Polyethylene glycol drug, and preparation method therefor and use thereof

Abstract

The present application relates to a polyethylene glycol drug, and a preparation method therefor and the use thereof. Specifically, the present application relates to a compound as represented by formula I or a pharmaceutically acceptable salt thereof, intermediate compounds thereof as represented by formula II to formula XX, a method for preparing the compound, and the use thereof in fighting tumors. Biological tests show that the compound of the present application has a significant inhibitory effect on tumors such as breast cancer, non-small cell lung cancer, melanoma, oral squamous cell carcinoma, osteosarcoma, etc.

Description

A polyethylene glycol drug and its preparation method and application

[0001] This application is based on the application with CN application number 202310714197.4 and application date June 15, 2023, and claims its priority. The disclosed content of the CN application is hereby introduced as a whole into this application. Technical Field

[0002] The present invention relates to the field of pharmaceutical chemistry, and in particular to polyethylene glycol drugs and their preparation methods and applications. Background Art

[0003] Over the past 30 years, the US FDA has approved 30 PEG-based drugs for marketing, and over 40 new drugs are in Phase I, II, and III clinical trials or NDAs, half of which are PEG-based small molecules. PEG is undisputedly the most successful artificial polymer carrier in clinical practice, the so-called "gold standard" carrier. PEG-based drugs are shifting from PEG-based large molecules to PEG-based small molecules, with small molecules accounting for 80-90% of the pharmaceutical market. Chongqing Apgre Biotechnology Co., Ltd.'s successful development of PEG-based small molecule dual drugs and PEGylated small molecules with active targeting components or enhancers, coupled with the fact that PEGylation technology is applicable not only to anti-tumor drugs but also to anti-infectives, gout, arthritis, pain, and other inflammatory conditions, as well as diabetes, has the potential to generate hundreds of product pipelines, potentially creating a massive industry worth hundreds of billions of dollars.

[0004] Recently, the Australian company STARPHARMA has developed a polyethylene glycol-lysine dendrimer peptide-chemotherapeutic drug monotherapy (including A Phase II clinical trial of a drug (e.g., cabazitaxel, docetaxel, and irinotecan) demonstrated excellent efficacy with significantly reduced toxicity and side effects. Pharmaceutical giants such as Astrazeneca, Merck, and Roche / Genentech have begun to participate in R&D in this field. Chongqing Apgrelide Biotechnology Co., Ltd. has also synthesized small molecule drugs (including single-agent, dual-agent, multi-agent, enhancer, and active targeting accessories) based on polyethylene glycol (PEG)-glutamic acid, aspartic acid, and lysine. Numerous pipeline products have demonstrated significantly improved efficacy and significantly reduced toxicity and side effects, and are currently advancing toward clinical trials. Recently, scientists from WINDOW Tx / Massachusetts Institute of Technology (MIT) and Harvard University published preclinical animal results of a bottlebrush-like polyethylene glycol triplet synthesized via ring-opening metastasis polymerization (ROMP) for the treatment of multiple spinal cord tumors. In order to more conveniently synthesize polyethylene glycol dual-drugs or multi-drugs or polyethylene glycol drugs with active targeting accessories in various proportions, this application designs methods for synthesizing various compounds such as polyethylene glycol-peptide-small molecule drugs based on certain fatty polyamine or polyhydroxy core structures, active targeting accessories, boron reagents, etc., and synthesizes these compounds. Biological tests have shown that these compounds have significant therapeutic effects.

[0005] Summary of the Invention

[0006] Compound

[0007] In one aspect, the present application provides a compound of formula I or a pharmaceutically acceptable salt thereof,

[0008] in,

[0009] M is a hydrocarbon group containing two or more (e.g., 2, 3, 4, 5, or 6) identical or different heteroatoms (e.g., N, O, or S), and M is connected to L1 and L1' through the heteroatoms;

[0010] Each L1 is independently selected from End 1 is connected to M, and end 2 is connected to L2;

[0011] Each L1' is independently selected from End 1 is connected to M, and end 2 is connected to L3; and L1 and L1' are different (for example, L1 is L1' is Or L1 is L1' is );

[0012] x1 and x2 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 at each occurrence;

[0013] Each L2 is independently selected from the residues of Lys, Cys, Thr, Ser, Asp or Glu;

[0014] Each PEG is independently selected from Its number average molecular weight is 5k-10k or 10k-40k, for example 5k or 10k;

[0015] Each L3 is independently a bond or One end is connected to L2 or L1', and the other end is connected to L4. 31 and L 32 independently selected from a bond and -NH(CH2) x3 C(O)-, x3 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, A1 is selected from a bond, an amino acid residue or a derivative thereof, or a polypeptide fragment consisting of two or more amino acids or a derivative thereof, and r1 is selected from 1, 2, 3, 4, 5 and 6;

[0016] Each L4 is independently a bond or End 1 is connected to L3, and end 2 is connected to L5. 41 and L 42 independently selected from a bond, -NH(CH2) x4 C(O)-、-NH(CH2) x4 NH-, -NH((CH2)2O) x4 CH2CH2NH- and -C(O)(CH2) x4 C(O)-, A2 and A3 are independently selected from a bond, an amino acid residue or a derivative thereof, or a polypeptide fragment consisting of two or more amino acids or a derivative thereof, and r2 and r3 are each independently selected from 1, 2, 3, 4, 5 and 6;

[0017] Each L5 is independently a bond or selected from -NH-, hydrazino (i.e., -NH-N=), amino acid residues or derivatives thereof, polypeptide fragments consisting of two or more amino acids or derivatives thereof, -NH(CH2) x5 C(O)-、-NH(CH2) x5 NH-, -NH((CH2)2O) x5 CH2CH2NH-、-NH((CH2)2O) x5 CO-, -C(O)(CH2) x5 C(O)-、 and any combination of the above; or

[0018] L4 and L5 junction formation Preferably, L4 and L5 are connected to form

[0019] x4 and x5 are each independently selected at each occurrence from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0020] Each D is independently selected from the group of cytotoxic drugs, preferably, the cytotoxic drug is selected from microtubule inhibitors, DNA intercalators, DNA topoisomerase inhibitors and RNA polymerase inhibitors; preferably, the cytotoxic drug is selected from PTX (paclitaxel), PCB (palbucillib), SN38 (7-ethyl-10-hydroxy-camptothecin), NPB (Niraparib, MK-4827), AXT (Axitinib), LPT (lapatinib), DOX (doxorubicin), Ac-C-PLGLAG-iRGD, folic acid, SB7 (SB-743921), IRN (Irinotecan), sodium dodecahydro-12-thiobenzoate, PPT-iRGD, 1,2,3,4,5,6,7,8,9,10,11-undecyl-12-thiobenzoate 10 AlkaneBSH(Sodium Mercaptododecaborate( 10 B))

[0021] Each n 11 and n 12 Independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;

[0022] Each n 21 and n 22 Independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;

[0023] Each n 31 and n 32 Independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;

[0024] Each of y1 and y2 is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10.

[0025] In some embodiments, M is a hydrocarbon group containing two or more (e.g., 2, 3, 4, 5, or 6) identical or different heteroatoms (e.g., N, O, or S), and M is connected to L1 through the heteroatoms;

[0026] Each L1 is independently selected from End 1 is connected to M, and end 2 is connected to L2, wherein x1 and x2 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;

[0027] Each L1' is independently selected from End 1 is connected to M, and end 2 is connected to L3, wherein x1 and x2 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; and L1 and L1' are different;

[0028] Each L2 is independently selected from the residues of Lys, Cys, Thr, Ser, Asp or Glu;

[0029] Each PEG is independently selected from Its number average molecular weight is 5k-10k or 10k-40k, for example 5k or 10k;

[0030] Each L3 is independently a bond or End 1 is connected to L2, and end 2 is connected to L4. 31 、L 32 and L 33 independently selected from a bond and -NH(CH2) x3 C(O)-, x3 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, A1 is selected from a bond, an amino acid residue or a derivative thereof, or a polypeptide fragment or a derivative thereof consisting of more than two amino acids, and when A1 is a polypeptide fragment or a derivative thereof, A1 is combined with one or more L 32 connect;

[0031] Each L4 is independently a bond or End 1 is connected to L3, and end 2 is connected to L5. 41 、L 42 and L 43 independently selected from a bond, -NH(CH2) x4 C(O)-、-NH(CH2) x6 NH-, -NH(CH2O) x4 CH2CH2NH-、-C(O)(CH2) x4 C(O)-, x4 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, A2 and A3 are independently selected from a bond, an amino acid residue or a derivative thereof, or a polypeptide fragment or a derivative thereof consisting of more than two amino acids, when A3 is a polypeptide fragment or a derivative thereof, A3 and one or more L 42 connect;

[0032] Each L5 is independently a bond or selected from -NH-, hydrazino (i.e., -NH-N=), amino acid residues or derivatives thereof, polypeptide fragments consisting of two or more amino acids or derivatives thereof, -NH(CH2) x5 C(O)-、-NH(CH2) x5 NH-, -NH(CH2O)x5 CH2CH2NH-、-NH(CH2O) x5 CO-, -C(O)(CH2) x5 C(O)-、 and any combination of the above, wherein each x5 is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; or,

[0033] L4 and L5 junction formation Preferably, L4 and L5 are connected to form

[0034] Each D is independently selected from the group of cytotoxic drugs, preferably, the cytotoxic drug is selected from microtubule inhibitors, DNA intercalators, DNA topoisomerase inhibitors and RNA polymerase inhibitors; preferably, the cytotoxic drug is selected from PTX (paclitaxel), PCB (palbucirib), SN38 (7-ethyl-10-hydroxy-camptothecin), NPB (Niraparib, MK-4827), AXT (Axitinib), LPT (lapatinib), DOX (doxorubicin), MI-AH-PLGLAG-iRGD, folic acid, SB7 (SB-743921), IRN (Irinotecan), sodium dodecahydro-12-thiobenzoate, PPT-iRGD, 1,2,3,4,5,6,7,8,9,10,11-undecyl-12-thiobenzoate 10 AlkaneBSH(Sodium Mercaptododecaborate( 10 B))

[0035] Each n 11 and n 12 Independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;

[0036] Each n 21 and n 22 Independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;

[0037] Each n 31 and n 32 Independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;

[0038] Each of y1 and y2 is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10.

[0039] In some embodiments, M is a C containing 2-4 identical or different heteroatoms.2-10 Hydrocarbon group.

[0040] In some embodiments, M is a C containing 2-4 heteroatoms independently selected from N and O. 2-6 Saturated hydrocarbon group.

[0041] In some embodiments, M is selected from the following structures:

[0042] In some embodiments, each of L1 and L1' is independently selected from

[0043] In some embodiments, L1 is L1' is

[0044] In some embodiments, L1 is L1' is

[0045] In some embodiments, M is connected to L1' through an N atom, or M is connected to L1' through an O atom. Preferably, M is connected to L1' through an N atom.

[0046] In some embodiments, n 11 =1, 2 or 3, and n 11 ≤n 12 , preferably, n 11 =1,n 12 =2, 3 or 4; n 11 =2,n 12 =3; or n 11 =3,n 12 =3.

[0047] In some embodiments, each L2 is independently a Lys residue.

[0048] In some embodiments, when L3 is When each L 31 and L 32 independently selected from a bond and -NH(CH2) x3 C(O)-, x3 is selected from 0, 1, 2, 3, 4, 5 and 6, A1 is selected from a bond, an amino acid residue or a derivative thereof, or a polypeptide fragment consisting of more than two amino acids or a derivative thereof, and r1 is selected from 1, 2, 3, 4, 5 and 6. In some embodiments, A1 is selected from Glu, Asp and GluGlu.

[0049] In some embodiments, each L3 is independently a bond or selected from the following structures:

[0050] -NH(CH2)2C(O)-,

[0051] In some embodiments, when L4 is When each L 41 and L 42 independently selected from a bond, -NH(CH2) x4 C(O)-、-NH(CH2) x4 NH- and -NH((CH2)2O) x4 CH2CH2NH- and -C(O)(CH2) x4 C(O)-, each x4 is independently selected from 0, 1, 2, 3, 4, 5 and 6, A2 and A3 are independently selected from a bond, an amino acid residue or a derivative thereof, or a polypeptide fragment consisting of more than two amino acids or a derivative thereof, and r1 is selected from 1, 2, 3, 4, 5 and 6. In some embodiments, each A2 and A3 is independently selected from Lys, Glu, Asp, GluGlu and Glu(Glu)2.

[0052] In some embodiments, each L4 is independently a bond or selected from the following structures:

[0053] LysNH(CH2)5COGlu(Glu)2, Lys(COC2H4CO)(NH(CH2CH2O)2CH2CH2NH), -NH(CH2)5COGlu, -NH(CH2)5COGlu(Glu)2 , -NH(CH2)5COGlu(Glu(NHCH2CH2NH)2)2, -NH(CH2)5COAsp and -NH(CH2)5COGlu(Glu(NH(CH2CH2O)2CH2CH2NH)2)2.

[0054] In some embodiments, each L4 is independently a bond or selected from the following structures:

[0055] LysNH(CH2)5COGlu(Glu)2, Lys(COC2H4CO)(NH(CH2CH2O)2CH2CH2NH), -NH(CH2)5COGlu, -NH(CH2)5COGlu(Glu)2 , -NH(CH2)5COGlu(Glu(NHCH2CH2NH)2)2, -NH(CH2)5COAsp and -NH(CH2)5COGlu(Glu(NH(CH2CH2O)2CH2CH2NH)2)2.

[0056] In some embodiments, the amino acid in L5 is selected from Glu, Gly, Phe, Leu and Cys; preferably, the polypeptide composed of two or more amino acids is selected from GlyPheLeuGly, Glu(Glu(Gly)2)2; preferably, the derivative is selected from acylated (e.g., acetylated) or alkylated (e.g., methylated) derivatives.

[0057] In some embodiments, L5 is selected from a bond, -NH-N=、GlyPheLeuGly、-NH(CH2) x5 C(O)-、-NH((CH2)2O) x5 CH2CH2NH-、-NH((CH2)2O) x5 CH2CH2NHGlu, -NH(CH2) x5 C(O)Glu(Glu(GlyNHN=)2)2、-NH((CH2)2O) x5 CO-, -C(O)(CH2) x5 C(O)-, -C(O)(CH2) x5 C(O)-GlyPheLeuGly- and Each x5 is independently selected from 1, 2, 3, 4, 5 and 6.

[0058] In some embodiments, L5 is selected from a bond, -NH-N=、GlyPheLeuGly、-NH(CH2) x5 C(O)-, -NH(CH2O) x5 CH2CH2NH-、-NH(CH2O) x5 CH2CH2NHGlu, -NH(CH2) x5 C(O)Glu(Glu(GlyNHN=)2)2, -NH(CH2O) x5 CO-, -C(O)(CH2) x5 C(O)-, -C(O)(CH2) x5 C(O)-GlyPheLeuGly- and Each x5 is independently selected from 1, 2, 3, 4, 5 and 6.

[0059] In some embodiments, L5 is selected from a bond, GlyPheLeuGly, -NH(CH2)5C(O)Glu(Glu(GlyNHN=)2)2, -NH(CH2)5C(O)-, -NH((CH2)2O)2CH2CH2NH-, -N H((CH2)2O)2CH2CH2NHGlu, -NH((CH2)2O)2CO-, -C(O)(CH2)2C(O)-, -C(O)(CH2)2C(O)-GlyPheLeuGly- and

[0060] In some embodiments, L5 is selected from a bond, GlyPheLeuGly, -NH(CH2)5C(O)Glu(Glu(GlyNHN=)2)2, -NH(CH2)5C(O)-, -NH(CH2O)2CH2CH2NH-, -NH(CH2O)2CH2CH2NHGlu, -NH(CH2O)2CO-, -C(O)(CH2)2C(O)-, -C(O)(CH2)2C(O)-GlyPheLeuGly-, and

[0061] In some embodiments, L4 and L5 are linked to form

[0062] x4 and x5 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 at each occurrence.

[0063] In some embodiments, L4 and L5 are linked to form

[0064] It should be understood that the general formula I has the following structure:

[0065] Wherein, L is a structure formed by connecting the aforementioned L4 and L5, and the remaining groups are as defined in any of the above items.

[0066] Herein, D is a group formed by linking the cytotoxic drug to the rest of the general formula via a reactive group thereon. In some embodiments, the reactive group is an amino group (-NH2), a secondary amine, a hydroxyl group (-OH), a sulfhydryl group (-SH), a carboxyl group (-COOH), or the like.

[0067] In some embodiments, D is selected from:

[0068] In some embodiments, in Formula I Have one or more of the following characteristics:

[0069] 1) L1' is When one end of L1' is a carbonyl group, one end of L1 is an alkylene group; when one end of L1' is an alkylene group, one end of L1 is a carbonyl group;

[0070] 2) L3 is a bond or is selected from the following structures:

[0071] 3) L4 is independently a bond or selected from the following structures:

[0072] Lys(COC2H4CO)(NH(CH2CH2O)2CH2CH2NH), -NH(CH2)5COGlu, -NH(CH2)5COGlu(Glu)2 and -NH(CH2)5COGlu(Glu(NH(CH2CH2O)2CH2CH2NH)2)2;

[0073] 4) L5 is selected from a bond, GlyPheLeuGly, -NH(CH2)5C(O)Glu(Glu(GlyNHN=)2)2, -NH(CH2)5C(O)-, -NH((CH2)2O)2CH2CH2NH- and -NH((CH2)2O)2CO-.

[0074] 5)n 11 =1, 2, or 3;

[0075] 6)n 21 =1 or 2;

[0076] 7)n 31 =1, 2, 3 or 4.

[0077] In some embodiments, in Formula I Have one or more of the following characteristics:

[0078] 1) L1 is When one end of L1 is an alkylene group, one end of L1' is a carbonyl group; when one end of L1 is a carbonyl group, one end of L1' is an alkylene group;

[0079] 2) L2 is a Lys residue;

[0080] 3) L3 is a bond or is selected from the following structures:

[0081] -NH(CH2)2C(O)-,

[0082] 4) L4 is independently a bond or selected from the following structures:

[0083] LysNH(CH2)5COGlu(Glu)2, -NH(CH2)5COGlu(Glu(NHCH2CH2NH)2)2 and -NH(CH2)5COGlu(Glu(NH(CH2CH2O)2CH2CH2NH)2)2;

[0084] 5) L5 is independently selected from the following structures:

[0085] GlyPheLeuGly, -NH(CH2)5C(O)Glu(Glu(GlyNHN=)2)2, -C(O)(CH2)2C(O)-, -C(O)(CH2)2C(O)-GlyPheLeuGly- and

[0086] 6)n 12 =2, 3 or 4;

[0087] 7)n 21 =1, 2, or 3;

[0088] 8)n 32 =1, 4 or 5.

[0089] In this article, when the specific selection of a divalent or higher-valent group in the general formula does not indicate its connection direction with other connected groups, the left end is connected to the group close to M and the right end is connected to the group close to D.

[0090] Herein, -y1D or -y2D in each general formula represents that the number of Ds to which one L5 can be connected is y1 or y2, respectively.

[0091] Herein, when L5 is -NH-N= or a group containing -NH-N=, -NH-N= is the structural fragment formed after L5 is connected to D. Before being connected to D (i.e., when L5 is present in an intermediate of the compound described herein), L5 can be -NH-NH-.

[0092] Herein, unless otherwise disclosed, the amino acids used in the preparation of the compounds and the amino acid residues in the structural formulas of the compounds are in the natural configuration (L-form, except glycine Gly).

[0093] In some embodiments, the compound is selected from:

[0094] intermediates

[0095] The present application prepares a dual-drug (or triple-drug) polyethylene glycol small molecule through unique molecular design and protecting group chemistry. Therefore, the present application also provides an intermediate compound of formula II-XX for synthesizing the compound described in the present application.

[0096] In one aspect, the present application provides a compound represented by formula II or a pharmaceutically acceptable salt thereof,

[0097] wherein Pg1 and Pg1′ are independently hydrogen or an amino protecting group, and Pg1 and Pg1′ are different; preferably, the amino protecting group is selected from an alkyl protecting group (e.g., Bn, Trt, DMB, or PMB) and an alkoxycarbonyl protecting group (e.g., Boc, Fmoc, Cbz, or Teoc); preferably, Pg1 is hydrogen and Pg1′ is an amino protecting group; or, Pg1 is an amino protecting group and Pg1′ is hydrogen;

[0098] The remaining groups are as defined in any of the above items.

[0099] In some embodiments, the compound is selected from:

[0100] In another aspect, the present application provides a compound of formula III or a pharmaceutically acceptable salt thereof,

[0101] wherein each Pg3 is independently hydrogen or selected from an amino and carboxyl protecting group, the amino protecting group is selected from an alkoxycarbonyl protecting group, such as Boc, Fmoc, Cbz or Teoc; the carboxyl protecting group is selected from an ester protecting group, such as a methyl ester, an ethyl ester, a tert-butyl ester, an allyl ester or a benzyl ester; preferably, each Pg3 is independently hydrogen or a carboxyl protecting group, such as an ester protecting group, such as a methyl ester, an ethyl ester, a tert-butyl ester, an allyl ester or a benzyl ester, preferably a tert-butyl ester or a benzyl ester; preferably, each Pg3 is the same, preferably all are tert-butyl esters or benzyl esters;

[0102] Pg4 is hydrogen or a side chain protecting group of L2, preferably, the protecting group is selected from an amino protecting group and a carboxyl protecting group, preferably, the amino protecting group is selected from an alkoxycarbonyl protecting group, such as Boc, Fmoc, Cbz or Teoc, preferably, the carboxyl protecting group is selected from an ester protecting group, such as methyl ester, ethyl ester, tert-butyl ester, allyl ester or benzyl ester, preferably, Pg4 is an amino protecting group, preferably, Pg4 is Boc or Cbz;

[0103] Pg5 is hydrogen or an amino protecting group, wherein the amino protecting group is selected from an alkoxycarbonyl protecting group, such as Boc, Fmoc, Cbz or Teoc; preferably, Pg5 is hydrogen or Fmoc;

[0104] Definitions of the remaining groups The definitions of the remaining groups are as defined in any of the above items.

[0105] In some embodiments, the compound is selected from:

[0106] In another aspect, the present application provides a compound of formula IV or a pharmaceutically acceptable salt thereof,

[0107] wherein each of Pg6 and Pg7 is independently hydrogen or selected from an amino protecting group, preferably, the amino protecting group is selected from an alkyl protecting group (e.g., Bn, Trt, DMB or PMB) and an alkoxycarbonyl protecting group (e.g., Boc, Fmoc, Cbz or Teoc);

[0108] The remaining groups are as defined in any of the above items.

[0109] In another aspect, the present application provides a compound of formula V or a pharmaceutically acceptable salt thereof,

[0110] wherein each group is as defined in any one of the above items.

[0111] In some embodiments, the compound is selected from:

[0112] In another aspect, the present application provides a compound represented by formula VI or a pharmaceutically acceptable salt thereof,

[0113] wherein each group is as defined in any one of the above items.

[0114] In another aspect, the present application provides a compound represented by formula VII or a pharmaceutically acceptable salt thereof,

[0115] wherein each group is as defined in any one of the above items.

[0116] In some embodiments, the compound is selected from:

[0117] In another aspect, the present application provides a compound represented by formula VIII or a pharmaceutically acceptable salt thereof,

[0118] wherein each of Pg2 and Pg2′ is independently hydrogen or a carboxyl protecting group, preferably, the carboxyl protecting group is selected from an ester protecting group, such as a methyl ester, an ethyl ester, a tert-butyl ester, an allyl ester or a benzyl ester;

[0119] Preferably, Pg2 is hydrogen, and Pg2' is a carboxyl protecting group; Pg2 is a carboxyl protecting group, and Pg2' is hydrogen; or, both Pg2 and Pg2' are carboxyl protecting groups (e.g., tert-butyl ester or benzyl ester), and Pg2 and Pg2' are different;

[0120] The remaining groups are as defined in any of the above items.

[0121] In some embodiments, the compound is selected from:

[0122] In another aspect, the present application provides a compound represented by formula IX or a pharmaceutically acceptable salt thereof,

[0123] wherein each group is as defined in any one of the above items.

[0124] In some embodiments, the compound is selected from:

[0125] In another aspect, the present application provides a compound represented by formula X or a pharmaceutically acceptable salt thereof,

[0126] wherein each group is as defined in any one of the above items.

[0127] In some embodiments, the compound is selected from:

[0128] In another aspect, the present application provides a compound represented by formula XI or a pharmaceutically acceptable salt thereof,

[0129] wherein each group is as defined in any one of the above items.

[0130] In some embodiments, the compound is selected from:

[0131] In another aspect, the present application provides a compound represented by formula XII or a pharmaceutically acceptable salt thereof,

[0132] wherein each group is as defined in any one of the above items.

[0133] In some embodiments, the compound is selected from:

[0134] In another aspect, the present application provides a compound represented by formula XIII or a pharmaceutically acceptable salt thereof,

[0135] wherein each group is as defined in any one of the above items.

[0136] In some embodiments, the compound is selected from:

[0137] In another aspect, the present application provides a compound represented by formula XIV or a pharmaceutically acceptable salt thereof,

[0138] wherein each group is as defined in any one of the above items.

[0139] In some embodiments, the compound is selected from:

[0140] In another aspect, the present application provides a compound represented by formula XV or a pharmaceutically acceptable salt thereof,

[0141] wherein Pg7′ is hydrogen or selected from amino and carboxyl protecting groups; preferably, the amino protecting group is selected from alkyl protecting groups (e.g., Bn, Trt, DMB, or PMB) and alkoxycarbonyl protecting groups (e.g., Boc, Fmoc, Cbz, or Teoc), and the carboxyl protecting group is selected from ester protecting groups (e.g., methyl ester, ethyl ester, tert-butyl ester, allyl ester, or benzyl ester);

[0142] The remaining groups are as defined in any of the above items.

[0143] In some embodiments, the compound is selected from:

[0144] In another aspect, the present application provides a compound represented by formula XVI or a pharmaceutically acceptable salt thereof,

[0145] wherein each group is as defined in any one of the above items.

[0146] In some embodiments, the compound is selected from:

[0147] In another aspect, the present application provides a compound represented by formula XVII or a pharmaceutically acceptable salt thereof,

[0148] wherein each Pg3′ is independently hydrogen or selected from an amino and a carboxyl protecting group, the amino protecting group being selected from an alkoxycarbonyl protecting group, such as Boc, Fmoc, Cbz or Teoc; the carboxyl protecting group being selected from an ester protecting group, such as a methyl ester, an ethyl ester, a tert-butyl ester, an allyl ester or a benzyl ester; preferably, each Pg3 is independently hydrogen or a carboxyl protecting group, such as an ester protecting group, such as a methyl ester, an ethyl ester, a tert-butyl ester, an allyl ester or a benzyl ester, preferably a tert-butyl ester or a benzyl ester; preferably, each Pg3 is the same, preferably all are tert-butyl esters or benzyl esters;

[0149] The remaining groups are as defined in any of the above items.

[0150] In some embodiments, the compound is selected from:

[0151] In another aspect, the present application provides a compound of formula XVIII or a pharmaceutically acceptable salt thereof,

[0152] wherein each group is as defined in any one of the above items.

[0153] In some embodiments, the compound is selected from:

[0154] In another aspect, the present application provides a compound represented by formula XIX or a pharmaceutically acceptable salt thereof,

[0155] wherein each group is as defined in any one of the above items.

[0156] In some embodiments, the compound is selected from:

[0157] In another aspect, the present application provides a compound represented by the general formula XX or a pharmaceutically acceptable salt thereof,

[0158] wherein each group is as defined in any one of the above items.

[0159] In some embodiments, the compound is selected from:

[0160] Pharmaceutical composition

[0161] In another aspect, the present application provides a pharmaceutical composition comprising an effective amount of the compound described in any one of the present application or a pharmaceutically acceptable salt thereof for treating and / or preventing a disease.

[0162] In some embodiments, the composition further contains one or more pharmaceutically acceptable excipients.

[0163] In some embodiments, the pharmaceutical composition is prepared in the form of an injection.

[0164] The present application further provides an injection comprising the compound described in any one of the present application or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0165] In some embodiments, the injection solution uses physiological saline as a carrier.

[0166] Medical uses and treatments

[0167] In another aspect, the present application provides use of a compound described herein or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing a disease (eg, cancer).

[0168] In another aspect, the present application provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in treating and / or preventing a disease (eg, cancer).

[0169] In another aspect, the present application provides a method for treating and / or preventing a disease (eg, cancer), comprising administering to a subject in need thereof a therapeutically and / or preventively effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.

[0170] Herein, the cancer is selected from the group consisting of colon cancer, leukemia, lymphoma, bladder cancer, bone cancer, brain tumor, medulloblastoma, glioma, breast cancer, adenoma / carcinoid, adrenocortical carcinoma, islet cell carcinoma, cervical cancer, endometrial cancer, ovarian cancer, colorectal cancer, skin cancer, esophageal cancer, eye cancer, gallbladder cancer, gastric cancer, head and neck cancer, liver cancer, melanoma, Kaposi's sarcoma, kidney cancer, oral cancer, lung cancer, nasopharyngeal cancer, neuroblastoma, ovarian cancer, pancreatic cancer, thyroid cancer, parathyroid cancer, penile cancer, prostate cancer, urethra cancer, vaginal cancer, vulvar cancer, anal cancer, sarcoma, and metastases of the aforementioned cancers.

[0171] Preparation method

[0172] In another aspect, the present application also relates to the use of the intermediates described herein (including compounds described in any one of Formula II to Formula XX or pharmaceutically acceptable salts thereof) in the preparation of drugs. In some embodiments, the drug is selected from the compound of Formula I described herein or a pharmaceutically acceptable salt thereof.

[0173] Furthermore, the present application provides a method for preparing the compound of general formula I and its intermediates.

[0174] In some embodiments, the compound of formula II is used as a starting material, and the L1 or L1' fragment is selectively inserted to obtain a compound of formula XIX or XX. Further, the compound of formula XIX or XX is inserted into the L1' or L1 fragment to obtain a compound of formula VIII.

[0175] In some embodiments, the L2 fragment and the L3 fragment are linked to provide a compound of Formula III.

[0176] In some embodiments, the L4 fragment and the L5 fragment are linked to provide a compound of Formula IV.

[0177] In some embodiments, the compound of formula V is obtained by the following method:

[0178] (1) reacting a compound of formula III with a compound of formula IV;

[0179] (2) the compound of formula III is sequentially linked to the L4 fragment and the L5 fragment;

[0180] (3) The compound of formula IV sequentially connects the L3 fragment and the L2 fragment.

[0181] In some embodiments, a compound of formula VIII is reacted with a compound of formula III, or sequentially reacted with an L2 fragment and an L3 fragment, to provide a compound of formula IX.

[0182] In some embodiments, the compound of formula IX is ligated into the L4 fragment to obtain the compound of formula X.

[0183] In some embodiments, the compound of formula IX and the compound of formula IV are reacted to provide the compound of formula XI.

[0184] In some embodiments, the compound of formula VIII is incorporated into the L3 fragment, or the compound of formula XIX is linked to the L1′-L3 fragment to obtain the compound of formula XIII.

[0185] In some embodiments, the compound of formula VIII is ligated into the L5-y1D fragment to provide the compound of formula XIV, wherein L3 and L4 are both bonds.

[0186] In some embodiments, the compound of formula XV is obtained by the following method:

[0187] (1) The compound of formula IX is sequentially inserted into the L3 fragment, the L4 fragment, and the L5 fragment;

[0188] Alternatively, (2) the compound of formula IX and Fragment reaction.

[0189] In some embodiments, the compound of formula XIV and the compound of formula III are reacted to provide the compound of formula XVI.

[0190] In some embodiments, the compound of formula XIII and the compound of formula V are reacted to provide the compound of formula XVII.

[0191] In some embodiments, the compound of formula XIV and the compound of formula VII are reacted to provide the compound of formula XVIII.

[0192] In the above embodiments, each fragment includes its protected form or deprotected form. The choice of protecting group can be determined according to the common technical knowledge in the art, or as defined above.

[0193] In the above embodiment, before or after each reaction, a step of protecting the amino group or the carboxyl group, or deprotecting the amino group or the carboxyl group is optionally included.

[0194] In some embodiments, the method for preparing the compound of formula I is selected from the following routes:

[0195] Route 1:

[0196] (1) reacting the compound of formula XII with PEG having an activated group to obtain intermediate 1-1;

[0197] (2) The intermediate 1-1 obtained in step (1) is mixed with Reaction to obtain the compound of general formula I;

[0198] Route 2:

[0199] (1) reacting the compound of formula IX with PEG having an activated group to obtain intermediate 2-1;

[0200] (2) The intermediate 2-1 obtained in step (1) is directly reacted with Reaction, or step-by-step connection fragments (e.g., stepwise connection of L3, L4, L5, and D, or L3-(L4) n21 , L5 and D, or L3-(L4) n21 , L5-y1D, or L3-(L4-(L5) n31 ) n21 and D), to obtain intermediate 2-2;

[0201] (3) reacting the intermediate 2-2 obtained in step (2) directly with a compound of formula VI, or reacting with a compound of formula IV and the cytotoxic drug in steps, or connecting L4 and L5-y2D in steps, or connecting L4, L5 and D in steps to obtain a compound of formula I;

[0202] Alternatively, swap the order of steps (2) and (3);

[0203] Route 3:

[0204] (1) reacting the intermediate 2-1 obtained in step (1) of route 2 with a compound of formula VI to obtain intermediate 3-1;

[0205] (2) The intermediate 3-1 obtained in step (1) is mixed with Reaction to obtain the compound of formula I;

[0206] Route 4:

[0207] (1) reacting the compound of formula X with PEG having an activated group to obtain intermediate 4-1;

[0208] (2) The intermediate 4-1 obtained in step (1) is mixed with Reaction to obtain intermediate 4-2, wherein n 31 '+n 31 ”=n 31 ;

[0209] (3) reacting the intermediate 4-2 obtained in step (2) with H-L5-y2D to obtain intermediate 4-3;

[0210] (4) reacting the intermediate 4-3 obtained in step (3) with H-L5-y1D to obtain the compound of formula I;

[0211] Alternatively, in step (2) Replace with At this point, step (4) will no longer be performed;

[0212] Alternatively, using the compound of formula XII as a raw material, carrying out steps (1), (2) and (4) to obtain the compound of formula I;

[0213] Route 5:

[0214] (1) reacting the compound of formula XI with PEG having an activated group to obtain intermediate 5-1;

[0215] (2) The intermediate 5-1 obtained in step (1) is directly reacted with Reaction or stepwise ligation fragments (e.g., stepwise connection of L3, L4, L5, and D, or L3-(L4) n21 , L5 and D, or L3-(L4) n21 , L5-y1D, or L3-(L4-(L5) n31 ) n21 and D), to obtain intermediate 5-2;

[0216] (3) reacting the intermediate 5-2 obtained in step (2) with the cytotoxic drug to obtain the compound of formula I;

[0217] Route 6:

[0218] (1) reacting a compound of formula XIV with a compound of formula VII to obtain intermediate 6-1;

[0219] (2) reacting the intermediate 6-1 obtained in step (1) with PEG having an activated group to obtain the compound of formula I;

[0220] Route 7:

[0221] (1) reacting the compound of formula XIII with PEG having an activated group to obtain intermediate 7-1;

[0222] (2) reacting the intermediate 7-1 obtained in step (1) with H-L4 to obtain intermediate 7-2;

[0223] (3) The intermediate 7-2 obtained in step (2) is mixed with Reaction to obtain intermediate 7-3;

[0224] (4) reacting the intermediate 7-3 obtained in step (3) with L5-y2Pg7 or L5'-y2Pg7 to obtain intermediate 7-4;

[0225] (5) reacting the intermediate 7-4 obtained in step (4) with the cytotoxic drug or L5″-y2D to obtain the compound of formula I; wherein L5′ and L5″ are connected to form L5;

[0226] Route 8:

[0227] (1) reacting the compound of formula XV with PEG having an activated group to obtain intermediate 8-1;

[0228] (2) reacting the intermediate 8-1 obtained in step (1) with a compound of formula VI to obtain intermediate 8-2;

[0229] (3) reacting the intermediate 8-2 obtained in step (3) with the cytotoxic drug to obtain the compound of formula I;

[0230] Route 9:

[0231] (1) reacting the compound of formula XVII with PEG having an activated group to obtain intermediate 9-1;

[0232] (2) reacting the intermediate 9-1 obtained in step (1) with H-L5-y1D to obtain intermediate 9-2;

[0233] (3) reacting the intermediate 9-2 obtained in step (2) with the cytotoxic drug to obtain the compound of formula I;

[0234] Route 10:

[0235] (1) reacting a compound of formula XIV with a compound of formula III to obtain intermediate 10-1;

[0236] (2) reacting the intermediate 10-1 obtained in step (1) with PEG having an activated group to obtain the intermediate 10-2;

[0237] (3) The intermediate 10-2 obtained in step (2) was reacted with H-L4-n 32 Pg6' reaction to obtain intermediate 10-3;

[0238] (4) reacting the intermediate 10-3 obtained in step (3) with H-L5-y2D to obtain the compound of formula I;

[0239] Optionally, before or after the reaction of any step in Schemes 1-10, a step of removing the protecting group and / or activating (eg, carbonyl activation) is further included;

[0240] Preferably, the PEG activating group is

[0241] The remaining compounds and groups are as defined in any of the above items.

[0242] Definition of terms

[0243] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

[0244] The terms "comprises," "comprising," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

[0245] As used herein, the term "pharmaceutically acceptable carrier" refers to a carrier that is pharmacologically and / or physiologically compatible with the subject and the active ingredient, which is well known in the art (see, for example, Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19 th ed. Pennsylvania: Mack Publishing Company, 1995), and include, but are not limited to, pH adjusters, surfactants, adjuvants, ionic strength enhancers, diluents, agents that maintain osmotic pressure, agents that delay absorption, and preservatives. For example, pH adjusters include, but are not limited to, phosphate buffers. Surfactants include, but are not limited to, cationic, anionic, or nonionic surfactants, such as Tween-80. Ionic strength enhancers include, but are not limited to, sodium chloride. Preservatives include, but are not limited to, various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. Agents that maintain osmotic pressure include, but are not limited to, sugars, NaCl, and their analogs. Agents that delay absorption include, but are not limited to, monostearate and gelatin. Diluents include, but are not limited to, water, aqueous buffers (such as buffered saline), alcohols, and polyols (such as glycerol). Preservatives include, but are not limited to, various antibacterial and antifungal agents, such as thimerosal, 2-phenoxyethanol, parabens, chlorobutanol, phenol, sorbic acid, and the like. Stabilizers have the meaning generally understood by those skilled in the art, and are capable of stabilizing the desired activity of the active ingredient in the drug, including but not limited to sodium glutamate, gelatin, SPGA, sugars (such as sorbitol, mannitol, starch, sucrose, lactose, dextran, or glucose), amino acids (such as glutamic acid, glycine), proteins (such as dried whey, albumin or casein) or their degradation products (such as lactalbumin hydrolysate), etc.

[0246] As used herein, the term "preventing" refers to methods performed to prevent or delay the occurrence of a disease, disorder, or symptom (eg, a tumor) in a subject.

[0247] As used herein, the term "treatment" refers to a method implemented in order to obtain a beneficial or desired clinical outcome. For the purposes of the present invention, beneficial or desired clinical outcomes include, but are not limited to, alleviating symptoms, reducing the scope of the disease, stabilizing (i.e., no longer worsening) the state of the disease, delaying or slowing the development of the disease, improving or alleviating the state of the disease, and alleviating symptoms (whether partially or completely), whether detectable or undetectable. In addition, "treatment" can also refer to extending survival compared to the expected survival (if not receiving treatment).

[0248] As used herein, the term "subject" refers to a mammal, such as a primate mammal, such as a human. In certain embodiments, the subject (eg, human) suffers from a tumor, or is at risk of suffering from the above-mentioned disease.

[0249] As used herein, the term "effective amount" refers to an amount sufficient to obtain or at least partially obtain the desired effect. For example, an effective amount for preventing a disease (e.g., a tumor) refers to an amount sufficient to prevent, stop, or delay the occurrence of a disease (e.g., a tumor); an effective amount for treating a disease refers to an amount sufficient to cure or at least partially stop the disease and its complications in a patient already suffering from the disease. Determining such an effective amount is well within the capabilities of those skilled in the art. For example, an amount effective for therapeutic use will depend on the severity of the disease to be treated, the overall state of the patient's own immune system, the patient's general condition such as age, weight and sex, the mode of administration of the drug, and other treatments administered simultaneously, etc.

[0250] The terms "cancer" and "tumor" are used interchangeably to refer to a broad category of diseases characterized by the uncontrolled growth of abnormal cells in the body. Unregulated cell division may lead to the formation of malignant tumors, or cells that invade adjacent tissues and may spread to distant parts of the body via the lymphatic system or bloodstream. Cancer includes both benign and malignant cancers, as well as dormant tumors or micrometastases. Cancer also includes blood cancers, particularly hematologic malignancies.

[0251] The term "hydrocarbon group" refers to a group obtained by losing a hydrogen atom from a corresponding hydrocarbon, including monovalent hydrocarbon groups, divalent hydrocarbon groups, and trivalent hydrocarbon groups. For example, C 2-10 Trivalent hydrocarbon group, C 2-6 A trivalent saturated hydrocarbon group.

[0252] The term "alkyl" is defined as a straight or branched chain saturated aliphatic hydrocarbon group. In some embodiments, the alkyl group has 1 to 12, such as 1 to 6, carbon atoms. For example, as used herein, the term "C1-6 "Alkyl" refers to a linear or branched group of 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl).

[0253] The term "alkylamino" refers to a group having the structure "alkyl-NH-", wherein the alkyl group is as defined above. 1-6 Alkylamino, C 1-4 Alkylamino, C 1-3 Alkylamino or C 1-2 Alkylamino, etc. Common alkylamino groups include (but are not limited to) methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, tert-butylamino, pentylamino, hexylamino, etc.

[0254] The structural formula of PTX is:

[0255] The structural formula of PCB is:

[0256] The structural formula of SN38 is:

[0257] The structural formula of NPB is:

[0258] The structural formula of AXT is:

[0259] The structural formula of LPT is:

[0260] The structural formula of DOX is:

[0261] The structural formula of Ac-C-PLGLAG-iRGD is:

[0262] The structural formula of SB7 is:

[0263] The structural formula of folic acid is:

[0264] The structural formula of sodium dodecahydrogen dodecaborate is

[0265] The structural formula of IRN is:

[0266] As used herein, the term "amino acid" mainly includes the following 20 common amino acids: alanine (Ala), arginine (Arg), aspartic acid (Asn), asparagine (Asp), cysteine ​​(Cys), glutamine (Gln), glutamic acid (Glu), glycine (Gly), histidine (His), leucine (Leu), isoleucine (Ile), lysine (Lys), methionine (methionine) (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr) and valine (Val). Except for glycine, the remaining amino acids are L-configuration. It is known that amino acid molecules contain two functional groups, amino and carboxyl groups. The "amino acid residue" described herein refers to the remaining portion after removing a hydrogen from the amino group and / or lacking a hydroxyl group from the carboxyl group in the amino acid molecule. DETAILED DESCRIPTION

[0267] The embodiments of the present disclosure will be described in detail below with reference to the examples. However, it should be understood by those skilled in the art that the following examples are only used to illustrate the embodiments of the present disclosure and should not be considered to limit the scope of the present disclosure. Where specific conditions are not specified in the examples, the experiments were carried out according to conventional conditions or the conditions recommended by the manufacturer. Where the manufacturer of the reagents or instruments is not specified, they are all conventional products that can be obtained commercially.

