Polyethylene glycol micromolecule medicine as well as preparation method and application thereof

Abstract

Relates to a polyethylene glycol micromolecule medicine and a preparation method and application thereof. Specifically, the invention relates to a compound as shown in a formula I or pharmaceutically acceptable salts thereof, intermediate compounds as shown in a formula II and a formula V thereof, a method for preparing the compound, and an application of the compound in tumor resistance. Biological tests show that the compound has a remarkable inhibiting effect on tumors such as breast cancer, intestinal cancer, non-small cell lung cancer, melanoma, oral squamous cell carcinoma and osteosarcoma.

Description

A polyethylene glycol small molecule drug and its preparation method and application

[0001] This application is based on the application with CN application number 202310959802.4 and application date July 28, 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 invention belongs to the field of medical technology, and in particular relates to a polyethylene glycol small molecule drug with a fatty polyamine core. Background Art

[0003] Since 1990, the US FDA has approved 30 PEGylated drugs for marketing, and over 40 new clinical drugs are in Phase I, II, and III clinical trials or NDAs, half of which are PEGylated small molecules. Clearly, PEGylated drugs are shifting from PEGylated macromolecules to PEGylated small molecules, with small molecules accounting for 80-90% of the drug market. With the successful development of PEGylated small molecule dual drugs and PEGylated small molecule drugs with active targeting components or enhancers by Chongqing Apgre Biotechnology Co., Ltd., and the application of PEGylated technology in addition to anti-tumor drugs, it is also suitable for anti-infection, gout, arthritis, mental illness, pain, and other inflammatory conditions, as well as diabetes. Hundreds of product pipelines are expected to emerge, ultimately forming a massive industry worth hundreds of billions of US dollars.

[0004] In recent years, Phase II clinical trials of PEG-lysine dendrimer peptides combined with chemotherapy drugs (including cabazitaxel, docetaxel, and irinotecan) by STARPHARMA, an Australian company, have demonstrated significantly improved efficacy and reduced toxicity. Pharmaceutical giants such as ASTRAZENECA, MERCK, and ROCHE / GENENTECH have entered this field of research and development. Chongqing Apgrelide Biotechnology Co., Ltd. has also developed a pipeline of PEG-peptides (including glutamic acid, aspartic acid, and lysine) combined with small molecule drugs (including single agents, dual agents, multidrugs, enhancers, and active targeting components) and has begun clinical translation. Recently, scientists from WINDOW Tx / Massachusetts Institute of Technology (MIT) and Harvard University published preclinical animal results of a bottlebrush-like PEG triplet synthesized via ring-opening metal polymerization (ROMP) for the treatment of multiple spinal cord tumors. Based on the above research and some related literature reports, in order to further improve the water solubility and cell membrane permeability of polyethylene glycol drugs, the inventors designed a variety of products such as polyethylene glycol-peptide-small molecule drugs with a fatty amine core structure, active targeting accessories, boron reagents, etc. Biological tests have shown that these compounds have significant therapeutic effects.

[0005] Summary of the Invention

[0006] One purpose of the present invention is to design and synthesize polyethylene glycol-polypeptide small molecule drugs with a fatty polyamine structure as the core to further improve the solubility of the drug and enhance its clinical efficacy.

[0007] Therefore, in one aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof,

[0008] in,

[0009] M is a chain or cyclic structure containing one or more identical or different heteroatoms, and M is connected to L1 through the heteroatoms;

[0010] Each L1 is independently selected from a bond, A group consisting of one or two identical or different L1s and one or more identical or different Ms in the following manner: L1-M-(L1) n 、L1-M-(L1-M-(L1) n ) n or L1-M-(L1-M-(L1-M-(L1) n ) n ) n, end 1 is connected to M, 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;

[0011] Each L2 is independently a residue of an amino acid whose side chain contains a functional group selected from -NH2, -OH, -SH and -COOH, and L2 is connected to L1, L3 and L3 through the N-terminus, C-terminus and the functional group of the amino acid. 41 Connection, preferably, L2 is connected to L3 through the functional group;

[0012] Each L3 is independently End 1 is connected to L2, and end 2 is connected to PEG;

[0013] Each PEG is independently selected from polyethylene glycol, amino-polyethylene glycol, methoxy-polyethylene glycol, carboxyl-polyethylene glycol, and cholesterol-polyethylene glycol;

[0014] Each L 41 Independently End 1 is connected to L2, and end 2 is connected to L 42 Connection, 3 ends with L 42 'Connect, where each L 411 、L 412 and L 413 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, -NH(CH2) x3 C(O)-, -CO(CH2) x3 C(O)-、-NH(CH2) x3 NH- and -NH(CH2)2(OCH2CH2) x3 NH- and any combination thereof, each x3 is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, A 41 is a bond or is selected from an amino acid residue or a derivative thereof or a polypeptide fragment consisting of two or more amino acids or a derivative thereof;

[0015] Each L 42 and L 42 'Independently a key or 1 end with L 41 Connection, both ends are the same as L 43 or L 43 'Connect, where each L 421 and L 422 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, -NH(CH2) x4 C(O)-, -CO(CH2) x4 C(O)-、-NH(CH2)x4 NH- and -NH(CH2)2(OCH2CH2) x4 NH- and any combination thereof, each x4 is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, A 42 is a bond or is selected from an amino acid residue or a derivative thereof or a polypeptide fragment consisting of two or more amino acids or a derivative thereof, t1 = n2 or n2';

[0016] Each L 43 and L 43 ' are independently selected from a bond, -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)2(OCH2CH2) x5 NH-, -C(O)(CH2) x5 C(O)-、 and any combination thereof, wherein each x5 is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;

[0017] Each D is independently selected from a cytotoxic drug group, preferably, the cytotoxic drug is selected from a microtubule inhibitor, a DNA intercalator, a DNA topoisomerase inhibitor and an RNA polymerase inhibitor; preferably, the cytotoxic drug is selected from PTX (paclitaxel), PCB (palbucillib), SN38 (7- and -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 dodecahydrogen dodecaborate, PPT-iRGD, disodium 11-hydrogen mercaptododecaborate, 11-hydrogen mercaptododecaborate ( 10 B) disodium iodide, disodium 11-hydrogenamino dodecaboride, disodium 11-hydrogenamino dodecaboride ( 10 B) disodium chloride,

[0018] each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0019] Each n1 and n1' is independently selected from 0, 1, 2, 3, 4, 5, 6, 7 and 8;

[0020] each n2 and n2' is independently selected from 1, 2, 3, 4, 5, 6, 7 and 8;

[0021] Each n3 and n3' is independently selected from 1, 2, 3, 4, 5, 6, 7 and 8.

[0022] In some embodiments, M is a chain or cyclic structure containing one or more identical or different heteroatoms, and M is connected to the group on its right side through the heteroatom;

[0023] Each L1 is independently selected from a bond, A group consisting of one or two identical or different L1s and one or more identical or different Ms in the following manner: L1-M-(L1) n 、 L1-M-(L1-M-(L1) n ) n or L1-M-(L1-M-(L1-M-(L1) n ) n ) n , end 1 is connected to M, 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;

[0024] Each L2 is independently a residue of an amino acid whose side chain contains a functional group selected from -NH2, -OH, -SH and -COOH, and L2 is connected to L1, L3 and L3 through the N-terminus, C-terminus and the functional group of the amino acid. 41 Connection, preferably, L2 is connected to L3 through the functional group;

[0025] Each L3 is independently 1 End 1 is connected to L2, and end 2 is connected to PEG;

[0026] Each PEG is independently selected from polyethylene glycol, amino-polyethylene glycol, methoxy-polyethylene glycol, carboxyl-polyethylene glycol, and cholesterol-polyethylene glycol;

[0027] Each L 41 Independently End 1 is connected to L2, and end 2 is connected to L 42 Connection, 3 ends with L 42 'Connect, where each L 411 、L 412 and L 413 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, -NH(CH2) x3 C(O)-, -CO(CH2) x3 C(O)-、-NH(CH2) x3 NH- and -NH(CH2)2(OCH2CH2) x3NH- and any combination thereof, each x3 is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, A 41 The amino acid residues or derivatives thereof or polypeptide fragments or derivatives thereof consisting of more than two amino acids are selected as bonds, and any of the amino acid residues or derivatives thereof or polypeptide fragments or derivatives thereof consisting of more than two amino acids provide 1, 2, 3, 4, 5 or 6 attachment sites (for example, when the attachment site is L 412 or L 413 When the amino acid residue or its derivative or the polypeptide fragment consisting of more than two amino acids or its derivative is provided, the linking site is connected to L 42 or L 42 ' connection; For example, when the connection site is A 41 When provided, the attachment site is associated with 1, 2, 3, 4, 5 or 6 L 412 or L 413 connect);

