar amount of ethylene oxide was changed to obtain a Y-type polyethylene glycol intermediate H2-H1-10 having the same structure as H2-H1-1. The structure was determined by ¹ H NMR test. M _n ≈50000 (n ₃ ≈ 909, n ₁ ≈n ₂ ≈ 114), PDI=1.05.

B: In a clean and sealed reactor, the intermediate H2-H1-10 is dissolved in dioxane, and diethylzinc/pyrogallol (molar ratio 2:1) dioxane solution is added and added. The metered epoxy compound (259) was protected by argon gas, CO ₂ was added under a pressure of ~20 bar, and reacted at room temperature for 72 hours, returned to atmospheric pressure, and methyl iodide was added to terminate the reaction. Diluted with dichloromethane, washed respectively with each of 10% HCl and twice with deionized water, dried over anhydrous MgSO _4, 0 deg.] C and precipitated with methanol, and dried in vacuo. The Y-type polyethylene glycol intermediate represented by 260 is obtained. The structure was determined by ¹ H NMR test. M _n ≈ 56000, PDI = 1.05.

C: The intermediate 260 obtained in the step B was added to a dry clean container, dissolved in 1 M HCl, stirred at room temperature overnight, concentrated, precipitated, filtered, recrystallized and dried to give a Y-type polyethylene glycol intermediate 261. . The structure was determined by ¹ H NMR test. M _n ≈ 56000, PDI = 1.05.

D: Using the preparation method of Example 1, the intermediate compound 261 was subjected to carboxyl modification with bromoacetic acid to obtain a carboxyl derivative 262 of Y-type polyethylene glycol. The structure was determined by ¹ H NMR test.

E: In a dry and clean 1 L round bottom flask, a Y-form intermediate (262, toluene azeotropic removal of water), 20 mL of triethylamine and 10 g of a reactive acetylene compound 263 were added, and the mixture was purged with nitrogen, and the solvent dichloromethane (200 mL) was added and stirred. To dissolve, another 20 g of dicyclohexanecarbodiimide (DCC) was added, and after reacting for 24 hours at room temperature, the insoluble matter was removed by filtration, concentrated, and recrystallized from isopropanol to give a white solid active acetyl compound (264). The structure was determined by ¹ H NMR test. M _n ≈ 56000, PDI = 1.05.

F: In a dry and clean 1 L round bottom flask, a Y-form intermediate (264) was dissolved in tetrahydrofuran, and then protected with nitrogen, and then a solution of TBAF in tetrahydrofuran (20 eq) was added thereto, and the mixture was reacted at room temperature for 24 hours, and then filtered to remove insolubles and concentrated. The isopropyl alcohol was recrystallized to give a white solid solid acetylene compound (G2-H1-1). The structure was determined by ¹ H NMR test. M _n = 54000, PDI = 1.05.

The hydrogen spectrum data of the Y-type polyethylene glycol G2-H1-1 in this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 0.96 (-CHCH ₃ ), 2.58 (-OCH ₂ CHCH ₃ ), 2.90 - 3.15 (ArCH ₂ CHO-), 3.35-3.80 (-OCH ₂ CH ₂ O-, -OCH ₂ CHO-), 4.45 (-OCH ₂ CH ₂ OCOO-), 5.63 (ArCHO-), 7.25-7.54 (Ar -H).

Example 18 Preparation of Heterofunctionalized Y-Type Polyethylene Glycol Derivative D5-E3-1

为

(不对称类型，U＝

L₁＝CH₂CH₂,L₂＝-C(＝O)CH₂-,L₃＝CH₂CH₂)，g₁＝g₂＝0,F₁为COC(CH₃)＝CH₂(q＝0,Z₂不存在,q₁＝0,Z₁不存在,R₀₁为COC(CH₃)＝CH₂),g₃＝0,k₃＝1,F₂为

(q＝1,Z₂为CH₂,q₁＝1,Z₁为对苯撑,R₀₁为CHO)。设计总分子量约40kDa，其中主链分子量约为10000Da，即n₃≈227,分支链分子量分别约为18000Da、12000Da，n₁≈409，n₂≈273。among them,

for

(Asymmetric type, U=

L ₁ =CH ₂ CH ₂ , L ₂ =-C(=O)CH ₂ -, L ₃ =CH ₂ CH ₂ ), g ₁ =g ₂ =0, F ₁ is COC(CH ₃ )=CH ₂ ( q=0, Z ₂ does not exist, q ₁ =0, Z ₁ does not exist, R ₀₁ is COC(CH ₃ )=CH ₂ ), g ₃ =0, k ₃ =1, F ₂ is

(q=1, Z ₂ is CH ₂ , q ₁ =1, Z ₁ is p-phenylene, and R ₀₁ is CHO). The designed total molecular weight is about 40 kDa, wherein the main chain molecular weight is about 10,000 Da, i.e., n ₃ ≈ 227, and the molecular weights of the branched chains are about 18,000 Da, 12,000 Da, n ₁ ≈ 409, n ₂ ≈ 273, respectively.

a. In a water-free oxygen-free round bottom flask, after adding primary amine 265 (7.5 mmol), dichloromethane (250 mL) and triethylamine (10 mmol), the polyethylene glycol sulfonate derivative was slowly added dropwise. _{266 (2.5mmol, M n = 18000} , PDI = 1.02) after methylene chloride solution (50 mL), reaction at 25 deg.] C 24h, washed with water, dried, concentrated, precipitated with diethyl ether to yield intermediate 267. The structure was determined by ¹ H NMR test. M _n ≈ 18000, PDI=1.02.

b. After adding intermediate 267 (2.0 mmol), dichloromethane (250 mL) and triethylamine (10 mmol) to an anhydrous and oxygen-free round bottom flask, the polyethylene glycol chloride derivative 268 was slowly added dropwise. After 2.5 mmol, M _n =12000, PDI=1.03) in dichloromethane (50 mL), the mixture was reacted at 25 ° C for 24 h, washed with water, dried, concentrated, and purified by anion exchange resin to obtain V-type polyethylene glycol intermediate 269. The structure was determined by ¹ H NMR test. M _n ≈30000, PDI=1.03.

c. Dissolving the V-type polyethylene glycol intermediate 269 in tetrahydrofuran, adding tetra-tert-butylammonium fluoride (TBAF), and reacting overnight, precipitating, filtering, and drying to obtain a hydroxyl-formed V-type polyethylene glycol intermediate. 270. The alkenyl group was modified by the preparation method of D5-E2-1 in Example 13 to obtain a polyethylene glycol methacrylate intermediate represented by 271. The structure was determined by ¹ H NMR test. M _n ≈30000, PDI=1.03.

d. Add the V-type polyethylene glycol intermediate 271 prepared in the step c to a dry and clean container, dissolve it with methanol, add 1 M hydrochloric acid to pH=1.0, react for 4 hours, concentrate, filter, and dry to obtain V. Type intermediate 272.

e. To a solution of the V-form intermediate 272 in tetrahydrofuran, an excess of potassium diphenylmethyl (20 mmol) was added, followed by addition of a heterofunctional linear polyethylene glycol 273 (M _n ≈ 10000, PDI=1.02), reaction temperature After reacting at 30 ° C for 12 hours, the solvent was concentrated, precipitated in anhydrous ethyl ether at 0 ° C, filtered, recrystallized, filtered, dried, and then selectively deprotected under acidic conditions using the method of Example 12 to obtain D5- A heterofunctional Y-type polyethylene glycol derivative represented by E3-1.

The hydrogen spectrum data of the Y-type polyethylene glycol D5-E3-1 in this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 2.01 (-OCOC(CH ₃ )=CH ₂ ), 3.35-3.80 ( -OCH ₂ CH ₂ O-, -OCH ₂ CH ₂ NCO-), 4.05 (-OCH ₂ CH ₂ OCO) 4.42 (NCOCH ₂ O-), 4.80 (-OCH ₂ Ar), 5.47-6.38 (-OCOC (CH) ₃ ) = CH ₂ ), 7.55-7.82 (Ar-H), 9.98 (-ArCHO). M _n ≈40000, PDI=1.05.

Example 19 Preparation of Heterofunctionalized Y-Type Polyethylene Glycol D4-C6-1

为

(对称类型，U＝

L₁＝L₂＝CH₂,L₃＝CH₂CH₂COO)，g₁＝g₂＝1,k₁≈k₂≈6,p₁＝p₂＝1,L₄＝CH₂CH₂O，G₁＝G₂＝

F₁为COCH₂NH₂(q＝1,Z₂为羰基,q₁＝1,Z₁为CH₂,R₀₁为NPG₅,具体为NHBoc,PG₅为叔丁基氧基羰基),g₃＝1,k₃＝2,p₃＝1,L₆为羰基,G₃＝

F₂为COOH(q＝0,Z₂不存在,q₁＝0,Z₁不存在,R₀₁为COOH)。设计总分子量约为43kDa，其中主链分子量约为20000Da，即n₃≈455,分支链分子量约为10000Da，n₁≈n₂≈227。Among them, in D4-C6-1,

for

(symmetric type, U=

L ₁ = L ₂ = CH ₂ , L ₃ = CH ₂ CH ₂ COO), g ₁ = g ₂ =1, k ₁ ≈ k ₂ ≈ 6, p ₁ = p ₂ =1, L ₄ = CH ₂ CH ₂ O, G ₁ = G ₂ =

F ₁ is COCH ₂ NH ₂ (q=1, Z ₂ is a carbonyl group, q ₁ =1, Z ₁ is CH ₂ , R ₀₁ is NPG ₅ , specifically NHBoc, PG ₅ is tert-butyloxycarbonyl), g ₃ =1, k ₃ = 2, p ₃ =1, L ₆ is a carbonyl group, G ₃ =

F ₂ is COOH (q = 0, Z ₂ is absent, q ₁ =0, Z ₁ is absent, and R ₀₁ is COOH). The designed total molecular weight is about 43 kDa, wherein the main chain molecular weight is about 20,000 Da, i.e., n ₃ ≈ 455, and the branched chain molecular weight is about 10,000 Da, n ₁ ≈ n ₂ ≈ 227.

a, in a water-free and oxygen-free closed reactor, adding tetrahydrofuran (125 mL), TBS-protected ethylene glycol 137b (2.5 mmol) and diphenylmethyl potassium (2.0 mmol); b, adding a calculated amount of ring Oxyethane, gradually warming to a temperature of 60 ° C, the reaction for 48 hours; adding an excess of potassium diphenylmethyl (20 mmol), then adding excess methanol (100 mmol), the reaction temperature is 30 ° C, the reaction time is 12 hours; The reaction kettle was opened, and the solvent was concentrated, and then precipitated in anhydrous diethyl ether at 0 ° C, filtered, and dried to obtain a V-type polyethylene glycol intermediate 274 protected with hydroxysilicon ether at both ends. The structure was determined by ¹ H NMR test. M _n ≈ 20000, PDI=1.03.

b. In a water-free and oxygen-free closed reaction vessel, tetrahydrofuran (125 mL), V-form intermediate 274 (2.5 mmol) and diphenylmethyl potassium (8.0 mmol) were added in sequence; and the calculated amount of EEGE 275 (Ethoxy ethyl) was added. Glycidyl ether), gradually warmed to a temperature of 60 ° C, the reaction was carried out for 48 hours; an excess of potassium diphenylmethyl (20 mmol) was added, then an excess of methyl iodide (50 mmol) was added, the reaction temperature was 30 ° C, and the reaction time was 12 hours; The reaction kettle was opened, and the solvent was concentrated, then precipitated in anhydrous ethyl ether (EtOAc), filtered, and dried to give the V-type polyethylene glycol intermediate 276. The structure was determined by ¹ H NMR test. M _n ≈ 22000, PDI=1.03. k ₁ ≈k ₂ ≈6.

d. Add the V-type polyethylene glycol intermediate 276 prepared in the step b to a dry and clean container, dissolve it with methanol, add 1 M hydrochloric acid to pH = 1.0, and react for 4 hours to obtain a V-form intermediate 277.

e. Add a V-form intermediate 277 and 1.5 equivalents of N-(tert-butoxycarbonyl)glycine (Boc-glycine, Boc-Gly) in anhydrous DCM to a dry clean round bottom flask, and add 1.5 equivalents of dichloroethane. Alkane (EDC), 0.5 equivalents of 4-dimethylaminopyridine (DMAP). The reaction was stirred for about 2 h under ice water bath conditions. The solution was washed successively with a saturated NaHCO ₃ solution, ultrapure water, 0.1 NHCl solution, and 20 mM NaCl. _Organic phase was dried over MgS04, filtered, concentrated by evaporation in vacuo, to give intermediate V-278. The structure was determined by ¹ H NMR test. M _n ≈ 22600, PDI=1.03.

f. Add the intermediate 278 prepared in the above step to a dry and clean container, dissolve it in tetrahydrofuran, add tetra-tert-butylammonium fluoride (TBAF), and react overnight to obtain a V-type polyethylene glycol with a hydroxyl group exposed. Body 279.

g, a solution of the intermediate 279 in dichloromethane was slowly added to the other end of the TBS-protected hydroxyl group of polyethylene glycol isocyanate 280 (M _n ≈ 20000, PDI = 1.03), stirred at room temperature for 1 h, added methanol, recrystallized, It was filtered and dried to obtain a Y-type polyethylene glycol represented by 281. Dissolved in tetrahydrofuran, tetra-tert-butylammonium fluoride (TBAF) was added, and after reacting overnight, a Y-type polyethylene glycol intermediate 282 was obtained. The structure was determined by ¹ H NMR. M _n ≈ 43000, PDI = 1.05.

h. The intermediate 282 was modified to the succinimide carbonate derivative 283 by the method of preparing A6-H2-1 in Example 1.

i. Add Y-type polyethylene glycol succinimide carbonate derivative 283 to a dry and clean round bottom flask, protect with nitrogen, add pH to 8.0 by adding PBS buffer, and add excess glutamic acid in PBS. The buffer solution was shaken, shaken at room temperature for 4 hours, and shaken at 4 ° C for 12 hours. Concentrate, filter, recrystallize, filter, and dry. The heterofunctional Y-type polyethylene glycol represented by D4-C6-1 was obtained. The structure was determined by ¹ H NMR. M _n ≈ 43000, PDI = 1.05.

The hydrogen spectrum data of the Y-type polyethylene glycol D4-C6-1 in this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): NMR (CDCl ₃ ) δ (ppm): 1.38 (-C (CH _{3 ) 3} ), 2.03-2.25 (HOOCCH ₂ CH ₂ CH-), 3.30 (-OCH ₃ ), 3.35-4.45 (-OCH ₂ CH ₂ O-, -OCH ₂ CH ₂ NCO-, -OCH(CH ₂ O) _{2 -, - OCH 2 CH 2} OCO -, - OCOCH 2 NHBoc).

Example 20 Preparation of Heterofunctionalized Y-Type Polyethylene Glycols H1-D16-1, H1-D16-2

为

(对称类型，U＝

L₁、L₂不存在,L₃＝

)，g₁＝g₂＝0,F₁为CH₂CH₂C(＝S)OCH₂CH₃(q＝0,Z₂不存在,q₁＝1,Z₁为CH₂CH₂,R₀₁为C(＝S)OCH₂CH₃),g₃＝0,F₂为CH₂CH₂OH(q＝0,Z₂不存在,q₁＝1,Z₁为CH₂CH₂,R₀₁为OH)。设计总分子量约为70kDa，其中主链分子量约为10000Da，即n₃≈227,分支链分子量约为30000Da，n₁≈n₂≈682。 among them,

for

(symmetric type, U=

L ₁ , L _{2 are} not present, L ₃ =

), g ₁ =g ₂ =0, F ₁ is CH ₂ CH ₂ C(=S)OCH ₂ CH ₃ (q=0, Z ₂ is absent, q ₁ =1, Z ₁ is CH ₂ CH ₂ ,R ₀₁ is C(=S)OCH ₂ CH ₃ ), g ₃ =0, F ₂ is CH ₂ CH ₂ OH (q=0, Z ₂ is absent, q ₁ =1, Z ₁ is CH ₂ CH ₂ ,R ₀₁ is OH). The designed total molecular weight is about 70 kDa, wherein the main chain molecular weight is about 10,000 Da, i.e., n ₃ ≈227, and the molecular weight of the branched chain is about 30,000 Da, n ₁ ≈n ₂ ≈ 682.

A, 1 L reaction flask was charged with Fmoc-protected substituted phosphoryl chloride, 500 mL of THF, and a linear polyethylene glycol 284 (2 molar equivalent) in THF was added dropwise under ice bath. After the dropwise addition, the mixture was stirred at room temperature for 5 hours, concentrated, and then recrystallized from isopropyl alcohol to afford white s. The structure was determined by ¹ H NMR. M _n ≈60000, PDI=1.05.

B. Add a V-type polyethylene glycol phosphate derivative intermediate (285) to a dry and clean 1 L round bottom flask. After dissolving in dichloromethane, add piperidine, react at room temperature for 3 hours, concentrate, and add PH=8. After the buffer solution was dissolved, the aldehyde (286) was added, and the mixture was stirred at room temperature for 3 hours. Then, sodium cyanoborohydride was added thereto, and the mixture was reacted at room temperature for 24 hours, and then the insolubles were removed by filtration, extracted with dichloromethane, dried, concentrated, and concentrated. Crystallization gave a Y-type polyethylene glycol compound containing an imine bond as a white solid H2-D16-1. The structure was determined by ¹ H NMR. M _n ≈70000, PDI=1.06.

C: The intermediate H2-D16-1 was dissolved in tetrahydrofuran, and tetra-tert-butylammonium fluoride (TBAF) was added. After reacting overnight, Y-type polyethylene glycol H1-D16-1 was obtained. The structure was determined by ¹ H NMR. M _n ≈70000, PDI=1.06.

D. In a water-free oxygen-free round bottom flask, polyethylene glycol H1-D16-1 (7.5 mmol) and methanol (250 mL) were added successively, then sodium cyanoborohydride (20 mmol) was added, and the reaction was carried out at 25 ° C for 24 h. Thereafter, it was washed with water, dried, concentrated, and dialyzed against water to give H1-D16-2.

The hydrogen spectrum data of the Y-type polyethylene glycol H1-D16-2 of this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 1.10 (-OCH ₂ CH ₃ ), 1.94 (-OCH ₂ CH ₂ CSO- ), 2.74 (-NHCH ₂ CH ₂ O-), 3.30 (-OCH ₃ ), 3.40-3.87 (-OCH ₂ CH ₂ O-, -OCH ₂ CH _{3 ,} -OCH ₂ CH ₂ CSO-, -ArCH ₂ NH -), 4.80 (-ArCH ₂ O-), 7.11-7.16 (Ar-H). M _n ≈70000, PDI=1.06.

