Polymer-drug conjugate, and intermediate and application thereof

Abstract

The invention relates to a polymer-drug conjugate with controllable and stable nanometer size, and an intermediate and application thereof. The invention relates to a polymer-drug conjugate which is shown as a formula (I), takes different polymer main bodies, and has controllable group coupling quantity, controllable group coupling sites and controllable nanometer size. The drug conjugate has one or more of the advantages of low kidney clearance rate, low liver and spleen clearance rate, long plasma half-life period, strong focus tissue drug accumulation capacity, strong focus tissue drug infiltration capacity, low toxic and side effects and excellent treatment effect. # imgabs0 #

Description

Polymer-drug conjugates, intermediates thereof and applications thereof

[0001] This application claims priority to Chinese patent application No. 2023104743553, filed on April 28, 2023. This application incorporates the entirety of the aforementioned Chinese patent application. Technical Field

[0002] The present invention belongs to the field of drug delivery and relates to a polymer-drug conjugate, an intermediate thereof and applications thereof. Background Art

[0003] Cancer is one of the world's greatest health problems, with millions of people tragically developing malignant tumors each year. With the accelerated aging of the global population and rising cancer rates, clinical demand for cancer treatment is on the rise, leading to steady growth in the global anti-cancer drug market, which is projected to reach approximately $230 billion by 2026. Chemotherapy remains the most important treatment for cancer, but these drugs often suffer from significant drawbacks, including high toxicity, severe side effects, drug resistance, and low in vivo delivery efficiency.

[0004] Tumor drug delivery is a very challenging field due to the significant differences in pathology and physiology between tumor tissue and healthy tissue. For example, the high density and closedness of tumor tissue, as well as the diversity and complexity of the tumor cell matrix, limit drug diffusion within tumor tissue and make it difficult to penetrate the tumor tissue matrix and interior. Nano-drug delivery systems are a very effective delivery method, offering advantages such as improved bioavailability, enhanced drug stability and solubility, further enhancing the targeted enrichment of drugs in tumor tissue, reducing the drug's toxic side effects on normal tissues, and improving the efficacy of tumor treatment.

[0005] The entire delivery process of nanomedicine involves multiple aspects, including in vivo circulation stability, tumor tissue penetration, and drug endocytosis by tumor cells. These processes are closely related to the size of the nanomedicine. For example, the molecular weight of ADC drugs (antibody-drug conjugates) is about 160,000, and its molecular size is usually at the nanometer level (about 10nm). However, ADC drugs are affected by environmental factors, enzymatic degradation, and storage conditions, resulting in unstable physical and chemical properties and prone to aggregation or depolymerization. The nanometer size changes during in vivo delivery due to instability. For example, ADC drugs will bind to proteins during blood circulation to form large nanometer-sized protein coronas. In addition, ADC drugs will also aggregate to form large nanometer-sized particles during storage. The formation of these large particles leads to poor permeability, thereby reducing drug efficacy.

[0006] The molecular weight of polypeptide drug conjugates (PDCs) is usually less than 5000, and their molecular size is small (less than 1nm). PDCs have strong permeability to tumor tissues during in vivo delivery, but PDCs are easily filtered and excreted by the kidneys, thereby shortening the drug's half-life in the body. In order to achieve better therapeutic effects, it is necessary to increase the dosage and frequency of PDC drugs, resulting in poor safety.

[0007] Polymer-drug conjugates are drug delivery systems formed by conjugating therapeutic drugs to polymers through specific linkers. For example, conjugating therapeutic drugs to dendrimer polymers can produce dendrimer-drug conjugates with a certain nanometer size. However, such conjugated drugs tend to aggregate to form nanoparticles larger than 50 nm in size during preparation production and storage (Zhang, Chengyuan, et al. Acta biomaterialia, 2017, 55: 153-162; Zhang, Chengyuan, et al. Polymer Chemistry, 2014 (5) 18: 5227-5235.), which makes the tissue distribution, tissue penetration and active drug release rate of the drug in the body uncertain. At the same time, due to the compact structure of dendrimers, the release rate of active drugs in the body is reduced, which in turn affects the efficacy of the drug. Usually, an increase in dosage is required to achieve an effective therapeutic effect, which in turn brings about drug safety issues. In addition, dendrimer-drug conjugates also have problems such as difficulty in synthesis and scale-up production, and high production costs.

[0008] Summary of the Invention

[0009] The technical problem to be solved by the present invention addresses the problems existing in the aforementioned types of conjugated drugs. The compounds of the present invention represent a novel class of polymer-drug conjugates, particularly those based on natural amino acid polypeptides, exhibiting excellent biocompatibility, minimal toxicity and side effects, and high safety. Through the rational design of the polypeptide molecule and linker, the number of conjugated groups and the nanometer size can be controlled. These novel polymer-drug conjugates are neutral, small, and stable nanoparticles. On the one hand, the uncharged surface of the nanoparticles prevents aggregation between the nanoparticles, thereby ensuring the stability of the small nanoparticles during preparation and storage. On the other hand, the neutral nature of the nanoparticles significantly reduces the likelihood of binding to blood proteins to form a large protein corona, thereby significantly improving the permeability of these novel polymer-drug conjugates in tumor tissue. Furthermore, the design of linkers within the linker that respond to different release mechanisms enables high selectivity for the drug to the target tissue and adjustable drug release rate, thereby improving efficacy while reducing toxicity and side effects. These novel polymer-drug conjugates utilize a stable connection at the coupling point, resulting in nanoparticles larger than the glomerular filtration threshold. They are stable in the bloodstream and have a long half-life, allowing for reduced dosage and frequency, ensuring a balance between efficacy and safety. Therefore, the compounds of this invention have broad application prospects and market potential.

[0010] The present invention solves the above technical problems through the following technical solutions.

[0011] The purpose of the present invention is to provide a polymer-drug conjugate with controllable number of group couplings and controllable nanometer size and stability as shown in formula (I)

[0012] The polymer-drug conjugate comprises:

[0013] (1) A polymer residue, as shown in formula (II), wherein the number of repeating units of the polymer main body is n,

[0014] The value of n is an integer selected from 4 to 100;

[0015] (2) Y is a branching center with at least three functionalities;

[0016] (3) P is the pharmacokinetic modulator residue;

[0017] (4) D is a pharmaceutically active agent residue, and D can be one or more drug residues;

[0018] (5) X is a terminal group;

[0019] (6)L 0 , L1 , L 2 Each independently is a covalent bond or a C1-C 40 The linker contains or does not contain heteroatoms, wherein the heteroatoms are O, S, Se, N, P, Si or B, and the number of the heteroatoms is one or more. When there are multiple heteroatoms, the heteroatoms are the same or different. The linker may contain or do not contain unsaturated groups. The L 0 Connect E and Y, the L 1 Connect P and Y, the L 2 Connect D and Y;

[0020] (7)Q is H, R a , a hydroxyl protecting group, a thiol protecting group, an amine protecting group or a residue as represented by formula (III),

[0021] (8) Any hydrogen atom in formula (I) may be replaced by a deuterium atom;

[0022] (9) Any chiral center in formula (I) may be in the R configuration, the S configuration, or a mixture of the R and S configurations.

[0023] In some embodiments, the nanosized particles of the polymer-drug conjugates have an average particle size range of 1-100 nm.

[0024] In some embodiments, the nanosized particles of the polymer-drug conjugates have an average particle size range of 1-50 nm.

[0025] In some embodiments, the polymer-drug conjugates have nanosized particles with an average size range of 5-30 nm.

[0026] In some embodiments, the polymer residue in the polymer-drug conjugate satisfies one or more of the following conditions:

[0027] (1) L is independently a covalent bond, or C1-C 10 A linker containing or not containing heteroatoms, wherein the heteroatom is O, S, Se, N, P, Si or B, and the number of the heteroatoms is one or more. When there are multiple heteroatoms, the heteroatoms are the same or different. The linker may contain or not contain unsaturated groups. The L connects the polymer main chain and E.

[0028] (2) E is independently a covalent bond, O, S, NR a ,C(=O),S(=O),S(=O)2,C(=O)NR a , or one of the following residues:

[0029] (3) A is independently a covalent bond, O, S, NR d ; where R d Selected from H, substituted or unsubstituted C1-C 10 Alkyl, or a residue represented by formula (III):

[0030] (4) T, U, V, W, Z and K are independently covalent bonds, O, S, NR d ,C(=O),S(=O),S(=O) 2、 The condition is that the following connection forms do not exist in the -TUVWZKA- chain: -OO-, -OS-, -SO-,

[0031] (5) The configuration of the chiral carbon atom in the polymer residue as shown in (II) may be R configuration, S configuration, or a mixture of R configuration and S configuration;

[0032] in,

[0033] n is an integer selected from 4 to 100;

[0034] a is selected from 0 or 1;

[0035] b is selected from 0 or 1;

[0036] c is selected from 0 or an integer from 1 to 10;

[0037] d is selected from 0 or 1;

[0038] e is selected from 0 or 1;

[0039] R'、R 1a and R 2a Selected from hydrogen, deuterium, C1~C 10 Alkyl, C1~C 10 Alkoxy, C3~C 10 Alkenyl, C3~C 10 Alkynyl, C3~C8 cycloalkyl, C2~C8 heterocycloalkyl, C6~C 10 Aryl or C5~C 10 heteroaryl;

[0040] R z Selected from hydrogen, C1~C 10 Alkyl, C1~C 10 Alkoxy, C3~C 10 Alkenyl, C3~C 10 Alkynyl, C3~C8 cycloalkyl, C2~C8 heterocycloalkyl, C6~C10 Aryl, C5~C 10 Heteroaryl, hydroxyl protecting group or residue represented by formula (III):

[0041] R e and R f Independently selected from hydrogen, deuterium, C1-C 10 Alkyl, C1~C 10 Alkoxy, C3~C 10 Alkenyl, C3~C 10 Alkynyl, C3~C8 cycloalkyl, C2~C8 heterocycloalkyl, C6~C 10 Aryl, C5~C 10 Heteroaryl or a residue represented by formula (IV):

[0042] R a Selected from H, C1~C 10 Alkyl, C1~C 10 Alkoxy, C3~C 10 Alkenyl, C3~C 10 Alkynyl, C3~C8 cycloalkyl, C2~C8 heterocycloalkyl, C6~C 10 Aryl, C5~C 10 Heteroaryl or amine protecting groups;

[0043] R d Selected from H, C1~C 10 Alkyl, C1~C 10 Alkoxy, C3~C 10 Alkenyl, C3~C 10 Alkynyl, C3~C8 cycloalkyl, C2~C8 heterocycloalkyl, C6~C 10 Aryl, C5~C 10 Heteroaryl, amino protecting group or residue represented by formula (III):

[0044] The heteroatom in the C2-C8 heterocycloalkyl group is O, S or N, and the number of the heteroatoms is one or more. When there are multiple heteroatoms, the heteroatoms are the same or different. 10 The heteroatom in the heteroaryl group is O, S or N, and the number of the heteroatoms is one or more. When there are multiple heteroatoms, the heteroatoms are the same or different.

[0045] In some embodiments, the polymer-drug conjugate satisfies one or more of the following conditions:

[0046] (1) The number of repeating units n of the polymer main body is selected from an integer of 5 to 70, preferably an integer of 20 to 40;

[0047] (2) The branching center Y is a branching center containing the following structure, or a multifunctional branching center composed of two or more branching structures:

[0048] Among them, Z 0 O, S, S(O), S(O)2, NR a , CHR 0 ;

[0049] R 0 Selected from H, D, halogen, nitro, cyano, C1-C 10 Alkyl, C1~C 10 Alkoxy, C3~C 10 Alkenyl, C3~C 10 Alkynyl, C3~C8 cycloalkyl, C2~C8 heterocycloalkyl, C6~C 10 Aryl, C5~C 10 heteroaryl or a group containing a primary amine, secondary amine, tertiary amine, hydroxyl, sulfhydryl, carboxyl, ester, amide, boric acid, borate, phosphoric acid, sulfonic acid, sulfoxide, aldehyde, or ketone functional group; the heteroatom in the C2-C8 heterocycloalkyl is O, S, or N, and the number of the heteroatoms is one or more. When there are multiple heteroatoms, the heteroatoms are the same or different; the C5-C 10 The heteroatom in the heteroaryl group is O, S or N, and the number of the heteroatoms is one or more. When there are multiple heteroatoms, the heteroatoms are the same or different;

[0050] Ar is C6~C 20 Aryl or C5~C 20 Heteroaryl; the C5~C 20 The heteroatom in the heteroaryl group is O, S or N, and the number of the heteroatoms is one or more. When there are multiple heteroatoms, the heteroatoms are the same or different;

[0051] f is 0 or an integer from 1 to 3.

[0052] Among them, R a The definition of is as described in formula (I).

[0053] In some embodiments, the branching center Y of the polymer-drug conjugate is a substituted or unsubstituted amino acid or a derivative thereof having a functionality of at least 3, wherein the amino acid is a natural amino acid or a non-natural amino acid, and the configuration of the amino acid is D-type, L-type, or a mixture of D / L configurations. When the amino acid is a mixture of D / L configurations, the L configuration accounts for greater than 0% and less than 100%. The branching center Y is preferably an amino acid with a functionality of at least 3, wherein the amino acid is selected from one or more of aspartic acid, glutamic acid, lysine, ornithine, arginine, citrulline, histidine, serine, threonine, tryptophan, tyrosine, hydroxyproline, cystine, cysteine, or selenocysteine, and the configuration of the amino acid is D-type, L-type, or a mixture of D / L configurations. When the amino acid is a mixture of D / L configurations, the L configuration accounts for greater than 0% and less than 100%.

[0054] In some embodiments, the linker L of the polymer-drug conjugate 0 and L 1 are each independently selected from a covalent bond, an environmentally responsive linker, or a non-environmentally responsive linker; L 2 It is an environmentally responsive linker with a structure of L 2a -L 2b , L 2a or L 2b Can exist alone or together; L 2a and L 2b Each is independently selected from a covalent bond, an environmentally responsive linker or a non-environmentally responsive linker; the polymer-drug conjugate structure is shown in formula (V):

[0055] Among them, X, R', T, U, V, W, Z, K, A, P, L 1 , Y, L 2a , L 2b , D, L 0 , E, L, a, and b are each defined as described in formula (I).

[0056] In some embodiments, the linker L of the polymer-drug conjugate 0 and L 1 is a covalent bond, L 2 It is an environmentally responsive linker with a structure of L 2a -L 2b , where L 2a Connected to Y, L 2b Connected to D, L 2a or L 2b Can exist alone or together; L 2a and L 2bEach is independently selected from a covalent bond, an environmentally responsive linker or a non-environmentally responsive linker; the structure of the polymer-drug conjugate is shown in formula (VI):

[0057] Among them, X, R', T, U, V, W, Z, K, A, P, Y, L 2a , L 2b , D, E, L, a, and b are each defined as described in compound formula (I).

[0058] In some embodiments, the polymer residue of the polymer-drug conjugate is selected from the following structures:

[0059] Among them, R a1 Selected from H, C1~C 10 Alkyl, C1~C 10 Alkoxy, C3~C 10 Alkenyl, C3~C 10 Alkynyl, C3~C8 cycloalkyl, C2~C8 heterocycloalkyl, C6~C 10 Aryl, C5~C 10 Heteroaryl, amino protecting group or residue represented by formula (III);

[0060] R a2 Selected from H, C1~C 10 Alkyl, C1~C 10 Alkoxy, C3~C 10 Alkenyl, C3~C 10 Alkynyl, C3~C8 cycloalkyl, C2~C8 heterocycloalkyl, C6~C 10 Aryl, C5~C 10 Heteroaryl or hydroxy protecting groups;

[0061] n is an integer selected from 4 to 100;

[0062] m is an integer selected from 0 to 5;

[0063] R a 、R e 、R f The respective definitions are as described in formula (I).

[0064] In some embodiments, when the electrophilic group of the Y molecule is 2 When connected, L 2a does not exist, then L 2 =L 2b The trifunctional branched center Y and the linker L0 , L 1 and L 2b The connection is selected from any of the following structures:

[0065] Preferably More preferably

[0066] Alternatively, when the nucleophilic group of Y molecule and L 2 When connected, L 2a Exist alone or L 2a and L 2b coexist, at this time L 2 =L 2a or L 2 =L 2a -L 2b The trifunctional branched center Y and the linker L 0 , L 1 , L 2a and L 2b The connection is selected from any of the following structures:

[0067] Preferably

[0068] Among them, L 0 , L 1 , L 2a , L 2b The respective definitions are as described in formula (I).

[0069] In some embodiments, the terminal group X is selected from OR, SR, NR 1 R 2 , carboxyl protecting group or L 2b -D, R, R 1 、R 2 Independently selected from H, C1-C 30 Alkyl, C1~C 30 Alkoxy, C3~C 30 Alkenyl, C3~C 30 Alkynyl, C3~C8 cycloalkyl, C2~C8 heterocycloalkyl, C6~C 20 Aryl or C5~C 20 Heteroaryl; R 1 、R 2The connected N atom can form a C2-C8 heterocycloalkyl group; the heteroatom in the C2-C8 heterocycloalkyl group is O, S or N, and the number of the heteroatoms is one or more. When there are multiple heteroatoms, the heteroatoms are the same or different; the C5-C 20 The heteroatom in the heteroaryl group is O, S or N, and the number of the heteroatoms is one or more. When there are multiple heteroatoms, the heteroatoms are the same or different. The terminal group X is preferably OR, SR, NR 1 R 2 , carboxyl protecting group or L 2b -D, R, R 1 、R 2 Independently selected from H or C1~C 10 alkyl.

[0070] In some embodiments, the environmentally responsive linker in the polymer-drug conjugate is one or more of an enzyme-responsive linker, a pH-responsive linker, a light-responsive linker, and a redox-responsive linker.

[0071] In some embodiments, the polymer-drug conjugate satisfies one or more of the following conditions:

[0072] (1) The enzyme-responsive linker can be cut by one or more of the following enzymes: secretory phospholipase A2, acid phosphatase, serum alkaline phosphatase, cytochrome P450, sulfatase, prostate-specific antigen, phospholipase A1, phospholipase A2, phospholipase B, phospholipase C, phospholipase D, neutrophil elastase, cysteine ​​protease-3, cathepsin, matrix metalloproteinase, β-glucuronidase, β-galactosidase, DTP, nitroreductase, reduced coenzyme II, aminopeptidase N, carboxylesterase, diaphorase, histone deacetylase, asparagine endopeptidase, urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor, collagenase; preferably, it is cut by one or more of the following enzymes: cysteine ​​protease-3, cathepsin, matrix metalloproteinase, elastase or β-glucuronidase;

[0073] (2) The pH-responsive linker comprises one or more of the following structures: a hydrazone, an imine, an oxime, a carboxylate, a thioester, a sulfate, a sulfonate, an orthoester, a carbonate, a carbamate, a substituted carbamate, a ketal, an acetal, a silyl ether, a phosphate, a borate, a phosphoramide, or a cis-aconitic acid group;

[0074] (3) The photoresponsive linker comprises one or more of o-nitrobenzene, coumarin, benzoin, BODIPY, or cyanine groups;

[0075] (4) The redox-responsive linker comprises one or more of the following structures: thioketal, phenylboronic acid, phenylboronic acid, oxalate, vinyl ether, thioether, aminoacrylate, disulfide, diselenide, 2,4-dinitrobenzenesulfonate, 2-azidomethylbenzoate, 4-azidobenzyl, unsaturated acid ester or azobenzene group.

[0076] In some embodiments, the enzyme-responsive linker in the polymer-drug conjugate linker comprises the following amino acid sequence: Cit-Phe, Lys-Lys, Phe-Lys, Arg-Arg, Val-Cit, Val-Ala, Val-Lys, Ala-Lys, Phe-Cit, Leu-Cit, Ile-Cit, Trp-Cit, Phe-Arg, Asn-Pro-Val, Gly-Pro-Nle, Glu-Val-Cit, Glu-Val-Ala, Gly-Phe-Gly, Gly-Phe-Phe, Gly-Leu-Gly, Gly-Val-Ala, Gly-Phe-Leu-Gl y, Gly-Phe-Phe-Leu, Gly-Leu-Leu-Gly, Gly-Phe-Tyr-Ala, Gly-Phe-Gly-Phe, Ala-Gly-Val-Phe, Gly-Phe-Phe-Gly, Gly-Gly-Phe-Gly, Asp-Glu-Val-A One or more of sp, Gly-Phe-Leu-Gly-Phe, Gly-Phe-Ala-Gly-Leu-Phe, Gly-Leu-Ala-Ala-Val-Ala, Gly-Gly-Phe-Leu-Gly-Phe or Gln-Ser-Phe-Arg-Phe-Lys.

[0077] In some embodiments, the polymer-drug conjugate satisfies one or more of the following conditions:

[0078] (1) The enzyme-responsive linker comprises the following structure:

[0079] ; Among them, R p Selected from H or C1-C10 alkyl; R p1 、R p2 Each independently selected from C1-C10 alkyl;

[0080] (2) The pH-responsive linker comprises the following structure:

[0081] Wherein, m = 0 to 4; Rp Selected from H or C1-C10 alkyl;

[0082] (3) The light-responsive linker comprises the following structure:

[0083] (4) The redox linker comprises the following structure:

[0084] In some embodiments, the linker L in the polymer-drug conjugate 2a is a covalent bond or a linker as shown in formula (VII):

[0085] The Q 1 Selected from One of the following; among them, R 3 and R 4 independently selected from H, D, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 alkenyl, C3-C6 alkynyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C 10 Aryl or C5~C 10 Heteroaryl; R 3 、R 4 The C atoms connected to it can form a C3-C8 alkyl or heterocycloalkyl group. The heteroatom in the C2-C8 heterocycloalkyl group is O, S or N, and the number of the heteroatoms is one or more. When there are multiple heteroatoms, the heteroatoms are the same or different. 10 The heteroatom in the heteroaryl group is O, S or N, and the number of the heteroatoms is one or more. When there are multiple heteroatoms, the heteroatoms are the same or different;

[0086] W 1 is a covalent bond or C0-C 20 A fragment containing or not containing heteroatoms, wherein the heteroatom is O, S, Se, N, P, Si or B, and the number of the heteroatoms is one or more. When there are multiple heteroatoms, the heteroatoms are the same or different. The W fragment may contain unsaturated bonds or not.

[0087] Z 1 Selected from One of the following, where R a The definition of is as described in formula (I).

[0088] In some embodiments, the linker L in the polymer-drug conjugate 2a Select from the following structures or covalent bonds:

[0089] in,

[0090] A 1 O, S, S(O), S(O)2, NR a , C(R 3 R 4 );

[0091] p is an integer selected from 0 to 16;

[0092] q is an integer selected from 0 to 16;

[0093] m is an integer selected from 0 to 4;

[0094] s1 is an integer selected from 0 to 16;

[0095] s2 is an integer selected from 1 to 15;

[0096] R s1 、R s2 、R s3 and R s4 are each independently selected from hydrogen or methyl;

[0097] R a The definition of is as described in formula (I).

[0098] In some embodiments, the pharmacokinetic modulator residue P in the polymer-drug conjugate is selected from a 1 , the terminal group is R b The polyethylene glycol derivative residue, the number of repeating units is b 1 The hyaluronic acid derivative residue, the number of repeating units is c 1 The polyphosphate residue, the number of repeating units is d 1 , the terminal group is R d1 The polysarcosine residues or repeating units are f 1 polyoxazoline residues;

[0099] Among them, a 1 An integer selected from 5 to 250, b 1 An integer selected from 5 to 250, c 1 An integer selected from 5 to 250, d 1 An integer selected from 5 to 250, f 1 An integer selected from 5 to 250; R b H, C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C3-C 10 Cycloalkyl, C3-C 10 Alkenyl, C3-C 10 Alkynyl or hydroxyl protecting group; R d1 H, C1-C 10 Alkyl, C1-C10 Alkoxy, C1-C 10 Heteroalkyl, C3-C 10 Cycloalkyl, C3-C 10 Alkenyl, C3-C 10 an alkynyl, hydroxyl or amino protecting group;

[0100] Preferably, the pharmacokinetic modulator residue P satisfies one or more of the following conditions:

[0101] (1) When the pharmacokinetic modulator residue P is a repeating unit with a 1 , the terminal group is R b When the polyethylene glycol derivative residue 1 An integer selected from 5 to 150, preferably an integer selected from 10 to 60, more preferably an integer selected from 15 to 50, such as 21, 43 or 44;

[0102] (2) When the pharmacokinetic modulator residue P is a repeating unit with a 1 , the terminal group is R b When the polyethylene glycol derivative residue is b C1-C 10 An alkyl group, preferably a C1-C6 alkyl group, more preferably a C1-C3 alkyl group, such as a methyl group, an ethyl group, a n-propyl group or an isopropyl group;

[0103] (3) When the pharmacokinetic modulator residue P is a repeating unit with the number of d 1 , the terminal group is R d1 When the polysarcosine residues d1 It is preferably hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-substituted amino or C1-C6 acyl, such as methylamino, carboxylic acid, methyl carboxylate or acetylamino.

[0104] In some embodiments, the pharmacokinetic modulator residue P in the polymer-drug conjugate is a repeating unit with a 1 , the terminal group is R b The polyethylene glycol derivative residue, the number of repeating units is b 1 The number of hyaluronic acid derivative residues or repeating units is d 1 The polycreatine derivative residue is selected from the following structures:

[0105] Among them, a 1 An integer selected from 5 to 150, b 1 An integer selected from 5 to 150, r is an integer selected from 0 to 8; the polyethylene glycol derivative residue is preferably a 1An integer selected from 20 to 45, b 1 is selected from an integer between 5 and 10, and r is selected from an integer between 0 and 3;

[0106] The polycreatine bioresidue is selected from the following structures:

[0107] Among them, c 1 An integer selected from 5 to 150, R c1 Selected from H, C1~C 10 Alkyl, C1~C 10 Alkoxy, C3~C 10 Alkenyl, C3~C 10 Alkynyl, C3~C8 cycloalkyl, C2~C8 heterocycloalkyl, C6~C 10 Aryl, C5~C 10 Heteroaryl or amino protecting group; R c2 Selected from OR c3 SR c3 or NR c4 R c5 , where R c3 Selected from H, C1~C 10 Alkyl, C3~C 10 Alkenyl, C3~C 10 Alkynyl, C3~C8 cycloalkyl, C2~C8 heterocycloalkyl, C6~C 10 Aryl or C5~C 10 heteroaryl; wherein R c4 、R c5 Each independently selected from H, C1-C 10 Alkyl, C1~C 10 Alkoxy, C3~C 10 Alkenyl, C3~C 10 Alkynyl, C3~C8 cycloalkyl, C2~C8 heterocycloalkyl, C6~C 10 Aryl, C5~C 10 Heteroaryl or amine protecting groups.

[0108] In some embodiments, the pharmacokinetic modulator residue P in the polymer-drug conjugate is a repeating unit with a 1 A methyl-terminated polyethylene glycol derivative residue, wherein the methyl-terminated polyethylene glycol derivative residue is selected from the following structures:

[0109] Among them, a 1 is selected from an integer between 5 and 150, and r is selected from an integer between 0 and 8;

[0110] The methyl-terminated polyethylene glycol derivative residue is preferably

[0111] In some embodiments, the polymer residue in the polymer-drug conjugate is selected from the following structures:

[0112] n is selected from integers of 4-100.

[0113] In some embodiments, the pharmaceutically active agent D in the polymer-drug conjugate has a reactive functional group selected from one or more of a primary amine, a secondary amine, a tertiary amine, a hydroxyl group, a sulfhydryl group, a carboxyl group, an ester group, an amide group, a boric acid, a boric acid ester, a phosphoric acid, a sulfonic acid, a sulfoxide group, an aldehyde group, and a ketone group.

[0114] In some embodiments, the pharmaceutically active agent in the polymer-drug conjugate is selected from the group consisting of: anesthetics, antacids, anti-infectives, cardiovascular drugs, diuretics, hematogenics, immunosuppressants, GLP-1 receptor agonists, hormones and analogs, ophthalmic drugs, pain treatment agents, respiratory drugs, anti-arthritis drugs, anticonvulsants, antihistamines, anti-inflammatory drugs, anti-ulcer drugs, behavior modification drugs, anti-tumor drugs, anti-cancer antigens, central nervous system drugs, psychiatric drugs, contraceptives, diabetes drugs, growth promoters, hemostatics, immunostimulants, immunomodulators, muscle relaxants, obesity treatment agents, osteoporosis drugs, tranquilizers, tranquilizers, urinary tract acidifiers, vitamins, polypeptide drugs, oligonucleotide drugs, mRNA drugs, antibody drugs, biologics, targeted protein degraders, PROTAC drugs, oligosaccharide drugs, or targeted drugs.

[0115] In some embodiments, the pharmaceutically active agent residue D in the polymer-drug conjugate is an anti-tumor drug residue, and the anti-tumor drug is selected from one or more of a tumor-targeted drug, a PROTAC drug (targeted protein degradation chimera), a molecular glue degrader, a tumor immunomodulator, or a chemotherapy drug.

[0116] In some embodiments, the pharmaceutically active agent residue D in the polymer-drug conjugate is selected from the group consisting of abemaciclib, abiraterone, abrocitinib, acalabrutinib, afatinib, aldesleukin, alectinib, alflutinib, almonertinib, altretamine, amcenestrant, aminoglutethimide, amsacrine, anastrozole, anlotinib, apalutamide, apatinib, arzoxifene, asciminib, asparaginase, avapritinib, avitinib, axitinib, azacitidine, baricitinib, belinostat, bendamustine, , bexarotene, bicalutamide, bicyclol, binimetinib, bleomycin, boanmycin, bortezomib, bosutinib, brigatinib, buserelin, busulfan, cabazitaxel, cabozantinib, calaspargase, calicheamycin, capec itabine, capmatinib, carboplatin, carfilzomib, carmustine, carmofur, cedazuidine, ceritinib, cetrorelix, chidamide, chlorambucil, cisplatin, cladribine, clofarabine, cobimetinib, colchicine,copanlisib,crizotinib,cyclophosphamide,cytarabine,dabrafenib,dacarbazine,dacomitinib,dactinomycin,dalpiciclib,darolutamide,dasatinib,daunorubicin,decitabine,degarelix,delgociclib,denileukin,deruxtecan,deucravacitinib,docetaxel,donafenib,doxorubicin,duvelisib,enasidenib,encorafenib,ensartinib,entrectinib,enzalutamide,enzastaurin,elacestrant,epirubicin,erdafitinib,eribulin,erlotinib,estradiol,estramustine,etoposide,everolimus,exemestane,fasudil,fedatinib,filgotinib,floxuridine,fludarabine,flumatinib,fluorouracil,flutamide,fluzoparib,formestane,fostamatinib,fruquintinib,fulvestrant,futibatinib,gefitinib,gemcitabine,gilteritinib,giredestrant,glasdegib,goserelin,histrelin,hydroxyurea,ibrutinib,ibudilast,icaritin,icotinib,idarubicin,idelalisib,ifosfamide,imatinib,imiquimod,infigratinib,ingenol mebutate,interferon alfa-2b,irinotecan,ivosidenib,ixabepilone,ixazomib,lanreotide,lapatinib,larotrectinib,lenalidomide,lenvatinib,letrozole,leucovorin,leuprolide,lomustine,lonafarnib,lorlatinib,lurbinectedin,maytansine,mechlorethamine,medroxyprogesterone,megestrol,melphalan,melphlan flufenamide,mercaptopurine,methotrexate,methoxsalen,methylprednisolone,midostaurin,mitomycin,mitotane,mitoxantrone,mitozolomide,mobocertinib,monomethylauristatin E,monomethylauristatin F,nelarabine,nandrolone,neratinib,nearsudil,nilotinib,nilutamide,nintedanib,niraparib,octreotide,olaparib,olmutinib,olverembatinib,omacetaxine,orelabrutinib,osimertinib,oxaliplatin,paclitaxel,pacritinib,palbociclib,pamidronate,pamiparib,panobinostat,pazopanib,peficitinib,pegaptanib,pegaspargase,peginteferon alfa-2b,pemigatinib,pemetrexed,pentetreotide,pentostatin,pexidartinib,phenoxybenzamine,pidotimod,plinabulin,plitidepsin,pomalidomide,ponatinib,porfimer,pralatrexate,pralsetinib,prednisolone,procarbazine,pyrotinib,quizartinib,radotinib,raloxifene,raltitrexed,regorafenib,ribociclib,rintatolimod,ripretinib,romidepsin,rucaparib,ruxolitinib,savolitinib,selinexor,selpercatinib,selumetinib,sonidegib,sorafenib,sotorasib,streptozocin,sunitinib,surufatinib,talazoparib,tamoxifen,tazemetostat,tegafur,temozolomide,temsirolimus,teniposide,tepotinib,teprenone,thalidomide,thioguanine,thiotepa,thyrotropin alfa,tipiracil,tipifarnib,tirabrutinib,tirbanibulin,tivozanib,trametinib,tofacitinib,topotecan,toremifene,trabectedin,tretinoin,trifluride,trilaciclib,triptorelin,tucatinib,upadaciti nib,umbralisib,utidelone,uroacitide,valrubicin,vandetanib,vemurafenib,venetoclax,vinblastine,vincristine,vindesine,vinflunine,vinorelbine,vismodegib,vorinostat,zanubrutinib,zoledronic acid,amatoxins,anthacyclines,anthracenes,anthramycins,auristatins,bryostatins,camptothecins,carmaphycins,combretastatins,cyclosporines,cryptomycins,ecteinascidins,ellipticenes,esperamicins,mustines,neothramycins,ozogamicins,phenoxazines,podophyllotoxins,pyrrolobenzodiazepines,sibiromycins,thailanstatins,tomamycns,tubulysins,taxanes,vinca alkaloids,7-epitaxel,2'-acetylpaclitaxel,10-deacetylpaclitaxel,10-deacetyl-7-epipaclitaxel,7-xylosylpaclitaxel,10-deacetyl-7-glutarylpaclitaxel,7-N,One or more of N-dimethylglycylpaclitaxel, 7-L-alanylpaclitaxel, lerontaxel, camptothecin, 9-aminocamptothecin, 9-nitrocamptothecin, lertotecan, gimatecan, belotecan, 10-hydroxycamptothecin, 10-hydroxy-ethyl-camptothecin (SN-38), isitecan, pirarubicin, aclarubicin, sirolimus, tacrolimus, progesterone, estrogen, rapamycin, plicamycin, harringtonine, or curcumin.

[0117] In some embodiments, the polymer-drug conjugate satisfies one or more of the following conditions:

[0118] (1) The anti-tumor drug is a tumor-targeting drug, selected from the group consisting of aldesleukin, abemaciclib, abiraterone, abrocitinib, acalabrutinib, afatinib, alectinib, alflutinib, almonertinib, amcenestrant, anastrozole, anlotinib, apalutamide, apatinib, arzoxifene, asciminib, avapritinib, avitinib, axitinib, baricitinib, belinostat, bexarotene, bicalutamide, binimetinib, bleomycin, boanmycin, bortezomib, bosutinib, brigatinib, buserelin, cabozantinib, capmatinib, carfilzomib, carmustine, ceritinib, cetrorelix, chidamide, cobimetinib, copanlisib, crizotinib, dabrafenib, dacomitinib, dalpici clib, darolutamide, dasatinib, degarelix, delgociclib, deucravacitinib, donafenib, duvelisib, enasidenib, encorafenib, ensartinib, entrectinib, enzalutamide, enzastaurin, elacestrant, erdafitinib, erlotinib, everolimus, fedatinib, filgotinib, flumatinib, fluzoparib, formestane, fostamatinib, fruquintinib, fulvestrant, futibatinib, gefitinib, gilteritinib, giredestrant, glasdegib, goserelin, histrelin, ibrutinib, ibudilast, icotinib, idarubicin, idelalisib, imatinib, imiquimod, infigratinib, ivosidenib, ixazomib, lanreotide, lapatinib,larotrectinib, lenalidomide, lenvatinib, letrozole, leucovorin, leuprolide, lonafarnib, lorlatinib, medroxyprogesterone, megestrol, methylprednisolone, midostaurin, mobocertinib, nandrolone, neratinib, nilotinib, nilutamide, nintedanib, niraparib, olaparib ,olmutinib,olverembatinib,orelabrutinib,osimertinib,pacritinib,palbociclib,pamidronate,pamiparib,panobinostat,pazopanib,peficitinib,pegaptanib,pemigatinib,pexidartinib,pidotimod,pomalidomide,ponatinib,pralsetinib,pyrotinib,quizartinib,ra one or more of dotinib, raloxifene, regorafenib, ribociclib, rintatolimod, ripretinib, rucaparib, ruxolitinib, savolitinib, selinexor, selpercatinib, selumetinib, sonidegib, sorafenib, sotorasib, sunitinib, surufatinib, talazoparib, tamoxifen, tazemetostat, temsirolimus, tepotinib, thalidomide, tipifarnib, tirabrutinib, tivozanib, trametinib, tofacitinib, toremifene, tretinoin, trilaciclib, triptorelin, tucatinib, upadacitinib, umbralisib, vandetanib, vemurafenib, venetoclax, vismodegib, vorinostat, zanubrutinib, or zoledronic acid;,

[0119] (2) The anti-tumor drug described above is a chemotherapy drug, selected from altretamine, aminoglutethimide, amsacrine, asparaginase, azacitidine, bendamustine, bexarotene, bicyclol, bleomycin, boanmycin, buserelin, busulfan, cabazitaxel, calaspargase, calicheamycin, capecitabine, carboplatin, carmustine, carmofur, cedazuidine, chlorambucil, cisplatin, cladribine, clofarabine, colchicine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, denileukin, deruxtecan, docetaxel, doxorubicin, epirubicin, eribulin, estradiol, estramustine, etoposide, exemestane, fasudil, floxuridine, fludarabine, fluorouracil, flutamide, formestane, gemcitabine, hydroxyurea, icaritin, idarubicin, ifosfamide, ingenol mebutate, irinotecan, ixabepilone, leucovorin, lomustine, lurbinctedin, maytansine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, melphlan flufenamide, mercaptopurine, methotrexate, methoxsalen, methylprednisolone, mitomycin, mitotane, mitoxantrone, mitozolomide, monomethylauristatin E, monomethylauristatin F, nelarabine, nandrolone, nearsudil, octreotide, omacetaxine, oxaliplatin,paclitaxel,pamidronate,pemetrexed,pentetreotide,pentostatin,phenoxybenzamine,plinabulin,plitidepsin,porfimer,pralatrexate,prednisolone, procarbazine, procarbazine, raltitrexed, romidepsin, streptozocin, tegafur, temozolomide, teniposide, teprenone, thioguanine, thiotepa, thyrotropin alfa,tipiracil,tirbanibulin,topotecan,trabectedin,trifluride,utidelone,uroacitide,valrubicin,vinblastine,vincristine,vindesine,vinflunine,vinorelbine,amatoxins,anthacyclines,anthracenes,anthramycins,auristatins,bryostatins,camptothecins,carma phycins,combretastatins,cyclosporines,cryptomycins,ecteinascidins,ellipticenes,esperamicins,mustines,neothramycins,ozogamicins,phenoxazines,podophyllotoxins,pyrrolobenzodiazepines,sibiromycins,thailanstatins,tomamycns,tubulysins,taxanes,vinca One or more of alkaloids, 7-epipaclitaxel, 2'-acetylpaclitaxel, 10-deacetylpaclitaxel, 10-deacetyl-7-epipaclitaxel, 7-xylosylpaclitaxel, 10-deacetyl-7-glutarylpaclitaxel, 7-N,N-dimethylglycylpaclitaxel, 7-L-alanylpaclitaxel, lerontaxel, camptothecin, 9-aminocamptothecin, 9-nitrocamptothecin, lertotecan, gimatine, belotecan, 10-hydroxycamptothecin, 10-hydroxy-7-ethylcamptothecin (SN-38), isotecan, pirarubicin, aclarubicin, sirolimus, tacrolimus, progesterone, estrogen, rapamycin, plicamycin, harringtonine, or curcumin.

[0120] In some embodiments, the nanometer size of the polymer-drug conjugate can be controlled by the following methods:

[0121] (1) Changing the type of hydrophilic or hydrophobic groups, adjusting the length of the hydrophilic or hydrophobic groups and their hydrophilicity index;

[0122] (2) regulating the type and length of the linker between the polymer and the drug;

[0123] (3) Changing different types of conjugated drugs, such as the molecular size and hydrophilicity of the drug;

[0124] By the above-mentioned method, the nano-sized particle size range of the polymer-drug conjugate can be controlled to be 20-100 nM; further, the nano-sized particle size range of the polymer-drug conjugate can be controlled to be 10-20 nM; further, the nano-sized particle size range of the polymer-drug conjugate can be controlled to be below 10 nM.

[0125] In some embodiments, the nanoparticle size of the polymer-drug conjugates of the present invention remains stable and uniform during production and storage, and common problems such as agglomeration do not occur.

[0126] In some embodiments, the pharmaceutically active agent residue D in the polymer-drug conjugate is selected from the following structures:

[0127] Among them, R t1 Selected from H or C1-C 20 Alkyl; R t1 Selected from NHR t1 、C1-C 20 alkyl.

[0128] In some embodiments, the linker L in the polymer-drug conjugate is 2a Selected from the following structures:

[0129] In some embodiments, the linker L in the polymer-drug conjugate is 2b The following structure is preferred:

[0130] In some embodiments, the polymer-drug conjugate is selected from the following structures:

[0131] Among them, Y 1 =

[0132] in,

[0133] L 2a , L 2b , D, and X are each defined as described in formula (I);

[0134] n is an integer between 10 and 70;

[0135] a 1 It is an integer between 5 and 150.

[0136] In some embodiments, the terminal group R b Preferably, it is methyl, and the number average molecular weight of the PEG residue is 550, 1000, 2000, 3000, 4000 or 5000.

[0137] In some embodiments, the polymer-drug conjugate satisfies one or more of the following conditions:

[0138] (1) The branching center Y is connected to the polymer residue via a linker L 0 The molar ratio of the branching center Y to the polymer structural unit is 0.5:1 to 1.5:1;

[0139] (2) The pharmacokinetic modulator residue P is connected to the branching center Y via a linker L 1 The molar ratio of the pharmacokinetic modulator residue to the polymer structural unit is 0.5:1 to 1.5:1;

[0140] (3) The pharmaceutical active agent residue D is connected to the trifunctional branched center Y through the linker L 2 The molar ratio of the pharmaceutically active agent residue D to the polymer structural unit is 0.5:1 to 1.5:1.

[0141] In some embodiments, the -L 2 -D is any of the following structures:

[0142] In some embodiments, the -L 2 -D is any of the following structures:

[0143] The present invention provides a compound represented by formula (I-1) or a pharmaceutically acceptable salt thereof:

[0144] in,

[0145] for:

[0146] The "#" terminal is connected to Q;

[0147] n is independently any integer from 4 to 100;

[0148] n1, n2, n3 and n4 are each independently 0, 1, 2, 3, 4 or 5;

[0149] X1 is a covalent bond or

[0150] Ring A is C6-C 10 Aromatic ring or 5-10 membered heteroaromatic ring;

[0151] X2 is a covalent bond, O, S or NH;

[0152] L 0 is a covalent bond;

[0153] Y is "#1" end and L 2 Connected, "#2" end and L 1 connected;

[0154] n5 and n6 are each independently 0, 1, 2, 3, 4 or 5;

[0155] L 1 is a covalent bond;

[0156] P is

[0157] R p is independently C1-C6 alkyl or is replaced by one or more R p-1 Substituted C1-C6 alkyl;

[0158] R p-1 are independently halogen, hydroxy, C1-C6 alkoxy or NR p1 R p2 ;

[0159] R p1 and R p2 Each is independently -H or C1-C6 alkyl;

[0160] n7 is independently any integer from 4 to 100;

[0161] L 2 for #3 -L 2a -L 2b_#4 , the "#3" end is connected to Y, and the "#4" end is connected to D;

[0162] L 2a For covalent bonds,

[0163] n8, n9, n10, n11, n12, n13 and n14 are each independently any integer from 1 to 20;

[0164] R s1 and R s2 Each is independently -H or C1-C6 alkyl;

[0165] Or, R s1 and R s2 Together with the carbon atoms to which they are attached, they form a C3-C6 cycloalkyl group or a 3-6 membered heterocycloalkyl group, wherein the heteroatoms in the 3-6 membered heterocycloalkyl group are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0166] X3, X4, X5, X6, X7 and X8 are each independently NR s3 or O, R s3 is H or C1-C6 alkyl;

[0167] L 2b For covalent bonds,

[0168] R x are independently -H or C1-C3 alkyl;

[0169] R y are independently H, C1-C3 alkyl or

[0170] R y1 and R y2 Each is independently -H or C1-C3 alkyl;

[0171] n' is independently 1 or 2;

[0172] X9 is O or NR s9 ;

[0173] R s4 、R s5 、R s6 、R s7 、R s8 and R s9 Each is independently -H or C1-C6 alkyl;

[0174] Or, "R s4 and R s5 ”, “R s6 and R s7 ”, “R s8 and R s9 ” or “R s4 and R s9 "Together with the atoms to which they are attached, they form a 5-6 membered heterocycloalkyl group, wherein the heteroatom in the 5-6 membered heterocycloalkyl group is N, O, or N and O, and the number of heteroatoms is 1 or 2;

[0175] n15, n16 and n17 are each independently 1, 2, 3 or 4;

[0176] D is the residue of a pharmaceutically active agent;

[0177] X is OH, NH2, -L2-D, -D or

[0178] Q is or -P.