[0028] Each L 42 and L 42 'Independently 1 end with L 41 Connection, both ends are the same as L 43 or L 43 'Connect, where each L 421 and L 422 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, -NH(CH2) x4 C(O)-, -CO(CH2) x4 C(O)-、-NH(CH2) x4 NH- and -NH(CH2)2(OCH2CH2) x4 NH- and any combination thereof, each x4 is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, A 42 The amino acid residues or derivatives thereof or polypeptide fragments or derivatives thereof consisting of more than two amino acids are selected as bonds, and any of the amino acid residues or derivatives thereof or polypeptide fragments or derivatives thereof consisting of more than two amino acids provide 1, 2, 3, 4, 5 or 6 attachment sites (for example, when the attachment site is L 422 When the amino acid residue or its derivative or the polypeptide fragment consisting of more than two amino acids or its derivative is provided, the linking site is connected to L 43 or L 43 ' connection; For example, when the connection site is A 42 When provided, the attachment site is associated with 1, 2, 3, 4, 5 or 6 L 422 connect);

[0029] Each L 43 and L 43 ' are independently selected from a bond, -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)2(OCH2CH2) x5 NH-, -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;

[0030] Each D is independently selected from the group of cytotoxic drugs, preferably, the cytotoxic drugs are selected from microtubule inhibitors, DNA intercalators, DNA topoisomerase inhibitors and RNA polymerase inhibitors; preferably, the cytotoxic drugs are selected from PTX (paclitaxel), PCB (palbucillib), SN38 (7- and -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 (BSH, Sodium Mercaptododecaborate), 1,2,3,4,5,6,7,8,9,10,11-undecyl-12-mercaptododecaborate 10 Sodium Mercaptododecaborate( 10 B))

[0031] each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0032] Each n1 and n1' is independently selected from 0, 1, 2, 3, 4, 5, 6, 7 and 8;

[0033] each n2 and n2' is independently selected from 1, 2, 3, 4, 5, 6, 7 and 8;

[0034] Each n3 and n3' is independently selected from 1, 2, 3, 4, 5, 6, 7 and 8.

[0035] In some embodiments, the compound is characterized by one or more of the following:

[0036] (1) M is selected from the group obtained by losing one or more (e.g., 1-10) hydrogen atoms from the following molecules:

[0037] wherein X and X' are independently selected from -OH, -NRR' and -SH, Z is selected from -C(RR')-, -O- and -N(R)-, R and R' are independently selected from hydrogen, C 1-6 Alkyl, amino or C 1-6 Alkylamino-substituted C 1-6 Alkyl, x7 and x8 are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, and x9 is selected from 1, 2, 3, 4, 5 and 6;

[0038] (2) L1 is selected from and one or more identical or different L1 and one or more identical or different M in the following manner: L1-M-(L1) n , wherein x1 and x2 are each independently selected from 1, 2, 3, 4, 5 and 6; preferably, L1 is selected from (For example, ), x1 and x2 are each independently selected from 1, 2, 3, 4, 5 and 6;

[0039] (3) L2 is selected from the following amino acid residues: Lys, Cys, Thr, Ser, Asp or Glu;

[0040] (4) PEG is methoxy-polyethylene glycol;

[0041] (5) PEG number average molecular weight is 5k-40k;

[0042] (6) Each L 411 independently selected from a bond, -NH(CH2) x3 C(O)-, -CO(CH2) x3 C(O)-、-NH(CH2) x3 NH-, -NH(CH2) x3 C(O)NH(CH2) x3 C(O)-、-NH(CH2)2(OCH2CH2) x3 NH- and -NH(CH2)2(OCH2CH2) x3 NH-, x3 is selected from 1, 2, 3, 4, 5 and 6; preferably, each L 411 independently selected from a bond, -NH(CH2)5C(O)-, and -NH(CH2)2C(O)-;

[0043] (7) Each L 412 independently selected from a bond, -NH(CH2) x3 C(O)-, -CO(CH2) x3 C(O)-、-NH(CH2) x3 NH-, -NH(CH2) x3 C(O)-A-, -NH(CH2) x3 C(O)NH(CH2) x3 C(O)-、-NH(CH2)2(OCH2CH2) x3 NH- and -NH(CH2)2(OCH2CH2) x3 NH-, wherein A is selected from an amino acid residue or a derivative thereof or a polypeptide fragment or a derivative thereof consisting of two or more amino acids, wherein the amino acid is selected from Glu and Asp, and preferably, the amino acid residue or a derivative thereof or the polypeptide fragment or a derivative thereof provides n1 (e.g., 1, 2, 3, 4, 5 or 6) attachment sites (e.g., the attachment site is optionally connected to L 42 or L 42 ' connection), each x3 is independently selected from 1, 2, 3, 4, 5 and 6; preferably, A is selected from Glu, Glu-Glu, Glu (Glu) 2; preferably, each L 412 independently selected from a bond, -NH(CH2)5C(O)-Glu(Glu)2, -NH(CH2)2NH- and -NH(CH2)2C(O)-;

[0044] (8) Each L 413 independently selected from a bond, -NH(CH2) x3 C(O)-、-NH(CH2) x3 NH-, -NH(CH2)2(OCH2CH2) x3 NH-, -CO(CH2) x3 C(O)-、-NH(CH2) x3 C(O)NH(CH2) x3 C(O)- and -NH(CH2) x3 C(O)NH(CH2) x3 NH-, each x3 is independently selected from 1, 2, 3, 4, 5 and 6; preferably, L 413 is -NH(CH2)2CO-; preferably, each L 413 are independently selected from a bond and -NH(CH2)2C(O)-; preferably, L 413 is -NH(CH2)2CO-;

[0045] (9)A 41 or A42 wherein the amino acid is selected from Glu, Gly, Asp, Lys, Cys, Thr and Ser;

[0046] (10) Each L 421 independently selected from a bond, -NH(CH2) x4 C(O)-, -CO(CH2) x4 C(O)-、-NH(CH2) x4 NH-, -NH(CH2)2(OCH2CH2) x4 NH- and any combination thereof, each x4 is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; preferably, each L 421 independently selected from a bond, -NH(CH2)5C(O)-, -CO(CH2)2C(O)-, -NH(CH2)2NH-, -NH(CH2)2(OCH2CH2)2NH-, and -NH(CH2)2NH-CO(CH2)2C(O)-;

[0047] (11) Each L 422 independently selected from a bond, -NH(CH2) x3 C(O)-A'-、-NH(CH2) x4 C(O)-, -CO(CH2) x4 C(O)-、-NH(CH2) x4 NH- and -NH(CH2)2(OCH2CH2) x4 NH-, wherein A' is selected from an amino acid residue or a derivative thereof or a polypeptide fragment or a derivative thereof consisting of two or more amino acids, wherein the amino acid is selected from Glu and Asp, and preferably, the amino acid residue or a derivative thereof or the polypeptide fragment or a derivative thereof provides t1 (e.g., 1, 2, 3, 4, 5 or 6) attachment sites (e.g., the attachment site is optionally connected to L 43 connection), each x4 is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;

[0048] (12)L 43 and L 43 ' wherein the amino acid is selected from Glu, Gly, Phe, Leu and Cys; preferably, each L 422 independently selected from a bond, -NH(CH2)2NH-, -NH(CH2)5C(O)-Glu(Glu)2, -NH(CH2)2C(O)-, -CO(CH2)2C(O)-, and -NH(CH2)2(OCH2CH2)2NH-;

[0049] (13)L 41 、L 42 、L42 '、L 43 and L 43 ' wherein the derivative is selected from acylated (eg acetylated) or alkylated (eg methylated) derivatives;

[0050] (14) Each x6 is independently selected from 1, 2, 3, 4, 5 and 6.

[0051] In some embodiments, A, L 411 、L 412 and L 413 Not a key at the same time.

[0052] In some embodiments, n1′=0, in which case the 41 Connected Does not exist.