Example 21 Preparation of Heterofunctionalized Y-Type Polyethylene Glycol C3-D4-4

为

(不对称类型，U＝

L₁、L₂为NHC(＝S)NHCH₂CH₂,L₃为CH₂CH₂S)，g₁＝g₂＝0,F₁为 COCH₂CH₂C(＝O)NHCH₂COOH(q＝1,Z₂为COCH₂CH₂C(＝O),q₁＝1,Z₁为NHCH₂,R₀₁为COOH),g₃＝0,F₂为CH₂CH₂NH₂(q＝0,Z₂不存在,q₁＝1,Z₁为CH₂CH₂,R₀₁为NH₂)。设计总分子量约为61kDa，其中主链分子量约为20000Da，即n₃≈455分支链分子量约为20000Da，n₁≈n₂≈455。Among them, in C3-D4-4,

for

(Asymmetric type, U=

L ₁ , L ₂ are NHC(=S)NHCH ₂ CH ₂ , L ₃ is CH ₂ CH ₂ S), g ₁ =g ₂ =0, and F ₁ is COCH ₂ CH ₂ C(=O)NHCH ₂ COOH ( q=1, Z ₂ is COCH ₂ CH ₂ C(=O), q ₁ =1, Z ₁ is NHCH ₂ , R ₀₁ is COOH), g ₃ =0, F ₂ is CH ₂ CH ₂ NH ₂ (q =0, Z ₂ is absent, q ₁ =1, Z ₁ is CH ₂ CH ₂ , and R ₀₁ is NH ₂ ). The designed total molecular weight is about 61 kDa, wherein the main chain molecular weight is about 20,000 Da, that is, the n ₃ ≈ 455 branched chain molecular weight is about 20,000 Da, n ₁ ≈ n ₂ ≈ 455.

Wherein, in C6-D4-4, U, L ₁ , L ₂ , L ₃ , g ₁ , g ₂ , F ₁ , g ₃ , n ₁ , n ₂ , n _{3 have} the same definitions as C3-D4-4, F ₂ is CH ₂ CH ₂ NPG ₅ (q=0, Z ₂ is absent, q ₁ =1, Z ₁ is CH ₂ CH ₂ , R ₀₁ is NPG ₅ , specifically NHBoc, PG ₅ is tert-butyloxy Carbonyl). Design total molecular weight is about 61kDa

a. Add the Fmoc-protected lysine acid chloride derivative (288, 20 equivalents) to a solution of heterofunctionalized linear polyethylene glycol thiol (287) in dichloromethane, and react at room temperature for 24 hours. after quenched with saturated ammonium chloride, saturated brine, dried, concentrated, and recrystallized to give a white intermediate (289), whose structure was characterized by _{H-NMR, M n ≈20000,} PDI = 1.02.

b. In a round bottom flask, add intermediate (289), protect with nitrogen, add dichloromethane to dissolve, slowly add piperidine (20 equivalents), react at room temperature for 6 hours, then add hetero-functionalized polyethylene. alcohol isothiocyanate compound (290,2.2 equiv). after 24 hours at room temperature, concentrated, membrane filtration, to give a white solid (291), to determine the structure of ¹ H NMR. M _n ≈60000, PDI=1.06.

c. After adding the compound (291) to the round bottom flask, the solution was dissolved in tetrahydrofuran, and then added to a solution of TBAF in tetrahydrofuran (20 equivalents), concentrated, washed with saturated brine, and then toluene and succinic anhydride were added and refluxed at 110 ° C. After 16 hours, it was returned to room temperature, acidified to pH = 3, extracted with dichloromethane, dried, concentrated and recrystallised. Dried over anhydrous dichloromethane and added glycine tert-butyl ester measurement, measurement of DMAP, the DCC, the reaction, to give a white intermediate (C6-D4-4), whose structure was characterized by H-NMR, M _n ≈20000, PDI=1.06.

The hydrogen spectrum data of the derivative C6-D4-4 is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 1.29-1.58 (-OC(CH ₃ ) ₃ , -SCOCHCH ₂ CH ₂ CH ₂ CH ₂ NH- ), 2.40-2.85 (-SCOCHCH ₂ -, -CH ₂ CH ₂ NHCSNH-, -OCOCH ₂ CH ₂ COOH), 2.95-3.04 (-OCH ₂ CH ₂ S-, BocNHCH ₂ CH ₂ O-), 3.40-3.87 (-OCH ₂ CH ₂ O-, -OCH ₂ CH ₂ S-), 4.45 (-CONHCH ₂ COOH).

d. After adding the compound (C6-D4-4) to the round bottom flask, after nitrogen protection, add dichloromethane to dissolve, and then slowly add trifluoroacetic acid (20 equivalents) under ice bath, and slowly return to room temperature. After reacting for 24 hours, it was dissolved in purified water, extracted with dichloromethane, dried, concentrated, and recrystallized to give Compound C3-D4-4.

The hydrogen spectrum data of the derivative C3-D4-4 is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 1.29-1.58 (-SCOCHCH ₂ CH ₂ CH ₂ CH ₂ NH-), 2.40-2.85 (-SCOCHCH ₂ -, -CH ₂ CH ₂ NHCSNH-, -OCOCH ₂ CH ₂ COOH), 2.95-3.04 (-OCH ₂ CH ₂ S-, BocNHCH ₂ CH ₂ O-), 3.40-3.87 (-OCH ₂ CH ₂ O- , -OCH ₂ CH ₂ S-), 4.45 (-CONHCH ₂ COOH).

Example 22 Preparation of Heterofunctionalized Y-Type Polyethylene Glycol C7-E4-1

为

(对称类型，U＝

L₁、L₂为OC(＝O)NHCH₂CH₂,L₃为

)， g₁＝g₂＝0,F₁为

g₃＝0,F₂为CH₂CH₂SPG₂(q＝0,Z₂不存在,q₁＝1,Z₁为CH₂CH₂,R₀₁为SPG₂,PG₂为叔丁基二甲基硅基)。设计总分子量约为71kDa，其中主链分子量约为10000Da，即n₃≈227,分支链分子量约为30000Da，n₁≈n₂≈682。Among them, in C7-E4-1,

for

(symmetric type, U=

L ₁ and L ₂ are OC(=O)NHCH ₂ CH ₂ , and L ₃ is

), g ₁ =g ₂ =0, F ₁ is

g ₃ =0, F ₂ is CH ₂ CH ₂ SPG ₂ (q=0, Z ₂ is absent, q ₁ =1, Z ₁ is CH ₂ CH ₂ , R ₀₁ is SPG ₂ , and PG ₂ is tert-butyl Methylsilyl). The designed total molecular weight is about 71 kDa, wherein the main chain molecular weight is about 10,000 Da, i.e., n ₃ ≈227, and the molecular weight of the branched chain is about 30,000 Da, n ₁ ≈n ₂ ≈ 682.

a. In a round bottom flask, a small molecule aldehyde 293 was added, protected with nitrogen, dissolved in dichloromethane, and an isocyanate derivative (294, 30 kD) was slowly added dropwise in an ice bath, and then returned to room temperature, after reacting for 8 hours. addition of excess activated silica gel, filtered, concentrated, and recrystallized to give intermediate 295, which is determined by the structure _{^{1 H-NMR, M n ≈60000}} , PDI = 1.06.

b. After adding polyethylene glycol propionaldehyde derivative 295 to a dry clean round bottom flask, add acetonitrile, stir at room temperature until completely dissolved, replace nitrogen, add hydroxylamine hydrochloride, and add sodium acetate to adjust to PH. After =8, the reaction was allowed to proceed overnight at room temperature, concentrated, and diethyl ether precipitated.

The crude product of the previous step was dissolved in N,N-dimethylformamide in a dry clean round bottom flask, and after replacing nitrogen, solid NCS (4 mmol) was added, and after reacting at room temperature overnight, saturated sodium hydrogencarbonate solution was added. After stirring for 4 hours at room temperature, it was diluted with a large amount of dichloromethane, washed with brine, dried, concentrated and evaporated. This product is used directly in the next step.

c. Add the polyethylene glycol cyanide 296 obtained in the above step to a dry clean 500 mL round bottom flask, add acetonitrile, stir at room temperature until completely dissolved, and slowly add the heterofunctionalized linear polyethylene glycol (297). after M _n ≈10000, the PDI = 1.02) in acetonitrile (100mL), 4 th hours of reaction at room temperature, concentrated, recrystallized from isopropanol to give the compound C7-E4-1.

The hydrogen spectrum data of the derivative C7-E4-1 is as follows:

¹ H NMR (CDCl ₃ ) δ (ppm): 0.08 (-SiCH ₃ ), 0.98 (-SiC(CH ₃ ) ₃ ), 1.24-2.13 (L3-H), 2.70-2.80 (TBSSCH ₂ CH ₂ O-, -NCH ₂ CH ₂ O-), 3.02-3.07 (-CHCHCO-, -OCONHCH ₂ CH ₂ O-), 3.40-3.87 (-OCH ₂ CH ₂ O-, -OCH ₂ CH ₂ N-), 4.65 (- CH ₂ CHO-), 5.78 (-CH=CH-).

Example 23 Preparation of Heterofunctionalized Y-Type Polyethylene Glycol B3-A1-1

为

(不对称类型，U＝

L₁、L₂为SC(＝O)NHCH₂CH₂,L₃为

)，g₁＝g₂＝0,F₁为(CH₂)₅CONHS(q＝0,Z₂不存在,q₁＝1,Z₁为(CH₂)₅,R₀₁为CONHS),g₃＝0,F₂为

设计总分子量约为32kDa，其中主链分子量约为30000Da，即n₃≈682,分支链聚乙二醇具有单分散性，n₁＝n₂＝12。Among them, in B3-A1-1,

for

(Asymmetric type, U=

L ₁ and L ₂ are SC(=O)NHCH ₂ CH ₂ , and L ₃ is

), g ₁ =g ₂ =0, F ₁ is (CH ₂ ) ₅ CONHS (q=0, Z ₂ is absent, q ₁ =1, Z ₁ is (CH ₂ ) ₅ , R ₀₁ is CONHS), g ₃ =0, F ₂ is

The designed total molecular weight is about 32 kDa, wherein the main chain molecular weight is about 30,000 Da, i.e., n ₃ ≈ 682, and the branched polyethylene glycol has monodispersity, n ₁ = n ₂ = 12.

The synthesis steps are as follows:

a. In a round bottom flask, after adding diamine hydrochloride (298), add anhydrous dichloromethane to dissolve, add triethylamine to alkaline, and slowly add monodisperse active ester derivative (299, n ₁ =n ₂ =12), after reacting at room temperature for 24 hours, the ion exchange resin was purified to obtain Intermediate 300, which was identified by ¹ H-NMR.

b. In a round bottom flask, add intermediate 300, nitrogen protection, dissolved in anhydrous dichloromethane, then slowly add trifluoroacetic acid under ice bath, react at room temperature for 3 hours, wash with water, and dry. After concentration, after adding a buffer solution of pH=8.0, the thiol compound 301 (M _n ≈30000 Da) was added, and the mixture was reacted at room temperature for 16 hours, extracted with dichloromethane, dried, concentrated, and recrystallized to give a white solid 302. this compound was identified by the ¹ _{H-NMR, M n ≈32000Da, PDI = 1.04} .

c. In a round bottom flask, compound 302 was added, protected with nitrogen, dissolved in anhydrous dichloromethane, and after adding NHS and DCC, the mixture was reacted at room temperature for 16 hours, concentrated, and recrystallized to give compound B3-A3-1.

The hydrogen spectrum data of the derivative B3-A3-1 are as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 1.25-1.92 (-NCH ₂ CH ₂ CH ₂ CH ₂ CH<, -OCOCH ₂ CH ₂ CH ₂ CH ₂ CO), 2.30-2.55 (-(CO) ₂ NCH ₂ CH ₂ -, Ar-CH ₃ , -OCH ₂ CH ₂ CONH-), 2.59-2.80 (-(O=)CCH ₂ CH ₂ C(=O , OCOCH ₂ CH ₂ CH ₂ CH ₂ CH<, -CH ₂ CH ₂ S-)-, 2.94 - 3.19 (-NCOCH ₂ CH <, ArCOCH <), 3.40-3.87 (-OCH ₂ CH ₂ O-, -OCH ₂ CH ₂ N-, -SCHCO(CH ₂ )-), 7.40-8.11 (Ar-H).

Example 24 Preparation of Heterofunctionalized Y-Type Polyethylene Glycol G4-C3-1

为

(对称类型，U＝

L₁、L₂为羰基,L₃为

)，g₁＝g₂＝0,F₁为CH₂CH₂NH₂(q＝0,Z₂不存在,q₁＝1,Z₁为CH₂CH₂,R₀₁为NH₂),g₃＝0,F₂为

设计总分子量约为31kDa，其中主链分子量约为30000Da，即n₃≈682,分支链聚乙二醇具有单分散性，n₁＝n₂＝9。among them,

for

(symmetric type, U=

L ₁ and L ₂ are a carbonyl group, and L ₃ is

), g ₁ =g ₂ =0, F ₁ is CH ₂ CH ₂ NH ₂ (q=0, Z ₂ is absent, q ₁ =1, Z ₁ is CH ₂ CH ₂ , R ₀₁ is NH ₂ ), g ₃ =0, F ₂ is

The designed total molecular weight is about 31 kDa, wherein the main chain molecular weight is about 30,000 Da, i.e., n ₃ ≈ 682, and the branched polyethylene glycol has monodispersity, n ₁ = n ₂ = 9.

The synthesis steps are as follows:

a. In the round bottom flask, the active ester compound 304 was added, protected with nitrogen, dissolved in dichloromethane, slowly dropped into a dichloromethane solution of small molecule amine 303, reacted at room temperature for 24 hours, concentrated, and subjected to column chromatography. After purification, a clear liquid 305 was obtained which was determined by ¹ H-NMR.

b. In a round bottom flask, after adding compound 305, dissolving in dichloromethane, adding piperidine, reacting at room temperature for 5 hours, concentrating, adding cuprous iodide, protecting with nitrogen, adding oxygen-depleted After the DMSO was dissolved, the azide compound 307 was added, and the mixture was heated to 60 ° C for 16 hours. After adding pure water, the mixture was extracted with dichloromethane, washed with saturated brine, dried, and recrystallized to give a white solid G4-C3-1. .

The hydrogen spectrum data of the derivative G4-C3-1 are as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 2.73 - 2.85 (Ar-CH ₂ -, OCH ₂ CH ₂ NH ₂ ), 3.04 (-OCONHCH ₂ CH ₂ O-), 3.40-3.97 (-OCH ₂ CH ₂ O-, -OCH ₂ CH ₂ N-, -OCH(CH ₂ N-) ₂ ), 4.25 (-OCOCH ₂ CH ₂ O-), 5.10-5.83 (CH=CH, CH=CH-), 7.50 (Ar-H).

Example 25 Preparation of Heterofunctionalized Y-Type Polyethylene Glycol H1-H2-9

为对称类型，g₁＝g₂＝g₃＝0,k₁＝k₂＝k₃＝1,F₁＝CH₂CH₂OTBS(q＝0,Z₂不存在,q₁＝0,Z₁＝CH₂CH₂,R₀₁＝OTBS),F₂＝CH₂CH₂OH(q＝0,Z₂无,q₁＝1,Z₁＝CH₂CH₂,R₀₁＝OH)。设计总分子量约为41kDa，其中主链具有单分散性，n₃＝16，分支链分子量约为20000Da，n₁≈n₂≈455。among them,

For the symmetry type, g ₁ = g ₂ = g ₃ =0, k ₁ = k ₂ = k ₃ =1, F ₁ = CH ₂ CH ₂ OTBS (q = 0, Z ₂ does not exist, q ₁ =0, Z ₁ =CH ₂ CH ₂ , R ₀₁ =OTBS), F ₂ =CH ₂ CH ₂ OH (q=0, Z _{2 is} absent, q ₁ =1, Z ₁ =CH ₂ CH ₂ , R ₀₁ =OH). The designed total molecular weight is about 41 kDa, wherein the main chain is monodisperse, n ₃ = 16, and the molecular weight of the branched chain is about 20,000 Da, n ₁ ≈n ₂ ≈ 455.

A: A preparation method of H1-H2-1 was carried out by using Example 1, and a V-form intermediate 308 was prepared using Compound 307 as a small molecule initiator. The structure was determined by ¹ H NMR. M _n ≈40000, PDI=1.04.

B: The V-type polyethylene glycol intermediate 308 was dissolved in tetrahydrofuran, and hydrochloric acid was added to pH = 1. After reacting overnight, it was precipitated, filtered, and dried to obtain a V-type polyethylene glycol intermediate 309.

C: After adding 309, dichloromethane (250 mL) and triethylamine (10 mmol) in an anhydrous oxygen-free round bottom flask, the polyethylene glycol sulfonate derivative 310 (2.5 mmol, single) was slowly added dropwise. After dispersing, 16-mer) dichloromethane solution (50 mL), the reaction was carried out at 25 ° C for 24 h, washed with water, dried, concentrated, and diethyl ether precipitated to afford Y-type polyethylene glycol intermediate 311. The structure was determined by ¹ H NMR test. M _n ≈ 41kDa, PDI=1.04.

D: Y-type polyethylene glycol intermediate 311 was dissolved in tetrahydrofuran, tetra-tert-butylammonium fluoride (TBAF) was added, and after reacting overnight, it was precipitated, filtered, and dried to obtain a hydroxyl group-exposed Y-type polyethylene glycol intermediate. H1-H2-9.

The hydrogen spectrum data of the Y-type polyethylene glycol H1-H2-9 in this example is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): ¹ H NMR (CDCl ₃ ) δ (ppm): 0.09 (-SiCH ₃ ), 1.38-1.40 (-SiC(CH ₃ ) ₃ ,CH ₃ C(CH ₂ ) ₂ -), 2.73-2.90 (-OCH ₂ CH ₂ S-, -CCH ₂ S-), 3.40-3.87 (-OCH ₂ CH ₂ O-, -OCH(CH ₂ O) ₂ -), 4.49 (-C≡CCH ₂ O-); M _n ≈ 41 kDa, PDI = 1.04.

Example 26 Preparation of a heterofunctionalized Y-type polyethylene glycol modified irinotecan having a targeting group (amide linkage)

Step a: Preparation of irinotecan-glycine-Boc (Compound 201, IRES-Gly-Boc): 294 mg of irinotecan (compound 200, 0.5 mmol, 1 equivalent), 175 mg were sequentially added 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 201 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 hydrochloride (Compound 202, IRES-GlyHCl): To a dry clean 100 mL round bottom flask was charged 2.23 g (3 mmol) of irinotecan-glycine-Boc (Compound 201, 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 201 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 EtOAc (EtOAc) elute The structure was determined by NMR.

Step c, Preparation of Y-type polyethylene glycol modified glycine-irinotecan with protected amino group (PG ₅ NY-PEG-(Gly-IRES) ₂ , compound 203): dry clean 100 mL round bottom flask 20 mL of an anhydrous DCM solution of 6.1 g (0.1 mmol, 1 equivalent of carboxyl group) of a heterofunctional Y-type polyethylene glycol carboxylic acid (Compound C6-D4-4, 61 kDa, prepared in Example 21) was added thereto, followed by the addition of 272 mg of irinotene. Kang-glycine hydrochloride (Compound 201, 0.4 mmol, 2 equivalents), 244 mg (2 mmol, 10 equivalents) of DMAP, 10 equivalents of 50% ethyl acetate. 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 203 was obtained. The structure was determined by NMR.

Step d, Preparation of Y-type polyethylene glycol modified glycine-irinotecan having a naked amino group (NH ₂ -Y-PEG-(Gly-IRES) ₂ , compound 204): Compound 203 obtained in step c is 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 concentrated with diethyl ether. The supernatant was poured out, and the mixture was evaporated to dryness, filtered, washed with diethyl ether and evaporated. Compound 204 was obtained. The structure was determined by NMR test. It was tested by high performance liquid chromatography with a molecular weight of approximately 62 kDa.