[0179] In some embodiments, for

[0180] In some embodiments, n is independently any integer from 20 to 60, such as 20 to 30 or 50 to 60, and further such as 28, 29, 30, 31, 59 or 60.

[0181] In some embodiments, for

[0182] In some embodiments, Y is

[0183] In some embodiments, n7 is each independently any integer from 20 to 50, such as 22, 28, 44 or 49.

[0184] In some embodiments, R p are independently methyl, methoxy, -CH2NH2 or -CH2NHCH3.

[0185] In some embodiments, P is

[0186] In some embodiments, n8, n9, n10, n11, n12, n13 and n14 are each independently any integer from 1 to 15, such as 1, 2, 3, 7 or 11.

[0187] In some embodiments, R s1 and R s2 are independently -H, or R s1 and R s2 Together with the carbon atom to which they are attached, they form a C3-C6 cycloalkyl group, such as cyclobutyl.

[0188] In some embodiments, Y is L 2a For covalent bonds, L 2b for

[0189] In some embodiments, Y is L 2a For covalent bonds, L 2b For covalent bonds,

[0190] In some embodiments, Y is L 2a For covalent bonds or L2b For covalent bonds,

[0191] In some embodiments, Y is L 2a A covalent bond or L 2b For covalent bonds,

[0192] In some embodiments, Y is L 2a For covalent bonds, L 2b For covalent bonds,

[0193] In some embodiments, Y is L 2a For covalent bonds, L 2b For covalent bonds,

[0194] In some embodiments, Y is L 2a For covalent bonds, L 2b For covalent bonds,

[0195] In some embodiments, Y is L 2a A covalent bond or L 2b For covalent bonds,

[0196] In some embodiments, Y is L 2 For covalent bonds,

[0197] In some embodiments, Y is L 2 For covalent bonds,

[0198] In some embodiments, X is OH, NH2, -D, -L 2b -D, The -L 2 -D is -L 2b -D,

[0199] In some embodiments, X is OH, NH2, -D, The -L 2 -D is

[0200] In some embodiments, Q is or -P, the -L 2 -D is

[0201] In some embodiments, Q is or -P, -L 2 -D is

[0202] In some embodiments, D is the residue of a pharmaceutically active agent as described in any of the above embodiments.

[0203] In some embodiments, D is a residue of a drug having an active functional group, wherein the active functional group is selected from one or more of a primary amine group, a secondary amine group, a hydroxyl group, and a thiol group; preferably, the drug is an anti-tumor drug, such as one or more of camptothecin, camptothecin derivatives, paclitaxel, paclitaxel derivatives, cisplatin, and cisplatin derivatives.

[0204] In some embodiments, D is any of the following structures:

[0205] Among them, R t1 Selected from H or C1-C 20 Alkyl; R t2Since NHR t1 、C1-C 20 alkyl.

[0206] In some embodiments, D is any of the following structures:

[0207] In some embodiments, the compound represented by formula (I-1) is a compound represented by formula (A) or formula (B):

[0208] The definitions of the variables are as described in any of the above schemes.

[0209] The present invention also provides any one of the compounds shown below:

[0210] The present invention also provides a pharmaceutical composition comprising the compound of any of the above schemes or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0211] The present invention also provides a use of the compound of any of the above schemes or the above pharmaceutical composition in the preparation of a medicament for preventing and / or treating a disease, wherein the disease is cancer, for example, one or more selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain cancer, nasopharyngeal cancer, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, bone cancer, osteosarcoma, seminoma, testicular tumor, uterine tumor, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder tumor, gallbladder cancer, bile duct cancer, choriocarcinoma and pediatric tumor, preferably one or more selected from pancreatic cancer, liver cancer, colon cancer, myeloma, lung cancer (e.g., small cell lung cancer), fibrosarcoma and breast cancer.

[0212] The present invention also provides a method for preventing and / or treating a disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any of the above schemes or a pharmaceutically acceptable salt thereof, wherein the disease is cancer, for example, one or more selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain cancer, nasopharyngeal cancer, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, bone cancer, osteosarcoma, seminoma, testicular tumor, uterine tumor, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder tumor, gallbladder cancer, bile duct cancer, choriocarcinoma and pediatric tumor, preferably one or more selected from pancreatic cancer, liver cancer, colon cancer, myeloma, lung cancer (e.g., small cell lung cancer), fibrosarcoma and breast cancer.

[0213] The present invention also provides a compound represented by formula (I-1-A), (I-1-B) or (I-1-C):

[0214] In the compound represented by formula (I-1-A), Y is "#1" end and L 2 Connected, "#2" end and L 1 connected;

[0215] In the compound represented by formula (I-1-B), Y is "#1" end and L 2 Connected, "#2" end and L 1 connected;

[0216] In the compound represented by formula (I-1-B), Y is "#1" end and L 2 Connected, "#2" end and L1 connected;

[0217] In the compounds represented by formula (I-1-A), (I-1-B) and (I-1-C), the definitions of the variables are as described in any of the above schemes.

[0218] The present invention also provides any one of the following compounds:

[0219] Unless otherwise stated, the terms used in this invention have the following meanings:

[0220] The term "number of repeating units n" can also be expressed as the degree of polymerization DP. Unless otherwise specified, the number of repeating units n in the present invention represents the number-average degree of polymerization, that is, the average number of repeating units contained in the polymer macromolecular chain. When the ε-poly-L-lysine backbone is synthesized by solid phase synthesis, the number of repeating units n is a single value. When ε-poly-L-lysine is synthesized by biological fermentation or other chemical polymerization methods, the number of repeating units n has a certain distribution, and its value is expressed as a quantitative average.

[0221] The amino protecting group, hydroxy protecting group and carboxyl protecting group of the present invention are suitable groups for protecting amino, hydroxy and carboxyl groups known in the art, as shown in the literature ("Protective Groups in Organic Synthesis", 5 Th Various types of protecting groups in Ed.TWGreene&P.GM Wuts).

[0222] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight or branched groups of 1 to 30 carbon atoms. Preferably, the alkyl group has 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms. Non-limiting examples include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 The invention also includes but is not limited to: 1,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1-ethyl-2-methylpropyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3,3-dimethylpentyl, 3,4-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, methyl, nonyl, decyl, undecyl, dodecyl, and various isomers thereof. The "alkyl" may be substituted or unsubstituted.

[0223] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent comprising 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 10 carbon atoms, and most preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, and cyclooctyl. Non-limiting examples of polycyclic cycloalkyls include, but are not limited to, spirocyclic, fused, and bridged cycloalkyls. The cycloalkyl group may be substituted or unsubstituted.

[0224] The term "alkenyl" refers to an alkyl group as defined herein consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably a C2-C10 alkenyl group, more preferably a C2-C6 alkenyl group, such as ethenyl, propenyl, 1-propenyl, etc. The alkenyl group may be substituted or unsubstituted.

[0225] The term "alkynyl" refers to an alkyl group as defined herein consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably a C2-C10 alkynyl group, more preferably a C2-C6 alkynyl group, such as ethynyl, 1-propynyl, 2-propynyl, etc. The "alkynyl" group may be substituted or unsubstituted.

[0226] The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent comprising 3 to 20 ring atoms, one or more of which is selected from N, O, Si, B, S(O) m 、P(O) m(wherein m is an integer from 0 to 2) heteroatoms, excluding the ring portion of -OO, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, the ring atoms are 3 to 12, of which 1 to 4 heteroatoms are contained. Non-limiting examples of monocyclic heterocycloalkyl groups include pyrrolyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, pyranyl, etc. Polycyclic heterocycloalkyl groups include spirocyclic, fused ring and bridged heterocycloalkyl groups. The "heterocycloalkyl" may be substituted or unsubstituted.

[0227] The term "alkoxy" refers to -O-(alkyl) and -O-(cycloalkyl), wherein alkyl and cycloalkyl are as defined herein. Non-limiting examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. The "alkoxy" may be substituted or unsubstituted.

[0228] The term "alkanethiol" refers to -S-(alkyl) and -S-(cycloalkyl), wherein alkyl and cycloalkyl are as defined herein. Non-limiting examples include, but are not limited to, methylmercapto, ethylmercapto, propylmercapto, butylmercapto, cyclopropylmercapto, cyclobutylmercapto, cyclopentylmercapto, cyclohexylmercapto, and the like. The "alkanethiol" may be substituted or unsubstituted.

[0229] The term "substituted or unsubstituted amino" refers to NH2, monosubstituted NH2 and disubstituted NH2. When substituted, the monosubstituted or disubstituted groups are preferably independently selected from deuterium, alkyl, hydroxyl, mercapto, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, amino, haloalkyl, hydroxyalkyl, carboxyl or carboxylate groups, and the like. The disubstituted groups may form a non-aromatic heterocyclic structure together with the nitrogen atom to which they are attached.

[0230] The term "aryl" refers to any stable conjugated hydrocarbon ring system of 6 to 18 carbon atoms, preferably 6 to 10 carbon atoms, which may be a monocyclic, bicyclic, tricyclic, or higher-ring aromatic group, such as phenyl, naphthyl, and anthracene. The aryl group may include an aromatic ring with an aryl group on a heterocycloalkyl or cycloalkyl ring. The "aryl" group may be substituted or unsubstituted.

[0231] The term "heteroaryl" refers to an aromatic ring system in which at least one carbon atom in the ring is replaced by a heteroatom selected from N, O, or S. It is preferably a 5- to 7-membered monocyclic structure or a 7- to 12-membered bicyclic structure, and more preferably a 5- to 6-membered heteroaryl group, such as pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, pyrazinyl, triazolyl, tetrazolyl, oxazolyl, indazolyl, etc. The heteroaryl group may include a heteroaryl ring fused with a heteroaryl, heterocycloalkyl, or cycloalkyl ring. The "heteroaryl" group may be substituted or unsubstituted.

[0232] The term "sulfone group" refers to The substituents are preferably alkyl, alkenyl, alkynyl, amino, alkoxy, alkanethio, alkylamino, cycloalkyl, haloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkanethio or heterocycloalkanethio.

[0233] The term "sulfoxide" refers to The substituents are preferably alkyl, alkenyl, alkynyl, amino, alkoxy, alkanethio, alkylamino, cycloalkyl, haloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkanethio or heterocycloalkanethio.

[0234] The term "alkylsulfoxide" refers to The substituent is preferably an alkyl group, which is as defined above.

[0235] The term "hydroxy" refers to -OH.

[0236] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0237] The term "nitro" refers to -NO2.

[0238] The term "amino" refers to -NH2.

[0239] The term "cyano" refers to -CN.

[0240] The term "carboxylic acid" refers to -C(O)OH.

[0241] The term "mercapto" refers to -SH.

[0242] The term "carboxylate" refers to -C(O)O-alkyl, aryl or cycloalkyl, wherein alkyl, aryl and cycloalkyl are as defined above.

[0243] The term "thioester" refers to a -C(O)S-alkyl, aryl or cycloalkyl group, wherein alkyl, aryl and cycloalkyl are as defined above.

[0244] The term "sulfate" refers to OS(O)2O-alkyl, aryl or cycloalkyl, wherein alkyl, aryl and cycloalkyl are as defined above.

[0245] The term "sulfonate" refers to S(O)2O-alkyl, aryl or cycloalkyl, wherein alkyl, aryl and cycloalkyl are as defined above.

[0246] The term "boric acid" refers to B(OH)2.

[0247] The term "boronate" refers to B(OR)2, R = alkyl, aryl or cycloalkyl, wherein alkyl, aryl and cycloalkyl are as defined above.

[0248] The term "substituted" refers to that one or more hydrogen atoms in a group are independently replaced by a corresponding number of deuterium or substituents.

[0249] "Pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness of the free base without other toxic side effects. It can be an acidic group, a basic group or an amphoteric group. Non-limiting examples include, but are not limited to: acidic salts include hydrochlorides, hydrobromides, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, nitrates, acetates, propionates, decanoates, octanoates, formates, acrylates, isobutyl phosphates, ... The pharmaceutically acceptable salts thereof include benzoate, methylbenzoate, phthalate, maleate, methanesulfonate, p-toluenesulfonate, benzenesulfonate, (D, L)-tartaric acid, citrate, maleate, (D, L-)malate, fumarate, stearate, oleate, cinnamate, laurate, glutamate, aspartate, trifluoromethanesulfonate, mandelate, ascorbate, salicylate, etc. When the compound of the present invention contains an acidic group, its pharmaceutically acceptable salt may also include: alkali metal salts (such as sodium salt or potassium salt), alkaline earth metal salts (such as calcium salt or magnesium salt), organic base salts (such as alkyl aromatic aminos, amino acids, etc.).

[0250] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically pharmaceutically acceptable salts or prodrugs, and other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, promote absorption of the active ingredient, and thereby exert its biological activity.

[0251] Unless otherwise indicated, the abbreviations of any protecting groups, amino acids and other compounds used in the present invention are based on their commonly used and recognized abbreviations or refer to IUPAC-IUBC Commission on Biochemical Nomenclature (see Biochem. 1972, 11, 942-944).

[0252] The positive effects of the present invention are that the compounds of the present invention have one or more of the following advantages:

[0253] (1) Through the rational design of peptide molecules and linkers, the number of group couplings and the nanometer size can be controlled;

[0254] (2) The nanoparticles formed by the compounds of the present invention have good stability;

[0255] (3) The compounds of the present invention have good tumor tissue penetration;

[0256] (4) The compounds of the present invention have good tumor inhibition effects and low toxic side effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0257] Figure 1 is a graph showing the nanoparticle size data of the target compound in Example 7

[0258] Figure 2 is a graph showing the nanoparticle size data of the target compound in Example 20

[0259] Figure 3 is a graph showing the nanoparticle size data of the target compound of Example 27

[0260] Figure 4 is a graph showing the nanoparticle size data of the target compound in Example 40

[0261] Figure 5 is a graph showing the nanoparticle size data of the target compound in Example 41

[0262] Figure 6 is a graph showing the nanoparticle size data of the target compound of Example 48

[0263] Figure 7 is a graph showing the nanoparticle size data of the target compound in Example 50

[0264] Figure 8 is a graph showing the nanoparticle size data of the target compound of Example 75

[0265] Figure 9 is a graph showing the nanoparticle size data of the target compound in comparative example 78.

[0266] Figure 10 is a graph showing the particle size data of the target compound of Example 71 stored at 25°C on day 0.

[0267] Figure 11 is a graph showing the particle size data of the target compound of Example 71 after storage at 25°C for 30 days.

[0268] Figure 12 is a graph showing the particle size data of the target compound of Example 71 after storage at 25°C for 60 days.

[0269] Figure 13 is a graph showing the particle size data of the target compound of Example 71 after storage at 25°C for 90 days.

[0270] FIG14 is a graph showing the inhibitory effects of the target compound of Example 20, the target compound of Example 52, and Abraxane on the BxPC-3 tumor model.

[0271] FIG15 is a graph showing the inhibitory effects of the target compounds of Example 71 and Example 78 of the present invention on the HepG2 tumor model.

[0272] FIG16 is a graph showing the inhibitory effects of the target compound of Example 71 of the present invention and irinotecan hydrochloride on the human colon cancer HT-29 tumor model.

[0273] FIG17 is a graph showing the inhibitory effect of the target compound of Example 71 of the present invention and irinotecan liposomes on the human myeloma NCI-H929 tumor model

[0274] FIG18 is a graph showing the inhibitory effect of the target compound of Example 71 of the present invention and irinotecan liposomes on the human small cell lung cancer NCI-H69 tumor model

[0275] Figure 19 is a graph showing the inhibitory effect of the target compound of Example 79 on the human fibrosarcoma HT-1080 tumor model

[0276] Figure 20 is a graph showing the inhibitory effect of the target compound of Example 80 on the human small cell lung cancer NCI-H69 tumor model

[0277] Figure 21 is a graph showing the inhibitory effect of the target compounds of Example 82, etc. on the human small cell lung cancer NCI-H69 tumor model

[0278] Figure 22 shows the inhibitory effect of the target compound of Example 84 on the human small cell lung cancer BCaP-37 tumor model

[0279] Figure 23 shows the inhibitory effects of the target compounds of Examples 80 and 93 on the human breast cancer cell MCF-7 tumor model

[0280] Figure 24 shows the inhibitory effect of the target compound of Example 100 on the human liver cancer cell HepG2 tumor model

[0281] Figure 25 is a nanoparticle size study of the target compound in Example 79

[0282] Figure 26 is a study of the nanoparticle size of the target compound in Example 80

[0283] Figure 27 is a study on the nanoparticle size of the target compound of Example 84

[0284] Figure 28 is a study of the nanoparticle size of the target compound in Example 85

[0285] Figure 29 is a nanoparticle size study of the target compound in Example 97

[0286] Figure 30 is a nanoparticle size study of the target compound of Example 112

[0287] FIG31 is a graph showing the particle size stability data of the target compound of Example 79 at 25°C on day 0.

[0288] FIG32 is a graph showing the particle size stability data of the target compound of Example 79 at 25°C on the 60th day.

[0289] FIG33 is a graph showing the particle size stability data of the target compound of Example 80 at 25°C on day 0.

[0290] FIG34 is a graph showing the particle size stability data of the target compound of Example 80 at 25°C on the 60th day.

[0291] Figure 35 shows the inhibitory effect of the target compounds of Example 71, etc. on the human breast cancer cell MCF-7 tumor model

[0292] Figure 36 shows the inhibitory effect of Example 79 on the human small cell lung cancer NCI-H69 tumor model

[0293] Figure 37 shows the inhibitory effect of Example 119 on the human liver cancer cell HepG2 tumor model DETAILED DESCRIPTION

[0294] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0295] The abbreviations used in this invention are shown in the following table:

[0296] While the invention has been described with respect to specific embodiments thereof, certain modifications and equivalents will be apparent to one of ordinary skill in the art and are intended to be included within the scope of this invention.

[0297] HPLC analysis method for drug molecule content:

[0298] Instrument: Agilent 1260HPLC;

[0299] Chromatographic column: two-way valve, 1m damping tube, column temperature 40 degrees;

[0300] Phase A: methanol, flow rate 0.3 ml / min, detection wavelength 254 nm, isocratic: 0.0-5.0 min, 100%, phase A.

[0301] General HPLC analysis method for compound purity and content:

[0302] Chromatographic conditions:

[0303] Solvent gradient conditions:

[0304] The structures of all compounds of the present invention can be determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). - 6The unit of measurement is ppm. NMR measurements were performed on a Bruker AVANCE-400 spectrometer. The deuterated solvents tested were deuterated chloroform (CDCl3), deuterated methanol (MeOD), and deuterated dimethyl sulfoxide (DMSO-D6), with tetramethylsilane (TMS) as the internal standard.

[0305] Low-resolution mass spectra (MS) were measured on an Agilent 6120 quadruple LCMS mass spectrometer.

[0306] The degree of polymerization of the polymer of the present invention is calculated by the nuclear magnetic integration method, where the nuclear magnetic integration of the terminal group (such as benzyl, benzoyl, Boc or acetyl, etc.) is A, the number of hydrogen atoms of the functional group is p, the nuclear magnetic integration of the amino acid α hydrogen is B, and the degree of polymerization is n=(B*p / A).

[0307] Example 1: Synthesis of Compound 1

[0308] Synthesis of compound 1-1

[0309] Linear α-octalysine was synthesized by standard Fmoc solid phase synthesis method, as shown below:

[0310] The resin used for solid phase synthesis was MBHA resin (25 g, loading = 0.65 mmol / g). After removing the Fmoc protecting group, the starting material was Fmoc-Lys(Boc)-OH (1.5 eq), the coupling reagents were HOBT (1.5 eq) and DIC (1.5 eq), the solvent was DMF, and nitrogen bubbling was used for the reaction for 2 h. A small amount of resin was taken for Kaiser test (color developer A: ninhydrin 1 g / 100 mL ethanol; color developer B: 20 ​​g phenol / 100 mL ethanol; color developer C: pyridine. A small amount of resin was added with a color developer in a volume ratio of A:B:C = 3:2:1, temperature 100°C, and color development for 3 minutes. If the resin turned blue, the feed amount was halved and additional feed was added. If the resin showed no color reaction, the reaction was complete and a washing step was performed (the solvent was removed by suction, and the mixture was washed twice with DMF, MeOH, DCM, and DMF in sequence). Fmoc was then removed using a 20% piperidine / DMF solution with stirring for 20 minutes. The washing, coupling, and Fmoc removal were repeated until the Fmoc of the eighth coupled lysine was removed and the next reaction was performed.

[0311] Benzoic acid (3.25 g, 26.6 mmol, 1.6 eq), HOBT (4.73 g, 35 mmol, 2 eq), and DIC (4.5 g, 35 mmol, 2 eq) were weighed and added to a 1 L glass beaker. 0.4 L of DMF was added and stirred to allow the benzoic acid to fully dissolve. The mixture was then added to the reactor. An appropriate amount of DMF was added to allow the reaction to proceed, sparging with nitrogen and allowing the reaction to proceed for 4 h. (During the reaction, a small amount of DMF was added every 30 min to flush the resin from the reactor walls into the reaction solution.) After the reaction, the reaction liquid was removed and operation 2 was performed. A small amount of resin was taken for Kaiser test, which showed colorless. The resin was drained and placed in a flask. The removal reagent TFA / water / triisopropylsilane 95 / 2.5 / 2.5 was precooled to 0 degrees and added to the resin (1.5 L / kg resin). It was removed under mechanical stirring for 2 hours, filtered, and the filter cake was washed with a suitable solvent. The removed liquid was concentrated and added to precooled MTBE for precipitation (more than 10 times the volume). The crude product was obtained by centrifugation, and acetonitrile / water / TFA (50 / 50 / 0.1) was added to dissolve it and lyophilized to obtain compound 1-1, 20.0 g, with a yield of 60%.

[0312] Synthesis of compound 1-2

[0313] Compound 1-1 (2.06 g) and N,N'-di-tert-butyloxycarbonyl-L-lysine p-nitrophenolate (5.61 g) were dissolved in DMF (24 mL). TEA (2.08 mL) was added, and the solution turned from colorless to dark yellow. The mixture was stirred at 20°C for 18 h. DCM was added, and the product was washed with water. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain compound 1-2 (3.60 g).

[0314] Synthesis of compounds 1-3

[0315] Compound 1-2 (3.6 g) was dissolved in DCM (150 ml) and TFA (50 mL) was added. Gas was generated and the solution became turbid. It was stirred at room temperature for 18 h. Most of the solvent was removed by rotary evaporation. Methyl tert-butyl ether was precipitated. After centrifugation, the supernatant was discarded and the precipitate was dissolved in methanol. Methyl tert-butyl ether was further used for precipitation and the solution was dried in vacuo to obtain compound 1-3, 3.98 g.

[0316] Synthesis of compounds 1-4

[0317] Compound 1-3 (1.32 g) and N,N'-di-tert-butyloxycarbonyl-L-lysine p-nitrophenolate (3.83 g) were dissolved in DMF (20 mL). TEA (2.121 mL) was added, causing the yellow color to deepen. The mixture was allowed to react at room temperature for 18 h. DCM was added, and the product was washed with water. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain crude compound 1-4, which was used directly in the next step.

[0318] Synthesis of compounds 1-5

[0319] Compound 1-4 was dissolved in DCM (30 mL), TFA (20 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation, and the mixture was repeatedly washed with methyl tert-butyl ether and dried in vacuo to obtain compound 1-5 as a white solid, 2.14 g.

[0320] Synthesis of compounds 1-6

[0321] Compound 1-5 (2.14 g) and BOC-LYS(Z)-ONP (6.96 g) were dissolved in DMF (40 ml), and TEA (3.84 mL) was added. The mixture was reacted at 25°C under nitrogen for 18 h. DCM was added, the mixture was washed with water, dried by spin drying, washed with acetonitrile, and dried in vacuo to obtain compound 1-6 as a white powder (3.66 g).

[0322] Synthesis of compounds 1-7

[0323] Compound 1-6 (1.50 g) was added to acetic acid (21 mL) and 10% Pd / C (750 mg). The mixture was purged with hydrogen and reacted at 25°C for 24 h. Celite was added and the mixture was filtered (0.45 μm filter membrane). The filter cake was washed with methanol. The filtrates were combined and rotary evaporated, and dried under vacuum to obtain compound 1-7 (1.56 g) as a light yellow solid.

[0324] Synthesis of compounds 1-8

[0325] Compound 1-7 (0.8 g, 69.3 μmol) was dissolved in DMSO / DMF (25 / 25 mL) and mPEG was added. 2k -NHS (14.08 g, 3.33 mmol) and DIPEA (4.73 ml, 28.6 mmol) were reacted at room temperature for 24 h. The product was precipitated with 4 volumes of methyl tert-butyl ether, frozen at -20 degrees for 1 h, centrifuged, and the solid suspended in methanol. The product was precipitated with methyl tert-butyl ether and centrifuged. The precipitate was dissolved in water and lyophilized to obtain compound 1-8, 7.87 g.

[0326] Synthesis of Compounds 1-9

[0327] Compound 1-8 (4 g, 51.59 μmol) was dissolved in DCM (32 mL), TFA (32 mL) was added, stirred at room temperature, reacted for 12 h, the solvent was removed by rotary evaporation, and lyophilized with water to obtain crude compound 1-9, which was used directly in the next step.

[0328] Synthesis of Compounds 1-10

[0329] Compound 1-9 (51.59 μmol) and diglycolic anhydride (406 mg, 3.5 mmol) were dissolved in DMF (9 mL). TEA (1.8 ml, 7.74 mmol) was added and stirred at 25°C under nitrogen. The reaction was allowed to proceed for 24 h. The product was precipitated with methyl tert-butyl ether and dissolved in methanol. Precipitation was continued with methyl tert-butyl ether, and the precipitate was dissolved in water, dialyzed for 1 day, and lyophilized to afford compound 1-10 (2.93 g) as a pale yellow solid.

[0330] Synthesis of compound 1-10-SM

[0331] Compound 1-10-SM1 (synthesis of Formula 7 in reference patent WO2014141094A1) (2.71 g), compound 1-10-SM2 (FMoc-Val-Cit-PAB-PNP) (3.36 g) were dissolved in DMF (34 mL), DIPEA (2.29 mL) was added, and the reaction was carried out at room temperature for 3 h, followed by addition of 40 mL of MTBE, filtration and vacuum drying to obtain 4.71 g of the intermediate, which was dissolved in 10% piperidine / DMF (32 mL), reacted at room temperature for 10 min, 210 mL of MTBE was added, filtered to obtain a light yellow filter cake, and vacuum dried to obtain compound 1-10-SM, 3.58 g, with a yield of 94.6%.

[0332] Synthesis of compound 1

[0333] Compound 1-10 (375 mg, 4.81 μmol) and compound 1-10-SM (280 mg, 308 μmol) were dissolved in DMF (9 mL). PyBOP (240 mg, 460 μmol) and DIPEA (229 μL, 1.38 mol) were added and stirred at 25°C for 18 h. Precipitation was completed with methyl tert-butyl ether (MTBE). Precipitation was complete at -20°C. The precipitate was dissolved in methanol and purified using an LH-20 gel column. The solvent was removed by rotary evaporation. The product was reconstituted with water, filtered, and lyophilized to yield 450 mg of compound 1.

[0334] Example 2: Synthesis of Compound 2

[0335] Synthesis of compound 2

[0336] Compound 1-10 (375 mg, 4.81 μmol) and compound 2-SM (280 mg, 308 μmol, prepared according to the synthetic method of Example 78 in patent WO2016046574A1) were dissolved in DMF (9 mL). PyBOP (240 mg, 460 μmol) and DIPEA (229 μL, 1.38 mol) were added and stirred at 25°C for 18 h. Precipitation was performed with methyl tert-butyl ether. After complete precipitation at -20°C, the precipitate was dissolved in methanol and purified using an LH-20 gel column. The solvent was removed by rotary evaporation, the mixture was reconstituted with water, filtered, and lyophilized to obtain compound 2 (460 mg).

[0337] Example 3: Synthesis of Compound 3

[0338] Synthesis of compound 3-SM1

[0339] ε-Poly-L-lysine hydrochloride (4.792 g, 29.09 mmol, molar number of structural units) was suspended in 100 g of DMSO, and triethylamine (8.89 g, 87.27 mmol) was added, followed by BOC-LYS(Z)-ONP (20.83 g, 46.63 mmol). The mixture was stirred at 30°C under nitrogen for 13 h, and the reaction was complete. The reaction mixture was placed in a beaker, 800 mL of acetonitrile was added, and the mixture was filtered. The filter cake was washed sequentially with acetonitrile, water, and acetonitrile, and dried in vacuo to yield 12.13 g (85%) of compound 3-SM1 as a white solid.

[0340] 1 H NMR(400MHz,DMSO-d6)7.74(m,62H),7.27(m,179H),6.90(m,28H),5.16–4.80(s,60H) ,4.31–4.01(br,30H),4.00–3.68(br,30H),3.12–2.82(m,120H),1.91–0.58(m,642H)

[0341] Synthesis of compound 3-SM2

[0342] The solid-phase synthesis method was adopted, the resin was dichlororesin (14.5 g, 0.67 mmol / g), and the solid-phase synthesis was carried out according to the standard Fmoc method. The starting material was Fmoc-Gly-OH, the coupling reagents were HOBT and DIC, the solvent was DMF, and the amino acids and reagents were Fmoc-Ala-OH, Fmoc-Leu-OH, Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Pro-OH and PEG-2K acid (prepared according to the synthesis method of compound 2 in patent US2021093729A1). The resin removal reagent was TFA / water / triisopropylsilane 95 / 2.5 / 2.5, pre-cooled to 0 degrees, added to the resin (1.5 L / kg resin), removed under mechanical stirring for 2 hours, filtered, and the filter cake was washed with a suitable solvent. The stripping liquid was concentrated and added to pre-cooled MTBE for precipitation (more than 10 times the volume). The crude product was obtained by centrifugation, acetonitrile / water / TFA (50 / 50 / 0.1) was added for dissolution, and lyophilized to obtain compound 3-SM2, 18.2 g.

[0343] Synthesis of compound 3-1

[0344] Compound 3-SM1 (10.01 g) and 0.19 g TsOH·H2O were dissolved in 50 mL DMSO at 40°C. 30% aqueous ammonia (0.93 g), PyBOP (3.45 g), and DIPEA (1.15 mL) were added and reacted at 25°C for 18 h. The reaction solution was added to 400 / 20 mL water / AcOH, resulting in a white precipitate. The mixture was filtered and the filter cake was washed with 500 mL of water. The filter cake was slurried with 400 mL of acetonitrile for 1 h. After filtration, the mixture was dried under vacuum at 35°C. This afforded 9.71 g of compound 3-1, with a yield of 97.2%.

[0345] Synthesis of compound 3-2

[0346] Compound 3-1 (9.71 g) was dissolved in 97 mL of acetic acid, and 31 mL of MeOH and 1.94 g of 10% Pd / C were added. The mixture was replaced with hydrogen three times and reacted in a 30°C water bath for 24 h. The mixture was passed through Celite and rinsed with MeOH. The filtrate was filtered through a 220 nm filter and the solvent was removed by rotary evaporation. 100 mL of MTBE was added to slurry the mixture, resulting in a thick precipitate. The supernatant was discarded, and 50 mL of MTBE was added to continue slurrying. The supernatant was discarded and dried under vacuum to give 8.96 g of the product with a yield of 94.5% (containing 26.98% AcOH).

[0347] 1.56 g of the product was dissolved in 15 mL of water and passed through IRA-900 resin (100 g). The sample fractions were combined and freeze-dried to obtain 1.11 g of product, which contained 0.11% acetic acid.

[0348] Synthesis of compound 3-3

[0349] Compound 3-2 (100 mg) (GPC Rt = 14.649 min) was added with 0.5 mL of DMF to form a paste. 0.5 mL of DMSO was added to dissolve the mixture. Compound 3-SM2 (1.0 g) was dissolved in 4 mL of DMF and added to the above system. 0.29 g of PyBOP and 98 μl of DIPEA were added and the mixture was allowed to react at room temperature for 2 h. 146.2 mg of PyBOP and 98 μl of DIPEA were added and the mixture was allowed to react at room temperature for 18 h. A 50 μL sample was taken, dried with nitrogen, and 1 mL of water was added. The molecular weight was characterized by GPC. The sample was precipitated with 40 mL of MTBE to form an oily precipitate. The mixture was centrifuged and the supernatant was discarded. The sample was dissolved in 4 mL of MeOH and precipitated with 40 mL of MTBE to form a lumpy solid. The supernatant was discarded. The process was repeated once. 0.98 g of crude product was obtained by vacuum drying with a yield >99%, which was directly used in the next step.

[0350] Synthesis of compound 3-4

[0351] Compound 3-3 (0.8 g) was dissolved in DCM (2.8 mL), and 1.2 mL of TFA was added. The mixture was reacted at 25°C overnight, concentrated in vacuo, and precipitated by adding MTBE (20 mL). The mixture was frozen with dry ice / ethanol, and a large precipitate formed. After returning to room temperature, the supernatant was discarded. The precipitate was dried in vacuo. 0.81 g of crude product was obtained with a yield of >99%, which was used directly in the next step.

[0352] Synthesis of compound 3-5

[0353] Compound 3-4 (772.1 mg) was dissolved in ethyl acetate (4 mL, 30°C), and 42 mg of succinic anhydride was added and stirred to dissolve. DIPEA (0.3 mL) was added and the mixture was allowed to react at 30°C for 2 h. The reaction solution became gel-like, and 3 mL of DMF was added to dissolve the system. The reaction was continued at 30°C overnight. The solution was concentrated under vacuum and precipitated by adding 40 mL of MTBE to form a thick precipitate. The solution was centrifuged and the precipitate was dissolved in MeOH / water. Purified by ultrafiltration (30K MW) and freeze-dried to obtain 513.0 mg of compound 3-4 in a 64.1% yield.

[0354] Synthesis of compound 3

[0355] Compound 3-5 (501 mg), 2-SM (270 mg) and HOBt (47 mg) were dissolved in 2 mL of DMF. PyBOP (181.3 mg) was added and stirred to dissolve. 86 μl of N-methylmorpholine was added and the mixture was reacted in a 30°C water bath for 4 h. 20 mL of MTBE was used to precipitate a pale yellow solid. The solid was centrifuged and 10 mL of MTBE was added to the precipitate and slurried for 10 min. The solid was centrifuged and dried under vacuum to obtain a crude product. The crude product was dissolved in 15 mL of MeOH and diluted with 15 mL of filtered water. The product was purified by ultrafiltration (30K MW) and lyophilized to obtain 654.9 mg of the product with a yield of 99.7%. The theoretical coupling amount of SN38 was 10.41%, and the measured amount was 10.5%.

[0356] Example 4: Synthesis of Compound 4

[0357] Synthesis of compound 4-1

[0358] ε-Poly-L-lysine hydrochloride (0.76 g) was dissolved in 1.12 mL of water, and 16 mL of DMSO and 2.76 mL of DIPEA were added, followed by N,N'-di-tert-butyloxycarbonyl-L-lysine p-nitrophenolate (3.6 g). The mixture was sonicated and stirred at room temperature for 14 h. The mixture was then hydrolyzed by adding 15 mL of 0.5 M NaOH and stirred at room temperature. The mixture was filtered and washed with water, slurried with acetonitrile, filtered, and dried under vacuum to obtain compound 4-1 as a white powder (2.0 g, yield 84.5%).

[0359] Synthesis of compound 4-2

[0360] Compound 4-1 (1.50 g) was dissolved in 15 mL of DCM, TFA (5 mL) was added, and the mixture was stirred at room temperature for 18 h. The solvent was removed by rotary evaporation, washed with MTBE, and dried in vacuo to obtain the crude compound 4-2, which was used directly in the next step.

[0361] Synthesis of compound 4-3

[0362] Compound 4-2 (1.5 g, 3.09 mmol) and DMSO (12.5 mL) were added to a 100 mL single-necked bottle and dissolved by ultrasonication. BOC-LYS(Z)-ONP (4.66 g, 9.29 mmol) and DIPEA (2.4 g, 18.58 mmol) were then added. The atmosphere was replaced with nitrogen three times and protected. The reaction was stirred at room temperature for 2 h. The Kaiser reagent sample showed a light blue color. The raw material was not completely reacted and the system was clear. Stirring was continued at room temperature for 16 h. The Kaiser reagent sample showed a colorless color. 0.5 N aqueous sodium hydroxide solution (20 mL) was added to the system. After stirring for 30 min, acetonitrile (40 mL) was added and stirred for another 15 min. The filter cake was washed with water until white. The solid was dried in vacuo at 40 ° C to obtain compound 4-3 as a white solid, 2.62 g, yield: 87.6%.

[0363] Synthesis of compound 4-4

[0364] Compound 4-3 (2.4 g, 0.079 mmol) and acetic acid (24 mL) were added to a 10 mL single-necked bottle, heated at 40 ° C to dissolve, and palladium carbon (960 mg, 40%) was added. The hydrogen was replaced three times and protected. The reaction was stirred at 30 ° C in an oil bath for 20 h, cooled to room temperature and filtered with celite. The filter cake was washed twice with methanol, and the filtrate was filtered once with a 0.22 filter head. The filtrate was concentrated under reduced pressure to obtain a viscous solid, which was slurried with MTBE to form a gray solid. The supernatant was poured out and repeated once. The mixture was dried with an oil pump to obtain compound 4-4, a dark solid of 1.86 g.

[0365] Synthesis of compound 4-5

[0366] Compound 4-4 (1.0 g) was weighed into a 50 mL centrifuge tube, methanol (16.6 mL) was added, and ultrasonic dissolution was performed. At the same time, PEG-2K-NHS (6.43 g, prepared by reacting PEG-2K acid and NHS with EDCI condensation agent) was weighed into a 100 mL single-necked bottle, acetonitrile (27 mL) was added, and the mixture was stirred to dissolve. Methanol (27 mL) was added, and the above-mentioned methanol solution of compound 4-4 was added. DIPEA (2.17 mL) was added and stirred at room temperature for 15 min. The raw material was sampled for GPC detection. The reaction was not complete. Stirring was continued for 45 min. The raw material was sampled for GPC detection. The reaction was complete. The reaction solution was directly filtered with a 0.22 filter head and purified by ultrafiltration (30K MW). It was concentrated and freeze-dried to obtain compound 4-5, 2.84 g, as a yellow-brown solid.

[0367] Synthesis of Compounds 4-6

[0368] Compound 4-5 (2.84 g, 0.097 mmol), TFA (4.26 mL) and DCM (9.94 mL) were added to a 50 mL single-necked flask. The mixture was stirred at room temperature for 16 h under nitrogen protection. A sample was taken and dried with nitrogen and sent for NMR monitoring. After the reaction was complete, the reaction solution was directly concentrated to obtain a crude product. Under stirring, 26 mL of MTBE (room temperature) was added to the crude product to form an oily precipitate. Under vigorous stirring, the oily precipitate was cooled to below -10 ° C, and blocky and powdery solids were precipitated. The mixture was heated to above 15 ° C while continuing to stir. Filter, and wash the flask and filter cake with 40 mL of MTBE. Dry under oil pump vacuum for 2 h to obtain compound 4-6, 2.75 g, as a white solid product.

[0369] Synthesis of Compounds 4-7

[0370] Compound 4-6 (2.75 g, 0.61 mmol) and ethyl acetate (14 mL) were added to a 50 mL single-necked bottle, replaced with nitrogen three times and protected, stirred and dissolved at 30 ° C, and succinic anhydride (158 mg, 1.57 mmol) was added and stirred and dissolved again. After the solution was clear, DIPEA (941 mg, 7.28 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at 30 ° C for 1 h and then naturally warmed to room temperature and continued to react for 16 h. 50 μL of the precipitate was sampled and added to MTBE, centrifuged, and the supernatant was poured out. Kaiser reagent The reaction mixture was transferred to a 100 mL flask and stirred at 100 ° C for three minutes to form a colorless product, indicating that the amino group had reacted completely. The reaction mixture was transferred to a 100 mL flask and stirred vigorously. MTBE (50 mL) was added, and a large amount of solid precipitated. After the addition, stirring was continued for 10 min, and the mixture was filtered. The filter cake was dissolved in ethyl acetate (18 mL) at 30 ° C. MTBE (60 mL) was added, and a large amount of solid precipitated. After the addition, stirring was continued for 10 min, and the mixture was filtered. The filter cake was washed twice with MTBE and the solid was dried in vacuo to obtain a white solid as compound 4-7, 2.54 g, with a yield of 71.8%.

[0371] Synthesis of compound 4

[0372] Compound 4-7 (1.2 g, 0.25 mmol, polymer structural unit measurement) and DMF (6 mL) were added to a 25 mL single-necked bottle and dissolved. 2-SM (0.65 g, 0.7 mmol) was then added and dissolved. HOBT (0.14 g, 1.01 mmol), PyBOP (0.49 g, 0.94 mmol), and NMM (0.23 g, 2.28 mmol) were then added in sequence. The atmosphere was replaced with nitrogen three times and protected. The reaction was stirred at room temperature for 16 h. Sampling HPLC detection showed that 2-SM was completely consumed, and additional 2-SM (116 mg, 0.13 mmol) and PyBOP (344 mg, 0.17 mmol) were added, and the reaction was stirred for 2 h. Sampling GPC detection showed that 18% of 2-SM remained and the reaction of raw materials 4-7 was complete. The reaction solution was precipitated in MTBE (56 mL) and centrifuged. The supernatant was poured out, and the crude product in the lower layer was dissolved in methanol (30 mL), filtered through a filter head, and diluted with water (30 mL) for a total of 60 mL. Ultrafiltration (30K MW) showed a purity of 99.95%, and lyophilization gave 1.44 g of a white solid.

[0373] Example 5: Synthesis of Compound 5

[0374] Synthesis of compound 5-1

[0375] Sarcosine (70 g, 0.78 mol) and water (800 mL) were added to a 1L three-necked flask, replaced with nitrogen three times and protected, cooled to 0°C with ice water, and potassium carbonate (130.3 g, 0.94 mol) was added in batches, and the temperature was controlled below 5°C. After the addition was complete, benzoyl chloride (135.3 g, 0.86 mmol) was added dropwise. After 70 minutes of addition, the temperature naturally rose to room temperature and stirred for 16 hours. Samples were taken for LCMS detection. The reaction of the raw materials was complete. The reaction solution was washed three times with MTBE, and then the pH was adjusted to 2-3 with concentrated hydrochloric acid. The MTBE extraction was performed three times. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 5-1 as a colorless transparent oil, 166.7 g.

[0376] Synthesis of compound 5-2

[0377] Compound 3-2 (200 mg, 0.56 mmol), compound 5-1 (5.63 g, 26.93 mmol) and DMSO (30 mL) were added to a 10 mL single-necked bottle, ultrasonically dissolved, and DIPEA (580.3 g, 4.49 mmol) was added. The nitrogen was replaced three times and protected. The mixture was stirred in an oil bath at 60 ° C for 16 h. The sample was taken for GPC detection. rt = 12.191 min, Mn = 3.87 * 104, Mw = 4.32 * 104, PDI = 1.11, which was very similar to the reference molecular weight rt = 12.31, Mn = 3.70 * 104, Mw = 3.98 * 104, PDI = 1.07. The reaction solution was precipitated in ethyl acetate (240 mL). A large amount of solid precipitated and was filtered. The filter cake was washed twice with ethyl acetate. The crude solid was dissolved with methanol (20 mL) and ultrafiltered (30K MW), a total of 1 L of excess solvent was lyophilized to obtain compound 5-2 as an orange-light yellow solid, 715 mg.

[0378] Synthesis of compound 5-3

[0379] Compound 5-2 (1.43 g, 0.598 mmol), acetic anhydride (91.7 mg, 0.898 mmol), pyridine (142 mg, 1.78 mmol), and DCM (40 mL) were added to a 50 mL single-necked flask and stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and ethyl acetate (7 mL) was added. A solid appeared at the bottom, and the supernatant was poured out. Ethyl acetate (10 mL) was added, crushed with a spoon, and stirred for 1 h. The mixture was filtered, and the filter cake was washed twice with ethyl acetate and dried under vacuum at 35°C to obtain 1.54 g of a white solid.

[0380] Synthesis of compound 5-4

[0381] Compound 5-3 (1.54 g, 0.64 mmol), trifluoroacetic acid (2.31 mL) and dichloromethane (5.39 mL) were added to a 25 mL single-necked bottle and stirred at room temperature for 16 h. The reaction solution was directly concentrated to obtain 3.04 g of a crude orange-yellow semi-oily semi-solid product.

[0382] Synthesis of compound 5-5

[0383] Compound 5-4 (3.04 g, 0.64 mmol, crude product) and DMF (8 mL) were added to a 25 mL single-necked bottle and dissolved by ultrasonication. Succinic anhydride (84 mg, 0.84 mmol) was added and stirred under nitrogen protection. When the solution was clear, DIPEA (501 mg, 3.87 mmol) was added. After the addition was complete, pH = 2. DIPEA (1.5 g, 11.62 mmol) was added, pH = 8, nitrogen was replaced three times and protected, and the reaction was stirred at room temperature for 16 h. The mixture was precipitated with MTBE and centrifuged. The supernatant was poured out, and ninhydrin / phenol / pyridine / =3 / 2 / 1 was added. The mixture was colorized at 100°C for 3 minutes, and the result was colorless. The reaction of the raw materials was completed. The reaction solution was slowly added dropwise to ethyl acetate (50 mL). A large amount of solid was precipitated. The mixture was filtered. The filter cake was washed with ethyl acetate and then DMF (8 mL) was added to dissolve the mixture. The mixture was slowly added dropwise to ethyl acetate (50 mL). A large amount of solid was precipitated. The mixture was filtered. The filter cake was washed with ethyl acetate and the solid was dried in vacuo to obtain 1.3 g of a white solid.