[0268] Example 1 Synthesis of Compound 81-214

[0269] 1.1 Preparation of 62-13

[0270] 6-Aminocaproic acid (15 g, 114.3554 mmol), 1,4-dioxane (200 ml), and purified water (100 ml) were added to a 1 L round-bottom flask. Ultrasonication was used to dissolve the mixture. After stirring at -5°C for 30 minutes, an aqueous sodium hydroxide solution (5 g NaOH + 20 ml purified water) was added. After stirring at -5°C for 30 minutes, di-tert-butyl dicarbonate (34.9 g, 160.09 mmol) was added and the mixture was allowed to stir at room temperature overnight. After the reaction was complete, the reaction mixture was transferred to a 2 L separatory funnel and extracted with purified water (300 ml) and ethyl acetate (350 ml). Dilute hydrochloric acid was added dropwise to adjust the pH until acidic. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (200 ml x 3). The combined organic phases were concentrated and evaporated to dryness to yield 24 g of the product.

[0271] 1.2 Preparation of 64-152

[0272] 6-Aminohexanoic acid (9.19 g, 70.06 mmol) was placed in a 1L round-bottom flask and dissolved in a 1 / 1 THF / H₂O solution (150 ml). The mixture was then stirred in a 0°C reaction bath for 1 hour. Anhydrous sodium carbonate (14.85 g, 140.12 mmol) was then added and ultrasonically dissolved. The reaction flask was then stirred in a 0°C reaction bath for another 30 minutes. Cbz-Cl (12.5494 g, 73.56 mmol) was then dissolved in THF (30 ml) and slowly added dropwise to the reaction flask. After the addition was complete, the reaction flask was removed from the 0°C reaction bath and stirred at room temperature for 2.5 hours. After the reaction was complete, the mixture was extracted with ethyl acetate (200 ml) and purified water (100 ml). The pH was adjusted to a slightly acidic state with dilute hydrochloric acid, and the organic phase was collected. The aqueous phase was then extracted again with ethyl acetate (200 ml). The combined organic phases were concentrated and dehydrated with anhydrous magnesium sulfate. 200-300 mesh silica gel powder (25 g) was then added and evaporated to dryness. Dry-load the sample and perform column chromatography using 30-70% ethyl acetate / petroleum ether as the eluent. The desired product was collected, concentrated, and dried to obtain 11.6 g of the product, with a yield of 62.41%.

[0273] 1.3 Preparation of 64-100

[0274] Boc-L-Leucine (30 g, 129.70 mmol), benzyl glycine hydrochloride (28.77 g, 142.67 mmol), HBTU (73.78 g, 194.56 mmol), and HOBT (26.28 g, 194.56 mmol) were added to a 1000 ml flask. DMF (50 ml) was added to dissolve the mixture, and the mixture was stirred at -5°C for approximately 20 minutes. DIEA (96.5 ml, 583.68 mmol) was then slowly added dropwise. After the addition was complete, stirring was continued at -5°C for 1 hour, and the mixture was then allowed to react at room temperature with stirring. Upon completion of the reaction, the reaction mixture was transferred to a 2 L separatory funnel and extracted with saturated sodium bicarbonate solution (250 ml) and ethyl acetate (300 ml). The aqueous phase was then extracted with ethyl acetate (200 ml x 3). The organic phases were combined, washed with saturated brine (200 ml x 2), dehydrated with anhydrous magnesium sulfate, concentrated, and evaporated to dryness to obtain 50.9873 g of the product.

[0275] 1.4 Preparation of 64-101

[0276] 64-100 (49.08 g, 129.70 mmol) was placed in a 1000 ml flask and dissolved in dichloromethane (60 ml). TFA (96.3 ml, 1297.0 mmol) was added with stirring and the mixture was stirred at room temperature overnight. After the reaction was complete, the reaction solution was concentrated and poured into a 2 L separatory funnel filled with saturated sodium bicarbonate solution (350 ml) and ethyl acetate (300 ml). The organic phase was collected and the aqueous phase was extracted with ethyl acetate (150 ml x 2). The organic phases were combined, concentrated, dehydrated with anhydrous magnesium sulfate, and evaporated to dryness to obtain 29.3 g of the product.

[0277] 1.5 Preparation of 64-102

[0278] 64-101 (29.3 g, 105.26 mmol), Boc-L-phenylalanine (33.51 g, 126.31 mmol), HBTU (59.88 g, 157.89 mmol) and HOBT (21.33 g, 157.89 mmol) were added to a 1000 ml flask, and DMF (200 ml) was added to dissolve them. The reaction was stirred at -5 degrees Celsius for 20 minutes, and DIEA (104.4 ml, 631.57 mmol) was slowly added dropwise. After the addition was complete, stirring was continued at -5 degrees Celsius for 1 hour, and then moved to room temperature and stirred overnight. After the reaction was completed, the reaction solution was transferred to a 2 L separatory funnel, and saturated sodium bicarbonate solution (350 ml) and ethyl acetate (300 ml) were added for extraction. The organic phase was collected, and the aqueous phase was extracted with ethyl acetate (200 ml x 3). The organic phases were combined, washed with saturated sodium chloride solution (250 ml x 2), concentrated, dehydrated with anhydrous magnesium sulfate, and evaporated to dryness to obtain 49.4 g of the product.

[0279] 1.6 Preparation of 64-105

[0280] Compound 64-102 (49.4 g, 93.98 mmol) was placed in a 1000 ml flask and dissolved in dichloromethane (60 ml). TFA (71.0 ml, 939.8 mmol) was added with stirring and the mixture was stirred at room temperature overnight. Upon completion of the reaction, the reaction solution was concentrated and poured into a 2 L separatory funnel containing saturated sodium bicarbonate solution (350 ml) and ethyl acetate (300 ml). Extraction was performed to obtain an organic phase, and the aqueous phase was further extracted with ethyl acetate (150 ml x 2). The combined organic phases were concentrated, dehydrated with anhydrous magnesium sulfate, and evaporated to dryness to yield 32.7 g of the product.

[0281] 1.7 Preparation of 64-106

[0282] 64-105 (32.7 g, 76.84 mmol), Boc-Gly-OH (16.15 g, 92.21 mmol), HBTU (45.71 g, 115.27 mmol) and HOBT (15.57 g, 115.27 mmol) were added to a 1000 ml flask, and DMF (200 ml) was added to dissolve them. The reaction was stirred at -5 degrees Celsius for about 20 minutes, and then DIEA (76.2 ml, 461.0832 mmol) was slowly added dropwise. After the addition was complete, stirring was continued at -5 degrees Celsius for 1 hour, and then moved to room temperature and stirred overnight. After the reaction was completed, the reaction solution was transferred to a 2 L separatory funnel, and saturated sodium bicarbonate solution (300 ml) and ethyl acetate (350 ml) were added for extraction. The organic phase was collected, and the aqueous phase was extracted with ethyl acetate (200 ml x 3). The combined organic phases were washed with saturated sodium chloride solution (250 ml x 2) and allowed to stand at room temperature for 1.5 hours to precipitate solids. The solids were filtered and the filter cake was washed with a 3 / 7 ethyl acetate / petroleum ether mixture (150 ml x 5) to obtain 34.6 g of the product.

[0283] 1.8 Preparation of 71-85

[0284] 64-106 (10 g, 17.16 mmol) was added to a hydrogenation reactor, along with a 10% Pd / C catalyst (0.1 g) and DMF (40 ml). Hydrogen was introduced at a pressure of 300 psi and the reaction was stirred at room temperature overnight. After the reaction, the reaction mixture was filtered through a Buchner funnel containing qualitative filter paper. The filter cake was washed with DMF (10 ml x 3) and the filtrate was collected and used as the raw material for the next step.

[0285] 1.9 Preparation of 64-134

[0286] 71-85 (8.45 g, 17.16 mmol), PCB (6.40 g, 14.30 mmol, purchased from Tianjin Famoxi), HBTU (8.13 g, 21.45 mmol), and HOBT (2.89 g, 21.45 mmol) were added to a 500 ml round-bottom flask. DMF (80 ml) was added to dissolve the mixture. The reaction was stirred at -5°C for approximately 20 minutes. DIEA (11.8 ml, 71.5076 mmol) was then slowly added dropwise. The mixture was stirred at -5°C for 1 hour. The mixture was removed and stirred at room temperature. After the reaction was completed, methyl tert-butyl ether (450 ml) was added to allow the mixture to settle. The solid precipitated and was filtered. The filter cake was redissolved in an appropriate amount of DMF and then methyl tert-butyl ether (450 ml) was added to allow the mixture to settle. This was repeated three times. The filter cake was collected and dried to yield 13.7 g of the product.

[0287] 1.10 64-135 Preparation

[0288] 64-134 (13.18 g, 14.30 mmol) was added to a 250 ml round-bottom flask, and dichloromethane (30 ml) was added. After dissolution with ultrasonication, TFA (10.6 ml, 143.0 mmol) was added and the reaction was stirred at room temperature overnight. After completion of the reaction, the mother liquor was concentrated and evaporated to dryness to remove the dichloromethane, and methyl tert-butyl ether (300 ml) was added to allow precipitation. The precipitated solid was filtered, and the filter cake was washed three times with methyl tert-butyl ether (40 ml). The filter cake was collected and vacuum dried to obtain 16.6 g of the product.

[0289] 1.11 Preparation of 81-189

[0290] 64-138 (5.6 g, 6.81 mmol) was placed in a 500 ml round-bottom flask and then DMF (10 ml) was added. The mixture was dissolved with ultrasonication. The mixture was stirred at 0°C for 5 minutes, and DIEA (5.62 ml, 34.05 mmol) was slowly added dropwise. The reaction was continued with stirring for 3 minutes, and then succinic anhydride (2.04 g, 20.42 mmol) was added. After the reaction was completed, methyl tert-butyl ether (450 ml) was added to precipitate the mixture. The mixture was treated with ultrasonication and allowed to stand. The upper liquid was poured out, and the lower oily substance was dissolved with an appropriate amount of a 1 / 9 methanol / dichloromethane mixed solvent. Methyl tert-butyl ether (200 ml) was added to precipitate the solid, which was filtered and the filter cake was collected and dried to obtain 5.5 g of the product.

[0291] 1.12 Preparation of 81-181

[0292] Reactants 71-85 (5.08 g, 10.32 mmol), lapatinib (5 g, 8.60 mmol, purchased from Shanghai Hengxin), HOBT (1.39 g, 10.32 mmol), and HBTU (3.91 g, 10.32 mmol) were placed in a reaction flask. DMF (20 ml) was added and dissolved with ultrasonication. The mixture was stirred at 0°C. DIEA (7.11 mmol, 43.02 mmol) was added dropwise. After complete addition, the mixture was brought to room temperature and stirred for 3 hours. After completion of the reaction, the mixture was extracted with deionized water (400 ml) and ethyl acetate (400 ml). The organic phase was collected and the aqueous phase was extracted again with ethyl acetate (200 ml). The combined organic phases were washed with saturated sodium bicarbonate solution (100 ml x 2). The organic phases were collected, dehydrated with anhydrous magnesium sulfate, concentrated, and evaporated to dryness to yield 8.48 g of the product.

[0293] 1.13 Preparation of 81-128

[0294] Reactant 81-181 (4.4 g, 4.168 mmol) was added to dichloromethane (10 ml) and then TFA (10 ml), and the mixture was stirred at room temperature. After the reaction, the dichloromethane was removed by rotary evaporation under reduced pressure, and methyl tert-butyl ether (200 ml) was added. A solid precipitated and the mixture was allowed to stand. The supernatant was discarded and dissolved in an appropriate amount of a 1 / 4 methanol / dichloromethane mixture. 200-300 mesh silica gel powder was added and evaporated to dryness. The sample was dry-loaded and subjected to column chromatography using 1% ammonia water / 2% methanol / dichloromethane as the eluent to collect the desired product. The product was concentrated and evaporated to dryness to obtain 3.97 g. 1 H-NMR(600MHz,DMSO-d6)δ9.85(s,1H),8.79-8.67(m,1H),8.56(s,1H),8.26 -7.96(m,5H),7.80(dd,J=4.9,8.8Hz,1H),7.74(ddd,J=2.6,8.8,13.7Hz,1H ),7.47(td,J=6.1,7.9Hz,1H),7.36-7.27(m,3H),7.26-7.03(m,7H),5.26(d ,J=2.0Hz,2H),4.74(d,J=29.3Hz,2H),4.62(d,J=7.9Hz,1H),4.39(dt,J=7. 5,15.6Hz,1H),4.33-4.22(m,1H),4.14(td,J=5.4,16.9,17.4Hz,2H),3.86( t,J=7.4Hz,1H),3.78(t,J=7.5Hz,1H),3.63(t,J=7.6Hz,1H),3.41-3.37(m, 3H),3.05-3.03(m,4H),2.84(ddd,J=5.8,8.7,14.4Hz,1H),1.90(s,2H),1.6 2(dd,J=6.6,13.3Hz,1H),1.50(dd,J=4.8,10.0Hz,2H),0.94-0.76(m,6H); FT MS ESI m / z[M+H + ]955.33

[0295] 1.14 Preparation of 59-60

[0296] Paclitaxel (20 g, 23.42 mmol, purchased from Yingyuanbei, Wuhan, referred to as PTX) and imidazole (7.98 g, 117.12 mmol) were added to a 250 ml round-bottom flask. DMF was added and dissolved with ultrasonication. N2 was purged to evacuate the air. TBDMS-Cl (21.2 g, 142.54 mmol) was added, the nitrogen flow was stopped, and the reaction was continued with stirring at room temperature. Upon completion of the reaction, the reaction solution was transferred to a 1 L separatory funnel and extracted with saturated sodium bicarbonate solution (200 ml) and ethyl acetate (200 ml). The aqueous phase was then extracted with ethyl acetate (150 ml x 2). The combined organic phases were washed with saturated sodium chloride solution (100 ml x 2), collected, concentrated, and added to 200-300 mesh silica gel powder, evaporated to dryness. The sample was dry-loaded and subjected to column chromatography using 0-100% ethyl acetate / petroleum ether as the eluent to collect the desired product. The product was concentrated and evaporated to dryness to obtain 22.7 g.

[0297] 1.15 Preparation of 59-67

[0298] 59-60 (2 g, 7.83 mmol) was dissolved in tetrahydrofuran (20 ml) and stirred at 0°C. DIEA (1.5 ml, 9.04 mmol) was slowly added dropwise, followed by pivaloyl chloride (1.1 ml, 9.04 mmol). After the additions were complete, the reaction mixture was allowed to react at room temperature for 3 h. After confirming the reaction was complete, the reaction mixture was stirred at 0°C. 64-152 (3.65 g, 3.76 mmol) was dissolved in THF (5 ml) and slowly added dropwise to the reaction mixture. DIEA (0.69 ml, 4.1459 mmol) was then added dropwise. After the additions were complete, the reaction mixture was allowed to react at room temperature with stirring. After the reaction was complete, the reaction mixture was removed and poured into a 2 L separatory funnel filled with pure water (300 ml) and ethyl acetate (300 ml). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (100 ml x 2). The organic phases were combined, concentrated to 150 ml, washed with dilute hydrochloric acid (200 ml × 2), and then washed with saturated sodium bicarbonate solution (200 ml × 2). The organic phases were collected and dried in a spin-drying machine to obtain 4.58 g of the product.

[0299] 1.16 Preparation of 59-69

[0300] 59-67 (4.58 g, 3.769 mmol) was dissolved in DMA (30 ml) pretreated with activated carbon and added to a hydrogenation reactor. 10% Pd / C catalyst (250 mg) was then added. A water pump was connected to the reactor, the air was evacuated, and hydrogen was introduced. This process was repeated three times. The hydrogen pressure was adjusted to 1.8 MPa, and the mixture was stirred at high speed at room temperature. After the reaction was completed, the mixture was filtered using a diatomaceous earth-containing filter funnel. The filtrate was poured into a 1 L separatory funnel. Saturated sodium chloride solution (300 ml) and ethyl acetate (300 ml) were added to the separatory funnel for extraction. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (100 ml × 2). The organic phases were combined and washed twice with saturated sodium chloride solution (200 ml). The organic phases were collected and concentrated, and then dissolved in a mixed solvent of dichloromethane and methanol. 200-300 mesh silica gel powder was added and evaporated to dryness. The sample was loaded by dry method and column chromatography was performed using 30% ethyl acetate / petroleum ether and 3-10% methanol / dichloromethane as eluents. The target product was collected and dried to obtain 4.08 g of the product.

[0301] 1.17 Preparation of 81-120

[0302] Boc-Glu-OH (3 g, 12.13 mmol), L-glutamic acid dibenzyl ester p-toluenesulfonate (12.72 g, 25.48 mmol), HBTU (9.66 g, 25.48 mmol), and HOBT (3.44 g, 25.48 mmol) were added to a 500 ml round-bottom flask. DMF (30 ml) was then added to dissolve the mixture. After stirring in an ice-water bath for 3 minutes, DIEA (16.03 ml, 97.04 mmol) was added dropwise and the reaction continued to stir at room temperature. Upon completion of the reaction, the reaction solution was transferred to a 2 L separatory funnel filled with purified water (200 ml) and ethyl acetate (200 ml) for extraction. The organic phase was collected and the aqueous phase was further extracted with ethyl acetate (50 ml x 2). The combined organic phases were washed with saturated sodium bicarbonate solution (50 ml x 2), dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and evaporated to dryness to yield 10.5 g of the product.

[0303] 1.18 Preparation of 81-121

[0304] 81-120 (10.5 g, 12.13 mmol) was placed in a 500 ml round-bottom flask, and dichloromethane (14 ml) was added. Dissolution was assisted by ultrasonication, followed by the addition of TFA (21 ml). The reaction mixture was stirred at room temperature. After the reaction was completed, TFA and dichloromethane were removed by rotary evaporation under reduced pressure. The reaction solution was transferred to a 1 L separatory funnel and extracted with purified water (300 ml) and ethyl acetate (350 ml). The aqueous phase was further extracted with ethyl acetate (100 ml x 3). The combined organic phases were neutralized with saturated sodium bicarbonate solution, dehydrated with anhydrous magnesium sulfate, concentrated under reduced pressure, and evaporated to dryness to obtain 9.28 g of the product.

[0305] 1.19 Preparation of 81-125

[0306] Compounds 62-13 (2.8 g, 12.13 mmol), 81-121 (9.28 g, 12.13 mmol), HBTU (5.05 g, 13.34 mmol), and HOBT (1.8 g, 13.34 mmol) were added to a 500 ml round-bottom flask. DMF (20 ml) was then added to dissolve the mixture. After stirring for 2 min in an ice-water bath, DIEA (8.01 ml, 48.52 mmol) was added and the mixture was stirred at room temperature. Upon completion of the reaction, the reaction solution was transferred to a 2 L separatory funnel and extracted with purified water (200 ml) and ethyl acetate (100 ml). The organic phase was collected, and the aqueous phase was extracted with ethyl acetate (100 ml x 3). The combined organic phases were washed with saturated sodium bicarbonate solution (100 ml x 2), the organic phases were collected, concentrated under reduced pressure, added with 200-300 mesh silica gel powder, evaporated to dryness, and dry-applied. Column chromatography was performed using 1-2.5% methanol / dichloromethane as the eluent to collect the desired product, concentrate, and evaporate to dryness to obtain 10.8 g of the product, with a yield of 91%. FT MS ESI m / z [M+Na + ]1002.34

[0307] 1.20 Preparation of 81-127

[0308] 81-125 (2 g, 2.04 mmol) was added to a hydrogenation reactor, along with a 10% Pd / C catalyst (0.2 g) and methanol (30 ml). Hydrogen was introduced at a pressure of 2 MPa and stirred at 30°C overnight. After the reaction, the reaction solution was filtered through a Buchner funnel containing filter paper, concentrated under reduced pressure, and evaporated to dryness to obtain the product.

[0309] 1.21 Preparation of 81-132

[0310] 81-127 (1.16 g, 1.875 mmol), 81-128 (8.95 g, 9.375 mmol), HBTU (3.55 g, 9.375 mmol), and HOBT (1.26 g, 9.375 mmol) were placed in a 500 ml round-bottom flask. DMF (15 ml) was added to dissolve the mixture, and the mixture was stirred at 0°C for 1 minute. DIEA (5.57 ml, 33.75 mmol) was then slowly added dropwise to continue the reaction. After the reaction, methyl tert-butyl ether (450 ml) was added to allow precipitation. The precipitated solid was filtered. The filter cake was re-dissolved in an appropriate amount of ethyl acetate, stirred at 37°C for 5 minutes, and filtered to collect the filter cake. This process was repeated three times. The filter cake was dissolved in an appropriate amount of DMA, and methyl tert-butyl ether was added dropwise with stirring until fine solid particles were produced. Then, an appropriate amount of methyl tert-butyl ether was added, the mixture was filtered, and the filter cake was dried to obtain 5.1 g of the product with a yield of 62.27%.

[0311] 1.22 Preparation of 81-136

[0312] 81-132 (5.1 g, 1.16 mmol) was added to a 500 ml round-bottom flask, and TFA (15 ml) was added. The reaction was stirred at room temperature. After the reaction was completed, dichloromethane and TFA were removed by rotary evaporation under reduced pressure. An appropriate amount of dichloromethane was added and the reaction was continued under reduced pressure until the product became a viscous oil. An appropriate amount of methyl tert-butyl ether was added to precipitate a solid. The solid was filtered and the filter cake was dried to obtain 4.95 g of the product. MALDI-TOF MS m / z [M+H + ]4269.65

[0313] 1.23 Preparation of 81-146

[0314] Reactants 81-136 (3.7 g, 0.866 mmol), Fmoc-Lys(Boc)-OH (0.6 g, 1.3 mmol), HOBT (0.175 g, 1.3 mmol), and HBTU (0.49 g, 1.3 mmol) were placed in a reaction flask. DMF (20 ml) was added and dissolved with ultrasonication. The mixture was stirred at 0°C for 2 min. DIEA (0.5 ml, 3.03 mmol) was added dropwise. After complete addition, the reaction was stirred at room temperature for 3 hours. After completion of the reaction, methyl tert-butyl ether (450 ml) was added and ultrasonicated. The mixture was allowed to stand, the supernatant was discarded, and methyl tert-butyl ether (200 ml) was added to allow precipitation. A solid precipitated and was filtered. The filter cake was redissolved in an appropriate amount of DMF and then repeatedly added with methyl tert-butyl ether (450 ml) to allow precipitation. The solid precipitated and was filtered. The filter cake was then re-dissolved in an appropriate amount of DMF and subsequently precipitated with methyl tert-butyl ether (450 ml) in small amounts. The solid was filtered and dried to yield 4.08 g of the product.

[0315] 1.24 Preparation of 81-147

[0316] Reactant 81-146 (4 g, 0.84 mmol) was dissolved in DMF (30 ml), followed by diethylamine (30 ml, 6.3574 mmol) and stirred at room temperature. After the reaction, n-hexane (50 ml) and methyl tert-butyl ether (450 ml) were added to allow the mixture to settle. Solids precipitated, and the supernatant was decanted. The solids were then dissolved in an appropriate amount of DMF. MTBE (450 ml) was then added in small amounts until a large amount of solid precipitated. The mixture was then filtered, and the filter cake was redissolved in an appropriate amount of DMF. MTBE (450 ml) was then added to allow the mixture to settle. This process was repeated three times. The filter cake was dried to yield 3.1 g of product.

[0317] 1.25 Preparation of 81-185

[0318] 81-189 (2.31 g, 2.508 mmol), HBTU (0.9511 g, 2.508 mmol), and HOBT (0.06 g, 0.495 mmol) were placed in a 50 ml round-bottom flask and dissolved in DMF (5 ml). The mixture was stirred at 0°C for 1 minute, and DIEA (1.72 ml, 10.45 mmol) was slowly added dropwise. After stirring at room temperature for 5 minutes, a DMF solution of 81-147 (9.4 g, 2.09 mmol) was added and the reaction continued. After the reaction, methyl tert-butyl ether (450 ml) was added to allow precipitation. The precipitated solid was filtered, and the filter cake was redissolved in an appropriate amount of DMF and then precipitated with methyl tert-butyl ether (450 ml). This process was repeated three times, and the filter cake was dried to obtain the product.

[0319] 1.26 Preparation of 81-203

[0320] 81-185 (5.5 g, 1.018 mmol) was added to a 500 ml round-bottom flask and dissolved in dichloromethane (3 ml). TFA (20 ml) was then added and stirred at room temperature. After completion of the reaction, the dichloromethane and TFA were removed by rotary evaporation. An appropriate amount of dichloromethane was added, and ultrasonic dissolution was used. Methyl tert-butyl ether (450 ml) was added to allow precipitation. The solid precipitated and was filtered. The filter cake was re-dissolved in an appropriate amount of DMF and then precipitated with methyl tert-butyl ether (450 ml). This process was repeated three times. The filter cake was dried to obtain the product.

[0321] 1.27 Preparation of 81-9

[0322] Boc-Asp(Obzl.)-OH (9.19 g, 28.45 mmol), H-β-Ala-Obzl.TsOH (10 g, 28.45 mmol), HBTU (15.1 g, 39.83 mmol), and HOBT (5.38 g, 39.83 mmol) were added to a 500 ml round-bottom flask and dissolved in an appropriate amount of DMF. The reaction was stirred at 0°C for approximately 3 minutes, followed by the slow addition of DIEA (21.16 L, 128.025 mmol). The reaction was stirred at room temperature overnight. After completion of the reaction, the reaction solution was transferred to a 1 L separatory funnel and extracted with purified water (300 ml) and ethyl acetate (200 ml). The organic phase was collected and extracted with ethyl acetate (200 ml x 2). The combined organic phases were washed with saturated sodium bicarbonate solution (100 ml x 2), concentrated, dehydrated with anhydrous magnesium sulfate, and evaporated to dryness to yield 13.78 g of the product.

[0323] 1.28 Preparation of 81-10

[0324] 81-9 (13.78 g, 28.45 mmol) was placed in a 250 ml round-bottom flask and dissolved in dichloromethane (20 ml). TFA (48.63 g, 426.59 mmol) was then added and stirred at room temperature. After completion of the reaction, the dichloromethane was removed by concentration under reduced pressure. The reaction solution was then transferred to a 1 L separatory funnel and extracted with purified water (100 ml) and ethyl acetate (200 ml). Sodium bicarbonate powder was added in small amounts several times to neutralize the TFA. The organic phase was collected and the aqueous phase was extracted with ethyl acetate (200 ml x 2). The organic phases were combined, dehydrated with anhydrous magnesium sulfate, and evaporated to dryness to obtain 10.92 g of the product.

[0325] 1.29 Preparation of 74-100

[0326] Compound 62-13 (2.63 g, 11.38 mmol), compound 81-10 (4.37 g, 11.38 mmol), HBTU (1.84 g, 13.65 mmol), and HOBT (5.17 g, 13.65 mmol) were placed in a 500 ml round-bottom flask. DMF (15 ml) was added to dissolve the mixture, and the mixture was stirred at 0°C for 2 minutes. DIEA (8.46 ml, 51.21 mmol) was then slowly added dropwise to continue the reaction. After the reaction, the reaction mixture was removed and poured into a 2 L separatory funnel. Pure water (300 ml) and ethyl acetate (300 ml) were added to the separatory funnel for extraction. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (100 ml x 2). The combined organic phases were washed with saturated sodium bicarbonate solution (200 ml x 2). The organic phase was collected, concentrated, and dehydrated with anhydrous magnesium sulfate. 200-300 mesh silica gel powder was added and evaporated to dryness. The sample was dry loaded and column chromatography was performed with 0.5-2% methanol / dichloromethane as eluent to collect the target product, which was evaporated to dryness to obtain 3.4 g of the product.

[0327] 1.30 Preparation of 74-101

[0328] 74-100 (3.4 g, 5.68 mmol) was added to a 500 ml round-bottom flask, and TFA (12.98 g) was added to dissolve the mixture. The reaction was stirred at room temperature. After completion of the reaction, the TFA was removed by rotary evaporation. The mixture was dissolved in an appropriate amount of ethyl acetate and poured into a 2-liter separatory funnel. Pure water (300 ml) and ethyl acetate (300 ml) were added to the separatory funnel for extraction. Sodium bicarbonate powder was added in small amounts several times to neutralize the TFA. The organic phase was collected, and the aqueous phase was extracted with ethyl acetate (100 ml x 2). The combined organic phases were concentrated, dehydrated over anhydrous magnesium sulfate, and evaporated to dryness to yield 2.83 g of the product.

[0329] 1.31 Preparation of 74-102

[0330] 74-101 (2.83 g, 5.68 mmol), Fmoc-Lys(Boc)-OH (2.66 g, 5.68 mmol), HBTU (2.58 g, 6.82 mmol), and HOBT (0.92 g, 6.82 mmol) were placed in a 500 ml round-bottom flask. DMF (15 ml) was added to dissolve the mixture, and the mixture was stirred at 0°C for 3 minutes. DIEA (4.23 ml, 25.59 mmol) was then slowly added dropwise to continue the reaction. After the reaction, the reaction mixture was removed and poured into a 2 L separatory funnel. Pure water (300 ml) and ethyl acetate (300 ml) were added to the separatory funnel for extraction. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (100 ml x 2). The organic phases were combined and washed with saturated sodium bicarbonate solution (200 ml × 2). The organic phases were collected, concentrated, and dehydrated with anhydrous magnesium sulfate. 200-300 mesh silica gel powder was added and evaporated to dryness. Dry loading was performed and column chromatography was performed using 0.5-1.5% methanol / dichloromethane as eluent. The product was collected, concentrated, and evaporated to dryness to obtain 5.39 g of the product.

[0331] 1.32 Preparation of 74-103

[0332] 74-102 (5.39 g, 5.68 mmol) was placed in a 500 ml round-bottom flask and dissolved in DMF (10 ml). Morpholine (7.43 ml, 85.32 mmol) was then added and the mixture was stirred at room temperature. After the reaction, the reaction mixture was poured into a 2 L separatory funnel. Pure water (300 ml) and ethyl acetate (300 ml) were added to the separatory funnel for extraction. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (100 ml x 2). The combined organic phases were washed with saturated sodium bicarbonate solution (200 ml x 2). The organic phases were collected, concentrated, and then dehydrated with anhydrous magnesium sulfate. 200-300 mesh silica gel powder was added and evaporated to dryness. The sample was dry-applied and subjected to column chromatography using 5-7% methanol / dichloromethane as the eluent. The product was collected, concentrated, and evaporated to dryness to obtain 1.4 g of the product.

[0333] 1.33 Preparation of 81-60

[0334] 3-(methylamine)propane-1,2-diol (3 g, 28.53 mmol), mono-tert-butyl succinate (4.96 g, 28.53 mmol), and HATU (11.39 g, 29.96 mmol) were placed in a 500 ml round-bottom flask. Acetonitrile (20 ml) was then added. Dissolution was assisted by ultrasonication, and the mixture was stirred at -5°C for 2 minutes. DIEA (24.75 ml, 149.8 mmol) was then slowly added dropwise to continue the reaction. After completion of the reaction, the acetonitrile was removed by rotary evaporation under reduced pressure, and methyl tert-butyl ether (200 ml) was added to allow the mixture to settle. The supernatant was discarded, and methyl tert-butyl ether (200 ml) was added to allow the mixture to settle. The supernatant was then discarded. This process was repeated several times until the product became a viscous oil. Add appropriate amount of dichloromethane and dissolve with ultrasonic assistance, add 200-300 mesh silica gel powder and evaporate to dryness, dry load, and perform column chromatography using 0-1.5% methanol / dichloromethane as eluent to collect the target product, concentrate, and evaporate to dryness to obtain 5.45 g of product with a yield of 3.15%. 1 H-NMR (600MHz, DMSO-d6) δ3.75-3.53(m,3H),3.43-3.14(m,4H),2.90(s,3H),2.57-2.45(m,2H),2.43-2.31(m,2H),1.35(s,9H); FT MS ESI m / z[M+H + ]262.16

[0335] 1.34 Preparation of 81-65

[0336] To a 500ml round-bottom flask, add ultra-dry THF (15ml) and 60% NaH (0.22g, 5.739mmol). Stir until no bubbles form, then add 81-60 (0.5g, 1.913mmol) and benzyl bromoacetate (1.75g, 7.653mmol). Stir under a nitrogen atmosphere. After the reaction is complete, remove the reaction solution and pour it into a 1L separatory funnel. Extract the solution with dilute hydrochloric acid (100ml) and ethyl acetate (200ml). Separate the organic phase, and extract the aqueous phase with ethyl acetate (100ml x 2). The combined organic phases were washed with saturated sodium chloride solution (50 ml × 2), the organic phases were collected, concentrated, and dehydrated with anhydrous magnesium sulfate. 200-300 mesh silica gel powder was added and evaporated to dryness. The sample was dry loaded and column chromatography was performed with 0.2-5% methanol / dichloromethane as the eluent to collect the target product. The product was concentrated and evaporated to dryness to obtain 0.23 g of the product with a yield of 21.69%. 1H-NMR(600MHz,DMSO-d6)δ7.44-7.27(m,10H),5.18-5.12(m,4H),4.22-4.17(m,,4H),3.76-3.7 1(m,1H),3.43-3.14(m,4H),3.01(s,3H),2.49-2.43(m,2H),2.42-2.30(m,2H),1.37(s,9H); FT MS ESI m / z[M+H + ]558.26

[0337] 1.35 Preparation of 81-82

[0338] Add raw material 81-65 (0.5 g, 0.896 mmol) and 10% Pd / C catalyst (20 mg) to a hydrogenation reaction apparatus. Then, add DMF (8 ml) to dissolve it. The pressure was hydrogenated to 2 MPa and allowed to react overnight at room temperature. After completion of the reaction, collect the reaction solution containing palladium on carbon.

[0339] 1.36 Preparation of 81-85

[0340] Compounds 81-82 (0.33 g, 0.896 mmol), 74-103 (1.42 g, 1.97 mmol), HBTU (0.74 g, 1.97 mmol), and HOBT (0.26 g, 1.97 mmol) were placed in a 50 ml round-bottom flask, and DMF (5 ml) was added to dissolve the mixture. The mixture was stirred at 0°C for 1 minute. DIEA (1.03 ml, 6.27 mmol) was then slowly added dropwise to continue the reaction. After the reaction, the palladium-carbon was removed by filtration, and n-hexane (50 ml) and methyl tert-butyl ether (450 ml) were added to precipitate. The mixture was treated with ultrasound, allowed to stand, and the supernatant was discarded. This process was repeated several times until the product became a viscous oil. Dichloromethane was then added and dissolved with ultrasound. 200-300 mesh silica gel powder was added and evaporated to dryness. The sample was dry-loaded and column chromatography was performed using 2-3% methanol / dichloromethane as the eluent to collect the desired product. The product was concentrated and evaporated to dryness to obtain 0.96 g of the product with a yield of 60%. FT MS ESI m / z [M+Na + ]1815.93

[0341] 1.37 Preparation of 81-197

[0342] Raw materials 81-85 (0.4 g, 0.223 mmol) and 10% Pd / C palladium-carbon catalyst (50 mg) were added to a hydrogenation reaction apparatus. Methanol (10 ml) was then added to dissolve the mixture. The hydrogenation apparatus was sealed and evacuated with a water pump. Hydrogen gas at approximately 2 MPa was then introduced three times. The hydrogen pressure was finally adjusted to 2.2 MPa, and the mixture was allowed to react overnight at room temperature. After completion of the reaction, the mixture was filtered using a Buchner funnel containing filter paper. The reaction apparatus was rinsed with methanol (3 ml x 3) and evaporated to dryness to obtain 0.31 g of the reaction product. 1 H-NMR(600MHz,DMSO-d6)δ12.10-12.01(m,4H),8.13-8.05(m,4H),8.02-7.90(m,4H ),7.44-7.37(m,2H),4.22-4.12(m,8H),3.76-3.71(m,3H),3.65-3.52(m,4H),3.43- 3.14(m,12H),3.08-3.00(m,5H),2.52-2.43(m,10H),2.42-2.30(m,2H),1.67-1.57 (m,2H),1.57-1.49(m,2H),1.49-1.41(m,4H),1.41-1.29(m,35H),1.28-1.10(m,8H)

[0343] 1.38 Preparation of 81-204

[0344] 81-197 (0.31 g, 0.217 mmol), 81-203 (5.3 g, 0.999 mmol), HBTU (0.378 g, 0.999 mmol), and HOBT (0.134 g, 0.999 mmol) were placed in a 50 ml round-bottom flask. DMF (20 ml) and NMP (10 ml) were added to dissolve the mixture. The mixture was stirred at 0°C for 1 minute. DIEA (0.57 ml, 3.472 mmol) was then slowly added dropwise to continue the reaction. After the reaction, methanol (450 ml) was added to allow precipitation. The precipitated solid was filtered. The filter cake was redissolved in appropriate amounts of DMF and NMP, and then methanol (450 ml) was added to allow precipitation. This process was repeated three times. The filter cake was dried to yield 4.89 g of the product.

[0345] 1.39 Preparation of 81-205

[0346] 81-204 (4.94 g, 0.218 mmol) was added to a 50 ml round-bottom flask, and TFA (35 ml) was added and stirred at room temperature for 20 hours. After completion of the reaction, an appropriate amount of dichloromethane was added to dissolve the mixture. The dichloromethane was removed by rotary evaporation, and methyl tert-butyl ether (30 ml) was added to precipitate a solid. The mixture was allowed to stand, the supernatant was discarded, and the mixture was evaporated to dryness. The solid was then dissolved in an appropriate amount of DMF, DIEA was added dropwise, and the mixture was shaken. MTBE (300 ml) was added to precipitate a solid, which was filtered with suction, and the filter cake was dried to obtain 4.5 g of the product.

[0347] 1.40 Preparation of 81-206

[0348] 81-205 (2 g, 0.896 mmol) was placed in a 50 ml round-bottom flask and then ultra-dry DMF (10 ml) was added. The mixture was dissolved with ultrasonic assistance and stirred at 0°C for 3 minutes. Then DIEA (0.148 ml, 0.896 mmol) was slowly added dropwise, and the reaction was continued with stirring for 5 minutes, after which M-SCM-10K (2 g, 0.188 mmol, purchased from Jiankai, batch: A3016-N230101) was added. After the reaction was completed, methyl tert-butyl ether (450 ml) was added for precipitation, solid precipitated, the supernatant was discarded, and methyl tert-butyl ether was added, ultrasonicated, allowed to stand, and the supernatant was discarded. This was repeated 5 times, and the solid powder was evaporated to dryness to obtain a solid powder. The solid powder was then dissolved in an appropriate amount of a mixed solvent of methanol / dichloromethane (volume ratio of 4:6), and 100-200 mesh silica gel powder was added and evaporated to dryness. The sample was dry-loaded and column chromatography was performed with 1% ammonia water / 6-9% methanol / dichloromethane as eluent. The target product was collected, concentrated, and evaporated to dryness to obtain 2.2 g of the product.

[0349] 1.41 Preparation of 81-212

[0350] 81-206 (1.9 g, 0.0437 mmol), 59-69 (0.141 g, 0.131 mmol), HBTU (0.049 g, 0.1313 mmol), and HOBT (0.0177 g, 0.1313 mmol) were placed in a 50 ml round-bottom flask and dissolved in DMF (10 ml). Triethylamine (0.1 ml) was then added dropwise to allow the reaction to proceed. After the reaction, methyl tert-butyl ether (45 ml) was added to allow the precipitation of a solid. The solid was then ultrasonicated, allowed to stand, and the supernatant was discarded. This process was repeated three times. The solid was then evaporated to dryness, and dissolved in an appropriate amount of a methanol / dichloromethane (4:6 by volume) mixture. A large amount of methyl tert-butyl ether was then added to allow the precipitation of a solid. The mixture was allowed to stand, the supernatant discarded, and the solid evaporated to dryness to yield 1.68 g of the product.

[0351] 1.42 Preparation of 81-214

[0352] 81-212 (1.68 g, 0.0378 mmol) was weighed and dissolved in an appropriate amount of THF, and then TBAF (0.477 g, 1.512 mmol) was added and stirred at room temperature for reaction. After the reaction is completed, methyl tert-butyl ether (300 ml) is added, and a solid precipitates. The solid is treated with ultrasound, allowed to stand, and the supernatant is poured out. An appropriate amount of methyl tert-butyl ether is added, treated with ultrasound, allowed to stand, and the supernatant is poured out. The solid is evaporated to dryness, and the solid is dissolved with an appropriate amount of a 4 / 6 methanol / dichloromethane mixed solvent. 100-200 mesh silica gel powder is added, evaporated to dryness, and dry-loaded. Column chromatography is performed with 1% triethylamine / 10% methanol / dichloromethane as an eluent to collect the target product, evaporated to dryness, and then dissolved with an appropriate amount of a ethanol / dichloromethane (volume ratio of 3:7) mixed solvent. Methyl tert-butyl ether (300 ml) is added, and the solid precipitates. It is filtered off, and this dissolution / precipitation process is repeated 3 times. The filter cake is dried to obtain 1.2 g of the product. 1 H-NMR(600MHz,DMSO-d6)δ10.16-10.04(m,5H),9.93-9.77(m,16H),8.96-8.80(m,5H),8.80-8.66(m,16H),8.60-8.47(m,15 H),8.29-7.89(m,169H),7.89-7.58(m,19H),7.58-7.36(m,22H),7.36-6.96(m,183H),6.72-6.59(m,10H),6.57-6.47(m,10 H),6.05--5.72(m,6H),5.57-5.36(m,7H),5.29-4.98(m,36H),4.85-4.65(m,30H),4.63-4.43(m,28H),4.43-4.29(m,50H), 4.29-3.91(m,44H),3.87-3.26(m,2053H),3.20-2.67(m,173H),2.65-2.24(m,65H),2.24-2.01(m,37H),1.95-1.78(m,17H), 1.78-1.07(m,195H),0.94-0.66(m,120H).