Step e, Preparation of folic acid-Y-type polyethylene glycol-bis(glycine-irinotecan) (Compound 205): To a 100 mL dry clean round bottom flask was charged 6.2 g of compound 204 (0.1 mmol), 52.7 mg of folic acid ( 0.12 mmol, 1.2 eq.), 18.3 mg of 4-dimethylaminopyridine (0.15 mmol, 1.5 eq.), a mixture of 30 mL of anhydrous dichloromethane and 6 mL of dimethylformamide was added and mixed, and 41.2 mg (0.2) was added. Methyl, 2 equivalents of DCC, 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 205. The structure was determined by NMR. It was tested by high performance liquid chromatography with a molecular weight of approximately 62 kDa.

Example 27 Preparation of a heterofunctionalized Y-type polyethylene glycol modified irinotecan having a fluorophore (amide linkage)

Preparation of Rhodamine B-Y type polyethylene glycol-bis(glycine-irinotecan) was prepared by the preparation method of Example 26, in which rhodamine B (compound 206) was used instead of the compound folic acid molecule (product 207).

The structure of product 207 is as follows:

Example 28 Preparation of a heterofunctionalized Y-type polyethylene glycol succinimide active ester derivative modified irinotecan (urethane linkage)

2 g of heterofunctional Y-type polyethylene glycol succinimide active ester derivative (H1-A6-1, molecular weight about 40 kDa, prepared in Example 2, 0.05 mol, 1 equivalent activity) was added to a dry clean 100 mL round bottom flask. Site), nitrogen protection, pH was adjusted to pH 8.0 by adding PBS buffer, and 15 mL of irinotecan-glycine hydrochloride (Compound 202, IRES-GlyHCl, 0.15 mol, 1.5 equivalents) in PBS buffered saline was added. The pH was adjusted to pH = 8.0, the reaction was shaken at 25 ° C for 4 hours, the reaction was shaken at 4 ° C for 12 hours, and the reaction was terminated by adding 3 ml of a glycine solution. The concentration of the Y-type polyethylene glycol was diluted to 0.5 mg/mL with a PBS buffered saline solution of pH=8.0, and then purified by agarose gel exchange resin to collect the heterofunctional polyethylene glycol-modified irinotecan. Concentrated by ultrafiltration. The GPC characterization results showed that there was no free PEG molecule; the purity was determined by SDS-PAGE electrophoresis, and the purity of the polyethylene glycol modified product was above 97%.

The structure of the polyethylene glycol modified product is as follows, wherein the main chain has a molecular weight of about 20,000 Da, i.e., n ₃ ≈ 455, and a branched chain molecular weight of about 10,000 Da, n ₁ ≈n ₂ ≈ 227.

Example 29 Preparation of a heterofunctionalized Y-type polyethylene glycol succinimide active ester derivative modified interferon alpha-2a (amide linkage)

800 mg (about 2 times molar ratio) of a heterofunctionalized Y-type polyethylene glycol succinimide active ester derivative (A1-H1-1, molecular weight of about 20 kDa, prepared in Example 1) was added to a dry clean 50 mL round bottom flask. ), nitrogen protection, pH was adjusted to pH 8.0 by adding PBS buffer, 8 mL of interferon α-2a (NH ₂ -IFN) in PBS buffered saline was added, and the reaction was shaken at 25 ° C for 4 hours at 4 ° C. The reaction was shaken for 12 hours, and the reaction was terminated by adding 1.5 ml of a 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 monomeric and dimeric components were separately collected and concentrated by ultrafiltration. MALDI-TOF-MS test showed that the molecular weight of the monomeric product (1 molecule of interferon combined with 1 point of polyethylene glycol) and the double product (1 molecule of interferon combined with 2 molecules of Y-type polyethylene glycol) were about 39kDa and 59kDa, respectively; The GPC characterization of the monomeric product showed no free PEG molecule; the purity of the monomeric product was determined by SDS-PAGE electrophoresis, and the purity of the modified polyethylene glycol product was over 97%.

The structure of the monomeric product is as follows, wherein the main chain has a molecular weight of about 10,000 Da, i.e., n ₃ ≈227, and the molecular weight of the branched chain is about 5000 Da, n ₁ ≈n ₂ ≈ 114.

Example 30 Preparation of Recombinant Human Granulocyte Colony Stimulating Factor (rhG-CSF) Modified with Heterofunctionalized Y-Glycolaldehyde Derivatives (Secondary Amine Bonding)

600 mg (about 1.5 times molar ratio) of a heterofunctional Y-type polyethylene glycol aldehyde derivative (D5-H1-1, molecular weight about 20 kDa, Example 12) was added to a dry clean 50 mL round bottom flask with nitrogen protection. Add PBS buffer to adjust the pH to pH=5.0, add 6mL rhG-CSF in PBS buffered saline solution, react at room temperature for 4 hours, add sodium cyanoborohydride, react at room temperature for about 24 hours, and add saturated ammonium chloride solution to quench Diluted with water to a protein concentration of about 0.1 mg/mL. Adjust the pH to about 5.0 with dilute hydrochloric acid, and elute with a gradient of 0-0.5 mol/L NaCl solution (containing 20 mmol/L NaAc, pH 5.0) by Resource S ion exchange column chromatography to collect mono- and double-polymerized 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 monomeric product (1 molecule of rhG-CSF combined with 1 molecule of Y-type polyethylene glycol) and the double-polymerized product (1 molecule of rhG-CSF combined with 2 molecules of Y-type polyethylene glycol) were approximately It is 39kDa, 59kDa; the GPC characterization of the monomeric product shows that there is no free PEG molecule; the purity of the monomeric product is determined by SDS-PAGE electrophoresis, and the purity of the modified polyethylene glycol product is above 97%.

The structure of the monomeric product is as follows, wherein the main chain has a molecular weight of about 8000 Da, i.e., n ₃ ≈ 182, and the molecular weight of the branched chain is about 6000 Da, n ₁ ≈ n ₂ ≈ 136.

Example 31 Preparation of a heterofunctionalized Y-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 220 mg (about 1.1 times molar ratio) of heterofunctional Y-type polyethylene glycol maleimide derivative (H1-E1-1, molecular weight about 40 kDa, implementation 2), reaction at 4 ° C for 24 h Add the cysteine solution to dilute at room temperature for 2 h, and dilute 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 polyethylene glycol modified component of single molecule exenatide and bimolecular exenatide was concentrated by Sephadex G25 desalting chromatography and ultrafiltration. Different components were subjected to SDS-PAGE electrophoresis and high performance liquid chromatography. The results showed that the molecular weights of the single-molecule exenatide and the double-molecule exenatide polyethylene glycol modified product were about 44 kDa and 48 kDa, respectively, and the purity was 97% or more.

Example 32 Preparation of folate-targeted Y-type polyethylene glycol modified irinotecan

L＝CH₂CH₂CONH,D＝Gly-IRES),D₃＝CH₂CH₂NHCO-FA(q＝0,Z₂不存在,L＝CH₂CH₂NHCO,D＝FA)。Wherein U, L ₁ , L ₂ , L ₃ , n ₁ , n ₂ , n ₃ , g ₁ , g ₂ , p ₁ , p ₂ , G ₁ , G ₂ , k ₁ , k ₂ , g ₃ , k The definition of ₃ is consistent with C6-D4-1, D ₁ = D ₂ = COCH ₂ CH ₂ CONH-Gly-IRES (q = 1, Z ₂ =

L = CH ₂ CH ₂ CONH, D = Gly-IRES), D ₃ = CH ₂ CH ₂ NHCO-FA (q = 0, Z ₂ is absent, L = CH ₂ CH ₂ NHCO, D = FA).

Using the method of Example 26, the C6-D4-1 (molecular weight about 25 kDa) prepared in Example 8 was used instead of the compound C6-D4-4 to prepare a folic acid-targeted Y-type polyethylene glycol-modified irinotecan (compound 208). ). The structure was determined by NMR. It was tested by high performance liquid chromatography with a molecular weight of approximately 28 kDa.

Example 33 Preparation of folate-targeted Y-type polyethylene glycol modified irinotecan

Using the method of Example 26, the C6-D4-3 (molecular weight about 32 kDa) prepared in Example 10 was used instead of the compound C6-D4-4 to prepare a folic acid-targeted Y-type polyethylene glycol-modified irinotecan (compound 209). ). The structure was determined by NMR. It was tested by high performance liquid chromatography with a molecular weight of approximately 35 kDa.

In compound 207, definitions of U, L ₁ , L ₂ , L ₃ , n ₁ , n ₂ , n ₃ , g ₁ , g ₂ , k ₁ , k ₂ , g ₃ , p ₃ , k ₃ and C6-D4 -3 consistent, D ₁ = D ₂ = CH ₂ CH ₂ CONH-Gly-IRES (q = 0, Z ₂ is absent, L = CH ₂ CH ₂ CONH, D = Gly-IRES), D ₃ = NHCO-FA (q=0, Z ₂ is absent, L=NHCO, D=FA).

Example 34 Preparation of Y-type polyethylene glycol modified cantharidin containing a fluorescent group

Step a, Preparation of a fluorescent group-containing Y-type polyethylene glycol derivative (Compound J1-C6-1): To a 100 mL dry clean round bottom flask was added 4.2 g of compound D4-C6-1 (43 kDa, 0.1 mmol). Prepared in Example 19, 1 equivalent of carboxyl group), 83.3 mg of 5-aminofluorescein (AFLN, compound 210, 0.24 mmol, 1.2 equivalents), 36.6 mg of 4-dimethylaminopyridine (0.3 mmol, 1.5 equivalents), added to 30 mL A mixed solution of anhydrous dichloromethane and 6 mL of dimethylformamide was mixed, and 82.4 mg (0.4 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), filtration, washing and drying in vacuo to give the product J1-C6-1. The structure was determined by NMR. It was tested by high performance liquid chromatography with a molecular weight of approximately 44 kDa.

Step b, preparation of Y-type polyethylene glycol derivative J1-C3-1 (compound 211) containing naked amino group and fluorescent group: Compound J1-C6-1 obtained in step a is dissolved in 18 mL of dichloromethane, and added 12 mL of trifluoroacetic acid, the mixture was stirred for 1 h, concentrated under reduced pressure, and the mixture was evaporated to diethyl ether. The mixture was evaporated to ethyl ether. The structure was determined by NMR test. It was tested by high performance liquid chromatography with a molecular weight of approximately 44 kDa.

Step c, Preparation of fluorogenic group-containing polyethylene glycol modified cantharidin (compound 213): To a 100 mL dry clean round bottom flask was added 2.2 g of compound 211 prepared in step c (0.05 mol, 1 equivalent Amino), 141 mg cantharidin (Compound 212, 0.72 mmol, 1.2 eq.), 110 mg of 4-dimethylaminopyridine (0.9 mmol, 1.5 eq.), a mixture of 30 mL of anhydrous dichloromethane and 6 mL of dimethylformamide The solution was mixed, and 247 mg (1.2 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 213. The structure was determined by NMR. It was tested by high performance liquid chromatography with a molecular weight of approximately 46 kDa.

Among them, the above reaction process is as follows:

Example 35 Pharmacokinetics and Tissue Distribution Experiment of Polyethylene Glycol Modified Interferon α-2a

(1) Preparation and purification of heterofunctionalized Y-type polyethylene glycol modified interferon alpha-2a (Y-PEG-IFN)

Referring to the heterofunctionalized Y-type polyethylene glycol A1-H1-1 in Example 1, the molecular weight of the polyethylene glycol in the branched chain was changed by the method of Example 1, and the branched chain hydroxyl group was prepared and the main chain was prepared. The compound A1-H1-2, the compound A1-H1-3, and the compound A1-H1-4 having a terminal succinimide propionate.

The heterofunctionalized Y-type polyethylene glycols A1-H1-1, A1-H1-2, A1-H1-3, and A1-H1-4 modified interferon α-2a were prepared by the method of Example 29, and the differences were collected. Functionalized Y-type polyethylene glycol to modify the monomerization of a single interferon alpha-2a molecule The compounds correspond to the compound 211, the compound 212, the compound 213, and the compound 214, respectively.

A linear polyethylene glycol-modified interferon alpha-2a (compound 215, compound 216) and two arms of polyethylene glycol modified interferon alpha-2a (compound 217, compound 218) were prepared as a control.

The molecular weight and the like of each of the above compounds 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 the interferon modified by Y-type polyethylene glycol was significantly longer than that of the linear polyethylene glycol and the modified product of the two-arm polyethylene glycol.

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 distribution of interferon with Y-type polyethylene glycol in the spleen, lung, liver, bladder and stomach was improved compared with the modified product of linear polyethylene glycol and two-arm polyethylene glycol. The distribution of the kidneys decreased significantly, reflecting a decrease in cardiotoxicity and impaired renal exclusion, consistent with the extended half-life described above.

Example 36: Pharmacokinetics and Tissue Distribution Experiment of Polyethylene Glycol Modified Recombinant Human Granulocyte Colony Stimulating Factor (rhG-CSF)

(1) Preparation and purification of heterofunctional Y-type polyethylene glycol modified G-CSF (H-PEG-rhG-CSF)

Referring to the heterofunctionalized Y-type polyethylene glycol D5-H1-1 in Example 12, the molecular weight of the polyethylene glycol in the branched chain was changed by the method of Example 12, and the branched chain hydroxyl group was prepared and the main chain was prepared. Compound compounds D5-H1-1, D5-H1-2, compound D5-H1-3, and compound D5-H1-4, which are propanal at the end.

The heterofunctionalized Y-type polyethylene glycol D5-H1-1, D5-H1-2, D5-H1-3, D5-H1-4 modified G-CSF was prepared by the method of Example 30, and the hetero-functionalization was collected. Y-type polyethylene glycol modifies the monomeric product of a single G-CSF molecule, which corresponds to compound 219, compound 220, compound 221, and compound 222, respectively.

Preparation of linear polyethylene glycol-modified G-CSF (Compound 223, Compound 224) and two-arm polyethylene glycol-modified G-CSF (Compound 225, Compound 226) were prepared as a control.

The molecular weight and the like of each of the above compounds are shown in Table 1.

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, respectively before administration and 0.5, 1, 2, 3, 4, 6, 8, 12, Blood was taken after 24, 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 use of the Y-type polyethylene glycol of the present invention to modify rhG-CSF 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 Y-type polyethylene glycol in bone marrow, kidney and other parts was significantly reduced.

Example 37: Polyethylene glycol modified irinotecan drug

(1) Preparation of polyethylene glycol modified irinotecan drug molecule

Using the methods of Example 2, Example 9, Example 21, Example 8, and Example 10, only the molecular weight of polyethylene glycol was changed, and H1 - A6-1, H1 - D4-1, and C6 - D4 were respectively prepared. 4. The hetero-functionalized polyethylene glycols 227, 228, 229, 230, and 231 having a hydroxyl group terminal at the end of the main chain of the structure represented by C6-D4-1 and C6-D4-3.

Starting from compounds 227, 228, 229, 230, and 231, the method of Example 28, Example 26 (Step c), Example 31, Example 32, and Example 33 were used to prepare Y-type polyethylene glycol modified. Irinotecan corresponds to compound 232, compound 233, compound 234, compound 235, and compound 236, respectively. Wherein each of the branches of H1-A6-1, C6-D4-4, and C6-D4-3 binds to one irinotecan molecule; the ends of each branch of H1-D4-1 and C6-D4-1 are respectively Six or four irinotecan molecules are linked; C6-D4-1, C6-D4-3, and C6-D4-4 all contain a targeting group (folate molecule).

Simultaneous preparation of linear polyethylene glycol modified single molecule irinotecan (compound 237), linear polyethylene glycol modified bimolecular irinotecan (compound 238), two-arm polyethylene glycol modified single molecule Polyethylene glycol (compound 239).

The molecular weight and other parameters are shown in Table 5.

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 cultured by adding eight kinds of PEGylated irinotecan drugs shown in Table 5 at the same concentration.

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 S9, S10, S11, S12, S13, SL5, SL6 and SV5 significantly inhibited cell proliferation in six cells. The inhibitory effects of S9, S10, S11, S12, S13, and SL6 were significantly higher than those of SL5 and SV5. The inhibitory effect on tumors/cancer cells from strong to weak is S10>S12>S9～S11～S13～SL6>SL5>SV5.