[0053] In some embodiments, the compound is characterized by one or more of the following:

[0054] (1) M is selected from the group consisting of the following molecules which lose one or more (e.g., 1-10) hydrogen atoms: EDA, DETA, AMDA, TAEA, TETA, TEPA, DAPO, APDO, APD, glycerol, MPE, TAN and TACD; preferably, M is selected from:

[0055] (2) L1 is selected from Each of x1 and x2 is independently selected from 0, 1, 2, 3, 4 and 5;

[0056] (3) L2 is selected from the group consisting of: Lys, Cys, Thr, or Ser;

[0057] (4) PEG number average molecular weight is 5k-10k or 10k-40k, for example, 5k or 10k;

[0058] (5)A 41 and A 42 Independently selected from bond, Glu, Lys, Glu-Asp, Glu-Glu, Glu(Glu)2, Glu(Glu)(Glu(Glu)(GlyGlu)), GluGluGly, GlyGlu;

[0059] (6) Each L 41 Independently selected from -NH(CH2)2CO-, -NH(CH2)5CO-,

[0060] (7) Each L 42 and L 42 'Independently selected from a bond, Glu, GlyGlu, -NH(CH2)5CO-, -CO(CH2)2CO-, -NH(CH2)2NH-, -NH(CH2)5CO-Glu, Glu(Glu)2, -NH(CH2)2(OCH2CH2)2NH-,

[0061] (8) Each L 43 and L 43 ' are independently selected from a bond, Cys(Ac)、-NH-N=、-GlyPheLeuGly-、-C(O)(CH2) x5 C(O)-, -Gly-NH-N=, Glu(GlyPheLeuGly-)2, GlyGlu(GlyPheLeuGly)2, -Glu(Gly-NHN=)2, -C(O)(CH2) x5 C(O)-Glu(GlyPheLeuGly)(Glu(GlyPheLeuGly)2), Glu(Glu)2, -NH(CH2) x5 C(O)-、-NH(CH2) x5 C(O)NH-, -NH(CH2)2(OCH2CH2) x5 NH-, -C(O)(CH2) x5 C(O)-NH(CH2) x5 C(O)-, and Each x5 is independently selected from 1, 2, 3, 4, 5 and 6.

[0062] In some embodiments, the compound is characterized by one or more of the following:

[0063] (1) L2 is selected from a Lys residue;

[0064] (2) Each L 43 and L 43 ' are independently selected from a bond, Cys(Ac), -GlyPheLeuGly-, -C(O)(CH2)2C(O)-, Gly-NHN=, -GlyGlu(GlyPheLeuGly-)2, Glu(GlyPheLeuGly-)2, -Glu(Gly-NHN=)2, -C(O)(CH2)2C(O)-Glu(GlyPheLeuGly)( Glu(GlyPheLeuGly)2), Glu(Glu)2, -NH(CH2)5C(O)-, -NH(CH2)5C(O)NH-, -NH(CH2)2 (OCH2CH2)2NH-, -C(O)(CH2)2C(O)-NHCH2C(O)-, -C(O)(CH2)2C(O)-NH(CH2)2C(O)-, and

[0065] 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.

[0066] In some embodiments, D is selected from:

[0067] In some embodiments, the compound is selected from the group consisting of:

[0068] In another aspect, the present invention provides a compound represented by formula II or a pharmaceutically acceptable salt thereof,

[0069] wherein each of Pg1, Pg2 and Pg2' is 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;

[0070] m1, m2 and m2' are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20;

[0071] The remaining groups are as defined in any of the above items.

[0072] In some embodiments, Pg1 is hydrogen or an amino protecting group, such as Boc, Fmoc, or Cbz.

[0073] In some embodiments, Pg2 and Pg2' are the same. In some embodiments, Pg2 and Pg2' are different. In some embodiments, Pg2 is hydrogen and Pg2' is an amino or carboxyl protecting group. In some embodiments, Pg2' is hydrogen and Pg2 is an amino or carboxyl protecting group. In some embodiments, Pg2 and Pg2' are both hydrogen.

[0074] In some embodiments, each Pg2 is independently hydrogen, -OBn, or O t Bu; each Pg2 'is independently hydrogen, -OBn or O t Bu.

[0075] In some embodiments, each Pg2' is independently hydrogen, -OBn, or O t Bu; each Pg2 is independently hydrogen, -OBn or O t Bu.

[0076] In some embodiments, L 412 or L 413 is -NH(CH2)2CO-, and at least one Pg2 or Pg3 is -OBn.

[0077] In some embodiments, A 41 is selected from amino acid residues or derivatives thereof or polypeptide fragments or derivatives thereof consisting of more than two amino acids, wherein the amino acid residues or derivatives thereof or polypeptide fragments or derivatives thereof provide 1, 2, 3, 4, 5 or 6 attachment sites; preferably, A 41 Contains Glu or Asp residues;

[0078] L 412 is the key;

[0079] L 413 is -NH(CH2)2CO-;

[0080] A 41 Directly with L 413 The linked amino acid (e.g., Glu or Asp) provides two such linking sites, one of which is linked to L. 413 , another connection Pg2, the Pg2 and L 413 The connected Pg2's are the same (for example, both are -OBn).

[0081] The compound of formula II can conveniently and efficiently remove the protecting groups Pg2 and / or Pg2' (when they are amino or carboxyl protecting groups) and can largely avoid the occurrence of side reactions, which is very beneficial for the synthesis of the target compound.

[0082] In some embodiments, the compound of Formula II is selected from:

[0083] In another aspect, the present invention provides a compound represented by formula III or a pharmaceutically acceptable salt thereof,

[0084] wherein Pg1′ is hydrogen or selected from an amino protecting group, such as an alkoxycarbonyl protecting group, and further such as Boc, Fmoc, Cbz or Teoc;

[0085] The remaining groups are as defined in any of the above items.

[0086] In some embodiments, Pg1' is hydrogen. In some embodiments, Pg1' is Fmoc. In some embodiments, Pg1' is different from Pg1.

[0087] In some embodiments, the compound of formula III is selected from:

[0088] In another aspect, the present invention provides a compound represented by formula IV or a pharmaceutically acceptable salt thereof,

[0089] M-[L1-(Pg3) n1 ]n

[0090] IV

[0091] wherein each Pg3 is independently hydrogen or selected from a carboxyl protecting group, such as an ester protecting group, preferably selected from a methyl ester, an ethyl ester, a tert-butyl ester, an allyl ester or a benzyl ester;

[0092] The remaining groups are as defined in any of the above items.

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

[0094] In another aspect, the present invention provides a compound represented by formula V or a pharmaceutically acceptable salt thereof,

[0095] Among them, m 21 and m 22 Each is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20, preferably, m 21 +m 22 =x4;

[0096] each n2′ is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20;

[0097] The remaining groups are as defined in any of the above items.

[0098] In some embodiments, the compound is selected from:

[0099] In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of the compound described above (especially the compound of formula I) or a pharmaceutically acceptable salt thereof for treating and / or preventing a disease.

[0100] In some embodiments, the composition further contains one or more pharmaceutically acceptable excipients.

[0101] In some embodiments, the pharmaceutical composition is prepared in the form of an injection.

[0102] In another aspect, the present invention provides use of any of the above compounds (especially compounds of formula I) or pharmaceutically acceptable salts thereof in the preparation of drugs for treating and / or preventing diseases (such as cancer).

[0103] In some embodiments, 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 these cancers.

[0104] In another aspect, the present invention provides an injection comprising any of the above compounds (especially the compound of formula I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition.

[0105] In some embodiments, the injection solution uses physiological saline as a carrier.

[0106] In another aspect, the present invention provides a method for preparing the compound of formula I or a pharmaceutically acceptable salt thereof as described above.

[0107] When the formula I and L 41 When the connected n1+n1' branches are all identical, the method comprises the following steps:

[0108] S1-1: reacting the compound of formula II with PEG attached with an activated group to obtain intermediate 1-1;

[0109] S1-2: The intermediate 1-1 is subjected to any of the following reactions to obtain the compound:

[0110] (1) Direct and provide Precursor reactions of fragments;

[0111] (2) Provide L in sequence 42 Fragment, L 43 fragments and precursor reactions of D fragments;

[0112] (3) Sequentially and provide fragments and precursor reactions of D fragments;

[0113] (4) Provide L in sequence 42 Fragment, L 43 -n3D fragment precursor reaction;

[0114] Preferably, step S1-1 is performed before or after step S1-2, or, when step S1-2 involves multiple steps, step S1-1 is performed after any step of S1-2 is completed;

[0115] When the formula I and L 41 connected Differently, it includes the following steps:

[0116] S2-1: reacting the compound of formula II with PEG attached with an activating group to obtain intermediate 2-1;

[0117] S2-2: The intermediate 2-1 is subjected to any of the following reactions to obtain the compound:

[0118] (1) Sequentially and provide Precursor reactions of fragments;

[0119] (2) Sequentially and provide Precursor reactions of fragments;

[0120] (3) First and provide The precursor reaction of the fragment is then followed by any of the following reactions:

[0121] 1) Provide L in sequence 42 Fragment, L 43 -n3D fragment precursor reaction;

[0122] 2) Provide L in sequence 42 Fragment, L 43 fragment and the precursor reaction of fragment D; 3) sequentially and provide fragments and precursor reactions of D fragments;

[0123] Preferably, step S2-1 is performed before or after step S2-2, or, when S2-2 involves multiple steps, step S2-1 is performed after any step of S2-2 is completed;

[0124] Optionally, before or after any of the above reactions, a step of removing the protecting group and / or activating (e.g., carbonyl or amino activation) is further included;

[0125] Preferably, the precursor is a compound that provides the corresponding fragment, either in free or activated form;

[0126] Preferably, the PEG activating group is preferably

[0127] Each group is as defined in any of the above items.