[0353] Example 2 Synthesis of Compound 76-258

[0354] 2.1 Preparation of 76-84

[0355] Trometamol (2.42 g, 20.00 mmol, purchased from LeYan) was placed in a 250 ml flask, DMSO (4 ml) was added, and the mixture was purged with N2 and cooled to 15°C. While stirring, 5 M aqueous sodium hydroxide solution (0.4 ml) was added, followed by the dropwise addition of tert-butyl acrylate (10.00 ml, 68.00 mmol). After the reaction was complete, saturated NaCl solution (200 ml) and ethyl acetate (200 ml) were added for extraction. After stratification, the organic phase was collected; the aqueous phase was then extracted with ethyl acetate (200 ml x 3). The combined organic phases were evaporated to dryness to a solid, then dissolved in a 1 / 4 methanol / dichloromethane solution. Silica gel powder (100 ml) was added and evaporated to dryness, resulting in a powdery solid. The product was dry-loaded and subjected to column chromatography using a mixture of 0.2% aqueous ammonia / 2-4% methanol / dichloromethane as the eluent. The desired product was collected, concentrated, and dried in a vacuum oven to yield 3.85 g of the product (38% yield). 1 H-NMR (600MHz, DMSO-d6) δ4.43-4.36(m,1H),4.13-4.06(m,1H),3.59-3.53(m,6H),3.20-3.17(m,6H),2.45-2.35(m,6H),1.40(s,27H); ESI[M+H + ]506.33

[0356] 2.2 Preparation of 76-88

[0357] Benzyl succinate (0.46 g, 2.18 mmol), HBTU (0.90 g, 2.37 mmol), and HOBT (0.32 g, 2.37 mmol) were weighed and added to a flask containing 76-84 (1.0 g, 1.98 mmol). An appropriate amount of DMF was then added to dissolve the mixture. DIEA (1.18 ml, 7.12 mmol) was slowly added dropwise at -5°C. After a half-hour reaction, the mixture was removed from the flask and stirred at room temperature overnight. After the reaction, saturated NaCl solution (200 ml) and ethyl acetate (200 ml) were added for extraction. After standing and stratification, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (200 ml x 3). The organic phases were combined and evaporated to dryness to a solid, then dissolved in a 1 / 4 methanol / dichloromethane mixed solution, silica gel powder (100 ml) was added and evaporated to dryness to obtain a powdery solid. The mixture was dry-loaded and subjected to column chromatography using a 20% ethyl acetate / petroleum ether mixed solvent as the eluent to collect the target product, which was concentrated and dried in a vacuum oven to obtain 0.87 g of the product. 1H-NMR(600MHz,DMSO-d6)δ7.38-7.32(m,5H),7.12(s,1H),5.07(s,2H),3.54-3 .51(m,12H),2.40-2.36(m,8H),1.40-1.38(m,27H),1.32-1.22(m,2H);ESI[M+H + ]696.39,[M+Na + ]718.37,[M+K + ]734.35

[0358] 2.3 Preparation of 76-89

[0359] To a flask containing 76-88 (0.87 g, 1.25 mmol) was added dichloromethane and ultrasonically shaken until completely dissolved. TFA (0.2 ml) was then added and the mixture was stirred at room temperature overnight. After the reaction was completed, the reaction solution was evaporated to an oil using a rotary evaporator. Methyl tert-butyl ether (60 ml) was then added. A powdery solid precipitated from the reaction solution and filtered. The filter cake was washed with methyl tert-butyl ether (40 ml x 3). The product had poor solubility. The filter cake was collected and dried in a vacuum oven to obtain the product. 1 H-NMR(600MHz,DMSO-d6)δ12.58-11.75(s,3H)7.38-7.32(m,5H),7.12(s,1 H),5.07(s,2H),3.54-3.51(m,12H),2.40-2.36(m,8H),1.32-1.22(m,2H).

[0360] 2.4 Preparation of 76-54

[0361] Fmoc-Glu(OtBu)-OH (10.00 g, 23.50 mmol), HBTU (10.69 g, 28.20 mmol), and HOBT (3.81 g, 28.20 mmol) were weighed and added to a flask containing β-alanine tert-butyl ester hydrochloride (4.48 g, 24.68 mmol). An appropriate amount of DMF was added to dissolve the mixture. DIEA (13.98 ml, 84.60 mmol) was slowly added dropwise at -5°C. After a half-hour reaction, the mixture was removed from the flask and stirred at room temperature overnight. After the reaction, saturated NaCl solution (200 ml) and ethyl acetate (200 ml) were added for extraction. After standing and separating, the organic phase was collected; the aqueous phase was extracted with ethyl acetate (200 ml x 3). The organic phases were combined and evaporated to dryness to obtain a crude solid product.

[0362] 2.5 Preparation of 76-55

[0363] To a flask containing 76-54 (23.50 mmol) was added DMF, followed by ultrasonic dissolution, followed by the addition of morpholine (40 ml, 470 mmol) and the reaction mixture was stirred at room temperature for 2 h. After the reaction, saturated NaCl solution (200 ml) and ethyl acetate (200 ml) were added for extraction. After stratification, the organic phase was collected; the aqueous phase was then extracted with ethyl acetate (200 ml x 3). The combined organic phases were evaporated to dryness to a solid, then dissolved in a 1 / 4 methanol / dichloromethane mixture. Silica gel powder (100 ml) was added and evaporated to dryness, resulting in a powdery solid. The product was dry-loaded and subjected to column chromatography using a 20% ethyl acetate / petroleum ether mixture as the eluent. The product was collected, concentrated, and dried in a vacuum oven to yield 6.89 g (88.7% yield).

[0364] 2.6 Preparation of 76-56

[0365] N'-Fmoc-N-benzyloxycarbonyl-L-lysine (2.90 g, 5.76 mmol), HBTU (2.62 g, 6.91 mmol), and HOBT (0.93 g, 6.91 mmol) were weighed and added to a flask containing 76-55 (2.0 g, 6.05 mmol). An appropriate amount of DMF was added to dissolve the mixture. DIEA (3.43 ml, 20.74 mmol) was slowly added dropwise at -5°C. After a half-hour reaction, the mixture was removed from the flask and stirred at room temperature overnight. After the reaction, saturated NaCl solution (200 ml) and ethyl acetate (200 ml) were added for extraction. After standing for decomposition, the organic phase was collected and the aqueous phase was extracted with ethyl acetate (200 ml x 3). The organic phases were combined and evaporated to dryness to obtain a crude solid product.

[0366] 2.7 Preparation of 76-58

[0367] To a flask containing 76-56 (5.76 mmol) was added DMF, followed by ultrasonic dissolution with morpholine (10 ml, 115.21 mmol). The mixture was stirred at room temperature for 2 h. After the reaction, saturated NaCl solution (200 ml) and ethyl acetate (200 ml) were added for extraction. After stratification, the organic phase was collected; the aqueous phase was further extracted with ethyl acetate (200 ml x 3). The combined organic phases were evaporated to dryness to a solid, then dissolved in a 1 / 4 methanol / dichloromethane mixture. Silica gel powder (100 ml) was added and evaporated to dryness, resulting in a powdery solid. The product was dry-loaded and subjected to column chromatography using a 20% ethyl acetate / petroleum ether mixture as the eluent. The desired product was collected, concentrated, and dried in a vacuum oven to yield 2.26 g of the product (66.2% yield). 1H-NMR(400MHz,DMSO-d6)δ8.14-7.97(m,2H),7.38-7.29(m,5H),7.26-7.21(s,1H),5.04-4.98(m,2H),4.26-4.18(s,1H),3.33 -3.25(m,2H),3.20-3.10(m,2H),2.98-2.94(m,2H),2.38-2.31(m,2H),2.19-2.11(m,2H),1.91-1.79(m,2 H),1.72-1.66(m,1H),1.59-1.47(m,2H),1.40-1.38(m,9H),1.38-1.37(m,9H),1.35-1.22(m,4H); ESI[M+H + ]593.35,[M+Na + ]615.33,[M+K + ]631.30

[0368] 2.8 Preparation of 76-99

[0369] 76-89 (0.28 g, 0.55 mmol), HBTU (0.75 g, 1.98 mmol), and HOBT (0.27 g, 1.98 mmol) were weighed and added to a flask containing 76-58 (1.07 g, 1.81 mmol). An appropriate amount of DMF was then added to dissolve the mixture. DIEA (1.0 ml, 5.94 mmol) was slowly added dropwise at -5°C. After a half-hour reaction, the mixture was removed from the flask and stirred at room temperature overnight. After the reaction, saturated NaCl solution (200 ml) and ethyl acetate (200 ml) were added for extraction. After standing and stratification, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (200 ml x 3). The organic phases were combined and evaporated to dryness to a solid, then dissolved in a 1 / 4 methanol / dichloromethane mixed solution, silica gel powder (100 ml) was added and evaporated to dryness to obtain a powdery solid. The mixture was dry-loaded and column chromatography was performed using a mixed solvent of dichloromethane and methanol as an eluent to collect the target product, which was concentrated and dried in a vacuum oven to obtain 0.82 g of the product. 1H-NMR(400MHz,DMSO-d6)δ8.02-7.97(m,3H),7.97-7.93(m,3H),7.93-7.88(m,3H),7.37-7.29(m,20H),7.24-7.17(m,3H),7.15 -7.13(m,1H),5.09-5.05(m,2H),5.02-4.96(m,6H),4.25-4.20(m,3H),4.20-4. 15(m,3H),3.58-3.50(m,12H),3.32-3.26(m,6H),3.18-3.12(m,3H),2.98-2.92( m,6H),2.44-2.30(m,15H),2.19-2.11(m,6H),1.85-1.79(m,3H),1.51-1.43(m, 6H),1.38-1.36(m,54H),1.34-1.32(m,6H),1.25-1.23(m,6H),1.23-1.21(m,6H)

[0370] 2.9 Preparation of 70-67

[0371] 71-85 (34.3 mmol), NPB (11.0 g, 34.3 mmol, purchased from Anhui Nuoquan), HBTU (15.6 g, 41.2 mmol), and HOBT (5.6 g, 41.2 mmol) were added to a 500 ml round-bottom flask. DMF (80 ml) was added to dissolve the mixture. The reaction was stirred at -5°C for approximately 20 minutes. DIEA (12.5 ml, 75.5 mmol) was then slowly added dropwise. The mixture was stirred at -5°C for 1 hour. The mixture was removed and stirred at room temperature. After the reaction was completed, methyl tert-butyl ether (450 ml) was added to allow the mixture to settle. The solid precipitated and was filtered. The filter cake was redissolved in an appropriate amount of DMF and then methyl tert-butyl ether (450 ml) was added to allow the mixture to settle. This process was repeated three times. The filter cake was collected and dried to yield 28.8 g of the product.

[0372] 2.10 Preparation of 70-68

[0373] 70-67 (34.3 mmol) was added to a 250 ml round-bottom flask, and dichloromethane (20 ml) was added. After dissolution with ultrasonication, TFA (51.8 ml, 686 mmol) was added and the reaction was stirred at room temperature overnight. After completion of the reaction, the mother liquor was concentrated and evaporated to dryness to remove the dichloromethane, and methyl tert-butyl ether (300 ml) was added to allow precipitation. The precipitated solid was filtered, and the filter cake was washed three times with methyl tert-butyl ether (40 ml). The filter cake was collected and dried under vacuum to obtain 13.0 g of the product.

[0374] 2.11 Preparation of 76-103

[0375] 76-99 (0.15 g, 0.07 mmol) and 10% Pd / C catalyst (0.05 g) were placed in a hydrogenation reactor. DMF (20 ml) was then added to dissolve the mixture. The hydrogenation reactor was sealed and evacuated with a water pump. Hydrogen was then introduced at approximately 2 MPa three times, with the pressure on the hydrogenation reactor adjusted to 1.8 MPa. The reaction was then allowed to proceed overnight at room temperature. Upon completion of the reaction, the reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with DMF (20 ml x 3). This yielded a DMF solution of the product, which served as the starting material for the next reaction. 1 H-NMR (400MHz, DMSO-d6) δ12.50-11.71(s,1H),8.02-7.97(m,3H),7.97-7.93(m,3H),7.93-7.88(m,3H),7.24-7.17(m,3H),7.15 -7.13(m,1H),4.25-4.20(m,3H),4.20-4.15(m,3H),3.58-3.50(m,12H ),3.32-3.26(m,6H),3.18-3.12(m,3H),2.98-2.92(m,6H),2.44-2.30( m,15H),2.19-2.11(m,6H),1.85-1.79(m,3H),1.51-1.43(m,6H),1.38 -1.36(m,54H),1.34-1.32(m,6H),1.25-1.23(m,6H),1.23-1.21(m,6H)

[0376] 2.12 Preparation of 76-104

[0377] 76-103 (0.07 mmol) was placed in a 250 ml flask and dissolved in DMF (20 ml). The mixture was then slowly added dropwise to a DMF solution containing DIEA (0.44 ml, 2.66 mmol) and M-SCM-10K (2.29 g, 0.22 mmol, purchased from Jiankai). The reaction was stirred at low speed at room temperature in the dark for one week. After the reaction was completed, n-hexane (25 ml) and methyl tert-butyl ether (200 ml) were added to allow the reaction to settle. The supernatant was decanted, and n-hexane and methyl tert-butyl ether were added to allow the reaction to settle. This process was repeated three times. The solid product was filtered, collected, and dried in a vacuum oven to obtain the product.

[0378] 2.13 Preparation of 76-123

[0379] 76-104 (0.46 g, 0.01 mmol), HBTU (0.01 g, 0.02 mmol), and HOBT (0.003 g, 0.02 mmol) were weighed and added to a flask containing 70-68 (0.01 g, 0.02 mmol). An appropriate amount of DMF was then added to dissolve the mixture. The mixture was placed at -5°C and DIEA (0.02 ml, 0.07 mmol) was slowly added dropwise. After the reaction was complete, the mixture was allowed to react for half an hour, removed from the flask, and stirred at room temperature overnight. After the reaction was complete, n-hexane (25 ml) and methyl tert-butyl ether (200 ml) were added to allow the mixture to settle. The supernatant was decanted, and n-hexane and methyl tert-butyl ether were added to allow the mixture to settle. This process was repeated three times. The solid product was filtered, collected, and dried to obtain the product.

[0380] 2.14 Preparation of 76-128

[0381] To a flask containing 76-123 (0.01 mmol) was added dichloromethane, followed by ultrasonic dissolution with TFA (10.0 ml). The mixture was stirred and reacted at room temperature overnight. After the reaction was complete, the reaction solution was evaporated to an oil using a rotary evaporator. Methyl tert-butyl ether (60 ml) was then added. A powdery solid precipitated from the reaction solution and was filtered. The filter cake was washed with methyl tert-butyl ether (40 ml x 3). The product had poor solubility. The filter cake was collected and dried in a vacuum oven to obtain the product.

[0382] 2.15 Preparation of 88-14

[0383] 6-Aminocaproic acid (4.6094 g, 35.1407 mmol) was placed in a 1 L round-bottom flask, and a THF / H2O solution (150 ml) was added to dissolve it. The mixture was then placed in a 0°C reaction bath and stirred for 1 hour. Anhydrous sodium carbonate (7.4491 g, 70.2814 mmol) was then added and dissolved by ultrasonication. The reaction flask was then placed in a 0°C reaction bath and stirred for 30 minutes. 9-Fluorenecarboxylic acid (Fmoc-Cl, 10.0 g, 38.6548 mmol) was then dissolved in THF (30 ml) and slowly added dropwise to the reaction flask. After the addition was complete, the reaction flask was removed from the 0°C reaction bath and stirred at room temperature for 2.5 hours. Finally, 1.0 mol / L aqueous hydrochloric acid (115 ml) was added dropwise to the reaction flask to adjust the pH of the reaction solution to 3.0. After the reaction, the reaction solution was transferred to a 1L separatory funnel and extracted with ethyl acetate (150ml x 3). The aqueous and organic phases were separated. The organic phases were combined and washed twice with 1.0N hydrochloric acid (250ml x 2). The aqueous and organic phases were separated. The organic phase was concentrated under reduced pressure and evaporated to dryness. Dichloromethane (100ml) was then added to dissolve it. Silica gel powder (60ml) was then added and evaporated to dryness. The sample was dry-loaded and column chromatography was performed using 20-50% ethyl acetate / petroleum ether as the eluent. The desired product was collected, concentrated, evaporated to dryness, and dried to obtain 12.0g of the product with a yield of 96.63%.

[0384] 2.16 Preparation of 88-4

[0385] In a 1L round-bottom flask, dissolve 1,2-bis(2-aminoethoxy)ethane (5.96g, 40.270mmol) in 1,4-dioxane (40ml) and place in a constant temperature 0°C reaction bath. Dissolve NaOH (1.932g) in pure water (20ml), add Boc2O (10.54g, 48.324mmol), and stir at room temperature for 2 hours. Monitor the reaction progress by TLC. After the reaction, add water (100ml), extract with methyl tert-butyl ether, and collect the organic phase. Adjust the pH of the aqueous phase to 1-2 with hydrochloric acid (1.0mol / L) and extract with ethyl acetate. The combined organic phases were rotary evaporated to dryness to obtain 9.88g of the product, with a yield of 98.8%.

[0386] 2.17 Preparation of 88-7

[0387] Fmoc-Glu-OH (3.45 g, 9.34 mmol), HBTU (7.79 g, 20.54 mmol), and HOBT (2.78 g, 20.54 mmol) were weighed and added to a flask containing 88-4 (5.10 g, 20.54 mmol). An appropriate amount of DMF was added to dissolve the mixture. DIEA (6.80 ml, 41.07 mmol) was slowly added dropwise at -5°C. After a half-hour reaction, the mixture was removed from the flask and stirred at room temperature overnight. After the reaction, saturated NaCl solution (200 ml) and ethyl acetate (200 ml) were added for extraction. After standing and stratification, the organic phase was collected and the aqueous phase was extracted with ethyl acetate (200 ml x 3). The organic phases were combined and evaporated to dryness.

[0388] 2.18 Preparation of 88-8

[0389] Acetonitrile was added to a flask containing 88-7 (9.34 mmol). After ultrasonic oscillation until complete dissolution, piperidine (13.90 ml, 140.03 mmol) was added and the mixture was stirred at room temperature for 2 h. After completion of the reaction, the mixture was evaporated to dryness to a solid, which was then dissolved in a 4 / 1 dichloromethane / methanol mixture. 200-300 mesh silica gel powder (30 g) was added and evaporated to dryness. The sample was dry-loaded and column chromatography was performed using 1% methanol / dichloromethane as the eluent to collect the desired product. The product was concentrated and evaporated to dryness to obtain 7.0 g.

[0390] 2.19 Preparation of 76-80

[0391] Fmoc-Glu-OH (0.72 g, 1.94 mmol), HBTU (1.77 g, 4.66 mmol), and HOBT (0.63 g, 4.66 mmol) were weighed and added to a flask containing 88-8 (2.60 g, 4.28 mmol). An appropriate amount of DMF was then added to dissolve the mixture. DIEA (2.31 ml, 13.97 mmol) was slowly added dropwise at -5°C. After a half-hour reaction, the mixture was removed from the flask and stirred at room temperature overnight. After the reaction, saturated NaCl solution (200 ml) and ethyl acetate (200 ml) were added for extraction. After standing for decomposition, the organic phase was collected and the aqueous phase was extracted with ethyl acetate (200 ml x 3). The organic phases were combined and evaporated to dryness.

[0392] 2.20 Preparation of 76-91

[0393] Acetonitrile was added to a flask containing 76-80 (1.5 g, 0.97 mmol), and the solution was dissolved with ultrasonication. Diethylamine (20 ml) was then added and stirred at room temperature for 2 h. After the reaction was complete, the solution was evaporated to dryness.

[0394] 2.21 Preparation of 76-92

[0395] 88-14 (0.36 g, 1.02 mmol), HBTU (0.44 g, 1.16 mmol), and HOBT (0.16 g, 1.16 mmol) were weighed and added to a flask containing 76-91 (0.97 mmol). An appropriate amount of DMF was then added to dissolve the mixture. The mixture was placed at -5°C and DIEA (0.58 ml, 3.49 mmol) was slowly added dropwise. After a half-hour reaction, the mixture was removed from the flask and stirred at room temperature overnight. After the reaction, n-hexane (30 ml) and methyl tert-butyl ether (200 ml) were added to allow sedimentation. The supernatant was decanted and methyl tert-butyl ether (100 ml) was added to allow sedimentation. The solid product was filtered and the filter cake was collected and vacuum dried to obtain the product.

[0396] 2.22 Preparation of 76-93

[0397] Acetonitrile was added to a flask containing 76-92 (0.97 mmol). Diethylamine (20 ml) was added after ultrasonic dissolution, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was evaporated to dryness to a solid, dissolved in a 4 / 1 dichloromethane / methanol mixture, and then 200-300 mesh silica gel powder (30 g) was added and evaporated to dryness. The sample was dry-loaded and column chromatography was performed using 1% methanol / dichloromethane as the eluent. The desired product was collected, concentrated, and evaporated to dryness to obtain 0.75 g of the product, with a yield of 54%. 1 H-NMR(400MHz,DMSO-d6)δ8.25-8.16(m,2H),8.12-8.06(m,2H),8.03-7.99(m,1H),7.89-7.85(m,1H),7.85-7.82(m,1H),6.80 -6.74(m,4H),4.23-4.17(m,2H),4.12-4.06(m,1H),3.50-3.47(m,16H),3.42-3.36(m,22H),3.29-3.23(m,4H),3.07- 3.04(m,8H),2.73-2.69(m,2H),2.16-2.08(m,8H),1.53-1.43(m,6H),1.38-1.36(m,36H),1.31-1.23(m,4H); ESI[M+H + ]1439.88

[0398] 2.23 Preparation of 76-146

[0399] 76-128 (0.47 g, 0.01 mmol), HBTU (0.04 g, 0.10 mmol), and HOBT (0.01 g, 0.10 mmol) were weighed and added to a flask containing 76-93 (0.14 g, 0.09 mmol). An appropriate amount of DMF was then added to dissolve the mixture. The mixture was placed at -5°C and DIEA (0.05 ml, 0.10 mmol) was slowly added dropwise. After the reaction was complete, the mixture was allowed to react for half an hour, removed from the flask, and stirred at room temperature overnight. After the reaction was complete, n-hexane (25 ml) and methyl tert-butyl ether (200 ml) were added to allow the mixture to settle. The supernatant was decanted, and n-hexane and methyl tert-butyl ether were added to allow the mixture to settle. This process was repeated three times. The solid product was filtered, collected, and dried to obtain the product.

[0400] 2.24 Preparation of 76-204

[0401] To a flask containing 76-146 (0.0068 mmol) was added dichloromethane, followed by ultrasonic dissolution with TFA (0.2 ml). The mixture was stirred and reacted at room temperature overnight. After the reaction was complete, the reaction solution was evaporated to an oil using a rotary evaporator. Methyl tert-butyl ether (60 ml) was then added. A powdery solid precipitated from the reaction solution and was filtered. The filter cake was washed with methyl tert-butyl ether (40 ml x 3). The product had poor solubility. The filter cake was collected and dried in a vacuum oven to obtain the product.

[0402] 2.25 Preparation of 76-229

[0403] (2-((tert-Butyloxycarbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2- 10 B) ethyl phenyl)propionate)(ethyl 2-((tert-butoxycarbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl-2- 10 B) phenyl)propanoate (2.0 g, 4.78 mmol, purchased from Lexdex) was added to a 250 ml flask. 4.0 M 1,4-dioxane hydrochloride (12 ml) was added to dissolve the mixture. The reaction flask was then stirred at room temperature for 2 hours. After the reaction, the liquid was evaporated to dryness using a vacuum rotary evaporator. The resulting mixture was then dissolved in dichloromethane (10 ml) and evaporated again using a vacuum rotary evaporator. This process was repeated multiple times to obtain a solid, which was then dried to obtain the product.

[0404] 2.26 Preparation of 76-230

[0405] 76-229 (4.78 mmol) was added to a 500 ml flask and dissolved in a 1 / 1 dichloromethane / acetonitrile mixture (20 ml) under ultrasonication. DIEA (3.16 ml, 19.11 mmol) was slowly added dropwise. After stirring for 5 minutes, succinic anhydride (1.44 g, 14.34 mmol, purchased from Innochem) was added and the reaction was stirred for 3 hours. The reaction was observed by TLC. The dichloromethane and acetonitrile were evaporated to dryness using a vacuum rotary evaporator. Dissolved in a dichloromethane / methanol mixture, silica gel powder was added and evaporated to dryness. The sample was dry-loaded and subjected to column chromatography using a 0-5% methanol / dichloromethane mixture as the eluent. The desired product was collected, concentrated, and dried in a vacuum oven to yield 1.28 g. 1 H-NMR(600MHz,DMSO-d6)δ12.10(s,1H),8.44-8.23(m,1H),7.66-7.49(m,2H),7.30-7.14(m,2H),4.46-4.35(m, 1H),4.08-3.99(m,2H),3.02-2.97(m,1H),2.95-2.87(m,1H),2.38-2.29(m,4H),1.28(s,12H),1.13-1.08(m,3H)

[0406] 2.27 Preparation of 76-258

[0407] 76-204 (0.78 g, 0.0068 mmol), 76-230 (0.2 g, 0.2448 mmol), EDCI (0.04 g, 0.10 mmol) and HOBT (0.01 g, 0.10 mmol) were added to a 250 ml round-bottom flask and dissolved with DMF (20 ml). The reaction flask was then stirred at 0 ° C for about 20 minutes, and then DIEA (0.1 ml, 0.61 mmol) was slowly added dropwise. After the addition was complete, the reaction flask was continued to stir at room temperature. After the reaction is completed, n-hexane (30 ml) and methyl tert-butyl ether (200 ml) are added for precipitation, the supernatant is poured out, and n-hexane and methyl tert-butyl ether are added for precipitation, and the process is repeated 3 times. The solid product is filtered to obtain a solid product, and the obtained solid product is dissolved in a 1 / 1 dichloromethane / methanol mixed solvent. The sample is dry-loaded and column chromatography is performed using a 1% ammonia water / 6-12% methanol / dichloromethane mixed solution as an eluent. The target product is collected, concentrated, and dried in a vacuum oven to obtain 0.50 g of the product. 1H-NMR(600MHz,DMSO-d6)δ10.10-9.63(m,24H),8.97-8.74(m,4H),8.61-7.47(m,150H),7.34-6.92(m,42H) ,6.72-6.49(m,4H),6.20-5.90(m,52H),4.57-4.30(m,24H),4.27-4.17(m,15H),4.05-3.98(m,40H),3.72- 3.38(m,2901H),3.21-3.10(m,94H),3.07-2.93(m,182H),2.93-2.83(m,30H),2.81-2.67(m,162H), 2.36-2.21(m,81H),2.18-2.01(m,49H),1.79-1.65(m,95H),1.57-1.03(m,277H),1.03-0.93(m,72H)

[0408] Example 3 Synthesis of Compound 88-206

[0409] 3.1 Preparation of 88-85

[0410] N'-Fmoc-N-benzyloxycarbonyl-L-lysine (4.0 g, 7.95 mmol), HBTU (3.32 g, 8.75 mmol), and HOBT (1.18 g, 8.75 mmol) were weighed and added to a flask containing tert-butyl β-alaninate (1.59 g, 8.75 mmol). An appropriate amount of DMF was added to dissolve the mixture. After incubation at -5°C, DIEA (2.29 ml, 17.51 ​​mmol) was slowly added dropwise. After a half-hour reaction, the mixture was removed from the flask and stirred at room temperature overnight. After completion of the reaction, saturated NaCl solution (200 ml) and ethyl acetate (200 ml) were added for extraction. After separation, the organic phase was collected and the aqueous phase was extracted with ethyl acetate (200 ml x 3). The combined organic phases were evaporated to dryness to yield 5 g of a crude product.

[0411] 3.2 Preparation of 88-86

[0412] To a flask containing 88-85 (5 g, 7.95 mmol), add DMF and ultrasonically shake until completely dissolved. Then, add morpholine (17 ml, 119 mmol) and stir at room temperature for 2 h. After the reaction, extract with saturated NaCl solution (200 ml) and ethyl acetate (200 ml). After stratification, the organic phase is collected; the aqueous phase is then extracted with ethyl acetate (200 ml x 3). The combined organic phases are evaporated to dryness to a solid. The solid is then dissolved in a 1 / 4 methanol / dichloromethane mixture, and silica gel powder (100 ml) is added and evaporated to dryness. The resulting powdery solid is dry-loaded and subjected to column chromatography using a methanol / dichloromethane mixture as the eluent. The desired product is collected, concentrated, and dried in a vacuum oven to yield 3.3 g.

[0413] 3.3 Preparation of 88-89

[0414] 76-89 (1.02 g, 1.93 mmol), HBTU (2.42 g, 6.38 mmol), and HOBT (0.86 g, 6.38 mmol) were weighed and added to a flask containing 88-86 (2.60 g, 6.38 mmol). An appropriate amount of DMF was then added to dissolve the mixture. DIEA (1.52 ml, 9.21 mmol) was slowly added dropwise at -5°C. After a half-hour reaction, the mixture was removed from the flask and stirred at room temperature overnight. After the reaction, saturated NaCl solution (200 ml) and ethyl acetate (200 ml) were added for extraction. After standing and stratification, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (200 ml x 3). The organic phases were combined and evaporated to dryness to a solid, and then dissolved in a methanol / dichloromethane (volume ratio of 1:4) mixed solvent. Silica gel powder (100 ml) was added and evaporated to dryness to obtain a powdery solid. The product was dry-loaded and column chromatography was performed using a dichloromethane / methanol mixed solvent as an eluent to collect the target product, concentrate it, and dry it in a vacuum oven to obtain 1.5 g of the product. 1H-NMR(600MHz,DMSO-d6)δ7.98-7.89(m,6H),7.39-7.28(m,20H),7.22-7.16(m,3H),7.15-7. 10(m,1H),5.08-5.05(m,2H),5.04-4.98(m,6H),4.20-4.14(m,3H),3.56-3.49(m,12H),3.30 -3.25(m,4H),3.20-3.13(m,3H),2.97-2.92(m,6H),2.44-2.40(m,2H),2.37-2.31(m,12H),1 .60-1.53(m,3H),1.50-1.40(m,5H),1.39-1.37(m,27H),1.27-1.14(m,8H),1.12-1.03(m,2H)

[0415] 3.4 Preparation of 88-90

[0416] 88-89 (0.13 g, 0.077 mmol) and 10% Pd / C catalyst (0.08 g) were placed in a hydrogenation reactor. DMF (30 ml) was then added to dissolve the mixture. The hydrogenation reactor was sealed and evacuated with a water pump. The mixture was then filled with hydrogen at approximately 2 MPa. This process was repeated three times. Finally, the pressure on the hydrogenation reactor was adjusted to 1.8 MPa. The reaction was then allowed to react overnight at room temperature. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filter cake was washed with DMF (20 ml x 3). The DMF solution of the product was obtained and used as the starting material for the next reaction. FT MS ESI m / z [M+H + ]1203.74316, [M+Na + ]1225.72241

[0417] 3.5 Preparation of 88-97

[0418] 88-90 (0.092 g, 0.077 mmol) was placed in a 250 ml flask and dissolved in DMF (20 ml). The mixture was then slowly added dropwise to a DMF solution containing DIEA (0.2 ml, 1.23 mmol) and M-SCM-10K (2.02 g, 0.24 mmol, purchased from Jiankai). The reaction was stirred at low speed at room temperature in the dark for one week. After completion of the reaction, n-hexane (25 ml) and methyl tert-butyl ether (200 ml) were added to allow the reaction to proceed. The supernatant was decanted, and n-hexane and methyl tert-butyl ether were added to allow the reaction to proceed. This process was repeated three times. The solid product was filtered, collected, and dried in a vacuum oven to obtain the product.

[0419] 3.6 Preparation of 88-103

[0420] 88-97 (2.53 g, 0.077 mmol), HBTU (0.032 g, 0.0847 mmol), and HOBT (0.012 g, 0.0847 mmol) were weighed and added to a flask containing 70-68 (0.059 g, 0.0847 mmol). An appropriate amount of DMF was then added to dissolve the mixture. The mixture was placed at -5°C and DIEA (0.10 ml, 0.3390 mmol) was slowly added dropwise. After the reaction was complete, the mixture was allowed to react for half an hour, then removed from the flask and stirred at room temperature overnight. After the reaction was complete, n-hexane (25 ml) and methyl tert-butyl ether (200 ml) were added to allow the mixture to settle. The supernatant was decanted, and n-hexane and methyl tert-butyl ether were added to allow the mixture to settle. This process was repeated three times. The solid product was filtered and collected and dried to give 1.1 g of the product with a yield of 44.00%.

[0421] 3.7 Preparation of 88-105

[0422] To a flask containing 88-103 (1.1 g, 0.0.0328 mmol) was added dichloromethane and ultrasonically shaken until completely dissolved. TFA (0.2 ml) was then added and the mixture was stirred at room temperature overnight. After the reaction was complete, the reaction solution was evaporated to an oil using a rotary evaporator. Methyl tert-butyl ether (60 ml) was then added. A powdery solid precipitated from the reaction solution and filtered. The filter cake was washed with methyl tert-butyl ether (40 ml x 3). The product had poor solubility. The filter cake was collected and dried in a vacuum oven to yield 0.9 g of the product.

[0423] 3.8 Preparation of 88-113

[0424] 88-105 (0.9 g, 0.027 mmol), HBTU (0.06 g, 0.16 mmol), and HOBT (0.02 g, 0.16 mmol) were weighed and added to a flask containing 76-93 (0.23 g, 0.16 mmol). An appropriate amount of DMF was then added to dissolve the mixture. The mixture was placed at -5°C and DIEA (0.2 ml, 0.8 mmol) was slowly added dropwise. After the reaction was complete, the mixture was allowed to react for half an hour, removed from the flask, and stirred at room temperature overnight. After the reaction was complete, n-hexane (25 ml) and methyl tert-butyl ether (200 ml) were added to allow the mixture to settle. The supernatant was decanted, and n-hexane and methyl tert-butyl ether were added to allow the mixture to settle. This process was repeated three times. The solid product was filtered, collected, and dried to obtain the product.

[0425] 3.9 Preparation of 88-192

[0426] To a flask containing 88-113 (0.8 g, 0.023 mmol) was added dichloromethane and ultrasonically shaken until completely dissolved. TFA (0.2 ml) was then added and the mixture was stirred at room temperature overnight. After the reaction was complete, the reaction solution was evaporated to an oil using a rotary evaporator. Methyl tert-butyl ether (60 ml) was then added. A powdery solid precipitated from the reaction solution and filtered. The filter cake was washed with methyl tert-butyl ether (40 ml x 3). The product had poor solubility. The filter cake was collected and dried in a vacuum oven to yield 0.78 g of the product.

[0427] 3.10 Preparation of 88-205

[0428] 88-203 (0.78 g, 0.02 mmol), HBTU (0.22 g, 0.6013 mmol), and HOBT (0.08 g, 0.0613 mmol) were weighed and added to a flask containing 6-maleimidocaproic acid (0.78 g, 0.4410 mmol). An appropriate amount of DMF was then added to dissolve the mixture. The mixture was placed at -5°C and DIEA (0.30 ml, 1.8040 mmol) was slowly added dropwise. After a half-hour reaction, the mixture was removed from the flask and stirred at room temperature overnight. After completion of the reaction, n-hexane (25 ml) and methyl tert-butyl ether (200 ml) were added to allow the mixture to settle. The supernatant was decanted, and n-hexane and methyl tert-butyl ether were then added to allow the mixture to settle. This process was repeated three times. The solid product was filtered, collected, and dried to obtain the product.

[0429] 3.11 Preparation of 88-206

[0430] 88-205 (0.68 g, 0.0176 mmoL) and Sodium mercaptododecaborate ( 10 B, BSH (0.0886 g, 0.4216 mmol, purchased from CATCHEM, Czech Republic) was placed in a 250 ml flask, dissolved in 10 ml of DMF, and stirred overnight. After the reaction, methyl tert-butyl ether and n-hexane were added, and the mixture was ultrasonically treated and allowed to stand for 20 minutes. Solid precipitated, and the supernatant was discarded. MTBE and n-hexane were added again, ultrasonically treated, and allowed to stand for 20 minutes. The supernatant was discarded, and the product was dried to obtain 0.6 g of the product, with a yield of 83.33%. 1H-NMR(600MHz,DMSO-d6)δ8.26-7.63(m,65H),4.24-4.15(m,12H),4.13-4.10(m,18H),3.90-3.83(m,33H),3.54-3.50(m,3256H),3.20- 3.16(m,73H),2.92-2.84(m,64H),2.26-2.19(m,32H),2.15-2.07(m,60H),1.49-1.43(m,72H),1.35-1.25(m,162H),1.03-0.94(m,176H)

[0431] Example 4 Synthesis of Compounds 78-131

[0432] 4.1 Preparation of 78-129

[0433] To a flask containing 59-69 (0.5 g, 0.4624 mmol), TBAF (2.9 g, 9.248 mmol) was added, followed by the addition of THF (15 ml) and ultrasonic oscillation until complete dissolution. The reaction was stirred at room temperature overnight. After the reaction was completed, the THF was removed by rotary evaporation under reduced pressure, and the mixture was extracted with ethyl acetate and purified water. The organic phase solution was collected, and the aqueous phase was extracted twice with ethyl acetate. The organic phase was collected, dehydrated with anhydrous sodium sulfate, and evaporated to dryness to obtain 0.3 g of the product.

[0434] 4.2 Preparation of 78-50

[0435] Add dichloromethane to a flask containing 76-84 (1 g, 1.98 mmol). Ultrasonicate until completely dissolved, then add TFA (2.2 ml). Stir and react at room temperature overnight. After the reaction is complete, use a rotary evaporator to evaporate the reaction solution to an oily state. Then add methyl tert-butyl ether (60 ml) and n-hexane (20 ml). The product is an oily substance adhering to the bottom of the flask. After decanting the supernatant, add methyl tert-butyl ether (60 ml) and n-hexane (20 ml). Repeat this process four times, then transfer to a vacuum oven to dry, and obtain 0.67 g of 78-50 product. ESI [M+H + ]338.14, [M+Na + ]360.13

[0436] 4.3 Preparation of 78-51

[0437] Mono-tert-butyl succinate (3g, 17.2mmol) and N-hydroxysuccinimide (2.6g, 22.4mmol) were weighed into a 500ml round-bottom flask, and dichloromethane (20ml) was added. After sonication, DCC (16.71g, 81.015mmol) was added and stirred overnight. After completion of the reaction, the filtrate was collected by filtration. The filtrate was concentrated and then added to a 4 / 1 mixture of n-hexane / petroleum ether to precipitate the product. The product was filtered and then washed three times with a mixture of n-hexane / petroleum ether. After drying, the product was dissolved in a mixed solvent, silica gel powder (40ml) was added, and the mixture was evaporated to dryness. The sample was dry-loaded and subjected to column chromatography using 20-40% ethyl acetate / petroleum ether as the eluent to obtain 3.5g of product 78-51 in a 75% yield. 1 H-NMR (600MHz, DMSO-d6) δ2.88-2.84(m,2H),2.80-2.77(s,4H),2.58-2.53(m,2H),1.41-1.37(m,9H); ESI[M+Na + ]294.09

[0438] 4.4 Preparation of 80-183

[0439] 78-50 (0.67 g, 1.98 mmol) and 78-51 (0.65 g, 2.41 mmol) were weighed and added to a 500 ml flask. An appropriate amount of DMF was added to dissolve the mixture. DIEA (3.7 ml, 21.9 mmol) was slowly added dropwise. After completion of the dropwise addition, the mixture was stirred and reacted at room temperature overnight. After completion of the reaction, methyl tert-butyl ether (60 ml) and n-hexane (20 ml) were added to allow precipitation. The product, an oil, adhered to the bottom of the flask. After decanting the supernatant, methyl tert-butyl ether (60 ml) and n-hexane (20 ml) were added again to allow precipitation. This process was repeated four times, and the mixture was dried in a vacuum oven to obtain 0.84 g of product 80-183.

[0440] 4.5 Preparation of 80-180

[0441] N'-Fmoc-N-benzyloxycarbonyl-L-lysine (3.5 g, 7 mmol), β-alanine benzyl ester (2.46 g, 7 mmol), HBTU (2.9 g, 7.7 mmol), and HOBT (1.0 g, 7.7 mmol) were weighed and added to a 500 ml flask. An appropriate amount of DMF was added to dissolve the mixture. The mixture was placed at -5°C and DIEA (2.3 ml, 14 mmol) was slowly added dropwise. After a half-hour reaction, the mixture was removed from the flask and stirred at room temperature overnight. After completion of the reaction, saturated sodium chloride solution and ethyl acetate (200 ml) were added for extraction. The mixture was collected, concentrated, evaporated to dryness, and dried to obtain 4.6 g of the 80-180 product.

[0442] 4.6 Preparation of 80-185

[0443] Reactant 80-180 (4.6 g, 7 mmol) was dissolved in DMF (30 ml); morpholine (9 ml, 105 mmol) was then added and the mixture was stirred at room temperature overnight. After completion of the reaction, saturated sodium bicarbonate solution and ethyl acetate (200 ml) were added for extraction. The organic phase was collected and concentrated, and 200-300 mesh silica gel powder was added. The mixture was evaporated to dryness and dry-applied. Column chromatography was performed using 1.5% methanol / dichloromethane as the eluent to collect the desired product. The product was concentrated and evaporated to dryness to obtain 3.09 g of product 80-185.

[0444] 4.7 Preparation of 80-186

[0445] 80-183 (0.84 g, 1.7 mmol), 80-185 (2.5 g, 5.6 mmol), HBTU (2.12 g, 5.6 mmol), and HOBT (0.76 g, 5.6 mmol) were weighed and added to a 500 ml flask. An appropriate amount of DMF was added to dissolve the mixture, and DIEA (1.7 ml, 10.2 mmol) was slowly added dropwise. The mixture was stirred and allowed to react overnight at room temperature. After the reaction was complete, methanol was added, followed by methyl tert-butyl ether (60 ml) and n-hexane (20 ml). A powdery solid precipitated from the reaction solution and was filtered. The filter cake was washed with methyl tert-butyl ether (40 ml x 3), dissolved in a mixed solvent, and then added with silica gel powder. The mixture was evaporated to dryness and dry-applied. The desired product was collected by column chromatography using 3% methanol / dichloromethane as the eluent. The product was concentrated and evaporated to dryness to obtain 0.8 g of 80-186. 1 H-NMR(600MHz,DMSO-d6)δ8.08-7.85(m,6H),7.46-7.24(m,30H),7.24-7.13(m,3H),5.08(s,6H),5.01(s,6H),4.17(s,3H),3.76-3.37(m, 18H),3.22(s,6H),3.02-2.70(m,8H),2.60(m,2H),2.39-2.29(m,6H),1.50(s,6H),1.35(s,9H),1.29-1.25(m,6H),1.22(s,6H); ESI[M+Na + ]1786.85

[0446] 4.8 Preparation of 78-108

[0447] 80-186 (1.0 g, 0.567 mmol) and 10% Pd / C catalyst (0.3 g) were placed in a hydrogenation reactor. DMF (30 ml) was then added to dissolve the product. The hydrogenation reactor was sealed, evacuated with a water pump, and filled with hydrogen at approximately 2 MPa. This process was repeated three times. The pressure on the hydrogenation reactor was adjusted to 1.8 MPa, and the reaction was allowed to proceed overnight at room temperature. After completion of the reaction, the reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with DMF (20 ml x 3). This yielded a DMF solution containing 0.49 g of the product 78-108, which served as the starting material for the next reaction. 1 H-NMR(600MHz,DMSO-d6)δ8.21-8.13(m,7H),4.16(s,3H),3.63(s,18H),2. 74(s,8H),2.31(s,6H),2.17(s,8H),1.51(s,12H),1.38(s,9H),1.23(s,6H)

[0448] 4.9 Preparation of 78-122

[0449] 78-108 (0.1 g, 0.09 mmol) was placed in a 50 ml round-bottom flask, and then ultra-dry DMF (3 ml) was added. Dissolution was assisted by ultrasonication, and the mixture was stirred at 0°C for 3 minutes. DIEA (0.2 ml, 1.23 mmol) was then slowly added dropwise. After stirring for 5 minutes, M-SCM-10K (3.0 g, 0.28 mmol) was added. After the reaction, methyl tert-butyl ether (450 ml) was added to allow precipitation. The solid precipitated and was filtered. The filter cake was re-dissolved in an appropriate amount of dichloromethane, added with 200-300 mesh silica gel powder, and evaporated to dryness. The sample was dry-applied and subjected to column chromatography using 1% ammonia / 9% methanol / dichloromethane as the eluent. The desired product was collected, concentrated, and evaporated to dryness to obtain 3.0 g of 78-122.