(38) 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 S9, S10, S11, S12, S13, SL5, SL6 and SV5 had obvious antitumor effect on the six cells compared with the blank control. The tumor inhibition rates of S9, S10, S11, S12, S13, and SL6 were significantly higher than those of SL5 and SV5. The tumor inhibition rate from high to low is S12>S11>S10～S13>S9>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 (101)

A heterofunctional polyethylene glycol derivative characterized by having a Y-type structure and having the formula shown in formula (1):

Wherein n ₁ and n ₂ represent the degree of polymerization of the two PEG branching strands, each independently satisfying 2 to 2000, and n ₃ represents the degree of polymerization of the main chain PEG, which satisfies 1 to 2000, and in the same molecule, n ₁ , n ₂ , n ₃ may be the same or different from each other; the PEG chains corresponding to n ₁ , n ₂ , and n ₃ are each independently polydisperse or monodisperse; The Y-type structure is based on a trivalent branched structure composed of U and L ₁ , L ₂ , and L ₃

Recorded as U _c ; U is a trivalent group; L _1, L _2, L ₃ are the number of oxyethylene units connected to n _1, n _2, n linker polyethylene glycol units _3, are each independently present or absent and can be each other in the same molecule Same or different; k ₁ , k ₂ , and k ₃ are each independently an integer of 1 or 2 to 250; G ₁ , G ₂ , and G ₃ are each independently a linking group of a trivalent or higher valence state; g ₁ , g ₂ , g ₃ are 0 or 1, and g ₁ = g ₂ ; L ₄ and L ₆ are each independently a divalent linking group; p ₁ , p ₂ , and p ₃ are each independently 0, 1, or 2 to 1000; When g _i =0, k _i (i=1, 2, 3) is 1, and G _i does not exist at this time; When g _i =1, k _i (i=1, 2, 3) is an integer of 2 to 250, in which case G _i exists, and the valence states of G ₁ , G ₂ , and G ₃ are respectively k ₁ +1, k ₂ +1, k ₃ +1; Wherein F ₁ and F ₂ are each independently represented as

And F ₁ ≠F ₂ ; wherein, q, q ₁ are each independently 0 or 1; Z ₁ and Z ₂ are each independently a divalent linking group; R ₀₁ is a functional group or a protected form thereof; the same molecule Wherein, Z ₂ , q, Z ₁ , q ₁ , and R _{01 of} F ₁ and F ₂ are each independently the same or different; In the same molecule, U, L ₁ , L ₂ , L ₃ , L ₄ , L ₆ , G ₁ , G ₂ , G ₃ , Z ₁ (F ₁ ), Z ₂ (F ₁ ), Z ₁ (F ₂ ) a linker formed by any one or any of Z ₂ (F ₂ ) with an adjacent hetero atom group may be stably present or degradable; When g ₁ =g ₂ =g ₃ =0, F ₁ and F ₂ are each independently selected from any one of a non-hydroxyl reactive group, a targeting group, a photo-sensitive group, and n _{3 is} selected from 11 ~1000. The heterofunctional polyethylene glycol derivative according to claim 1, wherein each of n ₁ and n ₂ independently satisfies 5 to 1000; preferably 10 to 1000; more preferably 20 to 500. The heterofunctional polyethylene glycol derivative according to claim 1, wherein said n ₃ satisfies 5 to 1000; preferably 10 to 1000; more preferably 20 to 500. The heterofunctional polyethylene glycol derivative according to claim 1, wherein the degradable condition is in light, heat, enzyme, redox, acid, alkaline, physiological conditions, in vitro simulated environment A condition; preferably any one of light, heat, enzyme, redox, acidic or basic conditions. The heterofunctional polyethylene glycol derivative according to claim 1, wherein the degradation property is selected from any of the following cases: (a) g _i (i = 1, 2 or 3) = 0 or 1, and the divalent nuclear structure of the trivalent branched structure U _c degrades at the divalent junction between the PEG branching chain, at UL ₁ -O At least one position in UL ₂ -O is degradable; (b) g _i (i=1, 2or3) = 0 or 1, and the divalent core structure of the trivalent branched structure degrades at the divalent junction between the trivalent core structure and the PEG backbone, and is degradable at the UL ₃ -O position ; (c) g _i (i = 1, 2 or 3) = 0 or 1, the trivalent branched structure contains a cyclic trivalent core structure CC ₃ , and CC ₃ is degradable; (d) g _i (i = 1, 2 or 3) = 0 or 1, degrading only at the position of -(Z ₂ ) _q -(Z ₁ ) _q1 -, which contains its adjacent group to the PEG side a connecting group formed; (e) g _i (i=1, 2or3)=1, degrading only at the position between the PEG chain and the terminal branching structure, including O-(L ₄ ) _p1 and the linkage with G ₁ , O-(L ₄ ) _p2 and the linkage to G ₂ , O-(L ₆ ) _p3 and the linkage to G ₃ ; (f) g _i (i=1, 2or3)=1, degradation occurs only in G(i=1, 2or3). The heterofunctional polyethylene glycol derivative according to claim 1, wherein the PEG branching chain corresponding to n ₁ or n ₂ is polydisperse. The heterofunctional polyethylene glycol derivative according to claim 6, wherein the number average molecular weight of the PEG branched chain corresponding to n ₁ or n ₂ 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, 4000, 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. The heterofunctional polyethylene glycol derivative according to claim 1, wherein the PEG branching chain corresponding to n ₁ or n ₂ is monodisperse. The heterofunctional polyethylene glycol derivative according to claim 8, wherein said n ₁ or n _{2 is} selected from 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, it is an integer of 5 to 50. The heterofunctional polyethylene glycol derivative according to claim 1, wherein the n ₃ corresponding PEG backbone is polydisperse. The heterofunctional polyethylene glycol derivative according to claim 10, wherein the number average molecular weight of the n ₃ corresponding PEG backbone is 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 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. The heterofunctional polyethylene glycol derivative according to claim 1, wherein the n ₃ corresponding PEG backbone is monodisperse. The heterofunctional polyethylene glycol derivative according to claim 12, wherein said n _{3 is} selected from an integer of from 1 to 70; more preferably an integer of from 3 to 70; more preferably an integer of from 5 to 70; more preferably An integer from 5 to 50. The heterofunctionalized polyethylene glycol derivative according to claim 1, wherein the PEG branching chain corresponding to n ₁ and n ₂ is polydisperse, and the PEG chain corresponding to n ₃ is monodisperse . The heterofunctionalized polyethylene glycol derivative according to claim 1, wherein the PEG branching chain corresponding to n ₁ and n ₂ is monodisperse, and the PEG chain corresponding to n ₃ is polydisperse . The heterofunctional polyethylene glycol derivative according to claim 1, wherein the PEG branched chain corresponding to n ₁ and n ₂ and the PEG chain corresponding to n ₃ are all polydisperse. The heterofunctionalized polyethylene glycol derivative according to claim 1, wherein the PEG branched chain corresponding to n ₁ and n ₂ and the PEG chain corresponding to n ₃ are monodisperse. The heterofunctional polyethylene glycol derivative according to claim 1, wherein the U is a symmetric type or an asymmetric type. The heterofunctional polyethylene glycol derivative according to claim 1, wherein the U is a branched structure or a cyclic structure. The heterofunctional polyethylene glycol derivative according to claim 1, wherein the U contains any one of a trivalent atomic core CM ₃ , a trivalent unsaturated bond core CB ₃ , and a trivalent cyclic core CC ₃ . Trivalent nuclear structure; 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. The heterofunctional polyethylene glycol derivative according to claim 1, wherein the U 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. The heterofunctional polyethylene glycol derivative according to claim 1, wherein said U contains an oxy group, a thio group, a secondary amino group, a divalent tertiary amino group, and one, two or three of the carbonyl groups are the same or Different divalent linking groups are capped; when participating in an initiator molecule constituting living anionic polymerization, they do not contain a carbonyl group or a secondary amino group. The heterofunctional polyethylene glycol derivative according to claim 1, wherein the U is selected from any 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. The heterofunctional polyethylene glycol derivative according to claim 1, wherein said U is a trivalent skeleton structure of an amino acid or a derivative thereof, but does not participate in an initiator molecule constituting living anionic polymerization; It is _L -form or _D -form; amino acids or derivatives thereof are derived from any of the following: serine, threonine, cysteine, tyrosine, hydroxyproline, aspartic acid, glutamic acid , asparagine, glutamine, lysine, arginine, citrulline, histidine, tryptophan. The heterofunctional polyethylene glycol derivative according to claim 1, wherein the U is selected from any 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. The heterofunctional polyethylene glycol derivative according to claim 1, wherein the U satisfies the existence of U _c (O-) ₃ stably. The heterofunctional polyethylene glycol derivative according to claim 26, wherein said U is selected from the group consisting of

Any of them. The heterofunctional polyethylene glycol derivative according to claim 1, wherein said U satisfies U _c (O-) ₃ degradable. The heterofunctional polyethylene glycol derivative according to claim 1, wherein said G ₁ , G ₂ and G _{3 are} selected from the group consisting of branched, ring-containing structures, combs, dendrimers, and hyperbranched One; and G ₁ and G _{2 have} the same structural type. The heterofunctional polyethylene glycol derivative according to claim 1, wherein the structures of G ₁ , G ₂ and G ₃ are each independently stable or degradable. The heterofunctional polyethylene glycol derivative according to any one of claims 1 to 18, wherein each of G ₁ , G ₂ and G _{3 is} independently selected from any one of the following groups: Structure: Trivalent group: U, U _c ,

a tetravalent group; containing one atomic CM ₄ , an unsaturated bond CB ₄ , a tetravalent nuclear structure of the cyclic structure CC ₄ , or comprising two trivalent core structures; (L ₄ ) _{p1 -} G ₁ , (L ₄ ) _{p2 -} G ₂ , (L ₆ ) _{p3 -} G ₃ each independently contain 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 the valence state is ≥4, the G of the k+1 valence contains a nuclear structure of 1 k+1 valence, or is directly connected or combined by 2 to k-1 low valence groups of 3 to k valence or 1 or One or more divalent spacers L _{10 are} indirectly combined; the low-valent groups of 3 to k valences may be the same or different, and their valence states may be the same or different; for a nuclear structure of k+1 valence, k ≥ 4 and containing a k+1 valent core structure, the k+1 valent 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 direct or indirect a combination of k+1 (k ≥ 4) valence G, the combination mode is selected from the group consisting of a comb combination method, a tree combination method, a branch combination method, a hyperbranched combination, and a ring combination method. Wherein G is G ₁ , G ₂ or G ₃ . The heterofunctional polyethylene glycol derivative according to claim 31, wherein said 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. The heterofunctionalized polyethylene glycol derivative according to claim 1, wherein any one of L ₄ and L ₆ is stable and is selected from any one of the following two types: (1) comprising a plurality of An oligopeptide or polypeptide formed by N- and C-terminal ends of an amino acid, which may be the same or different, but does not include a polypeptide fragment which is degradable by an in vivo enzyme; (2) L ₀ contains -(L ₁₁ O) _nj -, -(OL ₁₁ ) _nj -, -(R ₂₉ O) _nj -, -(OR ₂₉ ) _nj -, -(CH ₂ CH ₂ O) _nj -, -(OCH ₂ CH ₂ ) _nj - And wherein R _{29 is} selected from a C _3-20 alkylene group having a linear, branched or cyclic structure; wherein L ₁₁ is a C _1-20 alkylene group or a C _1-20 substituted group which is stably present An alkylene group; having a linear structure, a branched structure or a cyclic structure; wherein the integer nj is a repeating unit number of a monodisperse structure, and is selected from 2 to 20. The heterofunctional polyethylene glycol derivative according to claim 1, wherein said k ₁ , k ₂ and k ₃ are each independently selected from ₁ , ₂ , ₃ , 4, 5, 6, 7, 8 9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33 ～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. The heterofunctional polyethylene glycol derivative according to claim 1, wherein said R _{01 is} selected from the group consisting of: a reactive group, a variant of a reactive group, and a functional group having therapeutic targeting properties. a 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, or a deprotected form a variant; wherein the precursor of the reactive group is subjected to oxidation, reduction, hydration, dehydration, electron rearrangement, structural rearrangement, salt complexation and decomplexation, ionization, protonation, deprotonation At least one process can be converted to the structure of the reactive group; wherein the variant of the reactive group refers to a reactive group undergoing oxidation, reduction, hydration, dehydration, electron rearrangement, structural rearrangement, Salt complexation is an active form after at least one of decomplexation, ionization, protonation, deprotonation, substitution, deprotection, or a protected inactive form. The heterofunctional polyethylene glycol derivative according to claim 1, wherein said R _{01 is} selected from the group consisting of functional groups of the following class A to class H, class (AH)', and variants thereof Any of the functional groups: 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 p-nitrobenzene active ester, an o-nitrobenzene active ester, a benzotriazole active ester, 1, 3,5-trichlorobenzene active ester, 1,3,5-trifluorobenzene active ester, pentafluorobenzene active ester, imidazole active ester; wherein the similar structure of active ester group includes: 2-thione-3-thiazole Alkanoate (tetrahydrothiazole-2-thione-N-formate), 2-thioxothiazolidine-3-carboxylate, 2-thioketopyrrolidine-N-carboxylate, 2- Thiolpyrrolidine-N-formate, 2-thionebenzothiazole-N-formate, 1-oxo-3-thioxoisoindoline-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. The heterofunctional 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. A heterofunctional polyethylene glycol derivative according to claims 36-37, characterized in that 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 ; 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. The heterofunctional polyethylene glycol derivative according to claim 1, wherein R _{01 is} selected from the group consisting of functional groups of the following classes A to J, variants of class A to class H, and class I- Functional derivatives of class 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:

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 combination 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. The heterofunctional polyethylene glycol derivative according to claim 39, which is characterized in that The structure in which the mercapto group is protected, SPG ₂ is tert-butyl sulfide, trityl sulfide, substituted trityl sulfide, tert-butyldimethylsilyl sulfide, triisopropylsilyl Thioether, benzyl sulfide, substituted benzyl sulfide, p-nitrobenzyl sulfide, o-nitrobenzyl sulfide, acetyl thioester, benzoyl thioester, trifluoroacetyl thio Ester, tert-butyl disulfide, substituted phenyl disulfide or 2-pyridine disulfide; The alkynyl protecting group PG ₃ is trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, dimethyl(1,1,2-trimethylpropyl)silyl, two Methyl [1,1-dimethyl-3-(tetrahydrofuran-2H-2-oxo)propyl]silyl, biphenyldimethylsilyl, triisopropylsilyl, biphenyldiisopropyl Silicon-based or tert-butyldiphenylsilyl; The structure of the hydroxyl group protected OPG ₄ is methyl ether, 1-ethoxyethyl ether, tert-butyl ether, allyl ether, benzyl ether, p-methoxybenzyl ether, o-nitrobenzyl Ether, p-nitrobenzyl ether, 2-trifluoromethylbenzyl ether, methoxymethyl ether, 2-methoxyethoxymethyl ether, benzyloxymethyl ether, p-methoxybenzyl Oxymethyl methyl ether, methylthiomethyl ether, tetrahydropyranyl ether, trimethylsilyl ether, triethylsilyl ether, triisopropylsilyl ether, tert-butyldimethylsilyl ether , acetate, chloroacetate, trifluoroacetate or carbonate; The protected structure of the amino group NPG ₅ is formamide, acetamide, trifluoroacetamide, tert-butyl carbamate, 2-iodoethyl carbamate, benzyl carbamate, 9-methyl carbamate, 2-trimethylsilylcarbamate, 2-methylsulfonylcarbamate, 2-(p-toluenesulfonyl)carbamate, phthalimide, diphenylmethyleneamine, 1 ,3,5-dioxazacyclohexane, methylamino, triphenylmethylamino, tert-butylamino, allylamino, benzylamino, 4-methoxybenzylamino or benzylimine . The heterofunctionalized polyethylene glycol derivative according to claim 1, wherein the F ₁ and F ₂ have the same or different R ₀₁ ; and when the F ₁ and F ₂ have different R ₀₁ , corresponding The heterofunctional group is a hydroxyl group and a protected hydroxyl group, a hydroxyl group or a protected hydroxyl group and a non-hydroxyl reactive group, a hydroxyl group or a protected hydroxyl group and a targeting group, a hydroxyl group or a protected hydroxyl group and a photosensitive group. , active ester group and maleimide group, active ester group and aldehyde group, active ester group and azide group, active ester group and alkynyl group or protected alkynyl group, active ester group and acrylate group, active ester And methacrylate groups, active ester groups and acrylic groups, maleimide groups and azido groups, maleimide groups and alkynyl groups or protected alkynyl groups, maleimide groups and acrylic acid Ester group, maleimide group and methacrylate group, maleimide group and acrylic group, maleimide group and carboxyl group, maleimide group and amino group or protected amino group or amine Salt, maleimide group and isocyanate group, maleimide group and protected sulfhydryl group, aldehyde group and stack Base, aldehyde and acrylate groups, aldehyde and methacrylate groups, aldehyde and acrylate groups, aldehyde groups and epoxy groups, aldehyde groups and carboxyl groups, aldehyde groups and alkynyl groups or protected alkynyl groups, azides And fluorenyl or protected sulfhydryl groups, azido and amino groups or protected amino or amine salts, azido and acrylate groups, azido and methacrylate groups, azido and acrylate groups, azide Base and carboxyl group, acrylate group and amino group or protected amino or amine salt, acrylate group and isocyanate group, acrylate group and epoxy group, acrylate group and methacrylate group, acrylate group and carboxyl group, Acrylate group and carboxyl group, methacrylate group and amino group or protected amino or amine salt, methacrylate group and isocyanate group, methacrylate group and epoxy group, alkynyl group or protected alkynyl group Amino or protected amino or amine salt, alkynyl or protected alkynyl and isocyanate, alkynyl or protected alkynyl and acrylate, alkynyl or protected alkynyl and methacrylate Alkynyl or protected alkynyl and propylene Alkynyl, alkynyl or protected alkynyl and epoxy, alkynyl or protected alkynyl and carboxy, protected alkynyl and azide, acrylate and isocyanate, acrylate and acrylate, acrylic And epoxy groups, acrylate and carboxyl groups, carboxyl and sulfhydryl groups or protected sulfhydryl groups, carboxyl and amino groups or protected amino or amine salts, carboxyl and isocyanate groups, carboxyl and epoxy groups, amino groups or protected amino groups or Any one of an amine salt and a thiol or protected thiol group, a targeting group and a non-hydroxyl reactive group, a photosensitive group and a non-hydroxyl reactive group; the above active ester group may be similar to the active ester group Structural substitution; a similar structure of the active ester group is selected from the group consisting of 2-thione-3-thiazolidinecarboxylate, 2-thioxothiazolidine-3-carboxylate, 2-thioketopyrrolidine-N-carboxylate Any one of an acid ester, a 2-thione benzothiazole-N-formate, a 1-oxo-3-thioxoisoindoline-N-formate; wherein the amino group is a primary amino group Or secondary amino groups. The heterofunctional polyethylene glycol derivative according to claim 1, wherein said L ₁ , L ₂ , L ₃ , L ₄ , L ₆ , Z ₁ (F ₁ ), Z ₂ (F ₁ ) , Z ₁ (F ₂ ), Z ₂ (F ₂ ) are all divalent linking groups, and are each independently, and may be the same as each other in the same molecule, or may be independently a linear structure, a branched structure or a ring-containing structure. a structure; each independently having 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 the non-hydrogen atom is 1 type, or 2 types, or 2 or more types, a non-hydrogen atom is 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 ₁ , L ₂ , L ₃ , L ₄ , L ₆ , Z ₁ (F ₁ ), Z ₂ (F ₁ ), Z ₁ (F ₂ ), Z ₂ (F ₂ ) a divalent linking group consisting of or consisting of an adjacent hetero atom group is a stably present linker STAG or a degradable linker DEGG; The heterofunctional polyethylene glycol derivative according to claim 42, wherein the STAG is stable under any conditions of light, heat, enzyme, redox, acid, alkaline, physiological conditions, and in vitro simulated environment. Present in light, heat, It can be stably present under any conditions of enzyme, redox, acidity and alkaline. The heterofunctionalized ring, heterofused heterocyclic ring, substituted alkylene group, substituted heteroalkyl group, substituted divalent heteroalkyl group, substituted double bond, substituted triple bond, substituted diene according to claim 42 a substituted divalent cycloalkyl group, a substituted divalent cycloalkenyl group, a substituted divalent cycloalkene group, a substituted divalent cycloalkynyl group, a substituted aromatic ring, a substituted aliphatic heterocyclic ring, a substituted heterocyclic ring, Substituted arylheterocyclic, substituted heterofused heterocyclic ring, ether bond, thioether bond, urea bond, thiourea bond, carbamate group, thiocarbamate group, -P(=O)-, -P(=S)-, a divalent silicon group containing no 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 a stable divalent linkage consisting of any one of two or more than two groups of a divalent linking group, an enamino group, a triazole, a 4,5-dihydroisoxazole, an amino acid and a derivative thereof base. The heterofunctional polyethylene glycol derivative according to claim 42, wherein the STAG is any one of the following structures or a combination of two or more of the following 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. The heterofunctional polyethylene glycol derivative according to claim 45, wherein said R ₇ , R ₁₈ , R ₁₉ , R ₈ , R ₉ , R ₁₀ , R ₁₁ and R ₃₉ are each a H atom. The heterofunctional polyethylene glycol derivative according to claim 42, wherein the DEGG is degradable under any conditions of light, heat, enzyme, redox, acid, alkaline, physiological conditions, and in vitro simulated environment. ; preferably degradable under any conditions of light, heat, enzyme, redox, acid, and alkaline. The heterofunctional polyethylene glycol derivative according to claim 42, wherein the DEGG contains a disulfide bond, a vinyl ether bond, an ester group, a thioester group, a thioester group, a dithioester group, Carbonate group, thiocarbonate group, dithiocarbonate group, trithiocarbonate group, urethane group, thiocarbamate group, dithiocarbamate group, acetal, Cycloacetal, thioacetal, aza acetal, azacyclic acetal, nitrothia acetal, dithio acetal, hemiacetal, thio hemiacetal, aza hemiacetal, ketal, Thiokeketone, azathione, azacyclohexanone, azathioketal, imine bond, hydrazone bond, hydrazide bond, hydrazone bond, thioxanthene group, semicarbazone bond, thioscarbazide Bond, sulfhydryl, hydrazide, thiocarbonylhydrazide, azocarbonylhydrazide, thioazocarbonylcarbonyl, carbazate, mercapto thioformate, carbachol , thiocarbazone, azo, isourea, isothiourea, allophanate, thiourea, sulfhydryl, fluorenyl, aminoguanidino, aminoguanidino, imine Acid group, imidate thioester group, sulfonate Ester group, sulfinate group, sulfonyl hydrazide group, sulfonylurea group, maleimide, orthoester group, phosphate group, phosphite group, phosphite group, phosphonate group, phosphorus Silane ester group, silane ester group, carbon amide, thioamide, sulfonamide group, polyamide, phosphoramide, phosphoramidite, pyrophosphoramide, cyclophosphamide, ifosfamide, thiophosphoramide, aconitamide A combination of a benzyloxycarbonyl group, a polypeptide fragment, a nucleotide and a derivative thereof, a deoxynucleotide and a derivative thereof, a divalent linking group, or a combination of any two or more than two divalent linking groups. The heterofunctional polyethylene glycol derivative according to claim 42, 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 _{1 9} )-(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,

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. The heterofunctional polyethylene glycol derivative according to claim 49, 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(=N H)-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 Base, orthophosphate group, orthosulfate group, orthoester group, phosphate group, phosphite group, phosphite group, phosphonate group, phosphosilyl group, silane ester group, carbon amide, sulfur Amide, sulfonamide, polyamide, phosphoramide, phosphoramidite, pyrophosphamide, cyclophosphamide, ifosfamide, thiophosphoramide, aconityl, benzyloxycarbonyl, polypeptide fragments, nucleotides and a divalent linking group of a derivative thereof, a divalent linking group of a deoxynucleotide and a derivative thereof,

Wherein R ₃ is a methyl group, an ethyl group or a benzyl group. The heterofunctional polyethylene glycol derivative according to claim 1, wherein said g ₁ = g ₂ = g ₃ =0, and the formula (1) is represented by the formula (2); U, L _{1, L 2, L 3,} Z 1 (F 1), Z 2 (F 1), Z 1 (F 2), Z 2 (F 2) according to any one or any adjacent heteroatom form a group The linker can be stably present or degradable; Wherein F ₁ and F ₂ are each independently selected from any one of a non-hydroxyl reactive group, a targeting group, and a photo-sensitive group, and n _{3 is} selected from 11 to 1000.