[0128] In some embodiments, the compound of formula II wherein A 41 is selected from amino acid residues or derivatives thereof or polypeptide fragments or derivatives thereof consisting of more than two amino acids, wherein the amino acid residues or derivatives thereof or polypeptide fragments or derivatives thereof provide 1, 2, 3, 4, 5 or 6 attachment sites; preferably, A41 Contains Glu or Asp residues;

[0129] L 412 is the key;

[0130] L 413 is -NH(CH2)2CO-;

[0131] A 41 Directly with L 413 The linked amino acid (e.g., Glu or Asp) provides two such linking sites, one of which is linked to L. 413 , another connection Pg2, the Pg2 and L 413 The connected Pg2's are the same (for example, both are -OBn);

[0132] The remaining groups are as defined in any of the above items.

[0133] In some embodiments, the compound of formula II is obtained by reacting the compound of formula IV with a compound of formula III;

[0134] Preferably, before carrying out the reaction, a step of removing the protecting group is further included.

[0135] Definition of terms

[0136] 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.

[0137] 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.

[0138] 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 thed. Pennsylvania: Mack Publishing Company, 1995), and includes, but is 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.

[0139] 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.

[0140] 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).

[0141] 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.

[0142] 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.

[0143] 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.

[0144] 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.

[0145] 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 "C 1-6 "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).

[0146] 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.

[0147] The structural formula of AMDA is:

[0148] The structural formula of TACD is:

[0149] The structural formula of TEPA is:

[0150] The structural formula of DETA is:

[0151] The structural formula of TETA is:

[0152] The structural formula of TAN is:

[0153] The structural formula of TAEA is:

[0154] The structural formula of EDA is:

[0155] The structural formula of DAPO is:

[0156] The structural formula of APDO is:

[0157] The structural formula of APD is:

[0158] The structural formula of MPE is:

[0159] The structural formula of PT is:

[0160] The structural formula of PTX is:

[0161] The structural formula of PCB is:

[0162] The structural formula of SN38 is:

[0163] The structural formula of NPB is:

[0164] The structural formula of AXT is:

[0165] The structural formula of LPT is:

[0166] The structural formula of DOX is:

[0167] The structural formula of MI-AH-PLGLAG-iRGD is:

[0168] The structural formula of SB7 is:

[0169] The structural formula of folic acid is:

[0170] The structural formula of sodium dodecahydrogen dodecaborate is:

[0171] As used herein, the term "amino acid" primarily 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 (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr) and valine (Val). It is known that amino acid molecules contain two functional groups, amino and carboxyl groups. The "amino acid residue" herein refers to the remaining portion of an amino acid molecule after removing a hydrogen from the amino group and / or lacking a hydroxyl group from the carboxyl group.

[0172] Advantageous Effects of the Invention

[0173] The present invention provides a class of polyethylene glycol small molecules having a fatty polyamine core as shown in Formula I and pharmaceutically acceptable salts thereof. Furthermore, the present invention provides intermediates of the molecules, methods for their preparation, and applications in anti-tumor treatment. Biological tests have shown that the compounds of the present invention have a significant inhibitory effect on subcutaneous xenografts (e.g., subcutaneous xenografts of human breast cancer BT474 cells in NPG mice). BRIEF DESCRIPTION OF THE DRAWINGS

[0174] The accompanying drawings are used to provide a further understanding of the present invention and constitute a part of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention. In the accompanying drawings:

[0175] Figure 1 shows the growth inhibition rate of tumor cells A549 treated with different concentrations of 82-178;

[0176] Figure 2 shows the growth inhibition rate of tumor cells COLO-205 treated with different concentrations of 81-176;

[0177] Figure 3 shows the growth inhibition rate of tumor cells COLO-205 treated with different concentrations of 71-246;

[0178] Figure 4 shows the growth inhibition rate of human breast cancer cells BT-474 treated with different concentrations of 82-183;

[0179] Figure 5 shows the growth inhibition rate of human breast cancer cells BT-474 treated with different concentrations of 78-139;

[0180] Figure 6 shows the growth inhibition rate of human breast cancer cells BT-474 treated with different concentrations of 81-176;

[0181] Figure 7 shows the growth inhibition rate of human breast cancer cells BT-474 treated with different concentrations of 85-71;

[0182] Figure 8 shows the growth inhibition rate of human breast cancer cells BT-474 treated with different concentrations of 84-106;

[0183] Figure 9 shows the growth inhibition rate of human breast cancer cells BT-474 treated with different concentrations of 76-207;

[0184] Figure 10 shows the growth inhibition rate of human breast cancer cells BT-474 treated with different concentrations of 75-196;

[0185] Figure 11 shows the growth inhibition rate of human breast cancer cells BT-474 treated with different concentrations of 81-176;

[0186] FIG12 shows the detection results of the compounds of the present invention on the tumor volume of the human breast cancer BT474 cell subcutaneous transplanted tumor model in NPG mice;

[0187] FIG13 shows the test results of the compounds of the present invention on the tumor weight of the human breast cancer BT474 cell subcutaneous transplanted tumor model in NPG mice;

[0188] FIG14 shows the results of the test on the body weight of tumor-bearing mice in which the compounds of the present invention were used to establish a lung cancer A-549 cell transplantation tumor model (subcutaneous tumor);

[0189] FIG15 shows the detection results of the compounds of the present invention on the tumor volume of the lung cancer A-549 cell transplanted tumor model (subcutaneous tumor) in nude mice;

[0190] FIG16 shows the results of tumor inhibition test of the compounds of the present invention on a nude mouse transplanted tumor model (subcutaneous tumor) of lung cancer A-549 cells;

[0191] FIG17 shows the results of the test on the body weight of tumor-bearing mice in a nude mouse xenograft tumor model (subcutaneous tumor) of breast cancer MDA-MB-231 cells established by the compounds of the present invention;

[0192] FIG18 shows the detection results of the compounds of the present invention on the tumor volume of the breast cancer MDA-MB-231 cell transplanted tumor model (subcutaneous tumor) in nude mice;

[0193] FIG19 shows the tumor inhibition rate of the compounds of the present invention on the breast cancer MDA-MB-231 cell transplanted tumor model (subcutaneous tumor) in nude mice. DETAILED DESCRIPTION

[0194] The embodiments of the present invention will be described in detail below with reference to the examples, but it will be understood by those skilled in the art that the following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the invention. Where specific conditions are not specified in the examples, the methods were performed according to conventional conditions or the conditions recommended by the manufacturer. Where the manufacturers of the reagents or instruments are not specified, they are all conventional products that can be obtained commercially.

[0195] Example 1 Synthesis of Compound 71-215

[0196] 1.1 Preparation of 64-100

[0197] Boc-L-Leucine (30 g, 129.7073 mmol, purchased from Inochem), glycine benzyl ester hydrochloride (28.7710 g, 142.6780 mmol, purchased from Ark Pharm), HBTU (73.7853 g, 194.5610 mmol, purchased from Aladdin), and HOBT (26.2891 g, 194.5610 mmol, purchased from Aladdin) were added to a 1000 ml flask, and DMF (250 ml) was added to dissolve the mixture. The mixture was stirred at -5 ° C for about 20 minutes, and then DIEA (96.5 ml, 583.6829 mmol) was slowly added dropwise. After the addition was complete, stirring was continued at -5 ° C for 1 hour, and then the reaction was stirred at room temperature. After the reaction, the reaction solution was transferred to a 2L separatory funnel containing saturated sodium bicarbonate solution (250ml) and ethyl acetate (300ml) for extraction to obtain an organic phase. The aqueous phase was extracted with ethyl acetate (200ml x 3). The combined organic phases were washed with saturated brine (200ml x 2), concentrated, and dried to obtain 50.9873g of the product.