[0450] 4.10 Preparation of 78-125

[0451] 78-122 (1.8 g, 0.056 mmol), 81-203 (1.22 g, 0.23 mmol), HBTU (0.1 g, 0.26 mmol), and HOBT (0.037 g, 0.26 mmol) were weighed and added to a 500 ml flask. An appropriate amount of DMF was added to dissolve the mixture. DIEA (0.12 ml, 0.76 mmol) was slowly added dropwise with stirring. After the addition was complete, the mixture was stirred and allowed to react overnight at room temperature. After the reaction was complete, methanol, methyl tert-butyl ether (60 ml), and n-hexane (20 ml) were added. A powdery solid precipitated from the reaction solution and was filtered. The filter cake was washed with methyl tert-butyl ether (40 ml x 3), dissolved in a mixed solvent, and then added with silica gel powder. The mixture was evaporated to dryness and dry-applied. The desired product was collected by column chromatography using 7% methanol / dichloromethane as the eluent. The product was concentrated and evaporated to dryness to obtain 2.65 g of 78-125.

[0452] 4.11 Preparation of 78-128

[0453] To a flask containing 78-125 (2.65 g, 0.055 mmol), add dichloromethane and ultrasonically shake until completely dissolved. Then, add TFA (13.5 ml) and stir at room temperature overnight. After the reaction is complete, add methyl tert-butyl ether (60 ml) and n-hexane (20 ml) to allow precipitation. A powdery solid precipitates from the reaction solution and is filtered. The filter cake is washed with methyl tert-butyl ether (40 ml x 3) and dried in a vacuum oven to yield 2.5 g of 78-128.

[0454] 4.12 Preparation of 78-131

[0455] 78-128 (2.5 g, 0.052 mmol), 78-129 (0.1 g, 0.1 mmol), HBTU (0.041 g, 0.11 mmol), and HOBT (0.015 g, 0.11 mmol) were weighed and added to a 500 ml flask. An appropriate amount of DMF was added to dissolve the mixture. DIEA (0.04 ml, 0.234 mmol) was slowly added dropwise with stirring. After the addition was complete, the mixture was stirred and allowed to react overnight at room temperature. After the reaction was complete, methanol was added, followed by methyl tert-butyl ether (60 ml) and n-hexane (20 ml) to allow precipitation. A powdery solid precipitated from the reaction solution and was filtered. The filter cake was washed with methyl tert-butyl ether (40 ml x 3), dissolved in a mixed solvent, and then added with silica gel powder. The mixture was evaporated to dryness and dry-applied. The desired product was collected by column chromatography using 1% triethylamine / 8% methanol / dichloromethane as the eluent. The product was concentrated and evaporated to dryness to obtain 0.2 g of 78-131. 1H-NMR(600MHz,DMSO-d6)δ8.77-8.69(m,10H),8.58-8.49(m,10H),8.26-8.15(m,28H),8 .14-7.93(m,72H),7.91-7.82(m,14H),7.81-7.77(m,11H),7.76-7.63(m,15H),7.52-7. 43(m,16H),7.40-7.25(m,42H),7.25-7.16(m,78H),7.15-7.11(m,21H),7.11-7.08(m,1 2H),7.06-7.03(m,3H),7.03-6.96(m,16H),6.91-6.88(m,5H),5.30-5.22(m,21H),4.80- 4.67(m,18H),4.62-4.52(m,15H),4.42-4.32(m,15H),4.31-4.09(m,42H),3.88-3.71(m ,42H),3.69-3.58(m,62H),3.56-3.44(m,2876H),3.28-3.10(m,15H),3.09-2.97(m,60H) ,2.86-2.70(m,27H),2.65-2.58(m,15H),2.44-2.28(m,35H),2.28-2.03(m,36H),1.94- 1.67(m,30H),1.66-1.55(m,33H),1.54-1.41(m,63H),1.36-1.35(m,32H),1.34-1.34(m, 36H),1.23-1.22(m,90H)

[0456] Example 5 Synthesis of Compound 72-188

[0457] 5.1 Preparation of 59-223

[0458] 1,3-Diamino-2-hydroxypropane (4.5 g, 52.74 mmol) was added to a 250 mL flask, and methanol (40 mL) was added to dissolve it. The reaction was stirred at room temperature. Triethylamine (1 mL) was added and the reaction was continued at room temperature with stirring for 10 minutes. Boc-anhydride (35 g, 146.52 mmol) was slowly added and the reaction was stirred in a 45°C water bath for 20 minutes. The mixture was removed and stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and extracted with ethyl acetate (100 mL) and purified water (200 mL). The organic phases were collected and combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and evaporated to dryness. Then, n-hexane was added to dissolve the mixture, and the mixture was placed in a 65°C water bath and refluxed for 20 minutes. The mixture was cooled to room temperature. Solid precipitated and was filtered to obtain a solid product. The filter cake was collected and dried in a vacuum oven to obtain 10 g of the product. 1 H-NMR (600MHz, DMSO-d6) δ6.61(s,2H),4.76(s,1H),3.44(dd,J=10.8,5.4Hz,1H),2.89(d,J=50.2Hz,4H),1.38(s,18H)

[0459] 5.2 Preparation of 59-224

[0460] Sodium hydride (1.2 g, 46.35 mmol) was added to a 250 ml two-necked flask. Ultra-dry THF (20 ml) was added to dissolve the mixture. The reaction mixture was stirred in an ice-water bath. 59-223 (9.38 g, 32.305 mmol) and benzyl bromoacetate (7.7 ml, 48.46 mmol) were added sequentially. The reaction mixture was stirred at room temperature under nitrogen. Upon completion of the reaction, the reaction mixture was transferred to a 1 L separatory funnel containing 5% dilute formic acid solution. Ethyl acetate (200 ml) was added and extracted to obtain an organic phase. The aqueous phase was extracted with ethyl acetate (200 ml x 3). The combined organic phases were washed with saturated brine (200 ml x 2) and evaporated to dryness. The obtained solid product was dissolved in a dichloromethane / methanol mixed solvent, dry-loaded, and subjected to column chromatography using an 8-20% ethyl acetate / petroleum ether mixed solvent as the eluent. The target product was collected, concentrated, and dried in a vacuum oven to obtain 6.8 g of the product with a yield of 39.8%. 1 H-NMR (600MHz, DMSO-d6) δ7.37(t,J=11.2Hz,5H),6.66(s,2H),5.16(s,2H),4.24(s,2H),3.08-2.95(m,5H),1.37(s,18H)

[0461] 5.3 Preparation of 59-230

[0462] 59-224 (6.8 g, 15.507 mmol) was added to a reaction flask. 4M hydrochloric acid-1,4-dioxane (155.07 ml) was added and ultrasonically shaken until completely dissolved. The mixture was then stirred at room temperature for 5 hours. After the reaction, the reaction solution was concentrated and evaporated to dryness. Dichloromethane (30 ml) was added, ultrasonically treated, and then spin-dried. This process was repeated five times. Drying yielded 3.7 g of the product.

[0463] 5.4 Preparation of 59-231

[0464] 59-230 (3.7 g, 15.507 mmol), tert-butyl succinate (5.94 g, 34.1154 mmol), and HATU (12.97 g, 34.1154 mmol) were added to a 250 ml flask. DMF (50 ml) was added to dissolve the mixture. The reaction was stirred at 0°C for approximately 20 minutes. DIEA (23 ml, 139.563 mmol) was then slowly added dropwise. After the addition was complete, the reaction was continued at 0°C with stirring for 5 hours. After the reaction was complete, ethyl acetate (200 ml) and purified water (200 ml) were added for extraction. The aqueous phase was extracted with ethyl acetate (100 ml x 3). The organic phases were combined, concentrated to 150 ml, washed three times with purified water, and the ethyl acetate phase was collected. The product was dried by spin drying, dissolved in a dichloromethane / methanol mixed solvent, dry loaded, and subjected to column chromatography using a 0.5-1.5% methanol / dichloromethane mixed solution as the eluent. The target product was collected, concentrated, and dried in a vacuum oven to obtain 4.8 g of the product with a yield of 56.47%. 1 H-NMR(600MHz,DMSO-d6)δ7.83(s,2H),7.38(d,J=4.5Hz,5H),5.16(s,2H),4.28(s,2H) ,3.21-3.10(m,5H),2.39(t,J=6.8Hz,4H),2.30(t,J=7.0Hz,4H),1.37(d,J=3.5Hz,18H)

[0465] 5.5 Preparation of 72-129

[0466] 59-231 (2.5 g, 4.54 mmol) was added to a reaction flask, and dichloromethane (5 ml) was added. After ultrasonic oscillation until completely dissolved, TFA (15 ml, 181.6 mmol) was added and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction solution was concentrated and evaporated to dryness, dichloromethane was added, and the mixture was spin-dried. This process was repeated three times. Methyl tert-butyl ether was then added to allow the mixture to settle. The mixture was ultrasonically treated for 10 minutes, allowed to stand, and filtered. The filter cake was collected. This process was repeated three times and vacuum dried to obtain 1.52 g of the product in a yield of 76.38%.

[0467] 5.6 Preparation of 72-139

[0468] 72-129 (0.71 g, 1.634 mmol), 76-58 (2.13 g, 3.593 mmol), HBTU (1.8531 g, 4.901 mmol) and HOBT (0.66 g, 4.901 mmol) were added to a 250 ml round-bottom flask and dissolved with DMF (20 ml). The reaction flask was stirred at room temperature for about 20 minutes, and then DIEA (8.8 ml, 68.426 mmol) was slowly added dropwise. After the addition was complete, the reaction flask was stirred at room temperature. After the reaction is completed, n-hexane (30 ml) and methyl tert-butyl ether (200 ml) are added for precipitation, the supernatant is poured out, and n-hexane and methyl tert-butyl ether are added for precipitation. This process is repeated 4 times, and a solid product is obtained by filtration. The obtained solid product is dissolved in a dichloromethane / methanol mixed solvent, dry-loaded, and column chromatography is performed using a 3-4% methanol / dichloromethane mixed solution as an eluent. The target product is collected, concentrated, and dried in a vacuum oven to obtain 2.247 g of the product with a yield of 86.4%. 1H-NMR(600MHz,DMSO-d6)δ8.12(d,J=7.2Hz,2H),7.93-7.87(m,4H),7.73(s,2H),7.35(dt,J=12.1,5.6Hz,15H),7 .23(s,2H),5.15(s,2H),5.00(s,4H),4.25(s,2H),4.15(d,J=5.2Hz,5H),3.27(d,J=6.9Hz,2H),3.15(dd,J=12.9, 6.1Hz,6H),2.96(d,J=6.7Hz,4H),2.40-2.26(m,14H),2.20-2.13(m,4H),1.89(td,J=13.8,5.3Hz,2H),1.76-1.69 (m,2H),1.63(dd,J=14.0,8.6Hz,2H),1.52-1.46(m,2H),1.38(s,18H),1.37(s,18H),1.25(dd,J=12.2,6.2Hz,6H)

[0469] 5.7 Preparation of 72-142

[0470] 72-139 (0.5 g, 0.315 mmol) was added to a hydrogenation reactor, followed by a 10% Pd / C catalyst (0.03 g). Methanol (20 ml) was then added, and hydrogen was introduced at a pressure of 300 psi. The reaction was stirred at room temperature for 3 days. After completion of the reaction, the reaction solution was filtered through celite, and the filter cake was washed with methanol (15 ml x 3). The filtrate was placed in a 500 ml round-bottom flask and rotary evaporated. Dichloromethane was added to dissolve the product, and 0.05 ml of toluene was added. The product was then dried and the reaction was repeated 5 times to obtain 0.387 g of the product 72-142. 1H-NMR(600MHz,DMSO-d6)δ9.16-9.09(m,1H),8.18(dd,J=13.8,7.4Hz,2H),8.01(dd,J=23.7,7.9Hz, 2H),7.89(dd,J=6.1,3.0Hz,4H),5.12-5.10(m,4H),4.16(d,J=4.7Hz,5H),3.75(s,2H),3.27(dd,J= 11.9,6.1Hz,4H),3.20-3.13(m,4H),2.79-2.72(m,4H),2.43-2.28(m,14H),2.18(dd,J=15.9,9.5Hz ,4H),1.89(d,J=14.5Hz,2H),1.76-1.62(m,6H),1.50(dd,J=15.5,6.0Hz,6H),1.38(d,J=5.1Hz,36H)

[0471] 5.8 Preparation of 72-149

[0472] 72-142 (0.115 g, 0.0939 mmol) was placed in a 250 ml flask and dissolved in anhydrous DMF (30 ml). The reaction was placed at -5°C for 10 minutes, and DIEA (0.3 ml, 1.877 mmol) was slowly added dropwise. After stirring at low temperature for 30 minutes, M-SCM-10K (2 g, 0.1877 mmol, purchased from Jenka, Lot Number: A3016-N230101) was added. The reaction was placed at room temperature in the dark and stirred at low speed for one week. After the reaction, methyl tert-butyl ether (200 ml) and n-hexane (70 ml) were added, and the solid precipitated. The solid was filtered and the filter cake was washed with methyl tert-butyl ether (40 ml x 3). The filter cake was collected and the solid product was dissolved in a dichloromethane / methanol mixed solvent. The sample was dry-loaded and column chromatography was performed using a 1% ammonia water / 5-10% methanol / dichloromethane mixed solution as an eluent. The target product was collected, concentrated, and dried in a vacuum oven to obtain 2.01 g of the product with a yield of 76.8%. 1H-NMR(600MHz,DMSO-d6)δ9.16-9.13(m,1H),9.06-8.56(m,2H),8.26-8.202(m,2H),8.018-7.96(m,2H),7.729- 7.661(m,4H),4.181-4.114(m,3H),4.089-4.056(m,2H),4.02-3.96(m,2H),3.52-3.50(m,1914H),3.28-3.25(m, 4H),3.202-3.134(m,4H),3.10-3.06(m,4H),2.42-2.31(m,14H),2.21-2.15(m,4H),1.95-1.87(m,2H),1.77-1.6 9(m,2H),1.68-1.605(m,2H),1.56-1.48(m,2H),1.406-1.394(m,2H),1.388-1.369(m,36H),1.351-1.318(m,4H)

[0473] 5.9 Preparation of 72-154

[0474] 72-149 (2.01 g, 0.0901 mmol), 70-68 (0.13 g, 0.189 mmol), HBTU (0.0513 g, 0.135 mmol), and HOBT (0.0183 g, 0.135 mmol) were added to a 250 ml round-bottom flask and dissolved in DMF (20 ml). The reaction flask was then stirred at room temperature for approximately 20 minutes. DIEA (0.1 ml, 0.6051 mmol) was then slowly added dropwise. After the addition was complete, the reaction flask was allowed to continue stirring at room temperature. After completion of the reaction, n-hexane (30 ml) and methyl tert-butyl ether (200 ml) were added to allow the reaction to proceed. The supernatant was decanted, and n-hexane and methyl tert-butyl ether were then added to allow the reaction to proceed. This process was repeated four times, and the solid product was filtered to obtain. The obtained solid product was dissolved in a dichloromethane / methanol mixed solvent, dry-loaded, and subjected to column chromatography using a 1% ammonia solution / 5-7% methanol / dichloromethane mixed solution as the eluent. The target product was collected, concentrated, and dried in a vacuum oven to obtain 0.9 g of the product with a yield of 45%. 1H-NMR(600MHz,DMSO-d6)δ8.61-8.54(m,1H),8.25-8.21(m,1H),8.20-8.08(m,6H) ,8.075-8.008(m,4H),7.97-7.85(m,6H),7.75-7.71(m,2H),7.69-7.66(m,2H),7. 61-7.59(m,1H),7.54-7.51(m,1H),7.29-7.23(m,5H),4.6-4.56(m,1H),4.48-4.4 2(m,1H),4.39-4.33(m,1H),4.19-4.03(m,7H),3.98-3.93(m,3H),3.52-3.50(m,1 914H),3.27-3.26(m,1H),3.18-3.14(m,4H),3.08-3.03(m,8H),2.92-2.89(m,2H) ,2.81-2.72(m,4H),2.40-2.32(m,14H),2.2-2.14(m,4H),2.02-1.96(m,2H),1.93 -1.86(m,3H),1.82-1.77(m,2H),1.74-1.7(m,2H),1.66-1.6(m,4H),1.54-1.46(m ,6H),1.42-1.39(m,2H),1.38-1.36(m,36H),0.91-0.88(m,3H),0.86-0.84(m,3H)

[0475] 5.10 Preparation of 72-163

[0476] Compound 72-154 (0.9 g, 0.03916 mmol) was added to a 250 ml round-bottom flask, followed by dichloromethane (2 ml) and ultrasonic dissolution. TFA (10 ml, 3.13 mmol) was then added and stirred at room temperature. After completion of the reaction, the reaction solution was evaporated to an oil using a rotary evaporator. Methyl tert-butyl ether (60 ml) was then added, resulting in the precipitation of a powdery solid. The solid was filtered, and the filter cake was washed with methyl tert-butyl ether (40 ml x 3). The filter cake was collected and dried in a vacuum oven to yield 0.83 g of the product. 1H-NMR (600MHz, DMSO-d6) δ9.33-9.29(m,4H),8.59-8.56(m,1H),8.28-8.24(m,1H),8.23-8.15(m,4H),8.13-8.08(m,3H),8.07-8.05( m,2H),8.04-8.01(m,1H),8.0-7.85(m,6H),7.72-7.66(m,4H),7.62-7.57(m,1H),7.55-7.50(m,1H),7.29-7.27(m,1H),7.26-7.22(m ,4H),4.58-4.55(m,1H),4.45-4.43(m,1H),4.36-4.34(m,1H),4.11-4.05(m,7H),3.96-3.94(m,3H),3.52-3.50(m,1914H),3.21-3.0 2(m,13H),2.8-2.72(m,2H),2.65-2.60(m,4H),2.40-2.33(m,14H),2.22-2.15(m,4H),2.0-1.88(m,3H),1.82-1.72(m,4H),1.68-1.58 (m,4H),1.54-1.48(m,4H),1.46-1.33(m,6H),0.91-0.88(m,3H),0.85-0.83(m,3H)

[0477] 5.11 Preparation of 72-167

[0478] 72-163 (0.56 g, 0.0246 mmol), 76-93 (0.28 g, 0.1968 mmol), HBTU (0.075 g, 0.1476 mmol) and HOBT (0.027 g, 0.1476 mmol) were added to a 250 ml round-bottom flask and dissolved with DMF (40 ml). The reaction flask was stirred at room temperature for about 20 minutes, and then DIEA (0.07 ml, 0.4428 mmol) was slowly added dropwise. After the addition was complete, the reaction flask was continued to stir at room temperature. After the reaction is completed, n-hexane (30 ml) and methyl tert-butyl ether (200 ml) are added for precipitation, the supernatant is poured out, and n-hexane and methyl tert-butyl ether are added for precipitation, and the process is repeated 3 times. The solid product is filtered to obtain a solid product, and the obtained solid product is dissolved in a dichloromethane / methanol mixed solvent, dry-loaded, and column chromatography is performed using a 1% ammonia water / 6-10% methanol / dichloromethane mixed solution as an eluent. The target product is collected, concentrated, and dried in a vacuum oven to obtain 0.793 g of the product with a yield of 76.47%. 1H-NMR(600MHz,DMSO-d6)δ8.58-8.56(m,1H),8.28-8.17(m,17H),8.11-8.05(m,2 1H),8.03-8.00(m,5H),7.99-7.97(m,6H),7.87-7.85(m,6H),7.83-7.82(m,6H),7 .77-7.74(m,4H),7.71-7.68(m,4H),7.60-7.58(m,1H),7.53-7.51(m,1H),7.24-7 .22(m,5H),4.58-4.55(m,1H),4.45-4.43(m,1H),4.36-4.34(m,1H),4.21-4.17(m ,12H),4.09-4.06(m,7H),3.96-3.95(m,3H),3.52-3.50(m,1914H),3.43-3.38(m, 128H),3.19-3.15(m,45H),3.06-3.04(m,32H),2.76-2.74(m,2H),2.65-2.60(m,1 2H),2.37-2.31(m,14H),2.13-2.10(m,28H),1.87-1.78(m,32H),1.75-1.71(m,15 H),1.48-1.43(m,30H),1.37-1.36(m,144H),0.91-0.88(m,3H),0.85-0.83(m,3H)

[0479] 5.12 Preparation of 72-173

[0480] 72-167 (0.793 g, 0.0279 mmol) was added to a 250 ml round-bottom flask, followed by dichloromethane (5 ml) and ultrasonic dissolution. TFA (0.7 ml, 8.8 mmol) was then added and the reaction was stirred at room temperature. After completion of the reaction, the reaction solution was evaporated to an oil using a rotary evaporator. Methyl tert-butyl ether (60 ml) was then added, and a powdery solid precipitated from the reaction solution. The mixture was filtered, and the filter cake was washed with methyl tert-butyl ether (40 ml x 3). The filter cake was collected and dried in a vacuum oven to yield 0.649 g of the product.

[0481] 5.13 Preparation of 72-188

[0482] 72-173 (0.449 g, 0.0167 mmol), 76-230 (0.224 g, 0.5353 mmol), HBTU (0.152 g, 0.4014 mmol) and HOBT (0.054 g, 0.4014 mmol) were added to a 250 ml round-bottom flask and dissolved with DMF (30 ml). The reaction flask was stirred at room temperature for about 20 minutes, and then DIEA (0.2 ml, 1.204 mmol) was slowly added dropwise. After the addition was complete, the reaction flask was continued to stir at room temperature. After the reaction is completed, n-hexane (30 ml) and methyl tert-butyl ether (200 ml) are added for precipitation, the supernatant is decanted, and n-hexane and methyl tert-butyl ether are added for precipitation. This process is repeated three times, and a solid product is obtained by filtration. The obtained solid product is dissolved in a mixed solvent of dichloromethane and methanol, and the sample is dry-loaded. Column chromatography is performed using a mixed solution of 1% ammonia water / 5-10% methanol / dichloromethane as an eluent. The target product is collected, concentrated, and dried in a vacuum oven to obtain 0.053 g of the product with a yield of 8.55%. 1 H-NMR(600MHz,DMSO-d6)δ8.57(s,1H),8.35-8.28(m,16H),8.27-8.18(m ,17H),8.11-8.05(m,26H),8.00-7.99(m,12H),7.90-7.86(m,22H),7.75 -7.74(m,4H),7.70-7.68(m,36H),7.59-7.58(m,2H),7.18-7.16(m,36H) ,4.60-4.59(m,1H),4.43-4.38(m,18H),4.26-4.22(m,12H),4.04-4.00(m ,42H),3.52-3.50(m,1914H),3.44-3.40(m,128H),3.22-3.11(m,45H),3 .00-2.98(m,32H),2.92-2.91(m,32H),2.76-2.75(m,2H),2.62-2.60(m, 12H),2.40-2.19(m,78H),2.18-2.05(m,28H),1.66-1.62(m,47H),1.45- 1.43(m,30H),1.36-1.34(m,177H),1.11-1.08(m,48H),0.91-0.90(m,6H)

[0483] Example 6 Synthesis of Compound 70-261

[0484] 6.1 Preparation of 70-187

[0485] Fmoc-glycine (10 g, 33.64 mmol, purchased from Inochem), tert-butyloxycarbonyl hydrazide (5.78 g, 43.72 mmol), and DCC (6.94 g, 33.64 mmol) were weighed and placed in a flask. Ethyl acetate (30 ml) was added to completely dissolve the mixture. The mixture was allowed to react at 0°C for 2 hours, then removed from the flask and stirred at room temperature. The reaction was monitored by TLC after 4 hours. After the reaction, saturated NaCl solution (200 ml) and ethyl acetate (200 ml) were added for extraction. After standing for decomposition, the organic phase was collected and the aqueous phase was extracted with ethyl acetate (200 ml x 3). The organic phases were combined, concentrated and evaporated to dryness to a solid, and dried in a vacuum oven to obtain the product.

[0486] 6.2 Preparation of 70-193

[0487] To a flask containing 70-187 (33.64 mmol) was added THF (40 ml). Ultrasonication was used to dissolve the mixture, followed by the addition of diethylamine (68 ml, 672.8 mmol). The mixture was stirred at room temperature for 2 h. After completion, the reaction was monitored by TLC. The reaction solution was evaporated to dryness using a rotary evaporator, dissolved in dichloromethane (not completely dissolved), and evaporated to dryness again. This process was repeated five times. Finally, a methanol / dichloromethane mixture was added for dissolution. Silica gel powder was added and evaporated to dryness. The sample was dry-loaded and subjected to column chromatography using 0.8% ammonia water / 8% methanol / dichloromethane as the eluent. The desired product was collected and dried to yield 6.3 g, with a yield of 86.82%.

[0488] 6.3 Preparation of 70-196

[0489] Fmoc-Glu-OH (2.0 g, 5.4 mmol), H-Glu(OtBu)-OtBu.HCl (3.5 g, 11.9 mmol), HOBT (1.8 g, 13.0 mmol), and HBTU (4.9 g, 13.0 mmol) were added to a 500 ml flask and dissolved in DMF (60 ml). The reaction mixture was stirred at 0°C for approximately 20 minutes, and DIEA (4.0 ml, 23.8 mmol) was slowly added dropwise. After the addition was complete, the reaction mixture was stirred at room temperature and monitored by TLC. After completion of the reaction, the reaction mixture was transferred to a 1 L separatory funnel and extracted with saturated sodium bicarbonate solution (200 ml) and ethyl acetate (300 ml). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (100 ml x 3). The combined organic phases were washed with pure water (150 ml x 2), concentrated, and evaporated to dryness to obtain 5.9 g of the product (overproduction yield).

[0490] 6.4 Preparation of 70-197

[0491] To a flask containing 70-196 (11.9 g, 5.4 mmol) was added DMF (80 ml). After ultrasonic dissolution, morpholine (9.4 ml, 108 mmol) was added and stirred at room temperature for 2 h. After completion of the reaction, the mixture was filtered and extracted with saturated sodium bicarbonate solution (200 ml) and ethyl acetate (200 ml). After stratification, the organic phase was collected and the aqueous phase was extracted with ethyl acetate (200 ml x 3). The organic phases were combined and evaporated to dryness to obtain 4.5 g of a solid product (overproduction).

[0492] 6.5 Preparation of 70-198

[0493] 70-197 (4.5 g, 5.4 mmol), 88-14 (1.9 g, 5.4 mmol), HOBT (0.88 g, 6.5 mmol), and HBTU (2.5 g, 6.5 mmol) were weighed and added to a reaction flask. They were dissolved in DMF (40 ml). The reaction was stirred at 0°C for approximately 20 minutes. DIEA (2.0 ml, 11.9 mmol) was slowly added dropwise. After the addition was complete, the reaction mixture was continued to stir at 0°C. After the reaction was completed, the reaction solution was transferred to a 1 L separatory funnel and extracted with saturated sodium chloride solution (200 ml) and ethyl acetate (150 ml) to obtain the organic phase. The aqueous phase was extracted with ethyl acetate (200 ml x 2). The combined organic phases were washed with deionized water (250 ml x 2), concentrated, evaporated to dryness to a solid, and then dissolved in a 1 / 4 methanol / dichloromethane mixture (100 ml). Silica gel powder (100 ml) was added and evaporated to dryness to a powdery solid. The product was dry-loaded and subjected to column chromatography using a 0.5-5% methanol / dichloromethane mixture as the eluent. The target product was collected, concentrated, and dried in a vacuum oven to obtain 4.2 g of the product with a yield of 80.75%.

[0494] 6.6 Preparation of 70-199

[0495] To a flask containing 70-198 (4.2 g, 4.35 mmol) was added dichloromethane (15 ml), and after dissolution with ultrasonication, TFA (25.9 ml, 348.12 mmol) was added. The mixture was stirred at room temperature overnight, and the reaction progress was monitored by TLC. After completion of the reaction, the reaction solution was concentrated under reduced pressure to remove dichloromethane and most of the TFA, and then n-hexane (100 ml) and methyl tert-butyl ether (100 ml) were added to allow the mixture to settle, resulting in an oily solid. The supernatant was discarded, and ethyl acetate (15 ml) was added. The mixture was treated with ultrasonication to obtain a white turbid liquid. N-hexane (100 ml) was then added to allow the mixture to settle, resulting in a powdery solid. The mixture was filtered, and the filter cake was washed three times with methyl tert-butyl ether (40 ml). The filter cake was collected and dried under vacuum to obtain 3.0 g of the product with a yield of 93.8%.

[0496] 6.7 Preparation of 70-200

[0497] 70-193 (1.2 g, 5.94 mmol), 70-199 (1 g, 1.35 mmol), HBTU (2.5 g, 6.48 mmol), and HOBT (0.9 g, 6.48 mmol) were weighed and added to a 250 ml flask. DMF (30 ml) was then added to dissolve the mixture. The mixture was placed at -5°C and DIEA (2.0 ml, 11.88 mmol) was slowly added dropwise. After a half-hour reaction, the mixture was removed from the flask and stirred at room temperature overnight. The reaction progress was monitored by TLC. After completion of the reaction, n-hexane (25 ml) and methyl tert-butyl ether (200 ml) were added to allow sedimentation. The supernatant was decanted, and n-hexane and methyl tert-butyl ether were added to allow sedimentation. This process was repeated three times. The mixture was filtered and dried to obtain 2.5 g of a solid product.

[0498] 6.8 Preparation of 70-201

[0499] To a flask containing 70-200 (2.5 g, 1.35 mmol) was added THF (15 ml). After ultrasonic dissolution, diethylamine (2.0 ml, 27 mmol) was added and the mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction solution was evaporated to dryness, and the resulting solid product was dissolved in dichloromethane and methanol. The solid product was dry-loaded and subjected to column chromatography using 5-12% methanol / dichloromethane as the eluent. The desired product was collected, concentrated, and dried to obtain 0.9 g of the product, with a yield of 56.25%. 1H-NMR(600MHz,DMSO-d6)δ8.29(s,3H),8.14-8.06(m,5H),8.05-7.99(m,2 H),7.95(s,5H),5.13(s,2H),4.28-4.23(m,2H),4.19-4.15(m,1H),3.76-3 .67(m,8H),2.65-2.60(m,2H),2.20-2.16(m,6H),1.94-1.83(m,4H),1.80 -1.68(m,4H),1.43-1.53(m,4H),1.39(s,36H),1.29-1.22(m,2H);ESI[M+H + ]1203.628

[0500] 6.9 Preparation of 71-222

[0501] 1,3-Diamino-2-hydroxypropane (6 g, 66.5778 mmol) was weighed and added to a 250 ml flask. DMSO (7 ml) was added to dissolve the mixture. The reaction mixture was stirred at 15°C under nitrogen. 5 M aqueous sodium hydroxide solution (0.7 ml) was then added dropwise. After the addition was complete, the mixture was stirred for 10 minutes. Tert-butyl acrylate (38.6 ml, 266.3112 mmol) was then added dropwise. After the addition was complete, the mixture was stirred for 20 minutes. The reaction flask was removed and stirred at room temperature for 24 hours. After the reaction was completed, the reaction mixture was transferred to a 1 L separatory funnel and extracted with saturated sodium chloride solution (200 ml) and ethyl acetate (150 ml). The organic phase was obtained, and the aqueous phase was extracted with ethyl acetate (200 ml x 2). The combined organic phases were washed with deionized water (250 ml x 2), concentrated, evaporated to dryness, and then dissolved in 1 / 4 methanol / dichloromethane mixed solution (50 ml). Silica gel powder (100 ml) was added and evaporated to dryness to a powdery solid. The solid was dry-loaded and subjected to column chromatography using a 0-2% methanol / dichloromethane mixed solution as the eluent. The target product was collected, concentrated, and dried in a vacuum oven to obtain 1.0 g of the product. 1 H-NMR(600MHz,DMSO-d6)δ3.68-3.58(m,2H),3.37-3.34(m,1H),2.73-2.6 3(m,4H),2.62-2.56(m,3H),2.47-2.34(m,6H),2.29(d,6.6Hz,6H),1.39(d 36H)

[0502] 6.10 Preparation of 70-185

[0503] 71-222 (1.2 g, 2.0 mmol), benzyl succinate (0.46 g, 2.2 mmol), and HATU (0.92 g, 2.4 mmol) were added to a 250 ml flask. DMF (20 ml) was added to dissolve the mixture. The reaction was stirred at -5°C for approximately 20 minutes, followed by the slow dropwise addition of DIEA (1.0 ml, 4.4 mmol). After the addition was complete, the mixture was stirred at -5°C for another 20 minutes, then allowed to cool to room temperature with stirring. After the reaction was complete, saturated NaCl solution (100 ml) and ethyl acetate (100 ml) were added for extraction. After separation, the organic phase was collected. The aqueous phase was further extracted with ethyl acetate (200 ml x 3). The combined organic phases were evaporated to dryness, dissolved in a mixed solvent, added to silica gel powder, evaporated to dryness, and dry-applied. The product was purified by column chromatography using 30% ethyl acetate / petroleum ether as the eluent. The product was collected, concentrated, and dried to yield 1.3 g (85.44% yield). 1 H-NMR(600MHz,DMSO-d6)δ7.38-7.31(m,5H),5.06(s,2H),3.74-3.44(m,5H),3.38- 3.35(m,2H),3.17(s,1H),2.70-2.56(m,8H),2.41-2.26(m,9H),1.40-1.37(m,36H)

[0504] 6.11 Preparation of 70-186

[0505] To a flask containing 70-185 (0.3 g, 0.38 mmol) was added dichloromethane (5 ml), and after ultrasonic dissolution, TFA (4.9 ml, 66.356 mmol) was added. The mixture was stirred at room temperature to react. After the reaction, the reaction solution was concentrated to remove dichloromethane and most of the TFA. Then, n-hexane (200 ml) and methyl tert-butyl ether (200 ml) were added to allow sedimentation. The supernatant was discarded to obtain an oily solid. Ethyl acetate (15 ml) was added and ultrasonicated to obtain a white turbid liquid. Then, n-hexane (200 ml) was added to allow sedimentation to obtain a powdery solid. The solid was filtered, and the filter cake was washed three times with methyl tert-butyl ether (40 ml). The filter cake was collected and dried under vacuum to obtain 0.16 g of the product.

[0506] 6.12 Preparation of 70-204

[0507] 70-186 (0.16 g, 0.28 mmol), 76-58 (0.73 g, 1.24 mmol), HBTU (0.64 g, 1.69 mmol), and HOBT (0.23 g, 1.69 mmol) were added to a 500 ml flask and dissolved in DMF (60 ml). The reaction mixture was stirred at 0°C for approximately 20 minutes, and DIEA (20 ml, 121.8290 mmol) was slowly added dropwise. After the addition was complete, the reaction mixture continued to stir at 0°C. After completion of the reaction, the reaction mixture was transferred to a 1 L separatory funnel and extracted with saturated sodium chloride solution (100 ml) and ethyl acetate (150 ml) to obtain an organic phase. The aqueous phase was extracted with ethyl acetate (100 ml x 2). The combined organic phases were washed with deionized water (150 ml x 2), concentrated, evaporated to dryness, and then dissolved in a 1 / 4 methanol / dichloromethane mixture (50 ml). Silica gel powder (10 ml) was added and evaporated to dryness to obtain a powdery solid. The solid was dry-loaded and subjected to column chromatography using a 0.3% ammonia solution / 0-4% methanol / dichloromethane mixture as the eluent. The target product was collected, concentrated, and dried in a vacuum oven to obtain 0.5 g of the product. 1 H-NMR(600MHz,DMSO-d6)δ8.03-7.86(m,12H),7.40-7.30(m,J=6.6,25H),7.22-7.15 (m,5H),5.08-5.04(m,2H),5.01-4.96(m,8H),4.34-4.09(m,10H),4.06-3.95(m,2H) ,3.62-3.46(m,6H),3.22-3.10(m,6H),3.05-2.90(m,12H),2.86-2.80(m,2H),2.73- 2.63(m,6H),2.62-2.61(m,2H),2.39-2.38(m,2H),2.36-2.30(m,14H),2.21-2.11(m, 10H),1.88-1.79(m,6H),1.75-1.66(m,6H),1.64-1.55(m,6H),1.50-1.44(m,J =20.1,6H),1.38-1.37(m,32H),1.37-1.36(m,32H),1.26-1.23(m,8H); ESI[M+H + ]2867.570.

[0508] 6.13 Preparation of 70-208

[0509] Weigh 70-204 (0.3 g, 0.105 mmol) into a microhydrogenation reactor and dissolve in DMF (20 ml). Add 10% Pd / C catalyst (0.1 mg). Use a rubber-tipped pipette to flush the material from the reactor wall. Add a stirring magnet and seal the reactor. Evacuate the reactor with a water pump, introduce hydrogen, and evacuate again. Repeat this process three times. Finally, introduce hydrogen to stabilize the hydrogenation reactor pressure at 2 MPa. Stir overnight and monitor on a TLC plate. After completion of the reaction, filter through diatomaceous earth and collect the filtrate. A portion of the filtrate is then dried and characterized. 1 H-NMR(600MHz,DMSO-d6)δ8.09-7.83(m,12H),7.38-7.24(m,4H),5.02-4.89(m,2H),4.22-4.11(m,8H ),3.55-3.50(m,12H),3.19-3.13(m,12H),3.07-3.01(m,6H),2.91-2.86(m,4H),2.74-2.73(m,2H),2 .71-2.69(m,2H),2.63-2.60(m,2H),2.39-2.38(m,2H),2.38-2.32(m,12H),2.21-2.10(m,14H),1.87 -1.79(m,6H),1.75-1.67(m,6H),1.64-1.55(m,6H),1.51-1.45(m,6H),1.40-1.34(m,72H);ESI[M+Na + ]2269.371

[0510] 6.14 Preparation of 70-246

[0511] The filtrate of 70-208 (0.066 mmol) was taken, and DMF (15 ml) and DIEA (0.5 ml, 2.64 mmol) were added. After stirring for 30 min, M-SCM-10K (2.90 g, 0.27 mmol, purchased from Jiankai) was added. The reaction was stirred at low speed in the dark at room temperature. The reaction progress was monitored by TLC after two days. After the reaction was completed, the mixture was precipitated with methyl tert-butyl ether / n-hexane and filtered with a filtrate funnel to collect the filter cake. The mixture was washed twice with methyl tert-butyl ether and the filter cake was transferred to a flask and dried to obtain 2.8 g of the product with a yield of 94.11%.

[0512] 6.15 Preparation of 70-250

[0513] Reactants 70-246 (7.82.8 g, 0.64 mmol), 70-68 (70.06 g, 0.080 mmol), HOBT (12 g, 0.9 mmol), and HBTU (0.34 g, 0.9 mmol) were placed in a reaction flask. An appropriate amount of DMF was added, and the mixture was dissolved with ultrasonication. The mixture was stirred at 0°C, and DIEA (0.7 mmol, 4.4 mmol) was added dropwise. After complete addition, the mixture was brought to room temperature and stirred for 1 hour. The reaction progress was monitored by TLC. After completion of the reaction, the mixture was precipitated with methyl tert-butyl ether / n-hexane and filtered using a filtrate funnel to collect the filter cake. The above step was repeated twice. The filter cake was transferred to a flask, dissolved in a mixed solvent, and silica gel powder was added and evaporated to dryness. The sample was dry-loaded and subjected to column chromatography using 1% ammonia / 8% methanol / dichloromethane as the eluent. The product was collected and dried to yield 2.1 g, a yield of 70.71%. 1 H NMR (600MHz, DMSO-d6) δ8.20-7.81(m,12H),7.71-7.63(m,2H),7.41-7.21(m,1H),6.62-6.54(m,1H),4.25-4.15(m,8H),3.63-3.63( m,8H),3.51-3.50(m,3828H),3.24-3.24(m,12H),3.20-3.19(m,2H),3.18-3.16(m,3H),3.16-3.15(m,2H),3.15-3.14(m,2H),3.12- 3.11(m,1H),3.09-3.04(m,7H),2.63-2.61(m,6H),2.60-2.58(m,4H),2.41-2.37(m,6H),2.37-2.32(m,12H),1.88-1.78(m,6H),1.7 4-1.65(m,6H),1.64-1.54(m,6H),1.53-1.45(m,6H),1.40-1.36(m,72H),1.24-1.21(m,39H),0.91-0.88(m,3H),0.86-0.83(m,3H),

[0514] 6.16 Preparation of 70-251

[0515] Reagent 70-250 (0.044 mmol) was dissolved in dichloromethane (20 ml), followed by the addition of TFA (35 ml, 472 mmol). The reaction was stirred at room temperature and monitored by TLC. After completion of the reaction, the mixture was concentrated using a rotary evaporator, precipitated with methyl tert-butyl ether / n-hexane, and filtered using a filtrate funnel to collect the filter cake. The mixture was washed twice with methyl tert-butyl ether and dried to obtain 1.68 g of the product, with a yield of 85.81%.

[0516] 6.17 Preparation of 70-256

[0517] Reactants 70-251 (1.68 g, 0.0378 mmol), 70-201 (2.25 g, 1.87 mmol), HOBT (30 mg, 0.21 mmol), and HBTU (80 mg, 0.21 mmol) were placed in a reaction flask. An appropriate amount of DMF was added, and dissolution was assisted by ultrasound. The mixture was stirred at 0°C, and DIEA (0.1 ml, 0.4 mmol) was added dropwise. After complete addition, the mixture was brought to room temperature and stirred for 1 hour. The reaction progress was monitored by TLC. After completion of the reaction, the mixture was settled with methyl tert-butyl ether / n-hexane and filtered using a filtrate funnel to collect the filter cake. The mixture was rinsed twice with methyl tert-butyl ether and dried to yield 1.69 g of the product.