The heterofunctional polyethylene glycol derivative according to claim 1, wherein the g ₁ = g ₂ =1 and g ₃ =0, and the general formula (1) is represented by the general formula (3); Any one of L ₁ , L ₂ , L ₃ , L ₄ , G ₁ , G ₂ , Z ₁ (F ₁ ), Z ₂ (F ₁ ), Z ₁ (F ₂ ), Z ₂ (F ₂ ) or Any of the linking groups formed with adjacent hetero atom groups may be stably present or degradable.

The heterofunctional polyethylene glycol derivative according to claim 1, wherein the g ₁ = g ₂ =0 and g ₃ =1, and the formula (1) is as shown in the formula (4); Any one or any of L ₁ , L ₂ , L ₃ , L ₆ , G ₃ , Z ₁ (F ₁ ), Z ₂ (F ₁ ), Z ₁ (F ₂ ), and Z ₂ (F ₂ ) The linking group formed by adjacent hetero atom groups may be stably present or degradable.

The heterofunctional polyethylene glycol derivative according to claim 1, wherein said g ₁ = g ₂ = g ₃ =1, and the formula (1) is represented by the formula (5); U, L ₁ , L ₂ , L ₃ , L ₄ , L ₆ , G ₁ , G ₂ , G ₃ , Z ₁ (F ₁ ), Z ₂ (F ₁ ), Z ₁ (F ₂ ), Z ₂ (F ₂ ) Any one or any of the linking groups formed with adjacent hetero atom groups may be stably present or degradable.

The heterofunctional polyethylene glycol derivative according to claim 1, wherein G ₁ = G ₂ , and G ₁ and G ₃ are each independently selected from a branched structure or a dendritic structure. The heterofunctional polyethylene glycol derivative according to claim 1, wherein the G ₁ and G ₂ have a comb structure, or the G ₃ has a comb structure. The heterofunctional polyethylene glycol derivative according to claim 1, wherein the G ₁ and G ₂ have a hyperbranched structure, or the G ₃ has a hyperbranched structure. A bio-related substance modified by the heterofunctionalized polyethylene glycol derivative according to claim 1, wherein the formula is represented by formula (6), (7) or (8);

k ₁ , k ₂ , k ₃ , k ₄ , k ₅ , k ₆ are each independently an integer of 1 or 2 to 250; G ₁ , G ₂ , G ₃ , G ₄ , G ₅ , G ₆ are each independently a linking group of a trivalent or higher valence state; When g _i-3 =0, k _i (i=4, 5, 6) is 1, and G _i does not exist at this time; When g _i-3 =1, k _i (i=4, 5, 6) is an integer of 2 to 250, and G _i exists, and the valence states of G ₄ , G ₅ , and G ₆ are respectively k ₄ +1. , k ₅ +1, k ₆ +1; When g _i =0, k _i (i=1, 2, 3) is 1, and G _i does not exist at this time; When g _i =1, k _i (i=1, 2, 3) is an integer of 2 to 250, in which case G _i exists, and the valence states of G ₁ , G ₂ , and G ₃ are respectively k ₁ +1, k ₂ +1, k ₃ +1; Wherein D ₁ , D ₂ , and D ₃ are each independently represented as

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

Wherein E ₀₁ is R ₀₁ , protected R ₀₁ , deprotected R ₀₁ or blocked R ₀₁ ; and when g ₁ =g ₂ =g ₃ =0, R _{01 is} not a hydroxyl group; Wherein q and q ₁ are each independently 0 or 1; Z ₁ and Z ₂ are each independently a divalent linking group; R ₀₁ is a functional group or a protected form thereof; and D is a modified biologically relevant substance and a residue formed by the reaction of a heterofunctional Y-type polyethylene glycol; L is a functional group in the heterofunctional Y-type polyethylene glycol derivative or a linker formed by reacting the protected form with a biologically relevant substance ; Wherein, in the same molecule, D ₁ and D ₂ have the same Z ₂ , q, and D ₁ and D ₂ have the same or different L; in the same molecule, D of D ₁ and D ₂ are from the same biologically relevant substance, D of D ₁ and D ₃ are derived from different biologically related substances, and D of D ₂ and D ₃ are derived from different biologically related substances; in the same molecule, D ₁ and D ₂ may be formed after different reaction sites in the same molecule participate in the reaction. Residue In the general formula (6), D ₁ or D ₂ and D ₃ have the same or different Z ₂ , q, L; In the general formula (7), D ₁ or D ₂ and EF ₂ have the same or different Z ₂ , q; In the general formula (8), EF ₁ and D ₃ have the same or different Z ₂ , q; Wherein, in the same molecule, U, L ₁ , L ₂ , L ₃ , L ₄ , L ₆ , G ₁ , G ₂ , G ₃ , G ₄ , G ₅ , G ₆ , Z ₂ (D ₁ ), Z ₂ (D ₂ ), Z ₂ (EF ₁ ), Z ₂ (D ₃ ), Z ₂ (EF ₂ ), L(D ₁ ), L(D ₂ ), L(D ₃ ), Z ₁ (EF ₁ ) The linker formed by any one or any of Z ₁ (EF ₂ ) with an adjacent hetero atom group may be stably present or degradable. A bio-related substance modified with a heterofunctional polyethylene glycol derivative according to claim 58, wherein said G ₄ , G ₅ and G ₆ are represented as

And k ₁ ≥ k ₄ , and k ₂ ≥ k ₅ , and k ₃ ≥ k ₆ ; wherein EF ₄ , EF ₅ , EF _{6 are} expressed as

And EF ₄ = EF ₅ , and EF ₄ is different from EF ₆ . A bio-related substance modified with a heterofunctionalized polyethylene glycol derivative according to claim 59, wherein said k ₄ = k ₁ , G ₄ = G ₁ ; k ₅ = k ₂ , G ₅ = G ₂ ; k ₆ = k ₃ , G ₆ = G ₃ ; the general formula (6), the general formula (7), and the general formula (8) are represented by the general formula (12), the general formula (13), and the general formula (14), respectively. .

A bio-related substance modified with a heterofunctionalized polyethylene glycol derivative according to claim 59, wherein When g ₁ =g ₂ =g ₃ =0, k ₁ =k ₂ =k ₃ =1, the structures of the general formula (6), the general formula (7), and the general formula (8) are expressed as a general formula ( 15), general formula (16), general formula (17);

When g ₁ = g ₂ =1, g ₃ =0, k ₃ =1, k ₁ , k ₂ , and k ₃ are integers of 2 to 250, the general formula (6), the general formula (7), and the general formula The structure of (8) is represented by the general formula (18), the general formula (19), and the general formula (20);

g ₁ = g ₂ =0, g ₃ =1, k ₃ is an integer of 2 to 250, and when k ₁ , k ₂ , and k ₃ are 1, the general formula (6), the general formula (7), and the general formula The structures of (8) are represented by the general formula (21), the general formula (22), and the general formula (23);

When g ₁ =g ₂ =g ₃ =1, k ₁ =k ₂ =k ₃ =1, the structures of the general formula (6), the general formula (7), and the general formula (8) are respectively expressed as a general formula ( 24), general formula (25), general formula (26).

A bio-related substance modified with a heterofunctional polyethylene glycol derivative according to claim 58, wherein said G ₁ = G ₂ , k ₁ = k ₂ , and G ₁ and G ₃ are each independently selected from Branched structure or tree structure. The bio-related substance modified with the heterofunctional polyethylene glycol derivative according to claim 58, wherein the G ₁ and G ₂ have a comb structure, or G ₃ has a comb structure. The bio-related substance modified with the heterofunctional polyethylene glycol derivative according to claim 58, wherein the G ₁ and G ₂ have a hyperbranched structure, or G ₃ has a hyperbranched structure. The bio-related substance modified by the heterofunctionalized polyethylene glycol derivative according to claim 58, 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. The bio-related substance modified by the heterofunctionalized polyethylene glycol derivative according to claim 58, 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. The bio-related substance modified by the heterofunctionalized polyethylene glycol derivative according to claim 58, 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. The bio-related substance modified according to claim 58, 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, cardiovascular disease, anti-allergic drugs, anti-infectives, antibiotics, antivirals, antifungals, vaccines, central nervous system inhibitors, central nervous system Systemic stimulants, psychotropics, 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, antimalarials, antiemetics/emetics, tracheal dilating agents, Antithrombotic drugs, antihypertensive drugs, antiarrhythmic drugs, antioxidants, antiasthmatics, diuretics, lipid regulators, antiandrogens, antiparasitic drugs, anticoagulants, twins Medicament, hypoglycemic agents, nutraceuticals, additives, growth supplements, anti-inflammatory drugs, vaccines, antibodies, diagnostics, contrast agents, hypnotics, sedatives, psychostimulants, tranquilizers, anti-Parkinson's drugs, analgesics, Anxiolytic drugs, muscle infection agents and hearing disease preparations; among them, anti-cancer or anti-tumor drugs are used for treating 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, 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 cancer, 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, dimension Williams tumors, liposarcoma, endometrial sarcoma, rhabdomyosarcoma, any cell tumor cancer associated with AIDS neuroblasts one kind of primary or secondary cancer, sarcoma or carcinosarcoma. The bio-related substance modified by the heterofunctionalized polyethylene glycol derivative according to claim 58, wherein the reactive group in the biologically relevant substance is an amino group, a thiol group, a dithio group, a carboxyl group, a hydroxyl group or a carbonyl group. Or an aldehyde group, an unsaturated bond, or any of the introduced reactive groups. The bio-related substance modified by the heterofunctionalized polyethylene glycol derivative according to claim 58, 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. The bio-related substance modified with the heterofunctionalized polyethylene glycol derivative according to claim 58, 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. The bio-related substance modified with the heterofunctional polyethylene glycol derivative according to claim 71, 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. The bio-related substance modified by the heterofunctionalized polyethylene glycol derivative according to claim 58, wherein the biologically relevant substance has two kinds, and one of the biologically relevant substances is a targeting factor, a dye or Fluorescent substance. A bio-related substance modified with a heterofunctionalized polyethylene glycol derivative, characterized in that the hetero-functionalized poly The bio-related substance modified by the ethylene glycol derivative is represented by the formula (15), the formula (18), the formula (21) or the formula (24);

Wherein n ₁ and n ₂ represent the degree of polymerization of the two PEG branching strands, each independently satisfying 2 to 2000, and n ₃ represents the degree of polymerization of the main chain PEG, which satisfies 1 to 2000, and in the same molecule, n ₁ , n ₂ , n ₃ may be the same or different from each other; the three polyethylene glycol segments are each independently polydisperse or monodisperse; U is a trivalent group; L _1, L _2, L ₃ are the number of oxyethylene units connected to n _1, n _2, n linker polyethylene glycol units _3, are each independently present or absent and can be each other in the same molecule Same or different; p ₁ , p ₂ , and p ₃ are each independently 0, 1, or 2 to 1000; and L ₄ and L ₆ are each independently a divalent linking group; k ₄ , k ₅ , and k ₆ are each independently an integer of 1 or 2 to 250; G ₄ , G ₅ , and G ₆ are each independently a trivalent or higher valence linking group, and the valence states of G ₄ , G ₅ , and G ₆ are respectively k ₄ +1, k ₅ +1, k ₆ +1; Wherein D ₁ , D ₂ , and D ₃ are each independently represented as

Wherein q is 0 or 1; Z ₂ is a divalent linking group; D is a residue formed by reacting a modified bio-related substance with a hetero-functionalized Y-type polyethylene glycol; and L is a hetero-functionalized Y-type poly-B a linking group formed by reacting a functional group in a diol derivative or a protected form thereof with a biologically relevant substance; Wherein, in the same molecule, D ₁ and D ₂ have the same Z ₂ , q, and D ₁ and D ₂ have the same or different L; in the same molecule, D of D ₁ and D ₂ are from the same biologically relevant substance; Wherein D ₁ and D ₂ may be residues formed after different reaction sites in the same molecule participate in the reaction; Wherein, in the same molecule, U, L ₁ , L ₂ , L ₃ , L ₄ , L ₆ , G ₄ , G ₅ , G ₆ , Z ₂ (D ₁ ), Z ₂ (D ₂ ), Z ₂ (D _{3), L (D 1)} , L (D 2), L (D 3) in any one or any of the adjacent groups form a hetero atom linker may be stable or degradable; Wherein, any one of D ₁ and D ₃ is a residue of a targeting factor, and the other is a residue of a different biologically relevant substance. A bio-related substance modified with a heterofunctionalized polyethylene glycol derivative according to claim 74, wherein said 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 inhibitor, angiogenesis inhibitor, cytoskeletal letter Inhibitors, stem cells and Wnt gene inhibitors, protease inhibitors, protein tyrosine kinase inhibitors, apoptosis inhibitors, MAPK inhibitors, cell cycle regulatory inhibitors, TGF-beta/Smad inhibitors, neural signal suppression 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, autobigy inhibitors, ubiquitin Ubiquitin inhibitors, multi-target inhibitors, receptors, antibodies, gene targeting molecules, viruses, vaccines, biomacromolecules, vitamins, targeted drugs One type; 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. The bio-related substance modified by the heterofunctionalized polyethylene glycol derivative according to claim 74, 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 . The bio-related substance modified with the heterofunctionalized polyethylene glycol derivative according to claim 74, 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 , Pomrabi, Carfilzomib, Belinostat, Cabazitaxel, Abiraterone Acetate, Radium Dichloride 233 Injection, Luteinizing Hormone Releasing Hormone, Miltonin, Oblimersen, Navioklax, Secatinib, Vismodegib, Marimastat, Fucosyl GM1 composition, Alvocidib, havopiridol, vincristine, tipidifoni, depsipeptide, BSU21051, cationic porphyrin compound, UCN-01, ICR-62, piratinib, PKI-166, Carnitinib, PD158780, HKI-357, ZD6126, amifostine, Ombrabulin, Butatin, soblidotin, denibulin, Tozasertib, decitabine, AEE788, Orantinib, SU5416, Enzastaurin, oxaliplatin, celecoxib, aspirin, Obatolcax, AT-101, tamoxifen, bicacoda, Rofecoxib, NS-398, SC-58125, Batimastat, prasodastat, 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, hand mycin, genistein, erbstatin, lavendustin A, herbimycin A, tyrphostin, PD169540, CL-387785, CP-358744, CGP59326, CGP59326-A, oleic acid A and B, mycotoxin, Linmycin 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, Gerd's mildew, new system Phytocetin, azacitidine, aclarin A, cholesterol derivative thioguanine, MCC465, liver-targeted carbamazepine, liver-targeted ricin, etoposide, teniposide, polosa M, dexamethasone, talivirin, BIBW-2992, tumor necrosis factor alpha antibody, GRO-beta antibody, anti-CMV anti-CMV , anti-CD3 mAb, anti-human interleukin-8 monoclonal antibody, anti-Tac monoclonal antibody, respiratory polysaccharide virus antibody, abciximab, rituximab, trastuzumab, temimumab, tosi Mozambican, alemtuzumab, gemtuzumab, cetuximab, bevacizumab, adalimumab, golimumab, basiliximab, infliximab, Panitumab, ovavazumab, daclizumab, uzumuzumab, 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, afutuzumab, ramucirumab, Raxibacumab, siltuximab, fanolesomab, vedolizumab, dorlimomab aritox, imciromab penetetate, alefacept, abatacept, belatacept, aflibercept, Zinapax, abagovom Ab, abx-il8, actoxumab, adecatumumab, alirocumab, anifrolumab, anrukinzumab, anti-LAG-3, apolizumab, bapineuzumab, bavituximab, beralizumab, bertilimumab, bezlotoxumab, bispecific antibody MDX-447, blinatumomab, blossuzumab, 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, guselkumab, ibalizumab / Hu5A8, icrucumab, inclacumab, intetumumab , iratumumab, labetuzumab, lampalizu mab, 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, ponezumap, 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, tralkinuma b, tregalizumab, tremelimumab, tucotuzumab celmoleukin, tuvirumab, ublituximab, urelumab, vantictumab, visilizumab, volociximab, zalutumumab, zanolimumab, dorlimomab aritox, aducanumab, alacizumab pegol, anatumomab mafenatox, aselizumab, aselizumab, atumumab, 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)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, moromumumab, nacolomab tafenatox, n Ebacumab, 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, Any of 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 . A bio-related substance modified with a heterofunctionalized polyethylene glycol derivative, characterized in that the bio-related substance modified by the hetero-functionalized polyethylene glycol derivative is represented by the formula (15), the formula (18), and the formula ( 21) or (24);