[0384] Synthesis of compound 5

[0385] Compound 5-5 (600 mg, 0.25 mmol, polymer structural unit measurement) and DMF (10 mL) were added to a 25 mL single-necked bottle and dissolved by ultrasonication. 2-SM (401 mg, 0.44 mmol) was added, followed by HOBt (68 mg, 0.502 mmol), PyBOP (262 mg, 0.502 mmol) and N-methylmorpholine (115 mg, 1.13 mmol). The atmosphere was replaced with nitrogen three times and protected. The reaction was stirred at room temperature. After 3.5 h, sampling was carried out for HPLC detection, and 14% of 2-SM remained. The reaction was continued for 2 h, and sampling was carried out for HPLC detection, and 14% of 2-SM remained. The raw material reaction was completed, and the reaction solution was slowly added dropwise to ethyl acetate (88 mL). A large amount of solid precipitated, and the filter cake was filtered and washed with ethyl acetate. The solid was pulled dry to obtain 1.4 g of a crude product. The crude product was dissolved in methanol (15 mL), and it was insoluble. Water (15 mL) was added to dissolve it clearly. After filtration, it was ultrafiltered (30KMW) and freeze-dried to obtain 816 mg of a white solid.

[0386] Example 6: Synthesis of Compound 6

[0387] Synthesis of compound PEG8-1

[0388] Dissolve octaethylene glycol (25 g, 67.5 mmol, 1.0 eq) in dichloromethane (100 mL) at room temperature, add sodium metal (100 mg), and stir at 30°C under nitrogen for 3 h. Add tert-butyl 1-butene-4-olate (6.5 g, 50.6 mmol, 0.75 eq). Stir at room temperature for 16 h. LCMS confirms the reaction is complete. Add water (200 mL) and extract with 1.5 L of dichloromethane three times. Combine, wash with saturated sodium chloride, dry over sodium sulfate, and evaporate to dryness under reduced pressure (crude product 23 g) for direct reaction in the next step.

[0389] MS (ESI), m / z, 499.2 [M+H] + .

[0390] Synthesis of compound PEG8-2

[0391] Dissolve compound PEG8-1 (23 g, 46.1 mmol, 1.0 eq) and triethylamine (9.32 g, 92.3 mmol, 2.0 eq) in dichloromethane (100 mL) at room temperature. Under nitrogen, add p-toluenesulfonyl chloride (8.79 g, 46.1 mmol, 1.0 eq) at 30°C. Stir at room temperature for 16 h. LCMS analysis confirmed the reaction was complete. Concentrate under reduced pressure to obtain compound PEG8-2 as a white solid, which was used directly in the next step.

[0392] MS (ESI), m / z, 597.2 [M-56] + .

[0393] Synthesis of compound PEG8-3

[0394] Dissolve the crude compound PEG8-2 in acetonitrile / ammonia (150 mL / 150 mL) at room temperature. Stir at 40°C under nitrogen for 5 h. LCMS confirms the reaction is complete. Concentrate under reduced pressure to yield 20.7 g of the crude product, which is used directly in the next step.

[0395] MS (ESI), m / z, 498.2 [M+H] + .

[0396] Synthesis of compound PEG8-4

[0397] Compound PEG8-3 (20.7 g, 41.6 mmol, 1.0 eq) was dissolved in dichloromethane (100 mL) at room temperature. FmocOSU (14 g, 41.6 mmol, 1.0 eq) and DIPEA (21.5 g, 166.4 mmol, 4.0 eq) were added, and the mixture was stirred at 30°C under nitrogen for 2 h. LCMS confirmed the reaction was complete. The mixture was quenched with water, extracted with dichloromethane, and the combined organic phases were concentrated under reduced pressure to afford compound PEG8-4 as a colorless oil (18 g, impure, used directly in the next step).

[0398] MS (ESI), m / z, 720.2 [M+H] + .

[0399] Synthesis of compound PEG8

[0400] Compound PEG8-4 (18 g crude product) was dissolved in dichloromethane (15 mL) at room temperature. Trifluoroacetic acid (15 mL) was added under nitrogen. The mixture was stirred for 3 h. LCMS confirmed the reaction was complete, and the product was concentrated under reduced pressure to afford compound PEG8 as a colorless oil (7.3 g, 22% yield over four steps).

[0401] MS (ESI), m / z, 644.2 [M+H] + .

[0402] Synthesis of compound 6-1

[0403] Compound 2-SM (900 mg, 0.986 mmol), compound PEG8 (786 mg, 1.18 mmol) and DMF (20 mL) were added to a 50 mL single-necked bottle and dissolved by ultrasonication. PyBOP (617 mg, 1.18 mmol) and DIPEA (255 mg, 1.97 mmol) were added in sequence. The atmosphere was replaced with nitrogen three times and protected. The reaction was stirred at room temperature for 3 h. Samples were taken for TLC detection. After the reaction of the raw materials was completed, the reaction solution was slowly added dropwise to MTBE (160 mL) at -68 ° C. A large amount of solid precipitated. After naturally warming to room temperature, the solid particles turned into oil and sank to the bottom. The supernatant was poured out and the oil was transferred to a 50 mL single-necked bottle and concentrated under reduced pressure to give 2.1 g of a crude product, which was separated by wet loading silica gel column chromatography (50:1-30:1-20:1-10:1-5:1) to give 1.23 g of a white solid.

[0404] Synthesis of compound 6-2

[0405] Compound 6-1 (1.2 g, 0.71 mmol), N,N-dimethylethylamine (827 mg, 11.3 mmol) and DMF (10 mL) were added to a 50 mL single-necked bottle, replaced with nitrogen three times and protected, stirred at room temperature for 16 h, sampled for TLC detection, and the reaction of the raw materials was completed. The reaction solution was slowly added dropwise to MTBE (90 mL) to form an oily precipitate. The supernatant was poured out and the oil was dissolved in DCM (9 mL) and added dropwise to MTBE (90 mL) again. A large amount of solid precipitated and was filtered. The filter cake was washed twice with MTBE and the solid was dried in vacuo to obtain 982 mg of a white solid.

[0406] Synthesis of compound 6

[0407] To a 50 mL single-necked bottle, compound 6-2 (653 mg, 0.488 mmol), compound 5-5 (648 mg, 0.27 mmol, polymer structural unit measurement) and DMF (10 mL) were added, followed by HOBt (74 mg, 0.54 mmol), PyBOP (283 mg, 0.54 mmol) and N-methylmorpholine (124 mg, 1.22 mmol). The mixture was dissolved by ultrasonication, replaced with nitrogen three times and protected. The reaction was stirred at room temperature for 16 h. The reaction solution was slowly added dropwise to ethyl acetate (90 mL). A large amount of solid precipitated and was filtered. The filter cake was washed with ethyl acetate. The crude solid was dissolved with methanol (10 mL). If it was insoluble, water (10 mL) was added to dissolve it clearly, filtered, and ultrafiltered (30K MW). It was lyophilized to obtain 786 mg of a white solid.

[0408] Example 7: Synthesis of Compound 7

[0409] Synthesis of compound 7-1

[0410] Under nitrogen, 7-SM2 (513 mg, 0.62 mmol, 1.1 eq, obtained by referring to the synthesis method of Example 96 in US2016271270A1) and anhydrous DMF (5 mL) were added sequentially. After slight dissolution, the mixture was cooled to 0°C in an ice bath. 7-SM1 (573 mg, 0.56 mmol, 1.0 eq, obtained by referring to the synthesis method of compound 7 in J. Med. Chem. 2000, 43, 16, 3093–3102) and DIPEA (0.2 mL, 1.12 mmol, 2.0 eq) were then added. The reaction was stirred at 0°C for 2 hours. LCMS monitored the complete conversion of the starting material. The reaction solution was carried on to the next step without further treatment.

[0411] Synthesis of compound 7-2

[0412] Diethylamine (0.5 ml, 4.96 mmol, 8.0 eq) was added to the reaction mixture at 25°C. The reaction was stirred at room temperature for 1 hour. LCMS monitored the complete conversion of the starting material. The mixture was lyophilized to obtain product 7-2 (618 mg) as a white solid, with a combined yield of 80% for both steps.

[0413] 1H NMR (400MHz, DMSO-d6) δ10.19(s,1H),9.25–9.10(m,1H),8.68(d,J=7.6Hz,1H),8.15–7.95(m,5 H),7.88–7.80(m,2H),7.79–7.39(m,13H),7.33–7.13(m,4H),6.30(s,1H),6.12–5.97(m,1H),5 .90–5.78(m,1H),5.65–5.10(m,5H),4.98–4.82(m,3H),4.73–4.41(m,3H),4.19–3.94(m,3H),2 .92–2.67(m,7H),2.40–1.94(m,11H),1.88–1.56(m,8H),1.55–1.37(m,6H),1.08–0.90(m,13H).

[0414] Synthesis of compound 7-3

[0415] To a solution of compound 7-2 (860 mg, 0.626 mmol, 1.0 eq) in DMF (5.0 mL) at 25°C were added PEG-8 (416 mg, 0.626 mmol, 1.0 eq), PyBOP (489 mg, 0.939 mmol, 1.5 eq), and DIPEA (242 mg, 1.878 mmol, 3.0 eq). The mixture was stirred and allowed to react for 2 h. Upon completion of the reaction, the reaction solution was used directly in the next step without post-treatment.

[0416] Synthesis of compound 7-4

[0417] Diethylamine (2.0 mL) was added directly to the reaction mixture from the previous step (compound 7-3), and the reaction was stirred at 25°C for 2 h. After completion, the reaction solution was directly purified on a reverse-phase C18 column, initially using a CH3CN:H2O (0.05% NH3.H2O) = 5-95% to 95%-95% elution system to flush out impurities, followed by a CH3CN (0.05% TFA):H2O (0.05% TFA) = 95%-95% to flush out the desired product. The product solution was collected and spin-dried to yield 1.1 g of pure white solid.

[0418] MS (ESI), m / z, 1796.80 [M+H] +.

[0419] Synthesis of compound 7-5

[0420] To a solution of compound 7-4 (800 mg, 0.419 mmol, 1.5 eq) in DMF (8.0 mL) at 25°C were added 101B13 (660 mg, 0.279 mmol, 1.0 eq, based on polymer building block), PyBOP (218 mg, 0.419 mmol, 1.5 eq), and DIPEA (163 mg, 1.26 mmol, 4.5 eq). The mixture was allowed to cool to room temperature and stirred for 16 hours. After completion of the reaction, the reaction solution was concentrated under high vacuum to half its original volume and then ultrafiltered through a 30KMW ultrafiltration membrane. The pure product was lyophilized to yield 850 mg of a white colloidal solid with a PTX content of 17.8% (theoretical content: 21.0%).

[0421] Content test method: HPLC UV = 254nM, test the content of fragment 7-2 or 7-4 in compound 7, and then convert it into paclitaxel content.

[0422] Example 8: Synthesis of Compound 8

[0423] Synthesis of compound 8-1

[0424] To a solution of 7-2 (85 mg, 0.062 mmol, 1.0 eq) in DMF (5 mL) at room temperature under nitrogen was added N-Fmoc-8-aminooctanoic acid (23 mg, 0.062 mmol, 1.0 eq), DIPEA, and PyBOP (50 mg, 0.093 mmol, 1.5 eq). The mixture was stirred overnight. After completion of the reaction, the mixture was concentrated and purified by Pre-HPLC to afford 68 mg of a white solid in a 63% yield.

[0425] MS (ESI), m / z, 1736.2 [M+H] + .

[0426] Synthesis of compound 8-2

[0427] To compound 8-1 (68 mg, 0.039 mmol, 1.0 eq) in DMF (50 mL) was added diethylamine (0.2 mL) at room temperature under nitrogen. The mixture was stirred overnight. After the reaction, the mixture was concentrated and purified by Pre-HPLC to afford 42 mg of a white solid in a 70% yield.

[0428] MS (ESI), m / z, 1514.2 [M+H] + .

[0429] Synthesis of compound 8

[0430] To a solution of compound 8-2 (42 mg, 0.027 mmol, 1.5 eq) in DMF (5 mL) at room temperature (25°C) under hydrogen atmosphere were added 101B13 (44 mg, 0.018 mmol, 1.0 eq, based on polymer building block), DIPEA (0.1 mL), and PyBOP (28 mg, 0.054 mmol). The mixture was stirred overnight. After completion of the reaction, the mixture was concentrated and ultrafiltered using a 30KMW ultrafiltration membrane. The product was concentrated and lyophilized to yield 45 mg with a purity of 99%.

[0431] Example 9: Synthesis of Compound 9

[0432] Synthesis of compound 9-1

[0433] To a solution of [2-[2-(Fmoc-amino)ethoxy]ethoxy]acetic acid (168 mg, 0.436 mmol, 1.0 eq) in DMF (8 mL) was added DIPEA (225 mg, 1.744 mmol, 4.0 eq) and TSTU (131 mg, 0.436 mmol, 1.0 eq) at 0°C under nitrogen. The reaction mixture was stirred at room temperature for 1 hour. A solution of 7-2 (600 mg, 0.436 mmol, 1.0 eq) in DMF (4 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction was complete by LCMS, and the reaction solution was used directly in the next step.

[0434] Synthesis of compound 9-2

[0435] To a solution of compound 9-1 (500 mg, 0.287 mmol, 1.0 eq) in DMF (15 mL) was added diethylamine (420 mg, 5.74 mmol, 20.0 eq) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 1 hour. LCMS confirmed the completion of the reaction, and the reaction solution was purified on a C18 column (ACN / TFA 0.05% H2O) to afford compound 9-2 as a white solid (400 mg, 91% yield).

[0436] Synthesis of compound 9

[0437] To a solution of 101B13 (686 mg, 0.29 mmol, 1.0 eq, based on polymer structural unit), compound 9-2 (800 mg, 0.435 mmol, 1.5 eq), and PyBOP (227 mg, 0.435 mmol, 1.5 eq) in DMF (8 mL) was added DIPEA (150 mg, 1.16 mmol, 4.0 eq) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was pumped dry, and methyl tert-butyl ether was added and stirred for 20 minutes. The supernatant was removed, and the oily substance at the bottom of the flask was first dissolved in methanol, then filtered by adding an equal amount of water. Approximately 1.5 liters of solvent was ultrafiltered and sampled for HPLC analysis. The purity was 99% at 254 nm and 98% at 210 nm. Ultrafiltration was performed using a 30KMW ultrafiltration membrane. The methanol was concentrated and lyophilized to yield compound 9 as a white solid (361 mg, 85% yield).

[0438] Example 10: Synthesis of Compound 10

[0439] Synthesis of compound PEG4-1

[0440] At room temperature, tert-butyl 15-amino-4,7,10,13-tetraoxopentadecanoate (1.9 g, 5.91 mmol, 1.0 eq) and DIPEA (1.52 g, 11.8 mmol, 2.0 eq) were dissolved in dichloromethane (40 mL). FmocOSU (1.99 g, 5.91 mmol, 1.0 eq) was added under nitrogen. The mixture was stirred at room temperature for 16 h. LCMS confirmed the reaction was complete. Water was added to terminate the reaction, the layers were separated, and the aqueous phase was extracted with dichloromethane. The organic phase was concentrated and purified by column chromatography to obtain compound PEG4-1 as a colorless oil (3.4 g, 100% yield).

[0441] MS (ESI), m / z, 544.2 [M+H] + .

[0442] Synthesis of compound PEG4

[0443] Compound PEG4-1 (3.3 g, 6.07 mmol, 1.0 eq) was dissolved in dichloromethane (20 mL) at room temperature. TFA (10 mL) was added and stirred at 30°C under nitrogen for 3 h. LCMS confirmed the reaction was complete. The mixture was concentrated under reduced pressure to obtain a yellow oil (4 g, crude product), which was directly used in the next reaction.

[0444] MS (ESI), m / z, 488.2 [M+H] + .

[0445] Synthesis of compound 10-1

[0446] At room temperature and under nitrogen, compound PEG4 (3.6 g, 7.38 mmol, 1.0 eq) and DIPEA (9 mL) were dissolved in dichloromethane (90 mL). TSTU (3.3 g, 11.1 mmol, 1.5 eq) was added at 30°C under nitrogen and stirred at room temperature for 2 h. LCMS confirmed the reaction was complete. The product was concentrated under reduced pressure and separated by reverse-phase column chromatography (A = TFA (0.1% + H2O), B = acetonitrile). The prepared solution was extracted with ethyl acetate, dried over sodium sulfate, filtered, and dried under reduced pressure to afford a yellow oil (2.65 g, 61.6% yield).

[0447] MS (ESI), m / z, 585.2 [M+H] +.

[0448] The above intermediate (127.7 mg, 0.2184 mmol, 1.0 eq) and DIPEA (112.7 mg, 0.8736 mmol, 4.0 eq) were dissolved in DMSO (5 mL). Compound 7-2 (300 mg, 0.2184 mmol, 1.0 eq) was added under nitrogen at 30°C and stirred at room temperature for 1 h. The reaction was complete by LCMS and the mixture was directly used for the next step.

[0449] MS (ESI), m / z, 1843.0 [M+H] +.

[0450] Synthesis of compound 10-2

[0451] Under nitrogen, diethylamine (2.5 mL) was added to the reaction mixture of compound 10-1 and stirred at room temperature for 1 h. LCMS confirmed the reaction was complete. The product was separated by reverse-phase column chromatography (A = TFA (0.1% + H2O), B = acetonitrile) and lyophilized to obtain a white solid (226 mg, 69.7% yield).

[0452] MS (ESI), m / z, 1621.0 [M+H] + .

[0453] Synthesis of compound 10

[0454] At room temperature (25°C) and under nitrogen, 101B13 (80 mg, 0.034 mmol, 1.0 eq, based on polymer structural unit), compound 10-2 (82.7 mg, 0.051 mmol, 1.5 eq), PyBOP (26.5 mg, 0.051 mmol, 1.5 eq), DIPEA (0.025 mL, 0.136 mmol, 4.0 eq), and DMF (1.5 mL) were added sequentially. The reaction was stirred at room temperature for 15 h. HPLC monitoring confirmed complete conversion of the starting materials. MTBE (30 mL) was added to DMF, causing the solution to become turbid and a white solid to precipitate. The supernatant was removed by aspiration, and the white solid was washed with MTBE and aspirated. The remaining white solid was dissolved in MeOH and ultrafiltered (30 KMW) using a MeOH / water solution to remove small molecule impurities. HPLC monitoring confirmed complete removal of small molecule impurities. The solution was collected and the MeOH was removed by vortexing. The aqueous solution was lyophilized to obtain a white solid compound 10 (156 mg) with a purity of 99.33%.

[0455] Example 11: Synthesis of Compound 11

[0456] Synthesis of compound 11-1

[0457] At room temperature (25°C) and under nitrogen, DIPEA (225.4 mg, 1.747 mmol, 4.0 eq) and TSTU (131.5 mg, 0.437 mmol, 1.0 eq) were added to a solution of PEG12 (367 mg, 0.437 mmol, 1.0 eq) in DMSO (10 mL) in sequence. The reaction was stirred at room temperature for 1 hour, followed by the addition of 7-2 (600 mg, 0.437 mmol, 1.0 eq) and stirring at room temperature for 1 hour. LCMS confirmed the reaction was complete, and diethylamine (1 mL) was added. The reaction solution was stirred at room temperature for 1 hour. The product was concentrated and purified by reverse phase column chromatography to give a white solid (0.5 g, 58% yield).

[0458] MS (ESI), m / z, 1973.2 [M+H] + .

[0459] Synthesis of compound 11

[0460] To a DMF solution of compound 11-1 (500 mg, 0.253 mmol, 1.5 eq, based on polymer unit weight) at room temperature under nitrogen, 101B13 (399.5 mg, 0.169 mmol, 1.0 eq, based on polymer unit weight), PyBOP (131.8 mg, 0.253 mmol, 1.5 eq), and DIPEA (87.2 mg, 0.676 mmol, 4.0 eq) were added. The reaction mixture was stirred for 16 h. The reaction solution was ultrafiltered (30K MW) and lyophilized to afford compound 11 as a white solid (0.336 g, 45.9% yield). The PTX content was approximately 19.1%.

[0461] Example 12: Synthesis of Compound 12a

[0462] Synthesis of compound SAR5-1

[0463] At room temperature of 25°C and under nitrogen protection, DIC (1.7 g, 13.2 mmol, 2.0 eq) and DMAP (0.16 g, 1.32 mmol, 0.2 eq) were added to a dry CH2Cl2 solution (100 mL) of SAR5-SM2 (5.0 g, 6.61 mmol, 1.0 eq, according to the synthesis of Fmoc-Sar-Sar-OH in patent WO2019081455A1) and SAR5-SM1 (5.0 g, 13.2 mmol, 2.0 eq, according to the synthesis of Example 2 in patent US2012296074A1) and reacted for 12 h. TLC showed that the reaction was complete, and the mixture was concentrated to 20 mL. Acetonitrile (300 mL) was added, filtered, and dried in vacuo to obtain compound SAR5-1 as a white solid, 7.0 g, with a yield of 95%.

[0464] Synthesis of compound SAR5-2

[0465] At room temperature (25°C) and under nitrogen protection, piperidine (1 mL) and DBU (1 mL) were added to a THF solution (100 mL) of SAR5-1 (7.0 g, 6.25 mmol) and the mixture was stirred at room temperature for 1 h. TLC monitoring showed that the reaction was complete. The mixture was cooled to 5°C, 6N HCl was added to adjust the pH to 7, acetonitrile (300 mL) was added, the mixture was filtered, the solid was collected and dried in vacuo to obtain compound SAR5-2 as a white solid, 5.0 g, with a yield of 89%.

[0466] Synthesis of compound SAR5-3

[0467] At room temperature 25 ° C and under nitrogen protection, HBTU (2.5 g, 4.45 mmol, 1.0 eq) and SAR5-SM1 (2.5 g, 6.67 mmol, 1.5 eq) in dry THF (80 mL) were added HBTU (2.5 g, 6.67 mmol, 1.5 eq), HOBt (0.9 g, 6.67 mmol, 1.5 eq) and DIPEA (1.7 g, 13.4 mmol, 3.0 eq) and reacted for 2 h. TLC showed that the reaction was complete. n-propylamine (0.8 g) was added to quench the reaction and stirred for 1 h. Acetonitrile (500 mL) and diatomaceous earth (40 g) (assisted filtration) were added, filtered, and the solid was dissolved and filtered with 100 mL of THF. The filtrate was concentrated and dried in vacuo to obtain compound SAR5-3 as a white solid, 5.0 g, with a yield of 88%.

[0468] Synthesis of compound SAR5-4

[0469] At room temperature of 25°C and under nitrogen protection, piperidine (1 mL) and DBU (1 mL) were added to a THF solution (100 mL) of SAR5-3 (4.0 g, 3.2 mmol) and the reaction was stirred at room temperature for 1 h. TLC monitoring showed that the reaction was complete. The mixture was cooled to 5°C, 6N HCl was added to adjust the pH to 7, acetonitrile (400 mL) and diatomaceous earth (40 g) (assisted filtration) were added, and the mixture was filtered. The solid was dissolved in 100 mL of THF and filtered. The filtrate was concentrated and dried in vacuo to obtain compound SAR5-4 as a white solid, 3.0 g, with a yield of 91%.

[0470] Synthesis of compound SAR5-5

[0471] At room temperature 25 ° C and under nitrogen protection, HBTU (1.64 g, 4.33 mmol, 1.5 eq), HOBt (0.58 g, 4.33 mmol, 1.5 eq) and DIPEA (1.12 g, 8.65 mmol, 3.0 eq) were added to a dry THF solution (70 mL) of SAR5-4 (3.0 g, 2.88 mmol, 1.0 eq) and SAR5-SM1 (1.65 g, 2.88 mmol, 1.5 eq) and stirred for 2 h. TLC showed that the reaction was complete. N-propylamine (0.5 g) was added to quench the reaction and stirred for 1 h. Acetonitrile (500 mL) and diatomaceous earth (40 g) (assisted filtration) were added and filtered. The solid was dissolved and filtered with 100 mL of THF. The filtrate was concentrated and dried in vacuo to give compound SAR5-5 as a white solid, 3.5 g, with a yield of 86%.

[0472] Synthesis of compound SAR5

[0473] At room temperature (25°C) and under nitrogen protection, 50 mL of a pre-prepared solution (50 mL of dichloromethane was added with 5 mL of 2,2,2-trifluoroethanol and 0.5 mL of trifluoroacetic acid) was added to SAR5-5 (3.0 g, 2.88 mmol, 1.0 eq) and stirred for 0.5 h. TLC showed that the reaction was complete. Celite (40 g) was added (to assist filtration), filtered, and the filtrate was concentrated. Pre-HPLC separation and purification gave compound SAR5, 1.0 g, in a yield of 71%.

[0474] MS (ESI), m / z, 667.3 [M+H] + .

[0475] Synthesis of compound 12a-1

[0476] To a dry CH2Cl2 solution (5 mL) of SAR5 (291 mg, 0.44 mmol, 1.2 eq) in an ice-water bath at 5°C under nitrogen protection were added TSTU (165 mg, 0.55 mmol, 1.5 eq) and DIPEA (94 mg, 0.73 mmol, 3.0 eq) and stirred for 5 minutes (LCMS monitoring showed the formation of an active ester). A dichloromethane solution of 7-2 (500 mg, 0.36 mmol, 1.0 eq) (2 mL) was added and stirred for 5 minutes. The mixture was quenched with methanol and concentrated to give crude product 12a-1, which was used directly in the next reaction.

[0477] Synthesis of compound 12a-2

[0478] Under nitrogen, diethylamine (5 mL) was added to a dichloromethane solution of the crude compound 12a-1. The mixture was reacted at room temperature for 1 h and then concentrated. The crude product was separated and purified by Pre-HPLC (CH3CN / H2O, 0.05% TFA) to give the product 12a-2, 500 mg, as a colorless oil in a yield of 73%.

[0479] MS (ESI), m / z, 1799.1 [M+H] + .

[0480] Synthesis of compound 12a

[0481] To a solution of 101B13 (250 mg, 0.003 mmol, 1.0 eq) in dry DMF (5 mL) was added 12a-2 (276 mg, 0.15 mmol, 45.0 eq), PyBOP (142 mg, 0.27 mmol, 80.0 eq), and DIPEA (56 mg, 0.044 mmol, 128.0 eq) at room temperature (25°C) under nitrogen. The reaction mixture was then heated to 28°C for 12 h, concentrated, and filtered into methanol and water (1 / 1, 100 mL). The product was purified by ultrafiltration (30K MW), concentrated, and lyophilized to afford 12a (350 mg, 85% yield, 99% purity, and approximately 20% PTX content).

[0482] Example 13: Synthesis of Compound 12b

[0483] Synthesis of compound SAR9

[0484] Using SAR5-5 as the starting material, condensation and Fmoc removal were repeated twice, and finally the TAG protecting group was removed to obtain compound SAR9, 1.2 g, with a five-step yield of 50%.

[0485] MS (ESI), m / z, 951.3 [M+H] + .

[0486] Synthesis of compound 12b-1

[0487] To a dry CH2Cl2 solution (5 mL) of SAR9 (416 mg, 0.44 mmol, 1.2 eq) was added TSTU (165 mg, 0.55 mmol, 1.5 eq) and DIPEA (94 mg, 0.73 mmol, 3.0 eq) in an ice-water bath at 5°C under nitrogen protection, and the mixture was stirred for 5 minutes (LCMS monitoring showed that an active ester was formed). A dichloromethane solution of 7-2 (500 mg, 0.36 mmol, 1.0 eq) (2 mL) was added, and the reaction was stirred for 5 minutes. The mixture was quenched with methanol and concentrated to give the crude product 12b-1, which was used directly in the next reaction.

[0488] Synthesis of compound 12b-2

[0489] Under nitrogen, diethylamine (5 mL) was added to a dichloromethane solution of the crude compound 12b-1. The mixture was reacted at room temperature for 1 h and then concentrated. The crude product was separated and purified by Pre-HPLC (CH3CN / H2O, 0.05% TFA) to give product 12b-2, 650 mg, as a colorless oil in an 85% yield.

[0490] MS (ESI), m / z, 1041.1 [M / 2] + .

[0491] Synthesis of compound 12b

[0492] To a dry DMF solution (5 mL) of 101B13 (250 mg, 0.003 mmol, 1.0 eq) at room temperature (25°C) under nitrogen was added 12b-2 (319 mg, 0.15 mmol, 45.0 eq), PyBOP (142 mg, 0.27 mmol, 80.0 eq), and DIPEA (56 mg, 0.044 mmol, 128.0 eq). The reaction mixture was then heated to 28°C for 12 h, concentrated, filtered into methanol and water (1 / 1, 100 mL), purified by ultrafiltration (30K MW), and lyophilized to afford 400 mg of product 12b in 86% yield, 98% purity, and approximately 19% PTX content.

[0493] Example 14: Synthesis of Compound 13

[0494] Synthesis of compound 13-1

[0495] At room temperature and under nitrogen protection, 13-SM (5.0 g, 25 mmol, 1.0 eq), anhydrous DCM (50 mL), triethylamine (7.0 mL, 50 mmol, 2.0 eq) were added sequentially, followed by dropwise addition of benzyl chloroformate (4.6 mL, 32.5 mmol, 1.3 eq). The reaction was stirred at room temperature for 3 hours. LCMS monitored the complete conversion of the reaction starting materials. The mixture was concentrated and dissolved in a small amount of DCM, filtered, and separated by column chromatography (PE / EA = 1:1 to 1:3) to give the product 13-1 as a colorless oil, 7.6 g, in a yield of 91%.

[0496] 1 H NMR (400MHz, CDCl3) δ7.49–7.27(m,5H),5.14(s,2H),4.03–3.81(m,1H),3.60–3.13(m,4H),2.01–1.72(m,4H),1.43(s,9H).

[0497] Synthesis of compound 13-2

[0498] At room temperature and under nitrogen protection, 13-1 (669 mg, 2.0 mmol, 1.0 eq), anhydrous THF (6 mL), and iodomethane (0.3 mL, 5.0 mmol, 2.5 eq) were added in sequence. The mixture was cooled to 5 ° C with an ice-water bath and then NaH (475 mg, 11.4 mmol, 5.7 eq) was added. The reaction was slowly warmed to room temperature and stirred for 3 hours. LCMS monitored the complete conversion of the reaction raw materials. NH4Cl solution was added to quench the reaction, and the mixture was extracted with EA. The organic phases were combined and dried, spin-dried, and separated by column (PE / EA=2:1) ​​to obtain a colorless oily product 13-2, 378 mg, with a yield of 54%.

[0499] 1 H NMR (400MHz, CDCl3) δ7.41–7.28(m,5H),5.21–5.03(m,2H),4.19–3.85(m, 1H),3.58–3.02(m,4H),2.96–2.65(m,3H),2.05–1.76(m,4H),1.45(s,9H).

[0500] Synthesis of compound 13-3

[0501] At room temperature and under nitrogen protection, 13-2 (378 mg, 1.1 mmol, 1.0 eq), H2O (5 mL), THF (5 mL), and acetic acid (0.8 mL) were added in sequence. After replacing the system with H2 atmosphere using a balloon, Pd / C (113 mg, 0.11 mmol, 0.1 eq) was added. The reaction was stirred at room temperature for 3 hours. LCMS monitored the complete conversion of the reaction starting material. Filtered and spin-dried to obtain 398 mg of the oily product 13-3.

[0502] Synthesis of compound 13-4

[0503] Under nitrogen at room temperature, 13-3 (398 mg, 1.0 mmol, 1.0 eq), DMF (5 mL), DIPEA (0.52 mL, 3.0 mmol, 3.0 eq), and FMOC-Val-Cit-PAB-PNP (1.15 g, 1.5 mmol, 1.5 eq) were added sequentially. The reaction was stirred at room temperature for 1.5 hours. LCMS monitored the complete conversion of the reaction starting materials. Reverse-phase column chromatography was used to obtain 13-4, a white solid product (700 mg, 83% yield over two steps).

[0504] 1H NMR (400MHz, DMSO) δ10.06 (s, 1H), 8.12 (d, J = 7.7Hz, 1H), 7.89 (d, J = 7.5Hz, 2H), 7.75(t,J=7.8Hz,2H),7.62–7.53(m,2H),7.47–7.38(m,3H),7.35–7.27(m,4H), 6.12–5.84(m,1H),4.99(s,2H),4.51–4.21(m,5H),3.41–2.89(m,6H),2.86–2.6 4(m,3H),2.09–1.55(m,7H),1.38(d,J=4.9Hz,9H),0.87(dd,J=10.7,6.7Hz,6H).

[0505] Synthesis of compound 13-5

[0506] At room temperature, 13-4 (625 mg), DCM (10 mL), and TFA (10 mL) were added sequentially. The reaction was stirred at room temperature for 0.5 hours. LCMS monitored the complete conversion of the reaction starting materials. MTBE was added to the system to precipitate a white precipitate, which was filtered to obtain the product 13-5 as a white solid (750 mg).

[0507] 1 H NMR (400MHz, DMSO) δ10.09(s,1H),8.43–8.24(m,2H),8.14(d,J=7.5Hz,1H),7.90(d,J=7.5Hz,2H),7 .75(t,J=7.8Hz,2H),7.61(d,J=8.2Hz,2H),7.48–7.39(m,4H),7.37–7.29(m,4H),6.26–5.93(m,1H) ,5.42–4.90(m,2H),4.47–4.19(m,4H),4.06(d,J=7.1Hz,1H),3.93(dd,J=8.9,7.0Hz,1H),3.43–3.2 9(m,1H),3.06–2.91(m,3H),2.58(t,J=5.3Hz,2H),2.07–1.31(m,8H),0.87(dd,J=10.6,6.8Hz,6H).

[0508] Synthesis of compound 13-6

[0509] At room temperature and under nitrogen protection, 13-5 (750 mg, 1.0 mmol, 1.0 eq), 7-SM1 (1.5 g, 1.5 mmol, 1.5 eq), and DMF (5 mL) were added in sequence. The system was cooled to 5 ° C with an ice bath and DIPEA (0.36 mL, 2.0 mmol, 2.0 eq) was added. The reaction was stirred at 5 ° C for 1 hour. LCMS monitored the complete conversion of the reaction raw materials. Diethylamine (0.8 ml, 8.0 mmol, 8.0 eq) was added. The reaction was stirred at room temperature for 0.5 hours and LCMS monitored the complete conversion of the reaction raw materials. The mixture was lyophilized after preparation to give a white solid product 13-6, 404 mg, with a total yield of 36% for three steps.

[0510] 1 H NMR (400MHz, DMSO) δ10.21 (s, 1H), 9.32–9.02 (m, 1H), 8.70 (d, J = 7.5Hz, 1H), 8.18–8.04 (m, 3H), 8. 03–7.93(m,2H),7.88–7.79(m,2H),7.77–7.39(m,12H),7.37–7.15(m,3H),6.37–6.25(m,1H),6.0 9(s,1H),5.95–5.51(m,2H),5.46–5.15(m,2H),5.06–4.86(m,3H),4.58–4.48(m,1H),4.20–3.90( m,4H),3.31–2.71(m,9H),2.38–2.01(m,8H),1.94–1.57(m,12H),1.50(s,6H),1.07–0.92(m,12H).

[0511] Synthesis of compound 13-7

[0512] At room temperature and under nitrogen, PEG8 (86.3 mg, 0.13 mmol, 1.1 eq), DMF (1.5 mL), and DIPEA (0.18 mL, 0.36 mmol, 3.0 eq) were added sequentially. The reaction was stirred at room temperature for 0.5 h, with complete conversion of the starting material monitored by LCMS. The mixture was then cooled to 5°C in an ice bath, and 13-6 (180 mg, 0.12 mmol, 1.0 eq) was added. The mixture was stirred at 5°C for 1 h, with complete conversion monitored by LCMS. The reaction solution was carried on to the next step without further treatment. At room temperature and under nitrogen, diethylamine (0.1 mL, 0.95 mmol, 8.0 eq) was added to the reaction solution. The reaction was stirred at room temperature for 1 h, with complete conversion monitored by LCMS. The mixture was directly purified by reverse-phase column chromatography (MeCN / H2O-0.05% TFA) and lyophilized to afford 13-7 as a white solid (135 mg, yield 59% for both steps).

[0513] 1 H NMR(400MHz, DMSO)δ9.99(s,1H),9.28–9.02(m,1H),8.12(d,J=7.4Hz,1H),8.03–7.94(m,2H),7.92–7.38(m,21H),7.36–7.05(m,3H),6.30(s, 1H),6.08–5.15(m,6H),5.05–3.92(m,10H),3.04–2.66(m,10H),2.43– 1.54(m,28H),1.29–1.20(m,7H),1.04–0.99(m,6H),0.87–0.82(m,6H).

[0514] Synthesis of compound 13

[0515] At room temperature (25°C) and under nitrogen, 101B13 (93.6 mg, 0.04 mmol, 1.0 eq, based on polymer structural unit), 13-7 (115 mg, 0.059 mmol, 1.5 eq), PyBOP (30.7 mg, 0.059 mmol, 1.5 eq), DIPEA (0.03 mL, 0.16 mmol, 4.0 eq), and DMF (1 mL) were added sequentially. The reaction was stirred at room temperature for 15 hours, and HPLC monitored the complete conversion of the starting materials. MTBE (30 mL) was added to DMF, causing the solution to become turbid and a white solid to precipitate. The supernatant was removed by aspiration, and the white solid was washed with MTBE and aspirated. The remaining white solid was dissolved in MeOH, purified by ultrafiltration (30K MW), and lyophilized to obtain 13, a white solid product (155 mg) with a purity of 100%. The PTX content was approximately 20.8%.

[0516] Example 15: Synthesis of Compound 14

[0517] Synthesis of compound 14-1

[0518] To a solution of 14-SM (4.0 g, 24.15 mmol, 1.0 eq) in DCM (50 mL) was added triethylamine (4.9 g, 48.3 mmol, 2.0 eq) at room temperature (25°C) under nitrogen. CbzCl (4.9 g, 28.98 mmol, 1.2 eq) in DCM (10 mL) was added dropwise. After complete addition, the reaction mixture was stirred at room temperature for 4 hours. The reaction was complete by LCMS, concentrated, dissolved in DMF, and purified on a reverse phase column (ACN / TFA 0.05% H2O) to afford product 14-1 as a colorless oil (4.0 g, 63% yield).

[0519] Synthesis of compound 14-2

[0520] To a THF solution (30 mL) of 14-1 (3.0 g, 11.39 mmol, 1.0 eq) at room temperature (25°C) under nitrogen, borane dimethyl sulfide (2 M, 17 mL, 3.0 eq) was added portionwise. The reaction mixture was stirred at reflux for 6 hours. LCMS confirmed the reaction was complete. Methanol was added dropwise to the reaction solution and stirred for 30 minutes until no bubbles formed. The mixture was then refluxed for another hour until no bubbles formed. The reaction solution was concentrated to afford 14-2 as a white solid (2.8 g, 99% yield).

[0521] Synthesis of compound 14-3

[0522] To a solution of 14-2 (2.3 g, 9.22 mmol, 1.0 eq) in DCM (30 mL) was added Dess-Martin periodinane (4.3 g, 10.14 mmol, 1.1 eq) at 25°C under nitrogen. The reaction mixture was stirred at room temperature for 4 hours. LCMS confirmed the completion of the reaction. The reaction mixture was filtered, the filtrate was dried, and purified on a silica gel column to afford the product 14-3 as a colorless oil (2.1 g, 92% yield).

[0523] Synthesis of compound 14-4

[0524] To a solution of 14-3 (1.8 g, 7.28 mmol, 1.0 eq) in DCM (20 mL) was added a catalytic amount of acetic acid (0.2 mL), methylamine hydrochloride (984 mg, 14.56 mmol, 2.0 eq), and sodium cyanoborohydride (686 mg, 10.92 mmol, 1.5 eq) at room temperature (25°C) under nitrogen. The reaction mixture was stirred at room temperature for 16 hours. LCMS confirmed the reaction was complete, and the reaction solution was directly purified on a silica gel column to yield compound 14-4 as a white solid (1.5 g, 79% yield).

[0525] Synthesis of compound 14-5

[0526] To a solution of 14-4 (1.5 g, 5.72 mmol, 1.0 eq) in DCM (20 mL) was added triethylamine (1.73 g, 17.16 mmol, 3.0 eq) and Boc2O (2.5 g, 11.44 mmol, 2.0 eq) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 4 hours. LCMS confirmed the completion of the reaction, and the reaction mixture was spin-dried and purified on a silica gel column to afford the product 14-4 as a colorless oil (1.8 g, 87% yield).

[0527] Synthesis of compound 14-6

[0528] To a solution of 14-5 (1.8 g, 4.96 mmol, 1.0 eq) in methanol (30 mL) was added wet palladium on carbon (10%, 500 mg). The reaction mixture was stirred at 30°C under a hydrogen atmosphere for 2 hours. LCMS confirmed the completion of the reaction, and the reaction mixture was dried to afford product 14-6 as a colorless oil (1.1 g, 97% yield).

[0529] Synthesis of compound 14-7

[0530] To a solution of FMoc-Val-Cit-PAB-PNP (1.0 g, 1.3 mmol, 1.0 eq) in DMF (40 mL) was added 14-6 (300 mg, 1.3 mmol, 1.0 eq) and DIPEA (168 mg, 1.3 mmol, 1.0 eq) at room temperature under nitrogen. The reaction mixture was stirred at 15°C for 16 hours. LCMS confirmed the completion of the reaction, and the reaction solution was purified on a C18 column (ACN / TFA 0.05% H2O) to afford 14-7 as a white solid (500 mg, 45% yield).

[0531] Synthesis of compound 14-8

[0532] To a solution of 14-7 (120 mg, 0.14 mmol, 1.0 eq) in DCM (15 mL) was added TFA (5 mL) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 2 hours. LCMS confirmed the completion of the reaction. The reaction solution was concentrated to afford the product 14-8 as a brown oil (100 mg, 100% yield).

[0533] Synthesis of compound 14-9

[0534] To a solution of 14-8 (100 mg, 0.132 mmol, 1.0 eq) in DMF (10 mL) at room temperature and under nitrogen protection, DIPEA (34 mg, 0.264 mmol, 2.0 eq) and 7-SM1 (135 mg, 0.132 mmol, 1.0 eq) were added. The reaction mixture was stirred at 15°C for 16 hours. LCMS detection showed that the reaction was complete, and the reaction solution was purified by C18 column (ACN / TFA 0.05% H2O) to give product 14-9 as a white solid, 150 mg, which was dissolved in DMF (6 mL) and diethylamine (133 mg, 1.82 mmol, 20.0 eq) was added. The reaction mixture was stirred at room temperature for 1 hour. LCMS detection showed that the reaction was complete, and the reaction solution was directly separated and purified by reverse phase column chromatography to give product 14-9 as a white solid, 85 mg, 50% yield.

[0535] Synthesis of compound 14-10

[0536] To a solution of PEG8 (282 mg, 0.424 mmol, 1.0 eq) in DMSO (10 mL) at 0°C under nitrogen, DIPEA (219 mg, 1.69 mmol, 4.0 eq) and TSTU (128 mg, 0.424 mmol, 1.0 eq) were added, respectively. The reaction mixture was stirred at 0°C for 30 minutes and then at room temperature for 1 hour. A solution of 14-9 (128 mg, 0.424 mmol, 1.0 eq) in DMSO (10 mL) was added to the reaction mixture and stirred at room temperature for 2 hours. LCMS confirmed the reaction was complete, and diethylamine (604 mg, 8.255 mmol, 20.0 eq) was added. The reaction mixture was stirred at room temperature for 1 hour. LCMS confirmed the reaction was complete, and the reaction solution was purified on a C18 column (ACN / TFA 0.05% H2O) to obtain product 14-10 as a white solid, 800 mg, ~100% yield.

[0537] Synthesis of compound 14

[0538] At room temperature and under nitrogen protection, DIPEA (150 mg, 1.16 mmol, 4.0 eq) was added to a DMF (8 mL) solution of 101B13 (686 mg, 0.29 mmol, 1.0 eq, polymer structural unit measurement), 14-10 (800 mg, 0.435 mmol, 1.5 eq), and PyBOP (227 mg, 0.435 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was spin-dried on an oil pump, methyl tert-butyl ether was added and stirred for 20 minutes, the supernatant was removed, and the oil at the bottom of the bottle was first dissolved with methanol, then an equal amount of water was added and filtered, purified by ultrafiltration (30K MW), and lyophilized to give 14 as a white solid, 1.0 g, 83% yield. The PTX content was approximately 24.3%.

[0539] Example 16: Synthesis of Compound 15

[0540] Synthesis of compound 15-1

[0541] At room temperature and under nitrogen protection, 7-SM1 (260 mg, 1.17 mmol, 1.2 eq) and DIPEA (0.26 g, 2 mmol, 2.0 eq) were added to 15-SM (prepared according to the synthesis method in the literature ChemMedChem 2022, e202200279.) in DMF (10 mL) at 100 °C. Stir overnight. The reaction solution was concentrated and purified by Pre-HPLC to obtain 120 mg of a white solid, which was further dissolved in DMF (5 mL) and diethylamine (1 mL) was added. Stir overnight. The reaction solution was concentrated and purified by Pre-HPLC to obtain 100 mg of a white solid with a yield of 96%.