[0518] 6.18 Preparation of 70-257

[0519] Reactant 70-256 (1.69 g, 0.31 mmol) was dissolved in TFA (20 ml) and stirred at room temperature. The reaction progress was monitored by TLC. After completion of the reaction, the product was evaporated to dryness using a rotary evaporator, settled with methyl tert-butyl ether / n-hexane, and filtered using a filtrate funnel to collect the filter cake. The product was rinsed twice with methyl tert-butyl ether and dried in an oven to yield 1.49 g of product.

[0520] 6.19 Preparation of 70-261

[0521] Reactant 70-257 (1.49 g, 0.029 mmol) was dissolved in methanol (20 ml). TFA (0.1 ml, 1.173 mmol) and doxorubicin hydrochloride (0.68 g, 1.173 mmol) were then added. The mixture was stirred at low speed at room temperature in the dark, and the reaction progress was monitored by TLC. After completion of the reaction, the mixture was evaporated to dryness using a rotary evaporator, settled with methyl tert-butyl ether / n-hexane, and filtered using a filtrate funnel to collect the filter cake. The mixture was rinsed twice with methyl tert-butyl ether, collected, and dried to yield 0.26 g of the product. 1H-NMR(600MHz,DMSO-d6)δ9.32-9.29(m,1H),8.58-8.56(m,1H),8.53-8.50(m,1H),8.43-8.40(m,1H),8.23-8.19(m,15H ),8.18-8.09(m,25H),8.08-7.97(m,45H),7.97-7.90(m,96H),7.90-7.84(m,16H),7.84-7.72(m,40H),7.72-7.65(m,64 H),7.62-7.50(m,34H),7.29-7.27(m,5H),7.26-7.26(m,1H),5.71-5.32(m,64H),5.33-5.27(m,32H),5.01-4.93(m,64H ),4.61-4.56(m,64H),4.51-4.32(m,18H),4.25-4.14(m,64H),4.13-4.09(m,8H),4.02-3.98(m,99H),3.91-3.61(m,70H ),3.60-3.57(m,65H),3.52-3.50(m,3828H),3.24-3.24(m,6H),3.10-3.08(m,2H),3.03-3.01(m,12H),3.01-2.97(m,32 H),2.93-2.87(m,32H),2.80-2.75(m,8H),2.72-2.68(m,3H),2.65-2.60(m,16H),2.44-2.35(m,16H),2.27-2.15(m,48H ),2.15-2.12(m,42H),2.12-2.08(m,32H),2.05-1.94(m,32H),1.93-1.85(m,34H),1.84-1.74(m,24H),1.71-1.66(m,43 H),1.62-1.58(m,16H),1.56-1.47(m,32H),1.24-1.21(m,20H),1.17-1.13(m,96H),1.12-1.10(m,1H),0.85-0.83(m,6H)

[0522] Example 7 Synthesis of Compound 86-43

[0523] 7.1 Preparation of 69-280

[0524] 5-Maleimidocaproic acid (5 g, 23.67 mmol) was weighed and placed in a 500 ml reaction flask. NHS (3.59 g, 31.24 mmol) was added and dissolved in DMF (30 ml). DCC (6.25 g, 30.30 mmol) was then added and stirred at room temperature overnight. After the reaction, the white solid was removed by filtration. The crude product was then treated with n-hexane (200 ml) and ultrasonicated. The mixture was allowed to stand for 1 hour, and the supernatant was discarded. This process of adding n-hexane (200 ml), ultrasonicating, letting stand for 1 hour, and discarding the supernatant was repeated several times until the product became a viscous oil. 4.86 g of the product was obtained by drying. 1 H-NMR(600MHz,DMSO-d6)δ7.01(s,2H),3.40-3.36(m,2H),2.87-2.73(m,4H),2.65(t ,J=7.3Hz,2H),1.66-1.58(m,2H),1.50(tt,J=14.7,7.4Hz,2H),1.35-1.26(m,2H); FT MS ESI m / z[M+H + ]309.10

[0525] 7.2 Preparation of 69-237

[0526] 2-Amino-1,3-propanediol (3.644 g, 40.00 mmol) was weighed into a reaction flask and dissolved in DMSO (3 ml). The mixture was then purged with nitrogen and stirred at 15°C. A 5 mol / L NaOH solution (0.4 ml) and tert-butyl acrylate (13.16 ml, 90.6668 mmol) were added dropwise. The reaction was allowed to react at room temperature for 24 hours. After completion of the reaction, the mixture was extracted with deionized water (300 ml) and ethyl acetate (300 ml). The organic phase was collected, and the aqueous phase was extracted with ethyl acetate (300 ml x 2). The combined organic phases were evaporated to dryness and dissolved in an appropriate amount of a methanol / dichloromethane mixture. The sample was dry-applied and subjected to column chromatography using a 20% ethyl acetate / n-hexane mixture as the eluent. The desired product was collected, concentrated, and dried to yield 2.85 g. 1 H-NMR (600MHz, DMSO-d6) δ3.55(t,J=6.1Hz,4H),3.29(dd,J=10.2,5.7Hz,4H),3.27(m,1H),2.74(dd, J=10.9,4.2Hz,2H),2.40(t,J=6.1Hz,4H),2.28(t,J=6.6Hz,2H),1.91(s,1H),1.43-1.34(m,27H); FT MS ESI m / z[M+H + ]476.32

[0527] 7.3 Preparation of 69-243

[0528] 69-237 (0.7 g, 1.471 mmol), benzyl succinate (0.337 g, 1.618 mmol), HOBT (0.298 g, 2.2065 mmol), and HBTU (0.836 g, 2.2065 mmol) were weighed into a 250 ml reaction flask. DMF (10 ml) was added to dissolve the mixture, followed by the dropwise addition of DIEA (1.094 ml, 6.6195 mmol) and the reaction was stirred at room temperature. After completion of the reaction, the mixture was extracted with deionized water (300 ml) and ethyl acetate (300 ml). The organic phase was collected, and the aqueous phase was extracted with ethyl acetate (300 ml x 2). The combined organic phases were concentrated to obtain the crude product, which was then dissolved in 200-300 mesh silica gel powder and evaporated to dryness. The product was dry-applied and subjected to column chromatography using a 20% ethyl acetate / n-hexane mixture as the eluent. The desired product was collected, concentrated, and dried in a vacuum oven to yield 0.83 g. 1 H-NMR(600MHz,DMSO-d6)δ7.41-7.25(m,5H),5.08(s,2H),4.14-4.02(m,1H),3.63-3.42(m,10H),2.60(t, FT MS ESI m / z[M+H + ]666.38

[0529] 7.4 Preparation of 69-246

[0530] To a flask containing 69-243 (13.1871 g, 9.6699 mmol) was added dichloromethane (20 ml), and after sonication-assisted dissolution, TFA (7.2 ml, 96.699 mmol) was added. The mixture was stirred and reacted at room temperature overnight. After the reaction, the reaction solution was concentrated, and methyl tert-butyl ether (300 ml) was added. A solid precipitated and was filtered. The filter cake was washed with methyl tert-butyl ether (40 ml), collected, and dried to yield 0.56 g of the product. FT MS ESI m / z [M+H + ]498.523

[0531] 7.5 Preparation of 69-251

[0532] 69-246 (0.3 g, 0.6030 mmol), 88-86 (0.8109 g, 1.9899 mmol), HOBT (0.366 g, 2.713 mmol), and HBTU (1.028 g, 2.713 mmol) were placed in a reaction flask. DMF (20 ml) was added and dissolved with ultrasound. The mixture was stirred at 0°C. DIEA (1.345 ml, 8.1405 mmol) was added dropwise. After complete addition, the mixture was cooled to room temperature and stirred for reaction. After the reaction, methyl tert-butyl ether (400 ml) was added to the reaction mixture. A solid precipitated and was filtered to collect the filter cake. The filter cake was dissolved in an appropriate amount of a 1 / 4 dichloromethane / methanol mixture. 200-300 mesh silica gel powder was added and evaporated to dryness. The sample was dry-applied and subjected to column chromatography using 3% methanol / dichloromethane as the eluent to collect the desired product, which was then concentrated and dried to yield 0.45 g. 1 H-NMR(600MHz,DMSO-d6)δ8.08-7.86.(m,6H),7.51-7.24(m,20H),7.20-7.15(m, 3H),5.07(s,2H),5.05-4.98(m,6H),4.10(q,J=5.2Hz,3H),4.03(dd,J=14.2,7.1 Hz,1H),3.49-3.41(m,6H),3.23-3.14(m,16H),2.94(d,J=5.8Hz,4H),2.40 -2.29(m,12H),1.58-1.53(m,3H),1.40-1.36(m,36H),1.28-1.19(m,6H); FT MS ESI m / z[M+Na + ]1688.989

[0533] 7.6 Preparation of 69-257

[0534] 69-251 (1.0 g, 3.0640 mmol) was added to a hydrogenation reactor, along with 10% Pd / C catalyst (0.8 g) and DMF (20 ml). The reactor was sealed, evacuated, and then introduced with hydrogen. This process was repeated five times, followed by hydrogen pressure of 300 psi. The reaction mixture was stirred overnight at room temperature. After completion of the reaction, the reaction mixture was filtered through celite, the filter cake was washed with DMF (15 ml x 3), and the filtrate was placed in a 500 ml round-bottom flask as the starting material for the next step. FT MS ESI m / z [M+H + ]1173.732

[0535] 7.7 Preparation of 69-259

[0536] 69-257 (0.1 mmol) was added to a 50 ml round-bottom flask, and the mixture was stirred at -5°C for 30 minutes. DIEA (0.146 ml, 0.887 mol) was then slowly added dropwise. The reaction was stirred for 30 minutes, then removed from the flask. M-SCM-10K (2.10 g, 0.21 mmol, purchased from Jiankai, Lot Number: ZZ363P139) was added, and the reaction was continued at room temperature in the dark with slow stirring for 72 hours. After completion of the reaction, methyl tert-butyl ether (500 ml) was added to the reaction mixture. The precipitated solid was filtered, and the filter cake was dried to obtain the product. 1 H-NMR(600MHz,DMSO-d6)δ12.01(s,1H),8.08-7.86.(m,6H),7.20-7.15(m,3H),4.19-4.15(m,4H),3.53-3.48(m,2979H ),3.23-3.14(m,16H),2.65-2.57(m,6H),2.41-2.29(m,16H),1.58-1.53(m,3H),1.40-1.36(m,36H),1.28-1.19(m,6H)

[0537] 7.8 Preparation of 69-275

[0538] Reactants 69-259 (0.1 mmol), 70-68 (0.56 g, 0.48 mmol), HOBT (0.081 g, 0.6 mmol), and HBTU (0.227 g, 0.6 mmol) were placed in a reaction flask. An appropriate amount of DMF was added, and dissolution was assisted by ultrasound. The mixture was stirred at 0°C for 3 min. DIEA (0.297 mmol, 1.8 mmol) was then added dropwise. The mixture was removed and stirred at room temperature overnight. After completion of the reaction, methyl tert-butyl ether (300 ml) was added, and a solid precipitated. The filter cake was collected by suction filtration and dried to yield 1.25 g of the product.

[0539] 7.9 Preparation of 69-278

[0540] Weigh 69-275 (0.1 mmol) into a 50 ml round-bottom flask, then add TFA (10 ml) and stir at room temperature. After the reaction is complete, remove the TFA by rotary evaporation under reduced pressure, then add methyl tert-butyl ether (500 ml). The solid precipitates and is filtered. The filter cake is dried to obtain the product.

[0541] 7.10 86-4 Preparation

[0542] Reactants 69-278 (0.1 mmol), 76-93 (0.56 g, 0.48 mmol), HOBT (0.081 g, 0.6 mmol), and HBTU (0.227 g, 0.6 mmol) were placed in a reaction flask. DMF (50 ml) was added and sonicated for dissolution. The mixture was stirred at 0°C. DIEA (0.297 ml, 1.8 mmol) was added dropwise. The mixture was removed and allowed to stand at room temperature with continued stirring overnight. After the reaction, methyl tert-butyl ether (300 ml) was added, resulting in the precipitation of a solid. The solid was filtered, and the filter cake was collected and dried to yield 1.25 g of the product. 1 H-NMR(600MHz,DMSO-d6)δ9.33-9.24(m,1H),9.10-8.98(m,1H),8.62-8.51(m,1H),8 .30-7.76(m,34H),7.72-7.61(m,4H),7.61-7.55(m,1H),7.54-7.46(m,2H),7.37-6. 92(m,20H),4.57-4.26(m,14H),4.25-3.82(m,39H),3.81-3.28(m,3025H),3.28-3.2 1(m,15H),3.21-3.11(m,16H),3.10-2.96(m,29H),2.82-2.66(m,7H),2.65-2.45(m, 42H),2.42-2.26(m,6H),2.25-2.17(m,4H),2.17-2.03(m,20H),1.89-1.63(m,22 H),1.63-1.30(m,110H),1.30-1.11(m,37H),0.92-0.87(m,3H),0.87-0.77(m,3H)

[0543] 7.11 Preparation of 86-7

[0544] 86-4 (1.25 g, 0.0756 mmol) was weighed, dichloromethane (5 ml) and TFA (0.084 ml, 1.134 mmol) were added, and the mixture was stirred at room temperature. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and methyl tert-butyl ether (150 ml) and n-hexane (100 ml) were added. The solid precipitated and was filtered. The filter cake was dissolved in an appropriate amount of a 1 / 4 dichloromethane / methanol mixture, and 100-200 mesh silica gel powder was added. The mixture was evaporated to dryness, and the sample was dry-loaded and subjected to column chromatography using 1% ammonia water / 10-12% methanol / dichloromethane as the eluent to collect the desired product. The product was concentrated and dried to obtain 0.95 g.

[0545] 7.12 Preparation of 86-9

[0546] 86-7 (0.95 g, 0.0325 mmol) and 69-280 (0.18 g, 0.4528 mmol) were dissolved in DMF (10 ml), and DIEA (1.442 ml, 8.730 mmol) was added dropwise. The reaction was stirred at room temperature. After the reaction, methyl tert-butyl ether (300 ml) and n-hexane (100 ml) were added to the reaction solution. A solid precipitated and was dissolved in an appropriate amount of a 1 / 4 methanol / dichloromethane mixture. 100-200 mesh silica gel powder was added and evaporated to dryness. The sample was dry-applied and subjected to column chromatography using 1% aqueous ammonia / 15-20% methanol / dichloromethane as the eluent. The solid was collected and dried to obtain 0.89 g of the product.

[0547] 7.13 Preparation of 86-43

[0548] 86-9 (0.16 g, 0.004 mmol) was weighed into a 100 mL reaction flask, and methanol (3 mL) and 1,2,3,4,5,6,7,8,9,10,11-undecahydro-12-mercapto-Dodecaborate (2-), sodium (1:2) ( 10 B) (0.015 g, 0.073 mmol, purchased from CATCHEM, Czech Republic) was stirred at room temperature for three hours. After the reaction was completed, n-hexane (25 mL) and methyl tert-butyl ether (200 mL) were added to allow sedimentation. The supernatant was decanted, and n-hexane and methyl tert-butyl ether were then added to allow sedimentation. This process was repeated three times. The filter cake was collected by suction filtration to obtain a solid product, which was dried in a vacuum oven to obtain 0.15 g of the product. 1 H-NMR (600MHz, DMSO-d6) δ9.33-9.24(m,1H),9.10-8.98(m,1H),8.62-8.51(m,1H),8.30-7.76(m,34H),7. 72-7.61(m,4H),7.61-7.55(m,1H),7.54-7.46(m,2H),7.37-6.92(m,20H),4.57-4.26(m,14H),4.25-3.82( m,39H),3.81-3.28(m,3049H),3.28-3.21(m,27H),3.21-3.11(m,16H),3.10-2.96(m,29H),2.82-2.66(m, 31H),2.65-2.45(m,42H),2.42-2.26(m,30H),2.25-2.17(m,4H),2.17-2.03(m,20H),1.89--0.77(m,271H)

[0549] Example 8 Synthesis of Compound 87-35

[0550] 8.1 Preparation of 76-113

[0551] Fmoc-Glu(OtBu)-OH (2.35 g, 5.53 mmol), HBTU (2.52 g, 6.64 mmol), and HOBT (0.90 g, 6.64 mmol) were weighed and added to a flask containing 76-55 (1.92 g, 5.81 mmol). An appropriate amount of DMF was added to dissolve the mixture. DIEA (3.29 ml, 19.91 mmol) was slowly added dropwise at -5°C. After a half-hour reaction, the mixture was removed from the flask and stirred at room temperature overnight. After the reaction, saturated NaCl solution (200 ml) and ethyl acetate (200 ml) were added for extraction. After standing and separating, the organic phase was collected and the aqueous phase was extracted with ethyl acetate (200 ml x 3). The organic phases were combined, concentrated, evaporated to dryness, and dried in a vacuum oven to obtain the product.

[0552] 8.2 Preparation of 76-114

[0553] DMF was added to a flask containing 76-113 (5.53 mmol). After ultrasonic dissolution, morpholine (9.64 ml, 116.0 mmol) was added and stirred at room temperature for 2 h. After the reaction, saturated NaCl solution (200 ml) and ethyl acetate (200 ml) were added for extraction. After standing and separating the layers, the organic phase was collected and the aqueous phase was extracted with ethyl acetate (200 ml x 3). The organic phases were combined, evaporated to dryness, and dried in a vacuum oven to obtain the product.

[0554] 8.3 Preparation of 76-115

[0555] N'-Fmoc-N-benzyloxycarbonyl-L-lysine (2.65 g, 5.27 mmol), HBTU (2.40 g, 6.32 mmol), and HOBT (0.85 g, 6.32 mmol) were weighed and added to a flask containing 76-114 (5.53 mmol). An appropriate amount of DMF was added to dissolve the mixture. DIEA (3.13 ml, 18.96 mmol) was slowly added dropwise at -5°C. After a half-hour reaction, the mixture was removed from the flask and stirred at room temperature overnight. After the reaction, saturated NaCl solution (200 ml) and ethyl acetate (200 ml) were added for extraction. After standing for decomposition, the organic phase was collected and the aqueous phase was extracted with ethyl acetate (200 ml x 3). The organic phases were combined and evaporated to dryness.

[0556] 8.4 Preparation of 76-116

[0557] To a flask containing 76-115 (5.27 mmol) was added DMF. Morpholine (9.18 ml, 105.4 mmol) was added using ultrasonic dissolution, and the mixture was stirred at room temperature for 2 h. After completion of the reaction, saturated NaCl solution (200 ml) and ethyl acetate (200 ml) were added for extraction. After stratification, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (200 ml x 3). The organic phases were combined and evaporated to dryness. The product was purified by column chromatography using 1% ammonia / 5% methanol / dichloromethane as the eluent. The collected product was concentrated and dried in a vacuum oven to yield 2.85 g of the product, with a yield of 70%. 1 H-NMR(600MHz,DMSO-d6)δ8.17-7.98(m,2H),7.97-7.93(m,1H),7.39-7.28(m,5H),7.25 -7.16(m,1H),5.06-4.96(m,2H),4.27(s,1H),4.22-4.13(m,1H),3.31-3.27(m,1H),3.2 2-3.10(m,2H),3.02-2.93(m,2H),2.64-2.54(m,1H),2.40-2.30(m,2H),2.24-2.13(m,4 H),1.91-1.64(m,5H),1.63-1.46(m,2H),1.40-1.36(m,27H),1.32-1.23(m,2H);ESI[M+H + ]778.46

[0558] 8.5 Preparation of 70-173

[0559] In a 250ml flask, dissolve 3-amino-1-propanol (2ml, 27.10mmol) in DMSO (18ml). Stir in a water bath at 30°C for 10 minutes, then add 5.0M NaOH solution (0.4ml). Stirring continues for 10 minutes, followed by the addition of tert-butyl acrylate (8.3ml, 56.90mmol) and the reaction continues until complete. Transfer the reaction mixture to a 1L separatory funnel and extract with saturated brine (200ml) and ethyl acetate (200ml) to obtain an organic phase. The aqueous phase is then extracted with ethyl acetate (200ml x 3). The combined organic phases are washed with saturated brine (200ml x 2) and evaporated to dryness. The resulting product is dissolved in a mixture of dichloromethane and methanol, dry-loaded, and subjected to column chromatography using a 10% ethyl acetate / petroleum ether mixture as the eluent. The desired product is collected, concentrated, and dried in a vacuum oven to obtain the product.

[0560] 8.6 Preparation of 70-177

[0561] Benzyl succinate (0.80 g, 3.70 mmol), HBTU (1.50 g, 4.00 mmol), and HOBT (0.50 g, 4.00 mmol) were weighed and added to a flask containing 70-173 (1.07 g, 3.40 mmol). An appropriate amount of DMF was added to dissolve the mixture. DIEA (1.20 ml, 7.40 mmol) was slowly added dropwise at -5°C. After a half-hour reaction, the mixture was removed from the flask and stirred at room temperature overnight. After the reaction, saturated NaCl solution (200 ml) and ethyl acetate (200 ml) were added for extraction. After standing for separation, the organic phase was collected and the aqueous phase was extracted with EA (200 ml x 3). The combined organic phases were evaporated to dryness to a solid.

[0562] 8.7 Preparation of 76-117

[0563] A suitable amount of dichloromethane was added to a flask containing 70-177 (1.50 g, 2.88 mmol). After dissolution with ultrasonication, TFA (4.27 ml, 57.51 mmol) was added and the mixture was stirred at room temperature overnight. After the reaction, the reaction solution was evaporated to an oil using a rotary evaporator. Methyl tert-butyl ether (60 ml) was then added to allow precipitation. The product remained as an oil at the bottom of the flask. The methyl tert-butyl ether was discarded and the product was dried in a vacuum oven to obtain 1.26 g of the product with a yield of 100%. ESI [M+H + ]410.18,[M+Na + ]432.16

[0564] 8.8 Preparation of 76-118

[0565] 76-117 (0.71 g, 1.74 mmol), HBTU (1.58 g, 4.18 mmol), and HOBT (0.57 g, 4.18 mmol) were weighed and added to a flask containing 76-116 (2.85 g, 3.66 mmol). An appropriate amount of DMF was added to dissolve the mixture. DIEA (2.07 ml, 12.53 mmol) was slowly added dropwise at -5°C. After a half-hour reaction, the mixture was removed from the flask and stirred at room temperature overnight. After the reaction, saturated NaCl solution (200 ml) and ethyl acetate (200 ml) were added for extraction. After standing and separating, the organic phase was collected and the aqueous phase was extracted with ethyl acetate (200 ml x 3). The organic phases were combined, concentrated, evaporated to dryness, and dried in a vacuum oven to obtain 2.89 g of the product, with a yield of 86%. 1H-NMR(600MHz,DMSO-d6)δ8.17-8.07(m,1H),8.06-7.97(m,3H),7.97-7.89(m,2H),7.87-7.78(m,2H),7.39-7.27( m,15H),7.27-7.17(m,2H),5.07-4.97(m,6H),4.29-4.15(m,6H),4.06-4.00(m,1H),3.59-3.35(m,6H),3.31-3.25 (m,4H),3.24-3.11(m,3H),3.01-2.93(m,5H),2.70-2.60(m,2H),2.59-2.54(m,4H),2.43-2.28(m,8H),2.23-2.13 (m,8H),1.76-1.65(m,6H),1.65-1.55(m,3H),1.53-1.45(m,3H),1.39-1.36(m,54H),1.32-1.19(m,5H); ESI[M+Na + ]1951.04

[0566] 8.9 Preparation of 76-119

[0567] 76-118 (0.19 g, 0.10 mmol) and 10% Pd / C catalyst (0.01 g) were placed in a hydrogenation reactor. DMF (30 ml) was then added to dissolve the mixture. The hydrogenation reactor was sealed and evacuated with a water pump. Hydrogen gas at approximately 2 MPa was added. This evacuation / refilling cycle was repeated three times. The pressure on the hydrogenation reactor was adjusted to 1.8 MPa, and the reaction was allowed to proceed overnight at room temperature. Upon completion of the reaction, the reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with DMF (20 ml x 3). This DMF solution of the product was used as the starting material for the next reaction.

[0568] 8.10 Preparation of 76-120

[0569] 76-119 (0.10 mmol) was placed in a 250 ml flask and DMF (20 ml) was added. This solution was then slowly added dropwise to a DMF solution containing DIEA (0.95 ml, 5.75 mmol) and M-SCM-10K (2.0 g, 0.19 mmol, purchased from Jiankai). The reaction was placed in the dark at room temperature with low-speed stirring for one week. After the reaction was completed, n-hexane (25 ml) and methyl tert-butyl ether (200 ml) were added to allow the reaction to proceed. The supernatant was decanted, and n-hexane and methyl tert-butyl ether were added to allow the reaction to proceed. This was repeated three times, and the solid product was filtered to obtain a solid product, which was collected and dried in a vacuum oven to obtain the product.

[0570] 8.11 Preparation of 76-130

[0571] 76-120 (0.81 g, 0.04 mmol), HBTU (0.02 g, 0.13 mmol), and HOBT (0.01 g, 0.04 mmol) were weighed and added to a flask containing 70-68 (0.03 g, 0.04 mmol). An appropriate amount of DMF was then added to dissolve the mixture. The mixture was placed at -5°C and DIEA (0.02 ml, 0.13 mmol) was slowly added dropwise. After the reaction was complete, the mixture was allowed to react for half an hour, removed from the flask, and stirred at room temperature overnight. After the reaction was complete, n-hexane (25 ml) and methyl tert-butyl ether (200 ml) were added to allow the mixture to settle. The supernatant was decanted, and n-hexane and methyl tert-butyl ether were then added to allow the mixture to settle. This process was repeated three times. The solid product was filtered, collected, and dried to obtain the product.

[0572] 8.12 Preparation of 76-127

[0573] 70-199 (0.71 g, 0.96 mmol), HBTU (1.75 g, 4.61 mmol) and HOBT (0.62 g, 4.61 mmol) were added to a flask containing propargylamine (0.23 g, 4.22 mmol). An appropriate amount of DMF was added to dissolve the mixture. The mixture was placed at -5°C and DIEA (2.29 ml, 13.82 mmol) was slowly added dropwise. After the reaction was completed, the mixture was allowed to react for half an hour and then stirred at room temperature overnight. After the reaction was completed, saturated NaCl solution (200 ml) and ethyl acetate (200 ml) were added for extraction. After standing and stratification, the organic phase was collected and the aqueous phase was extracted with ethyl acetate (200 ml × 3). The organic phases were combined, concentrated and evaporated to dryness to a solid, and dried in a vacuum oven to obtain 0.66 g of the product. ESI [M+H + ]889.42,[M+Na + ]911.40

[0574] 8.13 Preparation of 76-129

[0575] DMF was added to a flask containing 76-127 (0.96 mmol). Morpholine (2 ml) was added after ultrasonic dissolution and the mixture was stirred at room temperature for 2 h. After the reaction, n-hexane (25 ml) and methyl tert-butyl ether (200 ml) were added to allow the mixture to settle. The supernatant was then decanted and n-hexane and methyl tert-butyl ether were added to allow the mixture to settle. This process was repeated three times. The solid product was filtered and dried in a vacuum oven to obtain 0.42 g of the product. ESI [M+H + ]667.35,[M+Na + ]689.34

[0576] 8.14 Preparation of 76-131

[0577] Weigh mono-tert-butyl succinate (3.0 g, 17.22 mmol) and HATU (7.86 g, 20.67 mmol) into a flask containing 3-amino-1-propanol (1.55 g, 20.67 mmol). Add an appropriate amount of DMF to dissolve the mixture. Place at -5°C and slowly add DIEA (10.25 ml, 62.01 mmol) dropwise. After a half-hour reaction, remove the mixture and stir at room temperature overnight. After completion of the reaction, add n-hexane (25 ml) and methyl tert-butyl ether (200 ml) to allow sedimentation. Pour the supernatant, then add n-hexane and methyl tert-butyl ether to allow sedimentation. Repeat this process three times. Filter the solid product, collect it, and dry it to obtain the product.

[0578] 8.15 Preparation of 76-157

[0579] 76-131 (1.02 g, 4.41 mmol) was weighed and dissolved in dry THF. DPPA (1.46 g, 5.29 mmol) and DBU (0.81 g, 5.29 mmol, purchased from Inochem) were slowly added dropwise at 0°C. After completion of the addition, the mixture was moved to room temperature for 2 hours. A THF solution of TBAA (1.50 g, 5.29 mmol) was then added dropwise. The mixture was stirred at 50°C for 12 hours. After completion of the reaction, saturated NH4Cl solution (200 ml) and ethyl acetate (200 ml) were added for extraction. The organic phase was collected, dried over anhydrous Na2SO4, and then concentrated and dried to obtain the product. 1 H-NMR(600MHz,DMSO-d6)δ7.93-7.85(m,1H),3.38-3.33(m,2H),3.12-3.06(m,2H ),2.42-2.38(m,2H),2.30-2.25(m,2H),1.66-1.60(m,2H),1.38(s,9H); ESI[M+Na + ]279.14,[2M+Na + ]535.30

[0580] 8.16 Preparation of 76-191

[0581] To a flask containing 76-157 (0.0068 mmol) was added dichloromethane, and after ultrasonic dissolution, TFA (0.2 ml) was added. The mixture was stirred and reacted at room temperature overnight. After the reaction was completed, the reaction solution was evaporated to an oil using a rotary evaporator. Methyl tert-butyl ether (60 ml) was then added. A powdery solid precipitated from the reaction solution and was filtered. The filter cake was washed with methyl tert-butyl ether (40 ml x 3). The product had poor solubility. The filter cake was collected and dried in a vacuum oven to obtain the product.

[0582] 8.17 Preparation of 76-193

[0583] 76-191 (3.32 g, 9.4014 mmol), HBTU (3 g, 7.9277 mmol), and HOBT (1.07 g, 7.9277 mmol) were weighed and added to a flask containing 76-192 (9.4014 mmol). An appropriate amount of DMF was then added to dissolve the mixture. The mixture was placed at -5°C and DIEA (3.93 ml, 22.7830 mmol) was slowly added dropwise. After a half-hour reaction, the mixture was removed from the flask and stirred at room temperature overnight. After the reaction, the mixture was precipitated with methyl tert-butyl ether and n-hexane, filtered, and dried to obtain 3.45 g of the product (100% yield).

[0584] 8.18 Preparation of 76-137

[0585] To a flask containing 76-130 (0.33 g) was added dichloromethane, and after ultrasonic dissolution, TFA (0.2 ml) was added. The mixture was stirred and reacted at room temperature overnight. After the reaction was completed, the reaction solution was evaporated to an oil using a rotary evaporator. Methyl tert-butyl ether (60 ml) was then added. A powdery solid precipitated from the reaction solution and was filtered. The filter cake was washed with methyl tert-butyl ether (40 ml x 3). The product had poor solubility. The filter cake was collected and dried in a vacuum oven to obtain the product.

[0586] 8.19 Preparation of 76-142

[0587] 76-137 (0.42 g, 0.02 mmol), HBTU (0.06 g, 0.13 mmol), and HOBT (0.02 g, 0.13 mmol) were weighed and added to a flask containing 76-129 (0.08 g, 0.12 mmol). An appropriate amount of DMF was then added to dissolve the mixture. The mixture was placed at -5°C and DIEA (0.07 ml, 0.40 mmol) was slowly added dropwise. After a half-hour reaction, the mixture was removed from the flask and stirred at room temperature overnight. After the reaction was complete, n-hexane (25 ml) and methyl tert-butyl ether (200 ml) were added to allow the mixture to settle. The supernatant was decanted, and n-hexane and methyl tert-butyl ether were added to allow the mixture to settle. This process was repeated three times. The solid product was filtered and collected and dried to yield 0.1 g.

[0588] 8.20 Preparation of 87-35

[0589] 76-142 (0.0532 mmol) and anhydrous CuSO4 (0.41 g, 2.55 mmol) were weighed and added to a flask containing anhydrous DMF (10 ml), and then 76-193 (0.96 g, 1.92 mmol) and sodium ascorbate (1.01 g, 5.11 mmol) were added. After dissolution with ultrasonic assistance, the reaction was stirred at room temperature under nitrogen protection overnight. After the reaction is completed, n-hexane (25 ml) and methyl tert-butyl ether (200 ml) are added to precipitate, and the mixture is filtered off. The solid is dissolved in dichloromethane, and then n-hexane (25 ml) and methyl tert-butyl ether (200 ml) are added to precipitate. This process is repeated three times, and a solid product is obtained by filtration. The solid product is dissolved in a 1 / 4 methanol / dichloromethane mixed solvent, and silica gel powder is added. The product is evaporated to dryness, and the sample is dry-loaded. Column chromatography is performed using a 1% ammonia water / 5-7% methanol / dichloromethane mixed solvent as an eluent. The target product is collected, evaporated to dryness, and dried in a vacuum oven to obtain 0.44 g of the product with a yield of 21.56%. 1 H-NMR(600MHz,DMSO-d6)δ8.68-7.67(m,130H),7.41-7.16(m,12H),7.10-6.92(m,10H),6.75-6.59(m,6H),4.60-4.23(m,118H),4.24-4.13(m, 72H),4.04-3.90(m,103H),3.57-3.48(m,2755H),3.15-3.00(m,120H),2.96-2.82(m,64H),2.42-2.30(m,14H),2.28 -2.02(m,68H),1.93-1.63(m,51H),1.52-1.43(m,15H),1.41-1.34(m,18H),1.29-1.20(m,72H),1.15-0.99(m,288H)

[0590] Example 9 Synthesis of Compound 75-236

[0591] 9.1 Preparation of 75-228

[0592] SN38 (2.0 g, 5.096 mmol) was weighed and added to a 250 ml flask. Dichloromethane (80 ml) was added and ultrasonically dissolved. TBDPS-Cl (5.3 ml, 20.387 mmol) and triethylamine (3.1 ml, 22.935 mmol) were then added. The mixture was stirred in a 30°C oil bath under reflux and reacted for 12 h. After the reaction, the reaction solution was transferred to a 1 L separatory funnel and extracted with 1 N hydrochloric acid solution (150 ml). The dichloromethane phase was collected and washed with sodium bicarbonate aqueous solution (150 ml x 2) and finally with saturated sodium chloride aqueous solution. The dichloromethane phase was collected and evaporated to dryness and dried in a vacuum oven to obtain 2.17 g of the product.

[0593] 9.2 Preparation of 75-231

[0594] To a reaction flask containing 75-228 (2.17 g, 3.44 mmol) were added succinic anhydride (2.06 g, 20.640 mmol) and pyridine (20 ml). Dissolution was assisted by ultrasonication, followed by the addition of DMAP (0.84 g, 6.880 mmol). The mixture was stirred overnight in a 45°C oil bath. After the reaction was complete as observed by TLC, a large amount of water was added to the reaction solution, and the pH of the solution was adjusted to 2 with hydrochloric acid. A solid precipitate was separated, filtered, and the filter cake was dried in a vacuum oven for 4 hours to yield 3.76 g of the product.

[0595] 9.3 Preparation of 75-211

[0596] Dissolve 1,3-diamino-2-propanol (2.0 g, 22.191 mmol) in dichloromethane (30 ml) and stir rapidly with a stirrer. Then add solid sodium sulfate (6.30 g, 44.383 mmol) and benzaldehyde (4.71 g, 44.383 mmol). Stir at room temperature for 18 hours, then filter and concentrate the filtrate. Dissolve the residue in anhydrous ethanol (20 ml) and cool to 0°C. Add solid NaBH4 (5.95 g, 56.082 mmol) in portions over 10 minutes each. Stir for 1 hour, add water (10 ml), concentrate, and dissolve in ethyl acetate (50 ml). Wash with hydrochloric acid (2 x 20 ml), and adjust the pH to alkaline with NaOH solution. The mixture was extracted with dichloromethane (30 ml x 3), the dichloromethane was combined, anhydrous magnesium sulfate was added to remove water, the mixture was filtered, concentrated and dried to obtain 4.6 g of the product with a yield of 57.14%. 1 H-NMR (600MHz, DMSO-d6) δ7.38-7.16(m,10H),3.74-3.42(m,8H),2.57-2.54(m,2H),2.50-2.47(m,2H); ESI[M+H + ]271.1796

[0597] 9.4 Preparation of 75-213

[0598] 75-211 (4.6 g, 17.013 mmol) was dissolved in DMSO (10 ml) and stirred in a 25°C water bath. A 5 mol / L NaOH solution was added dropwise. After stirring for 10 min, tert-butyl acrylate (14.75 ml, 102.082 mmol) was added dropwise. The reaction was allowed to react overnight and observed by TLC. The mixture was extracted three times with ethyl acetate / saturated NaCl solution. The combined organic phases were evaporated to dryness, dissolved in a mixed solvent, and silica gel powder was added. The mixture was evaporated to dryness, and the sample was dry-loaded and purified on a silica gel column using ethyl acetate / petroleum ether as the eluent. The product was collected and dried to obtain 2.22 g. 1 H-NMR(600MHz,DMSO-d6)δ7.32-7.17(m,10H),3.70-3.62(m,2H),3.53-3.50(m,4H),3.48-3.42(m,1H ),2.70-2.56(m,4H),2.47-2.42(m,2H),2.40-2.33(m,4H),2.33-2.27(m,4H),1.36(s,27H); ESI[M+H + ]655.42950

[0599] 9.5 Preparation of 75-214

[0600] 75-213 (2.22 g, 3.402 mmol) was placed in a hydrogenation reactor, and a 10% Pd / C catalyst (0.4 g) was added. Methanol (30 ml) was added to dissolve the catalyst, and hydrogen was introduced at a pressure of 200 psi. The reaction was stirred at room temperature overnight. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, and the diatomaceous earth was washed with methanol (5 ml × 3). The methanol solution was combined, and dichloromethane was added to the liquid, and the mixture was evaporated to dryness using a vacuum rotary evaporator. Dichloromethane and toluene (0.2 ml) were then added, and the mixture was treated with ultrasound and then evaporated to dryness. This operation was repeated 5 times. Dichloromethane was added again to dissolve the mixture with ultrasound, and the mixture was evaporated to dryness. This operation was repeated 5 times. Finally, 1.6 g of the product was obtained by concentration and drying.

[0601] 9.6 Preparation of 75-215

[0602] 75-214 (0.6 g, 1.264 mmol), benzyl succinate (0.55 g, 2.654 mmol), and HATU (1.15 g, 3.033 mmol) were added to a 250 ml flask. DMF (20 ml) was added to dissolve the mixture. The reaction was stirred at -5 degrees Celsius for approximately 20 minutes, followed by the slow dropwise addition of DIEA (0.9 ml, 5.561 mmol). After the addition was complete, the mixture was stirred at -5 degrees Celsius for another 20 minutes, then allowed to cool to room temperature with stirring. After the reaction was complete, n-hexane (30 ml) and methyl tert-butyl ether (200 ml) were added to allow the mixture to settle. The supernatant was decanted, and n-hexane and methyl tert-butyl ether were then added to allow the mixture to settle. This process was repeated five times. The solid product was filtered, and the filter cake was collected and dried in a vacuum oven to yield 1.08 g of the product. 1 H-NMR(600MHz,DMSO-d6)δ7.39-7.30(m,10H)5.11-5.06(m,4H),4.03(s,1H),3.79-3.36(m,8H), 3.30-3.25(m,2H),2.66 -2.53(m,8H),2.42-2.32(m,6H),1.41-1.35(m,27H);ESI[M+Na + ]877.442

[0603] 9.7 Preparation of 75-217

[0604] Dichloromethane (5 ml) was added to a flask containing 75-215 (1.08 g, 1.264 mmol), and TFA (5.6 ml, 75.84 mmol) was added after dissolution with ultrasonication. The mixture was stirred at room temperature to react. After the reaction, the reaction solution was concentrated and evaporated to dryness to remove dichloromethane and most of the TFA. Then, n-hexane (200 ml) and methyl tert-butyl ether (200 ml) were added to precipitate to obtain an oily solid. The supernatant was discarded, and ethyl acetate (15 ml) was added. The mixture was treated with ultrasonication to obtain a white turbid liquid. Then, n-hexane (200 ml) was added to precipitate to obtain a powdery solid. The mixture was filtered and the filter cake was washed three times with methyl tert-butyl ether (40 ml). The filter cake was collected and dried under vacuum to obtain 0.86 g of the product. ESI [M+Na + ]709.254

[0605] 9.8 Preparation of 75-220

[0606] 75-217 (0.86 g, 1.264 mmol), 76-58 (2.42 g, 4.171 mmol), HBTU (2.15 g, 5.688 mmol), and HOBT (0.77 g, 5.688 mmol) were added to a 500 ml round-bottom flask. DMF (15 ml) was added to dissolve the mixture. The reaction was stirred at -5°C for approximately 20 minutes. DIEA (2.8 ml, 17.064 mmol) was then slowly added dropwise. The mixture was stirred at -5°C for 1 hour. The mixture was then removed and stirred at room temperature. After the reaction was complete, the reaction solution was transferred to a 1 L separatory funnel and extracted with deionized water (250 ml) and ethyl acetate (200 ml) to obtain an organic phase (with a solid product precipitated). The aqueous phase was then extracted with ethyl acetate (200 ml x 2). The organic phases were combined and concentrated by rotary evaporation under reduced pressure. The obtained solid product was dissolved in a 4 / 1 dichloromethane / methanol mixed solvent, silica gel powder was added, evaporated to dryness, dry-loaded, and column chromatography was performed using a 2-6% methanol / dichloromethane mixed solution as an eluent. The organic solution containing the product components was collected, evaporated to dryness, and dried in a vacuum oven to obtain 1.1 g of the product. 1H-NMR(600MHz,DMSO-d6)δ8.05-7.86(m,9H),7.37-7.32(m,25H),7.24-7.17(m,3H), 5.07-5.06(m,4H),4.99(s,6H),4.27-4.13(m,6H),3.57-3.46(m,13H),3.30-3.28(m, 4H),3.20-3.11(m,6H),2.63-2.56(m,10H),2.55-2.52(m,8H),2.36-2.31(m,8H),2.1 9-2.13(m,6H),1.87-1.77(m,6H),1.52-1.43(m,6H),1.39(s,54H),1.24-1.23(m,6H)

[0607] 9.9 Preparation of 75-222

[0608] 75-220 (0.42 g, 1.3688 mmol) was placed in a hydrogenation reactor, followed by the addition of 10% Pd / C catalyst (0.1 g). DMF (30 ml) was added to dissolve the catalyst, and hydrogen was introduced at a pressure of 300 psi. The reaction was stirred at room temperature overnight. After completion of the reaction, the reaction solution was filtered through diatomaceous earth, the filter cake was washed with DMF (5 ml x 3), and the filtrate was placed in a 500 ml round-bottom flask. The mixture was then settled with methyl tert-butyl ether (150 ml) and n-hexane (80 ml). The supernatant was discarded, and methyl tert-butyl ether (150 ml) and n-hexane (80 ml) were added to settle the mixture. This process was repeated five times, and the mixture was filtered and dried to obtain 0.24 g of the product.