Wherein n ₁ and n ₂ represent the degree of polymerization of the two PEG branching strands, each independently satisfying 2 to 2000, and n ₃ represents the degree of polymerization of the main chain PEG, which satisfies 1 to 2000, and in the same molecule, n ₁ , n ₂ , n ₃ may be the same or different from each other; the three polyethylene glycol segments are each independently polydisperse or monodisperse; U is a trivalent group; L _1, L _2, L ₃ are the number of oxyethylene units connected to n _1, n _2, n linker polyethylene glycol units _3, are each independently present or absent and can be each other in the same molecule Same or different; p ₁ , p ₂ , and p ₃ are each independently 0, 1, or 2 to 1000; and L ₄ and L ₆ are each independently a divalent linking group; k ₄ , k ₅ , and k ₆ are each independently an integer of 1 or 2 to 250; G ₄ , G ₅ , and G ₆ are each independently a trivalent or higher valence linking group, and the valence states of G ₄ , G ₅ , and G ₆ are respectively k ₄ +1, k ₅ +1, k ₆ +1; Wherein D ₁ , D ₂ , and D ₃ are each independently represented as

Wherein q is 0 or 1; Z ₂ is a divalent linking group; D is a residue formed by reacting a modified bio-related substance with a hetero-functionalized Y-type polyethylene glycol; and L is a hetero-functionalized Y-type poly-B a linking group formed by reacting a functional group in a diol derivative or a protected form thereof with a biologically relevant substance; Wherein, in the same molecule, D ₁ and D ₂ have the same Z ₂ , q, and D ₁ and D ₂ have the same or different L; in the same molecule, D of D ₁ and D ₂ are from the same biologically relevant substance; Wherein D ₁ and D ₂ may be residues formed after different reaction sites in the same molecule participate in the reaction; Wherein, in the same molecule, U, L ₁ , L ₂ , L ₃ , L ₄ , L ₆ , G ₄ , G ₅ , G ₆ , Z ₂ (D ₁ ), Z ₂ (D ₂ ), Z ₂ (D _{3), L (D 1)} , L (D 2), L (D 3) in any one or any of the adjacent groups form a hetero atom linker may be stable or degradable; Any one of D ₁ and D ₃ is a residue of a fluorescent substance, and the other is a residue of a different biologically relevant substance. A bio-related substance modified with a heterofunctional polyethylene glycol derivative according to claim 78, wherein the fluorescent substance is selected from the group consisting of a fluorescent protein, a rhodamine, a phalloidin and a derivative thereof, and rhodamine. Class, cyanine dye, acridine, phycoerythrin, phycocyanin, methyl green, alizarin red, aniline blue, pyronine, fluorescein, hematoxylin, eosin, neutral red, alkaline Red, 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, II Any one of styrene, naphthalimide, coumarin, anthracene, phenanthridine, porphyrin, anthracene derivative, chromomycin A, and ethidium bromide. The bio-related substance modified with the heterofunctionalized polyethylene glycol derivative according to claim 78, 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. A bio-related substance modified with a hydroxyl group-containing or protected hydroxyl group-containing polyethylene glycol derivative, characterized in that the bio-related substance modified by the hydroxyl group-containing or protected hydroxyl group-containing polyethylene glycol derivative has the general formula Formula (27-1), Formula (28-1), Formula (27-2), Formula (28-2), (29-1), Formula (30-1), Formula (29-2) or Formula ( 30-2);

Wherein n ₁ and n ₂ represent the degree of polymerization of the two PEG branching strands, each independently satisfying 2 to 2000, and n ₃ represents the degree of polymerization of the main chain PEG, which satisfies 1 to 2000, and in the same molecule, n ₁ , n ₂ , n ₃ may be the same or different from each other; the three polyethylene glycol segments are each independently polydisperse or monodisperse; U is a trivalent group; L _1, L _2, L ₃ are the number of oxyethylene units connected to n _1, n _2, n linker polyethylene glycol units _3, are each independently present or absent and can be each other in the same molecule Same or different; p ₁ , p ₂ , and p ₃ are each independently 0, 1, or 2 to 1000; and L ₄ and L ₆ are each independently a divalent linking group; k ₄ , k ₅ , and k ₆ are each independently an integer of 1 or 2 to 250; G ₄ , G ₅ , and G ₆ are each independently a trivalent or higher valence linking group, and the valence states of G ₄ , G ₅ , and G ₆ are respectively k ₄ +1, k ₅ +1, k ₆ +1; Wherein D ₁ , D ₂ , and D ₃ are each independently represented as

Wherein q is 0 or 1; Z ₂ is a divalent linking group; D is a residue formed by reacting a modified bio-related substance with a hetero-functionalized Y-type polyethylene glycol; and L is a hetero-functionalized Y-type poly-B a linking group formed by reacting a functional group in a diol derivative or a protected form thereof with a biologically relevant substance; Wherein PG ₄ is a hydroxy protecting group; Wherein, in the same molecule, D ₁ and D ₂ have the same Z ₂ , q, and D ₁ and D ₂ have the same or different L; in the same molecule, D of D ₁ and D ₂ are from the same biologically relevant substance; Wherein D ₁ and D ₂ may be residues formed after different reaction sites in the same molecule participate in the reaction; Wherein, in the same molecule, U, L ₁ , L ₂ , L ₃ , L ₄ , L ₆ , G ₄ , G ₅ , G ₆ , Z ₂ (D ₁ ), Z ₂ (D ₂ ), Z ₂ (D _{3), L (D 1)} , L (D 2), L in (D ₃₎ according to any one or any of the adjacent groups form a hetero atom linker may be stable or degradable. The bio-related substance modified by the heterofunctionalized polyethylene glycol derivative according to claim 81, 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. The process for producing a heterofunctionalized polyethylene glycol derivative according to claim 1, wherein the heterofunctionalized polyethylene glycol derivative has a heterofunctional Y-form intermediate compound HA having a skeleton IM. The terminal linear functionalization or terminal branch functionalization modification of the two ends of the intermediate compound HA can be carried out independently to obtain a heterofunctional Y-type having the desired target functional group or its protected forms F ₁ and F ₂ polyethylene glycol derivatives; F _t wherein a main chain end of polyethylene glycol of F _2, branched-chain polyethylene glycol is end F _t F _1; and F ₁ ≠ F _2; The main chain end and the branch end of the compound HA are each independently a linear functionalized structure or a branched functionalized structure; when it is a linear functionalized structure, the polyethylene glycol chain end joining is only linked with one functional group or a protected form; when it is a branched functionalized structure, two or more functional groups or protected forms thereof are attached to the end of the polyethylene glycol chain; HA is a heterofunctional compound structure, two branched end has the same functional group or a protected form F _9, and the main chain terminal functional group or a protected form different F _7; F _7, At least one of F ₉ is not a target functional group or its protected form F _t . The method for producing a heterofunctionalized polyethylene glycol derivative according to claim 83, wherein in the heterofunctional Y-form intermediate compound HA, any one of F ₇ and F ₉ is a target functional group. Or its protected form F _t , hydroxyl or protected hydroxyl. The method for preparing a heterofunctionalized polyethylene glycol derivative according to claim 83, wherein in the heterofunctional Y-form intermediate compound HA, the combination of F ₇ and F ₉ is F _t and hydroxyl group, F Any of _t and a hydroxy protecting group, a hydroxy protecting group and a hydroxy group. The method for preparing a heterofunctional polyethylene glycol derivative according to claim 83, wherein the heterofunctionalized linear polyethylene glycol raw material used in the preparation method is polydisperse or monodisperse; The polyethylene glycol intermediates of the V-type structure and the Y-type structure are all hetero-functionalized structures; the preparation method may be selected from any of the following preparation routes: Route 1, the route of the first chain after the main chain, the steps of the route one are as follows: Step i, generation of a linear polyethylene glycol spindle: preparing a linear spindle end to be protected hydroxyl group, and the branching group is linked to two exposed hydroxyl intermediates IM1, and IM1 is not unstable under anionic polymerization conditions Non-hydroxyl group;

Step ii, the formation of two polyethylene glycol branched chains: starting from the intermediate IM1, the ethylene oxide polymerization is initiated by two bare hydroxyl groups of the branched group to form two polyethylene glycol branches having hydroxyl groups at the ends. a chain, a heterofunctional Y-type polyethylene glycol forming a structure of the formula (IM2);

Step iii, functionalization of the ends of the branched chain: starting from the compound (IM2), functionalizing the two branched chain ends to further obtain a functional group of the branched chain at the end of the branched chain or a heterofunctionalized form of the protected form F ₁ Y-type polyethylene glycol derivative; when terminal linear functionalization is carried out, a structure represented by formula (31) is obtained; when terminal branching functionalization is carried out, a structure represented by formula (32) is obtained;

Step iv, deprotection of the protected hydroxyl group at the end of the main chain: removal of the hydroxy protecting group PG ₄ at the end of the main chain polyethylene glycol, to obtain a naked hydroxyl group and a branch at the end of the main chain represented by the formula (IM3) or the formula (IM4) a heterofunctionalized Y-type polyethylene glycol having a terminal functional group or a protected form thereof;

Step v, functionalization of the end of the main chain: linear functionalization or branching functional modification of the terminal hydroxyl group of the main chain, resulting in heterofunctionalization of the main functional group or the branched chain end having the desired functional group or its protected form Y-type polyethylene glycol; starting from a heterofunctional Y-type polyethylene glycol derivative represented by the formula (IM3) or the formula (IM4), further functionalized by terminal linearization or terminal branching, 2) a heterofunctional Y-type polyethylene glycol derivative represented by formula (3), formula (4) or formula (5); corresponding to formula (2), formula (3), formula (4, respectively) ), general formula (5);

Route 2, the route of the main chain after the branch, the steps of the route 2 are as follows: Step i, Generation of a linear polyethylene glycol spindle: preparation of a linear spindle end containing a functional group or its protected form F ₇ , and a branching group linking two exposed hydroxyl intermediates IM1b, and IM1b is not contained in An unstable non-hydroxyl group under anionic polymerization conditions;

Step ii, the formation of two polyethylene glycol branched chains: starting from the intermediate IM1b, two bare ones connected by a branching group The hydroxyl group initiates the polymerization of ethylene oxide to form two polyethylene glycol branched chains terminated with a hydroxyl group to form a heterofunctional Y-type polyethylene glycol having the formula (IM2b);

Step iii, terminal functionalization modification: functionally modifying the main chain polyethylene glycol or branched polyethylene glycol terminal of the Y-form intermediate obtained in step ii, respectively, to obtain a functionalized group having a target or Protected form of the heterofunctionalized Y-type polyethylene glycol (2), (3), (4) or (5); the functionalized modification is a linear functional modification or a branched functionalization modification; Route 3, the route of the main chain after the first branch, the steps of the third route are as follows: Step i, by initiating the polymerization of ethylene oxide to form a V-type intermediate having two polyethylene glycol branched chains, and containing a branching group U; Wherein the branching group U is bonded to the protected hydroxyl group OPG ₄ or a functional group which is stable under anionic polymerization conditions or its protected form F ₁₀ , or UF ₁₀ together constitutes a functional group or a protected form thereof; _{10 is} not a hydroxy protecting group PG ₄ ; Wherein the branched polyethylene glycol-terminated linear or branched functional form functional form; functionalized linear or branched functionalized terminal functional group or a protected form F _9, F ₉ and the target function The functional group or its protected form F ₁ may be the same or different, and F ₉ may also be a hydroxy protecting group PG ₇ ; and F ₉ is required to be a functional group stable under anionic polymerization conditions or a protected form thereof; The V-type intermediate has any one of (52), (53), (54), (55), (56), (52b), (53b), (54b), (55b), (56b) structure;

Step ii, preparation of an intermediate having a naked hydroxyl group in the branching group: functionalizing the branching group U of the V-form intermediate obtained in step i to obtain a V-type intermediate (52c) in which a U is attached to a bare hydroxyl group. ), (53c), (54c), (55c), (56c);

Step iii, the formation of a linear polyethylene glycol spindle: starting from the bare hydroxyl group of the branched group U of the V-type intermediate obtained in the step ii, initiating polymerization of ethylene oxide to form a hydroxyl terminated linear polyethylene glycol spindle , obtaining a Y-form intermediate (52d), (53d), (54d), (55d) or (56d);

Step iv, each independently functionalizing the main chain polyethylene glycol or branched polyethylene glycol terminal of the Y-form intermediate obtained in the step iii to obtain a heterofunctional group having a target functionalized group or a protected form thereof Y-type polyethylene glycol (2), (3), (4) or (5); the functionalization modification is a linear functional modification or a branched functionalization modification; Route 4, branched 1-branched 2-main chain method, Step i: by initiating the polymerization of ethylene oxide or by reacting with a heterofunctionalized linear polyethylene glycol, two polyethylene glycol branched chains are successively introduced to respectively form divalent linking groups L ₁ and L ₂ to obtain a branch. a V-form intermediate of the group U; Wherein, the branching group may be bonded to the protected hydroxyl group OPG ₄ or other functional group or its protected form F ₁₀ , or UF ₁₀ together to form a functional group or a protected form thereof; OPG ₄ corresponds to the intermediate (52) , (53), (54), (55) or (56); F ₁₀ corresponds to the intermediate (52b), (53b), (54b), (55b) or (56b); Wherein, the polyethylene glycol branching chain end may be in a linear functionalized form or a branched functionalized form; a linear functionalized or branched functionalized terminal functional group or a protected form thereof is a functional group. The group or its protected form F ₉ , F ₉ may be the same or different from the target functional group or its protected form F ₁ , and F ₉ may also be a hydroxy protecting group PG ₇ ; Step ii: Preparation of Y-form intermediate; Y-form intermediate is (52d), (53d), (54d), (55d) or (56d), or IM7 or IM8; wherein F ₇ and target functional group The group or its protected form F ₂ may be the same or different; F ₇ may be a hydroxy protecting group; F ₇ and F ₉ in the same molecule are different; and any one of F ₇ and F ₉ is allowed to be a hydroxy protecting group;

Implemented in one of the following ways: Deprotecting the hydroxy protecting group PG ₄ from the branched group U of the V-form intermediate (52), (53), (54), (55) or (56) or chemically modifying it to introduce a bare hydroxyl group to initiate the epoxy B Alkyne polymerization, obtaining Y-type polyethylene glycol intermediate (52d), (53d), (54d), (55d) or (56d) with a linear spindle end hydroxyl group; Or containing functional group or a protected form of intermediate F V type (52b) ₁₀ of, (53b), (54b) , (55b) or (56b), by containing a functional group or a protected form F reaction between iso-functional linear polyethylene glycol ₇ generates divalent linking group L _3, to give intermediate Y-polyethylene glycol or IM8 IM7, which spindle end is a linear functional group or which is Protection form F ₇ ; Or chemically modifying the branching group U of the V-type polyethylene glycol intermediate (52b), (53b), (54b), (55b) or (56b) to form a divalent linking group L ₃ and introducing a new a functional group or a protected form thereof, and then reacted with a heterofunctionalized linear polyethylene glycol to obtain a Y-type polyethylene glycol intermediate IM7 or IM8; Step iii: functionally modifying the main chain polyethylene glycol or branched polyethylene glycol terminal of the Y-form intermediate obtained in the step ii, respectively, to obtain a heterofunctional group having a target functionalized group or a protected form thereof. Y-type polyethylene glycol (2), (3), (4) or (5); the functionalization modification is a linear functional modification or a branched functionalization modification; Route 5, main chain - branch 1 - branch 2 method, Step i: by the reaction between two heterofunctionalized linear polyethylene glycols, a divalent linking group L ₁ or L _{3 is formed} , which gives two functional groups at both ends or their protected forms F ₇ , F iso-functionalized polyethylene glycol intermediate IM5 _9, the two linear polyethylene glycol via chain or branched groups U U F ₁₀ is connected to substituted; F ₁₀ is a functional group or a protected form, or UF ₁₀ together constitute a functional group or a protected form thereof;

Step ii: linking the heterofunctionalized linear polyethylene glycol (60) having a functional group or its protected form F ₉ to the branched group of the polyethylene glycol intermediate IM5 obtained in the step i by a reaction At U, a divalent linking group L _{2 is formed} to obtain a heterofunctional Y-form intermediate represented by IM7;

Step iii: functionally modifying the main chain polyethylene glycol or branched polyethylene glycol terminal of the Y-form intermediate obtained in the step ii, respectively, to obtain a heterofunctional group having a target functionalized group or a protected form thereof. Y-type polyethylene glycol (2), (3), (4) or (5); the functionalization modification is a linear functional modification or a branched functionalization modification; Route 6: Branch-Chain Method, Polymerization-Coupling, Step i: starting from a functional group having a stable anionic polymerization condition or its protected form F ₁₀ and a small molecular initiator IN4 of two naked hydroxyl groups, the polymerization of ethylene oxide is initiated, and the ends of the two branched chains are obtained. a V-type intermediate of a hydroxyl group (51b); Step ii: linearly functionalizing the terminal hydroxyl group of the branched chain polyethylene glycol of the V-form intermediate obtained in the step ii to introduce a functional group or a protected form thereof F ₉ to obtain a V-form intermediate (54b); Step iii, the V-form intermediate obtained in step i and the heterofunctional linear polyethylene glycol (64b) having two functional groups or protected forms thereof F ₄ , F ₇ , between F ₁₀ and F ₄ The reaction produces a divalent linking group L ₃ to give a heterofunctional Y-type polyethylene glycol intermediate represented by IM7;

Step iv: linearly functionalizing or branching functionalizing the main chain polyethylene glycol terminal and the branched polyethylene glycol terminal, respectively, to obtain (2), (3), (4) or (5) respectively Heterofunctionalized Y-type polyethylene glycol; Route 7: Branch Chain - Main Chain Method, Coupling - Aggregation, Step i: a branching agent (59) having a protected hydroxyl group OPG ₄ , a branching group U, and a heterofunctionalized linear polyethylene glycol having two functional groups or a protected form thereof F ₉ (60) Coupling to form divalent linking groups L ₁ and L ₂ to obtain V-type intermediates in which two PEG branching ends are F ₉ and the branching group U is bonded to OPG ₄ ; Step ii: removing the hydroxy protecting group PG ₄ from the branched hydroxyl group of the branched group of the V-form intermediate (71) obtained in the step i to obtain a V-form intermediate (71c) having a bare hydroxyl group; Step iii, the naked hydroxyl group of the V-form intermediate (71c) obtained in the step ii is initiated to polymerize ethylene oxide to obtain a Y-type intermediate in which the terminal polyethylene glycol terminal is a hydroxyl group and the branched polyethylene glycol terminal is F ₉ . Body IM6; Step iv: linearly functionalizing or branching functionalizing the main chain polyethylene glycol terminal and the branched polyethylene glycol terminal, respectively, to obtain (73), (74), (75) or (76) respectively Heterofunctionalized Y-type polyethylene glycol;