[0542] MS (ESI), m / z, 1456.0 [M+H] +.

[0543] Synthesis of compound 15-2

[0544] To a solution of PEG8 (40 mg, 0.061 mmol, 1.3 eq) in DCM (20 mL) was added TSTU (40 mg, 0.13 mmol) at room temperature under nitrogen. The mixture was stirred for 15 min, and then a solution of 15-1 (90 mg, 0.061 mmol) in dichloromethane was added to the mixture, followed by stirring for 2 h. After completion of the reaction, the mixture was concentrated and purified by Pre-HPLC to afford 90 mg of a white solid in a 70% yield.

[0545] MS (ESI), m / z, 1051.2 [M / 2+H] + .

[0546] Synthesis of compound 15

[0547] To a solution of 101B13 (70 mg, 1.0 eq), 15-2 (86 mg, 0.05 mmol, 48.0 eq), and PyBOP (40 mg, 0.08 mmol, 80.0 eq) in DMF (2 mL) was added DIPEA (16 mg, 0.12 mmol, 128.0 eq) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 16 hours. Purification by ultrafiltration (30K MW) and lyophilization afforded 15 as a white solid (100 mg, 78% yield). The PTX content was approximately 19.3%.

[0548] Example 17: Synthesis of Compound 16a

[0549] Synthesis of compound 16a-1

[0550] Under dry ice ethanol at -60°C and nitrogen protection, 1.0 M lithium tert-butoxide (3.6 mL, 11.7 mmol, 5.0 eq) was added dropwise to a dry THF solution (50 mL) of paclitaxel (2.0 g, 2.34 mmol, 1.0 eq) and 16-SM1 (2.6 g, 7.03 mmol, 3.0 eq, prepared according to the synthesis method in Tetrahedron, 2018, 1951–1956) (2.0 eq was added dropwise first, and LCMS showed that the reaction was half complete. 5.0 eq was added continuously, and LCMS showed that most of the reaction was complete), and the reaction was stirred for 1 h. The reaction was quenched with ammonium chloride and water, and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with salt, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (SiO2, 0-100% EtOAc in PE / SiO2, with most of the product released, and finally 0-20% MeOH in CH2Cl2) to afford product 16a-1, 2.3 g, as a white solid in a 96% yield.

[0551] MS (ESI), m / z, 1162[M+1] + .

[0552] 1 H NMR(400MHz,Chloroform-d)δ8.25–8.04(m,2H),7.78(dd,J=7.5,4.3Hz,4H),7.65–7.45(m,6H),7.45–7.28(m,8H),7.11(d,J=9.0Hz,1H),6.71(s,1H) ,6.26(s,1H),6.20(t,J=9.0Hz,1H),5.75(dd,J=9.0,3.7Hz,1H),5.66(d,J =7.1Hz,1H),5.28(d,J=11.3Hz,1H),4.92(d,J=9.6Hz,2H),4.77(d,J=3.8H z,1H),4.63(dd,J=11.2,5.9Hz,1H),4.47(d,J=6.5Hz,2H),4.40(dd,J=10. 9,6.6Hz,1H),4.24–4.16(m,2H),4.12(q,J=7.1Hz,2H),3.75(dd,J=13.1,6 .5Hz,2H),3.64(d,J=15.3Hz,1H),2.50(dt,J=15.7,8.5Hz,1H),2.39(s,3H ),2.21(s,4H),2.04(s,3H),1.92–1.84(m,4H),1.67(s,3H),1.32–1.21(m, 6H),1.12(s,3H).

[0553] Synthesis of compound 16a-2

[0554] To a solution of 16a-1 (2.3 g, 1.98 mmol, 1.0 eq) in dry CH2Cl2 (10 mL) was added diethylamine (4 mL) at room temperature (10°C) under nitrogen. The reaction was then heated to 25°C for 12 h. LCMS indicated the reaction was complete. The product was concentrated, dissolved in dichloromethane, and added dropwise to MTBE. The product 16a-2 was filtered to obtain 1.7 g of a white solid in a 92% yield.

[0555] MS (ESI), m / z, 940[M+1] + .

[0556] Synthesis of compound 16a-3

[0557] To a solution of 16a-2 (1.5 g, 1.6 mmol, 1.0 eq) and Fmoc-Gly-Gly-Phe-OH (960 mg, 1.91 mmol, 1.2 eq) in dry DMF (10 mL) was added EDCI (460 mg, 1.39 mmol, 1.5 eq), HOBt (323 mg, 2.39 mmol, 1.5 eq), and DIPEA (411 mg, 3.19 mmol, 2.0 eq) in an ice-water bath at 5°C under nitrogen. The mixture was stirred for 1 h. LCMS indicated residual starting material. The reaction was allowed to proceed to room temperature (10°C) for 1 h. LCMS indicated that the starting material remained (unprogressed), but the reaction was more complex than before. Additional starting material and condensing agent were added with no effect. The mixture was poured into water, filtered, and the solid was dissolved in dichloromethane. The layers were separated, dried, concentrated, and purified by column chromatography (SiO2, 0-10% MeOH in CH2Cl2) to give product 16a-3, 1.2 g, as a foamy solid in a 70% yield. The product was used directly in the next reaction.

[0558] MS (ESI), m / z, 1423[M+1] + .

[0559] Synthesis of compound 16a-4

[0560] To a solution of 16a-3 (1.2 g, 0.84 mmol, 1.0 eq) in dry CH2Cl2 (10 mL) was added diethylamine (3-4 mL) at room temperature (10°C) under nitrogen. The reaction was then heated to 25°C for 3 h. LCMS indicated the reaction was complete. The product was concentrated and purified by Pre-HPLC (CH3CN / H2O, 0.05% TFA) to afford 16a-4, 900 mg, as a white solid in 82% yield and 93% purity.

[0561] MS (ESI), m / z, 1201[M+1] + .

[0562] Synthesis of compound 16a

[0563] To a solution of 101B13 (250 mg, 0.003 mmol, 1.0 eq) in dry DMF (5 mL) was added a solution of 16a-4 (196 mg, 0.16 mmol, 48.0 eq) in dry DMF (2 mL, sonicated), PyBOP (142 mg, 0.27 mmol, 80.0 eq), and DIPEA (56 mg, 0.44 mmol, 128.0 eq) at room temperature (25°C) under nitrogen. The reaction mixture was then heated to 28°C for 12 h, concentrated, filtered into methanol and water (1 / 1, 100 mL), purified by ultrafiltration (30K MW), and lyophilized to afford 16a (390 mg) as an oily solid in 96% yield and 100% purity, containing approximately 24.0% PTX.

[0564] Example 18: Synthesis of Compound 16b

[0565] Synthesis of compound 16b-1

[0566] To a solution of [2-[2-(Fmoc-amino)ethoxy]ethoxy]acetic acid (Fmoc-AEEA-OH, 115 mg, 0.30 mmol, 1.2 eq) in dry CH2Cl2 (5 mL) was added TSTU (113 mg, 0.37 mmol, 1.5 eq) and DIPEA (64 mg, 0.50 mmol, 2.0 eq) in an ice-water bath at 5°C under nitrogen protection. The mixture was stirred for 5 minutes (LCMS monitoring showed the formation of an active ester). A solution of 16a-4 in dichloromethane (300 mg, 0.25 mmol, 1.0 eq) was added and the reaction was stirred for 5 minutes. The mixture was quenched with methanol and concentrated. The mixture was then dissolved in dry dichloromethane (5 mL). Diethylamine (5 mL) was then added and the reaction was allowed to react at room temperature for 1-2 hours. The mixture was then concentrated directly. The crude product was separated and purified by Pre-HPLC (CH3CN / H2O, 0.05% TFA) to give product 16b-1, 300 mg, a colorless oil, which was used directly in the next reaction.

[0567] MS (ESI), m / z, 1346.5 [M+1] + .

[0568] Synthesis of compound 16b

[0569] To a solution of 101B13 (250 mg, 0.003 mmol, 1.0 eq) in dry DMF (5 mL) was added a solution of 16b-1 (206 mg, 0.15 mmol, 45.0 eq) in dry DMF (2 mL, sonicated), PyBOP (142 mg, 0.27 mmol, 80.0 eq), and DIPEA (56 mg, 0.44 mmol, 128.0 eq) at 25°C under nitrogen. The reaction mixture was then heated to 28°C for 12 h, concentrated, filtered into methanol and water (1 / 1, 100 mL), purified by ultrafiltration (30K MW), and lyophilized to afford 16b (310 mg) as an oily solid in 80% yield and 98.8% purity. The PTX content was approximately 22.3% (16b-1 was used as a standard for HPLC assay).

[0570] Example 19: Synthesis of Compound 16c

[0571] Synthesis of compound 16c-1

[0572] To a solution of PEG4 (146 mg, 0.30 mmol, 1.2 eq) in dry CH2Cl2 (5 mL) in an ice-water bath at 5°C under nitrogen protection were added TSTU (113 mg, 0.37 mmol, 1.5 eq) and DIPEA (64 mg, 0.50 mmol, 2.0 eq) and stirred for 5 minutes (LCMS monitoring showed the formation of an active ester). A solution of 16a-4 in dichloromethane (300 mg, 0.25 mmol, 1.0 eq) was added and stirred for 5 minutes. The mixture was quenched with methanol and concentrated, and then dissolved in dry dichloromethane (5 mL). Diethylamine (5 mL) was then added and the reaction was allowed to react at room temperature for 1-2 h. The mixture was then concentrated directly. The crude product was separated and purified by Pre-HPLC (CH3CN / H2O, 0.05% TFA) to give the product 16c-1, 350 mg, as a colorless oil, which was used directly in the next reaction.

[0573] MS (ESI), m / z, 1434.3 [M+1] + .

[0574] Synthesis of compound 16c

[0575] To a solution of 101B13 (250 mg, 0.003 mmol, 1.0 eq) in dry DMF (5 mL) was added a solution of 16c-1 (220 mg, 0.15 mmol, 45.0 eq) in dry DMF (2 mL, sonicated), PyBOP (142 mg, 0.27 mmol, 80.0 eq), and DIPEA (56 mg, 0.44 mmol, 128.0 eq) at 25°C under nitrogen. The reaction mixture was then heated to 28°C for 12 h, concentrated, filtered into methanol and water (1 / 1, 100 mL), purified by ultrafiltration (30K MW), and lyophilized to afford 16c (320 mg) as an oily solid in 81% yield and 99% purity, containing approximately 21.0% PTX.

[0576] Example 20: Synthesis of Compound 16d

[0577] Synthesis of compound 16d-1

[0578] To a solution of PEG8 (260 mg, 0.39 mmol, 1.2 eq) in dry CHCl (5 mL) in an ice-water bath at 5°C under nitrogen, TSTU (177 mg, 0.59 mmol, 1.0 eq) and DIPEA (126 mg, 0.98 mmol, 3.0 eq) were added and stirred for 5 minutes (LCMS monitoring indicated the formation of an active ester). 2 mL of a dichloromethane solution of 16a-4 (430 mg, 0.33 mmol, 1.0 eq) was added and stirred for 5 minutes. The mixture was quenched with methanol and concentrated. The mixture was dissolved in dry dichloromethane (5 mL) and then diethylamine (5 mL) was added. The reaction was allowed to react at room temperature for 3 hours and then concentrated. The crude product was purified by pre-HPLC (CHCN / HO, 0.05% TFA) to afford 16d-1 (260 mg, colorless oil, 46% yield). This product was used directly in the next step.

[0579] MS (ESI), m / z, 1625[M+1] + .

[0580] Synthesis of compound 16d

[0581] To a solution of 16d-1 (255 mg, 0.15 mmol, 45.0 eq) in dry DMF (5 mL) was added a solution of 101B13 (240 mg, 0.003 mmol, 1.0 eq) in dry DMF (2 mL, sonicated), PyBOP (136 mg, 0.26 mmol, 80.0 eq), and DIPEA (54 mg, 0.42 mmol, 128.0 eq) at room temperature (25°C) under nitrogen. The reaction mixture was then heated to 28°C for 12 h, concentrated, filtered into methanol and water (1 / 1, 100 mL), purified by ultrafiltration (30K MW), and lyophilized to afford product 16d (390 mg) as an oily solid in 96% yield and 100% purity, containing approximately 17.4% PTX.

[0582] Example 21: Synthesis of Compound 16e

[0583] Synthesis of compound PEG12-1

[0584] Dodecaethylene glycol (4.5 g, 8.24 mmol, 1.0 eq), TEBA (0.18 g, 0.824 mmol, 0.1 eq), and 20% sodium hydroxide solution (45 mL) were dissolved in toluene (45 mL) at room temperature. Under argon, a toluene solution of TsCl (1.57 g, 8.24 mmol, 1.0 eq) was added dropwise at 0°C. The mixture was stirred at room temperature for 16 h. LCMS confirmed the reaction was complete. Water was added to terminate the reaction. The layers were separated, and the aqueous layer was extracted with ethyl acetate, dried over sodium sulfate, evaporated to dryness under reduced pressure, and separated by column chromatography (dichloromethane:methanol = 10:1) to afford compound PEG12-1 as a colorless oil (5 g, 86.7% yield).

[0585] MS (ESI), m / z, 701.2 [M+H] + .

[0586] Synthesis of compound PEG12-2

[0587] At room temperature, compound PEG12-1 (5 g, 7.13 mmol, 1.0 eq) was dissolved in dichloromethane (100 mL). Sodium metal (100 mg) was added and stirred at 30°C under nitrogen for 3 h. 1-Butene-4-oic acid tert-butyl ester (2.03 g, 14.3 mmol, 2.0 eq) was added. The mixture was stirred at room temperature for 16 h. LCMS confirmed the reaction was complete. The solution was concentrated under reduced pressure and directly used for the next step.

[0588] MS (ESI), m / z, 773.2 [M-56] + .

[0589] Synthesis of compound PEG12-3

[0590] Dissolve the crude compound PEG12-2 in acetonitrile / ammonia (50 mL / 50 mL) at room temperature. Stir at 40°C under nitrogen for 5 h. LCMS confirms the reaction is complete. Concentrate under reduced pressure and proceed directly to the next step.

[0591] MS (ESI), m / z, 674.2 [M+H] + .

[0592] Synthesis of compound PEG12-4

[0593] Compound PEG12-3 (crude product) was dissolved in dichloromethane (100 mL) at room temperature. FmocOSU (2.8 g, 8.24 mmol, 1.0 eq) and DIPEA (2.12 g, 16.5 mmol, 2.0 eq) were added, and the mixture was stirred at 30°C under nitrogen for 16 h. LCMS confirmed the reaction was complete. The mixture was concentrated under reduced pressure and purified by normal-phase and reverse-phase column chromatography to obtain compound PEG12-4 as a colorless oil (3 g, impure, used directly in the next step).

[0594] MS (ESI), m / z, 896.2 [M+H] + .

[0595] Synthesis of compound PEG12

[0596] Dissolve compound PEG12 (crude) in dichloromethane (10 mL) at room temperature. Add trifluoroacetic acid (5 mL) under nitrogen. Stir for 16 h. LCMS confirms the reaction is complete. Concentrate under reduced pressure to obtain compound PEG12 as a colorless oil (1.53 g, 53.5% yield).

[0597] MS (ESI), m / z, 840.2 [M+H] + .

[0598] Synthesis of compound 16e-1

[0599] To a solution of PEG12 (126 mg, 0.15 mmol, 1.2 eq) in dry CH2Cl2 (5 mL) in an ice-water bath at 5°C under nitrogen, TSTU (56 mg, 0.19 mmol, 1.5 eq) and DIPEA (32 mg, 0.25 mmol, 2.0 eq) were added and stirred for 5 minutes (LCMS monitoring indicated the formation of an active ester). 2 mL of a dichloromethane solution of 16a-4 (150 mg, 0.12 mmol, 1.0 eq) was added and stirred for 5 minutes. The mixture was quenched with methanol and concentrated. The mixture was dissolved in dry dichloromethane (3 mL) and then diethylamine (5 mL) was added. The reaction was allowed to react at room temperature for 3 h and then concentrated. The crude product was purified by pre-HPLC (CH3CN / H2O, 0.05% TFA) to afford 16e-1 (200 mg, colorless oil, 78% yield). This product was used directly in the next step.

[0600] MS (ESI), m / z, 1786.3 [M+1] + .

[0601] Synthesis of compound 16e

[0602] To a solution of 16e-1 (100 mg, 0.06 mmol, 48.0 eq) in dry DMF (2 mL) was added a solution of 101B13 (85 mg, 0.001 mmol, 1.0 eq) in dry DMF (0.5 mL, sonicated), PyBOP (48 mg, 0.09 mmol, 80.0 eq), and DIPEA (19 mg, 0.15 mmol, 128.0 eq) at room temperature (25°C) under nitrogen. The reaction mixture was then heated to 28°C for 12 h, concentrated, filtered into methanol and water (1 / 1, 50 mL), purified by ultrafiltration (30K MW), and lyophilized to afford product 16e (120 mg) as an oily solid in 80% yield and 99% purity, with a PTX content of approximately 19.0%.

[0603] Example 22: Synthesis of Compound 16f

[0604] Synthesis of compound 16f-1

[0605] To a solution of SAR5 (199 mg, 0.30 mmol, 1.2 eq) in dry CH2Cl2 (5 mL) in an ice-water bath at 5°C under nitrogen, TSTU (113 mg, 0.37 mmol, 1.5 eq) and DIPEA (65 mg, 0.50 mmol, 2.0 eq) were added and stirred for 5 minutes (LCMS monitoring indicated the formation of an active ester). 2 mL of a dichloromethane solution of 16a-4 (300 mg, 0.25 mmol, 1.0 eq) was added and stirred for 5 minutes. The mixture was quenched with methanol and concentrated. The mixture was dissolved in dry dichloromethane (3 mL) and then diethylamine (5 mL) was added. The reaction was allowed to react at room temperature for 3 h and then concentrated. The crude product was purified by pre-HPLC (CH3CN / H2O, 0.05% TFA) to afford 16f-1 as a colorless oil (380 mg, 81% yield). This product was used directly in the next step.

[0606] MS (ESI), m / z, 1627.1[M+1] + .

[0607] Synthesis of compound 16f

[0608] To a solution of 101B13 (250 mg, 0.003 mmol, 1.0 eq) in dry DMF (5 mL) at room temperature (25°C) under nitrogen was added a solution of 16f-1 (250 mg, 0.15 mmol, 45.0 eq) in dry DMF (2 mL, sonicated), PyBOP (142 mg, 0.27 mmol, 80.0 eq), and DIPEA (56 mg, 0.44 mmol, 128.0 eq). The reaction mixture was then heated to 28°C for 12 h, concentrated, filtered into methanol and water (1 / 1, 100 mL), purified by ultrafiltration (30K MW), and lyophilized to afford 16f (315 mg) as an oily solid in 75% yield and 98.9% purity, containing approximately 20.8% PTX.

[0609] Example 23: Synthesis of Compound 16g

[0610] Synthesis of compound 16g-1

[0611] To a dry THF solution (50 mL) of 16g-SM (2.0 g, 2.07 mmol, 1.0 eq, prepared according to the synthesis method in J. Am. Chem. Soc. 2007, 129, 37, 11653–11661) and 16-SM1 (2.6 g, 7.03 mmol, 3.0 eq) was added dropwise 1.0 M lithium tert-butoxide (3.6 mL, 11.7 mmol, 5.0 eq) at -60°C under dry ice ethanol and nitrogen protection. The mixture was heated to -60°C and stirred for 1 h. The reaction was quenched by adding ammonium chloride and water, and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with salt, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (SiO2, 0-100% EtOAc in PE / SiO2, most of the product was obtained, and finally 0-20% MeOH in CH2Cl2) to obtain product 16g-1, 1.5 g, as a white solid, in a yield of 52%.

[0612] MS (ESI), m / z, 1276.5 [M+1] + .

[0613] Synthesis of compound 16g-2

[0614] To a solution of 16g-1 (1.0 g, 0.78 mmol, 1.0 eq) in dry CH2Cl2 (10 mL) was added diethylamine (4 mL) at room temperature (10°C) under nitrogen. The reaction was then heated to 25°C for 12 h. LCMS indicated the reaction was complete. The product was concentrated, dissolved in dichloromethane, and added dropwise to MTBE. The product 16g-2 was filtered to obtain 0.7 g of a white solid in an 85% yield.

[0615] MS (ESI), m / z, 1054.2[M+1] + .

[0616] Synthesis of compound 16g-3

[0617] Under nitrogen protection and an ice-water bath at 5°C, EDCI (136 mg, 0.71 mmol, 1.5 eq), HOBt (96 mg, 0.71 mmol, 1.5 eq) and DIPEA (122 mg, 0.95 mmol, 2.0 eq) were added to a dry DMF solution (5 mL) of 16g-2 (500 mg, 0.47 mmol, 1.0 eq) and Fmoc-Gly-Gly-Phe-OH (285 mg, 0.57 mmol, 1.2 eq). The mixture was returned to room temperature (20°C) and reacted for 1 h. LCMS detection showed that the reaction was complete. The mixture was concentrated and dissolved in dichloromethane (5 mL). Diethylamine (5 mL) was added and the reaction was stirred for 3 h. The mixture was directly concentrated and purified by column chromatography (SiO2, 0-10% MeOH in CH2Cl2) to give the product 16g-3, 0.37 g, as a foamy solid, with a yield of 60%.

[0618] MS (ESI), m / z, 1315.6 [M+1] + .

[0619] Synthesis of compound 16g-4

[0620] To a dry THF solution (5 mL) of 16g-3 (300 mg, 0.22 mmol, 1.0 eq) was added a hydrogen fluoride pyridine solution (1 mL) in an ice-water bath at 5°C under nitrogen protection. The temperature was restored to room temperature (20°C) and the reaction was allowed to react for 1 h. LCMS detected that the reaction was complete. The reaction was quenched with water, extracted with dichloromethane, and the organic phase was concentrated. The product was separated and purified by reverse phase column chromatography to obtain the product 16g-4, 0.15 g, in a yield of 55%.

[0621] MS (ESI), m / z, 1201.1[M+1] + .

[0622] Synthesis of compound 16g

[0623] To a solution of 101B13 (150 mg, 0.002 mmol, 1.0 eq) in dry DMF (3 mL) at room temperature (25°C) under nitrogen was added a solution of 16 g of -4 (110 mg, 0.09 mmol, 45.0 eq) in dry DMF (0.5 mL, sonicated), PyBOP (85 mg, 0.16 mmol, 80.0 eq), and DIPEA (34 mg, 0.26 mmol, 128.0 eq). The reaction mixture was then heated to 28°C for 12 h, concentrated, filtered into methanol and water (1 / 1, 100 mL), purified by ultrafiltration (30K MW), and lyophilized to afford 16 g, 150 mg, of the product as a white solid in a 67% yield and 99% purity, containing approximately 22.5% PTX.

[0624] Example 24: Synthesis of Compound 16h

[0625] Synthesis of compounds 16h-1, 16h-2, 16h-3 and 16h-4

[0626] The synthesis was carried out by referring to the relevant synthesis method in Example 17.

[0627] Synthesis of compound 16h

[0628] To a dry DMF solution (5 mL) of 101B13 (250 mg, 0.003 mmol, 1.0 eq) at room temperature (25°C) under nitrogen was added a dry DMF solution (2 mL, sonicated) of 16h-4 (177 mg, 0.15 mmol, 45.0 eq), PyBOP (142 mg, 0.27 mmol, 80.0 eq), and DIPEA (56 mg, 0.44 mmol, 128.0 eq). The reaction mixture was then heated to 28°C for 12 h, concentrated, filtered into methanol and water (1 / 1, 100 mL), purified by ultrafiltration (30K MW), and lyophilized to afford the product 16h as a white solid (350 mg, 95% yield, 100% purity, and approximately 22.5% docetaxel content).

[0629] Example 25: Synthesis of Compound 16i

[0630] Synthesis of compounds 16i-1, 16i-2, 16i-3 and 16i-4

[0631] The synthesis was carried out by referring to the relevant synthesis method in Example 16a.

[0632] Synthesis of compound 16i

[0633] To a dry DMF solution (5 mL) of 101B13 (250 mg, 0.003 mmol, 1.0 eq) at room temperature (25°C) under nitrogen, a dry DMF solution (2 mL, sonicated) of 16i-4 (182 mg, 0.15 mmol, 45.0 eq), PyBOP (142 mg, 0.27 mmol, 80.0 eq), and DIPEA (56 mg, 0.44 mmol, 128.0 eq) were added. The reaction mixture was then heated to 28°C for 12 h, concentrated, filtered into methanol and water (1 / 1, 100 mL), purified by ultrafiltration (30K MW), and lyophilized to afford 16i (330 mg) as a white solid in 89% yield and 99% purity, containing approximately 20.4% cabazitaxel.

[0634] Example 26: Synthesis of Compound 17a

[0635] Synthesis of compound 17a-1

[0636] At 0°C under nitrogen, Fmoc-Val-Cit-PAB-PNP (3.83 g, 5.0 mmol, 1.0 eq) and anhydrous DMF (20 mL) were added sequentially. After slight dissolution, N-methyl-2-hydroxyethylamine (0.42 ml, 5.25 mmol, 1.05 eq) was slowly added dropwise at 0°C. The reaction was stirred at 0°C for 2 hours. LCMS monitored the complete conversion of the reaction starting material. MTBE (100 mL) was added to precipitate, which was filtered, washed with MTBE, and dried to afford 3.2 g of the product 17a-1 as a yellow solid in a 91% yield.

[0637] Synthesis of compound 17a-2

[0638] At 0°C under nitrogen, 17a-1 (2.11 g, 3.0 mmol, 1.0 eq), anhydrous DMF (20 mL), di(p-nitrobenzene) carbonate (2.01 g, 6.6 mmol, 2.2 eq), and DIPEA (0.8 mL, 4.5 mmol, 1.5 eq) were added sequentially. The reaction was stirred at 0°C for 6 hours. LCMS monitored the complete conversion of the starting material. MTBE (100 mL) was added to precipitate, which was filtered, washed with MTBE, and dried to afford 17a-2 as a white solid (2.2 g, 86% yield).

[0639] Synthesis of compound 17a-3

[0640] Under nitrogen at room temperature, 17a-2 (434 mg, 0.5 mmol, 1.0 eq), paclitaxel (853.9 mg, 1.0 mmol, 2.0 eq), and anhydrous DMF (10 mL) were added sequentially. After slight dissolution, DMAP (45.8 mg, 0.375 mmol, 0.75 eq) was added. The reaction was stirred at room temperature for 15 hours. LCMS monitored the complete conversion of the starting material. The reaction solution was carried on to the next step without further treatment.

[0641] Synthesis of compound 17a-4

[0642] Diethylamine (0.4 mL, 4.0 mmol, 8.0 eq) was added to the reaction mixture of 17a-3 at room temperature under nitrogen. The reaction was stirred at room temperature for 1 hour. LCMS monitored the complete conversion of the starting material. The mixture was lyophilized to afford 560 mg of the product 17a-4 as a white solid, with a combined yield of 76% for both steps.

[0643] Synthesis of compound 17a

[0644] At 25°C under nitrogen, 101B13 (80 mg, 0.034 mmol, 1.0 eq, based on polymer building block), 17a-4 (75.2 mg, 0.051 mmol, 1.5 eq), PyBOP (26.5 mg, 0.051 mmol, 1.5 eq), DIPEA (0.025 mL, 0.136 mmol, 4.0 eq), and DMF (1.5 mL) were added sequentially. The reaction was stirred at room temperature for 15 hours, and complete conversion of the starting materials was monitored by HPLC. MTBE (30 mL) was added to DMF, causing the solution to become turbid and a white solid to precipitate. The supernatant was removed by aspiration, and the white solid was washed with MTBE and removed by aspiration. The remaining white solid was dissolved in MeOH, purified by ultrafiltration (30K MW), and lyophilized to yield product 17a (98 mg) as a white solid with a purity of 100.00%.

[0645] Example 27: Synthesis of Compound 17b

[0646] Synthesis of compound 17b-1

[0647] To a solution of PEG8 (176 mg, 0.265 mmol, 1.0 eq) in DMF (8 mL) at 0°C under nitrogen, DIPEA (137 mg, 1.06 mmol, 4.0 eq) and TSTU (80 mg, 0.265 mmol, 1.0 eq) were added. The reaction mixture was stirred at room temperature for 1 hour. A solution of 17a-4 (360 mg, 0.265 mmol, 1.0 eq) in DMF (5 mL) was added to the reaction mixture, and the reaction was stirred at room temperature for 3 hours. LCMS confirmed the completion of the reaction, and diethylamine (364 mg, 4.98 mmol, 20.0 eq) was added. The reaction mixture was stirred at room temperature for 1 hour. LCMS confirmed the completion of the reaction, and the reaction solution was purified on a C18 column (ACN / TFA 0.05% H2O) to obtain the product 17b-1 as a white solid, 300 mg, 68% yield.

[0648] Synthesis of compound 17b

[0649] To a solution of 101B13 (185 mg, 0.078 mmol, 1.0 eq, polymer building block), 17b-1 (210 mg, 0.117 mmol, 1.5 eq), and PyBOP (61 mg, 0.117 mmol, 1.5 eq) in DMF (6 mL) was added DIPEA (61 mg, 0.468 mmol, 4.0 eq) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was pumped dry, and methyl tert-butyl ether was added and stirred for 20 minutes. The supernatant was removed, and the oil at the bottom of the flask was first dissolved in methanol, purified by ultrafiltration (30K MW), and lyophilized to obtain compound 17b, 310 mg, in a 95% yield, with a paclitaxel content of approximately 22.5%.

[0650] Example 28: Synthesis of Compound 17c

[0651] Synthesis of compound 17c-1

[0652] Under nitrogen at room temperature, 16g-SM (500 mg, 0.52 mmol, 1.0 eq), 17a-2 (895 mg, 1.03 mmol, 2.0 eq), and anhydrous DMF (10 mL) were added sequentially. After slight dissolution, DMAP (64 mg, 0.52 mmol, 1.0 eq) was added. The reaction was stirred at room temperature for 12 hours. LCMS monitoring indicated near-complete conversion of the starting material. The reaction solution was carried on to the next step without further treatment.

[0653] Synthesis of compound 17c-2

[0654] Diethylamine (2 mL) was added to the reaction mixture of 17c-1 at room temperature under nitrogen. The reaction was stirred at room temperature for 1 hour. LCMS monitored the complete conversion of the starting material. The mixture was lyophilized to afford 17c-2 as a white solid (450 mg). The yield for the two steps was 59%.

[0655] Synthesis of compound 17c-3

[0656] To a dry THF solution (5 mL) of 17c-2 (300 mg, 0.20 mmol, 1.0 eq) was added a solution of hydrogen fluoride in pyridine (1 mL) in an ice-water bath at 5°C under nitrogen protection. The mixture was returned to room temperature (20°C) for 1 h. The reaction was complete after LCMS detection. The reaction was quenched with water and extracted with dichloromethane. The organic phase was concentrated and purified by reverse phase column chromatography to give the product 17c-3, 0.19 g, in a yield of 69%.

[0657] Synthesis of compound 17c

[0658] To a solution of 101B13 (200 mg, 0.003 mmol, 1.0 eq), 17c-3 (167 mg, 0.12 mmol, 45.0 eq), and PyBOP (113 mg, 0.22 mmol, 80 eq) in DMF (6 mL) was added DIPEA (45 mg, 0.35 mmol, 128.0 eq) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was pumped dry, and methyl tert-butyl ether was added and stirred for 20 minutes. The supernatant was removed, and the oil at the bottom of the flask was first dissolved in methanol, purified by ultrafiltration (30K MW), and lyophilized to obtain compound 17c, 220 mg, in a 72% yield, with a paclitaxel content of approximately 23.1%.

[0659] Example 29: Synthesis of Compound 18a

[0660] Synthesis of compound 18a-1

[0661] At room temperature and under nitrogen, Fmoc-Val-Cit-PAB-PNP (383.4 mg, 0.5 mmol, 1.0 eq), paclitaxel (853.9 mg, 1.0 mmol, 2.0 eq), and anhydrous DMF (10 mL) were added sequentially. After slight dissolution, DMAP (45.8 mg, 0.375 mmol, 0.75 eq) was added. The reaction was stirred at room temperature for 15 hours. LCMS monitored complete conversion of the reaction starting material. The reaction solution was carried on to the next step without further treatment.

[0662] Synthesis of compound 18a-2

[0663] Diethylamine (0.4 mL, 4.0 mmol, 8.0 eq) was added to the reaction mixture at room temperature under nitrogen. The reaction was stirred at room temperature for 1 hour. LCMS monitored the complete conversion of the starting material. The mixture was lyophilized to give 415 mg of the product 18a-2 as a white solid, with a combined yield of 60% for both steps.

[0664] 1H NMR (400MHz, DMSO) δ10.26 (s, 1H), 9.28 (d, J = 8.4Hz, 1H), 8.70 (d, J = 7.5Hz, 1H),8.09(d,J=5.5Hz,3H),8.03–7.95(m,2H),7.85–7.81(m,2H),7.76–7.70 (m,1H),7.68–7.42(m,12H),7.32(d,J=8.3Hz,2H),7.23–7.16(m,1H),6.31( s,1H),6.12–6.01(m,1H),5.83(t,J=9.1Hz,1H),5.53(t,J=8.6Hz,1H),5.43 (d,J=7.2Hz,1H),5.36(d,J=8.9Hz,1H),5.21–5.09(m,2H),4.96–4.89(m,1H ),4.65(s,1H),4.58–4.47(m,1H),4.12(dd,J=10.8,6.7Hz,1H),4.02(q,J=8 .3Hz,2H),3.70–3.64(m,1H),3.11–2.93(m,2H),2.39–2.23(m,4H),2.16–2. 03(m,4H),1.87–1.39(m,14H),1.04(s,3H),1.01(s,3H),0.98–0.93(m,7H).

[0665] Synthesis of compound 18a

[0666] At 25°C under nitrogen, 101B13 (80 mg, 0.034 mmol, 1.0 eq, based on polymer building block), 18a-2 (70 mg, 0.051 mmol, 1.5 eq), PyBOP (26.5 mg, 0.051 mmol, 1.5 eq), DIPEA (0.025 mL, 0.136 mmol, 4.0 eq), and DMF (1.5 mL) were added sequentially. The reaction was stirred at room temperature for 15 hours, and complete conversion of the starting materials was monitored by HPLC. MTBE (30 mL) was added to DMF, causing the solution to become turbid and a white solid to precipitate. The supernatant was removed by aspiration, and the white solid was washed with MTBE and removed by aspiration. The remaining white solid was dissolved in MeOH, purified by ultrafiltration (30K MW), and lyophilized to yield product 18a (94 mg) as a white solid with a purity of 99.92%.

[0667] Example 30: Synthesis of Compound 18b

[0668] Synthesis of compounds 18b-1, 18b-2, and 18b-3

[0669] The synthesis was carried out according to the synthesis method of Example 28.

[0670] Synthesis of compound 18b

[0671] To a solution of 101B13 (250 mg, 0.003 mmol, 1.0 eq) in dry DMF (5 mL) was added a solution of 18b-3 (208 mg, 0.15 mmol, 45.0 eq) in dry DMF (2 mL, sonicated), PyBOP (142 mg, 0.27 mmol, 80.0 eq), and DIPEA (56 mg, 0.44 mmol, 128.0 eq) at room temperature (25°C) under nitrogen. The reaction mixture was then heated to 28°C for 12 h, concentrated, purified by ultrafiltration (30K MW), and lyophilized to afford 18b as a white solid (340 mg, 87% yield, 99.1% purity, and approximately 19.4% paclitaxel content).

[0672] Example 31: Synthesis of Compound 19

[0673] Synthesis of compound 19-1

[0674] To a solution of 3,3-dimethylglutaric anhydride (6.43 g, 45.2 mmol, 1.0 eq) in DCM (50 mL) was added benzyl alcohol (5.87 g, 54.3 mmol, 1.2 eq), triethylamine (18.2 g, 180 mmol, 4.0 eq), and DMAP (1.66 g, 13.6 mmol, 0.3 eq) at 25°C. The reaction was stirred at this temperature for 2 h. The reaction was monitored by LCMS for completion, and the volatile solvent and base were removed by spin drying. DCM (200 mL) was added to redissolve the mixture and transfer it to a separatory funnel. The mixture was washed sequentially with 1 M HCl(aq) (200 mL) and saturated NaCl(aq) (200 mL). The combined organic phases were dried over anhydrous NaSO. The resulting crude product was purified by reverse-phase column chromatography using a 5-95% CHCN:H2O ratio. The collected solution was dried to give 7.8 g of the product as a colorless oil.

[0675] MS (ESI), m / z, 251.20 [M+H] + .

[0676] Synthesis of compound 19-2

[0677] To a solution of 19-1 (5.20 g, 20.8 mmol, 1.0 eq) in THF (100 mL) at 25°C, triethylamine (2.31 g, 22.9 mmol, 1.1 eq) and DPPA (6.30 g, 22.9 mmol, 1.1 eq) were added sequentially. The mixture was stirred at this temperature for 8 h. The reaction was monitored for completion by LCMS. 6 M HCl (aq) (50 mL) was added and the mixture was heated under reflux for 1 h. The heat source was removed and the reaction mixture was cooled to room temperature. The reaction mixture was evaporated to dryness. The crude product was purified using a reverse-phase column with CH3CN:H2O = 5-70%. The collected solution was evaporated to dryness to yield 2.50 g of a white solid.

[0678] MS (ESI), m / z, 222.20 [M-Cl] + .

[0679] Synthesis of compound 19-3

[0680] To a solution of 19-2 (2.5 g, 9.67 mmol, 1.0 eq) in methanol (150 mL) was added Pd / C (10 wt%, 500 mg) at 25°C. The atmosphere was replaced with hydrogen and the reaction was stirred for 2 h. Upon completion, the reaction mixture was filtered through a pad of Celite. The filtrate was dried to yield 2.2 g of a white solid.

[0681] MS (ESI), m / z, 132.20 [M-Cl] + .

[0682] Synthesis of compound 19-4

[0683] To a solution of 19-3 (3.35 g, 4.45 mmol, 1.0 eq) in DMF (10 mL) was added Fmoc-Val-Cit-PAB-PNP (2.07 g, 8.01 mmol, 1.8 eq) and DIPEA (2.88 g, 22.3 mmol, 5.0 eq) at 25°C. The mixture was stirred for 2 h. Completion of the reaction was monitored by LCMS. The product was concentrated and purified using a reverse-phase column with CH3CN (0.05% TFA):H2O (0.05% TFA) at a ratio of 5% to 80%. The collected solution was evaporated to dryness to yield 2.1 g of a white solid.

[0684] MS (ESI), m / z, 759.20 [M+H] + .

[0685] Synthesis of compound 19-5

[0686] Dissolve 19-4 (1.06 g, 1.40 mmol, 1.0 eq) in DMF (8.0 mL) at 25°C. Add DCM (20 mL). After stirring, add paclitaxel (1.44 g, 1.68 mmol, 1.0 eq), DMAP (512 mg, 4.20 mmol, 3.0 eq), and EDCI (802 mg, 4.20 mmol, 3.0 eq). After addition, stir and react for 1 h. The reaction mixture was used directly in the next step without further workup.

[0687] MS (ESI), m / z, 1595.20 [M+H] + .

[0688] Synthesis of compound 19-6

[0689] Diethylamine (6.0 mL) was added directly to the reaction solution of step 19-5, and the reaction was stirred at 25°C for 2 h. After the reaction was completed, the reaction solution was concentrated and poured into water (100 mL), and extracted with ethyl acetate (50 mL x 3). The organic phases were combined and dried. The crude product was first purified on a silica gel column with DCM / MeOH = 50:1 to 10:1 to obtain 1.1 g of crude product (paclitaxel and some DMAP were removed). The crude product was further purified on a C18 column with CH3CN (0.05% TFA):H2O (0.05% TFA) = 5%-95%. The product solution was collected and lyophilized to obtain 810 mg of pure white solid.

[0690] MS (ESI), m / z, 1373.20 [M+H-TFA] + .

[0691] Synthesis of compound 19

[0692] To a solution of 101B13 (250 mg, 0.003 mmol, 1.0 eq) in dry DMF (5 mL) was added a solution of 19-6 (210 mg, 0.15 mmol, 45.0 eq) in dry DMF (2 mL, sonicated), PyBOP (142 mg, 0.27 mmol, 80.0 eq), and DIPEA (56 mg, 0.44 mmol, 128.0 eq) at room temperature (25°C) under nitrogen. The reaction mixture was then heated to 28°C for 12 h, concentrated, purified by ultrafiltration (30K MW), and lyophilized to afford product 19 as a white solid (350 mg, 90% yield, 98.7% purity, and approximately 21.3% paclitaxel content).

[0693] Example 32: Synthesis of Compound 20a

[0694] Synthesis of compound 20a-1

[0695] To a solution of Boc-Leu-OH (2.0 g, 8.65 mmol, 1.0 eq) in DMF (20 mL) at room temperature under nitrogen was added benzyl glycine hydrochloride (1.7 g, 8.65 mmol, 1.0 eq), HATU (3.2 g, 8.65 mmol), and DIEA (2.2 g, 17.3 mmol, 2.0 eq). Stirring was continued overnight. Following completion of the reaction, methyl tert-butyl ether was added directly, and the mixture was filtered to afford 3.2 g of a white solid in a 99% yield.

[0696] MS (ESI), m / z, 379.2 [M+H] + .

[0697] Synthesis of compound 20a-2

[0698] To a solution of 20a-2 (3.2 g, 8.46 mmol, 1.0 eq) in DCM (20 mL) was added TFA (5 mL) at room temperature under nitrogen. The mixture was stirred overnight. After the reaction, the mixture was concentrated under reduced pressure and purified by column chromatography to afford 2.6 g of a white solid in 99% yield.

[0699] MS (ESI), m / z, 279.2 [M+H] + .

[0700] Synthesis of compound 20a-3

[0701] To 20a-2 (1.5 g, 5.39 mmol, 1.0 eq) in DMF (20 mL) was added Fmoc-Gly-Phe-OH (2.4 g, 5.39 mmol, 1.0 eq), HATU (3.2 g, 8.65 mmol), and DIEA (2.2 g, 17.3 mmol, 2.0 eq) at room temperature under nitrogen. The mixture was stirred overnight. After completion of the reaction, the product was purified by column chromatography to afford 2.5 g of a white solid in a 65.7% yield.

[0702] MS (ESI), m / z, 705.2 [M+H] + .

[0703] Synthesis of compound 20a-4

[0704] To a solution of 20a-3 (2.5 g, 3.55 mmol, 1.0 eq) in MeOH (20 mL) was added Pd / C (10 mg) at room temperature under nitrogen to displace the hydrogen atmosphere. Stirring was then carried out overnight. After completion of the reaction, the product was filtered and purified by column chromatography to afford 1.2 g of a white solid in a 57% yield.

[0705] MS (ESI), m / z, 615.2 [M+H] + .

[0706] Synthesis of compound 20a-5

[0707] To a solution of 20a-4 (1.2 g, 1.95 mmol, 1.0 eq) in DMF (20 mL) at room temperature under nitrogen was added p-aminobenzyl alcohol (0.3 g, 1.95 mmol, 1.0 eq), HATU (2.2 g, 1.95 mmol), and DIEA (1.2 g, 7.3 mmol, 2.0 eq). The mixture was stirred overnight. After completion of the reaction, the product was purified by column chromatography to afford 1.25 g of a white solid in 89% yield.

[0708] MS (ESI), m / z, 720.2 [M+H] + .

[0709] Synthesis of compound 20a-6

[0710] To 20a-5 (1.2 g, 1.66 mmol, 1.0 eq) in DMF (20 mL) was added di(p-nitrobenzene) carbonate (0.63 g, 2.0 mmol, 1.2 eq) and DIPEA (0.44 g, 3.4 mmol, 2.0 eq) at room temperature under nitrogen. The mixture was stirred overnight. After completion of the reaction, the product was purified by column chromatography to afford 0.95 g of a white solid in a 64.5% yield.

[0711] MS (ESI), m / z, 885.2 [M+H] + .

[0712] Synthesis of compound 20a-7

[0713] To a solution of 20a-6 (100 mg, 0.11 mmol, 1.0 eq) in DMF (20 mL) at room temperature under nitrogen was added 20a-SM (prepared according to the synthesis method described in J. Org. Chem. 2001, 66, 26, 8815–8830, 109 mg, 0.11 mmol, 1.0 eq) and DIPEA (28 mg, 0.22 mmol, 2.0 eq). The reaction was stirred overnight. After completion of the reaction, the product was purified by column chromatography to afford 0.1 g of a white solid in a 52% yield.

[0714] MS (ESI), m / z, 1714.2 [M+H] + .

[0715] Synthesis of compound 20a-8

[0716] Under nitrogen protection, diethylamine (0.2 mL) was added to a solution of 20a-7 (100 mg, 0.058 mmol, 1.0 eq) in DMF (50 mL) at room temperature and stirred overnight. After the reaction, 25 mg of a white solid was obtained by preparative purification in a 28% yield.

[0717] MS (ESI), m / z, 1491.2 [M+H] + .