[0198] 1.2 Preparation of 64-101

[0199] 64-100 (49.0890 g, 129.7073 mmol) was placed in a 1 L flask and dissolved in dichloromethane (60 ml). TFA (96.3 ml, 1297.073 mmol) was added with stirring. The reaction flask was left to react at room temperature with stirring overnight. Upon completion of the reaction, the reaction solution was transferred to a 2 L separatory funnel filled with 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 (1500 ml x 2). The organic phases were combined, concentrated, and evaporated to dryness to yield 29.3 g of the product.

[0200] 1.3 Preparation of 64-102

[0201] 64-101 (29.3 g, 105.2632 mmol), Boc-L-phenylalanine (33.5116 g, 126.3158 mmol, purchased from Accela), HBTU (59.8800 g, 157.8948 mmol), and HOBT (21.3347 g, 157.8948 mmol) were added to a 1-L flask. DMF (200 ml) was added to dissolve the mixture and stirred at -5°C for approximately 20 minutes. DIEA (104.4 ml, 631.5792 mmol) was then slowly added dropwise. After the addition was complete, stirring was continued at -5°C for 1 hour, then the mixture was brought to room temperature and stirred overnight. Upon completion of the reaction, the reaction mixture was transferred to a 2-L separatory funnel containing saturated sodium bicarbonate solution (350 ml) and ethyl acetate (300 ml) for extraction to obtain the organic phase. The aqueous phase was then extracted with ethyl acetate (200 ml x 3). The organic phases were combined, washed with saturated brine (250 ml x 2), concentrated, and evaporated to dryness to obtain 49.4 g of the product.

[0202] 1.4 Preparation of 64-105

[0203] 64-102 (49.4 g, 93.9807 mmol) was placed in a 1L flask and dissolved in dichloromethane (60 mL). TFA (71.0 mL, 939.807 mmol) was added with stirring, and the reaction flask was stirred at room temperature overnight. After the reaction was complete, the reaction solution was transferred to a 2L separatory funnel filled with saturated sodium bicarbonate solution (350 mL) and ethyl acetate (300 mL). Extraction was performed to obtain the organic phase, and the aqueous phase was extracted with ethyl acetate (150 mL x 2). The organic phases were combined, concentrated, and evaporated to dryness to yield 32.7 g of the product.

[0204] 1.5 Preparation of 64-106

[0205] 64-105 (32.7 g, 76.8472 mmol), Boc-Gly-OH (16.1545 g, 92.2166 mmol, purchased from Ark Pharm), HBTU (45.7153 g, 115.2708 mmol), and HOBT (15.5754 g, 115.2708 mmol) were added to a 1-L flask. DMF (200 ml) was added to dissolve the mixture. The mixture was stirred at -5°C for approximately 20 minutes, followed by the slow dropwise addition of DIEA (76.2 ml, 461.0832 mmol). After the addition was complete, the mixture was stirred at -5°C for 1 hour and then allowed to stir at room temperature overnight. Upon completion of the reaction, the reaction mixture was transferred to a 2-L separatory funnel containing saturated sodium bicarbonate solution (300 ml) and ethyl acetate (350 ml). Extraction was performed to obtain the organic phase, and the aqueous phase was extracted with ethyl acetate (200 ml x 3). The combined organic phases were washed with saturated brine (250 ml x 2). The organic phases were concentrated and allowed to stand at room temperature for 1.5 hours to precipitate solids, which were filtered. 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.

[0206] 1.6 Preparation of 71-85

[0207] 64-106 (10 g, 17.1618 mmol) was added to a hydrogenation reactor, followed by a 10% Pd / C catalyst (0.1 g). Dissolved in DMF (40 ml). The hydrogenation reactor was sealed, evacuated with a water pump, and then refilled with hydrogen. This process was repeated three times. The pressure in the hydrogenation reactor was adjusted to 2 MPa, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was filtered through celite, and the filter cake was washed with DMF (15 ml x 3). The filtrate was then charged into a 500 ml round-bottom flask and used as the raw material for the next step.

[0208] 1.7 Preparation of 64-134

[0209] 71-85 (8.4534 g, 17.1618 mmol), PCB (6.4012 g, 14.3015 mmol, purchased from Tianjin Famoxi), HBTU (8.1355 g, 21.4523 mmol), and HOBT (2.8986 g, 21.4523 mmol) were added to a 500 ml round-bottom flask, dissolved in DMF (80 ml), and 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, then removed and transferred to room temperature for stirring. After the reaction was completed, the reaction solution was transferred to a 1 L separatory funnel filled with deionized water (300 ml) and ethyl acetate (200 ml) to obtain an organic phase (with solid precipitation); the aqueous phase was then extracted with ethyl acetate (200 ml x 2). The organic phases were combined and concentrated by vacuum rotary evaporation. Deionized water (200 ml) was added to wash the solid, and the mixture was filtered. The filter cake was washed with n-hexane (40 ml × 4) and methyl tert-butyl ether (10 ml × 4). The filter cake was collected and dried to obtain 13.7 g of the product.

[0210] 1.8 Preparation of 64-135

[0211] To a flask containing 64-134 (13.1871 g, 14.3015 mmol) was added dichloromethane (30 ml). Ultrasonication was used to dissolve the mixture, followed by the addition of TFA (10.6 ml, 143.015 mmol). The mixture was stirred and allowed to react overnight at room temperature. After completion of the reaction, the reaction solution was concentrated and evaporated to dryness to remove dichloromethane and most of the TFA. The solid product was then precipitated with methyl tert-butyl ether (300 ml). The solid product was filtered, and the filter cake was washed with methyl tert-butyl ether (40 ml x 3). The filter cake was collected and dried under vacuum to yield 16.6 g of the product.

[0212] 1.9 Preparation of 64-109

[0213] Boc-glycine (10.0 g, 57.0841 mmol purchased from Aladdin), H-Glu(Obzl)-Obzl.TsOH (31.3699 g, 62.7926 mmol purchased from Ark Pharm), HBTU (32.4729 g, 85.6262 mmol) and HOBT (11.5698 g, 85.6262 mmol) were added to a 1 L round-bottom flask, dissolved with DMF (180 ml), stirred at -5 ° C for about 20 minutes, and then DIEA (42.5 ml, 256.8785 mmol) was slowly added dropwise. After the addition was complete, the reaction flask was placed at -5 ° C and stirred for 1 hour, then taken out and transferred to room temperature for stirring. After the reaction, the reaction mixture was transferred to a 2L separatory funnel filled with saturated brine (400ml) and ethyl acetate (300ml) for extraction to obtain an organic phase. The aqueous phase was extracted with ethyl acetate (200ml). The combined organic phases were washed with deionized water (250ml x 2), concentrated and evaporated to dryness, and then dissolved in a 20% methanol / dichloromethane mixture. 200-300 mesh silica gel powder was added, dry-loaded, and column chromatography was performed using a 0-40% ethyl acetate / petroleum ether mixture as the eluent. The product fractions were collected and evaporated to dryness to obtain 27.1661g of the product.

[0214] 1.10 Preparation of 71-48

[0215] 64-109 (2.3624 g, 4.8753 mmol) and 10% Pd / C catalyst (0.04 g) were added to a hydrogenation reactor. DMF (40 ml) was added to dissolve the mixture. The hydrogenation reactor was sealed, evacuated with a water pump, and then filled with hydrogen. This process was repeated three times. The pressure in the hydrogenation reactor was adjusted to 2 MPa, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was filtered through celite, and the filter cake was washed with DMF (15 ml x 3). The filtrate was charged into a 500 ml round-bottom flask and used as the raw material for the next step.