[0609] 9.10 Preparation of 75-224

[0610] 75-222 (0.088 g, 0.0482 mmol) was dissolved in anhydrous DMF (5 ml) in a 250 ml round-bottom flask. DIEA (0.95 ml, 5.787 mmol) was then added dropwise. The mixture was stirred for 30 minutes, followed by the addition of polymer M-SCM-10K (1.5 g, 0.1519 mmol). Ultrasonication was used to assist dissolution, and the reaction was allowed to proceed with low-speed stirring in the dark for 4 days. After the reaction was completed, methyl tert-butyl ether (150 ml) and n-hexane (70 ml) were added, and the supernatant was discarded. This process was repeated three times. The resulting solid was dissolved in a mixed solvent, silica gel powder was added, and the mixture was evaporated to dryness. The sample was dry-loaded and subjected to column chromatography using 1% ammonia / 5-10% methanol / dichloromethane as the eluent. The product (1.46 g) was collected and dried. 1H-NMR(600MHz,DMSO-d6)δ9.72-9.69(m,2H),8.09-8.04(m,12H),4.19-4.16(m,6H),3.86-3.83(m,13H),3.53-3.50(m,2871H),3.24-3.23(m ,4H),2.62-2.61(m,16H),2.39-2.38(m,16H),2.19-2.14(m,6H),1.88 -1.79(m,6H),1.53-1.45(m,6H),1.39-137(m,54H),1.25-1.21(m,6H)

[0611] 9.11 Preparation of 75-226

[0612] 75-224 (1.46 g, 0.0437 mmol), 70-68 (0.066 g, 0.0961 mmol), HBTU (0.049 g, 0.1311 mmol), and HOBT (0.017 g, 0.1311 mmol) were added to a 250 mL solution. DMF (7 mL) was added to dissolve the mixture. The reaction was stirred at room temperature for approximately 20 minutes. DIEA (0.1 mL, 0.3935 mmol) was then slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature overnight. TLC was then used for observation. After completion of the reaction, the mixture was precipitated with methyl tert-butyl ether (150 mL) and n-hexane (70 mL). The supernatant was discarded and the mixture was precipitated with methyl tert-butyl ether (150 mL) and n-hexane (70 mL). This process was repeated three times. Filtration and drying yielded 1.52 g of the product. 1 H-NMR(600MHz,DMSO-d6)δ8.58-8.55(m,2H),8.22-8.19(m,2H),8.13-8.01(m,16H),7.91-7.86(m,6H),7.70- 7.64(m,2H),7.54-7.51(m,2H),7.29-7.21(m,16H),7.20-7.14(m,4H),4.37-4.34(m,10H),4.06-4.04(m,9H) ,3.63-3.62(m,24H),3.53-350(m,2871H),3.44-3.43(m,10H),2.62-2.61(m,20H),2.39-2.38(m,8H),2.36-2 .34(m,6H),1.82-1.74(m,10H),1.53-1.47(m,16H),1.38-136(m,54H),1.24-1.22(m,6H),0.90-0.88(m,12H)

[0613] 9.12 Preparation of 75-227

[0614] 75-226 (1.52 g, 0.0437 mmol) was placed in a 250 ml flask and dissolved in dichloromethane (5 ml). TFA (0.4 ml, 5.249 mmol) was added while stirring. The reaction flask was left to react at room temperature with stirring overnight. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove dichloromethane and most of the TFA. The mixture was then precipitated with methyl tert-butyl ether (150 ml) and n-hexane (70 ml). The supernatant was discarded and the mixture was again precipitated with methyl tert-butyl ether (150 ml) and n-hexane (70 ml). This process was repeated three times. Filtration and drying yielded 1.34 g of the product.

[0615] 9.13 Preparation of 75-229

[0616] 75-227 (1.34 g, 0.0889 mmol), 76-93 (0.504 g, 0.3501 mmol), and HATU (0.106 g, 0.2801 mmol) were mixed and added to 250 ml of a flask. DMF (5 ml) was added to dissolve the mixture. The reaction was stirred at room temperature for approximately 20 minutes, followed by the slow dropwise addition of DIEA (0.2 ml, 1.0503 mmol). After the addition was complete, the mixture was stirred overnight at room temperature and observed by TLC. After the reaction was complete, the mixture was precipitated with methyl tert-butyl ether (150 ml) and n-hexane (70 ml). The supernatant was discarded, and the mixture was precipitated with methyl tert-butyl ether (150 ml) and n-hexane (70 ml). This process was repeated three times. Filtering and drying yielded 1.67 g of the product.

[0617] 9.14 Preparation of 75-232

[0618] 75-229 (0.1 g, 0.00232 mmol) was placed in a 250 ml flask and dissolved in dichloromethane (2 ml). TFA (0.08 ml, 1.1169 mmol) was added while stirring. The reaction flask was left to react at room temperature with stirring overnight. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the dichloromethane and most of the TFA. The mixture was then precipitated with methyl tert-butyl ether (150 ml) and n-hexane (70 ml). The supernatant was discarded and the mixture was again precipitated with methyl tert-butyl ether (150 ml) and n-hexane (70 ml). This process was repeated three times. Filtering and drying yielded 0.06 g of the product. 1H-NMR(600MHz,DMSO-d6)δ8.67-8.62(m,2H),8.60-8.54(m,2H),8.18-7.98(m,70H),7.65-7.49(m,10H),7.28-7.17( m,14H),5.34-5.17(m,48H),4.61-4.50(m,10H),4.45-4.31(m,18H),4.05-4.01(m,9H),3.61-3.61(m,108H),3.59-3. 57(m,108H),3.53-350(m,2871H),3.20-3.17(m,58H),2.99-2.94(m,54H),2.82-2.73(m,20H),2.62-2.61(m,12H),2 .40-2.36(m,8H),2.16-2.07(m,80H),1.76-1.73(m,14H),1.54-1.47(m,28H),1.29-1.18(m,30H),0.93-0.80(m,12H)

[0619] 9.15 Preparation of 75-235

[0620] 75-232 (0.06 g, 0.0014 mmol), 75-231 (0.037 g, 0.0517 mmol), and HATU (0.015 g, 0.0413 mmol) were mixed and added to a 50 ml flask. DMF (1 ml) was added to dissolve the mixture. The reaction was stirred at room temperature for approximately 20 minutes. DIEA (0.025 ml, 0.1551 mmol) was then slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature overnight. TLC was then used for observation. After the reaction was complete, the mixture was precipitated with methyl tert-butyl ether (150 ml) and n-hexane (70 ml). The supernatant was discarded and the mixture was precipitated with methyl tert-butyl ether (150 ml) and n-hexane (70 ml). This process was repeated three times. Filtering and drying yielded 0.04 g of the product.

[0621] 9.16 Preparation of 75-236

[0622] Dissolve 75-235 (0.04 g, 0.000679 mmol) in THF (1 ml), add TBAF (0.1 g, 0.326 mmol), and react for 2 h. Then concentrate under reduced pressure and precipitate with methyl tert-butyl ether (150 ml) and n-hexane (70 ml). Discard the supernatant and precipitate with methyl tert-butyl ether (150 ml) and n-hexane (70 ml). Repeat this process three times. Filter and dry to obtain 0.04 g of the product. 1H-NMR(600MHz,DMSO-d6)δ8.59-8.56(m,2H),8.24-8.22(m,2H),8.10-7.99(m,118H),7.85-7.81(m,24H),7.57-7.56(m,10H),7.41- 7.39(m,62H),6.82-6.80(m,24H),5.36-5.32(m,24H),5.17-5.02(m,48H),4.94-4.93(m,2H),4.26-4.16(m,48H),4.12-4.06(m,26H) ,4.05-4.03(m,4H),3.72-3.65(m,124H),3.64-3.61(m,108H),3.53-350(m,2871H),3.25-3.23(m,64H),3.09-3.07(m,54H),2.85-2. 75(m,168H),2.46-2.45(m,16H),2.14-2.12(m,90H),1.90-1.75(m,62H),1.48-1.45(m,24H),1.29-1.27(m,79H),0.91-0.90(m,60H)

[0623] Example 10 Synthesis of Compound 74-232

[0624] 10.1 Preparation of 74-182

[0625] 88-4 (4 g, 16.108 mmol), Fmoc-Glu-OtBu (6.853 g, 16.108 mmol), HBTU (7.330 g, 19.329 mmol), and HOBT (2.611 g, 19.329 mmol) were placed in a 500 ml round-bottom flask and sonicated with DMF (50 ml). After dissolution, DIEA (7.987 ml, 48.324 mmol) was added dropwise in an ice-water bath, and the reaction mixture was stirred at room temperature. After the reaction, pure water (200 ml) and ethyl acetate (200 ml) were added to a 2 L separatory funnel, and the reaction mixture was poured into the funnel for extraction. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (100 ml x 2). The combined organic phases were washed once with saturated sodium bicarbonate solution (200 ml). Finally, the water was removed with anhydrous magnesium sulfate and the mixture was rotary evaporated. Add appropriate amount of dichloromethane and 200-300 mesh silica gel powder, evaporate to dryness, dry sample, use dichloromethane and 0.5-1% methanol / dichloromethane as eluents for column chromatography, collect the target product, concentrate and evaporate to dryness to obtain the product.

[0626] 10.2 Preparation of 74-183

[0627] 74-182 (10.563 g, 16.108 mmol) was placed in a 500 ml round-bottom flask and sonicated with acetonitrile (50 ml). Diethylamine (23.562 ml, 322.16 mmol) was then added and stirred at room temperature for 2 h. After the reaction, the acetonitrile was removed by rotary evaporation. An appropriate amount of mixed solvent and 200-300 mesh silica gel powder were added and evaporated to dryness. The sample was dry-loaded and column chromatography was performed using dichloromethane and then 2-5% methanol / dichloromethane as eluents to collect the desired product, concentrate, and evaporate to dryness. The product was obtained in excess.

[0628] 10.3 Preparation of 74-184

[0629] 74-183 (1.5 g, 3.459 mmol), pteroic acid (0.981 g, 3.144 mmol, Shanghai Hengxin), HBTU (1.788 g, 4.716 mmol), and HOBT (0.637 g, 4.716 mmol) were placed in a 250 ml round-bottom flask and dissolved in DMSO (30 ml). DIEA (1.588 ml, 9.432 mmol) was slowly added dropwise at room temperature to continue the reaction. After the reaction, methyl tert-butyl ether (450 ml) was added to allow precipitation. The precipitated solid was filtered. After filtration, an appropriate amount of mixed solvent was added to dissolve the solid. 200-300 mesh silica gel powder was added and evaporated to dryness. The sample was dry-loaded and column chromatography was performed using 7-9% methanol / dichloromethane as the eluent to collect the desired product. The product was then concentrated and evaporated to dryness.

[0630] 10.4 Preparation of 74-185

[0631] Compound 74-184 (5 g, 4.25 mmol) was placed in a 500 ml round-bottom flask, followed by the addition of dichloromethane (4 ml) and TFA (2 ml) with stirring at room temperature. After completion of the reaction, the dichloromethane and most of the TFA were removed by rotary evaporation. Methyl tert-butyl ether (150 ml) was then added to allow precipitation. A solid precipitated, which was then ultrasonically treated and allowed to stand. The supernatant was discarded, filtered, and dried to yield 3.8 g of the product.

[0632] 10.5 Preparation of 74-141

[0633] Weigh a sufficient amount of D-Biotin (5 g, 20.465 mmol) into a 500 ml round-bottom flask, add DMF (30 ml), and stir in a 70°C oil bath until the solution becomes clear. After clarification, cool to room temperature. 88-4 (1.016 g, 4.093 mmol), HBTU (1.862 g, 4.911 mmol), and HOBT (0.663 g, 4.911 mmol) are then added dropwise. DIEA (10.147 ml, 61.395 mmol) is then added dropwise. The reaction is stirred at 25°C for 2 h. After the reaction is complete, pure water (200 ml) and ethyl acetate (200 ml) are added to a 2 L separatory funnel, and the reaction mixture is then poured into the funnel for extraction. The organic phase is separated, and the aqueous phase is extracted with ethyl acetate (100 ml x 2). The combined organic phases are washed with saturated sodium bicarbonate solution (200 ml), then dehydrated with anhydrous magnesium sulfate, and rotary evaporated. Add appropriate amount of methanol / dichloromethane mixed solvent and 200-300 mesh silica gel powder and evaporate to dryness. Dry load the sample and perform column chromatography with 1-6% methanol / dichloromethane as eluent to collect the target product. Concentrate and evaporate to dryness to obtain 1.5 g of the product with a yield of 15.46%. 1 H-NMR(600MHz,DMSO-d6)δ7.83(t,J=5.6,1H),6.76(s,1H),6.41(s,1H),6.35(s,1H),4 .30(dd,J=7.5,5.3,1H),4.15-4.10(m,1H),3.49(s,4H),3.40-3.35(m,4H),3.18(q,J= 5.9,2H),3.12-3.03(m,3H),2.82(dd,J=12.4,5.1,1H),2.58(d,J=12.4,1H),2.06(t,J =7.4,2H),1.60(dd,J=8.7,5.1,1H),1.55-1.42(m,3H),1.37(s,9H),1.33-1.26(m,2H)

[0634] 10.6 Preparation of 74-150

[0635] 74-141 (1.5 g, 3.160 mmol) was weighed and placed in a 100 ml round-bottom flask. TFA (4.693 ml) was added and the reaction was stirred at room temperature for 1 h. After the reaction, the TFA was partially removed by rotary evaporation. MTBE was then added to the solution to allow precipitation. The solution was then sonicated and the supernatant was discarded. This process was repeated four times until the product became a viscous oil. An appropriate amount of methanol / dichloromethane mixture was added for dissolution. 200-300 mesh silica gel powder was added and evaporated to dryness. The sample was dry-loaded and column chromatography was performed using 1% ammonia water / 6-10% methanol / dichloromethane as the eluent. The desired product was collected, concentrated, and evaporated to dryness to obtain 1.046 g of the product in an 87.23% yield. 1 H-NMR(600MHz,DMSO-d6)δ7.87(t,J=5.5,1H),6.41(s,1H),6.35(s,1H),4.32-4.29(m,1H ),4.14-4.11(m,1H),3.54-3.47(m,4H),3.42-3.35(m,4H),3.27(s,2H),3.20-3.17(m,2H) ,3.12-3.06(m,2H),2.82(dd,J=5.1,12.4Hz,1H),2.67(t,J=5.7Hz,2H),2.57(d,J=12.4H z,1H),2.06(t,J=7.4Hz,2H),1.64-1.57(m,1H),1.53-1.42(m,3H),1.35-1.23(m,2H).; FT MS ESI m / z[M+H + ]375.20

[0636] 10.7 Preparation of 74-152

[0637] 74-150 (1.026 g, 2.739 mmol), Fmoc-Glu(OtBu)-OH (1.165 g, 2.739 mmol), HBTU (1.246 g, 3.287 mmol), and HOBT (0.444 g, 3.287 mmol) were weighed and placed in a 100 ml round-bottom flask. DMF (15 ml) was added and sonicated to assist dissolution. DIEA (1.584 ml, 9.588 mmol) was added dropwise in an ice-water bath. After addition, the mixture was placed in a 25°C water bath and stirred for 2 h. After the reaction, methyl tert-butyl ether / petroleum ether was added and sonicated. The mixture was allowed to stand and the supernatant was decanted. This process was repeated four times until the product became a viscous oil. Add an appropriate amount of methanol / dichloromethane mixed solvent to dissolve, add 200-300 mesh silica gel powder and evaporate to dryness, dry load the sample, and perform column chromatography with 2-4% methanol / dichloromethane as eluent to collect the target product, concentrate and evaporate to dryness to obtain 1.847 g of the product with a yield of 86.26%. 1 H-NMR(600MHz,DMSO-d6)δ7.95-7.90(m,1H),7.89(d,J=7.5,2H),7.82(t,J =5.5,1H),7.73(t,J=7.7,2H),7.51(d,J=8.3,1H),7.42(t,J=7.4,2H),7.3 3(t,J=7.4,2H),6.41(s,1H),6.35(s,1H),4.29(dd,J=10.9,4.8,2H),4.23 (dd,J=16.2,6.8,2H),4.15-4.09(m,1H),3.98(d,J=5.4,1H),3.51-3.46(m ,4H),3.43-3.36(m,4H),3.28-3.22(m,1H),3.18(dd,J=11.8,5.2,3H),3.0 8(dd,J=4.4,2.7,1H),2.81(dd,J=5.1,12.4Hz,1H),2.57(d,J=12.4Hz,1H) ,2.26-2.18(m,2H),2.06(t,J=7.4,2H),1.90-1.82(m,1H),1.76-1.68(m,1 H),1.64-1.57(m,1H),1.53-1.43(m,3H),1.39(s,9H),1.34-1.20(m,2H); FT MS ESI m / z[M+H + ]782.37, [M+Na + ]804.35

[0638] 10.8 Preparation of 74-172

[0639] 74-152 (1.847 g, 2.362 mmol) was placed in a 100 ml round-bottom flask and dissolved in DMF (5 ml). Diethylamine (3.455 ml, 47.24 mmol) was then added and stirred at room temperature. After the reaction, methyl tert-butyl ether was added to allow precipitation. The mixture was ultrasonically treated and allowed to stand. Filtered and dried to obtain 0.978 g of the product, with a yield of 73.97%.

[0640] 10.9 Preparation of 74-173

[0641] 74-172 (0.978 g, 1.747 mmol), 88-14 (0.617 g, 1.747 mmol), HBTU (0.861 g, 2.271 mmol), and HOBT (0.306 g, 2.271 mmol) were placed in a 100 ml round-bottom flask. DMF (15 ml) was added and sonication was used to assist dissolution. DIEA (0.866 ml, 5.241 mmol) was added dropwise in an ice-water bath. After addition, the mixture was allowed to react at room temperature with stirring for 2 h. After the reaction, methyl tert-butyl ether (200 ml) was added to allow precipitation. The mixture was then sonicated and allowed to stand. The supernatant was decanted. This process was repeated four times until the product became a viscous oil. Add an appropriate amount of methanol / dichloromethane mixed solvent to dissolve, add 200-300 mesh silica gel powder and evaporate to dryness, dry load the sample, and perform column chromatography with 2-4% methanol / dichloromethane as eluent to collect the target product, concentrate and evaporate to dryness to obtain 1.23 g of the product with a yield of 78.69%. 1H-NMR(600MHz,DMSO-d6)δ7.96-7.91(m,2H),7.89(d,J=7.5,2H),7.86-7 .82(m,1H),7.68(d,J=7.5,2H),7.41(t,J=7.4,2H),7.35-7.31(m,2H),7 .29-7.24(m,1H)6.44(s,1H),6.37(s,1H),4.31-4.27(m,3H),4.21(d,J= 6.7,2H),4.14-4.11(m,1H),3.52-3.47(m,4H),3.43-3.36(m,4H),3.27- 3.21(m,1H),3.20-3.13(m,3H),3.10-3.07(m,1H),2.96(d,J=6.3,2H),2 .81(dd,J=12.4,5.1,1H),2.57(d,J=12.4,1H),2.21-2.16(m,2H),2.11( d,J=6.2,2H),2.06(t,J=7.4,2H),1.88-1.79(m,1H),1.73-1.64(m,1H), 1.64-1.56(m,1H),1.55-1.42(m,6H),1.38(s,9H),1.32-1.18(m,5H); FT MS ESI m / z[M+H + ]895.45, [M+Na + ]917.44

[0642] 10.10 Preparation of 74-223

[0643] 74-173 (3.54 g, 3.961 mmol) was placed in a 100 ml round-bottom flask and dissolved in DMF (10 ml). Diethylamine (5.794 ml, 79.22 mmol) was then added and stirred at room temperature. After the reaction, methyl tert-butyl ether (200 ml) was added to allow precipitation. The product was ultrasonically treated, allowed to stand, filtered, and dried to obtain 1.7 g of the product, with a yield of 63.83%.

[0644] 10.11 Preparation of 77-163

[0645] Paclitaxel (5 g, 5.86 mmol, abbreviated as PTX), succinic anhydride (2.1 g, 21.096 mmol), and DMAP (0.024 g, 0.3876 mmol) were placed in a 250 ml flask. A 11 / 1 mixture of anhydrous dichloromethane and DMA (24 ml) was added, and sonication was used to dissolve the mixture. The mixture was stirred at room temperature overnight. After the reaction, the mixture was spin-dried and dissolved in ethyl acetate (30 ml). The reaction mixture was transferred to a 500 ml separatory funnel and extracted with dilute hydrochloric acid (1%, w / v) (35 ml x 3). The ethyl acetate phase was collected and washed with purified water (40 ml x 3). The organic phase was then dried over anhydrous sodium sulfate, filtered, concentrated, and dried to yield 4.9 g of the product. 1 H-NMR (600MHz, DMSO-d6) δ12.26(s,1H),8.00-7.98(m,2H),7.86-7.84(m,2H),7.74(t,J=7.4Hz,1H),7.67(t,J=7.6Hz,2H ),7.56(d,J=7.4Hz,1H),7.52-7.44(m,7H),7.20(td,J=5.9,3.0Hz,1H),6.30(s,1H),5.82(t,J=8.8Hz,1H),5.55(t,J=8. 8Hz,1H),4.93-4.89(m,2H),4.64(s,1H),4.12(dd,J=6.6,4.1Hz,1H),4.06-3.98(m,3H),3.59(d,J=7.2Hz,1H),2.63(t,J =6.5Hz,3H),2.33(d,J=1.3Hz,2H),2.25(s,3H),2.11(s,3H),1.76(s,3H),1.51(d,J=11.3Hz,4H),1.01(t,J=13.8Hz,9H)

[0646] 10.12 Preparation of 77-164

[0647] 77-163 (2.24 g, 2.34 mmol), NHS (0.355 g, 3.0888 mmol), and DCC (0.618 g, 2.9952 mmol) were placed in a 100 ml flask and dissolved in dichloromethane (10 ml). The mixture was stirred and reacted at room temperature overnight. After the reaction was completed, the mixture was filtered and silica gel powder was added to the filtrate. The mixture was concentrated and dried. The sample was dry-applied and column chromatography was performed using a 1-2% methanol / dichloromethane mixture as the eluent to collect the desired product. The product was concentrated and dried to obtain 2.47 g.

[0648] 10.13 Preparation of 74-130

[0649] Weigh 69-246 (0.963 g, 1.937 mmol) into a 250 ml round-bottom flask and dissolve it in DMF (25 ml). Add DIEA (8.003 ml, 48.425 mmol) dropwise in an ice-water bath. Weigh 76-116 (4.592 g, 7.748 mmol), HBTU (2.938 g, 7.748 mmol), and HOBT (1.046 g, 7.748 mmol) into a beaker and pour them into the flask. The mixture is stirred at 30°C for reaction. After the reaction, add purified water (200 ml) and ethyl acetate (200 ml) to a 2 L separatory funnel, then pour the reaction mixture into the funnel for extraction. The organic phase is separated, and the aqueous phase is extracted with ethyl acetate (100 ml x 2). The combined organic phases are then washed with saturated sodium bicarbonate solution (200 ml). Finally, the water is removed with anhydrous magnesium sulfate and the mixture is rotary evaporated. Add an appropriate amount of methanol / dichloromethane mixed solvent to dissolve, add 200-300 mesh silica gel powder and evaporate to dryness, dry load the sample, and perform column chromatography with 1-5% methanol / dichloromethane as eluent to collect the target product, concentrate and evaporate to dryness to obtain 3.203 g of product with a yield of 74.436%. 1 H-NMR(600MHz,DMSO-d6)δ8.12-7.86(m,4H),7.80-7.71(m,5H),7.69(d,J=8.2Hz,1H),7.67-7.56(m,2H),7 .52-7.26(m,20H),5.14-4.94(m,8H),4.35-4.29(m,3H),4.27-4.19(m,3H),3.74-3.64(m,5H),3.60-3.49(m ,4H),3.43-3.36(m,6H),3.21-3.03(m,8H),2.69-2.57(m,4H),2.55-2.45(m,12H),2.26-2.15(m,6H),1.93- 1.80(m,4H),1.79-1.67(m,3H),1.67-1.56(m,3H),1.56-1.43(m,6H),1.43-1.34(m,2H),1.34-1.19(m,60H)

[0650] 10.14 Preparation of 74-214

[0651] 74-206 (1 g, 0.45 mmol) was weighed and placed in a 100 ml round-bottom flask. TFA (5 ml) was added and the reaction was stirred at room temperature for 1 h. After the reaction was completed, the TFA was partially removed by rotary evaporation under reduced pressure. Methyl tert-butyl ether (50 ml) was added, ultrasonicated, and rotary evaporation was performed under reduced pressure. Dichloromethane was added to dissolve the product, and then n-hexane / methyl tert-butyl ether was added to allow precipitation. The supernatant was discarded. This process was repeated several times until the product became a viscous oil. Finally, the product was concentrated by rotary evaporation and dried to obtain 0.84 g of the product. 1 H-NMR (600MHz, DMSO-d6) δ13.05-11.38(m,6H),8.12-7.86(m,4H),7.80-7.71(m,5H),7.69(d,J=8.2Hz,1H),7.6 7-7.56(m,2H),7.52-7.26(m,20H),5.14-4.94(m,8H),4.35-4.29(m,3H),4.27-4.19(m,3H),3.74-3.64(m,5H), 3.60-3.49(m,4H),3.43-3.36(m,6H),3.21-3.03(m,8H),2.69-2.57(m,4H),2.55-2.45(m,12H),2.26-2.15(m,6H) ,1.93-1.80(m,4H),1.79-1.67(m,3H),1.67-1.56(m,3H),1.56-1.43(m,6H),1.43-1.34(m,2H),1.34-1.19(m,6H)

[0652] 10.15 Preparation of 74-215

[0653] 74-214 (0.58 g, 0.31 mmol), 76-93 (2.68 g, 1.86 mmol), HBTU (0.962 g, 2.538 mmol), and HOBT (0.342 g, 2.538 mmol) were placed in a 100 ml round-bottom flask. DMF (8 ml) and NMP (8 ml) were then added and sonication was used to assist dissolution. The mixture was stirred at 0°C for 3 minutes, and DIEA (0.83 g, 5.07 mmol) was then added dropwise. After 3 minutes, the mixture was removed and the reaction was stirred at room temperature. After the reaction, methyl tert-butyl ether (150 ml) was added to the reaction solution to precipitate a solid, which was filtered off with suction. The filter cake was dissolved with an appropriate amount of 1 / 4 methanol / dichloromethane mixed solvent, and then 100-200 mesh silica gel powder was added and evaporated to dryness. The sample was dry loaded and column chromatography was performed using 1% ammonia water / 5-9% methanol / dichloromethane as eluent. The product was collected, concentrated, and evaporated to dryness to obtain 1.7 g of the product. 1H-NMR(600MHz,DMSO-d6)δ8.29-8.14(m,14H),8.14-8.02(m,14H),8.02-7.92(m,10H),7.91-7.76( m,15H),7.40-7.25(m,20H),6.82-6.68(m,11H),5.17-4.90(m,8H),4.30-4.00(m,24H),3.65-3.55 (m,17H),3.55-3.44(m,97H),3.44-3.35(m,79H),3.31-3.21(m,46H),3 .21-3.11(m,36H),3.11-2.93(m,60H),2.92-2.84(m,18H),2.67-2.52(m ,4H),2.47-2.37(m,2H),2.37-2.19(m,8H),2.19-1.95(m,52H),1.94-1. 58(m,37H),1.56-1.40(m,20H),1.40-1.30(m,225H),1.30-1.15(m,24H)

[0654] 10.16 Preparation of 74-216

[0655] Raw material 74-215 (1.3 g, 0.124 mmol) and 10% Pd / C catalyst (100 mg) were added to a hydrogenation reactor. Methanol (30 ml) was then added to dissolve the mixture. The reactor was sealed and filled with hydrogen, then evacuated five times. The hydrogen pressure was then refilled to 2 MPa, and the reaction was stirred in a 50°C oil bath overnight. After completion of the reaction, the mother liquor was filtered through a Buchner funnel containing filter paper, vacuum-evaporated, and dried to yield 1.23 g of the product. 1H-NMR(600MHz,DMSO-d6)δ12.01(s,1H),8.29-8.14(m,14H),8.14-8.02(m,14H),8.02-7.92(m,10H),7.91-7.76(m, 12H),6.82-6.68(m,11H),4.30-4.00(m,24H),3.65-3.55(m,17H),3.55-3.44(m,97H),3.44-3.35(m,79H),3.31-3. 21(m,46H),3.21-3.11(m,36H),3.11-2.93(m,60H),2.92-2.84(m,24H),2.67-2.52(m,4H),2.47-2.37(m,2H),2.37 -2.19(m,8H),2.19-1.95(m,52H),1.94-1.58(m,37H),1.56-1.40(m,20H),1.40-1.30(m,225H),1.30-1.15(m,24H)

[0656] 10.17 Preparation of 74-217

[0657] 74-216 (1.23 g, 0.124 mmol) was placed in a 100 ml round-bottom flask and then added to ultra-dry DMF (15 ml). Dissolution was assisted by ultrasound and stirred at 0°C for 3 minutes. DIEA (0.614 g, 3.72 mmol) was then slowly added dropwise. After stirring for 3 minutes, Y-NHS-10K (3.86 g, 0.375 mmol, purchased from J&K, batch number ZZ403P059) was added and the mixture was stirred at room temperature in the dark at a low speed. After the reaction, methyl tert-butyl ether (450 ml) was added to the reaction mixture. The solid precipitated and was filtered, and the filter cake was dried to obtain 4.5 g of the product.

[0658] 10.18 Preparation of 74-225

[0659] 74-217 (4 g, 0.098 mmol), 74-223 (0.263 g, 0.392 mmol), HBTU (0.148 g, 0.392 mmol), and HOBT (0.052 g, 0.392 mmol) were placed in a 100 ml round-bottom flask. DMF (10 ml) was added and dissolved with ultrasonication. The mixture was stirred at 0°C for 3 minutes. DIEA (0.194 g, 1.176 mmol) was then added dropwise. After 5 minutes, the mixture was removed and the reaction was stirred at room temperature. After the reaction, methyl tert-butyl ether (450 ml) was added to the reaction solution, and the solid precipitated and filtered. The filter cake was redissolved with an appropriate amount of 1 / 4 methanol / dichloromethane mixed solvent, and 100-200 mesh silica gel powder was added and evaporated to dryness. The sample was dry-loaded and column chromatography was performed using 1% ammonia water / 3-8% methanol / dichloromethane as eluent to collect the target product, concentrate, and dry-dry to obtain 1.74 g of the product.

[0660] 10.19 Preparation of 74-228

[0661] Compound 74-225 (1.74 g, 0.042 mmol) was placed in a 250 ml round-bottom flask, and TFA (10 ml) was added. The reaction was stirred at room temperature. After the reaction was complete, dichloromethane was added and the dichloromethane and most of the TFA were removed by rotary evaporation. This process was repeated three times to obtain an oily viscous solution. Methyl tert-butyl ether (100 ml) was then added to precipitate a solid. The solid was filtered and the filter cake was dried to obtain 0.92 g of the product.

[0662] 10.20 Preparation of 74-229

[0663] 74-228 (0.92 g, 0.024 mmol) was placed in a 100 ml round-bottom flask, and DMF (10 ml) was added. Dissolution was assisted by ultrasonication and stirred at 0°C for 3 minutes. DIEA (0.119 g, 0.72 mmol) and 77-164 (0.75 g, 0.72 mmol) were slowly added dropwise. After 3 minutes, the mixture was removed and stirred at room temperature overnight. After the reaction, methyl tert-butyl ether (150 ml) was added to the reaction solution, causing solid precipitation. The mixture was allowed to stand at room temperature for 4 hours, and the supernatant was decanted. An appropriate amount of dichloromethane was added to the solid to dissolve the product. Methyl tert-butyl ether (100 ml) was then added to the solid, which was filtered and the filter cake dried to yield 1.46 g of the product.

[0664] 10.21 Preparation of 74-230

[0665] 74-229 (1.46 g, 0.024 mmol) and TSTU (0.014 g, 0.048 mmol) were placed in a 100 ml round-bottom flask and dissolved in DMF (10 ml). Triethylamine (0.1 ml) was then added and the mixture was stirred at room temperature. After completion of the reaction, n-hexane (10 ml) and methyl tert-butyl ether (50 ml) were added to allow solid precipitation. The mixture was allowed to stand for 1 hour, and the supernatant was decanted. This process was repeated four times. The filter cake was then filtered and dried to yield 1.26 g of the product.

[0666] 10.22 Preparation of 74-232

[0667] 74-230 (1 g, 0.016 mmol) was placed in a 100 ml round-bottom flask, followed by DMF (10 ml). Dissolution was assisted by ultrasonication, and the mixture was stirred at 0°C for 3 minutes. DIEA (0.0074 ml, 0.0576 mmol) was then added dropwise, followed by 74-185 (0.01 g, 0.0176 mmol), and the reaction was stirred at room temperature. After the reaction, methyl tert-butyl ether (450 ml) and n-hexane (50 ml) were added to the reaction mixture, causing a solid to precipitate. After standing for 4 hours, the supernatant was decanted and the solid was dissolved in an appropriate amount of dichloromethane. Silica gel powder (100-200 mesh) was added and evaporated to dryness. The sample was dry-applied and subjected to column chromatography using 1% triethylamine / 5% methanol / dichloromethane as the eluent. The desired product was collected, concentrated, and evaporated to dryness to yield 0.62 g. 1 H-NMR(600MHz,DMSO-d6)δ9.31-9.11(m,24H),8.33-8.06(m,40H),8.04-7.79(m,18 5H),7.79-7.61(m,84H),7.61-7.38(m,170H),7.25-7.11(m,22H),6.40-6.24(m,24H ),5.91-5.74(m,24H),5.55-5.24(m,83H),5.02-4.79(m,44H),4.75-4.58(m,22H),4 .54-3.83(m,134H),3.82-2.85(m,2850H),2.70-2.00(m,454H),1.91-0.90(m,534H)

[0668] Example 11 Synthesis of Compounds 85-97

[0669] 11.1 Preparation of 85-83

[0670] 76-191 (0.70 g, 3.5115 mmol), N-(2-aminoethyl)maleimide hydrochloride (0.62 g, 3.5115 mmol), HOBT (0.71 g, 5.2672 mmol), and HBTU (1.9 g, 5.2672 mmol) were placed in a 100 mL flask and dissolved in DMF (15 mL). The reaction was stirred at -10°C for approximately 10 minutes. DIEA (2.3 mL, 14.046 mmol) was then slowly added dropwise. The reaction was continued at -10°C. TLC was used to monitor the reaction progress. After completion of the reaction, the reaction mixture was transferred to a 1 L separatory funnel and extracted with saturated brine (150 mL) and ethyl acetate (150 mL) to obtain the organic phase. The aqueous phase was then extracted with ethyl acetate (150 mL). The organic phases were combined, washed with deionized water (100 ml x 2), concentrated and evaporated to dryness. The product was dissolved in a 4 / 1 dichloromethane / methanol mixed solvent, silica gel powder was added, evaporated to dryness, and dry-loaded. Column chromatography was performed using a 60-80% ethyl acetate / petroleum ether mixed solution as the eluent. The organic solution containing the product components was collected, concentrated, and dried in a vacuum oven to obtain 0.17 g of the product.

[0671] 11.2 Preparation of 85-55

[0672] 75-217 (1.6 g, 2.4093 mmol), 88-86 (3.24 g, 7.9508 mmol), HBTU (4.11 g, 10.8418 mmol), and HOBT (1.46 g, 10.8418 mmol) were placed in a 250 ml reaction flask and dissolved in DMF (30 ml). The reaction was stirred at room temperature for approximately 20 minutes, followed by the slow dropwise addition of DIEA (5.9 ml, 36.1395 mmol) and continued stirring at room temperature. After completion of the reaction, n-hexane (250 ml) and methyl tert-butyl ether (70 ml) were added to allow the reaction to settle. The supernatant was then decanted, and n-hexane and methyl tert-butyl ether were added to allow the reaction to settle. This process was repeated five times. The solid product was obtained by filtration and dissolved in a dichloromethane / methanol mixed solvent. Silica gel powder was added and evaporated to dryness. The sample was dry loaded and column chromatography was performed using a 2-6% methanol / dichloromethane mixed solution as the eluent. The target product was collected, concentrated, and dried in a vacuum oven to obtain 2.64 g of the product with a yield of 60.17%. 1H-NMR(600MHz,DMSO-d6)δ8.07-7.87(m,6H),7.36-7.28(m,25H),7.24-7.19(m,3H),5.08-5.05(m,4H),4. 99(s,6H),4.22-4.09(m,5H),3.69-3.61(m,2H),3.61-3.54(m,2H),3.54-3.47(m,2H),3.44-3.37(m,2H),3 .29-3.23(m,4H),3.17-3.15(m,4H),2.99-2.90(m,7H),2.73-2.51(m,8H),2.49-2.44(m,2H),2.44-2.36(m ,2H),2.36-3.28(m,10H),1.61-1.50(m,4H),1.49-1.41(m,4H),1.37(s,27H),1.26-1.21(m,6H); ESI[M+Na + ]1877.680

[0673] 11.3 Preparation of 85-78

[0674] To a flask containing 85-55 (2.64 g, 1.4230 mmol) was added dichloromethane (5 ml), and after dissolution with ultrasonication, TFA (6.2 ml, 42.691 mmol) was added. The mixture was stirred at room temperature to react. After completion of the reaction, the reaction solution was concentrated and evaporated to dryness to remove dichloromethane and most of the TFA. Methyl tert-butyl ether (300 ml) was added to allow precipitation to precipitate the solid product. The solid product was filtered, and the filter cake was washed three times with methyl tert-butyl ether (40 ml). The filter cake was collected and dried in vacuo to obtain 2.4 g of the product. 1 H-NMR(600MHz,DMSO-d6)δ11.0(s,3H),8.08-7.90(m,6H),7.36-7.29(m,25H),7.2 4-7.17(m,3H),5.08-5.04(m,4H),4.99(s,6H),4.23-4.11(m,4H),3.70-3.44(m,12 H),3.22-3.16(m,4H),2.98-2.91(m,6H),2.70-2.61(m,4H),2.59-2.53(m,4H),2.4 0-2.28(m,12H),1.60-1.50(m,4H),1.50-1.40(m,4H),1.28-1.13(m,10H);ESI[M+H + ]1684.76807

[0675] 11.4 Preparation of 85-80

[0676] 85-78 (0.25 g, 0.1482 mmol), 70-201 (0.6 g, 0.48901 mmol), HBTU (0.25 g, 0.6669 mmol) and HOBT (0.09 g, 0.6669 mmol) were added to a 250 ml round-bottom flask and dissolved with DMF (16 ml). The reaction flask was then stirred at -5 °C for about 20 minutes, and then DIEA (0.4 ml, 2.223 mmol) was slowly added dropwise. After the addition was complete, the reaction flask was stirred at -5 °C for 1 hour, and then taken out and transferred to room temperature for stirring. After the reaction is completed, n-hexane (30 ml) and methyl tert-butyl ether (100 ml) are added to precipitate, and the supernatant is poured out. This process is repeated three times, and the solid product is filtered to obtain the solid product. The solid product is dissolved in a 20% methanol / dichloromethane mixed solvent, and silica gel powder is added and evaporated to dryness. The sample is dry loaded and column chromatography is performed using a 1% ammonia water / 7-15% methanol / dichloromethane mixed solution as an eluent. The organic solvent containing the product components is collected and evaporated to dryness, and the product is dried in a vacuum oven to obtain 0.2 g of the product with a yield of 23.33%. 1 H-NMR(600MHz,DMSO-d6)δ8.36-8.22(m,9H),8.18-7.98(m,24H),7.37-7.29(m,25H),7.21-7.01 (m,24H),5.09-5.04(m,4H),4.98(s,6H),4.33-4.19(m,12H),4.15-4.05(m,25H),3.72-3.68(m,1 2H),3.29-3.27(m,4H),3.02-2.97(m,6H),2.91-2.88(m,4H),2.56-2.52(m,6H),2.25-2.06(m,42 H),1.98-1.88(m,16H),1.73-1.71(m,6H),1.52-1.46(m,12H),1.39(s,108H),1.25-1.23(m,18H)

[0677] 11.5 Preparation of 85-82

[0678] 85-80 (0.2 g, 0.0381 mmol) was dissolved in anhydrous DMF by heating and placed in a hydrogenation reactor. 10% Pd / C catalyst (0.1 g) was then added. The hydrogenation reactor was sealed, filled with hydrogen, and then evacuated with a water pump. This process was repeated three times. The pressure on the hydrogenation reactor was adjusted to 2.0 MPa, and the mixture was stirred overnight in a 43°C oil bath. After the reaction, the reaction solution was filtered through diatomaceous earth and the diatomaceous earth was washed with DMF (5 ml x 3) to obtain a liquid product. Methyl tert-butyl ether and n-hexane were added to allow the mixture to settle, the supernatant was decanted, and methyl tert-butyl ether and n-hexane were added again. This process was repeated three times. Finally, the product (0.17 g) was filtered and dried. 1 H-NMR(600MHz,DMSO-d6)δ9.70-9.56(m,2H),8.20-7.89(m,54H),5.11(s, 6H),4.31-4.11(m,12H),3.81-3.64(m,27H),3.12-3.05(m,20H),3.03-2.9 7(m,10H),2.64-2.60(m,6H),2.42-2.34(m,10H),2.30-2.03(m,42H),1.75 -1.69(m,6H),1.44-1.42(m,12H),1.40-1.37(m,108H),1.28-1.21(m,18H)

[0679] 11.6 Preparation of 85-84

[0680] 85-82 (0.17 g, 0.0381 mmol) was placed in a 250 ml flask and dissolved in anhydrous DMF (10 ml). The reaction was allowed to react at 0°C for 30 minutes, followed by the slow addition of DIEA (0.2 ml, 1.4287 mmol). After stirring at low temperature for 10 minutes, Y-NHS-10K (1.17 g, 0.1143 mmol) was added and the reaction mixture was stirred at low speed at room temperature in the dark for one week. After the reaction was completed, methyl tert-butyl ether (100 ml) and n-hexane (30 ml) were added to precipitate a solid, which was filtered and washed with methyl tert-butyl ether (40 ml x 3). The filter cake was collected and dried in a vacuum oven to obtain 1.07 g of the product. 1H-NMR(600MHz,DMSO-d6)δ9.70-9.56(m,2H),8.22-7.79(m,57H),4.19-4.12(m,12H),3.71-3.69(m,27H),3.54-3.49(m,2727H),3.06- 2.96(m,30H),2.41-2.36(m,16H),2.21-2.15(m,42H),1.74-1.70(m,6H),1.46-1.45(m,12H),1.41-1.38(m,108H),1.21-1.16(m,18H)

[0681] 11.7 Preparation of 85-87

[0682] 85-84 (0.5 g, 0.0142 mmol), 76-129 (0.028 g, 0.0426 mmol), HBTU (0.016 g, 0.0426 mmol), and HOBT (0.0057 g, 0.0426 mmol) were placed in a 250 ml flask and dissolved in DMF (15 ml). The reaction was stirred at room temperature for approximately 20 minutes, followed by the slow addition of DIEA (0.02 ml, 0.1279 mmol) in the dark. After completion of the reaction, n-hexane (250 ml) and methyl tert-butyl ether (70 ml) were added to allow the reaction to settle. The supernatant was then decanted, and n-hexane and methyl tert-butyl ether were added to allow the reaction to settle. This process was repeated five times, and the solid product was filtered and dried in a vacuum oven to yield 0.51 g of the product. 1 H-NMR(600MHz,DMSO-d6)δ8.32-7.95(m,73H),4.25-4.11(m,24H),4.01-3.95(m,8H),3.75-3.70(m,27H),3.54-3.49(m,2727 H),3.16-3.05(m,42H),2.81-2.76(m,16H),2.17-2.09(m,72H),1.54-1.49(m,22H),1.41-1.38(m,108H),1.27-1.25(m,26H)

[0683] 11.8 Preparation of 85-85

[0684] 85-87 (0.51 g, 0.0142 mmol) and 85-83 (0.054 g, 0.1704 mmol) were placed in a reaction flask and dissolved in anhydrous DMF (16 ml). The reaction flask was then filled with nitrogen. CuSO4 (0.036 g, 0.2272 mmol) and sodium ascorbate (0.09 g, 0.4544 mmol) were then added. The reaction flask was stirred and reacted at room temperature overnight. After the reaction was complete, n-hexane (25 ml) and methyl tert-butyl ether (200 ml) were added to allow the mixture to settle. The supernatant was then decanted, and n-hexane and methyl tert-butyl ether were added to allow the mixture to settle. This process was repeated three times. The solid product was filtered and collected and dried to yield 0.44 g of the product. 1 H-NMR(600MHz,DMSO-d6)δ8.54-8.21(m,33H),8.18-7.89(m,32H),7.76-7.67(m,8H),7.21-6.92(m,24H),6.85- 6.62(m,16H),4.52-4.41(m,24H),4.38-4.30(m,18H),4.21-4.11(m,33H),3.87-3.81(m,44H),3.54-3.49(m,272 7H),3.25-3.22(m,20H),3.09-3.06(m,6H),2.90-2.88(m,4H),2.64-2.60(m,10H),2.46-2.35(m,48H),2.25-2. 05(m,56H),1.94-1.80(m,16H),1.79-1.63(m,20H),1.55-1.47(m,16H),1.41-1.38(m,108H),1.26-1.25(m,26H)

[0685] 11.9 Preparation of 85-89

[0686] 85-85 (0.1 g, 0.0025 mmol) and Ac-C-PLGLAG-iRGD (0.032 g, 0.0204 mmol) were added to a 100 ml flask, and DMSO (6 ml) was added to dissolve the mixture. The mixture was stirred and reacted at room temperature overnight. After the reaction, n-hexane (20 ml) and methyl tert-butyl ether (200 ml) were added to allow the mixture to settle. The supernatant was decanted, and n-hexane and methyl tert-butyl ether were added to allow the mixture to settle. This process was repeated six times. The solid product was filtered and dried in a vacuum oven to yield 0.129 g of the product.