[0718] Synthesis of compound 20a

[0719] To a solution of 101B13 (250 mg, 0.003 mmol, 1.0 eq) in dry DMF (5 mL) was added a solution of 20a-8 (229 mg, 0.15 mmol, 45.0 eq) in dry DMF (2 mL, sonicated), PyBOP (142 mg, 0.27 mmol, 80.0 eq), and DIPEA (56 mg, 0.44 mmol, 128.0 eq) at room temperature (25°C) under nitrogen. The reaction mixture was then heated to 28°C for 12 h, concentrated, purified by ultrafiltration (30K MW), and lyophilized to afford product 20a as a white solid (350 mg, 90% yield, 98.7% purity, and approximately 21.3% paclitaxel content).

[0720] Example 33: Synthesis of Compound 20b

[0721] Synthesis of compound 20b-1

[0722] To a solution of PEG8 (80 mg, 0.13 mmol, 1.3 eq) in DCM (20 mL) was added TSTU (40 mg, 0.13 mmol) at room temperature under nitrogen. The mixture was stirred for 15 min, followed by the addition of a dichloromethane solution of 20a-8 (150 mg, 0.1 mmol) and continued stirring for 2 h. After completion of the reaction, the product was purified and purified to afford 120 mg of a white solid in a 56% yield.

[0723] MS (ESI), m / z, 1069.2 [M / 2+H] + .

[0724] To the above intermediate (120 mg, 0.056 mmol, 1.0 eq) in DMF (50 mL) was added diethylamine (0.2 mL) at room temperature under nitrogen and stirred overnight. After the reaction, 51 mg of a white solid was obtained by preparative purification with a yield of 47%.

[0725] MS (ESI), m / z, 1914.2 [M+H] + .

[0726] Synthesis of compound 20b

[0727] To a solution of 101B13 (100 mg, 0.001 mmol, 1.0 eq) in dry DMF (2 mL) was added a solution of 20b-1 (117 mg, 0.06 mmol, 45.0 eq) in dry DMF (0.5 mL, sonicated), PyBOP (57 mg, 0.11 mmol, 80.0 eq), and DIPEA (23 mg, 0.17 mmol, 128.0 eq) at room temperature (25°C) under nitrogen. The reaction mixture was then heated to 28°C for 12 h, concentrated, filtered into methanol and water (1 / 1, 100 mL), purified by ultrafiltration (30K MW), and lyophilized to afford product 20b (150 mg) as a white solid in 85% yield and 99.7% purity, containing approximately 19.3% paclitaxel.

[0728] Example 34: Synthesis of Compound 21

[0729] Synthesis of compound 21-1

[0730] To a solution of 21-SM (190 mg, 0.18 mmol, 1.0 eq, synthesized according to ChemMedChem 2022, e202200279) in DMF (10 mL) was added Fmoc-Val-Cit-PAB-PNP (260 mg, 1.17 mmol, 1.2 eq) and DIPEA (0.26 g, 2 mmol, 2.0 eq) at room temperature under nitrogen and stirred overnight. After completion of the reaction, the mixture was concentrated and purified by Pre-HPLC to afford 120 mg of a white solid in a 40% yield.

[0731] The above compound was dissolved in DMF (5 mL) and diethylamine (0.2 mL) was added. The reaction mixture was stirred overnight. After the reaction was completed, it was directly concentrated and purified by Pre-HPLC to obtain 100 mg of a white solid with a yield of 96%.

[0732] MS (ESI), m / z, 1456.0 [M+H] + .

[0733] Synthesis of compound 21-2

[0734] To a solution of PEG8 (40 mg, 0.061 mmol, 1.3 eq) in DCM (20 mL) was added TSTU (40 mg, 0.13 mmol) at room temperature under nitrogen and stirred for 15 min. A solution of 21-1 (90 mg, 0.061 mmol) in dichloromethane was then added and stirred for 2 h. After the reaction, preparative purification afforded 90 mg of a white solid in a 70% yield.

[0735] To the above compound (90 mg, 0.98 mmol, 1.0 eq) in DMF (20 mL) was added diethylamine (0.26 g, 2 mmol, 2.0 eq) and stirred overnight. After the reaction was complete, the mixture was concentrated and purified by Pre-HPLC to give 70 mg of a white solid.

[0736] MS (ESI), m / z, 1880.2 [M+H] + .

[0737] Synthesis of compound 21

[0738] To a solution of 101B13 (60 mg, 0.001 mmol, 1.0 eq) in dry DMF (2 mL) at room temperature (25°C) under nitrogen was added a solution of 21-2 (69 mg, 0.04 mmol, 45.0 eq) in dry DMF (0.5 mL, sonicated), PyBOP (34 mg, 0.07 mmol, 80.0 eq), and DIPEA (14 mg, 0.10 mmol, 128.0 eq). The reaction was then heated to 28°C for 12 h, concentrated, purified by ultrafiltration (30K MW), and lyophilized to afford product 21 as a white solid (90 mg, 85% yield, 100% purity, and approximately 21.2% paclitaxel content). (21-2 was used as a standard for HPLC assay).

[0739] Example 35: Synthesis of Compound 22

[0740] Synthesis of compound 22-1

[0741] To a solution of Fmoc-Val-Cit-PAB-PNP (2.0 g, 2.6 mmol, 1.0 eq) in DMF (20 mL) was added p-aminobenzyl alcohol (321 mg, 2.6 mmol, 1.0 eq) and DIPEA (0.67 g, 5.2 mmol, 2.0 eq) at room temperature under nitrogen and stirred overnight. After the reaction, methyl tert-butyl ether was added directly and filtered to afford 2.2 g of a white solid in a 95.9% yield with 90% purity.

[0742] MS (ESI), m / z, 751.2 [M+H] +.

[0743] Synthesis of compound 22-2

[0744] To a solution of 22-1 (2.2 g, 2.9 mmol, 1.0 eq) in DMF (20 mL) was added di(p-nitrobenzene) carbonate (790 mg, 2.6 mmol, 1.0 eq) and DIPEA (0.67 g, 5.2 mmol, 2.0 eq) at room temperature under nitrogen and stirred overnight. After completion of the reaction, the mixture was concentrated and purified by Pre-HPLC to afford 1.9 g of a white solid in a 75.9% yield.

[0745] MS (ESI), m / z, 916.2 [M+H] + .

[0746] Synthesis of compound 22-3

[0747] Under nitrogen protection at room temperature, 22-2 (94 mg, 0.1 mmol, 1.0 eq) and DIPEA (30 mg, 10.2 mmol, 2.0 eq) were added to a solution of 20a-SM (100 mg, 0.1 mmol, 1.0 eq) in DMF (10 mL) and stirred overnight. After the reaction was completed, the mixture was directly concentrated and purified by Pre-HPLC to give 100 mg of a white solid in 57% yield. To the above intermediate (100 mg, 0.057 mmol, 1.0 eq) in DMF (510 mL) was added diethylamine (0.2 mL) and stirred overnight. After the reaction was completed, the mixture was directly concentrated and purified by Pre-HPLC to give 75 mg of a white solid in 86% yield.

[0748] MS (ESI), m / z, 1522.2 [M+H] + .

[0749] Synthesis of compound 22

[0750] At room temperature (25°C) under nitrogen, 101B13 (50 mg, 0.02 mmol, 1.0 eq, based on polymer building block), 22-3 (51.9 mg, 0.03 mmol, 1.5 eq), PyBOP (15.6 mg, 0.03 mmol, 1.5 eq), DIPEA (0.015 mL, 0.08 mmol, 4.0 eq), and DMF (0.8 mL) were added sequentially. The reaction was stirred at room temperature for 15 hours, and complete conversion of the starting materials was monitored by HPLC. MTBE (30 mL) was added to DMF, causing the solution to become turbid and a white solid to precipitate. The supernatant was removed by aspiration, and the white solid was washed with MTBE and removed by aspiration. The remaining white solid was dissolved in MeOH, purified by ultrafiltration (30K MW), and lyophilized to yield 22, a white solid product (81 mg) with a purity of 99.85%.

[0751] Example 36: Synthesis of Compound 23

[0752] Synthesis of compound 23-1

[0753] To a solution of dimethylpropylenediamine (3.0 g, 29.35 mmol, 1.0 eq) in DCM (40 mL) was added triethylamine (8.9 g, 88.05 mmol, 3.0 eq) and Boc2O (16 g, 73.38 mmol, 2.5 eq), respectively, at room temperature at 25°C under nitrogen. The reaction mixture was stirred at room temperature for 2 hours. LCMS confirmed the reaction was complete, and the reaction solution was dried and purified on a silica gel column to afford 23-1 as a white solid (8.3 g, 94% yield).

[0754] Synthesis of compound 23-2

[0755] To a THF solution (40 mL) of 23-1 (4.0 g, 13.22 mmol, 1.0 eq) was added NaH (1.3 g, 60%, 33.05 mmol, 2.5 eq) in portions under nitrogen at 0°C. The reaction mixture was stirred at 0°C for 2 hours, followed by the addition of iodomethane (9.4 g, 66.10 mmol, 5.0 eq) and the reaction was stirred at room temperature for 16 hours. LCMS confirmed the reaction was complete, and the reaction solution was added portionwise to ice water. The mixture was extracted with ethyl acetate and purified on a silica gel column to afford 23-2 as a colorless oil (4.0 g, 91% yield).

[0756] Synthesis of compound 23-3

[0757] To a solution of 23-2 (4.0 g, 12 mmol, 1.0 eq) in DCM (25 mL) was added TFA (5 mL) at 25°C under nitrogen. The reaction mixture was stirred at room temperature for 2 hours. The reaction was complete by TLC analysis, and the reaction solution was dried to afford the product 23-3 as a colorless oil (1.6 g, 100% yield).

[0758] Synthesis of compound 23-4

[0759] At room temperature (25°C) and under nitrogen, triethylamine (2.5 g, 24.56 mmol, 2.0 eq) was added to a DCM solution (30 mL) of 23-3 (1.6 g, 12.28 mmol, 1.0 eq). The reaction mixture was cooled to 0°C, and a DCM solution (10 mL) of Boc2O (2.7 g, 12.28 mmol, 1.0 eq) was added dropwise. The mixture was stirred for 1 hour, then allowed to warm to room temperature and stirred for another 3 hours. The reaction was complete by LCMS, and the reaction solution was dried and purified on a silica gel column to give the product 23-4 as a colorless oil (600 mg, 21% yield).

[0760] Synthesis of compound 23-5

[0761] To a solution of Fmoc-Val-Cit-PAB-PNP (1.0 g, 1.3 mmol, 1.0 eq) in DMF (10 mL) was added 23-4 (299 mg, 1.3 mmol, 1.0 eq) and DIPEA (336 mg, 2.6 mmol, 2.0 eq) at room temperature under nitrogen. The reaction mixture was stirred at 15°C for 16 hours. LCMS confirmed the completion of the reaction, and the reaction solution was purified on a C18 column (ACN / TFA 0.05% H2O) to afford 23-5 as a white solid (500 mg, 45% yield).

[0762] Synthesis of compound 23-6

[0763] To a solution of 23-5 (500 mg, 0.583 mmol, 1.0 eq) in DCM (15 mL) was added TFA (5 mL) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 2 hours. LCMS confirmed the reaction was complete, and the reaction solution was dried to afford product 23-6 as a brown oil (440 mg, 100% yield).

[0764] Synthesis of compound 23-7

[0765] To a solution of 23-6 (100 mg, 0.132 mmol, 1.0 eq) in DMF (10 mL) was added DIPEA (70 mg, 0.528 mmol, 4.0 eq) and 7-SM1 (135 mg, 0.132 mmol, 1.0 eq) at room temperature under nitrogen. The reaction mixture was stirred at 15°C for 16 hours. LCMS confirmed the completion of the reaction, and the reaction solution was purified on a C18 column (ACN / TFA 0.05% H2O) to afford 23-7 as a white solid (100 mg, 46% yield).

[0766] Synthesis of compound 23-8

[0767] To a solution of 23-7 (100 mg, 0.06 mmol, 1.0 eq) in DMF (5 mL) was added diethylamine (90 mg, 1.2 mmol, 20.0 eq) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 1 hour. LCMS confirmed the completion of the reaction. The reaction solution was used to prepare the product 23-8 as a white solid (13.5 mg, 16% yield).

[0768] Synthesis of compound 23

[0769] To a solution of 101B13 (250 mg, 0.003 mmol, 1.0 eq) in dry DMF (5 mL) at room temperature (25°C) under nitrogen was added a solution of 23-8 (217 mg, 0.15 mmol, 45.0 eq) in dry DMF (2 mL, sonicated), PyBOP (142 mg, 0.27 mmol, 80.0 eq), and DIPEA (56 mg, 0.44 mmol, 128.0 eq). The reaction mixture was then heated to 28°C for 12 h, concentrated, purified by ultrafiltration (30K MW), and lyophilized to afford product 23 as a white solid (360 mg, 91% yield, 99.7% purity, and approximately 22.3% paclitaxel content).

[0770] Example 37: Synthesis of Compound 24

[0771] Synthesis of compound 24-1

[0772] To a solution of trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (2.0 g, 14 mmol, 1.0 eq) in DCM (40 mL) was added triethylamine (2.8 g, 28 mmol, 2.0 eq) at room temperature under nitrogen. The reaction mixture was cooled to 0°C, and a solution of Boc2O (3.06 g, 14 mmol, 1.0 eq) in DCM (10 mL) was added dropwise. The mixture was stirred for 1 hour after addition, then allowed to warm to room temperature and stirred for another 1 hour. The reaction was complete by LCMS, concentrated, and purified on a silica gel column to afford product 24-1 as a colorless oil (1.5 g, 44% yield).

[0773] Synthesis of compound 24-2

[0774] To a solution of Fmoc-Val-Cit-PAB-PNP (500 mg, 0.65 mmol, 1.0 eq) in DMF (10 mL) was added 24-1 (157 mg, 0.65 mmol, 1.0 eq) and DIPEA (336 mg, 2.6 mmol, 4.0 eq) at room temperature under nitrogen. The reaction mixture was stirred at 15°C for 16 hours. LCMS confirmed the completion of the reaction, and the reaction solution was purified on a C18 column (ACN / TFA 0.05% H2O) to afford 24-2 as a white solid (300 mg, 53% yield).

[0775] Synthesis of compound 24-3

[0776] To a solution of 24-2 (300 mg, 0.34 mmol, 1.0 eq) in DCM (15 mL) was added TFA (5 mL) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 1 hour. LCMS confirmed the reaction was complete, and the reaction solution was dried to afford product 24-3 as a brown oil (270 mg, 100% yield).

[0777] Synthesis of compound 24-4

[0778] To a solution of 24-3 (60 mg, 0.077 mmol, 1.0 eq) in DMF (5 mL) was added DIPEA (40 mg, 0.308 mmol, 2.0 eq) and 7-SM1 (80 mg, 0.077 mmol, 1.0 eq) at room temperature under nitrogen. The reaction mixture was stirred at 15°C for 16 hours. LCMS confirmed the completion of the reaction, and the reaction solution was purified on a C18 column (ACN / TFA 0.05% H2O) to afford 24-4 as a white solid (100 mg, 79% yield).

[0779] Synthesis of compound 24-5

[0780] To a solution of 24-4 (100 mg, 0.06 mmol, 1.0 eq) in DMF (5 mL) was added diethylamine (90 mg, 1.2 mmol, 20.0 eq) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 1 hour. LCMS confirmed the reaction was complete, and the product 24-5 was obtained as a white solid (13.5 mg, 16% yield).

[0781] Synthesis of compound 24

[0782] To a solution of 101B13 (250 mg, 0.003 mmol, 1.0 eq) in dry DMF (5 mL) was added a solution of 24-5 (219 mg, 0.15 mmol, 45.0 eq) in dry DMF (2 mL, sonicated), PyBOP (142 mg, 0.27 mmol, 80.0 eq), and DIPEA (56 mg, 0.44 mmol, 128.0 eq) at room temperature (25°C) under nitrogen. The reaction mixture was then heated to 28°C for 12 h, concentrated, purified by ultrafiltration (30K MW), and lyophilized to afford product 24 as a white solid (350 mg, 89% yield, 100% purity, and approximately 18.9% paclitaxel content).

[0783] Example 38: Synthesis of Compound 25

[0784] Synthesis of compound 25-1

[0785] To a solution of Fmoc-Val-Cit-PAB-PNP (1.0 g, 1.3 mmol, 1.0 eq) in DMF (15 mL) was added N-Boc-N-methylethylenediamine (227 mg, 1.3 mmol, 1.0 eq) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 4 hours. LCMS confirmed the completion of the reaction, and the reaction solution was purified on a C18 column (ACN / TFA 0.05% H2O) to afford product 25-1 as a white solid (800 mg, 77% yield).

[0786] Synthesis of compound 25-2

[0787] To a solution of 25-1 (800 mg, 0.99 mmol, 1.0 eq) in DCM (15 mL) was added TFA (5 mL) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 1 hour. LCMS confirmed the completion of the reaction, and the reaction solution was dried to afford the product 25-2 as a brown oil (700 mg, 100% yield).

[0788] Synthesis of compound 25-3

[0789] To a solution of 25-2 (100 mg, 0.142 mmol, 1.0 eq) in DMF (5 mL) was added DIPEA (74 mg, 0.568 mmol, 4.0 eq) and 7-SM1 (145 mg, 0.142 mmol, 1.0 eq) at room temperature under nitrogen. The reaction mixture was stirred at 15°C for 16 hours. LCMS confirmed the completion of the reaction, and the reaction solution was purified on a C18 column (ACN / TFA 0.05% H2O) to afford 25-3 as a white solid (100 mg, 44% yield).

[0790] Synthesis of compound 25-4

[0791] To a solution of 25-3 (120 mg, 0.075 mmol, 1.0 eq) in DMF (6 mL) was added diethylamine (110 mg, 1.5 mmol, 20.0 eq) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 1 hour. LCMS confirmed the completion of the reaction, and the reaction solution was purified on a C18 column (ACN / TFA 0.05% H2O) to afford the product 25-4 as a white solid (90 mg, 88% yield).

[0792] Synthesis of compound 25

[0793] To a dry DMF solution (5 mL) of 101B13 (250 mg, 0.003 mmol, 1.0 eq) at room temperature (25°C) under nitrogen was added a dry DMF solution (2 mL, sonicated) of 25-4 (208 mg, 0.15 mmol, 45.0 eq), PyBOP (142 mg, 0.27 mmol, 80.0 eq), and DIPEA (56 mg, 0.44 mmol, 128.0 eq). The reaction mixture was then heated to 28°C for 12 h, concentrated, purified by ultrafiltration (30K MW), and lyophilized to afford the product 25 as a white solid (370 mg). The yield was 95%, the purity was 98.5%, and the paclitaxel content was approximately 22.3%.

[0794] Example 39: Synthesis of Compound 26

[0795] Synthesis of compound 26-1

[0796] To a DCM solution (30 mL) of Docetaxel (2.0 g, 2.47 mmol, 1.0 eq) was added pyridine (300 mg, 3.71 mmol, 1.5 eq) at -50°C under nitrogen, followed by a DCM solution (10 mL) of p-nitrobenzoyl chloride (550 mg, 2.72 mmol, 1.1 eq). The reaction mixture was stirred at -50°C for 5 hours. LCMS was performed to determine the completion of the reaction. The product was washed with sodium bisulfate solution and then with sodium chloride solution twice, dried over anhydrous sodium sulfate, and the solvent was evaporated. The product 26-1 was purified on a silica gel column (PE / EA = 1:1) to give 1.0 g of a white solid in a 42% yield.

[0797] Synthesis of compound 26-2

[0798] To a solution of 7-SM2 (692 mg, 0.966 mmol, 1.0 eq) in DMF (10 mL) was added DIPEA (250 mg, 1.932 mmol, 2.0 eq) and 26-1 (940 mg, 0.966 mmol, 1.0 eq) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 4 hours. The reaction was complete by LCMS, and the reaction solution was used directly in the next step.

[0799] Synthesis of compound 26-3

[0800] To a solution of 26-2 (1.0 g, 0.645 mmol, 1.0 eq) in DMF (15 mL) was added diethylamine (943 mg, 12.90 mmol, 20.0 eq) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 1 hour. LCMS confirmed the completion of the reaction. The reaction solution was purified on a C18 column (ACN / TFA 0.05% H2O) to afford 26-3 as a white solid (600 mg, 70% yield).

[0801] Synthesis of compound 26-4

[0802] To a solution of PEG8 (300 mg, 0.452 mmol, 1.0 eq) in DMF (8 mL) at 0°C under nitrogen was added DIPEA (233 mg, 1.81 mmol, 4.0 eq) and TSTU (136 mg, 0.452 mmol, 1.0 eq), respectively. The reaction mixture was stirred at room temperature for 1 hour. A solution of 26-3 (600 mg, 0.452 mmol, 1.0 eq) in DMF (5 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction was complete by LCMS, and the reaction solution was used directly in the next step without post-treatment.

[0803] Synthesis of compound 26-5

[0804] To a solution of 26-4 (500 mg, 0.253 mmol, 1.0 eq) in DMF (15 mL) was added DEA (370 mg, 5.06 mmol, 20.0 eq) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 1 hour. LCMS confirmed the completion of the reaction. The reaction solution was purified on a C18 column (ACN / TFA 0.05% H2O) to afford product 26-5 as a white solid (350 mg, 78% yield).

[0805] Synthesis of compound 26

[0806] To a solution of 101B13 (686 mg, 0.29 mmol, 1.0 eq, polymer structural unit measurement), 26-5 (800 mg, 0.435 mmol, 1.5 eq), and PyBOP (227 mg, 0.435 mmol, 1.5 eq) in DMF (8 mL) was added DIPEA (150 mg, 1.16 mmol, 4.0 eq) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was spin-dried on an oil pump, and methyl tert-butyl ether was added and stirred for 20 minutes. The supernatant was removed and the oil at the bottom of the bottle was first dissolved in methanol, purified by ultrafiltration (30K MW), and lyophilized to give 26 as a white solid, 384 mg, 98% yield.

[0807] Example 40: Synthesis of Compound 27

[0808] Synthesis of compound 27-1

[0809] Paclitaxel (2 g, 2.34 mmol) was dissolved in 40 mL of DCM, and EDCI (449 mg, 2.34 mmol) was added. The mixture was stirred for 25 minutes, followed by DMAP (343 mg, 2.81 mmol) and 5 minutes of stirring. N-Benzyloxycarbonyl-glycine (735 mg, 3.51 mmol) was then added and allowed to react at room temperature for 16 hours. The reaction solution was concentrated and purified by reverse-phase C18 lyophilization to afford compound 27-1 (2.1 g, 86% yield) as a white solid.

[0810] MS (ESI), m / z, 1045.0 [M+H] + .

[0811] Synthesis of compound 27-2

[0812] Compound 27-1 (1.1 g, 1.05 mmol) was added to THF (28 mL) and MeOH (1.1 mL), and MsOH (93 mg, 0.97 mmol) and 10% Pd / C (396 mg) were added in sequence. The gas was replaced with hydrogen three times and reacted under a hydrogen balloon atmosphere for 16 h. After the reaction, the mixture was filtered and concentrated to 3 mL, 100 mL of n-heptane was added for slurrying, and the mixture was filtered. The filter cake was purified by reverse phase to obtain 27-2 (1 g, yield 100%) as a white solid.

[0813] MS (ESI), m / z, 911.0 [M+H] + .

[0814] Synthesis of compound 27

[0815] Compound 101B13 (1000 mg, 0.42 mmol, based on polymer building block) was added to DMF (10 mL), followed by 27-2 (710 mg, 0.63 mmol), PyBOP (330 mg, 0.63 mmol), and DIPEA (295 μL, 1.69 mmol). The mixture was stirred at room temperature for 2 h. 100 mL of MTBE was added, the supernatant removed, and the oil dissolved in methanol. The mixture was purified by ultrafiltration (30K MW) and lyophilized to afford 27 (1.3 g, 93% yield) with 100% purity and approximately 25.0% paclitaxel content.

[0816] Example 41: Synthesis of Compound 28a

[0817] Synthesis of compound 28a-1

[0818] Paclitaxel (1.5 g, 1.76 mmol) was dissolved in 30 mL of DCM, and EDCI (337 mg, 1.76 mmol) was added. The mixture was stirred for 25 minutes, followed by DMAP (257 mg, 2.11 mmol). After stirring for 5 minutes, N-benzyloxycarbonyl-glycyl-glycine (702 mg, 2.63 mmol) was added and allowed to react at room temperature for 16 hours. The reaction solution was concentrated and purified by reverse-phase C18 purification and lyophilized to afford 28a-1, 1.3 g (67% yield) as a white solid.

[0819] Synthesis of compound 28a-2

[0820] Compound 28a-1 (1.3 g, 1.18 mmol) was added to THF (33 mL), followed by MsOH (104 mg, 1.09 mmol) and 10% Pd / C (468 mg), followed by MeOH (1.3 mL). The atmosphere was replaced with hydrogen three times and the reaction was allowed to proceed under a hydrogen balloon for 16 h. After completion of the reaction, the mixture was filtered and concentrated to 3 mL, slurried with 80 mL of n-heptane, and filtered. The resulting filter cake was purified by reverse phase chromatography to afford 28a-2 (1.1 g, 96% yield) as a white solid.

[0821] MS (ESI), m / z, 968.0 [M+H] + .

[0822] Synthesis of compound 28a

[0823] Compound 101B13 (1000 mg, 0.42 mmol, based on polymer building blocks) was added to DMF (10 mL), followed by 28a-2 (610 mg, 0.63 mmol), PyBOP (330 mg, 0.63 mmol), and DIPEA (295 μL, 1.69 mmol). The mixture was stirred at room temperature for 2 h. 100 mL of MTBE was added, the supernatant removed, and the oil dissolved in methanol, purified by ultrafiltration, and lyophilized to afford 28a (1.3 g, 93% yield). The paclitaxel content was approximately 24.6%.

[0824] Examples 42-47: Synthesis of Compounds 28b-g

[0825] Referring to the synthesis of Example 41, the synthesis was carried out according to different raw materials.

[0826] Example 48: Synthesis of Compound 29

[0827] Synthesis of compound 29-1

[0828] To a solution of N-Cbz-1,2-diaminoethane (1.0 g, 5.1 mmol, 1.0 eq) in dichloromethane (20 mL) was added diglycolic anhydride (900 mg, 7.7 mmol, 1.5 eq) and DMAP (1.2 g, 10.2 mmol, 2.0 eq) at room temperature under nitrogen and stirred overnight. After completion of the reaction, the mixture was concentrated and purified by Pre-HPLC to afford 1.2 g of a white solid in a 75.9% yield.

[0829] MS (ESI), m / z, 311.2 [M+H] + .

[0830] Synthesis of compound 29-2

[0831] To a 50 mL solution of 29-1 (1.0 g, 3.22 mmol, 1.0 eq) and DMAP (780 mg, 6.44 mmol) in DCM was added paclitaxel (2.7 g, 3.22 mmol) at room temperature (25°C) under nitrogen. The reaction was stirred overnight. After completion of the reaction, the product was isolated and purified by column chromatography to obtain 520 mg of the product in a 15% yield.

[0832] MS (ESI), m / z, 1146.2 [M+H] + .

[0833] Synthesis of compound 29-3

[0834] Under hydrogen at 25°C, to a solution of 29-2 (0.9 g, 0.45 mmol, 1.0 eq) and 10% Pd / C (10 mg) in MeOH (20 mL) was added TFA (1 mL) and stirred overnight. After completion of the reaction, the product was purified by normal phase column chromatography to afford 700 mg of the product in 88% yield.

[0835] MS (ESI), m / z, 1012.2 [M+H] + .

[0836] Synthesis of compound 29

[0837] To a solution of 29-3 (0.15 g, 0.14 mmol, 1.5 eq) in DMF (10 mL) at 25°C under hydrogen atmosphere was added 101B13 (0.233 g, 0.098 mmol, 1.0 eq, based on polymer building blocks), DIPEA (0.2 mL), and PyBOP (0.073 g, 0.14 mmol). The reaction was stirred overnight. The product was concentrated, ultrafiltered (30K MW), and lyophilized to yield 320 mg of product with a purity of 98%. HPLC analysis revealed a paclitaxel content of 21%.

[0838] Example 49: Synthesis of Compound 30

[0839] Synthesis of compound 30-1

[0840] Paclitaxel (1.5 g, 1.76 mmol) was dissolved in 30 mL of DCM, and EDCI (337 mg, 1.76 mmol) was added. The mixture was stirred for 25 minutes, followed by DMAP (257 mg, 2.11 mmol). After stirring for 5 minutes, 8-benzyloxycarbonylamino-3,6-dioxaoctanoic acid (899 mg, 2.63 mmol) was added and allowed to react at room temperature for 16 hours. The reaction solution was concentrated and purified by reverse-phase C18 lyophilization to afford 30-1 (1.3 g, 68% yield) as a white solid.

[0841] MS (ESI), m / z, 1101.80 [M+H] + .

[0842] Synthesis of compound 30-2

[0843] Compound 30-1 (1.36 g, 1.20 mmol) was added to THF (34 mL) and MeOH (1.3 mL), followed by MsOH (72 μL, 1.1 mmol) and 10% Pd / C (489 mg). The atmosphere was replaced with hydrogen three times and the mixture was allowed to react under a hydrogen balloon for 16 h. After completion of the reaction, the mixture was filtered and concentrated to 5 mL. 80 mL of n-heptane was added for slurrying, followed by filtration. The resulting filter cake was purified by reverse phase chromatography to afford 30-2 (1.1 g, 92% yield) as a white solid.

[0844] MS (ESI), m / z 999.0 [M+H] + .

[0845] Synthesis of compound 30

[0846] Compound 101B13 (1000 mg, 0.42 mmol, based on polymer structural unit) was added to DMF (10 mL), followed by 30-2 (630 mg, 0.63 mmol), PyBOP (330 mg, 0.63 mmol), and DIPEA (295 μL, 1.69 mmol). The mixture was stirred at room temperature for 2 h. 100 mL of MTBE was added, the supernatant removed, and the oil dissolved in methanol, purified by ultrafiltration, and lyophilized to afford compound 30 (1.2 g, 86% yield). The paclitaxel content was approximately 25.1%.

[0847] Example 50: Synthesis of Compound 31

[0848] Synthesis of compound 31-1

[0849] To a solution of 3-2 (1.5 g, 3.62 mmol, 1.0 eq) in methanol / acetonitrile (40 mL / 40 mL), mPEG was added dropwise at room temperature. 2k A solution of 2-NHS (9.9 g, 4.70 mmol, 1.3 eq) in methanol (20 mL) was added. DIPEA (2.34 g, 18.1 mmol, 5.0 eq) was then added and stirred at room temperature overnight. After the reaction was complete, the reaction solution was spin-dried and slurried in 100 mL of MTBE at room temperature to obtain 11 g of crude product, which was directly used in the next reaction without purification.

[0850] Synthesis of compound 31-2

[0851] To a solution of 31-1 (11.0 g, crude) in DCM (20 mL) was added TFA (20 mL) and stirred at room temperature overnight. The reaction mixture was spin-dried and the TFA was thoroughly removed using an oil pump. Ultrafiltration was performed using a 30K MW ultrafiltration membrane with a MeOH / H2O ratio of 1:1. The pure solution was lyophilized to yield 7.0 g of dry product.

[0852] Synthesis of compound 31

[0853] To a solution of 31-2 (1.0 g, 0.423 mmol, 1.0 eq, based on polymer building block) in DMF (10 mL) were added 31-SM (synthesized according to the method described in Bioconjugate Chem. 2012, 23, 8, 1610–1622, 493 mg, 0.508 mmol, 1.2 eq), PyBOP (0.634 mmol, 1.5 eq), and DIPEA (164 mg, 1.269 mmol, 3.0 eq). The mixture was stirred at room temperature overnight. After completion of the reaction, the reaction solution was concentrated under high vacuum to half its original volume, purified by ultrafiltration (30K MW), and lyophilized to yield 900 mg of the product with a purity of 98%. HPLC analysis revealed a paclitaxel content of 21.1%.

[0854] Example 51: Synthesis of Compound 32

[0855] Synthesis of compound 32-1

[0856] To a solution of cabazitaxel (700 mg, 0.837 mmol, 1.0 eq) in DCM (8.0 mL) were added diglycolic anhydride (292 mg, 2.512 mmol, 3.0 eq), DMAP (409 mg, 3.35 mmol, 4.0 eq), and DIPEA (432 mg, 3.35 mmol, 4.0 eq) at 25°C. The mixture was stirred for 4 h. Upon completion, the reaction solution was transferred to a separatory funnel and washed with 0.2 M citric acid (50 mL x 3). The mixture was separated and the organic phase was washed with water. The organic phase was then dried and the crude product was purified on a C18 column using 5-95% CH3CN:H2O (0.05% TFA) as the eluent to yield 720 mg of pure product.

[0857] MS (ESI), m / z, 952.00 [M+H] + .

[0858] Synthesis of compound 32

[0859] To a solution of 32-1 (500 mg, 0.525 mmol, 1.5 eq) in DMF (5.0 mL) were added 31-2 (827 mg, 0.350 mmol, 1.0 eq, based on polymer unit weight), PyBOP (273 mg, 0.525 mmol, 1.5 eq), and DIPEA (135 mg, 1.05 mmol, 3.0 eq). The mixture was stirred at room temperature overnight. After completion of the reaction, the reaction solution was concentrated under high vacuum to half its original volume, purified by ultrafiltration (30K MW), and lyophilized to yield 750 mg of the product. The purity was 98%, and the cabazitaxel content was 26.0% by HPLC.

[0860] Example 52: Synthesis of Compound 33a

[0861] Synthesis of compound 33a-1

[0862] Cysteamine hydrochloride (1.50 g, 13.2 mmol, 1.0 eq) was dissolved in methanol (18 mL) at room temperature. Under nitrogen, the mixture was cooled to 0°C, and triethylamine (1.85 mL, 26.4 mmol, 2.0 eq) and 2-hydroxyethyl disulfide (1.50 g, 13.2 mmol, 1.0 eq) in dichloromethane were added. The mixture was stirred at room temperature for 16 h. LCMS confirmed the reaction was complete. The reaction mixture was cooled to 0°C, and di-tert-butyl dicarbonate (4.32 g, 19.8 mmol, 1.5 eq) was added. The mixture was stirred at room temperature for 4 h. The reaction mixture was then filtered through silica (100-200 mesh) and separated by normal phase separation (petroleum ether:ethyl acetate = 3:1) to afford compound 33a-1 as a colorless oil (0.9 g, 26.9% yield).

[0863] MS (ESI), m / z, 154.0 [M-100] + .

[0864] Synthesis of compound 33a-2

[0865] 33a-1 (300 mg, 1.18 mmol, 1.0 eq) was dissolved in dichloromethane (20 mL) at room temperature. Under nitrogen, triethylamine (120 mg, 1.18 mmol, 1.0 eq) and di(p-nitrobenzene) carbonate (360 mg, 1.18 mmol, 1.0 eq) were added, respectively. The mixture was stirred at room temperature for 16 h. 4-Dimethylaminopyridine (144.6 mg, 1.18 mmol, 1.0 eq) and paclitaxel (1010 mg, 1.18 mmol, 1.0 eq) were then added. The mixture was stirred at room temperature for 2 h. The reaction was terminated by LCMS analysis. The mixture was dried under reduced pressure, separated by reverse phase separation (A = TFA (0.1% + H2O), B = acetonitrile), and lyophilized to afford compound 33a-2 as a white solid (0.8 g, 59.7% yield).

[0866] MS (ESI), m / z, 1133.0 [M+H] + .

[0867] Synthesis of compound 33a-3

[0868] 33a-2 (800 mg, 0.706 mmol, 1.0 eq) was dissolved in formic acid (10 mL) at room temperature. The mixture was stirred at room temperature under nitrogen for 2 h. The reaction was monitored for completion by LCMS. The product was concentrated and separated by reverse phase separation (A = TFA (0.1% + H2O), B = acetonitrile), and lyophilized to afford compound 33a-3 as a white solid (0.4 g, 54.8% yield).

[0869] MS (ESI), m / z, 1033.0 [M+H] + .

[0870] Synthesis of compound 33a

[0871] To a solution of 101B13 (1220 mg, 0.516 mmol, 1.0 eq, based on polymer unit) in DMF (20 mL) at room temperature and under nitrogen was added 33a-3 (800 mg, 0.774 mmol, 1.5 eq), PyBOP (403 mg, 0.774 mmol, 1.5 eq), and DIPEA (266 mg, 2.06 mmol, 4 eq). The mixture was stirred at 20°C for 16 h. The reaction solution was concentrated, ultrafiltered (30K MW), and lyophilized to afford compound 33a as a white solid (1.5 g, 85.7% yield). The product was 100% pure, and the paclitaxel content was 24.7% as determined by HPLC.

[0872] Examples 53-66: Synthesis of Compounds 33b-o

[0873] Referring to the synthesis of Example 52, the synthesis was carried out according to different raw materials.

[0874] Example 67: Synthesis of Compound 34

[0875] Synthesis of compound 34-1

[0876] At room temperature and nitrogen, diethylamine (1.5 mL) was added to a solution of 33-SM (prepared by referring to the compound described in Eur. J. Org. Chem. 2021, 2383–2387, 1.02 g, 0.676 mmol, 1.0 eq) in DMF (6 mL). The mixture was stirred at room temperature for 2 h. After completion of the reaction, the concentrated solution was directly sampled and purified using a reverse-phase column (CH3CN:H2O = 5-95%). The collected solution was spin-dried to give 680 mg of the pure product as a white solid.

[0877] MS (ESI), m / z, 1287.80 [M+H] + .

[0878] Synthesis of compound 34-2

[0879] To a solution of 34-1 (680 mg, 0.529 mmol, 1.0 eq) in DMF (5.0 mL) at room temperature under nitrogen was added PEG8 (351 mg, 0.529 mmol, 1.0 eq), PyBOP (413 mg, 0.794 mmol, 1.5 eq), and DIPEA (205 mg, 1.588 mmol, 3.0 eq). The mixture was stirred at room temperature for 2 h. After completion, diethylamine (1.5 mL) was added directly to the reaction solution and stirred for 2 h. The product was then purified using a C18 reverse-phase column, initially using a CH3CN:H2O (0.05% NH3.H2O) elution system of 5-95% to 95%-95% to flush out impurities. The desired product was then flushed out using a CH3CN (0.05% TFA):H2O (0.05% TFA) elution system of 95%-95%. The product solution was collected and dried in a spin-drying process to obtain 1.14 g of pure white solid.

[0880] MS (ESI), m / z, 1711.10 [M+H] + .

[0881] Synthesis of compound 34

[0882] To a solution of 34-2 (1.14 g, 0.63 mmol, 1.5 eq) in DMF (8.0 mL) at room temperature under nitrogen was added 101B13 (994 mg, 0.42 mmol, 1.0 eq, based on polymer unit), PyBOP (328 mg, 0.63 mmol, 1.5 eq), and DIPEA (217 mg, 1.26 mmol, 4.0 eq). The mixture was returned to room temperature and stirred for 16 hours. After completion, the reaction solution was concentrated under high vacuum and purified by ultrafiltration (30K MW). The pure product was lyophilized to yield 810 mg of dry product. The purity was 98.9%, and the paclitaxel content was 19.2% as determined by HPLC.

[0883] Example 68: Synthesis of Compound 35

[0884] Synthesis of compound 35-1

[0885] At room temperature and under nitrogen protection, PEG 1k -CO2H (3.7g, 3.7mmol, 1.0eq) was dissolved in dichloromethane and TSTU (1.4g, 4.4mmol, 1.2eq) and DIPEA (1.4g, 5.5mmol, 1.5eq) were added, stirred for 0.5h, concentrated, and the residue was dissolved in 30mL of acetonitrile and then added with 25mL of methanol. Subsequently, the polymer (1.15g, 2.75mmol, 1.0eq) was dissolved in 30mL of methanol and then added to the above solution, and DIPEA (2.2ml, 12.4mmol, 4.5eq) was added. The reaction was stirred at room temperature for 2 hours. After being spin-dried for the solvent, the product 35-1 was purified by MTBE beating twice to obtain 3.6g as a white solid.

[0886] Synthesis of compound 35-2

[0887] To a solution of 35-1 (2.6 g) in dry DCM (30 mL) was added TFA (10 mL) at room temperature under nitrogen. The reaction was stirred at room temperature for 15 hours. LCMS monitored complete conversion of the starting material. The reaction solution was spin-dried, washed several times with MTBE, and then pumped dry to afford 35-2 as an oily product (2.9 g, TFA salt).

[0888] Synthesis of compound 35-3

[0889] To a solution of 35-2 (2.0 g, 0.05 mmol) in DMF (10 mL) was added DIPEA (750 mg, 5.85 mmol, 128.0 eq) at room temperature (25°C) under nitrogen, followed by succinic anhydride (200 mg, 2.06 mmol, 45.0 eq). The mixture was stirred for 12 h. The reaction was nearly complete as determined by ninhydrin. MTBE (100 mL) was added, stirred for 10 min, and the supernatant was decanted. This was repeated three times, and the residue was dried under vacuum to afford 35-3 (1.5 g).

[0890] Synthesis of compound 35

[0891] To a solution of 35-3 (500 mg, 0.01 mmol, 1.0 eq) in dry DMF (10 mL) was added 7-2 (712 mg, 0.52 mmol, 45.0 eq), PyBOP (480 mg, 0.92 mmol, 80.0 eq), and DIPEA (190 mg, 1.48 mmol, 128.0 eq) at room temperature (25°C) under nitrogen. The reaction mixture was then heated to 28°C for 12 h, concentrated, purified by ultrafiltration (30K MW), and lyophilized to afford 35 as a white solid (870 mg, 89% yield, 98.9% purity, and approximately 41.3% paclitaxel content).

[0892] Example 69: Synthesis of Compound 36a

[0893] Synthesis of compound 36a-1

[0894] At room temperature under nitrogen, compound 36a-SM (CAS: 159857-60-0, 5.0 g, 6.703 mmol, 1.0 eq) was dissolved in dichloromethane (50 mL). Diethylamine (10 mL) was added and stirred for 16 h. LCMS confirmed the reaction was complete. The product was concentrated and purified by column chromatography to afford a white solid (3 g, 85.5% yield).

[0895] Synthesis of compound 36a-2

[0896] To compound 36a-1 (0.7 g, 1.34 mmol, 1.0 eq) in dichloromethane (50 mL) was added DIPEA (0.35 g, 2.67 mmol, 2.0 eq) and Fmoc-Val-NHC (0.7 g, 1.604 mmol, 1.2 eq) at room temperature under nitrogen. The mixture was stirred at room temperature for 16 h. LCMS analysis indicated that the reaction was complete, with the precipitation of solids. Filtration under reduced pressure afforded a white solid (1 g, 88.5% yield).

[0897] Synthesis of compound 36a-3

[0898] To a solution of compound 36a-2 (0.9 g, 1.065 mmol, 1.0 eq) in THF / DMF (10 mL / 5 mL) at room temperature under nitrogen was added pyridine (0.25 g, 3.195 mmol, 3.0 eq) and p-nitrophenyl chloroformate (0.65 g, 3.195 mmol). The mixture was stirred at room temperature for 16 h. LCMS analysis indicated that the reaction was essentially complete. The reaction solution was added to methyl tert-butyl ether, the solid was filtered, and the mixture was dried under reduced pressure to afford a white solid (0.76 g, 72% yield).

[0899] Synthesis of compound 36a-4

[0900] To a solution of compound 36a-3 (0.39 g, 0.386 mmol, 1.0 eq) in DMF (5 mL) was added 20a-SM (0.374 g, 0.386 mmol, 1.0 eq) and DIPEA (0.099 g, 0.772 mmol, 2.0 eq) at room temperature under nitrogen. The reaction was stirred at room temperature for 16 h. LCMS confirmed the reaction was complete. The product was then directly used for the next step.

[0901] Synthesis of compound 36a-5

[0902] Diethylamine (1 mL) was added to the reaction mixture under nitrogen at room temperature and stirred for 1 h. LCMS confirmed the reaction was complete. The mixture was added to methyl tert-butyl ether, the solid was filtered, and dried under reduced pressure to give a white solid (0.61 g, 86.6% yield).

[0903] Synthesis of compound 36a-6

[0904] To a solution of PEG8 (250 mg, 0.377 mmol, 1.0 eq) in DMSO (5 mL) at 25°C under nitrogen was added DIPEA (97.4 mg, 0.755 mmol, 2.0 eq) and TSTU (113.6 mg, 0.377 mmol, 1.0 eq) in sequence. To the reaction mixture was added 36a-5 (610 mg, 0.377 mmol, 1.0 eq). Stirring was performed at room temperature for 1 hour. LCMS confirmed the reaction was complete. The reaction mixture was added to methyl tert-butyl ether, the solid was filtered, and the mixture was dried under reduced pressure to afford a white solid (0.33 g, 42.5% yield).

[0905] Synthesis of compound 36a-7

[0906] To a solution of 101B13 (250 mg, 0.003 mmol, 1.0 eq) in dry DMF (5 mL) was added a solution of 36a-6 (312 mg, 0.15 mmol, 45.0 eq) in dry DMF (2 mL, sonicated), PyBOP (142 mg, 0.27 mmol, 80.0 eq), and DIPEA (56 mg, 0.44 mmol, 128.0 eq) at room temperature (25°C) under nitrogen. The reaction mixture was then heated to 28°C for 12 h, concentrated, and used directly in the next step.