[0216] 1.11 Preparation of 71-50

[0217] 71-48 (1.4836 g, 4.8753 mmol), 64-135 (8.8162 g, 10.7257 mmol), HBTU (5.5467 g, 14.6259 mmol), and HOBT (1.9763 g, 14.6259 mmol) were placed in a 500 ml flask and dissolved in DMF (40 ml). The mixture was stirred at -5°C for approximately 20 minutes, followed by the slow dropwise addition of DIEA (9.6 ml, 58.5036 mmol). After the addition was complete, the reaction flask was allowed to react at -5°C for 1 hour, then removed from the flask and stirred at room temperature. After the reaction was complete, n-hexane (300 ml) and methyl tert-butyl ether (50 ml) were added to allow sedimentation, and the supernatant was decanted. This process was repeated five times to obtain a solid product, which was collected by suction filtration and dried in a vacuum oven to yield 8.9 g of the product. 1 H-NMR(600MHz,DMSO-d6)δ8.08-7.90(m,10H),7.51-6.90(m,18H),4.56-4.58(m,2 H),4.37-4.36(m,3H),4.22-3.97(m,8H),3.70-3.68(m,2H),3.63-3.59(m,12H),3 .20-3.08(m,12H),2.43(s,6H),2.31(s,6H),2.25-2.24(m,4H),1.92-1.84(m,6H) ,1.79-1.72(m,6H),1.59-1.58(m,6H),1.51(s,4H),1.36(s,9H),0.9-0.84(m,12H)

[0218] 1.12 Preparation of 71-60

[0219] To a flask containing 71-50 (8.9 g, 4.6543 mmol) was added dichloromethane (30 ml). Ultrasonication was used to dissolve the product, followed by the addition of TFA (3.5 ml, 46.543 mmol). The mixture was stirred at room temperature overnight. After completion of the reaction, the reaction solution was concentrated and evaporated to dryness to remove the dichloromethane and most of the TFA. The solid product was then precipitated with methyl tert-butyl ether (300 ml). The solid product was filtered, and the filter cake was washed with methyl tert-butyl ether (40 ml x 3). The filter cake was collected and dried under vacuum to yield 8.7 g of the product.

[0220] 1.13 Preparation of 64-152

[0221] 6-Aminocaproic acid (9.19 g, 70.06 mmol, purchased from Inotech) was placed in a 1L round-bottom flask and dissolved in a 1 / 1 THF / H2O solution (200 ml). The mixture was stirred in a 0°C water bath for 1 hour. Anhydrous sodium carbonate (14.85 g, 140.12 mmol) was then added, dissolved with ultrasonication, and stirred in a 0°C water bath for 30 minutes. Cbz-Cl (12.5494 g, 73.56 mmol) was then slowly added dropwise to the reaction flask. After the addition was complete, the reaction flask was removed from the 0°C water bath and stirred at room temperature for 2.5 hours. Finally, 1N aqueous hydrochloric acid solution (115 ml) was added dropwise to the reaction flask to adjust the pH of the reaction solution to 3.0. After the reaction was completed, the reaction solution was transferred to a 1L separatory funnel and extracted with ethyl acetate (130 ml) to obtain the organic phase. The aqueous phase was then extracted with ethyl acetate (200 ml). The organic phases were combined and washed with 1N aqueous hydrochloric acid solution (200 ml × 2), then concentrated and evaporated to dryness. Dichloromethane (100 ml) was added for dissolution, and 200-300 mesh silica gel powder was added and evaporated to dryness. The product was dry-loaded and column chromatography was performed using a 15-30% ethyl acetate / petroleum ether mixed solution as the eluent. The product components were collected and evaporated to dryness to obtain 11.6 g of the product with a yield of 62.41%.

[0222] 1.14 Preparation of 64-124

[0223] 6-Aminocaproic acid (4.6094 g, 35.1407 mmol) was placed in a 1 L round-bottom flask and dissolved in a 1 / 1 THF / H2O solution (150 ml). The mixture was stirred in a 0°C water bath for 1 hour. Anhydrous sodium carbonate (7.4491 g, 70.2814 mmol) was then added to the reaction flask, dissolved with ultrasound, and stirred in a 0°C water bath for 30 minutes. 9-Fluorenechloroformic 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 water bath and stirred at room temperature for 2.5 hours. Finally, 1.0 M aqueous hydrochloric acid (115 ml) was added dropwise to the reaction flask to adjust the pH to 3.0. After the reaction, the reaction solution was transferred to a 1L separatory funnel and extracted with ethyl acetate (150ml) to obtain an organic phase. The aqueous phase was further extracted with ethyl acetate (200ml). The organic phases were combined, washed with 1.0M hydrochloric acid (250ml x 2), concentrated and evaporated to dryness, and then dissolved in dichloromethane (100ml). 200-300 mesh silica gel powder was added and evaporated to dryness. The sample was dry-loaded and subjected to column chromatography using a 20-50% ethyl acetate / petroleum ether mixture as the eluent. The product fractions were collected and evaporated to dryness to obtain 12.0g of the product, with a yield of 96.63%.

[0224] 1.15 Preparation of 59-60

[0225] Paclitaxel (20 g, 23.42 mmol, purchased from Wuhan Yingyuanbei, abbreviated as PTX) and imidazole (7.98 g, 117.12 mmol, purchased from Innochem) were dissolved in DMA (50 ml) using ultrasonic technology. N2 was purged to evacuate the air, and TBDMS-Cl (21.2 g, 142.54 mmol, purchased from Innochem) was added. The nitrogen flow was stopped, and the reaction was continued with stirring at room temperature. After the reaction was completed, the reaction solution was transferred to a 1 L separatory funnel filled with ethyl acetate (200 ml) and purified water (200 ml) to obtain an organic phase. Ethyl acetate (150 ml x 2) was added to the aqueous phase for extraction. The combined organic phases were washed with saturated brine (100 ml x 2), concentrated, and evaporated to dryness to obtain 22.7 g of the product.

[0226] 1.16 Preparation of 59-67

[0227] 59-60 (2 g, 7.8387 mmol) was dissolved in dichloromethane (35 ml) and stirred at 0°C. DIEA (1.5 ml, 9.04569 mmol) was slowly added dropwise. After complete addition, pivaloyl chloride (1.1 ml, 9.04569 mmol) was added dropwise. After complete addition, the mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC. The reaction solution was then stirred at 0°C. 64-152 (3.65 g, 3.7693 mmol) was dissolved in 20 ml of dichloromethane and slowly added dropwise to the reaction solution. DIEA (0.69 ml, 4.1459 mmol) was then added dropwise. After complete addition, DMAP (0.57 g, 4.64805 mmol) was added. The reaction flask was stirred at room temperature. After the reaction, the mixture was evaporated to dryness using a vacuum rotary evaporator. Ethyl acetate (200 ml) was added for dissolution, and the mixture was transferred to a 2-L separatory funnel filled with pure water (300 ml) for extraction to obtain an organic phase. The aqueous phase was then extracted with ethyl acetate (100 ml x 2). The combined organic phases were concentrated to 150 ml, washed with dilute hydrochloric acid (200 ml x 2), and then washed with saturated sodium bicarbonate solution (200 ml x 2). The organic phase was collected and evaporated to dryness to obtain 4.58 g of the product.

[0228] 1.17 Preparation of 59-69

[0229] Compound 59-67 (4.58 g, 3.769 mmol) was dissolved in activated carbon-treated DMA (90 ml) in a hydrogenation reactor. 10% Pd / C catalyst (80 mg) was added. The hydrogenation reactor was sealed, evacuated with a water pump, and then refilled with hydrogen. This process was repeated three times. The pressure on the hydrogenation reactor was adjusted to 1.8 MPa, and the reaction was stirred at room temperature. After the reaction, the reaction solution was filtered through diatomaceous earth, and the filter cake was washed with DMA (10 ml x 3). The filtrate was poured into a 1 L separatory funnel filled with pure water (300 ml) and ethyl acetate (300 ml) for extraction to obtain the organic phase. The aqueous phase was then extracted with ethyl acetate (100 ml x 2). The combined organic phases were washed with saturated brine (200 ml × 3), the organic phases were collected and evaporated to dryness, the obtained solid was dissolved in a 4 / 1 dichloromethane / methanol mixed solvent, and then silica gel powder was added and evaporated to dryness. The sample was dry loaded and column chromatography was performed using a 0.2% triethylamine / 3% methanol / dichloromethane mixed solution as the eluent. The product components were collected and evaporated to dryness to obtain 4.08 g of the product.