[0687] 11.10 Preparation of 85-96

[0688] TFA (0.1 ml, 1.34 mmol) was added to a flask containing 85-89 (0.129 g, 0.0025 mmol), and the mixture was dissolved with ultrasound. The mixture was stirred at room temperature overnight. After the reaction, the reaction solution was concentrated and evaporated to dryness, dissolved in DMF (5 ml), neutralized by adding excess DIEA, and precipitated with methyl tert-butyl ether (200 ml) and n-hexane (100 ml). The supernatant was poured out and precipitated with methyl tert-butyl ether (200 ml) and n-hexane (100 ml) to precipitate the solid product. The solid product was filtered and the filter cake was washed three times with methyl tert-butyl ether (40 ml). The filter cake was collected and dried in vacuo to obtain 0.126 g of the product.

[0689] 11.11 Preparation of 85-97

[0690] Reactants 85-96 (0.126 g, 0.0025 mmol) and DOX (0.034 g, 0.06 mmol) were placed in a reaction flask and dissolved in methanol (20 ml). TFA (0.003 ml, 0.0375 mmol) was then added and stirred at room temperature. Reaction progress was monitored by TLC. After completion of the reaction, the solid was filtered, and the filtrate was evaporated to dryness using a rotary evaporator. The resulting powder was precipitated with methyl tert-butyl ether, resulting in a solid that was filtered and the filter cake collected. The solid product was washed three times with a 2% methanol / dichloromethane mixture. The filtrate was collected, concentrated, and dried to yield 0.061 g of the product. 1H-NMR(600MHz,DMSO-d6)δ9.10-9.04(m,24H),8.44-8.39(m,49H),8.30-8.27(m,32H),8.08-7.99(m,112H),7.85-7.82(m,56H),7.30-7.18(m,4 8H),4.97-4.95(m,64H),4.91-4.86(m,60H),4.35-4.31(m,50H),4.26-4 .24(m,64H),4.20-4.17(m,109H),3.87-3.82(m,100H),3.64-3.63(m,80 H),3.54-3.49(m,2727H),3.24-3.23(m,90H),3.06-3.01(m,36H),2.93 -2.91(m,24H),2.76-2.72(m,14H),2.63-2.60(m,28H),2.41-2.38(m,24 H),2.17-2.14(m,172H),1.88-1.87(m,40H),1.70-1.67(m,84H),1.52-1 .47(m,88H),1.28-1.26(m,42H),1.19-1.18(m,36H),0.89-0.86(m,96H)

[0691] Example 12 Synthesis of Compound 85-26

[0692] 12.1 Preparation of 71-252

[0693] Axitinib (5 g, 12.938 mmol, referred to as AXT) and 4-nitrobenzene chloroformate (5.215 g, 25.875 mmol) were weighed and added to THF (approximately 500 ml). Ultrasonication was used to dissolve the mixture into a homogeneous phase. The mixture was stirred in an oil bath at 75°C under reflux for 4 hours. After the reaction, methyl tert-butyl ether (150 ml) and n-hexane (100 ml) were added to the reaction solution to precipitate a solid product, which was filtered and vacuum dried to obtain 7.4 g of the product. ESI [M+H + ]552.132

[0694] 12.2 Preparation of 71-251

[0695] Compounds 71-252 (3.0 g, 5.4389 mmol) and 88-4 (1.35 g, 5.4389 mmol) were weighed and added to a reaction flask. Triethylamine (2.3 ml, 16.3169 mmol) was added, dissolved in DMF (26 ml), and stirred at room temperature. After completion of the reaction, n-hexane and methyl tert-butyl ether were added to the reaction solution to allow precipitation, resulting in a powdery solid. The supernatant was decanted and dissolved in a 20% methanol / dichloromethane mixture. Silica gel powder (20 ml) was added and evaporated to dryness. The sample was dry-loaded and subjected to column chromatography using a 0-2% methanol / dichloromethane mixture as the eluent. The desired product was collected, concentrated, and dried in a vacuum oven to obtain 2.57 g of the product in a 69.45% yield. 1 H-NMR (600MHz, DMSO-d6) δ8.65(d,J=4.5Hz,1H),8.47-8.37(m,2H),8.35(s,1H),8.30(d,J=8.4Hz,1H),7. 98-7.93(m,1H),7.86(dd,J=7.6,1.6Hz,1H),7.82(d,J=16.3Hz,1H),7.72(d,J=7.8Hz,1H),7.51(dd,J=7. 3,1.6Hz,1H),7.40-7.28(m,4H),7.12(d,J=7.6Hz,1H),6.76(s,1H),3.64-3.54(m,4H),3.49(ddd,J=17.7 ,8.4,4.4Hz,4H),3.38(d,J=12.1Hz,2H),3.10-3.00(m,2H),2.76(d,J=4.6Hz,3H),1.34(s,9H); ESI[M+Na + ]683.26147

[0696] 12.3 Preparation of 71-263

[0697] 71-251 (2.57 g, 3.8923 mmol) was weighed and dissolved in dichloromethane (5 ml). TFA (2.9 ml, 38.923 mmol) was then added and stirred at room temperature. After the reaction was completed, the reaction solution was concentrated and methyl tert-butyl ether (150 ml) and n-hexane (100 ml) were added to the reaction solution for precipitation. The solid product was precipitated and filtered. The solid was dissolved in a mixed solvent of 20% methanol / dichloromethane and silica gel powder was added and mixed evenly. The product was evaporated to dryness and dry-loaded. Column chromatography was performed using 1% ammonia water / 5% methanol / dichloromethane as the eluent. The target product solution fraction was collected, concentrated, and evaporated to dryness to obtain 2.18 g of the product.

[0698] 12.4 Preparation of 71-284

[0699] 71-263 (2.18 g, 3.8922 mmol), 81-127 (0.54 g, 0.8846 mmol), HBTU (2.01 g, 5.3076 mmol), and HOBT (0.717 g, 5.3076 mmol) were placed in a 500 ml reaction flask. DMF (50 ml) was added and dissolved with ultrasound. The reaction was stirred at 0°C for approximately 20 minutes. DIEA (2.6 ml, 17.692 mmol) was then slowly added dropwise. The reaction was continued at 0°C for 1 hour, and then the reaction was moved to room temperature with stirring. After completion of the reaction, n-hexane (250 ml) and methyl tert-butyl ether (70 ml) were added to allow sedimentation. The supernatant was decanted, and n-hexane and methyl tert-butyl ether were added to allow sedimentation. This process was repeated four times. The solid product was obtained by filtration and dissolved in a 20% methanol / dichloromethane mixed solvent. Silica gel powder was added and evaporated to dryness. The sample was dry loaded and column chromatography was performed using a 2-5% methanol / dichloromethane mixed solution as an eluent. The target product was collected, concentrated, and dried in a vacuum oven to obtain 2.12 g of the product with a yield of 86.17%. 1 H-NMR(600MHz,DMSO-d6)δ8.64-8.61(m,4H),8.43-8.40(m,4H),8.38-8.35(m,4H),8.34-8.31(m,4H),8.27-8.26(m,4 H),8.22-8.16(m,2H),8.09-8.03(m,2H),7.99-7.89(m,6H),7.85-7.76(m,10H),7.72-7.66(m,4H),7.53-7.47(m,4H) ,7.35-7.30(m,16H),7.13-7.06(m,4H)4.25-4.13(m,3H),3.60-3.42(m,40H),3.26-3.21(m,2H),3.17-3.12(m,8H),2 .78-2.74(m,12H),2.21-1.97(m,10H),1.91-1.77(m,4H),1.46-1.40(m,2H),1.33(s,9H),1.25-1.12(m,4H); ESI[M+Na + ]2810.351

[0700] 12.5 Preparation of 71-289

[0701] Dichloromethane (5 ml) was added to a flask containing 71-284 (2.12 g, 0.7612 mmol), and dissolution was assisted by ultrasound. TFA (1.2 ml, 15.224 mmol) was then added and stirred at room temperature for reaction. After the reaction, the reaction solution was concentrated and evaporated to dryness to remove dichloromethane and most of the TFA. The solid product was precipitated with methyl tert-butyl ether (300 ml) and filtered. The filter cake was washed three times with methyl tert-butyl ether (40 ml). The filter cake was collected and dried under vacuum to obtain 2.04 g of the product. ESI [M+H + ]2688.391

[0702] 12.6 Preparation of 71-264

[0703] 70-186 (0.27 g, 0.4748 mmol), 88-86 (0.92 g, 2.2794 mmol), HBTU (1.08 g, 2.8492 mmol), and HOBT (0.38 g, 2.8492 mmol) were placed in a 250 mL solution of DMF (20 mL) and dissolved. The mixture was stirred at room temperature for approximately 20 minutes, followed by the slow dropwise addition of DIEA (1.6 mL, 9.4975 mmol) and continued stirring at room temperature. After completion of the reaction, the reaction mixture was transferred to a 1 L separatory funnel and extracted with saturated sodium chloride solution (200 mL) and ethyl acetate (150 mL) to yield an organic phase. The aqueous phase was then extracted with ethyl acetate (200 mL x 2). The combined organic phases were washed with deionized water (250 mL x 2). The organic phases were concentrated, evaporated to dryness, and dried in a vacuum oven to yield 0.68 g of the product, with a yield of 68.0%. 1 H-NMR(600MHz,DMSO-d6)δ8.03-7.92(m,8H),7.34-7.28(m,25H),7.24-7.15(m,4 H),5.07(s,2H),4.99(s,8H),4.21-4.14(m,4H),3.73-3.44(m,7H),3.28-3.26(m, 2H),3.17-3.16(m,6H),2.97-2.92(m,8H),2.74-2.55(m,10H),2.35-2.24(m,16H) ,1.58-1.52(m,4H),1.50-1.41(m,6H),1.37(s,36H),1.26-1.13(m,14H);ESI[M+H + ]2127.15796

[0704] 12.7 Preparation of 71-274

[0705] 71-264 (0.48 g, 0.2257 mmol) was placed in a hydrogenation reactor, followed by the addition of 10% Pd / C catalyst (0.1 g). Methanol (20 ml) was then added to dissolve the product. Hydrogen was introduced, and the pressure was adjusted to 1.8 MPa. The reaction was stirred at room temperature overnight. After the reaction, the reaction solution was filtered through diatomaceous earth, which was then washed with methanol (5 ml x 3). The methanol solution was combined, and dichloromethane was added to the solution. The product was evaporated to dryness using a vacuum rotary evaporator. Dichloromethane and toluene (0.2 ml) were then added and ultrasonicated, and the product was evaporated to dryness. This process was repeated five times. Dichloromethane was then added and ultrasonicated to dissolve the product, and the product was evaporated to dryness. This process was repeated five times, and the product was dried in a vacuum oven to yield 0.33 g of the product. 1 H-NMR(600MHz,DMSO-d6)δ11.0(s,1H),8.68-7.73(m,8H),5.11(s,8H),4.17 -4.14(m,4H),4.06-3.85(m,10H),3.77-3.43(m,11H),3.30-3.22(m,4H),3.2 1-3.14(m,4H),2.80-2.57(m,10H),2.37-2.32(m,10H),2.30-2.12(m,8H),1. 61-1.52(m,4H),1.52-1.45(m,4H),1.39(s,36H),1.35-1.22(m,8H); ESI[M+H + ]1499.96240

[0706] 12.8 Preparation of 71-278

[0707] 71-274 (0.05 g, 0.0333 mmol) was placed in a 250 ml flask and dissolved in anhydrous DMF (15 ml). The reaction was allowed to react at 0°C for 30 minutes, followed by the slow addition of DIEA (0.3 ml, 1.6668 mmol). After stirring at low temperature for 10 minutes, M-SCM-10K (1.56 g, 0.1466 mmol, purchased from Jiankai, Lot Number: A3016-N230101) was added. The reaction was placed in the dark at room temperature with slow stirring for one week. After the reaction was completed, methyl tert-butyl ether (200 ml) and n-hexane (70 ml) were added to allow precipitation. The solid precipitated and was filtered. The filter cake was washed with methyl tert-butyl ether (40 ml x 3). The filter cake was collected and dried in a vacuum oven to obtain 1.06 g of the product. 1H-NMR(600MHz,DMSO-d6)δ9.05-9.04(m,1H),8.11-7.85(m,12H),4.17-4.13(m,4H),3.88-3.82(m,15H),3.51-3.50(m,38 28H),2.65-2.59(m,24H),2.40-2.37(m,10H),1.59-1.52(m,8H),1.50-1.43(m,8H),1.39-1.37(m,36H),1.30-1.25(m,8H)

[0708] 12.9 Preparation of 71-295

[0709] 71-278 (1.0 g, 0.0233 mmol), 71-289 (0.094 g, 0.035 mmol), HBTU (0.013 g, 0.035 mmol), and HOBT (0.0046 g, 0.0047 mmol) were placed in a 250 ml flask and dissolved in DMF (30 ml). The mixture was stirred at room temperature for approximately 20 minutes, followed by the slow dropwise addition of DIEA (0.1 ml, 0.607 mmol) and continued stirring at room temperature. After completion of the reaction, n-hexane (250 ml) and methyl tert-butyl ether (70 ml) were added to allow the reaction to settle. The supernatant was decanted, and n-hexane and methyl tert-butyl ether were then added to allow the reaction to settle. This process was repeated five times. The solid product was obtained by filtration, and the solid product was dissolved in a mixed solvent of dichloromethane and methanol, dry-loaded, and column chromatography was performed using a 10% methanol / dichloromethane mixed solution as an eluent to collect the target product, concentrate, and dry in a vacuum oven to obtain 0.53 g of the product. 1 H-NMR(600MHz,DMSO-d6)δ8.65-8.60(m,4H),8.41-8.32(m,12H),8.27-8.24(m,4H),8.10-8.07(m,2H),8.01-7 .90(m,12H),7.86-7.76(m,12H),7.71-7.62(m,10H),7.55-7.48(m,4H),7.35-7.29(m,16H),7.13-7.12(m,4H), 4.20-4.17(m,7H),3.63-3.61(m,43H),3.51-3.50(m,3828H),3.18-3.12(m,22H),3.07-3.02(m,12H),2.77-2. 73(m,24H),2.36-2.32(m,10H),2.15-2.04(m,14H),1.51-1.43(m,18H),1.39-1.37(m,36H),1.28-1.26(m,12H)

[0710] 12.10 Preparation of 85-10

[0711] To a flask containing 71-295 (0.53 g, 0.0114 mmol) was added TFA (0.5 ml, 0.9153 mmol), dissolved with ultrasound, and stirred at room temperature overnight. After the reaction, the reaction solution was concentrated and evaporated to dryness to remove most of the TFA. The solid product was then precipitated with methyl tert-butyl ether (300 ml) and filtered. The filter cake was washed with methyl tert-butyl ether (40 ml x 3) and then collected and dried under vacuum to obtain 0.5 g of the product. 1 H-NMR(600MHz,DMSO-d6)δ10.04-9.89(m,4H),8.65-8.57(m,4H),8.45-8.30(m,12H),8.29-8.24(m,6H),8.14-8.09(m,18H), 7.86-7.74(m,10H),7.75-7.60(m,10H),7.53-7.47(m,4H),7.35-7.26(m,12H),7.19-7.16(m,4H),4.21-4.15(m,7H),3.64-3 .62(m,43H),3.51-3.50(m,3828H),3.25-3.22(m,12H),3.20-3.10(m,12H),3.09-3.0(m,10H),2.85-2.66(m,24H),2.40-2.3 3(m,10H),2.15-2.04(m,8H),1.90-1.77(m,6H),1.60-1.53(m,4H),1.51-1.43(m,6H),1.40-1.35(m,8H),1.28-1.14(m,12H)

[0712] 12.11 Preparation of 85-16

[0713] 85-10 (0.5 g, 0.0108 mmol), 76-93 (0.093 g, 0.0651 mmol), HBTU (0.024 g, 0.0651 mmol), and HOBT (0.0087 g, 0.0651 mmol) were added to a 250 ml round-bottom flask and dissolved in DMF (20 ml). The mixture was stirred at room temperature for approximately 20 minutes, followed by the slow dropwise addition of DIEA (0.041 ml, 0.2172 mmol). After the addition was complete, the reaction flask was allowed to continue stirring at room temperature. After the reaction was complete, n-hexane (150 ml) and methyl tert-butyl ether (100 ml) were added to allow the mixture to settle. The supernatant was then decanted, and n-hexane and methyl tert-butyl ether were then added to allow the mixture to settle. This process was repeated three times. The solid product was obtained by filtration, and the solid product was dissolved in a dichloromethane / methanol mixed solvent, dry-loaded, and column chromatography was performed using a 1% ammonia water / 5-8% methanol / dichloromethane mixed solution as an eluent to collect the target product, concentrate, and dry in a vacuum oven to obtain 0.31 g of the product. 1 H-NMR(600MHz,DMSO-d6)δ8.65-8.57(m,4H),8.43-8.30(m,12H),8.28-8.18(m,16H),8.13-8.06(m,16H),8.02-7.93(m,12H),7.90- 7.78(m,18H),7.75-7.63(m,10H),7.53-7.45(m,8H),7.42-7.38(m,4H),7.36-7.23(m,12H),7.14-7.13(m,4H),7.02-6.95(m,12H),4 .26-4.23(m,20H),4.11-4.07(m,40H),3.98-3.94(m,18H),3.70-3.59(m,112H),3.51-3.50(m,3828H),3.17-3.15(m,70H),2.75-2. 73(m,12H),2.70-2.66(m,32H),2.13-2.10(m,80H),1.48-1.43(m,16H),1.47-1.46(m,26H),1.37-1.36(m,144H),1.26-1.25(m,28H)

[0714] 12.12 Preparation of 85-23

[0715] TFA (0.1 ml, 0.9577 mmol) was added to a flask containing 85-23 (0.31 g, 0.0059 mmol), and dissolution was assisted by ultrasound. The reaction was stirred at room temperature overnight. After completion of the reaction, the reaction solution was concentrated to remove most of the TFA, and then methyl tert-butyl ether (200 ml) and n-hexane (100 ml) were added for sedimentation. The supernatant was poured out and then precipitated with methyl tert-butyl ether (200 ml) and n-hexane (100 ml) to precipitate the solid product. The solid product was filtered and the filter cake was washed six times with methyl tert-butyl ether (40 ml). The filter cake was collected and dried in vacuo to obtain 0.27 g of the product.

[0716] 12.13 Preparation of 85-26

[0717] 85-23 (0.27 g, 0.0053 mmol), 81-189 (0.12 g, 0.1291 mmol), HBTU (0.048 g, 0.1291 mmol), and HOBT (0.017 g, 0.1291 mmol) were added to a 250 ml round-bottom flask and dissolved in DMF (15 ml). The mixture was stirred at room temperature for approximately 20 minutes, followed by the slow dropwise addition of DIEA (0.07 ml, 0.4304 mmol). After the addition was complete, the reaction flask was allowed to continue stirring at room temperature. After the reaction was complete, n-hexane (150 ml) and methyl tert-butyl ether (100 ml) were added to allow the mixture to settle. The supernatant was then decanted, and n-hexane and methyl tert-butyl ether were then added to allow the mixture to settle. This process was repeated three times. The solid product was obtained by filtration, and the solid product was dissolved in a mixed solvent of dichloromethane and methanol, dry-loaded, and column chromatography was performed using a mixed solution of 1% ammonia water / 5-10% methanol / dichloromethane as an eluent to collect the target product, concentrate, and dry in a vacuum oven to obtain 0.2 g of the product. 1H-NMR(600MHz,DMSO-d6)δ8.39-8.35(m,16H),8.18-8.15(m,18H),8.11-8.05(m,80H),7.93-7.86(m,96H),7.27-7.20(m,130H), 4.56-4.48(m,15H),4.37-4.32(m,36H),4.26-4.16(m,60H),4.04-3.98(m,58H),3.96-3.92(m,36H),3.66-3.60(m,156H),3.51-3 .50 (m, 3828H), 3.25-3.22 (m, 50H), 3.15-2.12 (m, 66H), 3.07-3.02 (m, 50H), 2.81-2.76 (m, 50H), 2.75-2.72 (m, 26H), 2.28-2.20 (m, 76H), 2.19-2.05 (m, 132H), 1.79-1.76 (m, 65H), 1.61-1.56 (m, 68H), 1.54-1.48 (m, 96H), 1.25-1.20 (m, 34H), 0.92-0.83 (m, 96H) Example 13 Synthesis of Compound 75-209

[0718] 13.1 Preparation of 75-129

[0719] 71-274 (0.05 g, 0.0333 mmol) was added to a 250 ml round-bottom flask, followed by the addition of ultra-dry DMF (10 ml). The mixture was ultrasonically dissolved and stirred at -5°C for 10 minutes. DIEA (0.44 ml, 2.666 mmol) was then slowly added dropwise. Stirring continued for 10 minutes before the addition of Y-NHS-10K (1.49 g, 0.1466 mmol). The reaction was allowed to react at room temperature in the dark at low speed. After the reaction was complete, methyl tert-butyl ether (450 ml) was added to allow the solid to settle. The solid was filtered. The filter cake was redissolved in DMF and then further added with methyl tert-butyl ether (450 ml) to allow the solid to settle. This process was repeated three times. The filter cake was dried to yield 1.49 g of the product. 1H-NMR(600MHz,DMSO-d6)δ10.31-10.29(m,1H),8.14-8.08(m,12H),4.56-4.54(m,4H),3.59-3.55(m,13H),3.53-3.50(m,3840H),2.72-2.64(m, 14H),2.49-2.28(m,12H),2.40-2.38(m,2H),2.14-2.11(m,8H),1.81- 1.77(m,8H),1.53-1.49(m,8H),1.39-1.37(m,36H),1.25-1.23(m,8H)

[0720] 13.2 Preparation of 75-182

[0721] 75-129 (0.75 g, 0.0178 mmol), 74-185 (0.01 g, 0.0178 mmol), HBTU (0.01 g, 0.0267 mmol), and HOBT (0.003 g, 0.0267 mmol) were mixed in a flask. DMF (5 ml) was added and dissolved with ultrasound. After placing in a -5°C constant temperature reaction bath for 30 min, DIEA (0.1 ml, 0.08 mmol) was added dropwise. The reaction was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After completion of the reaction, the mixture was precipitated with methyl tert-butyl ether (300 ml) and n-hexane (100 ml), and the supernatant was decanted. This process was repeated three times. Finally, the solid was filtered and dissolved in a methanol / dichloromethane mixed solvent. Silica gel powder was added and evaporated to dryness. The solid was placed in an oven and dry-loaded. Column chromatography was performed using dichloromethane and 2-4% methanol / dichloromethane as eluents. 0.39 g of the product was collected and dried. 1 H-NMR(600MHz,DMSO-d6)δ10.31-10.29(m,1H),9.05-9.04(m,1H),8.56-8.45(m,3H),8.03-7.98(m,1 4H),7.56(m,2H),6.68(m,2H),4.28-4.21(m,5H),4.08-4.06(m,2H),3.88-3.82(m,4H),3.65-3.60(m ,21H),3.53-3.50(m,3840H),3.29-3.07(m,4H),2.76-2.72(m,2H),2.63-2.61(m,16H),2.56-2.52(m ,16H),2.10-2.05(m,4H),1.79-1.76(m,8H),1.60-1.53(m,8H),1.39-1.37(m,36H),1.25-1.22(m,8H)

[0722] 13.3 Preparation of 75-187

[0723] To a 250 ml flask containing raw material 75-182 (0.39 g, 0.00912 mmol) was added TFA (0.2 ml, 0.7299 mmol), and the reaction was stirred for 2 hours and observed by TLC. After completion of the reaction, the mixture was concentrated under reduced pressure, and methyl tert-butyl ether and n-hexane were added to allow precipitation. The supernatant was decanted, and this process was repeated three times. Filtration and drying yielded 0.34 g of the product. 1 H-NMR(600MHz,DMSO-d6)δ10.57-10.29(m,5H),9.05-9.04(m,1H),8.56-8.45(m,3H),8.15-8.03(m ,14H),7.57-7.55(m,2H),6.68-6.64(m,2H),4.55-4.53(m,5H),4.39-4.37(m,2H),3.88-3.82(m,4H ),3.65-3.54(m,21H),3.53-3.50(m,3840H),3.14-3.07(m,4H),2.76-2.72(m,2H),2.63-2.61(m,1 6H),2.56-2.52(m,16H),2.10-2.05(m,4H),1.79-1.76(m,8H),1.64-1.56(m,8H),1.27-1.22(m,8H)

[0724] 13.4 Preparation of 75-192

[0725] 75-187 (0.26 g, 0.0071 mmol), 70-201 (0.03 g, 0.0284 mmol), HBTU (0.016 g, 0.0423 mmol), and HOBT (0.005 g, 0.0423 mmol) were mixed in a 250 ml flask. DMF (5 ml) was added and dissolved with ultrasound. After placing in a -5°C constant temperature reaction bath for 30 min, DIEA (0.2 ml, 0.1269 mmol) was added dropwise. The reaction was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After completion of the reaction, the mixture was precipitated with methyl tert-butyl ether (100 ml) and n-hexane (50 ml). The supernatant was decanted, and methyl tert-butyl ether (100 ml) and n-hexane (50 ml) were added for precipitation. This process was repeated three times. The obtained solid was dissolved in a mixed solvent, and 0.7 g of silica gel powder was added, evaporated to dryness, placed in an oven, dry-loaded, and subjected to column chromatography using 2-6% methanol / dichloromethane as an eluent. The product 0.25 g was collected and dried. 1H-NMR(600MHz,DMSO-d6)δ10.30-10.29(m,1H),9.09-9.08(m,1H),8.83-8.73(m,16H),8.3 5-7.65(m,64H),7.55-7.54(m,2H),7.29-7.11(m,4H),6.55-6.53(m,2H),4.29-4.15(m,21H ),3.83-3.66(m,50H),3.53-3.50(m,3840H),3.10-3.08(m,4H),2.84-2.60(m,26H),2.41-2 .37(m,8H),2.25-2.05(m,5H),1.52-1.47(m,16H),1.40-1.37(m,144H),1.27-1.22(m,24H)

[0726] 13.5 Preparation of 75-199

[0727] To a 250ml flask containing 75-192 (0.25g, 0.00406mmol) was added TFA (0.1ml, 1.301mmol), and the reaction was stirred for 2 hours. The reaction progress was monitored by TLC. After completion, methyl tert-butyl ether (80ml) and n-hexane (30ml) were added to allow the reaction to settle. After decanting the supernatant, methyl tert-butyl ether (100ml) and n-hexane (50ml) were added to allow the reaction to settle. This process was repeated three times. Filtration yielded 0.24g of the product. 1 H-NMR(600MHz,DMSO-d6)δ10.30-10.29(m,1H),9.09-9.08(m,1H),8.56-8.50(m,16H) ,8.31-7.76(m,46H),7.52-7.51(m,2H),7.21-7.14(m,4H),6.50-6.49(m,2H),4.28-4. 20(m,21H),3.87-3.63(m,50H),3.53-3.50(m,3840H),3.12-3.08(m,4H),2.82-2.63( m,26H),2.42-2.36(m,8H),2.21-2.01(m,92H),1.55-1.48(m,16H),1.25-1.22(m,24H)

[0728] 13.6 Preparation of 75-209

[0729] 75-199 (0.24 g, 0.00400 mmol), DOX-HCl (0.0409 g, 0.070 mmol), and methanol (3 ml) were mixed and dissolved with ultrasonication. TFA (0.05 ml) was then added and allowed to react for 48 hours. After the reaction, the methanol and TFA were evaporated by concentration, and methyl tert-butyl ether and n-hexane were added to settle. After the supernatant was poured out, methyl tert-butyl ether (100 ml) and n-hexane (50 ml) were added to settle. This process was repeated three times. The product was dissolved in ethyl acetate (10 ml) and settled in petroleum ether (30 ml). This process was repeated three times. The solid was filtered to obtain 0.22 g of the product. 1 H-NMR(600MHz,DMSO-d6)δ10.30-10.29(m,1H),9.04-9.03(m,1H),8.42-8.27(m,16H),8.11-7.75(m,96H),7.55 -7.54(m,2H),7.19-7.08(m,22H),5.49-5.27(m,64H),4.63-4.40(m,16H),4.30-4.19(m,39H),4.01-3.98(m,16H ),3.85-3.73(m,50H),3.63-3.56(m,65H),3.53-3.50(m,3840H),3.44-3.41(m,64H),3.25-3.23(m,36H),2.74-2 .72(m,8H),2.63-2.60(m,26H),2.25-2.10(m,124H),1.52-1.49(m,23H),1.35-1.32(m,48H),1.20-1.14(m,48H)

[0730] Example 14 Synthesis of Compounds 77-162

[0731] 14.1 Preparation of 82-49

[0732] 3-Amino-1,2-propanediol (5.0 g, 54.879 mmol) was weighed and added to a 500 ml flask. DMSO (20 ml) was added to completely dissolve the mixture. A 5.0 mol / L NaOH solution (2.0 ml) was added at 15°C under nitrogen and stirred for 5 minutes. Tert-butyl acrylate (23.9 ml, 164.637 mmol) was then slowly added dropwise. The mixture was stirred and reacted at room temperature for 24 hours. After the reaction, saturated NaCl solution (200 ml) and ethyl acetate (200 ml) were added for extraction. After standing and separating, the organic phase was collected and the aqueous phase was extracted with ethyl acetate (200 ml x 3). The organic phases were combined and evaporated to dryness to a solid, then dissolved in 1 / 4 methanol / dichloromethane solution, silica gel powder (100 ml) was added and evaporated to dryness to obtain a powdery solid. The solid was dry-loaded and subjected to column chromatography using a 20% ethyl acetate / petroleum ether mixed solution as the eluent. The product was collected, concentrated, and dried in a vacuum oven to obtain 2.22 g of the product with a yield of 8.51%.

[0733] 14.2 Preparation of 77-82

[0734] 82-49 (1 g, 2.1025 mmol), benzyl succinate (0.48 g, 2.3128 mmol), HBTU (0.96 g, 2.523 mmol), and HOBT (0.34 g, 2.523 mmol) were weighed and added to a 500 ml flask. An appropriate amount of DMF was added to dissolve the mixture. The mixture was placed at -5°C and DIEA (0.83 ml, 5.046 mmol) was slowly added dropwise. After half an hour of reaction, the mixture was removed from the flask and stirred at room temperature overnight. After the reaction, saturated NaCl solution (200 ml) and ethyl acetate (200 ml) were added for extraction. After standing and stratification, the organic phase was collected and the aqueous phase was extracted with ethyl acetate (200 ml x 3). The combined organic phases were evaporated to dryness to a solid, and then dissolved in a 1 / 4 methanol / dichloromethane mixed solution. Silica gel powder (100 ml) was added and evaporated to dryness to obtain a powdery solid. The solid was dry-loaded and subjected to column chromatography using ethyl acetate / petroleum ether as eluent. The product was collected, concentrated, and dried in a vacuum oven to obtain 1.1 g. 1 H-NMR(600MHz,DMSO-d6)δ7.44-7.26(m,5H),5.12-5.05(m,2H),3.75-3.66(m,1H),3.63-3.47 (m,5H),3.44-3.33(m,3H),2.68-2.52(m,4H),2.45-2.34(m,5H),1.44-1.34(m,27H);ESI[M+H + ]666.38

[0735] 14.3 Preparation of 77-83

[0736] 77-82 (0.476 g, 0.7157 mmol), TFA (1.59 mL, 21.471 mmol) and dichloromethane (5 mL) were placed in a 250 mL flask to dissolve, and the reaction was stirred at room temperature until completion. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and then normal hexane (20 mL) and methyl tert-butyl ether (50 mL) were added to sedimentation. The supernatant was poured out, and normal hexane and methyl tert-butyl ether were added to sedimentation. This was repeated 3 times. Suction filtration gave a solid product, which was dried in a vacuum oven to give 0.4175 g of the product.

[0737] 14.4 Preparation of 77-135

[0738] 76-58 (3.28 g, 5.53 mmol), 77-83 (0.8346 g, 1.67 mmol), HBTU (2.216 g, 5.845 mmol), and HOBT (0.789 g, 5.845 mmol) were weighed and added to a 500 ml flask. An appropriate amount of DMF was then added to dissolve the mixture. DIEA (1.932 ml, 11.69 mmol) was slowly added dropwise at -5°C. After a half-hour reaction, the mixture was removed from the flask and stirred at room temperature overnight. After the reaction, saturated NaCl solution (200 ml) and ethyl acetate (200 ml) were added for extraction. After standing and stratification, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (200 ml x 3). The organic phases were combined and evaporated to dryness to a solid. The solid was then dissolved in a 1 / 4 methanol / dichloromethane mixture. Silica gel powder (100 ml) was added and evaporated to dryness to obtain a powdery solid. The solid was dry-loaded and subjected to column chromatography using 3-5% CH3OH / CH2Cl2 as the eluent. The solid was collected, concentrated, and dried in a vacuum oven to obtain 2.5 g of the product with a yield of 87.38%. ESI [M+Na + ]2244.59

[0739] 14.5 Preparation of 77-144

[0740] 77-135 (0.8 g, 0.3601 mmol), TFA (0.268 mL, 3.601 mmol) and dichloromethane (5 mL) were placed in a 250 mL flask and dissolved, and the reaction was stirred at room temperature until completion. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and then n-hexane (20 mL) and methyl tert-butyl ether (50 mL) were added to allow the solution to settle. The supernatant was decanted, and then n-hexane and methyl tert-butyl ether were added to allow the solution to settle. This was repeated three times. Finally, suction filtration gave a solid product, which was dried in a vacuum oven to give 0.9605 g of the product.

[0741] 14.6 Preparation of 77-146

[0742] 77-144 (0.678 mmol, 0.3601 mmol), HBTU (1.229 g, 3.24 mmol), and HOBT (0.437 g, 3.24 mmol) were weighed and added to a flask containing 76-93 (3.3 g, 2.376 mmol). An appropriate amount of DMF was then added to dissolve the mixture. DIEA (1.07 ml, 6.481 mmol) was slowly added dropwise at -5°C. After a half-hour reaction, the mixture was removed from the flask and stirred at room temperature overnight. After completion of the reaction, n-hexane (25 ml) and methyl tert-butyl ether (200 ml) were added to allow the mixture to settle. The supernatant was then decanted, and n-hexane and methyl tert-butyl ether were added to allow the mixture to settle. This process was repeated three times. The solid product was filtered, collected, and dried to yield 2.5 g of the product (60% yield). 1 H-NMR(600MHz,DMSO-d6)δ8.22(s,11H),8.03(m,23H),7.81m,19H),7.33(s,21H),7.20(s,3H),6. 76(s,19H),6.41(s,2H),5.02(m,8H),4.14(m,23H),3.48(s,92H),3.44-3.33(m,117H),3.24(s,2 5H),3.17(s,37H),3.05(m,46H),2.99-2.91(m,16H),2.60(m,6H),2.39(s,8H),2.21(s,7H),2.10 (s,48H),1.79(m,44H),1.47(s,19H),1.35(m,216H),1.30-1.20(m,27H),1.05(s,5H),0.97(m,5H)

[0743] 14.7 Preparation of 77-149

[0744] 77-146 (1.5 g, 0.14402 mmol) and 10% Pd / C catalyst (0.01 g) were placed in a hydrogenation reactor, followed by the addition of CH3OH (30 ml) to dissolve the mixture. The hydrogenation reactor was sealed, evacuated with a water pump, and filled with hydrogen at approximately 2 MPa. This process was repeated three times, with the pressure on the hydrogenation reactor adjusted to 1.8 MPa. The reaction was then allowed to react overnight at 30 degrees Celsius. After completion of the reaction, the reaction solution was filtered through a Buchner funnel using diatomaceous earth. The filter cake was washed with methanol (3 mL x 3). The filtrate was placed in a 500 mL round-bottom flask and subjected to vacuum rotary evaporation. The methanol was then removed by azeotropic distillation with toluene to obtain 1.2 g of the product.

[0745] 14.8 Preparation of 77-155

[0746] 77-149 (0.85 g, 0.0853 mmol) was placed in a 250 ml flask and dissolved in DMF (15 ml). The reaction was stirred at -5°C for 10 minutes, followed by the slow addition of DIEA (2.2 ml, 13.216 mmol). Stirring was continued at low temperature for 30 minutes, followed by the addition of M-SCM-10K (3 g, 0.2816 mmol, purchased from Jiankai, Lot Number: ZZ390P163). The reaction was stirred at room temperature in the dark for one week. After the reaction was completed, methyl tert-butyl ether (200 mL) and n-hexane (70 mL) were added to allow precipitation. A solid precipitated and was filtered. The filter cake was washed with methyl tert-butyl ether (40 mL x 3), collected, and dried in a vacuum oven to yield 3.5 g of the product (98% yield).

[0747] 14.9 Preparation of 77-159

[0748] 77-155 (3.5 g, 0.08534 mmol), HBTU (0.161 g, 0.426 mmol) and HOBT (0.057 g, 0.426 mmol) were weighed and added into a flask containing 70-68 (0.292 g, 0.426 mmol). An appropriate amount of DMF was added to dissolve the mixture. DIEA (0.061 ml, 0.8534 mmol) was slowly added dropwise at -5°C. After the addition was complete, the mixture was reacted for half an hour and then taken out and stirred at room temperature for overnight. After the reaction is completed, n-hexane (25 ml) and methyl tert-butyl ether (200 ml) are added for precipitation, the supernatant is poured out, and n-hexane and methyl tert-butyl ether are added for precipitation. This process is repeated three times, and a solid product is obtained by filtration. The solid product is then dissolved in a 1 / 4 methanol / dichloromethane mixed solution, and silica gel powder (100 ml) is added and evaporated to dryness to obtain a powdery solid. The solid is dry-loaded and subjected to column chromatography using 3-5% CH3OH / CH2Cl2 as the eluent. The product is collected, concentrated, and dried in a vacuum oven to obtain 3.8 g of the product.

[0749] 14.10 Preparation of 77-161

[0750] To a flask containing 77-159 (3.8 g, 0.08534 mmol) was added dichloromethane (5 ml), and after dissolution with ultrasonication, TFA (1.5 ml, 14 mmol) was added. The mixture was stirred and reacted at room temperature overnight. After the reaction, most of the TFA in the reaction solution was removed using a rotary evaporator. Then, n-hexane and methyl tert-butyl ether were added to allow the solution to settle. The supernatant was discarded, and n-hexane and methyl tert-butyl ether were added to allow the solution to settle. This process was repeated three times, and finally, the solution was evaporated to dryness until solid, and dried in a vacuum oven to obtain 3.39 g of the product.