[0907] Synthesis of compound 36a

[0908] To a 10 mL solution of crude 36a-7 in dry DCM at 25°C under nitrogen, 1 mL of dichloroacetic acid and 1 mL of anisole were added and stirred for 1 h. MTBE (50 mL) was added and the mixture was filtered. The solid was dissolved in methanol and water, purified by ultrafiltration (30K MW), and lyophilized to afford 36a (300 mg) as a white solid with a purity of 98.5% and a paclitaxel content of approximately 19.3%.

[0909] Example 70: Synthesis of Compound 36b

[0910] Synthesis of compound 36b-1

[0911] To a solution of compound 36b-SM (synthesized according to Chem. Eur. J. 2015, 21, 1–10, 100 mg, 0.115 mmol, 1.0 eq) in DMF (5 mL) was added 20a-SM (11.3 mg, 0.115 mmol, 1.0 eq) and DIPEA (14.8 mg, 0.115 mmol, 1.0 eq) at room temperature under nitrogen. The reaction was stirred for 16 h. LCMS confirmed the reaction was complete. The reaction was then carried on to the next step.

[0912] MS (ESI), m / z, 1699.2 [M+H] + .

[0913] Synthesis of compounds 36b-2, 36b-3 and 36b-4

[0914] Synthesis of 36a-5, 36a-6 and 36a-7 in reference example 69

[0915] Synthesis of compound 36b

[0916] To a solution of 36b-4 (crude product, 300 mg) in dry DMF (5 mL) at 25°C under nitrogen was added Pd(PPh3)4 (15 mg), Bu3SnH (3 drops), and AcOH (4 drops). Complete conversion of the starting material was monitored by HPLC. MTBE (50 mL) was added, the mixture was filtered, and the solid was dissolved in methanol and water. Purified by ultrafiltration (30K MW), and lyophilized to afford product 36b (230 mg) as a white solid with a purity of 99.5% and a paclitaxel content of approximately 22.5%.

[0917] Example 71: Synthesis of Compound 37a

[0918] Synthesis of compound 101B01

[0919] ε-Poly-L-lysine hydrochloride (4.792 g, 29.09 mmol, molar number of structural units) was suspended in 100 g of DMSO, and triethylamine (8.89 g, 87.27 mmol) was added. α-Boc-ε-Cbz-L-lysine-NHS active ester (10102, prepared in Example 2) (20.83 g, 46.63 mmol) was added. The mixture was stirred at 30 degrees Celsius under nitrogen for 13 hours until the reaction was complete. The reaction solution was placed in a beaker, 800 ml of ACN was added, and the filter cake was washed with acetonitrile, water, and acetonitrile in sequence and dried in vacuo to obtain the product ε-PolyLys 30 -[Lys(α-Boc,ε-Cbz)] 30 (101B01) was obtained as a white solid, 12.13 g (85%).

[0920] 1 H NMR(400MHz,DMSO-d6)7.74(m,62H),7.27(m,179H),6.90(m,28H),5.16–4.80(s,60H) ,4.31–4.01(br,30H),4.00–3.68(br,30H),3.12–2.82(m,120H),1.91–0.58(m,642H).

[0921] Synthesis of compound 101B02

[0922] α-[Boc-Lys(Cbz)] 30 -ε-PolyLys 30 (101B01) (2.92 g) was dissolved in 30 ml of acetic acid + 30 ml of methanol, heated to dissolve, 591 mg of palladium carbon (10%) was added, hydrogen was added, and the mixture was stirred at 25 degrees for 18 h. Celite was added, the mixture was filtered, and the filtrate was concentrated by rotary evaporation. Methyl tert-butyl ether was precipitated and dried in vacuo to obtain α-[Boc-Lys(NH3 +COO - )] 30 -ε-PolyLys 30 (101B02) is a white powder.

[0923] 1 H NMR (400MHz, D2O) δ4.20–3.98(m,30H),3.88(t,J=7.0Hz,31H),3.04(s,61H),2.87(t,J=7.6Hz,59H),1.84(s,122H),1.78–1.10(m,594H).

[0924] Synthesis of compound 101B06

[0925] α-[Boc-Lys(NH3 + COO - )] 30 -ε-PolyLys 30 (101B02) (prepared in Example 46) (4.76 g) was dissolved in 20 ml of water, 1014-2K (10.00 g) was dissolved in 20 ml of acetonitrile, the two solutions were mixed, triethylamine (1.39 ml) was added, and the mixture was stirred for 10 min, 1014-2K (20.00 g) acetonitrile solution (40 ml) was added, triethylamine (2.79 ml) was added, and the mixture was reacted at 25 degrees for 4 h, water was added, ultrafiltration was performed, and the filtrate was concentrated and lyophilized to obtain α-[Boc-Lys(mPEG 2k )] 30 -ε-PolyLys 30 18.4 g of white powdery product (101B06).

[0926] 1 H NMR(400MHz,D2O)δ4.25(s,32H),4.09(s,95H),3.93-3.45(m,5537H),3.41(s,95H),3.36–2.90(m,126H),2.20-0.86(m,645H).

[0927] Synthesis of compound 101B07

[0928] 101B06 (9.0 g) was dissolved in dichloromethane (90 ml), TFA (30 ml) was added, and the mixture was stirred at room temperature for 6 h. The solvent was removed by rotary evaporation, and the dichloromethane was dried in vacuo to obtain 8.84 g of 101B07 as a white solid (97.6%).

[0929] 1H NMR(400MHz,D2O)δ4.23(br,35H),4.04(br,94H),3.70(br,5255H),3.38(br,92H),3.25(m,128H),2.10–1.11(m,376H).

[0930] Synthesis of compound 101B13

[0931] 101B07 (27.37 g) was dissolved in 104 ml of DMF, and 2.373 g of succinic anhydride and 8.174 ml of DIPEA were added. The mixture was stirred at room temperature for 4 h. A small amount of methyl tert-butyl ether was added to precipitate the product. Ninhydrin was used for color development at 100°C for 3 min, resulting in a colorless product. 300 ml of MTBE was added to precipitate the product, which was centrifuged. The supernatant was diluted and analyzed by GPC, revealing no product. The product was dissolved in 100 ml of ACN, and 350 ml of MTBE was slowly added to precipitate the product. The solution was removed, and the colloidal precipitate was dissolved in 100 ml of ACN. 400 ml of MTBE was slowly added to precipitate the product. The product was filtered and dried under vacuum to yield 21.8 g (8.7 mmol, 76%) of compound 101B13.

[0932] 1 H NMR(400MHz,D2O)δ4.16(br,61H),4.00(br,63H),3.64(br,5113H),3.32(br,91H),3.27–2.84(m,124H),2.80–2.30(br,127H),2.14–0.71(br,366H).

[0933] Synthesis of compound 37a

[0934] 101B13 (0.705 g), 2-SM (0.384 g), and PyBOP (0.293 g) were dissolved in 6 mL of DMF, and DIPEA was added. The mixture was stirred at room temperature for 4 h. MTBE was added to precipitate the precipitate, and 60 mL of methanol and 70 mL of water were added. The precipitate was purified by ultrafiltration and lyophilized to obtain the final product 37a (0.832 g) as a light yellow cotton-like product.

[0935] HPLC analysis method D, RT = 13.824 min.

[0936] 1H NMR(400MHz,DMSO-d6)δ8.12(br,62H),7.89(br,66H),7.61(br,132H),7.28(br,98H),5.35(br,112H),4.98(b r,70H),4.26(br,150H),3.84(br,77H),3.50(br,6237H),3.23(br,90H),3.18–2.74(m,374H),1.34(m,899H).

[0937] Example 72: Synthesis of Compound 37b

[0938] Synthesis of compound 101B01-D

[0939] ε-Poly-L-lysine hydrochloride (4.7 g, 29.09 mmol, molar number of structural units) was suspended in 100 g DMSO, triethylamine (8.89 g, 87.27 mmol) was added, and α-Boc-ε-Cbz-D-lysine-NHS active ester (synthesized according to the method in the literature Bioorganic & Medicinal Chemistry, 2005, 13 (7): 2523-2536., 20.83 g, 46.63 mmol) was added. The reaction was stirred at 30 degrees under nitrogen protection for 13 hours. The reaction was completed. The reaction solution was placed in a beaker, 800 ml of ACN was added, and the filter cake was washed with acetonitrile, water, and acetonitrile in sequence, and vacuum dried to obtain the product ε-PolyLys 30 -[Lys(α-Boc,ε-Cbz)] 30 (101B01-D) was obtained as a white solid, 12.13 g (85%).

[0940] Synthesis of compound 101B02-D

[0941] Place 40 mL of acetic acid in a 250 mL flask, add 101B01-D (3.65 g, 7.44 mmol), stir, and heat to 40°C to dissolve. Add 40 mL of methanol to the above reaction flask, add palladium on carbon, evacuate, and stir at 30°C under hydrogen. Add diatomaceous earth, filter with suction, and wash the filter cake with methanol. The resulting light brown filtrate is filtered through a 0.22 μm nylon filter membrane. After filtration, the solution is concentrated by rotary evaporation until it becomes viscous. Methyl tert-butyl ether is precipitated. The supernatant is discarded, and the remaining solvent is removed by water pump. The product is freeze-dried to obtain 3.6 g of white solid product.

[0942] Synthesis of compound 101B06-D

[0943] 101B02-D (1.5 g, 3.4 mmol) was first dissolved in 20 mL of MeOH. PEG-2K-NHS (8.69 g, 4.1 mmol) was then dissolved in 37 mL of ACN. Once completely dissolved, 37 mL of MeOH was added, followed by the pre-dissolved 101B02-D and a 7 mL MeOH rinse. DIPEA was added. The reaction was allowed to react for 15 min. A sample was taken and dried with nitrogen, dissolved in water, and filtered for GPC control. After the reaction was complete, 1.07 g of HOAc was added to adjust the pH. The reaction solution was filtered through a 0.22 μm nylon filter, rinsed with MeOH, and purified by ultrafiltration using an equal volume of water. After ultrafiltration, the solution was concentrated and then washed three times with 50 mL of water until a viscous solution was obtained. 20 mL of ethyl acetate was added. The product was precipitated into 200 mL of MTBE and filtered to yield 4.4 g of a white solid.

[0944] Synthesis of compound 101B07-D

[0945] Dissolve 101B06-D (4 g, 1.69 mmol) in DCM (14 mL) and allow to dissolve. Add TFA (6 mL). No significant exotherm is observed. Under nitrogen, allow the reaction to proceed overnight at room temperature. Take a 50 μL sample, dry it under nitrogen, and perform NMR analysis. NMR analysis indicates complete reaction of the starting material. Concentrate the mixture by rotary evaporation at 37°C. Add 40 mL of MTBE to the crude product with stirring, resulting in an oily precipitate. Cool the oily precipitate to below -10°C with vigorous stirring, allowing the precipitation of lumpy and powdery solids. Heat the mixture to above 15°C with stirring. Filter the mixture, rinse the flask and filter cake with 40 mL of MTBE, and dry it under vacuum with an oil pump for 2 h to obtain 4 g of a white solid.

[0946] Synthesis of compound 101B13-D

[0947] Weigh 101B07-D (4 g, 1.76 mmol) into a 100 mL round-bottom flask, add EtOAc (20 mL), and stir to dissolve at 30°C under nitrogen. Once dissolved, add succinic anhydride (0.23 g, 2.29 mmol) and stir to dissolve. Add DIPEA dropwise at 30°C. After addition is complete, add one drop of the solution to water to a pH of 8. Stir at room temperature for 4 h. A 50 μL sample is taken and precipitated with MTBE. Centrifuge and develop with ninhydrin / phenol / pyridine (50 μL / 100 μL / 50 μL) at 100°C for 3 min. A pale purple color is observed, indicating complete amino reaction. Transfer the sample to a 250 mL flask and add 60 mL of MTBE with vigorous stirring. Continue stirring for 10 min after addition and filter. Add 20 mL of EtOAc to the filter cake and heat at 30°C to dissolve. Then, add 60 mL of MTBE with vigorous stirring. Continue stirring for 10 minutes after the addition, filter, and dry in vacuo at 35°C for 1 hour to obtain 3.5 g of a white solid product.

[0948] Synthesis of compound 37b

[0949] 101B13-D (1.5 g, 601.44 μmol, based on polymer unit weight) and 2-SM (877.6 mg, 962.31 μmol) were weighed and dissolved in 5 mL of DMF. HOBt (162.77 mg, 1202.89 μmol) was added and stirred to dissolve. PyBOP (626 mg, 1202.89 μmol) was added and stirred to dissolve. N-methylmorpholine (297.5 μL, 2706.50 μmol) was then added. The reaction was stirred at room temperature overnight under nitrogen. HPLC analysis of a sample showed 9.6% residual 10114A. The reaction solution was precipitated into 50 mL of MTBE and centrifuged. The precipitate was dissolved in 25 mL of MeOH and purified by ultrafiltration. Lyophilization yielded 1.6242 g of a white solid product with a purity of 99.97% and an SN-38 conjugation content of 11.7%.

[0950] Example 73: Synthesis of Compound 1D

[0951] Synthesis of Compounds 1-1D-1-10D

[0952] The product was prepared by using D-lysine as the starting material and referring to the synthesis method of 1-1-1-10 in Example 1.

[0953] Synthesis of compound 1D

[0954] Compound 1-10D (376 mg, 4.81 μmol) and compound 2-SM (280 mg, 308 μmol) were dissolved in DMF (9 mL). PyBOP (240 mg, 460 μmol) and DIPEA (230 μL, 1.40 mol) were added and stirred at room temperature for 24 h. Precipitation was completed with methyl tert-butyl ether and allowed to stand at -20°C. The precipitate was dissolved in methanol and purified using an LH-20 gel column. The mixture was concentrated, reconstituted with water, filtered, and lyophilized to yield 420 mg of compound 1D.

[0955] Example 74: Synthesis of Compound 38

[0956] Synthesis of compound 38

[0957] To a DMF solution (5 mL) of 101B13 (0.41 g) and 38-SM (0.24 g) was added PyBOP (0.13 g) and DIPEA (0.13 mL) at room temperature under nitrogen. The mixture was stirred overnight at room temperature. 50 mL of MTBE was added to the reaction solution to precipitate it. The mixture was centrifuged and then dried in dichloromethane. The precipitate was then dissolved in 70 mL of methanol and 30 mL of water. The product was purified by ultrafiltration (30K MW) and lyophilized to obtain 450 mg of the final product (38) as a red solid with an HPLC purity of 98.8%.

[0958] Example 75: Synthesis of Compound 39a

[0959] Synthesis of compound 21601

[0960] At 25°C under nitrogen, 101B13 (500 mg, 0.21 mmol, 1.0 eq, calculated based on the molar weight of polymerized units), amine hydrochloride (62.6 mg, 0.32 mmol, 1.5 eq), PyBOP (165.0 mg, 0.32 mmol, 1.5 eq), DIPEA (0.19 mL, 1.06 mmol, 5.0 eq), and DMF (4.0 mL) were added sequentially. The reaction was stirred at room temperature for 15 hours, and complete conversion of the starting materials was monitored by HPLC. MTBE (40 mL) was added to DMF, causing the solution to become turbid and a white solid to precipitate. The supernatant was removed by aspiration, and the white solid was washed with MTBE and aspirated. The remaining white solid was dissolved in MeOH and ultrafiltered using a MeOH / water solution to remove small molecule impurities. Complete removal of small molecule impurities was monitored by HPLC. The collected solution was vortexed to remove the MeOH, and the aqueous solution was lyophilized to yield product 216D01 (455 mg) as a white solid.

[0961] Synthesis of compound 216D03

[0962] 216D01 (277 mg, 0.11 mmol, 1.0 eq) and NaOH solution (0.1 M, 5.6 ml, 0.56 mmol, 5.0 eq) were added sequentially at 25°C. The reaction was stirred at room temperature for 4 hours. Complete conversion of the starting material was monitored by HPLC. The solution was ultrafiltered with water to remove small molecule impurities and lyophilized to afford the product 216D03 (244 mg) as a white solid.

[0963] Synthesis of compound 39a

[0964] To a solution of 216DO3 (55 mg, 0.022 mmol, 1.0 eq) in water (0.5 ml) at 25°C was added a Ba(OH)2 solution (0.1 M, 0.22 ml, 0.022 mmol, 1.0 eq). The reaction was stirred at room temperature for 10 minutes. To this solution was added a 39a-SM solution (synthesized according to the method described in Angewandte Chemie, 2016, 128(7): 2596-2600, 0.2 M, 0.5 ml, 0.11 mmol, 5.0 eq). The reaction was stirred at room temperature for 15 hours. HPLC monitored the complete conversion of the reaction starting material. The product was purified by ultrafiltration (30K MW) and lyophilized to obtain 39a, 51 mg, as a white solid with a purity of 98.5%.

[0965] Example 76: Synthesis of Compound 39b

[0966] Synthesis of compound 39b

[0967] To a solution of 31-2 (1.0 g, 0.423 mmol, 1.0 eq, polymer unit weight) in DMF (10 mL) were added 3b-SM (synthesized according to the method of European Journal of Inorganic Chemistry, 2014, 2014(3):484-492, 250 mg, 0.508 mmol, 1.3 eq), PyBOP (0.61 mmol, 1.5 eq), and DIPEA (170 mg, 1.27 mmol, 3.0 eq). The reaction was stirred at room temperature for 12 h. The reaction mixture was concentrated, purified by ultrafiltration (30K MW), and the pure solution was lyophilized to obtain 860 mg of the product with a purity of 99%.

[0968] Example 77: Synthesis of Compound 40

[0969] Synthesis of compound 40-1

[0970] The reaction was stirred at 0°C under nitrogen, followed by the addition of fulvestrant (1.82 g, 3.0 mmol, 1.0 eq), anhydrous DCM (10 mL), and DIPEA (1.1 mL, 6.0 mmol, 2.0 eq). After stirring briefly to dissolve the starting materials, p-nitrophenyl chloroformate (726 mg, 3.6 mmol, 1.2 eq) was added. The reaction was then slowly warmed to room temperature and stirred for 1 hour. LCMS monitoring confirmed complete conversion of fulvestrant. The reaction solution was carried on to the next step without further treatment.

[0971] Synthesis of compound 40-2

[0972] To the above reaction solution were added DMF (30 mL), 7-SM2 (3.24 g, 3.9 mmol, 1.3 eq), and DIPEA (1.1 mL, 6.0 mmol, 2.0 eq). The reaction was stirred at room temperature for 4 hours, and the reaction was complete as monitored by LCMS. Diethylamine (2.4 mL, 24 mmol, 8.0 eq) was added. The reaction was stirred at room temperature for 1 hour, and the reaction was complete as monitored by LCMS. The product was concentrated and purified by reverse phase column chromatography (MeCN / H2O-0.05% TFA) to afford product 40-2 as a white solid (2.86 g). The total yield of the three-step reaction was 77%.

[0973] 1 H NMR (400MHz, CDCl3) δ9.66(s,1H),8.28(s,1H),7.75–7.45(m,2H),7.25–7.03(m,2H),6.76(d,J= 10.3Hz,2H),5.88(s,1H),5.29–4.92(m,4H),4.77(s,1H),3.71(s,1H),3.65–2.56(m,24H),2.58 –1.99(m,22H),1.95–1.09(m,38H),1.04–0.71(m,13H).

[0974] Synthesis of compound 40

[0975] At 25°C under nitrogen, 101B13 (1.73 g, 0.73 mmol, 1.0 eq, based on polymer building block), 40-2 (1.36 g, 1.1 mmol, 1.5 eq), PyBOP (572.4 mg, 1.1 mmol, 1.5 eq), DIPEA (0.54 mL, 2.92 mmol, 4.0 eq), and DMF (10 mL) were added sequentially. The reaction was stirred at room temperature for 15 hours. HPLC monitored complete conversion of the starting materials. MTBE (60 mL) was added to DMF, causing the solution to become turbid and a white solid to precipitate. The product was purified by ultrafiltration (30K MW) and lyophilized to afford 40, 2.1 g, as a white solid with a purity of 100.00%.

[0976] Example 78 (Comparative Example): Synthesis of Compound 41

[0977] Synthesis of compound 101A01

[0978] To a solution of dibenzylamine (BHA, 2.50 g) in CH3CN / DMF (20 / 10 mL) in an ice-water bath at 5°C under nitrogen, DIPEA (2.53 g) was added, followed by 10101 (7.02 g) in portions. The reaction mixture was stirred for 12 hours. 0.5N sodium hydroxide solution (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to yield 3.8 g of crude product BHA-Lys(α,ε-Boc) (101A01) in a 55% yield. MS (ESI), m / z, 512.2 [M+H] + .

[0979] Synthesis of compound 101A02:

[0980] Under nitrogen at room temperature (25°C), TFA (2 mL) was added to a dichloromethane solution (10 mL) of 101A01 (3.80 g) and the mixture was stirred for 12 h. The reaction mixture was concentrated, dissolved in dichloromethane (10 mL), and MTBE (30 mL) was added and concentrated to yield the product 101A02, a foamy solid BHA-Lys(α,ε-NH3+CF3COO-) (101A02), 3.0 g, in 89% yield. MS (ESI), m / z, 312.1 [M+H] + .

[0981] Synthesis of compound 101A03:

[0982] To a DMF solution (10 mL) of 101A02 (TFA salt, 1.00 g) was added DIPEA (1.70 g) in an ice-water bath at 5°C under nitrogen. 10101 (1.91 g) was then added portionwise. The reaction mixture was stirred for 12 hours. 0.5N sodium hydroxide solution (50 mL) was poured into the reaction mixture, stirred for 1 hour, and filtered. The filter cake was washed with 0.5N sodium hydroxide solution and dried under vacuum to yield the product 101A03 as a white solid (1.50 g, 84% yield). MS (ESI), m / z, 968.5 [M+H] + .

[0983] Synthesis of compound 101A04:

[0984] At room temperature (25°C) and under nitrogen, TFA (2 mL) was added to a dichloromethane solution (10 mL) of 101A03 (1.5 g, 1.55 mmol) and stirred for 12 h. The reaction mixture was concentrated to obtain product 101A04 as a foamy solid (1.50 g, 95% yield).

[0985] 1 H NMR(400MHz,D2O)δ7.41–7.19(m,10H),6.03(s,1H),4.36(t,J=7.4Hz,1H),3.94(t,J=6.5Hz,1H),3.85 –3.76(m,1H),3.10(t,J=7.3Hz,2H),2.90(t,J=7.9Hz,2H),2.63(t,J=7.7Hz,2H),2.03–0.99(m,18H).

[0986] MS (ESI), m / z, 568.3 [M+H] + .

[0987] Synthesis of compound 101A05:

[0988] To a DMF solution (30 mL) of 101A04 (TFA salt, 1.50 g) was added DIPEA (2.60 g) in an ice-water bath at 5°C under nitrogen. 10101 (prepared in Example 1) (3.01 g) was then added, and the reaction mixture was stirred for 12 hours. 0.5N sodium hydroxide solution (100 mL) was poured into the reaction mixture, stirred for 1 hour, filtered, and the solid collected. The product 101A05 was dried under vacuum to obtain 2.3 g of a white solid (83% yield).

[0989] MS (ESI), m / z, 941.0 [M / 2+H] + .

[0990] Synthesis of compound 101A06:

[0991] At room temperature (25°C) and under nitrogen, TFA (10 mL) was added to a dichloromethane solution (10 mL) of 101A05 (2.30 g) and stirred for 4 h. The reaction mixture was concentrated, dissolved in dichloromethane / MeOH, and concentrated with MTBE to afford product 101A06 as a foamy solid (2.41 g, 98.5% yield). MS (ESI), m / z, 540.8 [M / 2+H]. +

[0992] 1 H NMR(400MHz,D2O)δ7.45–7.11(m,10H),6.02(s,1H),4.32–4.09(m,3H),4.01–3.92(m,2H ),3.85(t,J=6.7Hz,1H),3.78(t,J=6.7Hz,1H),3.22–2.80(m,14H),1.94–1.06(m,42H).

[0993] Synthesis of compound 101A07:

[0994] To a DMF solution (20 mL) of 101A06 (TFA salt, 2.40 g) was added DIPEA (3.73 g) in an ice-water bath at 5°C under nitrogen. 10101 (prepared in Example 1) (5.41 g) was then added, and the reaction mixture was stirred for 12 hours. 0.5N sodium hydroxide solution (150 mL) was poured into the reaction mixture, stirred for 1 hour, filtered, and the collected solid was dissolved in acetonitrile. Water (1 / 1 volume) was added to precipitate the solid, stirred for 1 hour, filtered, and dried under vacuum to yield the product 101A07 as a white solid (3.82 g, 85% yield).

[0995] Synthesis of compound 101A08:

[0996] At room temperature (25°C) and under nitrogen, TFA (10 mL) was added to a dichloromethane solution (10 mL) of 101A07 (3.0 g) and stirred for 4 h. The reaction mixture was concentrated, dissolved in acetonitrile (30 mL), and MTBE (150 mL) was added for precipitation. The solid was filtered and dried under vacuum to yield product 101A08 as a white solid (2.9 g, 91% yield). MS (ESI), m / z, 702.7 [M / 3+H]. + .

[0997] 1 H NMR(400MHz,D2O)δ7.64–6.97(m,10H),6.02(s,1H),4.31–4.04(m,7H),3.96 (t,J=6.7Hz,4H),3.90–3.79(m,5H),3.30–2.77(m,30H),1.93–0.96(m,90H).

[0998] Synthesis of compound 101A09:

[0999] To a DMF solution (20 mL) of 101A08 (TFA salt, 2.50 g) was added DIPEA (3.94 g) and then 10101 (5.94 g) in an ice-water bath at 5°C under nitrogen protection. The reaction mixture was stirred for 12 h. 0.5 N sodium hydroxide solution (100 mL) was poured into the reaction mixture, stirred for 1 h, and filtered to collect the solid. The product 101A09 was dried in vacuo to obtain a white solid (3.7 g, yield 80%).

[1000] Synthesis of compound 101A10:

[1001] Under nitrogen at 25°C, TFA (10 mL) was added to a dichloromethane solution (10 mL) of 101A09 (3.0 g) and stirred for 12 h. The reaction mixture was concentrated, dissolved in acetonitrile (20 mL), and MTBE (100 mL) was added for precipitation. The solid was filtered and vacuum-dried to obtain the product 101A10 as a white solid (3.0 g, 94% yield). MS (ESI), m / z, 832.1 [M / 5+H]. + .

[1002] 1 H NMR(400MHz,D2O)δ7.45–7.03(m,10H),6.01(s,1H),4.34–4.06(m,16H),4.0 2–3.92(m,8H),3.90–3.79(m,8H),3.29–2.72(m,62H),2.00–0.93(m,186H).

[1003] Synthesis of compound 101A11:

[1004] To a DMF solution (20 mL) of 101A10 (TFA salt, 2.0 g) was added DIPEA (3.3 g) in an ice-water bath at 5°C under nitrogen protection. 10102 (4.79 g) was then added. The reaction mixture was stirred for 6 h. 0.5 N sodium hydroxide solution (100 mL) was poured into the reaction mixture, stirred for 1 h, and filtered. The collected solid was suspended in CH3CN (50 mL). An aqueous solution (200 mL) was added, stirred for 1 h, and filtered. This reaction was repeated twice. The collected solid was dried in vacuo to obtain the product 101A11 as a white solid (3.8 g, yield 94%).

[1005] Synthesis of compound 101A12:

[1006] To a solution of 101A11 (2.50 g, 0.16 mmol) in acetic acid (50 mL, filtered through Celite if not clear) was added Pd / C or Pd(OH)2 (10%, 1.0 g, 10 mL) at room temperature (25°C) under nitrogen. The hydrogen atmosphere was replaced with a hydrogen balloon and the reaction was stirred for 24 h (30°C). The reaction solution was concentrated, dissolved in methanol (20 mL), and MTBE (100 mL–200 mL) was added for precipitation. The product was filtered and the solid was collected and dried under vacuum to obtain the product 101A12 as an off-white solid, 1.7 g, in an 80% yield. MS (ESI), m / z, 832.1 [M / 5+H]. + .

[1007] 1H NMR(400MHz,D2O)δ7.53–6.98(m,10H),6.02(s,1H),4.15(s,34H),3.89(d, J=26.3Hz,38H),3.38–2.71(m,126H),1.86(s,118H),2.21–0.70(m,669H).

[1008] Synthesis of compound 101A13-2K

[1009] To a solution of 101A12 (1.0 g) in DMF (10 mL) at 25°C under nitrogen, DIPEA (0.96 g) was added, followed by PEG-2K-NHS (6.48 g). The reaction mixture was stirred for 12 h. MTBE (100 mL) was added to the reaction mixture, filtered, and the filter cake was dried under vacuum to afford the product 101A13-2K, 4.0 g, in a 70% yield.

[1010] Synthesis of compound 101A14-2K

[1011] To a solution of 101A13-2K (4.0 g) in dichloromethane (50 mL) was added TFA (30 mL) at 25°C under nitrogen and stirred for 12 h. MTBE was then added, and the mixture was cooled to -20°C for crystallization. The resulting solid was filtered and vacuum dried to afford the product 101A14-2K as an off-white solid (3.8 g, 95% yield).

[1012] Synthesis of compound 101A15-SA-2K

[1013] To a solution of 101A14-2K (1.0 g, 0.013 mmol) in DMF (5 mL) was added DIPEA (166 mg, 1.29 mmol, 100.0 eq) at 25°C under nitrogen, followed by succinic anhydride (82 mg, 0.82 mmol, 64.0 eq). The reaction was stirred for 12 h. After completion, MTBE (50 mL) was added, stirred for 10 minutes, and the supernatant was decanted. This reaction was repeated three times, and the residue was dried under vacuum to afford the product, 101A15-SA-2K, 0.8 g, in a 76% yield.

[1014] Synthesis of compound 41

[1015] To a DMF solution (5 mL) of 101A15-SA-2K (838 mg, 0.01 mmol, 1.0 eq) in an ice-water bath at 5°C under nitrogen was added DIPEA (170 mg, 1.32 mmol, 128.0 eq), 1-10-SM (451 mg, 0.49 mmol, 48.0 eq), and PyBOP (429 mg, 0.82 mmol, 80.0 eq). The reaction was stirred at room temperature for 12 h. HPLC analysis confirmed the reaction was complete, and MTBE (50 mL) was added. The mixture was stirred for 10 minutes, and the supernatant was decanted. The residue was purified by ultrafiltration (30K MW) and lyophilized to afford the final product 41 (900 mg) as a pale yellow solid with an HPLC purity of 99.3%.

[1016] Example 79: Synthesis of Compound 42

[1017] Synthesis of compound 42-1

[1018] Under nitrogen protection, to a solution of poly-L-lysine hydrobromide (2 g, 9.56 mmol) in water (3 mL) were added DIPEA (3.7 g, 28.7 mmol) and DMSO (40 mL), followed by 10102 (7.2 g, 14.35 mmol). The reaction was stirred at room temperature for 16 h, acetonitrile (100 mL) was added for precipitation and filtered, and the filter cake was collected to obtain 5.45 g of the product as a white solid.

[1019] 1 H NMR (400MHz, DMSO-d6) δ7.99–7.57(m,58H),7.48–7.12(m,191H),7.02–6.83(m,28H),5.16–4. 84(m,66H),4.30–4.06(m,31H),3.97–3.74(m,34H),3.12–2.82(m,133H),1.77–1.01(m,708H).

[1020] Synthesis of compound 42-2

[1021] A mixture of 42-1 (5.45 g, 11.11 mmol) and acetic acid (55 mL) was heated to dissolve, methanol (55 mL) and 10% palladium carbon (927 mg) were added, and hydrogen was replaced three times. The reaction was stirred for 16 h, filtered through celite, and MTBE was added to the filtrate to make a pulp, filtered, and the solid was dried in vacuo to obtain 1.77 g of a white solid.

[1022] 1H NMR(400MHz,D2O)δ4.27–4.19(m,30H),4.09–3.94(m,30H),3.31–3.11(m,69H),3.01(t,J=7.6Hz,62H),1.86–1.29(m,646H).

[1023] Synthesis of compound 42-3

[1024] To a solution of 42-2 (900 mg, 0.16 mmol) in methanol (25 mL) was added a solution of PEG-2K-NHS (5.6 g, 2.64 mmol) in acetonitrile (25 mL), followed by the addition of DIPEA (1.4 g, 10.8 mmol). The reaction was stirred at room temperature for 30 min. The reaction solution was purified by ultrafiltration, and the ultrafiltrate was lyophilized to obtain 4.74 g of a white solid with a GPC purity of 99%.

[1025] Synthesis of compound 42-4

[1026] A mixed solution of 42-3 (1 g, 0.42 mmol), TFA (3 mL) and DCM (7 mL) was stirred at room temperature for 16 h. The reaction solution was slowly precipitated into MTBE (90 mL). A large amount of solid precipitated, which was filtered and dried in vacuo to obtain 1 g of a white solid.

[1027] Synthesis of compound 42-5

[1028] To a solution of 42-4 (1 g, 0.42 mmol) in DMF (8 mL) was added succinic anhydride (63 mg, 0.63 mmol), followed by DIPEA (326 mg, 2.52 mmol). The reaction was stirred at room temperature for 16 h. The reaction solution was slowly added dropwise to MTBE (90 mL). A large amount of solid precipitated, which was filtered. The filter cake was washed twice with MTBE and the solid was dried in vacuo to obtain 799 mg of a white solid.

[1029] Synthesis of compound 42

[1030] To a solution of 42-5 (778 mg, 0.33 mmol), 2-SM (525 mg, 0.57 mmol), HOBt (89 mg, 0.66 mmol) and PyBOP (342 mg, 0.66 mmol) in DMF (8 mL) was added NMM (150 mg, 1.48 mmol). The mixture was stirred at room temperature for 16 h. The reaction solution was slowly added dropwise to MTBE (80 mL), and a large amount of solid precipitated. The solid was collected and dissolved in methanol (40 mL) and water (40 mL). Purified by ultrafiltration, the ultrafiltrate was lyophilized to give 623 mg of a white solid with HPLC purity of 99% and an SN38 coupling amount of 11.71%.

[1031] Example 80: Synthesis of Compound 43

[1032] Synthesis of compound 43-1

[1033] Under nitrogen protection and ice bath, molecular sieves (4.14 g) and DIPEA (94 μL) were added to a solution of BLG-NCA (5.694 g, 40.0 eq) and di-tert-butyl glutamate hydrochloride (160 mg, 1.0 eq) in anhydrous DMF (56 mL). The reaction was stirred for 2 h, filtered, and the filtrate was precipitated with methanol. The solid was centrifuged and dried in vacuo to obtain 3.30 g (17.3 mmol, 70%). The degree of polymerization was 58.8 (Benzyl CH2) as characterized by NMR.

[1034] 1 H NMR (400MHz, TFA-d) δ8.09–7.84(m,327H),5.95–5.71(m,122H),5.57–5.31(m,64H),3.46–3.07(m,138H),3.07–2.56(m,133H).

[1035] Synthesis of compound 43-2

[1036] Dissolve 43-1 in 4.6 mL of TFA, cool to 0°C, add 2.25 mL of hydrobromic acid, and react overnight at 0°C. Add 5V of MTBE to precipitate, filter, and vacuum dry to obtain 773.5 mg of a white powder (yield > 99%).

[1037] 1 H NMR(400MHz,D2O)δ4.41–4.23(m,59H),3.20(s,19H),2.99(s,15H),2.83(d,J=0.8Hz, 13H), 2.24 (dd, J=6.3, 2.6Hz, 131H), 2.11–1.80 (m, 130H), 1.22 (s, 25H), 1.19 (s, 57H).

[1038] Synthesis of compound 43-3

[1039] 43-2 (400 mg) was dissolved in 5 mL of DMF, and DIPEA (0.54 mL) was added, followed by 136 mg of Teoc-NHS. The mixture was stirred at room temperature for 2 h, and MTBE was added for precipitation. The mixture was centrifuged, and the solid was collected and dried in vacuo to obtain 415 mg of the product.

[1040] Synthesis of compound 43-4

[1041] 43-3 (0.42 g, 3.21 mmol, 1.0 eq), HOBt (0.12 g, 0.90 mmol, 0.28 eq) and N2-tert-butyloxycarbonyl-L-lysine tert-butyl ester (1.26 g, 4.18 mmol, 1.3 eq) were dissolved in 5 mL of DMF, followed by the addition of PyBOP (3.18 g, 6.11 mmol, 1.9 eq) and NMM (1.48 mL, 14.1 mmol, 4.4 eq). The mixture was reacted at room temperature for 2 h, and 100 mL of MTBE was added for precipitation. The mixture was centrifuged and dried in vacuo to obtain 927.1 mg (69.8%) of the product as a yellow solid.

[1042] 1 H NMR (400MHz, DMSO) δ8.50–7.45(m,98H),7.28–6.86(m,39H),6.71(d,J=6.6Hz,10H),4.51–3.88(m,48H),3.85–3.47(m,48 H),3.14–2.86(m,99H),2.10(s,80H),1.94–1.79(m,82H),1.78–1.65(m,48H),1.65–1.46(m,104H),1.44–1.13(m,964H).

[1043] Synthesis of compound 43-5

[1044] 43-4 (0.74 g, 1.79 mmol) was dissolved in 6 mL of DCM, and 6 mL of TFA was added. The mixture was stirred at room temperature for 8 h, concentrated, and MTBE was added for precipitation. The mixture was centrifuged, and the solid was collected and dried in vacuo to obtain 705 mg of a light yellow solid.

[1045] 1 H NMR(400MHz,D2O)δ4.48–4.20(m,47H),4.15–3.90(m,51H),3.29–3.07(m,130H),2.34(br,89H),2.21–1.82(m,193H),1.67–1.33(m,200H).

[1046] Synthesis of compound 43-6

[1047] 43-5 (0.51 g, 1.38 mmol, 1.0 eq) was dissolved in 3.8 mL of water, and DIPEA (0.84 mL, 4.84 mmol, 3.5 eq) was added. A solution of PEG-2K-NHS (2.93 g, 1.38 mmol, 1.0 eq) in acetonitrile (8 mL) was added dropwise to the solution. The mixture was stirred at room temperature for 3 h and the reaction was monitored by GPC. The reaction solution was purified by ultrafiltration (30K MW) using 40% ethanol. The concentrate was collected, concentrated, and lyophilized to yield 2.2 g (71% yield).

[1048] 1 H NMR(400MHz,D2O)δ4.30(br,92H),4.13(s,99H),4.01–3.49(m,8017H),3.40(d,J=1.3Hz ,151H),3.29–3.05(m,145H),2.34(br,89H),2.18–1.66(m,178H),1.63–1.44(m,106H).

[1049] Synthesis of compound 43

[1050] 43-6 (0.87 g, 0.38 mmol, 1.0 eq), 2-SM (0.63 g, 0.69 mmol, 1.8 eq), and HOBt (0.11 g, 0.76 mmol, 2.0 eq) were dissolved in 6 mL of DMF. PyBOP (0.40 g, 0.76 mmol, 2.0 eq) and NMM (0.17 g, 1.72 mmol, 4.5 eq) were added, and the mixture was stirred at room temperature for 1 h. MTBE was added for precipitation, and the solid was collected, dried, and dissolved in 40% ethanol. The concentrate was collected by ultrafiltration (30K MW), concentrated, and lyophilized to obtain 997 mg of a white solid with a yield of 82.5%. The SN-38 coupling amount was 11.76%.

[1051] Example 81: Synthesis of Compound 44

[1052] Synthesis of compound 42

[1053] To a solution of 42-5 (778 mg, 0.33 mmol), 6-2 (750 mg, 0.57 mmol), HOBt (89 mg, 0.66 mmol) and PyBOP (342 mg, 0.66 mmol) in DMF (8 mL) was added NMM (150 mg, 1.48 mmol), and the reaction was stirred at room temperature for 16 h. MTBE (50 mL) was added and stirred for 30 min. The supernatant was decanted, and the residue was dried and dissolved in methanol (40 mL) and water (40 mL). It was purified by ultrafiltration (30K MW) (methanol and water as the ultrafiltrate), and the ultrafiltrate was lyophilized to give 520 mg of a light yellow solid with HPLC purity of 98.2% and an SN38 coupling amount of 11.2%.

[1054] Example 82: Synthesis of Compound 45

[1055] Synthesis of compound 45-1

[1056] Under nitrogen protection and ice bath, HATU (1.40 g, 3.70 mmol, 1.5 eq) and DIPEA (0.95 g, 7.39 mmol, 3.0 eq) were added to a solution of 45-SM (synthesized according to the method of compound 13 in patent WO2015095223A2, 1.0 g, 2.46 mmol, 1.0 eq) and Fmoc-ethylenediamine (0.83 g, 2.96 mmol, 1.2 eq) in anhydrous DMF (10 mL). The reaction was restored to room temperature and stirred for 12 h. The reaction was quenched with water, extracted with dichloromethane, and the organic phase was washed with salt, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (dichloromethane and methanol system) to give 1.4 g of the product in a yield of 85%.

[1057] MS (ESI), m / z, 671.3 [M+H] + .

[1058] Synthesis of compound 45-2

[1059] Under nitrogen protection and ice bath, to a solution of 45-1 (1.4 g, 2.09 mmol, 1.0 eq) in anhydrous DMF (10 mL) were added di(p-nitrobenzene) carbonate (0.95 g, 3.13 mmol, 1.5 eq) and DIPEA (0.81 g, 6.27 mmol, 3.0 eq). The reaction was returned to room temperature and stirred for 2 h. The reaction was quenched with water, extracted with dichloromethane, and the organic phase was washed with salt, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 1.6 g of the crude product in a yield of 92%.

[1060] MS (ESI), m / z, 836.2 [M+H] + .

[1061] Synthesis of compound 45-3

[1062] Under nitrogen protection and ice bath, to a solution of 45-2 (1.6 g, 1.92 mmol, 1.0 eq) in anhydrous DMF (10 mL) were added 10113A (prepared according to the method of compound 10113A in patent WO2023078464A1) di(p-nitrobenzene) carbonate (1.16 g, 1.92 mmol, 1.0 eq) and DIPEA (0.74 g, 5.75 mmol, 3.0 eq), the reaction mixture was returned to room temperature and stirred for 12 h, quenched with water, extracted with dichloromethane, the organic phase was washed with salt, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (dichloromethane and methanol system) to give 2.0 g of the product in a yield of 87%.

[1063] MS (ESI), m / z, 1203.2 [M+H] + .

[1064] Synthesis of compound 45-4

[1065] Under nitrogen protection and ice bath, diethylamine (3 mL) was added to a solution of 45-3 (1.9 g, 1.58 mmol, 1.0 eq) in anhydrous DMF (10 mL). The mixture was returned to room temperature and stirred for 12 h. The reaction was concentrated and directly purified by reverse phase column chromatography (0.05% TFA, H2O and methanol) to give 1.3 g of the product in a yield of 84%.

[1066] MS (ESI), m / z, 981.1 [M+H] + .

[1067] Synthesis of compound 45

[1068] To a solution of 42-5 (700 mg, 0.32 mmol) and 45-4 (470 mg, 0.48 mmol) in DMF (10 mL) at room temperature and under nitrogen protection were added PyBOP (312 mg, 0.60 mmol) and DIPEA (190 mg, 1.48 mmol), and the reaction was stirred for 20 h. MTBE (50 mL) was added and stirred for 30 min. The supernatant was decanted, and the residue was dried and dissolved in methanol (50 mL) and water (50 mL). It was purified by ultrafiltration (30K MW) (methanol and water as the ultrafiltrate), and the ultrafiltrate was lyophilized to give 630 mg of a light yellow solid with an HPLC purity of 99.3% and an SN38 coupling amount of 9.8%.

[1069] Example 83: Synthesis of Compound 46

[1070] Synthesis of compound 46-1

[1071] Under an ice-water bath and nitrogen, to a solution of cysteamine hydrochloride (1.50 g, 13.2 mmol, 1.0 eq) in methanol (18 mL) was added triethylamine (1.85 mL, 26.4 mmol, 2.0 eq) and 2-hydroxyethyl disulfide (1.50 g, 13.2 mmol, 1.0 eq) in dichloromethane. The mixture was stirred at room temperature for 16 h. The solution was cooled to 0°C and di-tert-butyl dicarbonate (4.32 g, 19.8 mmol, 1.5 eq) was added. The mixture was stirred at room temperature for 4 h. LCMS analysis was performed and the reaction was terminated. The reaction solution was directly concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain the compound as a colorless oil (0.9 g, 26.9% yield).

[1072] MS (ESI), m / z, 154.0 [M-100] + .

[1073] Synthesis of compound 46-2

[1074] To a CH2Cl2 solution (25 mL) of 46-1 (1.90 g, 7.5 mmol, 1.5 eq) at 0°C, Et3N (757 mg, 7.5 mmol, 1.5 eq) and bis(p-nitrobenzene) carbonate (2.28 g, 7.5 mmol, 1.5 eq) were added sequentially. The reaction was stirred for 2 h. DMAP (610 mg, 5.00 mmol, 1.0 eq) and 10-TBDPS-protected SN38 (3.15 g, 5.00 mmol, 1.0 eq) were added to the reaction solution. The mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction solution was poured into saturated aqueous ammonium chloride and washed thoroughly (150 mL x 3). The organic phases were combined, dried over anhydrous Na2SO4, concentrated under reduced pressure, and passed through a silica gel column with PE / EA = 1:1 as the eluent to obtain 2.1 g of the product.

[1075] MS (ESI), m / z, 909.1 [M+H] + .

[1076] Synthesis of compound 46-3

[1077] A formic acid solution (20 mL) of 46-2 (1.7 g, 1.80 mmol, 1.0 eq) was stirred at 0°C for 2 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure and purified on a C18 reverse phase column (CH3CN / H2O = 5-75%) to obtain 1.2 g of a yellow solid.