Wherein, when (60) is polydisperse, the number average molecular weights of the two polyethylene glycol branched chains are identical; When (60) has, but is dispersible, the degree of polymerization of the two polyethylene glycol branches is numerically equal; Route 8: Branch-chain method, even legal, Step i: a branching agent (59b) having two different functional groups or protected forms thereof F ₁₀ and F ₁₃ , a branching group U, and two molecules having a functional group or a protected form thereof F ₉ Coupling of the heterofunctionalized linear polyethylene glycol (60) to form the divalent linking groups L ₁ and L ₂ , resulting in a V-shaped intermediate with two PEG branching ends ending at F ₉ and a branched group U linking F ₁₀ (71b); wherein F ₉ and F ₁₀ are different functional groups or protected forms thereof; F ₁₀ and F ₁₃ are different functional groups or protected forms thereof; Step ii: Form V obtained from step i (71b) and heterofunctionalized linear polyethylene glycol (64b) having two functional groups or protected forms thereof F ₄ , F ₇ , through F ₁₀ and F ₄ The reaction between the two forms a divalent linking group L ₃ to obtain a heterofunctional Y-type polyethylene glycol intermediate represented by IM9; Step iv: linearly functionalizing or branching functionalizing the main chain polyethylene glycol terminal and the branched polyethylene glycol terminal, respectively, to obtain (2), (3), (4) or (5) respectively Heterofunctionalized Y-type polyethylene glycol;

Route 9, the main chain - branching method, Step i: having a functional group or a protected form F linear polyethylene glycol (64b) ₇ of the reaction, reaction with a functional group or a protected form of small molecule compounds (62) F ₃ divalent a linking group L ₃ to obtain a polyethylene glycol intermediate (46c) having a functional group or a protected form F ₇ and a branched group U;

Step ii: The polyethylene glycol intermediate (46c) obtained in step i is coupled with two molecules of linear polyethylene glycol (60) having a functional group or its protected form F _{9 to} form a divalent linking group L ₁ And L ₂ to obtain a heterofunctional Y-type polyethylene glycol intermediate represented by IM9; Step iii: linearly functionalizing or branching functionalizing the main chain polyethylene glycol terminal and the branched polyethylene glycol terminal, respectively, to obtain (73), (74), (75) or (76) respectively The heterofunctionalized Y-type polyethylene glycol is shown. The method for producing a heterofunctional polyethylene glycol derivative according to claim 83, wherein the method for preparing the heterofunctional polyethylene glycol derivative is carried out by any one of the following methods: Method 1, the main chain-branched method, obtaining a polyethylene glycol spindle by a polymerization method, a) a co-initiation system consisting of a small molecule initiator (IN1) containing 1 naked hydroxyl group and 2 protected hydroxyl groups OPG ₇ and a base, deprotonating the bare hydroxyl group, then initiating polymerization of ethylene oxide to form polyethylene a linear spindle of the diol, an oxygen anion intermediate is obtained, and a proton source is added to obtain an intermediate (34) having a linear main chain terminal hydroxyl group and a branching group linking the two protected hydroxyl groups OPG ₇ ; b) linearly functionalizing the polyethylene glycol terminal hydroxyl group of the linear spindle of the intermediate (34) obtained in the step a) to obtain an intermediate (35b) having a functional group or a protected form thereof F ₇ ; ₇ stable under anionic polymerization conditions; c) removing the two hydroxy protecting groups PG ₇ from the intermediate (35b) obtained in step b) to obtain an intermediate IM1b having two naked hydroxyl groups; d) The intermediate IM1b obtained in step c) is combined with a base to form a co-initiation system. After deprotonation of the two exposed hydroxyl groups, polymerization of ethylene oxide is initiated to form two polyethylene glycol branched chains to obtain an oxygen anion intermediate. Adding a proton source to obtain a Y-type polyethylene glycol intermediate (IM2b) having a hydroxyl group at the end of the branch chain; e) linearly functionalizing the terminal hydroxyl group of the branched chain of the Y-form obtained in step d) to obtain Y-type polyethylene glycol (105) or branching functionalization to obtain Y-type polyethylene glycol (106); f) linearly functionalizing the terminal polyethylene glycol end of the Y-form intermediate (105) obtained in the step e) to obtain the structure represented by the formula (2), or performing branching functionalization to obtain the formula (4) Structure; Or linearly functionalizing the main chain polyethylene glycol terminal of the Y-form intermediate (106) obtained in the step e) to obtain the structure represented by the formula (3), or performing branching functionalization to obtain the formula (5) structure;

Wherein PG ₇ is a hydroxy protecting group selected from the group consisting of a silyl ether, a benzyl group, an acetal, a ketal or a tert-butyl group; F ₁ is a target functional group or a protected form thereof; and F ₇ is stably present under anionic polymerization conditions. And F _{7 is} not equal to F ₁ , a hydrogen atom, a hydroxyl group-containing functional group, or any of OPG ₇ ; F ₇ may be the same or different from the target functional group or its protected form; n ₁ , n ₂ The PEG chain corresponding to n ₃ has polydispersity; Method 2, using a heterofunctionalized linear polyethylene glycol as a polyethylene glycol spindle, a) using a heterofunctionalized linear polyethylene glycol (36b) as a starting material, and alkylating with a small molecular branching compound (37) to form a divalent linking group L ₃ to obtain an intermediate having two protected hydroxyl groups. (35b); wherein, F ₇ and F ₄ are different functional groups or protected forms thereof; b), c), d), e) repeat steps c), d), e), f) of method one; Wherein, step e): linearly functionalizing the terminal polyethylene glycol end of the Y-form intermediate (105) obtained in the step d) to obtain a structure represented by the formula (2), or performing branching functionalization to obtain a formula ( 4) the structure shown; Or linearly functionalizing the main chain polyethylene glycol terminal of the Y-form intermediate (106) obtained in the step d) to obtain the structure represented by the formula (3), or performing branching functionalization to obtain the formula (5) structure;

Wherein, the PG ₇ hydroxy protecting group is a silyl ether, a benzyl group, an acetal, a ketal or a tert-butyl group; F ₁ is a target functional group or a protected form thereof; and F ₇ is stably present under anionic polymerization conditions, F _{7 is} not equal to F ₄ , F ₁ , a hydrogen atom, a hydroxyl group-containing functional group, or any of OPG ₇ ; F _{3 is} not equal to OPG ₇ ; the PEG chain corresponding to n ₁ and n _{2 is} polydisperse; n ₃ Corresponding PEG chains are polydisperse or monodisperse; F ₇ may be the same or different from the target functional group F ₂ ; Method 3, an asymmetric glycerol branching group, Step a) Deprotonation (K, THF) of the heterofunctionalized linear polyethylene glycol (111) containing a functional group or its protected form F ₇ at the other end to give an oxygen anion intermediate, and a chloromethyl group Alkylation of ethylene oxide to obtain an intermediate having a glycidyl ether group represented by (39b); Step b) under basic conditions, the epoxy group in the intermediate (39b) obtained in step a) undergoes a ring opening reaction to obtain an intermediate (112) having two naked hydroxyl groups; c) The intermediate (112) obtained in the step b) is combined with a base to form a co-initiation system. After deprotonation of the two exposed hydroxyl groups, polymerization of ethylene oxide is initiated to form two polyethylene glycol branched chains to obtain an oxygen anion. An intermediate, a proton source is added to obtain a Y-type polyethylene glycol intermediate (113) having a hydroxyl group at the end of the branch chain; wherein the branch group is

Structure

Where U is

L ₁ is absent, L ₂ =CH ₂ , L ₃ =CH ₂ ; d) linearly functionalizing the terminal hydroxyl group of the branched chain of the Y-form obtained in step c) to obtain Y-type polyethylene glycol (114) or branching functionalization to obtain Y-type polyethylene glycol (115); e) linearly functionalizing the terminal polyethylene glycol end of the Y-form intermediate (114) obtained in the step d) to obtain the structure represented by the formula (2), or performing branching functionalization to obtain the formula (4) Structure; Or linearly functionalizing the main chain polyethylene glycol terminal of the Y-form intermediate (115) obtained in the step d) to obtain the structure represented by the formula (3), or performing branching functionalization to obtain the formula (5) structure;

among them,

L ₁ is absent, L ₂ =CH ₂ , L ₃ =CH ₂ ; F ₁ is a target functional group or a protected form thereof, and F _{7 is} not equal to a glycidyl ether group, F ₁ , a hydrogen atom, or a hydroxyl group-containing A functional group, any one of OPG ₇ ; wherein, the polyethylene glycol chain corresponding to n ₁ and n ₂ has polydispersity; and the polyethylene glycol chain corresponding to n ₃ is polydisperse or monodisperse. The method for preparing a hetero-functionalized polyethylene glycol derivative according to claim 87, wherein in the method 1, F ₇ is a hydroxy protecting group PG ₄ different from PG ₇ ; According to the steps a) to d), intermediates represented by (34), (35), IM1, and IM2 are respectively obtained; e) linearly functionalizing the terminal hydroxyl group of the branched chain of the Y-form obtained in step d) to obtain Y-type polyethylene glycol (31) or branching functionalization to obtain Y-type polyethylene glycol (32); f) removal of the hydroxy protecting group PG ₄ to obtain a hydroxyl group Y intermediate IM3 (corresponding to 31) and IM4 (corresponding to 32) at the end of the main chain; and then linearly functionalizing the terminal polyethylene glycol end of IM3 to obtain a formula (2) the structure shown, or branched functionalization to obtain the structure shown in formula (4); Or linearly functionalizing the terminal polyethylene glycol end of IM4 to obtain a structure represented by formula (3), or performing branching functionalization to obtain a structure represented by formula (5); The preparation process is as follows:

Wherein PG _{4 is} selected from the group consisting of a silyl ether, a benzyl group, an acetal, a ketal or a tert-butyl group. The method for producing a heterofunctional polyethylene glycol derivative according to claim 87, wherein in the second method, the small molecule branched compound (37) is an amine derivative having two protected hydroxyl groups (107) a heterofunctionalized linear polyethylene glycol (36b) is a heterofunctionalized polyethylene glycol polyethylene glycol sulfonate or a halogenated product; Step a) an alkylation reaction to give an intermediate (108) having two protected hydroxyl groups; According to the steps b), c), d), e), a heterofunctional group of a nitrogen atom branching center represented by the formula (2), (3), (4) or (5) wherein U is a nitrogen atom is obtained. Y-type polyethylene glycol; The preparation process is as follows:

Wherein PG _{4 is} selected from the group consisting of a silyl ether, a benzyl group, an acetal, a ketal or a tert-butyl group. The method for preparing a heterofunctional polyethylene glycol derivative according to claim 87, wherein in the third method, F ₇ is a hydroxy protecting group selected from the group consisting of a silyl ether, a benzyl group, an acetal, a ketal or Tert-butyl; The reaction starting material (111) is a heterofunctionalized linear polyethylene glycol (111b) having one end of the hydroxyl group and a protected hydroxyl group at one end, and (39), (112b), and (113b) are obtained through steps a), b), and c), respectively. The intermediate shown; the Y-form intermediate represented by (114b) or (115b) is obtained via step d); the hydroxy protecting group PG _{4 of the} main chain polyethylene glycol is removed by step e) to obtain a main chain a Y-form intermediate (114c) or (115c) having a hydroxyl group at the end; linearly functionalizing the terminal polyethylene glycol terminal of (114c) via step f) to obtain a structure represented by formula (2), or branching Functionalization gives the structure shown in formula (4); or linearly functionalizing the terminal polyethylene glycol end of (115c) via step f) to give the structure shown in formula (3), or branching functionalization a structure represented by the formula (5); wherein the structure of the branch group in the formulas (2), (3), (4), (5) is satisfied

L ₁ is absent, L ₂ =CH ₂ , L ₃ =CH ₂ ; wherein (111b) is polydisperse or monodisperse;

Wherein the PG ₄ hydroxy protecting group is selected from the group consisting of a silyl ether, a benzyl group, an acetal, a ketal or a tert-butyl group; F ₁ is a target functional group or a protected form thereof, and F _{1 is} not equal to OPG ₄ . The method for producing a heterofunctional polyethylene glycol derivative according to claim 83, wherein the method for preparing the heterofunctional polyethylene glycol derivative is carried out by the following method: Branch-chain polymerization, a) a co-initiation system consisting of a small molecule initiator (IN3) containing two exposed hydroxyl groups and one protected hydroxyl group OPG ₄ , and deprotonating the bare hydroxyl group to initiate polymerization of ethylene oxide to form two a polyethylene glycol branched chain, an oxygen anion intermediate is obtained, and two branched chain ends obtained by adding a proton source are terminated by a hydroxyl group, and a branched group is bonded to a V-type intermediate (51) which is protected by a hydroxyl group OPG ₄ ; b) linearly functionalizing the branch end of the V-form intermediate (51) obtained in the step a to obtain a V-form intermediate represented by (54), or performing the main chain end of the V-form intermediate (51) Branching functionalization modification to give a V-form intermediate as shown in (56); wherein the functional group or its protected form F ₉ is stably present under anionic polymerization conditions; c) the V-form intermediate (54) or (56) obtained in step b, the hydroxy-protecting group PG ₄ linked to the branch group is removed, to obtain a V-form intermediate (54c) or (56c) having one naked hydroxyl group. ; d) The intermediate (54c) or (56c) obtained in the step c) is combined with a base to form a co-initiation system, and after deprotonation of the exposed hydroxyl group, polymerization of ethylene oxide is initiated to form a linear polyethylene glycol spindle to obtain oxygen. Anion intermediate, adding a proton source to obtain a Y-type polyethylene glycol intermediate (54d) or (56d) having a hydroxyl group at the end of the main chain; e) linearly functionalizing the ends of the main chain polyethylene glycol of the Y-form intermediate (54d) obtained in the step d) and the branched polyethylene glycol to obtain the formulas (2), (3), (4) Or a heterofunctional Y-type polyethylene glycol as shown in (5); Or functionally modifying the main chain polyethylene glycol terminal and the branch chain end of the Y-form intermediate (56c) obtained in the step d) independently to obtain the heterofunctional Y-type poly group represented by (3) or (5). Ethylene glycol; wherein a linear functional modification or a branched functionalization modification is performed on the end of the main chain, and a linear functionalization modification is performed on the end of the branched chain;

Wherein PG ₄ is a hydroxy protecting group selected from the group consisting of a silyl ether, a benzyl group, an acetal, a ketal or a tert-butyl group; F _{9 is} not OPG ₄ and is stably present under anionic polymerization conditions; F ₉ and a target functional group The group or its protected form F ₁ may be the same or different; the PEG chains corresponding to n ₁ , n ₂ , and n ₃ are polydisperse. The method for producing a heterofunctionalized polyethylene glycol derivative according to claim 83, wherein the method for preparing the heterofunctional Y-type polyethylene glycol derivative is carried out by any one of the following methods: Branched 1-branched 2-main chain method, Method 1, coupling-coupling-even law, a) a heterofunctionalized linear polyethylene glycol containing a functional group or its protected form F _{10 and} a branching agent (62) with two different functional groups or protected forms thereof F ₉ , F ₁₁ (60), reacting between the branched groups U and F ₁₁ to form a divalent linking group L ₁ , introducing a first branched chain to form an intermediate represented by the formula (63); b) the intermediate compound (63) obtained in the step a) and the heterofunctionalized linear polyethylene glycol (60b) containing two functional groups F ₉ and F ₁₂ or a protected form thereof, a branched group a reaction between U and F ₁₂ to form a divalent linking group L ₂ and a second branched chain to give an intermediate represented by (54b); c) step b) to give intermediate (54b), containing two different functional groups, or a protected form F isobutyl functionalized linear polyethylene glycol (64b) _7, F _4, dried and F ₁₀ a reaction between F ₄ to form a divalent linking group L ₃ to obtain a heterofunctional Y-type polyethylene glycol intermediate represented by IM7; d) independently linearly functionalizing or branching functionalizing the polyethylene glycol end and the branched polyethylene glycol end of the main chain, respectively, as shown in (2), (3), (4) or (5) Heterofunctionalized Y-type polyethylene glycol;

Wherein F ₄ , F ₇ , F ₉ , F ₁₀ , F ₁₁ , F ₁₂ are all functional groups or protected forms thereof; and two functional groups present in the same molecule or protected forms thereof Different; (F ₁₁ , F ₉ ), (F ₁₀ , F ₉ ), (F ₁₂ , F ₉ ), (F ₇ , F ₄ ), (F ₇ , F ₉ ) are heterofunctionalized pairs; n ₁ , n ₂ , n ₃ corresponding to the PEG chains are each independently polydisperse or monodisperse; any of F ₇ and F ₉ may be a target functional group or a protected form thereof; Method 2, coupling-coupling-polymerization, a) a branched small molecule compound (59) containing a protected hydroxyl group OPG ₄ and a heterofunctionalized linear polyethylene glycol (60) containing two different functional groups or protected forms thereof F ₉ , F ₁₁ , Directly reacting the branched group U with F ₁₁ to form a divalent linking group L ₁ , and introducing the first branched chain to form a compound represented by the formula (61); b) (61) obtained in step a) and a heterofunctionalized linear polyethylene glycol (60b) containing a functional group or a protected form thereof F ₉ , via F ₉ and F ₁₂ functional groups or The reaction between the protected forms forms a divalent linking group L ₂ and introduces a second branched chain to form a V-form intermediate as shown in (54); c) the V-form intermediate (54) or (56) obtained in step b, the hydroxy-protecting group PG ₄ linked to the branch group is removed, to obtain a V-form intermediate (54c) or (56c) having one naked hydroxyl group. ; d) The intermediate (54c) or (56c) obtained in the step c) is combined with a base to form a co-initiation system, and after deprotonation of the exposed hydroxyl group, polymerization of ethylene oxide is initiated to form a linear polyethylene glycol spindle to obtain oxygen. Anion intermediate, adding a proton source to obtain a Y-type polyethylene glycol intermediate (54d) or (56d) having a hydroxyl group at the end of the main chain; e) linearly functionalizing the ends of the main chain polyethylene glycol of the Y-form intermediate (54d) obtained in the step d) and the branched polyethylene glycol to obtain the formulas (2), (3), (4) Or a heterofunctional Y-type polyethylene glycol as shown in (5); Or functionally modifying the main chain polyethylene glycol terminal and the branch chain end of the Y-form intermediate (56c) obtained in the step d) independently to obtain the heterofunctional Y-type poly group represented by (3) or (5). Ethylene glycol; wherein a linear functional modification or a branched functionalization modification is performed on the end of the main chain, and a linear functionalization modification is performed on the end of the branched chain;

Wherein, PG ₄ is a hydroxy protecting group, which is a silyl ether, a benzyl group, an acetal, a ketal or a tert-butyl group; F ₉ , F ₁₁ and F ₁₂ are all functional groups or protected forms thereof; F ₉ is an anion Stable in the polymerization conditions; two functional groups present in the same molecule or their protected forms are different; (F ₁₁ , F ₉ ), (OPG ₄ , F ₉ ), (F ₁₂ , F ₉ ), (OH, F ₉ ) are all heterofunctionalized pairs; wherein, n ₁ , n ₂ correspond to PEG chains, each independently being polydisperse or monodisperse; n ₃ corresponding PEG chains are polydisperse; F ₉ and target The functional group or its protected form F ₁ may be the same or different; Method three, polymerization-coupling-even law, a) a small molecule initiator (67) having a functional group or a protected form thereof, F ₁₀ and a hydroxyl group, and a base-constituting co-initiation system, after deprotonating the exposed hydroxyl group, initiating polymerization of ethylene oxide to form a poly The ethylene glycol chain is obtained as an oxygen anion intermediate, and a proton source is added to obtain an intermediate (69) having a hydroxyl group at the end of the PEG chain; F ₁₀ is a functional group which is stable under anionic polymerization conditions or a protected form thereof; b) linearly functionalizing the terminal hydroxyl group of the polyethylene glycol chain of the intermediate (69) obtained in the step a), and capping with a functional group or its protected form F _{9 to} obtain an intermediate (63); c) the intermediate compound (63) obtained in the step b) and the heterofunctionalized linear polyethylene glycol (60b) containing two functional groups F ₉ and F ₁₂ or a protected form thereof, a branched group a reaction between U and F ₁₂ to form a divalent linking group L ₂ and a second branched chain to give a compound represented by (54b); d) step c) to give the intermediate (54b), containing two different functional groups, or a protected form F _7, iso-functionalized linear polyethylene glycol (64b) F _4, dried and F ₁₀ a reaction between F ₄ to form a divalent linking group L ₃ to obtain a heterofunctional Y-type polyethylene glycol represented by IM7; e) linearly functionalizing or branching functionalizing the main chain polyethylene glycol terminal and the branched polyethylene glycol terminal independently, respectively, as shown in (2), (3), (4) or (5) Heterofunctionalized Y-type polyethylene glycol;