[0230] 1.18 Preparation of 71-70

[0231] 64-124 (6.5712 g, 18.5936 mmol), di-tert-butyl L-glutamate hydrochloride (5.0 g, 16.9033 mmol purchased from Innochem), HBTU (7.0514 g, 18.5936 mmol), and HOBT (2.5124 g, 18.5936 mmol) were added to a 1 L round-bottom flask and dissolved in DMF (70 ml). The reaction flask was stirred at -5°C for approximately 20 minutes, and then DIEA (6.1 ml, 37.1873 mmol) was slowly added dropwise. After the addition was complete, the reaction was stirred at -5°C for 1 hour and then transferred to room temperature and stirred. After the reaction was completed, the reaction solution was transferred to a 1 L separatory funnel filled with saturated brine (250 ml) and ethyl acetate (200 ml) for extraction to obtain an organic phase. Ethyl acetate (200 ml) was then added to the aqueous phase for extraction. The combined organic phases were washed with deionized water (250 ml x 2), concentrated and evaporated to dryness, then dissolved in a 20% methanol / dichloromethane mixture. Silica gel powder was then added and evaporated to dryness. Dry-loading was performed on a column chromatography using a 0-50% ethyl acetate / petroleum ether mixture as the eluent. The product fractions were collected, concentrated, and evaporated to dryness to yield 9.06 g of the product, with a yield of 90.13%.

[0232] 1.19 Preparation of 71-71

[0233] To a flask containing 71-70 (5.0 g, 8.4070 mmol) was added dichloromethane (20 ml), and dissolution was assisted by ultrasound. TFA (12.5 ml, 168.1407 mmol) was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction solution was evaporated to dryness to remove dichloromethane and most of the TFA, and then n-hexane (30 ml) and methyl tert-butyl ether (200 ml) were added for sedimentation. The supernatant was decanted to form an oily solid. The solid was dissolved in ethyl acetate (20 ml), and then precipitated with methyl tert-butyl ether (100 ml). The solid product was filtered to obtain a solid product. This process was repeated 6 times. The filter cake was collected and dried under vacuum to obtain 4.5526 g of the product.

[0234] 1.20 Preparation of 71-73

[0235] 71-71 (0.8276 g, 1.7151 mmol), 59-69 (4.08 g, 3.7732 mmol), HBTU (1.9513 g, 5.1453 mmol), and HOBT (0.6952 g, 5.1453 mmol) were added to a 1 L round-bottom flask and dissolved in DMF (70 ml). The reaction flask was stirred at -5°C for approximately 20 minutes, followed by the slow addition of DIEA (2.3 ml, 13.7208 mmol). After the addition was complete, the reaction flask was stirred at -5°C for 1 hour, then transferred to room temperature and stirred. After the reaction was complete, the reaction solution was transferred to a 1 L separatory funnel filled with saturated brine (250 ml) and ethyl acetate (200 ml) for extraction to obtain the organic phase. The aqueous phase was then extracted with ethyl acetate (200 ml). The combined organic phases were washed with deionized water (250 ml x 2), concentrated and evaporated to dryness, and then dissolved in a 4 / 1 dichloromethane / methanol mixed solvent. 200-300 mesh silica gel powder was added and evaporated to dryness. The sample was dry-loaded and column chromatography was performed using a 1-3% methanol / dichloromethane mixed solution as the eluent. The product components were collected, evaporated to dryness, and dried in a vacuum oven to obtain 3.6 g of the product. 1H-NMR(600MHz,DMSO-d6)δ8.0-7.81(m,13H),7.75-7.61(m,10H),7.55-7.47(m,10H),7.43-7.39(m,6H),7.34-7.31(m,2H) ,7.26-7.20(m,3H),6.04(s,2H),5.88-5.85(m,2H),5.54-5.39(m,6H),5.00-4.98(m,2H),4.77-4.75(m,4H),4.29-4.28(m, 2H),4.21-4.15(m,2H),4.07(s,2H),3.75-3.73(m,2H),3.03-2.95(m,6H),2.45(s,6H),2.18-2.03(m,16H),1.65(s,10H),1 .57(s,6H),1.48-1.43(m,6H),1.40-1.34(m,6H),1.24-1.20(m,12H),1.02-0.98(m,12H),0.80(s,18H),0.08-0.03(m,12H)

[0236] 1.21 Preparation of 71-94

[0237] Compound 71-73 (1.0 g, 0.3832 mmol) was placed in a 250 ml flask and dissolved in DMF (6 ml). Morpholine (0.4 ml, 3.832 mmol) was then added and stirred at room temperature for 2 hours. After the reaction was complete, n-hexane (25 ml) and methyl tert-butyl ether (200 ml) were added to allow the reaction to settle. The supernatant was decanted and this process was repeated four times. The solid product was filtered and dried in a vacuum oven to yield 0.65 g of product, with a yield of 71.42%.

[0238] 1.22 Preparation of 71-95

[0239] Compound 71-94 (0.32 g, 0.1345 mmol) and TBAF (0.85 g, 2.6913 mmol) were placed in a 250 mL flask, dissolved in tetrahydrofuran (10 mL), and stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was evaporated to dryness using a rotary evaporator under reduced pressure, dissolved in ethyl acetate (60 mL), and then transferred to a 1 L separatory funnel filled with deionized water (70 mL x 2) for extraction. The resulting organic phase was evaporated to dryness using a rotary evaporator under reduced pressure and dried in a vacuum oven to yield 0.12 g of the product (41.37% yield).

[0240] 1.23 Preparation of 71-6

[0241] Add tert-butyl acrylate (6.5622 g, 51.1992 mmol) to the reaction flask, add methanol (15 ml) to dissolve it, then place the reaction mixture in a dark place and cool it to 0°C, then dissolve N-methyl-2,2'-diaminoethylenediamine (1 g, 8.5332 mmol) in methanol (5 ml) and slowly add it dropwise to the reaction flask, then stir at 1°C for 45 hours, then heat the reaction mixture to room temperature and continue to react at room temperature for 24 hours. After the reaction is completed, the reaction solution is evaporated to dryness under reduced pressure to remove the solvent and excess tert-butyl acrylate, n-hexane is added to the reaction solution to dissolve it, and then evaporated to dryness under reduced pressure. This is repeated 4 times. The resulting solid product is dissolved in a 4 / 1 dichloromethane / methanol mixed solvent, 200-300 mesh silica gel powder is added and evaporated to dryness, dry-loaded, and column chromatography is performed using a 0-4% methanol / dichloromethane mixed solution as an eluent. The product components are collected, evaporated to dryness, and dried in a vacuum oven to obtain 4.6 g of the product with a yield of 85.69%. 1 H-NMR(600MHz,DMSO-d6)δ2.65-2.63(m,8H),2.51-2.50(m,1H),2.46-2.44(m,4H),2.37(s,3H),2.29-2.27(m,8H),2.16(s,3H),1.39(s,36H)

[0242] 1.24 Preparation of 71-54

[0243] 71-6 (1.0 g, 1.5876 mmol) was added to a 100 ml flask, and 1,4-dioxane hydrochloride (31.7 ml, 127.008 mmol) was added to dissolve the mixture. The mixture was then stirred in a 50°C water bath overnight. After the reaction, the reaction mixture was evaporated to dryness using rotary evaporation, dissolved in dichloromethane (10 ml), and evaporated to dryness using rotary evaporation. This process was repeated three times to obtain a solid, which was then dried in an oven to yield 0.64 g of the product.

[0244] 1.25 Preparation of 71-26

[0245] Boc-Asp(Obzl.)-OH (10.2010 g, 31.5488 mmol), H-β-Ala-Obzl.TsOH (11.0868 g, 31.5488 mmol), HBTU (13.161 g, 34.7036 mmol), and HOBT (4.6892 g, 34.7036 mmol) were added to a 500 ml round-bottom flask, dissolved in DMF (40 ml), and stirred at -5°C for approximately 20 minutes. DIEA (11.4 ml, 69.4072 mmol) was then slowly added dropwise. The mixture was stirred at -5°C for 1 hour and then transferred to room temperature for overnight stirring. After completion of the reaction, the reaction solution was transferred to a 1 L separatory funnel containing saturated sodium bicarbonate solution (300 ml) and ethyl acetate (200 ml) for extraction to obtain the organic phase. The aqueous phase was then extracted with ethyl acetate (200 ml). The combined organic phases were washed with deionized water (100 ml x 2), concentrated, and evaporated to dryness to obtain 15.686 g of the product.

[0246] 1.26 Preparation of 71-28

[0247] 71-26 (13.7881 g, 28.4560 mmol) was placed in a 250 ml round-bottom flask and dissolved in dichloromethane (40 ml). TFA (21.1 ml, 284.560 mmol) was added while stirring, and the reaction flask was left to react at room temperature with stirring. After the reaction, the reaction solution was concentrated and evaporated to dryness to remove the dichloromethane and most of the TFA. The reaction solution was then transferred to a 1 L separatory funnel filled with saturated brine (200 ml) and ethyl acetate (200 ml) for extraction to obtain the organic phase. The aqueous phase was further extracted with ethyl acetate (200 ml). The combined organic phases were washed with deionized water (200 ml x 2), concentrated, and dried to yield 10.6 g of the product.