[1078] MS (ESI), m / z, 809.0 [M+H] + .

[1079] Synthesis of compound 46-4

[1080] At room temperature and under nitrogen protection, PyBOP (312 mg, 0.60 mmol) and DIPEA (190 mg, 1.48 mmol) were added to a solution of 42-5 (700 mg, 0.32 mmol) and 46-3 (390 mg, 0.48 mmol) in DMF (10 mL). The reaction was stirred for 20 h, MTBE (50 mL) was added and stirred for 30 minutes, the supernatant was decanted, and the residue was dried to obtain 900 mg of crude product, which was used directly in the next step.

[1081] Synthesis of compound 46

[1082] To a THF solution (5 mL) of compound 46-4 (900 mg) was added TBAF solution (1.0 M in THF, 1.0 mL) at room temperature under nitrogen. The reaction was stirred at room temperature for 20 h. MTBE (50 mL) was added and stirred for 30 min. The supernatant was decanted and the residue was dried and dissolved in methanol (50 mL) and water (50 mL). The product was purified by ultrafiltration (30K MW) (methanol and water as the ultrafiltrate). The ultrafiltrate was lyophilized to give 520 mg of a light yellow solid with an HPLC purity of 99.3% and an SN38 coupling amount of 11.0%.

[1083] Example 84: Synthesis of Compound 47

[1084] Synthesis of compound 47

[1085] To a solution of 42-5 (700 mg, 0.32 mmol) and 16a-4 (577 mg, 0.48 mmol) in DMF (10 mL) at room temperature and under nitrogen protection were added PyBOP (312 mg, 0.60 mmol) and DIPEA (190 mg, 1.48 mmol). The reaction was stirred for 24 h, MTBE (50 mL) was added and stirred for 30 min, the supernatant was decanted, the residue was dried and dissolved in methanol (60 mL) and water (40 mL), and purified by ultrafiltration (30K MW) (methanol and water as the ultrafiltrate). The ultrafiltrate was lyophilized to give 580 mg of a white solid with an HPLC purity of 97.8% and a PTX coupling amount of 19.0%.

[1086] Example 85: Synthesis of Compound 48

[1087] Synthesis of compound 48

[1088] To a solution of 42-5 (700 mg, 0.32 mmol) and 33a-3 (516 mg, 0.50 mmol) in DMF (10 mL) were added PyBOP (312 mg, 0.60 mmol) and NMM (150 mg, 1.48 mmol) at room temperature under nitrogen protection. The reaction was stirred for 12 h, MTBE (50 mL) was added and stirred for 30 min, the supernatant was decanted, the residue was dried and dissolved in methanol (60 mL) and water (40 mL), and purified by ultrafiltration (30K MW) (methanol and water as the ultrafiltrate). The ultrafiltrate was lyophilized to give 580 mg of a white solid with an HPLC purity of 98.5% and a PTX coupling amount of 19.5%.

[1089] Example 86: Synthesis of Compound 49

[1090] Synthesis of compound 49-1

[1091] To a DMF solution (10 mL) of 43-6 (0.87 g, 0.38 mmol, 1.0 eq) and 46-3 (0.56 g, 0.69 mmol, 1.8 eq) at room temperature under nitrogen was added PyBOP (0.40 g, 0.76 mmol, 2.0 eq) and NMM (0.17 g, 1.72 mmol, 4.5 eq). The mixture was stirred at room temperature for 12 h. MTBE (50 mL) was added and stirred for 30 min. The supernatant was decanted and the residue was dried to obtain 1.1 g of a crude product, which was used directly in the next step.

[1092] Synthesis of compound 49

[1093] To a THF solution (10 mL) of 49-1 (1.1 g crude product) was added TBAF solution (1.0 M in THF, 2.0 mL) at room temperature under nitrogen. The reaction was stirred at room temperature for 20 h. MTBE (50 mL) was added and stirred for 30 min. The supernatant was decanted, and the residue was dried and dissolved in methanol (50 mL) and water (50 mL). The product was purified by ultrafiltration (30K MW) (methanol and water as the ultrafiltrate). The ultrafiltrate was lyophilized to give 730 mg of a light yellow solid with an HPLC purity of 99.5% and an SN38 coupling amount of 10.5%.

[1094] Example 87: Synthesis of Compound 50

[1095] Synthesis of compound 50

[1096] To a solution of 43-6 (730 mg, 0.32 mmol) and 16a-4 (577 mg, 0.48 mmol) in DMF (10 mL) at room temperature and under nitrogen protection were added PyBOP (312 mg, 0.60 mmol) and DIPEA (190 mg, 1.48 mmol). The reaction was stirred for 24 h, MTBE (50 mL) was added and stirred for 30 min, the supernatant was decanted, the residue was dried and dissolved in methanol (50 mL) and water (50 mL), and purified by ultrafiltration (30K MW) (methanol and water as the ultrafiltrate). The ultrafiltrate was lyophilized to give 580 mg of a white solid with an HPLC purity of 99.9% and a PTX coupling amount of 16.5%.

[1097] Example 88: Synthesis of Compound 51

[1098] Synthesis of compound 50

[1099] To a solution of 43-6 (730 mg, 0.32 mmol) and 33a-3 (516 mg, 0.50 mmol) in DMF (10 mL) at room temperature and under nitrogen protection were added PyBOP (312 mg, 0.60 mmol) and NMM (150 mg, 1.48 mmol), and the reaction was stirred for 12 h. MTBE (50 mL) was added and stirred for 30 min. The supernatant was decanted, and the residue was dried and dissolved in methanol (60 mL) and water (40 mL). It was purified by ultrafiltration (30K MW) (methanol and water as the ultrafiltrate), and the ultrafiltrate was lyophilized to give 490 mg of a white solid with an HPLC purity of 97.9% and a PTX coupling amount of 18.4%.

[1100] Example 89: Synthesis of Compound 52

[1101] Synthesis of compound 52-1

[1102] The starting material (R)-1-(BOC-amino)-2-propanol (2.0 g, 11.41 mmol) was dissolved in DCM (20 mL). TsCl (2.6 g, 13.70 mmol), DMAP (1.4 g, 11.41 mmol), and triethylamine (3.8 mL, 27.39 mL) were added. The mixture was stirred at room temperature for 12 h. LCMS analysis indicated the formation of the product. The reaction mixture was washed with saturated brine and purified water, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 52-1 as a light yellow solid (3.7 g, 98% yield).

[1103] MS (ESI), m / z, 330.4 [M+H] + .

[1104] Synthesis of compound 52-2

[1105] 52-1 (2.4 g, 7.29 mmol) was dissolved in DMF (10 mL), followed by the addition of KSAc (998 mg, 8.74 mmol). The mixture was heated to 60°C and stirred for 12 h. LCMS indicated complete reaction. The reaction mixture was cooled to room temperature, and 100 mL of ethyl acetate was added. The mixture was then washed with water (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford compound 52-2 as a yellow solid (1.7 g, 100% yield).

[1106] MS (ESI), m / z, 330.4 [M+H] + .

[1107] Synthesis of compound 52-3

[1108] To a solution of compound 52-2 (1.7 g, 7.29 mmol) in MeOH (20 mL) was added potassium carbonate (2.0 g, 14.57 mmol) and stirred at room temperature for 12 h. The mixture was filtered and concentrated, and the crude product was purified by normal phase silica gel column to obtain 52-3 (1.0 g, 72% yield) as a colorless oil.

[1109] 1 H NMR (400MHz, Chloroform-d) δ5.17 (s, 1H), 3.38–3.22 (m, 2H), 2.98 (p, J = 6.7Hz, 1H), 1.30 (d, J = 6.9Hz, 3H).

[1110] Synthesis of compound 52-4

[1111] At room temperature under nitrogen protection, a solution of compound 52-3 (1.0 g) and HCl in dioxane (4.0 M, 5 mL) was stirred for 2 h and concentrated to obtain 0.6 g of the product.

[1112] Synthesis of compound 52-5

[1113] To a mixed solvent of 52-SM2 (6.0 g, 14.47 mmol, 1.0 eq) in DCM (20 mL) and THF (20 mL) was added aqueous ammonia (25% wt, 3.0 g, 21.71 mmol, 1.5 eq) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. LCMS confirmed the reaction was complete. The reaction solution was dried and purified on a silica gel column to afford the product 52-5 as a white solid (3.5 g, 83% yield).

[1114] MS (ESI), m / z, 293.0 [M+H] + .

[1115] Synthesis of compound 52-6

[1116] To a solution of 52-5 (3.5 g, 11.98 mmol, 1.0 eq) in acetic acid (15 mL) and acetic anhydride (50 mL) was added paraformaldehyde (719 mg, 23.97 mmol, 2.0 eq) at room temperature under nitrogen. The reaction mixture was heated to 50°C and stirred for 16 hours. LCMS confirmed the reaction was complete. The reaction solution was spin-dried and slurried with a DCM / MTBE mixed solvent to give product 52-6 as a white solid (2.5 g, 57% yield).

[1117] MS (ESI), m / z, 365.0 [M+H] + .

[1118] Synthesis of compound 52-7

[1119] To a solution of 52-6 (2.0 g, 5.49 mmol, 2.0 eq) and paclitaxel (2.35 g, 2.75 mmol, 1.0 eq) in anhydrous tetrahydrofuran (40 mL) was added dropwise tert-butyl lithium (1.0 M, 5.49 mL, 2.0 eq) at -78°C under nitrogen. The mixture was stirred at -78°C for 0.5 h. LCMS confirmed the reaction was complete. The mixture was quenched with saturated aqueous ammonium chloride, extracted with EA, and purified on a silica gel column to afford 52-7 as a white solid (2.0 g, 63% yield).

[1120] MS (ESI), m / z, 1158.0 [M+H] + .

[1121] Synthesis of compound 52-8

[1122] To a solution of 52-7 (400 mg, 0.345 mmol, 1.0 eq) in methanol (15 mL) was added 52-4 (44 mg, 0.345 mmol, 1.0 eq) at room temperature under nitrogen. The mixture was stirred for 2 hours. LCMS confirmed the reaction was complete. The reaction solution was dried and purified on a C18 column (TFA) to afford 52-8 as a white solid (200 mg, 51% yield).

[1123] MS (ESI), m / z, 1138.0 [M+H] + .

[1124] Synthesis of compound 52

[1125] To a solution of 43-6 (730 mg, 0.32 mmol) and 52-8 (570 mg, 0.50 mmol) in DMF (10 mL) at room temperature and under nitrogen protection were added PyBOP (312 mg, 0.60 mmol) and NMM (150 mg, 1.48 mmol), and the reaction was stirred for 12 h. MTBE (50 mL) was added and stirred for 30 minutes. The supernatant was decanted, and the residue was dried and dissolved in methanol (60 mL) and water (40 mL). It was purified by ultrafiltration (30K MW) (methanol and water as the ultrafiltrate), and the ultrafiltrate was lyophilized to give 850 mg of a white solid with an HPLC purity of 98.9% and a PTX coupling amount of 17.9%.

[1126] Example 90: Synthesis of Compound 53

[1127] Synthesis of compound 53-1

[1128] To a solution of H-Lys(Me)2-OH·HCl (2.0 g, 9.52 mmol) in DMF (10 mL) were added 53-SM (4.2 g, 9.52 mmol) and DIPEA (3.7 g, 28.57 mmol) at room temperature under nitrogen protection. The reaction was stirred for 12 h, quenched with water, extracted with dichloromethane, concentrated, and purified by column chromatography (dichloromethane and methanol) to give 3.5 g of a white solid.

[1129] MS (ESI), m / z, 496.2 [M+H] + .

[1130] Synthesis of compound 53-2

[1131] To a solution of 16a-2 (1.5 g, 1.6 mmol, 1.0 eq) and 53-1 (950 mg, 1.91 mmol, 1.2 eq) in dry DMF (10 mL) in an ice-water bath at 5°C under nitrogen was added EDCI (460 mg, 1.39 mmol, 1.5 eq), HOBt (323 mg, 2.39 mmol, 1.5 eq), and DIPEA (411 mg, 3.19 mmol, 2.0 eq). The mixture was stirred for 2 h. The reaction was quenched with water and extracted with dichloromethane. The organic phase was dried, concentrated, and purified by column chromatography (SiO2, 0-10% MeOH in CHCl2) to afford 53-2, 1.5 g, in a 66% yield.

[1132] MS (ESI), m / z, 1417.0 [M+H] + .

[1133] Synthesis of compound 53-3

[1134] At room temperature and under nitrogen protection, diethylamine (3 mL) was added to a dry CH2Cl2 solution (10 mL) of 53-2 (1.2 g), and the reaction was stirred for 2 h. The mixture was concentrated and purified by Pre-HPLC (CH3CN / H2O, 0.05% TFA) to give the product 53-3, 900 mg, as a white solid, in a yield of 89%.

[1135] MS (ESI), m / z, 1195.0 [M+H] + .

[1136] Synthesis of compound 53

[1137] At room temperature and under nitrogen protection, PyBOP (312 mg, 0.60 mmol) and NMM (150 mg, 1.48 mmol) were added to a solution of 43-6 (730 mg, 0.32 mmol) and 53-3 (600 mg, 0.50 mmol) in DMF (10 mL) and stirred for 12 h. MTBE (50 mL) was added and stirred for 30 minutes. The supernatant was decanted and the residue was dried and dissolved in methanol (60 mL) and water (40 mL). It was purified by ultrafiltration (30K MW) (methanol and water as the ultrafiltrate). The ultrafiltrate was lyophilized to give 890 mg of a white solid with an HPLC purity of 99.2% and a PTX coupling amount of 19.9%.

[1138] Example 91: Synthesis of Compound 54

[1139] Synthesis of compound 54-1

[1140] Under nitrogen protection and an ice bath, HATU (6.6 g, 17.4 mmol, 1.5 eq) and DIPEA (4.5 g, 34.9 mmol, 3.0 eq) were added to a solution of 54-SM (2.0 g, 11.6 mmol, 1.0 eq) and N-Boc-ethylenediamine (2.2 g, 14.0 mmol, 1.2 eq) in anhydrous DMF (20 mL). The reaction was returned to room temperature and stirred for 12 h. The reaction was quenched with water and extracted with dichloromethane. The organic phase was washed with salt, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (dichloromethane and methanol system) to give 2.9 g of the product in a yield of 79%.

[1141] MS (ESI), m / z, 315.2 [M+H] + .

[1142] Synthesis of compound 54-2

[1143] To a solution of 54-1 (2.0 g) in ethanol (20 mL) was added 4.0 M NaOH (20 mL), and the reaction was stirred at room temperature for 12 h. The mixture was cooled in an ice-water bath, neutralized with dilute hydrochloric acid, and extracted with dichloromethane. The organic phases were combined, washed with salt, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product, which was used directly in the next reaction.

[1144] MS (ESI), m / z, 287.2 [M+H] + .

[1145] Synthesis of compound 54-3

[1146] At room temperature and under nitrogen protection, HATU (4.0 g, 10.49 mmol, 1.5 eq) and DIPEA (2.7 g, 21.0 mmol, 3.0 eq) were added to a solution of 54-2 (2.0 g, 7.0 mmol, 1.0 eq) and H-Lys(Me)2-OH·HCl (1.8 g, 8.4 mmol, 1.2 eq) in DMF (50 mL). The reaction was stirred for 12 h, quenched with water, extracted with dichloromethane, concentrated, and purified by column chromatography (dichloromethane and methanol) to give 2.3 g of a white solid.

[1147] MS (ESI), m / z, 443.2 [M+H] + .

[1148] Synthesis of compound 54-4

[1149] To a dichloromethane solution (20 mL) of 54-3 (2.0 g) was added TFA (7 mL), and the mixture was stirred at room temperature for 4 h. The mixture was cooled in an ice-water bath and concentrated to obtain a crude product, which was used directly in the next reaction.

[1150] MS (ESI), m / z, 343.0 [M+H] + .

[1151] Synthesis of compound 54-5

[1152] To a THF solution (40 mL) of 54-4 (crude product) was added Fmoc-OSu (1.8 g, 1.2 eq) and DIPEA (1.7 g, 3.0 eq), and the reaction was stirred at room temperature for 4 h. The reaction was quenched with water and extracted with dichloromethane. The organic phase was directly concentrated and purified by column chromatography (dichloromethane and methanol) to give 1.9 g of a white solid.

[1153] MS (ESI), m / z, 565.0 [M+H] + .

[1154] Synthesis of compound 54-6

[1155] To a solution of 16a-2 (2.0 g, 2.1 mmol, 1.0 eq) and 54-5 (1.4 g, 2.6 mmol, 1.2 eq) in dry DMF (30 mL) was added EDCI (610 mg, 3.2 mmol, 1.5 eq), HOBt (431 mg, 3.2 mmol, 1.5 eq), and DIPEA (824 mg, 6.4 mmol, 3.0 eq) in an ice-water bath at 5°C under nitrogen. The mixture was stirred for 2 h. The reaction was quenched with water and extracted with dichloromethane. The organic phase was dried, concentrated, and purified by column chromatography (SiO2, 0-10% MeOH in CHCl2) to afford 54-6, 2.4 g, in a 76% yield.

[1156] MS (ESI), m / z, 1486.2 [M+H] + .

[1157] Synthesis of compound 54-7

[1158] At room temperature and nitrogen protection, diethylamine (3 mL) was added to a dry CH2Cl2 solution (10 mL) of 53-6 (1.2 g), and the reaction was stirred for 2 h. The mixture was concentrated and purified by Pre-HPLC (CH3CN / H2O, 0.05% TFA) to give the product 54-7, 850 mg, as a white solid, in a yield of 83%.

[1159] MS (ESI), m / z, 1264.0 [M+H] + .

[1160] Synthesis of compound 54

[1161] To a solution of 43-6 (730 mg, 0.32 mmol) and 54-7 (632 mg, 0.50 mmol) in DMF (10 mL) at room temperature and under nitrogen protection were added PyBOP (312 mg, 0.60 mmol) and NMM (150 mg, 1.48 mmol), and the reaction was stirred for 12 h. MTBE (50 mL) was added and stirred for 30 min. The supernatant was decanted, and the residue was dried and dissolved in methanol (60 mL) and water (40 mL). It was purified by ultrafiltration (30K MW) (methanol and water were ultrafiltrate), and the ultrafiltrate was lyophilized to give 1.1 g of a white solid with an HPLC purity of 98.6% and a PTX coupling amount of 18.3%.

[1162] Example 92: Synthesis of Compound 55

[1163] Synthesis of compound 55-1

[1164] To a solution of 42-2 (900 mg, 0.16 mmol) in methanol (25 mL) was added a solution of PEG-1K-NHS (prepared according to the synthesis method of compound 10104-1k in patent WO2023078464A1) (2.8 g, 2.64 mmol) in acetonitrile (25 mL), followed by the addition of DIPEA (1.4 g, 10.8 mmol). The reaction was stirred at room temperature for 30 min, the reaction solution was purified by ultrafiltration, and the ultrafiltrate was freeze-dried to obtain 2.5 g of a white solid with a GPC purity of 99%.

[1165] Synthesis of compound 55-2

[1166] A mixed solution of 55-1 (1.5 g), TFA (4 mL) and DCM (10 mL) was stirred at room temperature for 20 h. The reaction solution was slowly precipitated into MTBE (100 mL), filtered, and dried in vacuo to obtain 1.1 g of a white solid.

[1167] Synthesis of compound 55-3

[1168] To a solution of 55-2 (0.56 g, 0.42 mmol) in ethyl acetate (8 mL) was added succinic anhydride (63 mg, 0.63 mmol), followed by DIPEA (326 mg, 2.52 mmol). The reaction was stirred at room temperature for 12 h. The reaction solution was slowly added dropwise to MTBE (80 mL). A large amount of solid precipitated, which was filtered. The filter cake was washed twice with MTBE and the solid was dried in vacuo to obtain 450 mg of a white solid.

[1169] Synthesis of compound 55

[1170] To a solution of 55-3 (450 mg, 0.33 mmol), 2-SM (525 mg, 0.57 mmol), HOBt (89 mg, 0.66 mmol) and PyBOP (342 mg, 0.66 mmol) in DMF (10 mL) was added NMM (150 mg, 1.48 mmol). The mixture was stirred at room temperature for 24 h. The reaction solution was slowly added dropwise to MTBE (100 mL), and a large amount of solid precipitated. The solid was collected and dissolved in methanol (40 mL) and water (40 mL). Purified by ultrafiltration, the ultrafiltrate was lyophilized to give 520 mg of a white solid with HPLC purity of 99.3% and an SN38 coupling amount of 16.8%.

[1171] Example 93: Synthesis of Compound 56

[1172] Synthesis of compound 56-1

[1173] To 42-2 (500 mg, 1.3 mmol), NCA (4.3 g, 37.4 mmol), benzoic acid (815 mg, 6.7 mmol) and DCM (20 mL) was added DIPEA (430 mg, 3.4 mmol), and the reaction was stirred at room temperature for 2 h. Acetic anhydride (272 mg, 2.7 mmol) and DIPEA (860 mg, 6.7 mmol) were added, and nitrogen was replaced three times and protected. The reaction was stirred at room temperature for 16 h, and the mixture was slowly added dropwise to MTBE (100 mL). A solid precipitated, which was filtered and dried in vacuo to obtain 1.1 g of a white solid with a degree of polymerization of 28 and a GPC purity of >99%.

[1174] Synthesis of compound 56-2

[1175] A mixed solution of 56-1 (1.1 g), TFA (3 mL) and DCM (8 mL) was stirred at room temperature for 12 h. The reaction solution was slowly precipitated into MTBE (90 mL). A large amount of solid precipitated, which was filtered and dried in vacuo to obtain 0.9 g of a white solid.

[1176] Synthesis of compound 56-3

[1177] To a solution of 56-2 (0.9 g, 0.4 mmol) in DMF (8 mL) was added succinic anhydride (80 mg, 0.8 mmol), followed by DIPEA (650 mg, 5.0 mmol). The reaction was stirred at room temperature for 12 h. The reaction solution was slowly added dropwise to MTBE (100 mL). A solid precipitated and was filtered. The filter cake was dried in vacuo to obtain 750 mg of a white solid.

[1178] Synthesis of compound 56

[1179] To a solution of 56-3 (700 mg, 0.3 mmol), 2-SM (500 mg, 0.5 mmol), HOBt (80 mg, 0.6 mmol) and PyBOP (310 mg, 6 mmol) in DMF (8 mL) was added NMM (150 mg, 1.48 mmol). The reaction was stirred at room temperature for 16 h. The reaction solution was slowly added dropwise to MTBE (70 mL), and a solid precipitated. The solid was collected and dissolved in methanol (40 mL) and water (40 mL). Purified by ultrafiltration, the ultrafiltrate was lyophilized to give 590 mg of a white solid with HPLC purity of 98.9% and an SN38 coupling amount of 10.6%.

[1180] Example 94: Synthesis of Compound 57

[1181] Synthesis of compound 57-1

[1182] Dissolve tert-butyl 2-(2-(2-aminoethoxy)ethoxy)ethylcarbamate in DMF to prepare a 50 mg / mL solution. Dissolve tert-butyric acid in the above solution to prepare a 114.8 mg / mL solution. Dissolve 2.0 g of 57-SM (synthesized according to the method described in J. Am. Chem. Soc. 2021, 143, 10, 3697–3702) in 15 mL of DCM. Add 1 mL of the above DMF solution and stir at room temperature. GPC was used to control the polymerization degree, which was approximately 30. MTBE was added and the mixture was centrifuged and dried to obtain 1.5 g of the compound.

[1183] Synthesis of compound 57-2

[1184] To a solution of 57-1 (1.5 g) in acetic acid (10 mL) and methanol (10 mL) was added 10% Pd / C (0.2 g). The atmosphere was replaced with hydrogen and heated at 50°C for 12 h. The solution was concentrated, precipitated with MTBE, filtered, and dried to yield 1.0 g. NMR analysis revealed the absence of aromatic peaks, indicating a complete reaction.

[1185] Synthesis of compound 57-3

[1186] To a DMF solution of 57-2 (100 mg, 0.02 mmol, 1.0 eq) (10 mL) were added 57-SM2 (2.48 g, 1.10 mmol, 45.0 eq) (synthesized according to the example method in patent WO2020102852A1), PyBOP (570 mg, 1.10 mmol, 45.0 eq), and DIPEA (280 mg, 2.20 mmol, 90.0 eq), and stirred at room temperature overnight. The mixture was concentrated, dissolved in methanol and water, and purified by ultrafiltration (30K MW) using a methanol and water system. The concentrate was collected, concentrated, and lyophilized to obtain 1.2 g of the product.

[1187] Synthesis of compound 57-4

[1188] 57-3 (1.0 g) was dissolved in 10 mL of dichloromethane, and 10 mL of TFA was added. The mixture was stirred overnight. The reaction solution was concentrated directly, dissolved in dichloromethane, and reconcentrated. This was repeated three times to obtain 1.0 g of a crude mixture, which was used directly in the next step.

[1189] Synthesis of compound 57-5

[1190] The crude product of 57-4 (1.0 g) was dissolved in 10 mL of DMF, and succinic anhydride (100 mg) and DIPEA (0.2 mL) were added. The solution was alkaline as detected by pH paper. The product was stirred at room temperature overnight, concentrated, dissolved in methanol and water, and purified by ultrafiltration using a methanol and water system (30K MW). The concentrate was collected and lyophilized to obtain 0.8 g of the product.

[1191] Synthesis of compound 57

[1192] To a 10 mL DMF solution of 57-5 (800 mg, 0.01 mmol, 1.0 eq) were added 2-SM (0.5 g, 0.49 mmol, 45.0 eq), PyBOP (256 mg, 0.49 mmol, 45.0 eq), and DIPEA (180 mg, 1.40 mmol, 128.0 eq). The mixture was stirred at room temperature overnight. The mixture was concentrated, dissolved in methanol and water, and purified by ultrafiltration using a methanol-water system (30K MW). The concentrate was collected, concentrated, and lyophilized to give 0.9 g of the product with a purity of 99% and an SN38 coupling content of 11.2%.

[1193] Examples 95-118: Synthesis of Compounds 58-81

[1194] Referring to the synthesis method of Examples 79-80, synthesis was performed according to different polymer backbones:

[1195] Example 119: Synthesis of Compound 82

[1196] Synthesis of compound 82-2

[1197] The starting material 82-1 was synthesized according to the synthesis method of Example 1 using the Fmoc solid-phase synthesis method. The resin used for solid-phase synthesis was MBHA resin (25 g, Loading = 0.65 mmol / g). After removal of the Fmoc protecting group, solid-phase synthesis was performed. The starting material was Boc-D-Lys(Fmoc)-OH (1.5 eq), the coupling reagents were PyBOP (1.5 eq) and NMM (1.5 eq), the solvent was DMF, the Fmoc removal reagent was 20% piperidine / DMF solution, and the resin removal reagent was TFA / water / triisopropylsilane 95 / 2.5 / 2.5.

[1198] 82-1 (4.8 g, 29.1 mmol, molar number of structural units) was suspended in 100 g of DMSO, and triethylamine (8.9 g, 87.3 mmol) and Boc-Lys(Z)-ONP (23.0 g, 46.6 mmol) were added. The mixture was stirred at 30°C under nitrogen for 13 h, and the reaction was complete. The reaction solution was placed in a beaker, 800 ml of ACN was added, and the mixture was filtered. The filter cake was washed sequentially with acetonitrile, water, and acetonitrile, and dried in vacuo to obtain 11.5 g of product 82-2 as a white solid.

[1199] Synthesis of compound 82-3

[1200] 82-2 (5.0 g) was dissolved in 50 ml of acetic acid and 50 ml of methanol, heated to dissolve, and 1.2 g of palladium on carbon (10%) was added to displace the hydrogen atmosphere. The mixture was stirred at 40°C for 24 h. Celite was added, the mixture was filtered, and the filtrate was concentrated by rotary evaporation. Methyl tert-butyl ether was precipitated and dried in vacuo to obtain the product 82-3 as a white powder.

[1201] Synthesis of compound 82-4

[1202] To an aqueous solution (20 mL) of 82-3 (4.00 g) was added an acetonitrile solution (25 mL) of PEG-2K-NHS (6.8 g) and 2.2 mL of DIPEA. The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The mixture was extracted with dichloromethane and dried over anhydrous sodium sulfate to give the product 82-4 (9.8 g).

[1203] Synthesis of compound 82-5

[1204] 82-4 (8.0 g) was dissolved in 50 mL of dichloromethane, and 22 mL of TFA was added under nitrogen protection. The mixture was stirred at room temperature overnight and concentrated under reduced pressure to obtain compound 82-5 (6.8 g).

[1205] Synthesis of compound 82-6

[1206] To a DMF solution (21 mL) of 82-5 (6.2 g) was added DIPEA (4.0 mL) and succinic anhydride (1.3 g), and the mixture was stirred at room temperature for 12 h. The product was precipitated with methyl tert-butyl ether, filtered, and the filter cake was dried under vacuum to obtain the product 82-6 (6.0 g).

[1207] Synthesis of compound 82

[1208] To a solution of 82-6 (500 mg, 0.01 mmol, 1.0 eq) and 2-SM (280 mg, 0.31 mmol, 45.0 eq) in DMF (10 mL) were added DIPEA (113 mg, 0.87 mmol, 128.0 eq) and PyBOP (228 mg, 0.44 mmol, 64.0 eq), respectively, at room temperature (25°C) under nitrogen. The reaction mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated, methyl tert-butyl ether was added, and stirred for 10 minutes. The supernatant was removed, and the residue was purified by ultrafiltration using a methanol-water system (30K MW). The concentrate was collected, concentrated, and lyophilized to afford compound 82 as a white solid, 0.6 g, in 86% yield, with 99% HPLC purity and 11.8% SN38 coupling.

[1209] Example 120: Synthesis of Compound 83

[1210] Synthesis of compound 83

[1211] To a solution of 82-6 (250 mg, 0.003 mmol, 1.0 eq) in dry DMF (5 mL) was added a solution of 16a-4 (196 mg, 0.16 mmol, 48.0 eq) in dry DMF (2 mL, sonicated), PyBOP (142 mg, 0.27 mmol, 80.0 eq), and DIPEA (56 mg, 0.44 mmol, 128.0 eq) at room temperature (25°C) under nitrogen. The reaction mixture was then heated to 28°C for 12 h, concentrated, filtered into methanol and water (1 / 1, 100 mL), purified by ultrafiltration (30K MW), and lyophilized to afford product 83 (360 mg, 99% purity, with a PTX content of approximately 23.6%).

[1212] Example 121: Synthesis of Compound 84

[1213] Synthesis of compound 84

[1214] To a solution of 82-6 (1220 mg, 0.516 mmol, 1.0 eq, based on polymer unit) in DMF (20 mL) was added 33a-3 (800 mg, 0.774 mmol, 1.5 eq), PyBOP (403 mg, 0.774 mmol, 1.5 eq), and DIPEA (266 mg, 2.06 mmol, 4 eq) at room temperature under nitrogen. The mixture was stirred at 20°C for 12 h. The reaction solution was concentrated, and 50 mL of MTBE was added and stirred for 10 minutes. The supernatant was discarded, and the residue was dissolved in methanol and water, ultrafiltered (30K MW), concentrated, and lyophilized to obtain compound 84 as a white solid (1.4 g) with a purity of 98.6% and a paclitaxel content of 24.7%.

[1215] Example 122: Synthesis of Compound 85

[1216] Synthesis of compound 85

[1217] To a solution of 42-5 (778 mg, 0.33 mmol) and 29-3 (580 mg, 0.57 mmol) in DMF (8 mL) were added HOBt (89 mg, 0.66 mmol), PyBOP (342 mg, 0.66 mmol) and NMM (150 mg, 1.48 mmol) at room temperature under nitrogen protection. The reaction was stirred at room temperature for 12 h. MTBE (50 mL) was added and stirred for 30 minutes. The supernatant was decanted, the residue was dried, dissolved in methanol (40 mL) and water (40 mL), and purified by ultrafiltration (30K MW) (methanol and water as ultrafiltrate). The ultrafiltrate was lyophilized to give 520 mg of a light yellow solid with an HPLC purity of 99.7% and a PTX coupling amount of 21.3%.

[1218] Example 123: Synthesis of Compound 86

[1219] Synthesis of compound 86

[1220] To a solution of 43-6 (700 mg, 0.32 mmol) and 29-3 (490 mg, 0.48 mmol) in DMF (10 mL) at room temperature and under nitrogen protection were added PyBOP (312 mg, 0.60 mmol) and DIPEA (190 mg, 1.48 mmol), and the reaction was stirred for 24 h. MTBE (50 mL) was added and stirred for 30 min. The supernatant was decanted, and the residue was dried and dissolved in methanol (60 mL) and water (40 mL). It was purified by ultrafiltration (30K MW) (methanol and water as the ultrafiltrate), and the ultrafiltrate was lyophilized to give 690 mg of a white solid with an HPLC purity of 98.8% and a PTX coupling amount of 22.6%.

[1221] Example 124: Synthesis of Compound 87

[1222] Synthesis of compound 87-1

[1223] Under nitrogen protection, DIPEA (3.7 g, 28.7 mmol) and DMSO (40 mL) were added to a solution of poly-L-lysine hydrobromide (2 g, 9.56 mmol) in water (3 mL), followed by the addition of 10102-R (synthesized according to the method of 10102 based on D-amino acid starting materials; 7.2 g, 14.35 mmol). The reaction was stirred at room temperature for 24 h, and acetonitrile (100 mL) was added for precipitation and filtered. The filter cake was collected to obtain 5.2 g of the product as a white solid.

[1224] Synthesis of compound 87-2

[1225] A mixture of 87-1 (5.2 g, 11.0 mmol) and acetic acid (55 mL) was heated and dissolved, methanol (55 mL) and 10% palladium carbon (927 mg) were added, and hydrogen was replaced three times. The reaction was stirred for 16 h, filtered through celite, and MTBE was added to the filtrate for slurrying. The solid was filtered and vacuum dried to obtain 1.6 g of a white solid.

[1226] Synthesis of compound 87-3

[1227] To a solution of 87-2 (900 mg, 0.16 mmol) in methanol (25 mL) was added a solution of PEG-2K-NHS (5.6 g, 2.64 mmol) in acetonitrile (25 mL), followed by addition of DIPEA (1.4 g, 10.8 mmol). The reaction was stirred at room temperature for 30 min. The reaction solution was purified by ultrafiltration, and the ultrafiltrate was lyophilized to obtain 4.6 g of a white solid with a GPC purity of 99%.

[1228] Synthesis of compound 87-4

[1229] A mixed solution of 87-3 (1.0 g, 0.42 mmol), TFA (3 mL) and DCM (7 mL) was stirred at room temperature for 16 h. The reaction solution was slowly precipitated into MTBE (90 mL). A large amount of solid precipitated, which was filtered and dried in vacuo to obtain 1.05 g of a white solid.

[1230] Synthesis of compound 87-5

[1231] To a solution of 87-4 (1 g, 0.42 mmol) in DMF (8 mL) was added succinic anhydride (63 mg, 0.63 mmol) and then DIPEA (326 mg, 2.52 mmol). The reaction was stirred at room temperature for 16 h. The reaction solution was slowly added dropwise to MTBE (90 mL). A large amount of solid precipitated and was filtered. The filter cake was washed twice with MTBE and the solid was dried in vacuo to obtain 810 mg of a white solid.

[1232] Synthesis of compound 87

[1233] To a solution of 87-5 (770 mg, 0.32 mmol), 2-SM (525 mg, 0.57 mmol), HOBt (89 mg, 0.66 mmol) and PyBOP (342 mg, 0.66 mmol) in DMF (8 mL) was added NMM (150 mg, 1.48 mmol). The mixture was stirred at room temperature for 16 h. The reaction solution was slowly added dropwise to MTBE (80 mL), and a large amount of solid precipitated. The solid was collected and dissolved in methanol (40 mL) and water (40 mL). The product was purified by ultrafiltration, and the ultrafiltrate was lyophilized to give 832 mg of a white solid with an HPLC purity of 99.2% and an SN38 coupling amount of 12.21%.

[1234] Example 125: Synthesis of Compound 88

[1235] Synthesis of compound 88-1

[1236] To a solution of 42-4 (1 g, 0.42 mmol) in DMF (8 mL) was added diglycolic anhydride (73 mg, 0.63 mmol), followed by DIPEA (326 mg, 2.52 mmol). The reaction was stirred at room temperature for 24 h. The reaction solution was slowly added dropwise to MTBE (90 mL). A large amount of solid precipitated, which was filtered. The filter cake was washed twice with MTBE and the solid was dried in vacuo to obtain 823 mg of a white solid.

[1237] Synthesis of compound 88

[1238] To a solution of 87-5 (760 mg, 0.32 mmol), 2-SM (525 mg, 0.57 mmol), HOBt (89 mg, 0.66 mmol) and PyBOP (342 mg, 0.66 mmol) in DMF (8 mL) was added NMM (150 mg, 1.48 mmol). The mixture was stirred at room temperature for 16 h. The reaction solution was slowly added dropwise to MTBE (80 mL), and a large amount of solid precipitated. The solid was collected and dissolved in methanol (40 mL) and water (40 mL). The product was purified by ultrafiltration, and the ultrafiltrate was lyophilized to give 795 mg of a white solid with an HPLC purity of 97.9% and an SN38 coupling amount of 11.90%.

[1239] Biological Evaluation Example 1: Study on Nanoparticle Size of the Compounds of the Invention

[1240] Sample Preparation: Transfer the required volume of purified water or water for injection to a glass bottle and filter through a 0.22 μm filter. Weigh an appropriate amount of sample and dissolve it in 0.5 mL of the aforementioned water for injection. Filter through a 0.22 μm aqueous filter. Place in a 10 mL volumetric flask and dilute to volume with diluent (final compound concentration 10 mg / mL). Shake gently to avoid bubbles and set aside.

[1241] Sample testing: Slowly transfer the sample solution to a cuvette using a dropper for testing. The testing instrument is a Zeta sizer Pro Blue nanoparticle sizer.

[1242] Test results: The nanoparticle size data of the compound of the present invention are shown in Figures 1 to 8 and Table 1.

[1243] Table 1 Nanoparticle size data of the compounds of the present invention

[1244] The results in Table 1 show that the average particle size of the compounds of the present invention is in the range of 10-30 nM, and they are all unimodal (see Figures 1-8) with a narrow particle size dispersion coefficient, indicating that the compounds of the present invention are unimodal small nano-sized particles; while the control example 78 presents a multimodal morphology. It can be seen from Figure 9 that the multimodal position is at a particle size of about 100 nM, indicating that Example 78 is prone to aggregation and produces large-sized particles, resulting in a poor dispersion coefficient.

[1245] Biological Evaluation Example 2: Nanoparticle Size Stability Study of Compound Example 71

[1246] Sample Preparation: Transfer the required volume of purified water or water for injection to a glass bottle and filter through a 0.22 μm filter. Weigh an appropriate amount of sample and dissolve it in 0.5 mL of the aforementioned water for injection. Filter through a 0.22 μm aqueous filter. Place in a 10 mL volumetric flask and dilute to volume with diluent (final compound concentration 10 mg / mL). Shake gently to avoid bubbles and set aside.

[1247] Sample testing: After the test time arrives, samples are taken and slowly transferred to a cuvette using a dropper for testing. The testing instrument is a nanometer particle sizer 0 - Zeta sizer Pro Blue.

[1248] Test results: The research data on particle size stability of Example 71 of the present invention are shown in Table 2 and Figures 10-13.

[1249] Table 2 Particle size stability study of Example 71 of the present invention

[1250] The results in Table 2 show that the particle size of the compound of the present invention (Compound of Example 71) is very stable and does not change significantly whether it is kept refrigerated at 2-8°C or stored at room temperature at 25°C, and it always maintains a single distribution of small nano-sized particles (see Figures 10-13), indicating that the compound of Example 71 will not aggregate during long-term storage and its physicochemical properties are very stable.

[1251] Biological Evaluation Example 3: Pharmacodynamic Study of Compounds Example 20, Example 52, and Abraxane in the BxPC-3 Mouse Model

[1252] Experimental animals and inoculation methods

[1253] Female BALB / c nude mice, 4-5 weeks old, weighing 18-20 g, were housed in the experimental environment for one week. BxPC-3 tumors were subcutaneously inoculated on the right back of the nude mice. The tumors grew to an average volume of 150 mm. 3 The mice were divided into groups and dosed at 4 ℃ and 8 ℃, with 6 mice in each group.

[1254] Preparation of test samples

[1255] Weigh an appropriate amount of the compound, add a certain volume of normal saline, dissolve it by ultrasonic treatment, filter it through a 0.2 μM filter membrane, and reserve it for use.

[1256] Administration of the test drug

[1257] The administration dose and administration regimen are shown in Table 3. The tumor volume under the skin of nude mice was measured 2-3 times a week (the calculation formula for tumor volume is: V = 0.5a × b 2 , where a and b represent the major axis and minor axis of the tumor respectively), the body weight of the mice was weighed, and the data were recorded.

[1258] Table 3

[1259] Note: The administration volume is 10 mg / mL.

[1260] Analysis and evaluation

[1261] Experimental evaluation index: The tumor growth inhibition rate TGI (%) or relative tumor proliferation rate T / C (%) was used for evaluation, where T is the experimental group and C is the control group.

[1262] Calculation of relative tumor proliferation rate T / C (%): If T > T0, T / C (%) = (T - T0) / (C - C0) × 100%; if T < T0, T / C (%) = (T - T0) / T0 × 100%, where T and C are the tumor volumes at the end of the experiment; T0 and C0 are the tumor volumes at the start of the experiment.

[1263] Calculation of tumor growth inhibition rate TGI (%): TGI (%) = (1 - T / C) × 100%.

[1264] Evaluation criteria: T / C (%) > 40 (i.e., TGI (%) < 60%) is ineffective; T / C (%) ≤ 40 (i.e., TGI (%) ≥ 60%) is effective, and after statistical processing, P < 0.05 is considered effective.

[1265] Results of the pharmacodynamic experiment

[1266] The inhibitory effects of Compound Example 20, Example 52 and Abraxane on the BxPC-3 tumor model are shown in Figure 14.

[1267] As shown in Figure 14 of the experimental results, after intravenous injection once a week for a total of 1 time and observing for 28 days, the tumor inhibition rates of Example 20 and 52 at a dose of 30 mg / kg reached 90.3 and 88.56% respectively, showing significant differences compared with the blank control, and significantly superior to the pharmacodynamic effect of the positive control albumin-bound paclitaxel (tumor inhibition rate was 44.95%), indicating that the compounds of the present invention have high permeability and excellent therapeutic effects on refractory tumors caused by high dense matrix barriers.

[1268] Biological evaluation Example 4: Pharmacodynamic study of Compound Example 71 and Example 78 on HepG2 model

[1269] Experimental animals and inoculation method

[1270] BALB / c nude mice, female, 4 - 5 weeks old, weighing 20 - 25 g. After arrival, they were raised in the experimental environment for one week. HepG2 tumor masses were subcutaneously inoculated on the right back of the nude mice, and grouping and drug administration were started when the tumor growth reached ~170 mm 3 with 6 mice in each group.

[1271] Preparation of test samples

[1272] Weigh an appropriate amount of the compound, add a certain volume of normal saline, dissolve it by shaking, filter it through a 0.2 μM filter membrane, and set aside for use.

[1273] Administration of test drugs

[1274] The dosing dose and dosing regimen are shown in Table 4. The subcutaneous tumor volume of the nude mice was measured 2 - 3 times a week (the formula for calculating the tumor volume is: V = 0.5a × b 2 , where a and b represent the major and minor axes of the tumor respectively), the body weight of the mice was weighed, and the data were recorded.

[1275] Table 4 Note: The dosing volume is 10 mg / mL.

[1276] Analysis and evaluation

[1277] Experimental evaluation index: The tumor growth inhibition rate TGI (%) or relative tumor proliferation rate T / C (%) was used for evaluation, where T is the experimental group and C is the control group.

[1278] Calculation of relative tumor proliferation rate T / C (%): If T > T0, T / C (%) = (T - T0) / (C - C0) × 100%; if T < T0, T / C (%) = (T - T0) / T0 × 100%, where T and C are the tumor volumes at the end of the experiment; T0 and C0 are the tumor volumes at the start of the experiment.

[1279] Calculation of tumor growth inhibition rate TGI (%): TGI (%) = (l - T / C) × 100%.

[1280] Evaluation criteria: T / C (%) > 40 (i.e., TGI (%) < 60%) is ineffective; T / C (%) ≤ 40 (i.e., TGI (%) ≥ 60%) is effective, and after statistical processing, P < 0.05 is considered effective.

[1281] Results of pharmacodynamic experiments

[1282] The inhibitory effects of compounds Example 71 and Example 78 on the HepG2 tumor model are shown in FIG15 .

[1283] The experimental results are shown in Figure 15. After intravenous administration once weekly for a total of one dose, the tumor inhibition rates of Examples 71 and 78 at a dose of 10 mg / kg reached 99.89% and 81.41%, respectively, after 29 days of observation. Compound Example 71 of the present invention exhibited a very strong inhibitory effect on tumor growth in a HepG2 cell nude mouse model, achieving complete tumor regression, significantly outperforming Control Example 78. This demonstrates that the stable, small nano-sized compounds of the present invention exhibit significantly better tumor tissue permeability and tumor inhibition than the unstable Control Example 78, which is prone to aggregation into large nanoparticles.