Wherein F ₄ , F ₇ , F ₁₀ , F ₉ , F ₁₂ are all functional groups or protected forms thereof; F ₁₀ is stably present under anionic polymerization conditions; two functional groups present in the same molecule The group or its protected form is different; (F ₁₀ , hydroxyl), (F ₁₀ , F ₉ ), (F ₁₂ , F ₉ ), (F ₇ , F ₄ ), (F ₇ , F ₉ ) are all heterofunctional a pair of PEG chains corresponding to n ₁ having polydispersity, n ₂ , n ₃ corresponding to PEG chains are each independently polydisperse or monodisperse; any one of F ₇ and F ₉ may be a target functional group A group or its protected form. The method for preparing a heterofunctional polyethylene glycol derivative according to claim 92, wherein in the first method, UF ₁₀ is a primary amine, and the synthesis steps are as follows: a) having a functional group or a protected form F ₉ heterologous functional linear amine derivative of polyethylene glycol (116) having a functional group or are different linear polyethylene functionalized protected form F ₉ II The alkylation reaction of the sulfonate, halogenated or aldehyde derivative (60b) of the alcohol forms a V-type secondary amine intermediate (117); b) the V-type secondary amine intermediate (117) obtained in step a) is reacted with a heterofunctionalized linear polyethylene glycol active derivative (64b) containing a functional group or its protected form F ₁₂ , F ₉ Base or amidation reaction to obtain a Y-type polyethylene glycol intermediate (118) of a nitrogen atom branching center; c) independently linearly functionalizing or branching functionalizing the polyethylene glycol terminal and the branched polyethylene glycol terminal of the main chain, respectively, as shown in (2), (3), (4) or (5) Heterofunctionalized Y-type polyethylene glycol of the nitrogen atom branching center;

Wherein U is a nitrogen atom N; F ₄ , F ₇ , F ₉ , F ₁₁ , F ₁₂ are all functional groups or protected forms thereof; and two functional groups present in the same molecule or The protected form is different; (F ₁₁ , F ₉ ), ((F ₁₂ , F ₉ ), (F ₇ , F ₄ ), (F ₇ , F ₉ ) are all heterofunctionalized pairs. The method for preparing a hetero-functionalized polyethylene glycol derivative according to claim 92, wherein in the third method, F ₁₀ in the reagent (67) is a protected amino group NHPG ₅ , and the structure thereof is as defined in (122) Show; the preparation process is as follows: a) using one end of the hydroxyl group as the protected amino NHPG ₅ small molecule initiator (122) as a raw material, through step a) to obtain a PEG chain end hydroxyl group intermediate (123); b) linearly functionalizing the terminal hydroxyl group of the polyethylene glycol chain of the intermediate (123) obtained in the step a), and capping with a functional group or its protected form F _{9 to} obtain an intermediate (124); c) deprotecting the protected amino group NHPG ₅ from the intermediate (124) obtained in step b) to obtain a primary amine intermediate (116) of polyethylene glycol; d), e), f) repeat the steps in 2.3.3.1. respectively to obtain a heterofunctional Y-form represented by (2), (3), (4) or (5) and having a branching center of a nitrogen atom Polyethylene glycol The synthesis steps are as follows:

Wherein, U is a nitrogen atom N; wherein PG ₅ is an amino protecting group, and NHPG ₅ is an amino group protected structure selected from the group consisting of a carbamate, an amide, an imide, an N-alkylamine, and an N-aryl group. Amine, imine, enamine, imidazole, pyrrole or hydrazine; F ₄ , F ₇ , F ₉ , F ₁₂ are all functional groups or protected forms thereof; and two functions present in the same molecule a group or a protected form thereof; (NHPG ₅ , F ₉ ), (NH ₂ , F ₉ ), (F ₁₂ , F ₉ ), (F ₇ , F ₄ ), (F ₇ , F ₉ ) Is a heterofunctional pair. The method for producing a heterofunctionalized polyethylene glycol derivative according to claim 83, wherein the method for preparing the heterofunctional Y-type polyethylene glycol derivative is carried out by the following method: Main chain / branch 1 - branch 2, a) using two heterofunctionalized linear polyethylene glycols as starting materials to form a divalent linking group L ₁ or L ₃ to obtain a heterofunctional polyethylene glycol intermediate IM5 having two polyethylene glycol blocks; polyethylene glycol segment spindle end to a functional group or a protected form terminated F _7; polyethylene glycol as an end of one of the branched segment to a functional group or a protected form capped F ₉ a junction of two polyethylene glycol chains having a branching group U, U linked to a functional group or a protected form thereof F ₁₀ , or UF ₁₀ together forming a functional group or a protected form thereof;

When the divalent linking group L ₁ is formed, U is located at the end of the main chain polyethylene glycol raw material; the structures of the raw materials of the main chain polyethylene glycol and the branched polyethylene glycol are as shown in (46c) and (60), respectively;

When the divalent linking group L ₃ is formed, U is located at the end of the branched polyethylene glycol raw material; the structures of the raw materials of the main chain polyethylene glycol and the branched polyethylene glycol are as shown in (64b) and (63), respectively;

b) intermediate IM5 obtained in step a), and a heterofunctionalized linear polyethylene glycol (60b) containing two functional groups F ₉ and F ₁₂ or a protected form thereof, between F ₁₀ and F ₁₂ Reaction to form a divalent linking group L ₂ to obtain a Y-form intermediate IM7;

c) independently linearly functionalizing or branching functionalizing the main chain polyethylene glycol terminal and the branched polyethylene glycol terminal to obtain the results shown in (2), (3), (4) or (5) Heterofunctionalized Y-type polyethylene glycol; Wherein F ₄ , F ₇ , F ₉ , F ₁₀ , F ₁₁ , F ₁₂ are all functional groups or protected forms thereof; two functional groups present in the same molecule or different protected forms thereof (F ₇ , F ₄ ), (F ₇ , F ₁₀ ), (F ₁₁ , F ₉ ), (F ₇ , F ₉ ), (F ₁₂ , F ₉ ) are all heterofunctionalized pairs; ₁ , n ₂ , n ₃ corresponding to the PEG chains are each independently polydisperse or monodisperse; any of F ₇ and F ₉ may be a target functional group or a protected form thereof. The method for preparing a heterofunctional polyethylene glycol derivative according to claim 95, wherein the UF ₁₀ is NH ₂ ; the structure of the main chain polyethylene glycol raw material (46c) is as shown in (125); The preparation process is as follows: a) having a functional group or a protected form F iso-functionalized polyethylene glycol amine derivative ₇ (125) having a functional group or a functional heterologous F is a protected form of a linear polyethylene glycol ₉ The sulfonate, halogenated or aldehyde derivative (60) undergoes an alkylation reaction to form a secondary amine intermediate (126); b) alkylation of the secondary amine intermediate (126) obtained in step a) with a heterofunctionalized linear polyethylene glycol reactive derivative (60b) containing a functional group or its protected form F ₁₂ , F ₉ Or amidation reaction to obtain a Y-type polyethylene glycol intermediate (118) of a nitrogen atom branching center; c) independently linearly functionalizing or branching functionalizing the polyethylene glycol terminal and the branched polyethylene glycol terminal of the main chain, respectively, as shown in (2), (3), (4) or (5) Heterofunctionalized Y-type polyethylene glycol of the nitrogen atom branching center;

Wherein U is a nitrogen atom N; F ₇ , F ₉ , F ₁₁ , F ₁₂ are all functional groups or protected forms thereof; and two functional groups present in the same molecule or protected forms thereof Different; (F ₇ , NH ₂ ), (F ₁₁ , F ₉ ), (F ₇ , F ₉ ), (F ₁₂ , F ₉ ) are all heterofunctionalized pairs. The method for producing a heterofunctionalized polyethylene glycol derivative according to claim 83, wherein the method for preparing the heterofunctional Y-type polyethylene glycol derivative is carried out by the following method: Branch-host method, coupling-polymerization, a) a small initiator (IN4) having two protected hydroxyl groups and a base co-initiation system, after deprotonating two exposed hydroxyl groups, initiating polymerization of ethylene oxide to form a polyethylene glycol branching chain, Obtaining an oxygen anion intermediate, adding a proton source to obtain a V-type intermediate (51b) having a hydroxyl group terminal at the PEG chain; F ₁₀ or UF ₁₀ is a functional group stable under anionic polymerization conditions or a protected form thereof; b) linearly functionalizing the terminal hydroxyl group of the PEG branch chain of the V-form intermediate (51b) to obtain the V-form intermediate represented by (54b), or performing branching functionalization to obtain V as shown in (56b) Type intermediate c) a V-form intermediate (54b) or (56b) obtained in step b), and a heterofunctionalized linear polyethylene glycol (64b) containing two different functional groups or protected forms thereof F ₇ , F ₄ a reaction between F ₁₀ and F ₄ to form a divalent linking group L ₃ to give a hetero-functionalized Y-type polyethylene glycol intermediate IM7 or (IM8); e) linearly functionalizing or branching functionalization of the main chain polyethylene glycol terminal and the branched polyethylene glycol terminal of IM7, respectively, to obtain (2), (3), (4) or (5) a heterofunctionalized Y-type polyethylene glycol as shown; Or independently functionalize the functionalization or branching functionalization of the main chain polyethylene glycol terminal and the branched polyethylene glycol terminal of IM8, respectively, to obtain the heterofunctional Y-type poly group represented by (3) or (5), respectively. Ethylene glycol

Wherein _{F 4, F 7, F 9} , F 10 , or both functional groups are in protected form; F ₁₀ or UF ₁₀ is stable under anionic polymerization conditions a functional group or a protected form; present in the same Two functional groups in one molecule or different protected forms; (F ₁₀ , OH), (F ₁₀ , F ₉ ), (F ₇ , F ₉ ) are heterofunctionalized pairs; wherein, n ₁ The PEG chain corresponding to n ₂ has polydispersity; the PEG chain corresponding to n ₃ is polydisperse or monodisperse; and any of F ₇ and F ₉ may be a target functional group or a protected form thereof. The method for producing a heterofunctionalized polyethylene glycol derivative according to claim 97, wherein the UF ₁₀ is a protected amino NPG ₅ ; and the structure of the small molecule initiator IN4 is as shown in (129). The corresponding reaction process is as follows; Obtaining the intermediates represented by (130), (131) or (130), (132) through the steps a) and b) respectively; c) removing the amino protecting group PG ₅ at the branched group from the V-form intermediate (131) or (132) obtained in the step b) to obtain a V-type polyethylene glycol amine derivative (117) or (133) ; d) a V-form intermediate (117) or (133) obtained in step c), and a heterofunctionalized linear polyethylene glycol containing two different functional groups or protected forms thereof F ₇ , F ₄ ( 64b), a reaction between F ₁₀ and F ₄ to form a divalent linking group L ₃ to obtain a heterofunctional Y-type polyethylene glycol intermediate (118) or (134); e) linearly functionalizing or branching functionalizing the (PEG) main chain polyethylene glycol terminal and the branched polyethylene glycol terminal, respectively, to obtain (2), (3), (4) or 5) a heterofunctionalized Y-type polyethylene glycol of the nitrogen atom branching center shown; Or linearly functionalizing or branching functionalizing the main chain polyethylene glycol terminal and the branched polyethylene glycol terminal of (134), respectively, to obtain the nitrogen atom branching represented by (3) or (5), respectively. Central heterofunctional Y-type polyethylene glycol;

Wherein, U is a nitrogen atom N; wherein PG ₅ is an amino protecting group, and NHPG ₅ is an amino group protected structure selected from the group consisting of a carbamate, an amide, an imide, an N-alkylamine, and an N-aryl group. Alkylamine, imine, enamine, imidazole, pyrrole or hydrazine; F ₄ , F ₇ , F ₉ are all functional groups or protected forms thereof; two functional groups present in the same molecule or It is protected in different forms; (NPG ₅ , F ₉ ), (F ₇ , F ₉ ) are all heterofunctionalized pairs. The method for producing a heterofunctionalized polyethylene glycol derivative according to claim 83, wherein the method for preparing the heterofunctional Y-type polyethylene glycol derivative is carried out by the following method: Branch-main chain, coupling-polymerization, a) a small molecule compound (59c) having one protected hydroxyl OPG ₄ and two functional groups or a protected form thereof F ₁₃ and two molecules having a functional group or a protected form thereof F ₁₁ , F ₉ The functionalized linear polyethylene glycol (60) reacts to form a divalent linking group L ₁ , L ₂ through the reaction between F ₁₃ and F _{11 to} obtain a V-form intermediate (71); b) removing the hydroxy protecting group PG ₄ from the V-form intermediate (71) to obtain a V-form intermediate (71c) having a bare hydroxyl group; c) Step a) to obtain a V-form intermediate (71c) and a base co-initiation system, after deprotonating the exposed hydroxyl group, initiate polymerization of ethylene oxide to form a polyethylene glycol main chain, and obtain an oxygen anion intermediate a heterofunctional Y-type polyethylene glycol intermediate IM6 having a hydroxyl group terminal at the end of the PEG chain; F ₉ is a functional group stable under anionic polymerization conditions or a protected form thereof; d) independently linearly functionalizing or branching functionalizing the terminal polyethylene glycol terminal hydroxyl group and the branched polyethylene glycol terminal, respectively, to obtain (73), (74), (75) or (76) Heterofunctionalized Y-type polyethylene glycol,

The schematic of the synthetic route is as follows:

Wherein PG ₄ is a hydroxy protecting group selected from the group consisting of a silyl ether, a benzyl group, an acetal, a ketal or a tert-butyl group; and F ₉ , F ₁₁ and F ₁₃ are all functional groups or protected forms thereof; F ₉ is a functional group that is stable under anionic polymerization conditions or a protected form thereof; two functional groups present in the same molecule or a protected form thereof; (OPG ₄ , F ₁₃ ), (F ₁₁ , F ₉ ), (OPG ₄ , F ₉ ), (OH, F ₉ ) are all heterofunctionalized pairs; wherein, the PEG branching chains corresponding to n ₁ and n ₂ are both polydisperse or monodisperse; n ₁ ≈n ₂ in the case of polydispersity, n ₁ =n _{2 in the} same monodispersity; PEG chain corresponding to n _{3 is} polydisperse; F ₉ may be the same as the target functional group or its protected form F ₁ Or different. The method for producing a heterofunctionalized polyethylene glycol derivative according to claim 83, wherein the method for preparing the heterofunctional Y-type polyethylene glycol derivative is carried out by the following method: Branch-main chain, coupling-even law, a) a small molecule compound (59b) having a functional group or a protected form thereof F ₁₀ or UF ₁₀ and 2 functional groups or a protected form thereof F ₁₃ and 2 molecules having a functional group or The heterofunctionalized linear polyethylene glycol (60) of the protected forms F ₁₁ and F ₉ is reacted to form a divalent linking group L ₁ and L ₂ by the reaction between F ₁₃ and F _{11 to} obtain a V-form intermediate (71b). ; b) to step a) of the V-shaped intermediate (71b), containing two different functional groups, or a protected form F isobutyl functionalized linear polyethylene glycol (64b) _7, F _4, dried a reaction between F ₁₀ and F ₄ to form a divalent linking group L ₃ to obtain a heterofunctional Y-type polyethylene glycol intermediate IM9 of a nitrogen atomic branching center; c) linearly functionalizing or branching functionalization of the main chain polyethylene glycol terminal and the branched polyethylene glycol terminal of IM9, respectively, to obtain (73), (74), (75) or (76) a heterofunctionalized Y-type polyethylene glycol as shown;

Wherein F ₄ , F ₇ , F ₉ , F ₁₀ , F ₁₁ , F ₁₃ are all functional groups or protected forms thereof; two functional groups present in the same molecule or different protected forms thereof (F ₁₀ , F ₁₃ ), (F ₁₁ , F ₉ ), (F ₁₀ , F ₉ ), (F ₇ , F ₄ ), (F ₇ , F ₉ ) are all heterofunctionalized pairs; ₁ , n ₂ corresponds to the PEG branch chain is polydisperse or the same monodisperse; the same polydispersity n ₁ ≈ n ₂ , the same monodispersity n ₁ = n ₂ ; n ₃ corresponding PEG The chain is polydisperse or monodisperse; any of F ₇ and F ₉ may be a target functional group or a protected form thereof. The method for producing a heterofunctional polyethylene glycol derivative according to claim 83, wherein the method for preparing the heterofunctional polyethylene glycol derivative is carried out by the following method: Main chain coupling branching method, a) containing two different functional groups, or a protected form F _7, F ₄ iso-functionalized linear polyethylene glycol (64b), and a functional group or a protected form F ₃ (1 th) , F ₁₃ (two) small molecule compound (62) reacts, and a reaction between F ₄ and F ₃ forms a divalent linking group L ₃ to obtain a polyethylene glycol intermediate (46c) having the structure shown by (46c). ); b) the polyethylene glycol intermediate (46c) obtained in step a) is reacted with two molecules of a heterofunctionalized linear polyethylene glycol (60) having a functional group or a protected form thereof F ₁₁ , F ₉ , via U The reaction between F ₁₁ forms a divalent linking group L ₁ , L ₂ to obtain a Y-form intermediate IM9; c) linearly functionalizing or branching functionalization of the main chain polyethylene glycol terminal and the branched polyethylene glycol terminal of IM9, respectively, to obtain (73), (74), (75) or (76) a heterofunctionalized Y-type polyethylene glycol as shown;

Wherein F ₃ , F ₄ , F ₇ , F ₉ , F ₁₁ , F ₁₃ are all functional groups or protected forms thereof; two functional groups present in the same molecule or different protected forms thereof (F ₇ , F ₄ ), (F ₃ , F ₁₃ ), (F ₇ , F ₁₃ ), (F ₁₁ , F ₉ ), ((F ₇ , F ₉ ) are all heterofunctionalized pairs; The PEG branch chains corresponding to n ₁ and n ₂ are both polydisperse or monodisperse; n ₁ ≈ n ₂ in the case of polydispersity, n ₁ =n _{2 in the} same monodispersity; n ₃ corresponds The PEG chain is polydisperse or monodisperse; any of F ₇ and F ₉ may be a target functional group or a protected form thereof.