[0751] 14.11 Preparation of 77-162

[0752] DIEA (1.345 ml, 8.14 mmol) and DMF (15 ml) were added to 76-164 (2.09 g, 1.99 mmol) and dissolved. A DMF solution of 77-161 (3 g, 0.07538 mmol) was then added dropwise and stirred overnight. After completion, n-hexane (25 ml) and methyl tert-butyl ether (200 ml) were added to the solution to allow precipitation. The supernatant was decanted, and n-hexane and methyl tert-butyl ether were added to allow precipitation. This process was repeated three times. The solid product was filtered and dissolved in a 1 / 4 methanol / dichloromethane mixture. Silica gel powder (100 ml) was added and evaporated to dryness, resulting in a powdery solid. The solid was dry-loaded and subjected to column chromatography using 3-8% CH3OH / CH2Cl2 and then 0.5% ammonia / 8% CH3OH / CH2Cl2 as eluents. The product was collected, concentrated, and dried in a vacuum oven to yield 0.9 g of the product in a 19% yield. 1 H-NMR(600MHz,DMSO-d6)δ9.30-9.18(m,24H),8.29-8.19(m,12H),8.12-8.04(m,22H),8. 01-7.92(m,80H),7.90-7.80(m,71H),7.78-7.69(m,31H),7.68-7.61(m,48H),7.58-7.52( m,28H),7.51-7.38(m,142H),7.27-7.21(m,8H),7.20-7.14(m,24H),6.32-6.25(m,24H),5 .85-5.78(m,24H),5.56-5.49(m,24H),5.45-5.37(m,24H),5.36-5.30(m,24H),4.96-4.86 (m,48H),4.67-4.61(m,24H),4.23-4.16(m,24H),4.15-4.05(m,148H),4.05-3.95(m,54H ),3.58-3.43(m,2394H),3.24-3.23(m,12H),3.19-3.15(m,307H),2.63-2.56(m,60H),2.4 0-2.35(m,48H),2.26-2.19(m,74H),2.13-2.04(m,105H),1.81-1.73(m,104H),1.66-1.60 (m,30H),1.51-1.48(m,66H),1.36-1.32(m,20H),1.24-1.21(m,18H),1.05-0.96(m,135H)

[0753] Example 15 Synthesis of Compound 81-231

[0754] 15.1 Preparation of 74-171

[0755] 74-150 (3.9 g, 10.413 mmol), Boc-Lys(Fmoc)-OH (4.878 g, 10.413 mmol), HBTU (4.738 g, 12.495 mmol), and HOBT (1.688 g, 12.495 mmol) were placed in a 250 ml round-bottom flask. DMF (30 ml) was added and dissolved with ultrasonication. The mixture was stirred at 0°C for 3 minutes. DIEA (5.163 ml, 31.239 mmol) was then slowly added dropwise. After 5 minutes, the mixture was removed and stirred at room temperature. After the reaction, petroleum ether and methyl tert-butyl ether were added to allow the mixture to settle. After standing, the supernatant was decanted and this process was repeated several times until the product became a viscous oil. The product was then dissolved in an appropriate amount of a 2 / 8 methanol / dichloromethane mixture, 200-300 mesh silica gel powder was added and evaporated to dryness. Dry loading was performed on a column chromatography using 2-4% methanol / dichloromethane as the eluent, and the product was collected, concentrated, and evaporated to dryness to obtain 7.7 g.

[0756] 15.2 Preparation of 81-207

[0757] 74-171 (1.5 g, 1.818 mmol) was placed in a 500 ml round-bottom flask. 4 M HCl-dioxane (10 ml) was added and dissolved with ultrasonication. The mixture was stirred at room temperature. After completion of the reaction, the mixture was concentrated and evaporated to dryness. Methyl tert-butyl ether (50 ml) was then added and ultrasonicated, followed by rotary evaporation. This process was repeated several times until the product became a viscous oil. Drying yielded 1.31 g of the product.

[0758] 15.3 Preparation of 81-209

[0759] 81-207 (1.317 g, 1.818 mmol), mono-tert-butyl succinate (0.316 g, 1.818 mmol), HBTU (0.827 g, 2.18 mmol), and HOBT (0.294 g, 2.18 mmol) were placed in a 250 ml round-bottom flask. DMF (10 ml) was added and sonicated for dissolution. The mixture was stirred at 0°C for 1 minute. DIEA (1.05 ml, 6.363 mmol) was then slowly added dropwise, and the reaction was stirred at room temperature. After the reaction was complete, n-hexane and methyl tert-butyl ether were added, sonicated, allowed to stand, and the supernatant discarded. This process was repeated several times until the product became a viscous oil. An appropriate amount of dichloromethane was then added, sonicated for dissolution, and washed twice with saturated sodium bicarbonate. The organic phase was collected, dehydrated with anhydrous magnesium sulfate, and evaporated to dryness after addition of 200-300 mesh silica gel powder. The sample was loaded by dry method and column chromatography was performed using 6% methanol / dichloromethane as eluent to collect the target product, which was concentrated and dried to obtain 0.6 g of the product.

[0760] 15.4 Preparation of 81-213

[0761] Raw material 81-209 (0.6 g, 0.68 mmol) was placed in a 500 ml round-bottom flask, and acetonitrile (10 ml) was added followed by diethylamine (25 ml) and stirred at room temperature. After the reaction, the diethylamine and acetonitrile were removed by rotary evaporation under reduced pressure. An appropriate amount of dichloromethane was added to dissolve the mixture. 200-300 mesh silica gel powder was added and evaporated to dryness. The mixture was dry-applied and subjected to column chromatography using 1% aqueous ammonia / 15% methanol / dichloromethane as the eluent. The organic phase containing the product was collected, concentrated, and evaporated to dryness to yield 0.3 g of the product.

[0762] 15.5 Preparation of 81-210

[0763] 81-205 (9.6 g, 0.72 mmol) was placed in a 500 ml round-bottom flask, followed by the addition of ultra-dry DMF (15 ml). Ultrasonication was used to dissolve the mixture, and the mixture was stirred at 0°C for 3 minutes. DIEA (0.185 ml, 1.12 mmol) was then slowly added dropwise, followed by Y-NHS-10K (16.47 g, 1.58 mmol, purchased from J&K, batch number: ZZ403P059). The mixture was stirred at room temperature in the dark under nitrogen protection. After completion of the reaction, methyl tert-butyl ether (200 ml) was added to allow precipitation of the solid. The solid was then ultrasonically treated, allowed to stand, and the supernatant discarded. This process was repeated five times. The solid was obtained by rotary evaporation under reduced pressure, and then an appropriate amount of 1 / 4 methanol / dichloromethane mixed solvent (100 ml) was added to dissolve it. 100-200 mesh silica gel powder was added and evaporated to dryness. The sample was dry loaded and column chromatography was performed using 10% methanol / dichloromethane as eluent. The organic phase solution containing the product was collected, concentrated, and evaporated to dryness to obtain 2.57 g of the product. 1 H-NMR(600MHz,DMSO-d6)δ10.18-10.00(m,5H),9.97-9.73(m,16H),8.96- 8.84(m,5H),8.82-8.66(m,16H),8.64-8.46(m,15H),8.37-7.61(m,169H), 7.55-7.41(m,19H),7.39-6.94(m,173H),6.77-6.62(m,12H),6.62-6.48( m,6H),5.88-5.74(m,4H),5.35-5.13(m,32H),4.89-4.65(m,30H),4.65-4. 44(m,23H),4.44-3.93(m,54H),3.91-3.24(m,2003H),3.20-3.08(m,20H) ,3.08-2.86(m,114H),2.86-2.66(m,26H),2.65-2.58(m,28H),2.43-2.25( m,25H),2.25-1.98(m,31H),1.92-1.78(m,17H),1.78-1.65(m,21H),1.65- 1.53(m,34H),1.53-1.38(m,53H),1.38-1.06(m,66H),0.94-0.66(m,120H)

[0764] 15.6 Preparation of 81-218

[0765] 81-210 (2.57 g, 0.06 mmol), 81-213 (0.23 g, 0.36 mmol), HBTU (0.136 g, 0.36 mmol), and HOBT (0.0486 g, 0.36 mmol) were placed in a 50 ml round-bottom flask. DMF (20 ml) was added and sonicated to dissolve the mixture. The mixture was stirred at 0°C for 1 minute. DIEA (0.56 ml, 3.4 mmol) was then slowly added dropwise. After 10 minutes, the mixture was removed and stirred at room temperature. After the reaction, methyl tert-butyl ether (200 ml) was added to allow precipitation of solids. After sonication, the mixture was allowed to stand and the supernatant was decanted. This process was repeated five times. The solid crude product was dried by rotary evaporation under reduced pressure, and then dissolved in an appropriate amount of 1 / 4 methanol / dichloromethane mixed solvent (100 ml). 100-200 mesh silica gel powder was added and evaporated to dryness. The product was loaded by dry method and subjected to column chromatography using 1% ammonia water / 10% methanol / dichloromethane as eluent. The product was collected, concentrated, and evaporated to dryness to obtain 1.4 g. 1 H-NMR(600MHz,DMSO-d6)δ10.18-10.00(m,5H),9.97-9.73(m,16H),8.96-8.84(m,5H),8.82-8.66(m,16H),8.64-8.46(m,15H),8.37-7.61(m,1 72H),7.55-7.41(m,19H),7.39-6.94(m,173H),7.16-7.08(m,1H),6.77 -6.62(m,12H),6.62-6.48(m,7H),6.44-6.40(m,1H),6.29(s,1H),6.18( s,1H),5.88-5.74(m,4H),5.35-5.13(m,32H),4.89-4.65(m,30H),4.65 -4.44(m,23H),4.44-3.93(m,60H),3.91-3.26(m,2001H),3.20-3.08(m ,28H),3.08-2.86(m,114H),2.86-2.66(m,29H),2.65-2.58(m,29H),2. 43-2.25(m,29H),2.25-1.98(m,33H),1.92-1.78(m,17H),1.78-1.65(m, 21H),1.65-1.53(m,39H),1.53-1.38(m,58H),1.38-1.06(m,80H),0.94-0.66(m,120H)

[0766] 15.7 Preparation of 81-225

[0767] 81-218 (1.4 g, 0.0328 mmol) was placed in a 500 ml round-bottom flask and dissolved in dichloromethane (10 ml). TFA (20 ml) was then added and the reaction was stirred at room temperature. After the reaction was completed, the dichloromethane and most of the TFA were removed by rotary evaporation under reduced pressure. Methyl tert-butyl ether (300 ml) was added to allow the solution to settle. A solid precipitated. The solution was ultrasonically treated, allowed to stand, and the supernatant was decanted. This process was repeated once and evaporated to dryness under reduced pressure to obtain a crude solid product. An appropriate amount of DMF was added and dissolved with ultrasonication. A small amount of DIEA was added dropwise to adjust the pH to a weak alkaline state. Methyl tert-butyl ether (200 ml) was added to allow the solution to settle. A solid precipitated. The solution was ultrasonically treated, allowed to stand, and the supernatant was decanted. This process was repeated three times. The solution was evaporated to dryness under reduced pressure and then dried to obtain 1.3 g of the product. 1 H-NMR(600MHz,DMSO-d6)δ12.01(s,1H),10.18-9.73(m,21H),8.96-8.84 (m,5H),8.82-8.66(m,16H),8.64-8.46(m,15H),8.37-7.61(m,172H),7.5 5-7.41(m,19H),7.39-6.94(m,173H),7.16-7.08(m,1H),6.77-6.62(m,12 H),6.62-6.48(m,7H),6.44-6.40(m,1H),6.29(s,1H),6.18(s,1H),5.88- 5.74(m,4H),5.35-5.13(m,32H),4.89-4.65(m,30H),4.65-4.44(m,23H), 4.44-3.93(m,60H),3.91-3.26(m,2001H),3.20-2.86(m,142H),2.86-2.6 6(m,29H),2.65-2.58(m,29H),2.43-2.25(m,29H),2.25-1.98(m,33H),1. 92-1.78(m,17H),1.78-1.53(m,60H),1.53-1.06(m,129H),0.94-0.66(m, 120H)

[0768] 15.8 Preparation of 81-231

[0769] 81-225 (1.3 g, 0.0305 mmol), 65-121 (0.094 g, 0.0976 mmol), HBTU (0.037 g, 0.0976 mmol), and HOBT (0.013 g, 0.0976 mmol) were placed in a 100 ml round-bottom flask. DMF (10 ml) was then added and sonicated. The mixture was stirred at 0°C for 2 minutes. DIEA (0.1 ml, 0.605 mmol) was then slowly added dropwise. After 2 minutes, the mixture was removed and stirred at room temperature. After the reaction, methyl tert-butyl ether (450 ml) was added to allow precipitation. The mixture was allowed to stand at 2-8°C for 15 hours before decanting. The solid was then dissolved in a 1 / 4 anhydrous ethanol / dichloromethane mixture (50 ml). MTBE (600 ml) was added to precipitate the solid and filter. This process was repeated three times. The filter cake was dried to yield 1.2 g of the product. 1 H-NMR(600MHz,DMSO-d6)δ10.18-10.00(m,5H),9.97-9.73(m,16H),8.96-8.84(m,6H),8.82-8.66(m,16H),8.64-8.46(m,15H),8.3 7-7.61(m,180H),7.55-7.41(m,22H),7.39-6.94(m,179H),6.77-6.62(m,12H),6.62-6.40(m,8H),6.29(s,1H),6.18(s,1H),5.89- 5.74 (m, 5H), 5.47-5.13 (m, 34H), 4.92-4.65 (m, 33H), 4.66-3.94 (m, 110H), 3.91-3.26 (m, 2018H), 3.20-3.08 (m, 28H), 3.08-2.86 (m, 106H), 2.86-2.58 (m, 58H), 2.43-2.25 (m, 30H), 2.25-1.65 (m, 83H), 1.65--1.38 (m, 92H), 1.38-1.02 (m, 77H), 0.94-0.66 (m, 120H) Example 16 Synthesis of Compounds 84-102

[0770] 16.1 Preparation of 84-87

[0771] Irinotecan (5 g, 8.52 mmol), succinic anhydride (1.7 g, 17.04 mmol) and pyridine (15 ml) were placed in a 250 ml flask and dissolved. DMAP (1.04 g, 8.52 mmol) was then added and stirred in an oil bath at 45°C for 24 h. After the reaction was complete, an appropriate amount of toluene was added and evaporated under reduced pressure. An appropriate amount of dichloromethane was then added. The organic phase was washed with 0.1 N hydrochloric acid and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, concentrated, added with silica gel powder, evaporated to dryness, dry-loaded, and subjected to column chromatography using 4% methanol / dichloromethane as the eluent. 2.5 g of the product was obtained after drying.

[0772] 16.2 Preparation of 84-97

[0773] 84-87 (2.5 g, 3.644 mmol), TSTU (1.2 g, 4.0084 mmol), and DMF (10 ml) were dissolved in a 50 ml flask. Triethylamine (1.2 ml, 9.15 mmol) was then added and the mixture was stirred at room temperature. After completion of the reaction, n-hexane (30 ml) and methyl tert-butyl ether (200 ml) were added to allow precipitation. The supernatant was decanted, and n-hexane and methyl tert-butyl ether were added to allow precipitation. This process was repeated four times. The resulting product was dissolved in a mixed solvent of dichloromethane and methanol, dry-loaded, and subjected to column chromatography using 3% methanol / dichloromethane as the eluent. The product was collected, concentrated, and dried in a vacuum oven to yield 2 g.

[0774] 16.3 Preparation of 84-43

[0775] Add 74-100 (1.5 g, 2.5096 mmol) to a hydrogenation reactor, along with 10% Pd / C catalyst (0.08 g) and DMF (15 ml). Hydrogen was introduced at a pressure of 300 psi and the reaction was stirred overnight at room temperature. After completion of the reaction, the reaction mixture was filtered through a Buchner funnel with filter paper. The filter cake was washed with DMF (15 ml x 3). The filtrate was then transferred to a 250 ml round-bottom flask and used as the starting material for the next step.

[0776] 16.4 Preparation of 84-45

[0777] 84-43 (0.45 g, 1.0938 mmol), 70-68 (1.75 g, 2.5159 mmol), HBTU (1.08 g, 2.8439 mmol), HOBT (0.4 g, 2.8439 mmol) and DMF (2 ml) were stirred and dissolved in a 250 ml flask. The reaction flask was then placed at -5 °C and stirred for about 20 minutes. DIEA (1.5 ml, 8.7504 mmol) was then slowly added dropwise. After the addition was complete, the reaction was stirred at -5 °C for 1 hour and then the reaction flask was transferred to room temperature and stirred. After the reaction is completed, n-hexane (30 ml) and methyl tert-butyl ether (200 ml) are added for precipitation, the supernatant is poured out, and n-hexane and methyl tert-butyl ether are added for precipitation. This is repeated 4 times, and a solid product is obtained by filtration. The obtained solid product is dissolved in a mixed solvent of dichloromethane and methanol, dry-loaded, and column chromatography is performed with 3% methanol / dichloromethane as an eluent. The product is collected, concentrated, and dried in a vacuum oven to obtain 0.86 g.

[0778] 16.5 Preparation of 84-76

[0779] Dissolve 84-45 (0.86 g, 0.4856 mmol), TFA (0.72 ml, 9.7116 mmol), and dichloromethane (0.5 ml) in a 50 ml flask and stir at room temperature until the reaction is complete. After completion, n-hexane (30 ml) and methyl tert-butyl ether (20 ml) are added to allow the reaction to settle. The supernatant is then decanted, and n-hexane and methyl tert-butyl ether are then added to allow the reaction to settle. This process is repeated four times. The solid product is filtered and dried in a vacuum oven to yield 0.8 g.

[0780] 16.6 Preparation of 84-29

[0781] 3-Isoamino-1,2-propanediol (8 g, 76.089 mmol), benzyl bromide (15.6 g, 91.3068 mmol), K2CO3 (31.54 g, 228.267 mmol), and acetonitrile (35 ml) were stirred in a 500 ml flask at 30°C in a water bath. After the reaction, the white solid was filtered off. Dichloromethane was added to the filtrate, followed by silica gel powder, which was evaporated to dryness. The sample was dry-applied and subjected to column chromatography using 0.5% aqueous ammonia / 1% methanol / dichloromethane as the eluent. The product was collected, concentrated, and dried to obtain 9.2 g. 1H-NMR (600MHz, DMSO-d6) δ7.34-7.19(m,5H),4.55(s,1H),3.69(q,J=5.7Hz,1H),3.60(d,J=14.2Hz,1H),3.55-3.45(m,2H),3.43 FT MS ESI m / z[M+H + ]196.13

[0782] 16.7 Preparation of 84-30

[0783] In a 250ml flask, 84-29 (5g, 25.6082mmol) was dissolved in DMSO (18ml). Stirred in a water bath at 30°C for 10 minutes, 5.0M NaOH solution (1ml) was added, and stirring continued for 10 minutes. Tert-butyl acrylate (7.88g, 61.4597mmol) was added and the reaction continued until complete. The reaction mixture was transferred to a 1L separatory funnel and extracted with saturated brine (200ml) and ethyl acetate (200ml) to obtain an organic phase. The aqueous phase was then extracted with ethyl acetate (200ml x 3). The combined organic phases were washed with saturated brine (200ml x 2) and evaporated to dryness. The resulting product was dissolved in a mixture of dichloromethane and methanol, dry-applied, and subjected to column chromatography using 10% ethyl acetate / petroleum ether as the eluent. The product fractions were collected, concentrated, and dried in a vacuum oven to yield 4.4g of the product. 1 H-NMR(600MHz,DMSO-d6)δ7.33-7.19(m,5H),3.74-3.66(m,2H),3.59-3.55(m,2H),3.54-3.51( m,1H),3.49-3.45(m,3H),3.38-3.34(m,1H),2.45-2.33(m,6H),2.13(s,3H),1.40-1.37(m,18H)

[0784] 16.8 Preparation of 84-31

[0785] 84-30 (4.4 g, 9.7434 mmol) was added to a hydrogenation reactor, along with 10% Pd / C catalyst (0.3 g) and methanol (30 ml). Hydrogen was introduced at a pressure of 300 psi and the reaction was stirred at room temperature overnight. After the reaction, the reaction solution was filtered through a Buchner funnel with filter paper and rinsed with methanol (15 ml x 3). The filtrate was collected, vacuum evaporated, and dried to yield 3 g, which was used as the starting material for the next step. 1 H-NMR (600MHz, DMSO-d6) δ3.71(dt,J=9.6,5.9Hz,1H),3.62(dt,J=9.6,6.3Hz,1H),3.59-3.54(m,2H),3.46-3.42(m,1H),3.41-3 .36(m,1H),3.23(s,1H),2.53-2.47(m,2H),2.45(dd,J=12.2,6.6Hz,1H),2.42-2.36(m,4H),2.26(s,3H),1.40-1.33(m,18H); FT MS ESI m / z[M+H + ]362.25

[0786] 16.9 Preparation of 84-35

[0787] In a 250ml flask, dissolve benzyl succinate (1.84g, 8.8251mmol) in DMF (10ml) with stirring. Place the flask at -5°C and slowly add DIEA (5.3ml, 32.0912mmol) dropwise. Stir for 5 minutes, then add HATU (3.66g, 9.6274mmol). Continue stirring for 10 minutes, then add 84-31 (2.9g, 8.0228mmol). Place the flask at -5°C and stir for 1 hour. Remove the flask and stir at room temperature. After completion of the reaction, transfer the reaction mixture to a 1L separatory funnel and extract with saturated brine (200ml) and ethyl acetate (200ml) to obtain the organic phase. The aqueous phase is then extracted with ethyl acetate (200ml x 3). The organic phases were combined, washed with saturated brine (200 ml x 2), and evaporated to dryness. The obtained product was dissolved in a mixed solvent of dichloromethane and methanol, dry-loaded, and subjected to column chromatography using 20% ​​ethyl acetate / petroleum ether as eluent. The product was collected, concentrated, and dried in a vacuum oven to obtain 3.06 g. 1H-NMR(600MHz,DMSO-d6)δ7.38-7.34(m,5H),5.08-5.06(m,2H),3.74-3.67(m,1H),3.61-3.49(m,4H),3.44-3.34(m ,2H),3.33-3.14(m,2H),2.90(s,3H)2.66-2.51(m,4H),2.45-2.39(m,2H),2.37-2.31(m,2H),1.46-1.33(m,18H); FT MS ESI m / z[M+H + ]552.31,[M+Na + ]574.29

[0788] 16.10 Preparation of 84-36

[0789] A 250ml flask was charged with 84-35 (3.06g, 5.5468mmol) and dichloromethane (10ml). TFA (16.5ml, 221.872mmol) was added and stirred to dissolve. The reaction flask was then left to react at room temperature for 2 hours. After the reaction, the liquid was evaporated to dryness using a vacuum rotary evaporator, dissolved in dichloromethane (10ml), and evaporated again using a vacuum rotary evaporator. This step was repeated several times, followed by dissolution in dichloromethane, neutralization with DIEA, vacuum rotary evaporation, and finally oven drying. 2.4g of product was obtained.

[0790] 16.11 Preparation of 84-38

[0791] 84-36 (2.4 g, 3.0675 mmol), 76-58 (4 g, 6.7485 mmol), HBTU (3.5 g, 9.2025 mmol), HOBT (1.2 g, 9.2025 mmol) and DMF (25 ml) were dissolved in a 250 ml flask, and then stirred at -5 ° C f...

Claims

1. A compound represented by general formula I or a pharmaceutically acceptable salt thereof, in, M is a hydrocarbon group containing two or more (e.g., 2, 3, 4, 5 or 6) identical or different heteroatoms (e.g., N, O or S), and M is bonded to L via the heteroatoms. 1 and L 1 'connect; Each L 1 Independently selected from Terminal 1 is connected to M, terminal 2 is connected to L 2 connected; Each L 1 'Independently selected from Terminal 1 is connected to M, terminal 2 is connected to L 3 connected; and, L 1 and L 1 'different; x 1 and x 2 is independently selected at each occurrence from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each L 2 residues independently selected from Lys, Cys, Thr, Ser, Asp or Glu; Each PEG is independently selected from Its number average molecular weight is 5k-10k or 10k-40k, for example, 5k or 10k; Each L 3 Independently for keys or 1 end with L 2 or L 1 'Connect, both ends are same as L 4 connection, where each L 31 and L 32 are independently selected from a bond and -NH(CH 2 ) x3 C(O)-,x 3 Selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, A 1 is selected from a bond, an amino acid residue or a derivative thereof, or a polypeptide fragment consisting of two or more amino acids or a derivative thereof, and r1 is selected from 1, 2, 3, 4, 5 and 6; Each L 4 Independently for keys or 1 end with L 3 Connection, both ends are the same as L 5 connection, where each L 41 and L 42 are independently selected from a bond, -NH(CH 2 ) x4 C(O)-、-NH(CH 2 ) x4 NH-、-NH((CH 2 ) 2 O) x4 CH 2 CH 2 NH- and -C(O)(CH 2 ) x4 C(O)-,A 2 and A 3 are independently selected from a bond, an amino acid residue or a derivative thereof, or a polypeptide fragment consisting of two or more amino acids or a derivative thereof, and r2 and r3 are each independently selected from 1, 2, 3, 4, 5 and 6; Each L 5 are independently a bond or selected from -NH-, hydrazino (i.e., -NH-N=), an amino acid residue or a derivative thereof, a polypeptide fragment consisting of two or more amino acids or a derivative thereof, -NH(CH 2 ) x5 C(O)-、-NH(CH 2 ) x5 NH-、-NH((CH 2 ) 2 O) x5 CH 2 CH 2 NH-、-NH((CH 2 ) 2 O) x5 CO-、-C(O)(CH 2 ) x5 C(O)-, and any combination of the above; or, L 4 and L 5 Connection Formation x 4 and x 5 is independently selected at each occurrence from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Each D is independently selected from the group of cytotoxic drugs, preferably, the cytotoxic drug is selected from microtubule inhibitors, DNA intercalators, DNA topoisomerase inhibitors and RNA polymerase inhibitors; preferably, the cytotoxic drug is selected from PTX (paclitaxel), PCB (pabloxilibu), SN38 (7-ethyl-10-hydroxy-camptothecin), NPB (Niraparib, MK-4827), AXT (Axitinib), LPT (lapatinib), DOX (doxorubicin), Ac-C-PLGLAG-iRGD, folic acid, SB7 (SB-743921), IRN (Irinotecan), sodium dodecahydro-12-thiophene borate, PPT-iRGD, 1,2,3,4,5,6,7,8,9,10,11-11-hydro-12-thiophene borate 10 AlkaneBSH(Sodium Mercaptododecaborate( 10 B))、 Each n 11 and n 12 Independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; Each n 21 and n 22 Independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; Each n 31 and n 32 Independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; Each y 1 and 2 Independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, in, M is a C containing 2 to 4 identical or different heteroatoms. 2-10 Hydrocarbon; Preferably, M is a C containing 2-4 heteroatoms independently selected from N and O. 2-6 Saturated hydrocarbon group; Preferably, M is selected from the following structures: Preferably, M is connected through N atoms and L 1 ' connection, or M through O atoms and L 1 ' connection, further preferably, M through the N atom and L 1 'connect; Preferably, n 11 = 1, 2 or 3, and n 11 ≤n 12 , further preferably, n 11 =1,n 12 =2, 3 or 4; n 11 =2,n 12 =3; or n 11 =3,n 12 =3.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, in, Each L 1 and L 1 'Independently selected from Preferably, L 1 for L 1 'for Preferably, L 1 for L 1 'for 4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, in, Each L 2 is independently a Lys residue.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, in, When L 3 for When each L 31 and L 32 are independently selected from a bond and -NH(CH 2 ) x3 C(O)-,x 3 Selected from 0, 1, 2, 3, 4, 5 and 6, A 1 is selected from a bond, an amino acid residue or a derivative thereof, or a polypeptide fragment consisting of two or more amino acids or a derivative thereof, preferably, A 1 is selected from the group consisting of Glu, Asp and GluGlu, r1 is selected from the group consisting of 1, 2, 3, 4, 5 and 6; Preferably, each L 3 are independently a bond or selected from the following structures: -NH(CH 2 ) 2 C(O)-、 6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, in, When L 4 for When each L 41 and L 42 are independently selected from a bond, -NH(CH 2 ) x4 C(O)-、-NH(CH 2 ) x4 NH- and -NH((CH 2 ) 2 O) x4 CH 2 CH 2 NH- and -C(O)(CH 2 ) x4 C(O)-, each x 4 is independently selected from 0, 1, 2, 3, 4, 5 and 6, A 2 and A 3 are independently selected from a bond, an amino acid residue or a derivative thereof, or a polypeptide fragment consisting of two or more amino acids or a derivative thereof, preferably, each A 2 and A 3 Independently selected from Lys, Glu, Asp, GluGlu and Glu(Glu) 2 , r1 is selected from 1, 2, 3, 4, 5 and 6; Preferably, each L 4 are independently a bond or selected from the following structures: LysNH(CH 2 ) 5 COGlu(Glu) 2 、Lys(COC 2 H 4 CO)(NH(CH 2 CH 2 O) 2 CH 2 CH 2 NH)、-NH(CH 2 ) 5 COGlu、-NH(CH 2 ) 5 COGlu(Glu) 2 、-NH(CH 2 ) 5 COGlu(Glu(NHCH 2 CH 2 NH) 2 ) 2 、-NH(CH 2 ) 5 COAsp和、-NH(CH 2 ) 5 COGlu(Glu(NH(CH 2 CH 2 O) 2 CH 2 CH 2 NH) 2 ) 2 。 7. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, in, L 5 wherein the amino acids are selected from Glu, Gly, Phe, Leu and Cys; preferably, the polypeptide consisting of two or more amino acids is selected from GlyPheLeuGly, Glu(Glu(Gly) 2 ) 2 ; Preferably, the derivative is selected from acylated (eg acetylated) or alkylated (eg methylated) derivatives; Preferably, L 5 Select from key, -NH-N=、GlyPheLeuGly、-NH(CH 2 ) x5 C(O)-、 -NH((CH 2 ) 2 O) x5 CH 2 CH 2 NH-、-NH((CH 2 ) 2 O) x5 CH 2 CH 2 NHGlu、-NH(CH 2 ) x5 C(O)Glu(Glu(GlyNHN=) 2 ) 2 、-NH((CH 2 ) 2 O) x5 CO-、-C(O)(CH 2 ) x5 C(O)-、-C(O)(CH 2 ) x5 C(O)-GlyPheLeuGly-O Each x 5 Independently selected from 1, 2, 3, 4, 5 and 6; Preferably, L 5 Select from key, GlyPheLeuGly, -NH(CH 2 ) 5 C(O)Glu(Glu(GlyNHN=) 2 ) 2 、-NH(CH 2 ) 5 C(O)-、-NH((CH 2 ) 2 O) 2 CH 2 CH 2 NH-、-NH((CH 2 ) 2 O) 2 CH 2 CH 2 NHGlu、-NH((CH 2 ) 2 O) 2 CO-、-C(O)(CH 2 ) 2 C(O)-、-C(O)(CH 2 ) 2 C(O)-GlyPheLeuGly- and 8. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, in, The compound is selected from:

9. A compound represented by general formula II or a pharmaceutically acceptable salt thereof, in, Pg 1 and Pg 1 ' is independently hydrogen or an amino protecting group, and Pg 1 and Pg 1 'Different; preferably, the amino protecting group is selected from an alkyl protecting group (eg, Bn, Trt, DMB or PMB) and an alkoxycarbonyl protecting group (eg, Boc, Fmoc, Cbz or Teoc; preferably, Pg 1 For hydrogen, Pg 1 ' is an amino protecting group; or, Pg 1 is an amino protecting group, Pg 1 ' is hydrogen; The remaining groups are as defined in any one of claims 1-8.

10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

11. A compound of formula III or a pharmaceutically acceptable salt thereof, in, Each Pg 3 are independently hydrogen or selected from amino and carboxyl protecting groups, wherein the amino protecting group is selected from alkoxycarbonyl protecting groups, such as Boc, Fmoc, Cbz or Teoc; the carboxyl protecting group is selected from ester protecting groups, such as methyl ester, ethyl ester, tert-butyl ester, allyl ester or benzyl ester; preferably, each Pg 3 is independently hydrogen or a carboxyl protecting group, such as an ester protecting group, such as methyl ester, ethyl ester, tert-butyl ester, allyl ester or benzyl ester, preferably tert-butyl ester or benzyl ester; preferably, each Pg 3 The same, preferably tert-butyl ester or benzyl ester; Pg 4 is hydrogen or L 2 Preferably, the protecting group is selected from an amino protecting group and a carboxyl protecting group. Preferably, the amino protecting group is selected from an alkoxycarbonyl protecting group, such as Boc, Fmoc, Cbz or Teoc. Preferably, the carboxyl protecting group is selected from an ester protecting group, such as methyl ester, ethyl ester, tert-butyl ester, allyl ester or benzyl ester. Preferably, Pg 4 is an amino protecting group, preferably, Pg 4 is Boc or Cbz; Pg 5 is hydrogen or an amino protecting group selected from alkoxycarbonyl protecting groups, such as Boc, Fmoc, Cbz or Teoc; preferably, Pg 5 is hydrogen or Fmoc; The remaining groups are as defined in any one of claims 1 to 8.

12. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

13. A compound of formula IV or a pharmaceutically acceptable salt thereof, in, Each Pg 6 and Pg 7 are independently hydrogen or selected from amino protecting groups, preferably, the amino protecting groups are selected from alkyl protecting groups (such as Bn, Trt, DMB or PMB) and alkoxycarbonyl protecting groups (such as Boc, Fmoc, Cbz or Teoc); The remaining groups are as defined in any one of claims 1 to 8.

14. A compound of formula V or a pharmaceutically acceptable salt thereof, in, Each group is as defined in any one of claims 1 to 13.

15. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

16. A compound represented by the general formula VI or a pharmaceutically acceptable salt thereof, in, Each group is as defined in any one of claims 1 to 15.

17. A compound represented by the general formula VII or a pharmaceutically acceptable salt thereof, in, Each group is as defined in any one of claims 1 to 16.

18. The compound according to claim 17 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

19. A compound represented by the general formula VIII or a pharmaceutically acceptable salt thereof, in, Each Pg 2 and Pg 2 ' is independently hydrogen or a carboxyl protecting group, preferably, the carboxyl protecting group is selected from an ester protecting group, such as methyl ester, ethyl ester, tert-butyl ester, allyl ester or benzyl ester; Preferably, Pg 2 For hydrogen, Pg 2 ' is a carboxyl protecting group; Pg 2 is a carboxyl protecting group, Pg 2 ' is hydrogen; or, Pg 2 and Pg 2 ' are carboxyl protecting groups (e.g., tert-butyl ester or benzyl ester), and Pg 2 and Pg 2 'different; The remaining groups are as defined in any one of claims 1 to 18.

20. The compound of claim 19 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

21. A compound represented by the general formula IX or a pharmaceutically acceptable salt thereof, in, Each group is as defined in any one of claims 1-20.

22. The compound of claim 21 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

23. A compound represented by the general formula X or a pharmaceutically acceptable salt thereof, in, Each group is as defined in any one of claims 1 to 22.

24. The compound according to claim 23 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

25. A compound represented by the general formula XI or a pharmaceutically acceptable salt thereof, wherein each group is as defined in any one of claims 1 to 24.

26. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

27. A compound represented by the general formula XII or a pharmaceutically acceptable salt thereof, in, Each group is as defined in any one of claims 1-26.

28. The compound according to claim 27 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

29. A compound represented by the general formula XIII or a pharmaceutically acceptable salt thereof, Wherein each group is as defined in any one of claims 1 to 28.

30. The compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

31. A compound represented by general formula XIV or a pharmaceutically acceptable salt thereof, in, Each group is as defined in any one of claims 1-30.

32. The compound of claim 31 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

33. A compound represented by the general formula XV or a pharmaceutically acceptable salt thereof, in, Pg 7 ' is hydrogen or selected from amino and carboxyl protecting groups; preferably, the amino protecting group is selected from alkyl protecting groups (such as Bn, Trt, DMB or PMB) and an alkoxycarbonyl protecting group (e.g., Boc, Fmoc, Cbz or Teoc), wherein the carboxyl protecting group is selected from an ester protecting group (e.g., methyl ester, ethyl ester, tert-butyl ester, allyl ester or benzyl ester); The remaining groups are as defined in any one of claims 1-32.

34. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

35. A compound represented by the general formula XVI or a pharmaceutically acceptable salt thereof, Wherein each group is as defined in any one of claims 1 to 34.

36. The compound of claim 35 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

37. A compound represented by general formula XVII or a pharmaceutically acceptable salt thereof, in, Each Pg 3 ' are independently hydrogen or selected from amino and carboxyl protecting groups, the amino protecting group is selected from alkoxycarbonyl protecting groups, such as Boc, Fmoc, Cbz or Teoc; the carboxyl protecting group is selected from ester protecting groups, such as methyl ester, ethyl ester, tert-butyl ester, allyl ester or benzyl ester; preferably, each Pg 3 is independently hydrogen or a carboxyl protecting group, such as an ester protecting group, such as methyl ester, ethyl ester, tert-butyl ester, allyl ester or benzyl ester, preferably tert-butyl ester or benzyl ester; preferably, each Pg 3 The same, preferably tert-butyl ester or benzyl ester; The remaining groups are as defined in any one of claims 1 to 36.

38. The compound of any one of claims 37 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

39. A compound of formula XVIII or a pharmaceutically acceptable salt thereof, in, Each group is as defined in any one of claims 1-38.

40. The compound according to claim 39 or a pharmaceutically acceptable salt thereof, in, The compound is selected from:

41. A compound represented by the general formula XIX or a pharmaceutically acceptable salt thereof, in, Each group is as defined in any one of claims 1-40.

42. The compound of claim 41 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

43. A compound represented by the general formula XX or a pharmaceutically acceptable salt thereof, in, Each group is as defined in any one of claims 1-42.

44. The compound of claim 43 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

45. A pharmaceutical composition comprising an effective amount of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof for treating and / or preventing a disease; Preferably, the composition further contains one or more pharmaceutically acceptable excipients; Preferably, the pharmaceutical composition is prepared in the form of an injection.

46. ​​An injection comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 45; Preferably, the injection solution uses physiological saline as a carrier.

47. Use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing a disease (e.g., cancer); Preferably, the cancer is selected from the group consisting of colon cancer, leukemia, lymphoma, bladder cancer, bone cancer, brain tumor, medulloblastoma, glioma, breast cancer, adenoma / carcinoid, adrenal cortical carcinoma, pancreatic islet cell carcinoma, cervical cancer, endometrial cancer, ovarian cancer, colorectal cancer, Skin cancer, esophageal cancer, eye cancer, gallbladder cancer, stomach cancer, head and neck cancer, liver cancer, melanoma, Kaposi's sarcoma, kidney cancer, oral cancer, lung cancer, nasopharyngeal cancer, neuroblastoma, ovarian cancer, pancreatic cancer, thyroid cancer, parathyroid cancer, penile cancer, prostate cancer, urethral cancer, vaginal cancer, vulvar cancer, anal cancer, sarcoma, and metastases of the above cancers.

48. Use of the compound according to any one of claims 9 to 44 or a pharmaceutically acceptable salt thereof in the preparation of a medicament, preferably, the medicament is selected from the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

49. A method for preparing a compound of formula I according to any one of claims 1 to 8, which is selected from the following routes: Route 1: (1) reacting the compound of formula XII with PEG having an activated group to obtain intermediate 1-1; (2) The intermediate 1-1 obtained in step (1) is Reaction to obtain the compound of general formula I; Route 2: (1) reacting the compound of formula IX with PEG having an activated group to obtain intermediate 2-1; (2) The intermediate 2-1 obtained in step (1) is directly reacted with Reaction, or step-by-step connection fragments (e.g., step-by-step connection of L 3 , L 4 , L 5 and D, or L 3 -(L 4 ) n21 , L 5 and D, or L 3 -(L 4 ) n21 , L 5 -y 1 D, or L 3 -(L 4 -(L 5 ) n31 ) n21 and D), to obtain intermediate 2-2; (3) reacting the intermediate 2-2 obtained in step (2) directly with the compound of formula VI, or reacting with the compound of formula IV and the cytotoxic drug in steps, or connecting L in steps. 4 , L 5 -y 2 D, or step-by-step connection L 4 , L 5 and D, to obtain a compound of formula I; Alternatively, the order of step (2) and step (3) is swapped; Route 3: (1) reacting the intermediate 2-1 obtained in step (1) of route 2 with a compound of formula VI to obtain intermediate 3-1; (2) The intermediate 3-1 obtained in step (1) is Reaction to obtain the compound of formula I; Route 4: (1) reacting the compound of formula X with PEG having an activated group to obtain intermediate 4-1; (2) The intermediate 4-1 obtained in step (1) is Reaction to obtain intermediate 4-2, wherein n 31 '+n 31 ” = n 31 ; (3) The intermediate 4-2 obtained in step (2) was reacted with HL 5 -y 2 D reaction to obtain intermediate 4-3; (4) The intermediate 4-3 obtained in step (3) was reacted with HL 5 -y 1 D reaction to obtain the compound of formula I; Alternatively, replace step (2) Replace with At this point, step (4) will no longer be performed; Alternatively, using the compound of formula XII as a raw material, carrying out steps (1), (2) and (4) to obtain the compound of formula I; Route 5: (1) reacting the compound of formula XI with PEG having an activated group to obtain intermediate 5-1; (2) The intermediate 5-1 obtained in step (1) is directly reacted with Reaction or step-wise ligation fragments (e.g., step-by-step connection of L 3 , L 4 , L 5 and D, or L 3 -(L 4 ) n21 , L 5 and D, or L 3 -(L 4 ) n21 , L 5 -y 1 D, or L 3 -(L 4 -(L 5 ) n31 ) n21 and D), to obtain intermediate 5-2; (3) reacting the intermediate 5-2 obtained in step (2) with the cytotoxic drug to obtain the compound of formula I; Route 6: (1) reacting a compound of formula XIV with a compound of formula VII to obtain intermediate 6-1; (2) reacting the intermediate 6-1 obtained in step (1) with PEG having an activated group to obtain the compound of formula I; Route 7: (1) reacting the compound of formula XIII with PEG having an activated group to obtain intermediate 7-1; (2) The intermediate 7-1 obtained in step (1) was reacted with HL 4 Reaction to obtain intermediate 7-2; (3) The intermediate 7-2 obtained in step (2) Reaction to obtain intermediate 7-3; (4) Resuspending the intermediate 7-3 obtained in step (3) with L 5 -y 2 Pg 7 or L 5 '-y 2 Pg 7 Reaction to obtain intermediate 7-4; (5) reacting the intermediate 7-4 obtained in step (4) with the cytotoxic drug or L 5 ”-y 2 D reaction to obtain the compound of formula I; Among them, L 5 ' and L 5 "Connect to form the L 5 ; Route 8: (1) reacting the compound of formula XV with PEG having an activated group to obtain intermediate 8-1; (2) reacting the intermediate 8-1 obtained in step (1) with a compound of formula VI to obtain intermediate 8-2; (3) reacting the intermediate 8-2 obtained in step (3) with the cytotoxic drug to obtain the compound of formula I; Route 9: (1) reacting the compound of formula XVII with PEG having an activated group to obtain intermediate 9-1; (2) The intermediate 9-1 obtained in step (1) was reacted with HL 5 -y 1 D reaction to obtain intermediate 9-2; (3) reacting the intermediate 9-2 obtained in step (2) with the cytotoxic drug to obtain the compound of formula I; Route 10: (1) reacting a compound of formula XIV with a compound of formula III to obtain an intermediate 10-1; (2) reacting the intermediate 10-1 obtained in step (1) with PEG having an activated group to obtain the intermediate 10-2; (3) The intermediate 10-2 obtained in step (2) and HL 4 -n 32 Pg 6 'Reaction to obtain intermediate 10-3; (4) The intermediate 10-3 obtained in step (3) was reacted with HL 5 -y 2 D reaction to obtain the compound of formula I; Optionally, before or after the reaction of any step in Schemes 1-10, a step of removing the protecting group and / or activating (eg, carbonyl activation) is further included; Preferably, the PEG activated group is preferably The remaining compounds and groups are as defined in any one of claims 1-44.

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