[1284] Biological Evaluation Example 5: Pharmacodynamic Study of Compound Example 71 and Irinotecan Hydrochloride on Human Colon Cancer HT-29 Nude Mouse Tumor Model

[1285] Experimental animals and inoculation methods

[1286] Female BALB / c nude mice, 4-5 weeks old, weighing 20-25 g, were housed in the experimental environment for one week upon arrival. A 3*3 mm HT-29 tumor mass was subcutaneously inoculated into the right anterior scapula to establish a human colon cancer HT-29 subcutaneous xenograft model. The tumors were grown to an average volume of 900 mm. 3 The mice were randomly divided into two groups according to the tumor size, with 6 mice in each group.

[1287] Preparation of test samples

[1288] Weigh an appropriate amount of compound, dilute with 5% glucose buffer, shake to dissolve, filter with a 0.2 μM filter membrane, and set aside.

[1289] Administration of test drugs

[1290] The dosage and administration schedule are shown in Table 5. The subcutaneous tumor volume of nude mice was measured 2-3 times a week (the calculation formula of tumor volume is: V = 0.5a × b 2 , a and b represent the long diameter and short diameter of the tumor, respectively), weigh the mice, and record the data.

[1291] Table 5 Note: The dosage volume is 10 mg / mL.

[1292] Analysis and Evaluation

[1293] Experimental evaluation index: Tumor growth inhibition rate TGI (%) or relative tumor proliferation rate T / C (%) was used for evaluation, where T was the experimental group and C was the control group.

[1294] Calculation of relative tumor proliferation rate T / C(%): If T>T0, T / C(%)=(T - T0) / (C - C0)×100%; if T<T0, T / C(%)=(T - T0) / T0×100%, where T and C are the tumor volumes at the end of the experiment; T0 and C0 are the tumor volumes at the start of the experiment.

[1295] Calculation of tumor growth inhibition rate TGI(%): TGI(%)=(1 - T / C)×100%.

[1296] Evaluation criteria: T / C(%)>40 (i.e., TGI(%)<60%) is ineffective; T / C(%)≤40 (i.e., TGI(%)≥60%) is effective, and after statistical processing, P<0.05 is considered effective.

[1297] Results of the pharmacodynamic experiment

[1298] The inhibitory effects of compound example 71 and irinotecan hydrochloride on the human colon cancer HT - 29 nude mouse tumor model are shown in Figure 16.

[1299] As shown in Figure 16, the experiment results show that after intravenous injection once a week for a total of 3 times and observing until day 34, the average tumor size in the irinotecan hydrochloride group was 4000 mm 3 , while the average tumor size in the example 71 group was 600 mm at day 34 3 and, and it shrank to 100 mm by day 79 3 , significantly better than the irinotecan group. It shows that compound example 71 of the present invention can have a very significant inhibitory effect on large tumors in the human colon cancer HT - 29 nude mouse model, while the irinotecan hydrochloride control group has no obvious effect. ...

Claims

1. A stable polymer-drug conjugate having a controllable number of group couplings and a controllable nanometer size as shown in formula (I) The polymer-drug conjugate comprises: (1) A polymer residue, as shown in formula (II), wherein the number of repeating units of the polymer main body is n, The value of n is selected from an integer from 4 to 100; (2) Y is a branching center with at least three functionalities; (3) P is the pharmacokinetic modulator residue; (4) D is a pharmaceutically active agent residue, and D can be one or more drug residues; (5) X is a terminal group; (6)L 0 , L 1 , L 2 Each is independently a covalent bond or a C1-C 40 A heteroatom-containing or heteroatom-free linker, wherein The heteroatom is O, S, Se, N, P, Si or B, and the number of the heteroatom is one or more. When there are multiple heteroatoms, the heteroatoms are the same or different. The linker may contain an unsaturated group or not. The L 0 Connect E and Y, the L 1 Connect P and Y, the L 2 Connect D and Y; (7)Q is H, R a , a hydroxyl protecting group, a thiol protecting group, an amine protecting group or a residue as shown in formula (III): (8) Any hydrogen atom in formula (I) may be replaced by a deuterium atom; (9) Any chiral center in formula (I) may be in R configuration, S configuration, or a mixture of R and S configurations.

2. The polymer-drug conjugate according to claim 1, characterized in that: The nanometer size refers to an average nanometer particle size ranging from 1 to 100 nanometers.

3. The polymer-drug conjugate according to claim 1, characterized in that: The nanometer size is an average nanometer particle size ranging from 1 to 50 nanometers.

4. The polymer-drug conjugate according to claim 1, characterized in that: The nanometer size is an average nanometer particle size ranging from 5 to 30 nanometers.

5. The polymer-drug conjugate according to claim 1, characterized in that: The polymer residue as shown in (II) satisfies one or more of the following conditions: (1) L is independently a covalent bond, or C1-C 10 A linker containing or not containing heteroatoms, wherein the heteroatom is O, S, Se, N, P, Si or B, the number of the heteroatoms is one or more, and when it is multiple, the heteroatoms are the same or different; the linker may contain an unsaturated group or not; the L connects the polymer main chain and E; (2) E is independently a covalent bond, O, S, NR a ,C(=O),S(=O),S(=O)2,C(=O)NR a , or one of the following residues: (3) A is independently a covalent bond, O, S, NR d ; where R d is selected from H, substituted or unsubstituted C1-C 10 Alkyl, or a residue as represented by formula (III): (4) T, U, V, W, Z and K are independently covalent bonds, O, S, NR d ,C(=O),S(=O),S(=O)2, or The condition is: -TUVWZKA- The following connection forms do not exist in the chain:- OO-、-OS-、-SO-、 or (5) The configuration of the chiral carbon atom in the polymer residue as shown in (II) may be R configuration, S configuration, or a mixture of R configuration and S configuration; in, n is an integer selected from 4 to 100; a is selected from 0 or 1; b is selected from 0 or 1; c is selected from 0 or an integer from 1 to 10; d is selected from 0 or 1; e is selected from 0 or 1; R'、R 1a and R 2a Selected from hydrogen, deuterium, C1~C 10 Alkyl, C1~C 10 Alkoxy, C3~C 10 Alkenyl, C3~C 10 Alkynyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C 10 Aryl or C5~C 10 heteroaryl; R z Selected from hydrogen, C1~C 10 Alkyl, C1~C 10 Alkoxy, C3~C 10 Alkenyl, C3~C 10 Alkynyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C 10 Aryl, C5~C 10 Heteroaryl, hydroxyl protecting group or a residue as shown in formula (III): R e and R f Independently selected from hydrogen, deuterium, C1-C 10 Alkyl, C1~C 10 Alkoxy, C3~C 10 Alkenyl, C3~C 10 Alkynyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C 10 Aryl, C5~C 10 Heteroaryl or a residue represented by formula (IV): R a Selected from H, C1~C 10 Alkyl, C1~C 10 Alkoxy, C3~C 10 Alkenyl, C3~C 10 Alkynyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C 10 Aryl, C5~C 10 Heteroaryl or amine protecting groups; R d Selected from H, C1~C 10 Alkyl, C1~C 10 Alkoxy, C3~C 10 Alkenyl, C3~C 10 Alkynyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C 10 Aryl, C5~C 10 Heteroaryl, amine protecting group or residue represented by formula (III): The heteroatom in the C2-C8 heterocycloalkyl is O, S or N, and the number of the heteroatoms is one or more. When there are more than one heteroatoms, the heteroatoms are the same or different. 10 The heteroatom in the heteroaryl group is O, S or N, and the number of the heteroatom is one or more. When there are multiple heteroatoms, the heteroatoms are the same or different.

6. The polymer-drug conjugate according to claim 1, characterized in that: The polymer-drug conjugate meets one or more of the following conditions: (1) The number of repeating units n of the polymer main body is selected from an integer of 5 to 70, preferably an integer of 20 to 40; (2) The branch center Y is a branch center having the following structure, or a multifunctional branch center consisting of two or more branch structures: Among them, Z 0 O, S, S(O), S(O)2, NR a , CHR 0 ; R 0 Selected from H, D, halogen, nitro, cyano, C1~C 10 Alkyl, C1~C 10 Alkoxy, C3~C 10 Alkenyl, C3~C 10 Alkynyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C 10 Aryl, C5~C 10 heteroaryl or a group containing a primary amine, secondary amine, tertiary amine, hydroxyl, thiol, carboxyl, ester, amide, boric acid, boric ester, phosphoric acid, sulfonic acid, sulfoxide, aldehyde, or ketone functional group; the heteroatom in the C2-C8 heterocycloalkyl is O, S, or N, and the number of the heteroatoms is one or more. When there are multiple heteroatoms, the heteroatoms are the same or different; the C5-C 10 The heteroatom in the heteroaryl group is O, S or N, and the number of the heteroatoms is one or more. When there are multiple heteroatoms, the heteroatoms are the same or different; Ar is C6~C 20 Aryl or C5~C 20 Heteroaryl; the C5~C 20 The heteroatom in the heteroaryl group is O, S or N, and the number of the heteroatoms is one or more. When there are multiple heteroatoms, the heteroatoms are the same or different; f is 0 or an integer from 1 to 3; Among them, R a The definition is as stated in claim 1.

7. The polymer-drug conjugate according to claim 1, 5 or 6, characterized in that: The branching center Y is a substituted or unsubstituted amino acid or a derivative thereof having a functionality of at least 3, the amino acid is a natural amino acid or a non-natural amino acid, the configuration of the amino acid is D-type or L-type or a mixture of D / L configurations, and when the amino acid is a mixture of D / L configurations, the L configuration accounts for more than 0% and less than 100%; the branching center Y is preferably an amino acid having a functionality of at least 3, the amino acid is selected from one or more of aspartic acid, glutamic acid, lysine, ornithine, arginine, citrulline, histidine, serine, threonine, tryptophan, tyrosine, hydroxyproline, cystine, cysteine ​​or selenocysteine, the configuration of the amino acid is D-type or L-type or a mixture of D / L configurations, and when the amino acid is a mixture of D / L configurations, the L configuration accounts for more than 0% and less than 100%.

8. The polymer-drug conjugate according to claim 1, characterized in that: The linker L 0 and L 1 Each is independently selected from a covalent bond, an environmentally responsive linker or a non-environmentally responsive linker; L 2 It is an environmentally responsive linker with a structure of L 2a -L 2b , L 2a or L 2b Can exist alone or together; L 2a and L 2b Each is independently selected from a covalent bond, an environmentally responsive linker or a non-environmentally responsive linker; the polymer-drug conjugate structure is shown in formula (V): Among them, X, R', T, U, V, W, Z, K, A, P, L 1 , Y, L 2a , L 2b , D, L 0 , E, L, a, and b are respectively defined as described in claims 1 and 5.

9. The polymer-drug conjugate according to claim 8, characterized in that: The linker L 0 and L 1 is a covalent bond, L 2 It is an environmentally responsive linker with a structure of L 2a -L 2b , where L 2a Connected to Y, L 2b Connected to D, L 2a or L 2b Can exist alone or together; L 2a and L 2b Each is independently selected from a covalent bond, an environmentally responsive linker or a non-environmentally responsive linker; the structure of the polymer-drug conjugate is shown in formula (VI): Among them, X, R', T, U, V, W, Z, K, A, P, Y, L 2a , L 2b , D, E, L, a, and b are respectively defined as described in claims 1 and 5.

10. The polymer-drug conjugate according to claim 1, 5, 8 or 9, characterized in that: The polymer residue is selected from the following structures: Among them, R a1 Selected from H, C1~C 10 Alkyl, C1~C 10 Alkoxy, C3~C 10 Alkenyl, C3~C 10 Alkynyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C 10 Aryl, C5~C 10 Heteroaryl, amine protecting group or residue represented by formula (III): R a2 Selected from H, C1~C 10 Alkyl, C1~C 10 Alkoxy, C3~C 10 Alkenyl, C3~C 10 Alkynyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C 10 Aryl, C5~C 10 Heteroaryl or hydroxy protecting groups; n is an integer selected from 4 to 100; m is an integer selected from 0 to 5; R a , R e , R f The respective definitions are as given in claim 5.

11. The polymer-drug conjugate according to claim 1, 8 or 9, characterized in that: When the electrophilic group of Y molecule 2 When connected, L 2a does not exist, then L 2 =L 2b The trifunctional branch center Y and the linker L 0 , L 1 and L 2b The connection is selected from any of the following structures: Preferably More preferably Alternatively, when the nucleophilic group of Y molecule is 2 When connected, L 2a Alone or L 2a and L 2b coexistence, at this time L 2 =L 2a or L 2 =L 2a -L 2b The trifunctional branch center Y and the linker L 0 , L 1 , L 2a and L 2b The connection is selected from any of the following structures: Preferably Among them, L 0 , L 1 , L 2a , L 2b Respective definitions are as described in claims 1, 8-9.

12. The polymer-drug conjugate according to any one of claims 1, 8 or 9, characterized in that: The terminal group X is selected from OR, SR, NR 1 R 2 , carboxyl protecting group or L 2b -D, R, R 1 , R 2 Independently selected from H, C1~C 30 Alkyl, C1~C 30 Alkoxy, C3~C 30 Alkenyl, C3~C 30 Alkynyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C 20 Aryl or C5~C 20 Heteroaryl; R 1 , R 2 The connected N atom can form a C2-C8 heterocycloalkyl group; the heteroatom in the C2-C8 heterocycloalkyl group is O, S or N, and the number of the heteroatom is one or more. When there are multiple heteroatoms, the heteroatoms are the same or different; the C5-C 20 The heteroatom in the heteroaryl group is O, S or N, and the number of the heteroatoms is one or more. When there are multiple heteroatoms, the heteroatoms are the same or different; the terminal group X is preferably OR, SR, NR 1 R 2 , carboxyl protecting group or L 2b -D, R, R 1 , R 2 Independently selected from H or C1~C 10 alkyl.

13. The polymer-drug conjugate according to any one of claims 1, 8, 9 or 11, characterized in that: The environmental responsive linker is one or more of an enzyme responsive linker, a pH responsive linker, a light responsive linker, and a redox responsive linker.

14. The polymer-drug conjugate according to any one of claims 1, 8, 9, 11 or 13, characterized in that: The polymer-drug conjugate meets one or more of the following conditions: (1) The enzyme-responsive linker can be cut by one or more of the following enzymes: secretory phospholipase A2, acid phosphatase, serum alkaline phosphatase, cytochrome P450, sulfatase, prostate-specific antigen, phospholipase A1, phospholipase A2, phospholipase B, phospholipase C, phospholipase D, neutrophil elastase, cysteine ​​protease-3, cathepsin, matrix metalloproteinase, β-glucuronidase, β-galactosidase, DTP, nitroreductase, reduced coenzyme II, aminopeptidase N, carboxylesterase, diaphorase, histone deacetylase, asparagine endopeptidase, urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor, collagenase; preferably, it is cut by one or more of the following enzymes: cysteine ​​protease-3, cathepsin, matrix metalloproteinase, elastase or β-glucuronidase; (2) The pH-responsive linker comprises one or more of the following structures: hydrazone, imine, oxime, carboxylate, thioester, sulfate, sulfonate, orthoester, carbonate, carbamate, substituted carbamate, ketal, acetal, silyl ether, phosphate, borate, phosphoramide or cis-aconitic acid group; (3) The photoresponsive linker comprises the following structures: one or more of o-nitrobenzene, coumarin, benzoin, BODIPY or cyanine groups; (4) The redox-responsive linker comprises one or more of the following structures: thioketal, phenylboronic acid, phenylboronic acid, oxalate, vinyl ether, thioether, aminoacrylate, disulfide, diselenide, 2,4-dinitrobenzenesulfonate, 2-azidomethylbenzoate, 4-azidobenzyl, unsaturated acid ester or azobenzene group.

15. The polymer-drug conjugate according to claims 13-14, characterized in that: The enzyme-responsive linker comprises the following amino acid sequence: Cit-Phe, Lys-Lys, Phe-Lys, Arg-Arg, Val-Cit, Val-Ala, Val-Lys, Ala-Lys, Phe-Cit, Leu-Cit, Ile-Cit, Trp-Cit, Phe-Arg, Asn-Pro-Val, Gly-Pro-Nle, Glu-Val-Cit, Glu-Val-Ala, Gly-Phe-Gly, Gly-Phe-Phe, Gly-Leu-Gly, Gly-Val-Ala, Gly-Phe-Leu-Gly, Gly-Phe- Phe-Leu, Gly-Leu-Leu-Gly, Gly-Phe-Tyr-Ala, Gly-Phe-Gly-Phe, Ala-Gly-Val-Phe, Gly-Phe-Phe-Gly, Gly-Gly-Phe-Gly, Asp-Glu-Val-Asp, Gl One or more of y-Phe-Leu-Gly-Phe, Gly-Phe-Ala-Gly-Leu-Phe, Gly-Leu-Ala-Ala-Val-Ala, Gly-Gly-Phe-Leu-Gly-Phe or Gln-Ser-Phe-Arg-Phe-Lys.

16. The polymer-drug conjugate according to claims 13-15, characterized in that: The polymer-drug conjugate meets one or more of the following conditions: (1) The enzyme-responsive linker comprises the following structure: Among them, R p Selected from H or C1-C10 alkyl; R p1 , R p2 Each independently selected from C1-C10 alkyl; (2) The pH-responsive linker comprises the following structure: Wherein, m = 0 to 4; R p Selected from H, substituted C1-C10 alkyl; (3) The photoresponsive linker comprises the following structure: (4) The redox linker comprises the following structure:

17. The polymer-drug conjugate according to any one of claims 8, 9 and 11, characterized in that: The linker L 2a is a covalent bond or a linker as shown in formula (VII): The Q 1 Selected from One of the following; among them, R 3 and R 4 independently selected from H, D, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 alkenyl, C3-C6 alkynyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C 10 Aryl or C5~C 10 Heteroaryl; R 3 , R 4 The connected C atom can form a C3-C8 alkyl or heterocycloalkyl, wherein the heteroatom in the C2-C8 heterocycloalkyl is O, S or N, and the number of the heteroatom is one or more. When there are multiple heteroatoms, the heteroatoms are the same or different; the C5-C 10 The heteroatom in the heteroaryl group is O, S or N, and the number of the heteroatoms is one or more. When there are multiple heteroatoms, the heteroatoms are the same or different; W 1 is a covalent bond or C0-C 20 A fragment containing or not containing heteroatoms, wherein the heteroatom is O, S, Se, N, P, Si or B, and the number of the heteroatoms is one or more, and when it is multiple, the heteroatoms are the same or different; the W fragment may contain unsaturated bonds or not; Z 1 Selected from One of the following, where R a The definition is as stated in claim 5.

18. The polymer-drug conjugate according to claim 17, characterized in that: The linker L 2a Select from the following structures or covalent bonds: in, A 1 is O, S, S(O), S(O)2, NR a , C(R 3 R 4 ); p is an integer selected from 0 to 16; q is an integer selected from 0 to 16; m is an integer selected from 0 to 4; s1 is an integer selected from 0 to 16; s2 is an integer selected from 1 to 15; R s1 , R s2 , R s3 and R s4 are each independently selected from hydrogen or methyl; R a The definition is as stated in claim 5.

19. The polymer-drug conjugate according to any one of claims 1, 8 or 9, characterized in that: The pharmacokinetic modulator residue P is selected from a 1 , the terminal group is R b The polyethylene glycol derivative residue, the number of repeating units is b 1 The hyaluronic acid derivative residue, the number of repeating units is c 1 The polyphosphate residues and the number of repeating units are d 1 , the terminal group is R d1 The polysarcosine residues or repeating units are f 1 of polyoxazoline residues; Among them, a 1 An integer selected from 5 to 250, b 1 An integer selected from 5 to 250, c 1 An integer selected from 5 to 250, d 1 An integer selected from 5 to 250, f 1 An integer selected from 5 to 250; R b H, C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C3-C 10 Cycloalkyl, C3-C 10 Alkenyl, C3-C 10 An alkynyl or hydroxyl protecting group; R d1 H, C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Heteroalkyl, C3-C 10 Cycloalkyl, C3-C 10 Alkenyl, C3-C 10 an alkynyl group, a hydroxyl protecting group or an amino protecting group; Preferably, the pharmacokinetic modulator residue P satisfies one or more of the following conditions: (1) When the pharmacokinetic modulator residue P is a repeating unit with a 1 , the terminal group is R b When the polyethylene glycol derivative residue is 1 An integer selected from 5 to 150, preferably an integer selected from 10 to 60, more preferably an integer selected from 15 to 50, such as 21, 43 or 44; (2) When the pharmacokinetic modulator residue P is a repeating unit with a 1 , the terminal group is R b When the residue of a polyethylene glycol derivative is b C1-C 10 An alkyl group, preferably a C1-C6 alkyl group, more preferably a C1-C3 alkyl group, such as a methyl group, an ethyl group, a n-propyl group or an isopropyl group; (3) When the pharmacokinetic modulator residue P is a repeating unit with the number of d 1 , the terminal group is R d1 When the polysarcosine residues d1 It is preferably hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-substituted amino or C1-C6 acyl, for example methylamino, carboxylic acid, carboxylic acid methyl ester or acetylamino.

20. The polymer-drug conjugate according to claim 19, characterized in that: The pharmacokinetic modulator residue P is a repeating unit with a 1 , the terminal group is R b The polyethylene glycol derivative residue, the number of repeating units is b 1 The number of hyaluronic acid derivative residues or repeating units is d 1 The polycreatine derivative residue is selected from the following structures: Among them, a 1 An integer selected from 5 to 150, b 1 An integer selected from 5 to 150, r is an integer selected from 0 to 8; the polyethylene glycol derivative residue is preferably a 1 An integer selected from 20 to 45, b 1 is selected from an integer between 5 and 10, r is selected from an integer between 0 and 3; R b The definition as in claim 19; The polycreatine bioresidue is selected from the following structures: Among them, c 1 An integer selected from 5 to 150, R c1 Selected from H, C1~C 10 Alkyl, C1~C 10 Alkoxy, C3~C 10 Alkenyl, C3~C 10 Alkynyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C 10 Aryl, C5~C 10 Heteroaryl or amine protecting group; R c2 Selected from OR c3 , SR c3 or NR c4 R c5 , where R c3 Selected from H, C1~C 10 Alkyl, C3~C 10 Alkenyl, C3~C 10 Alkynyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C 10 Aryl or C5~C 10 Heteroaryl; wherein R c4 , R c5 Each independently selected from H, C1-C 10 Alkyl, C1~C 10 Alkoxy, C3~C 10 Alkenyl, C3~C 10 Alkynyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C 10 Aryl, C5~C 10 Heteroaryl or amine protecting groups.

21. The polymer-drug conjugate according to claim 20, characterized in that: The pharmacokinetic modulator residue P is a repeating unit with a 1 A methyl-terminated polyethylene glycol derivative residue, wherein the methyl-terminated polyethylene glycol derivative residue is selected from the following structures: Among them, a 1 is selected from an integer between 5 and 150, and r is selected from an integer between 0 and 8; The methyl-terminated polyethylene glycol derivative residue is preferably 22. The polymer-drug conjugate according to claim 1, 5, 8, 9 or 10, characterized in that: The polymer residue is selected from the following structures: Wherein, n is selected from an integer of 4-100.

23. The polymer-drug conjugate according to claim 1, 8 or 9, characterized in that: The pharmaceutically active agent D has an active functional group, and the active functional group is selected from one or more of primary amine, secondary amine, tertiary amine, hydroxyl, sulfhydryl, carboxyl, ester, amide, boric acid, boric ester, phosphoric acid, sulfonic acid, sulfoxide, aldehyde, and ketone.

24. The polymer-drug conjugate according to claim 1, 8, 9 or 23, characterized in that: The pharmaceutically active agent is selected from: anesthetics, antacids, anti-infective drugs, cardiovascular drugs, diuretics, hematinics, immunosuppressants, GLP-1 receptor agonists, hormones and analogs, ophthalmic drugs, pain therapeutics, respiratory drugs, anti-arthritis drugs, anticonvulsants, antihistamines, anti-inflammatory drugs, anti-ulcer drugs, behavior correction drugs, anti-tumor drugs, anti-cancer antigens, central nervous system drugs, mental disease drugs, contraceptives, diabetes drugs, growth promoters, hemostatics, immunostimulants, immunomodulators, muscle relaxants, obesity therapeutics, osteoporosis drugs, tranquilizers, tranquilizers, urethral acidifiers, vitamins, polypeptide drugs, oligonucleotide drugs, mRNA drugs, antibody drugs, biological products, targeted protein degraders, PROTAC drugs (targeted protein degradation chimeras), molecular glue degraders, oligosaccharide drugs or targeted drugs. One or more.

25. The polymer-drug conjugate according to any one of claims 1, 8, 9, 23 or 24, characterized in that: The pharmaceutically active agent residue D is an anti-tumor drug residue, and the anti-tumor drug is selected from one or more of tumor targeted drugs, targeted protein degraders, PROTAC drugs, molecular glue degraders, tumor immunomodulators or chemotherapy drugs.

26. The polymer-drug conjugate according to claim 25, characterized in that The anti-tumor drugs described above are selected from abemaciclib, abiraterone, abrocitinib, acalabrutinib, afatinib, aldesleukin, alectinib, alflutinib, almonertinib, altretamine, amcenestrant, aminoglutethimide, amsacrine, anastrozole, anlotinib, apalutamide, apatinib, arzoxifene, asciminib, asparaginase, avapritinib, avitinib, axitinib, azacitidine, baricitinib, belinostat, bendamustine, bexarotene, bicalutamide, bicyclol, binimetinib, bleomycin, boanmycin, bortezomib, bosutinib, brigatinib, buserelin, busulfan, cabazitaxel, cabozantinib, calaspargase, calicheamycin, capecitabine, capmatinib, carboplatin, carfilzomib, carmustine, carmofur, cedazuidine, ceritinib, cetrorelix, chidamide, chlorambucil, cisplatin, cladribine, clofarabine, cobimetinib, colchicine,copanlisib,crizotinib,cyclophosphamide,cytarabine,dabrafenib,dacarbazine,dacomitinib,dactinomycin,dalpiciclib,darolutamide,dasatinib,daunorubicin,decitabine,degarelix,delgociclib,denileukin,deruxtecan,deucravacitinib,docetaxel,donafenib,doxorubicin,duvelisib,enasidenib,encorafenib,ensartinib,entrectinib,enzalutamide,enzastaurin,elacestrant,epirubicin,erdafitinib,eribulin,erlotinib,estradiol,estramustine,etoposide,everolimus,exemestane,fasudil,fedatinib,filgotinib,floxuridine,fludarabine,flumatinib,fluorouracil,flutamide,fluzoparib,formestane,fostamatinib,fruquintinib,fulvestrant,futibatinib,gefitinib,gemcitabine,gilteritinib,giredestrant,glasdegib,goserelin,histrelin,hydroxyurea,ibrutinib,ibudilast,icaritin,icotinib,idarubicin,idelalisib,ifosfamide,imatinib,imiquimod,infigratinib,ingenol mebutate,interferon alfa-2b,irinotecan,ivosidenib,ixabepilone,ixazomib,lanreotide,lapatinib,larotrectinib,lenalidomide,lenvatinib,letrozole,leucovorin,leuprolide,lomustine,lonafarnib,lorlatinib,lurbinectedin,maytansine,mechlorethamine,medroxyprogesterone,megestrol,melphalan,melphlan flufenamide,mercaptopurine,methotrexate,methoxsalen,methylprednisolone,midostaurin,mitomycin,mitotane,mitoxantrone,mitozolomide,mobocertinib,monomethylauristatin E,monomethylauristatin F,nelarabine,nandrolone,neratinib,nearsudil,nilotinib,nilutamide,nintedanib,niraparib,octreotide,olaparib,olmutinib,olverembatinib,omacetaxine,orelabrutinib,osimertinib,oxaliplatin,paclitaxel,pacritinib,palbociclib,pamidronate,pamiparib,panobinostat,pazopanib,peficitinib,pegaptanib,pegaspargase,peginteferon alfa-2b,pemigatinib,pemetrexed,pentetreotide,pentostatin,pexidartinib,phenoxybenzamine,pidotimod,plinabulin,plitidepsin,pomalidomide,ponatinib,porfimer,pralatrexate,pralsetinib,prednisolone,procarbazine,pyrotinib,quizartinib,radotinib,raloxifene,raltitrexed,regorafenib,ribociclib,rintatolimod,ripretinib,romidepsin,rucaparib,ruxolitinib,savolitinib,selinexor,selpercatinib,selumetinib,sonidegib,sorafenib,sotorasib,streptozocin,sunitinib,surufatinib,talazoparib,tamoxifen,tazemetostat,tegafur,temozolomide,temsirolimus,teniposide,tepotinib,teprenone,thalidomide,thioguanine,thiotepa,thyrotropin alfa,tipiracil,tipifarnib,tirabrutinib,tirbanibulin,tivozanib,trametinib,tofacitinib,topotecan,toremifene,trabectedin,tretinoin,tri fluride,trilaciclib,triptorelin,tucatinib,upadacitinib,umbralisib,utidelone,uroacitide,valrubicin,vandetanib,vemurafenib,venetoclax, vinblastine,vincristine,vindesine,vinflunine,vinorelbine,vismodegib,vorinostat,zanubrutinib,zoledronic acid,amatoxins,anthacyclines,anthracenes,anthramycins,auristatins,bryostatins,camptothecins,carmaphycins,combretastatins,cyclosporines,cryptomycins,ecteinascidins,ellipt icenes,esperamicins,mustines,neothramycins,ozogamicins,phenoxazines,podophyllotoxins,pyrrolobenzodiazepines,sibiromycins,thailanstatins,tomamycns,tubulysins,taxanes,vinca alkaloids, 7-epi-paclitaxel, 2'-acetyl-paclitaxel, 10-deacetyl-paclitaxel, 10-deacetyl-7-epi-paclitaxel, 7-xylosyl-paclitaxel, 10-deacetyl-7-glutaryl-paclitaxel, 7-N,One or more of N-dimethylglycylpaclitaxel, 7-L-alanylpaclitaxel, lerontaxel, camptothecin, 9-aminocamptothecin, 9-nitrocamptothecin, lutetatecan, gimatidecan, belotecan, 10-hydroxycamptothecin, 10-hydroxy-ethyl-camptothecin (SN-38), isitecan, pyrarubicin, aclarubicin, sirolimus, tacrolimus, progesterone, estrogen, rapamycin, plicamycin, harringtonine or curcumin.

27. The polymer-drug conjugate according to claim 25 or 26, characterized in that: The polymer-drug conjugate meets one or more of the following conditions: (1) The anti-tumor drug is a tumor-targeting drug, selected from the group consisting of aldesleukin, abemaciclib, abiraterone, abrocitinib, acalabrutinib, afatinib, alectinib, alflutinib, almonertinib, amcenestrant, anastrozole, anlotinib, apalutamide, apatinib, arzoxifene, asciminib, avapritinib, avitinib, axitinib, baricitinib, belinostat, bexarotene, bicalutamide, binimetinib, bleomycin, boanmycin, bortezomib, bosutinib, brigatinib, buserelin, cabozantinib, capmatinib, carfilzomib, carmustine, ceritinib, cetrorelix, chidamide, cobimetinib, copanlisib, crizotinib, dabrafenib, dacomitinib, dalpici clib, darolutamide, dasatinib, degarelix, delgociclib, deucravacitinib, donafenib, duvelisib, enasidenib, encorafenib, ensartinib, entrectinib, enzalutamide, enzastaurin, elacestrant, erdafitinib, erlotinib, everolimus, fedatinib, filgotinib, flumatinib, fluzoparib, formestane, fostamatinib, fruquintinib, fulvestrant, futibatinib, gefitinib, gilteritinib, giredestrant, glasdegib, goserelin, histrelin, ibrutinib, ibudilast, icotinib, idarubicin, idelalisib, imatinib, imiquimod, infigratinib, ivosidenib, ixazomib, lanreotide, lapatinib,larotrectinib, lenalidomide, lenvatinib, letrozole, leucovorin, leuprolide, lonafarnib, lorlatinib, medroxyprogesterone, megestrol, methylprednisolone, midostaurin, mobocertinib, nandrolone, neratinib, nilotinib, nilutamide, nintedanib, niraparib, olaparib ,olmutinib,olverembatinib,orelabrutinib,osimertinib,pacritinib,palbociclib,pamidronate,pamiparib,panobinostat,pazopanib,peficitinib,pegaptanib,pemigatinib,pexidartinib,pidotimod,pomalidomide,ponatinib,pralsetinib,pyrotinib,quizartinib,ra one or more of dotinib, raloxifene, regorafenib, ribociclib, rintatolimod, ripretinib, rucaparib, ruxolitinib, savolitinib, selinexor, selpercatinib, selumetinib, sonidegib, sorafenib, sotorasib, sunitinib, surufatinib, talazoparib, tamoxifen, tazemetostat, temsirolimus, tepotinib, thalidomide, tipifarnib, tirabrutinib, tivozanib, trametinib, tofacitinib, toremifene, tretinoin, trilaciclib, triptorelin, tucatinib, upadacitinib, umbralisib, vandetanib, vemurafenib, venetoclax, vismodegib, vorinostat, zanubrutinib, or zoledronic acid;, (2) The anti-tumor drug is a chemotherapy drug selected from altretamine, aminoglutethimide, amsacrine, asparaginase, azacitidine,bendamustine,bexarotene,bicyclol,bleomycin,boanmycin,buserelin,busulfan,cabazitaxel,calaspargase,calicheamycin,capecitabine,carboplatin,carmustine,carmofur,cedazuidine,chlorambucil,cisplatin,cladribine,clofarabine,colchicine,cyclophosphamide,cytarabine,dacarbazine,dactinomycin,daunorubicin,decitabine,denileukin,deruxtecan,docetaxel,doxorubicin,epirubicin,eribulin,estradiol,estramustine,etoposide,exemestane,fasudil,floxuridine,fludarabine,fluorouracil,flutamide,formestane,gemcitabine,hydroxyurea,icaritin,idarubicin,ifosfamide,ingenol mebutate,irinotecan,ixabepilone,leucovorin,lomustine,lurbinctedin,maytansine,mechlorethamine,medroxyprogesterone,megestrol,melphalan,melphlan flufenamide,mercaptopurine,methotrexate,methoxsalen,methylprednisolone,mitomycin,mitotane,mitoxantrone,mitozolomide,monomethylauristatin E,monomethylauristatin F,nelarabine,nandrolone,nearsudil,octreotide,omacetaxine,oxaliplatin,paclitaxel,pamidronate,pemetrexed,pentetreotide,pentostatin,phenoxybenzamine,plinabulin,plitidepsin,porfimer,pralatrexate,prednisolone,procarbazine,procarbazine,raltitrexed,romidepsin,streptozocin,tegafur,temozolomide,teniposide,teprenone,thioguanine,thiotepa,thyrotropin alfa,tipiracil,tirbanibulin,topotecan,trabectedin,trifluride,utidelone,uroacitide,valrubicin,vinblastine,vincristine,vindesine,vinflunine,vinorelbine,amatoxins,anthacyclines,anthracenes,anthramycins,auristatins,bryostatins,camptothecins,carma phycins,combretastatins,cyclosporines,cryptomycins,ecteinascidins,ellipticenes,esperamicins,mustines,neothramycins,ozogamicins,phenoxazines,podophyllotoxins,pyrrolobenzodiazepines,sibiromycins,thailanstatins,tomamycns,tubulysins,taxanes,vinca Alkaloids, 7-epipaclitaxel, 2'-acetylpaclitaxel, 10-deacetylpaclitaxel, 10-deacetyl-7-epipaclitaxel, 7-xylosylpaclitaxel, 10-deacetyl-7-glutarylpaclitaxel, 7-N,N-dimethylglycylpaclitaxel, 7-L-alanylpaclitaxel, lerontaxel, camptothecin, 9-aminocamptothecin, 9-nitrocamptothecin, lutetatecan, gimatidecan, belotecan, 10-hydroxycamptothecin, 10-hydroxy-7-ethylcamptothecin (SN-38), isitecan, pyrarubicin, aclarubicin, sirolimus, tacrolimus, progesterone, estrogen, rapamycin, plicamycin, harringtonine or curcumin.

28. The polymer-drug conjugate according to claim 1, 5, 8 or 9, characterized in that: The pharmaceutically active agent residue D is selected from the following structures: Among them, R t1 Selected from H or C1-C 20 Alkyl; R t2 Selected from NHR t1 、C1-C 20 alkyl.

29. The polymer-drug conjugate according to claim 8, 9, 11, 17 or 18, characterized in that: The linker L 2a Select from the following structures:

30. The polymer-drug conjugate according to any one of claims 8, 9 or 11, characterized in that: The linker L 2b Selected from the following structures:

31. The polymer-drug conjugate according to claim 1, 5, 8, 9, 11 or 12, characterized in that: The polymer-drug conjugate is selected from the following structures: in, L 2a , L 2b The respective definitions are as described in any one of claims 1, 4-15; D is defined as in any one of claims 1, 19-24; X is defined as in any one of claims 1 and 12; n is an integer between 10 and 70; a 1 It is an integer between 5 and 150.

32. The polymer-drug conjugate according to claim 19, 20 or 21, characterized in that: R b The PEG residue is methyl and has a number average molecular weight of 550, 1000, 2000, 3000, 4000 or 5000.

33. The polymer-drug conjugate according to any one of claims 1, 8 or 9, characterized in that: The polymer-drug conjugate meets one or more of the following conditions: (1) The branch center Y is connected to the polymer residue via a linker L 0 The molar ratio of the branch center Y to the polymer structural unit is 0.5:1 to 1.5:1; (2) The pharmacokinetic modulator residue P is connected to the branch center Y via a linker L 1 The molar ratio of the pharmacokinetic modulator residue to the polymer structural unit is 0.5:1 to 1.5:1; (3) The pharmaceutically active agent residue D is connected to the trifunctional branch center Y via a linker L 2 The molar ratio of the pharmaceutically active agent residue D to the polymer structural unit is 0.5:1 to 1.5:

1.

34. The polymer-drug conjugate according to any one of claims 1 to 32, characterized in that: -L 2 -D is any of the following: Case 1: The -L 2 -D is any of the following structures: Case 2: The -L 2 -D is any of the following structures:

35. A compound represented by formula (I-1) or a pharmaceutically acceptable salt thereof: in, for: The "#" terminal is connected to Q; n is independently any integer from 4 to 100; n1, n2, n3 and n4 are each independently 0, 1, 2, 3, 4 or 5; X1 is a covalent bond or Ring A is C6-C 10 Aromatic ring or 5-10 membered heteroaromatic ring; X2 is a covalent bond, O, S or NH; L 0 It is a covalent bond; Y is "#1" end and L 2 Connected, "#2" end and L 1 connected; n5 and n6 are each independently 0, 1, 2, 3, 4 or 5; L 1 It is a covalent bond; P is R p is independently C1-C6 alkyl or is replaced by one or more R p-1 Substituted C1-C6 alkyl; R p-1 are independently halogen, hydroxy, C1-C6 alkoxy or NR p1 R p2 ; R p1 and R p2 Each is independently -H or C1-C6 alkyl; n7 is independently any integer from 4 to 100; L 2 for #3 -L 2a -L 2b_#4 , the "#3" end is connected to Y, and the "#4" end is connected to D; L 2a For covalent bonds, n8, n9, n10, n11, n12, n13 and n14 are each independently any integer from 1 to 20; R s1 and R s2 Each is independently -H or C1-C6 alkyl; Or, R s1 and R s2 The carbon atoms to which they are connected together form a C3-C6 cycloalkyl group or a 3-6-membered heterocycloalkyl group, wherein the heteroatoms in the 3-6-membered heterocycloalkyl group are selected from one or more of N, O and S, and the number of the heteroatoms is 1, 2 or 3; X3, X4, X5, X6, X7 and X8 are each independently NR s3 or O, R s3 is H or C1-C6 alkyl; L 2b For covalent bonds, R x are independently -H or C1-C3 alkyl; R y are independently H, C1-C3 alkyl or R y1 and R y2 Each is independently -H or C1-C3 alkyl; n' is independently 1 or 2; X9 is O or NR s9 ; R s4 , R s5 , R s6 , R s7 , R s8 and R s9 Each is independently -H or C1-C6 alkyl; Or, "R s4 and R s5 ”、"R s6 and R s7 ”、"R s8 and R s9 ” or "R s4 and R s9 "Together with the atoms to which they are connected, they form a 5-6 membered heterocycloalkyl group, wherein the heteroatom in the 5-6 membered heterocycloalkyl group is N, O, or N and O, and the number of the heteroatom is 1 or 2; n15, n16 and n17 are each independently 1, 2, 3 or 4; D is a pharmaceutically active agent residue; X is OH, NH2, -L2-D, -D or Q is or -P.

36. The compound of formula (I-1) or a pharmaceutically acceptable salt thereof according to claim 35, characterized in that: It meets one or more of the following conditions: (1) for (2) n is independently any integer of 20-60, such as 20 to 30 or 50 to 60, and further such as 28, 29, 30, 31, 59 or 60; (3)Y is (4) n7 is each independently any integer from 20 to 50, such as 22, 28, 44 or 49; (5)R p are independently methyl, methoxy, -CH2NH2 or -CH2NHCH3; (6) n8, n9, n10, n11, n12, n13 and n14 are each independently any integer from 1 to 15, such as 1, 2, 3, 7 or 11; (7)R s1 and R s2 Each is independently -H, or R s1 and R s2 Together with the carbon atom to which they are attached they form a C3-C6 cycloalkyl group, for example a cyclobutyl group.

37. The compound of formula (I-1) or a pharmaceutically acceptable salt thereof according to claim 35, characterized in that: It meets one or more of the following conditions: (1) for (2)P is (3)Y is L 2a For covalent bonds, L 2b for (4)Y is L 2a is a covalent bond or L 2b For covalent bonds, (5)Y is L 2a For covalent bonds, L 2b For covalent bonds, (7)Y is L 2a For covalent bonds, L 2b For covalent bonds, (8)X is OH, NH2, -D, -L 2b -D. The Medium, -L 2 -D is -L 2b -D. (9) Q is or -P, described Medium, -L 2 -D is 38. The compound of formula (I-1) or a pharmaceutically acceptable salt thereof according to claim 35, characterized in that: It meets one or more of the following conditions: (1)Y is L 2a For covalent bonds, L 2b For covalent bonds, (2)Y is L 2a is a covalent bond or L 2b For covalent bonds, (3)Y is L 2a For covalent bonds, L 2b For covalent bonds, (4)Y is L 2a is a covalent bond or L 2b For covalent bonds, (5) X is OH, NH2, -D, The Medium, -L 2 -D is (6) D is the residue of a pharmaceutically active agent according to any one of claims 23 to 28.

39. The compound of formula (I-1) or a pharmaceutically acceptable salt thereof according to claim 35, characterized in that: It meets one or more of the following conditions: (1)Y is L 2 For covalent bonds, (2)Y is L 2 For covalent bonds, (3) D is a residue of a drug having an active functional group, wherein the active functional group is selected from one or more of a primary amine group, a secondary amine group, a hydroxyl group and a thiol group; preferably, the drug is an anti-tumor drug, such as one or more of camptothecin, camptothecin derivatives, paclitaxel, paclitaxel derivatives, cisplatin and cisplatin derivatives; The D is, for example, 40. The compound of formula (I-1) or a pharmaceutically acceptable salt thereof according to any one of claims 35 to 39, characterized in that: The compound represented by formula (I-1) is a compound represented by formula (A) or formula (B): In the compound represented by formula (A) or formula (B), the definition of each variable is as described in any one of claims 35-39.

41. Any one of the following compounds:

42. A pharmaceutical composition comprising the compound according to any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

43. Use of a compound as claimed in any one of claims 1 to 41, a pharmaceutically acceptable salt thereof or a pharmaceutical composition as claimed in claim 42 in the preparation of a medicament for preventing and / or treating a disease, wherein the disease is cancer, for example, one or more selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain cancer, nasopharyngeal cancer, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, bone cancer, osteosarcoma, seminoma, testicular tumor, uterine tumor, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder tumor, gallbladder cancer, bile duct cancer, choriocarcinoma and pediatric tumor, preferably one or more selected from pancreatic cancer, liver cancer, colon cancer, myeloma, lung cancer (e.g. small cell lung cancer), fibrosarcoma and breast cancer.

44. A method for preventing and / or treating a disease, comprising administering to an individual in need thereof a therapeutically effective amount of a compound as described in any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof, wherein the disease is cancer, for example, selected from one or more of breast cancer, ovarian cancer, prostate cancer, melanoma, brain cancer, nasopharyngeal cancer, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, bone cancer, osteosarcoma, seminoma, testicular tumor, uterine tumor, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder tumor, gallbladder cancer, bile duct cancer, choriocarcinoma and pediatric tumor, preferably one or more of pancreatic cancer, liver cancer, colon cancer, myeloma, lung cancer (e.g. small cell lung cancer), fibrosarcoma and breast cancer.

45. A compound represented by formula (I-1-A), (I-1-B) or (I-1-C): In the compound represented by formula (I-1-A), Y is "#1" end and L 2 Connected, "#2" end and L 1 connected; In the compound represented by formula (I-1-B), Y is "#1" end and L 2 Connected, "#2" end and L 1 connected; In the compound represented by formula (I-1-B), Y is "#1" end and L 2 Connected, "#2" end and L 1 connected; In the compounds represented by formula (I-1-A), (I-1-B) and (I-1-C), the definitions of the variables are as described in any one of claims 35 to 41.

46. ​​A compound of any one of the following:

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