[0248] 1.27 Preparation of 71-29

[0249] 71-28 (10.6 g, 28.4560 mmol), Fmoc-Glu(OtBu)-OH (13.3178 g, 31.3016 mmol), HBTU (11.8708 g, 31.3016 mmol purchased from Adamas), and HOBT (4.2295 g, 31.3016 mmol purchased from Innochem) were placed in 500 ml of DMF (50 ml) and dissolved. The mixture was stirred at -5°C for approximately 20 minutes, followed by the slow dropwise addition of DIEA (15.0 ml, 91.0592 mmol). The reaction was continued at -5°C for 1 hour, and the reaction flask was moved to room temperature and stirred overnight. After completion of the reaction, the reaction solution was transferred to a 1 L separatory funnel filled with saturated brine (200 ml) and ethyl acetate (200 ml) for extraction to obtain the organic phase. The aqueous phase was then extracted with ethyl acetate (200 ml). The combined organic phases were washed with deionized water (200 ml x 2) and evaporated to dryness. The resulting solid product was dissolved in a 4 / 1 dichloromethane / methanol mixture, added with 200-300 mesh silica gel powder and evaporated to dryness. The product was dry-loaded and subjected to column chromatography using a 0-1% methanol / dichloromethane mixture as the eluent. The product fractions were collected, evaporated to dryness, and dried in a vacuum oven to obtain 20.9 g of the product.

[0250] 1.28 Preparation of 71-43

[0251] 71-29 (8 g, 10.1025 mmol) was placed in a 500 ml flask and dissolved in DMF (30 ml). Morpholine (8.8 ml) was added and the reaction was stirred at room temperature for 1 hour. After completion, the reaction solution was transferred to a 1 L separatory funnel filled with saturated brine (200 ml) and ethyl acetate (200 ml). Extraction was performed to obtain an organic phase. The aqueous phase was further extracted with ethyl acetate (200 ml). The combined organic phases were washed with deionized water (200 ml x 2), evaporated to dryness, and dried in a vacuum oven to yield 6.2 g of the product.

[0252] 1.29 Preparation of 71-46

[0253] 71-43 (5.7549 g, 10.1025 mmol), Fmoc-Lys(Boc)-OH (5.2068 g, 11.1126 mmol), HBTU (4.2144 g, 11.1126 mmol), and HOBT (1.5016 g, 11.1126 mmol) were placed in 500 mL of DMF (40 mL) and dissolved. The mixture was stirred at -5°C for approximately 20 minutes. DIEA (3.7 mL, 22.2255 mmol) was then slowly added dropwise. The reaction was continued at -5°C for 1 hour. The reaction flask was then moved to room temperature and stirred overnight. After completion of the reaction, the reaction solution was transferred to a 1 L separatory funnel filled with saturated brine (200 mL) and ethyl acetate (200 mL) for extraction to obtain the organic phase. The aqueous phase was then extracted with ethyl acetate (200 mL). The combined organic phases were washed with deionized water (200 ml × 2) and evaporated to dryness. The obtained solid product was dissolved in a dichloromethane / methanol (4 / 1) mixed solvent, 200-300 mesh silica gel powder was added and evaporated to dryness, dry-loaded, and column chromatography was performed using a 0-1.5% methanol / dichloromethane mixed solution as the eluent. The product components were collected, evaporated to dryness, and dried in a vacuum oven to obtain 8.9 g of the product. 1 H-NMR (600MHz, DMSO-d6) δ8.17(d,J=7.9Hz,1H),8.05(d,J=7.4Hz,1H),7.97-7.87(m,3H),7.71(d,J=16.8Hz,2H) ,7.37(d,J=72.0Hz,16H),5.12(d,J=99.6Hz,5H),4.56(dd,J=14.1,7.7Hz,1H),4.26(d,J=53.6Hz,5H),4.00(t,J= 26.4Hz,2H),3.28(d,J=44.2Hz,2H),2.74(d,J=202.6Hz,5H),2.22(d,J=54.9Hz,2H),1.87(d,J=35.3Hz,1H),1.74 (d,J=37.5Hz,1H),1.61(d,J=27.6Hz,1H),1.52(d,J=36.1Hz,1H),1.35(d,J=12.8Hz,18H),1.22(d,J=11.9Hz,2H)

[0254] 1.30 Preparation of 71-55

[0255] 71-46 (5 g, 4.9011 mmol) was placed in a 250 ml flask and dissolved in DMF (20 ml). Morpholine (4.3 ml) was added and the reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was transferred to a 1 L separatory funnel filled with saturated brine (200 ml) and ethyl acetate (200 ml). Extraction was performed to obtain an organic phase, and the aqueous phase was further extracted with ethyl acetate (200 ml). The combined organic phases were washed with deionized water (200 ml x 2), evaporated to dryness, and then dissolved in a 4 / 1 dichloromethane / methanol mixture. 200-300 mesh silica gel powder was added and evaporated to dryness. The sample was dry-loaded and column chromatography was performed using a 1-3% methanol / dichloromethane mixture as the eluent. The product fractions were collected, evaporated to dryness, and dried in a vacuum oven to yield 4.1 g of the product.

[0256] 1.31 Preparation of 71-56

[0257] 71-54 (0.4516 g, 1.1139 mmol), 71-55 (3.9082 g, 4.9011 mmol), HBTU (2.5346 g, 6.6834 mmol), and HOBT (0.9031 g, 6.6834 mmol) were placed in 500 mL of DMF (25 mL) and dissolved. The mixture was stirred at -5°C for approximately 20 minutes, followed by the slow dropwise addition of DIEA (2.2 mL, 13.3668 mmol). The reaction was continued at -5°C for 1 hour, and then the reaction mixture was moved to room temperature and stirred overnight. After completion of the reaction, the reaction mixture was transferred to a 1 L separatory funnel containing saturated brine (200 mL) and ethyl acetate (200 mL) for extraction to obtain the organic phase. The aqueous phase was then extracted with ethyl acetate (200 mL). The combined organic phases were washed with deionized water (200 ml × 2), evaporated to dryness, and the resulting solid product was dissolved in a 4 / 1 dichloromethane / methanol mixed solvent. 200-300 mesh silica gel powder was added and evaporated to dryness. The sample was dry loaded and column chromatography was performed using a 2-4% methanol / dichloromethane mixed solution as the eluent. The product components were collected, evaporated to dryness, and dried in a vacuum oven to obtain 2.1 g of the product. 1H-NMR(600MHz,DMSO-d6)δ8.16-7.98(m,20H),7.36-7.34(m,40H),5.08-5.06(m,20H), 4.57-4.56(m,6H),4.21-4.20(m,8H),3.34-3.31(m,19H),3.29-3.25(m,10H),2.75-2.7 0(m,16H),2.49-2.48(m,8H),2.35-2.31(m,8H),2.22-2.20(m,8H),1.88-1.83(m,4H),1 .77-1.71(m,4H),1.61-1.60(m,4H),1.48-1.46(m,4H),1.35(s,72H),1.24-1.21(m,8H)

[0258] 1.32 Preparation of 71-77

[0259] 71-56 (1 g, 0.2837 mmol) and 10% Pd / C catalyst (0.1 g) were added to a hydrogenation reactor. NMP (30 ml) was added to dissolve the mixture. The hydrogenation reactor was sealed, evacuated with a water pump, and then filled with hydrogen. This process was repeated three times. The pressure on the hydrogenation reactor was adjusted to 2 MPa, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was filtered through celite, and the filter cake was washed with DMF (15 ml x 3). The filtrate was charged into a 250 ml round-bottom flask and used as the raw material for the next step.

[0260] 1.33 Preparation of 71-82

[0261] 71-77 (0.1 g, 0.0357 mmol), 71-60 (0.5686 g, 0.3138 mmol), HBTU (0.1623 g, 0.4279 mmol), and HOBT (0.0578 g, 0.4279 mmol) were added to a 1 L round-bottom flask and dissolved in NMP (40 ml). The mixture was stirred at room temperature for approximately 20 minutes, followed by the slow dropwise addition of DIEA (0.3 ml, 11.5691 mmol). After the addition was complete, the reaction flask was allowed to react at room temperature with stirring. After completion of the reaction, n-hexane (30 ml) and methyl tert-butyl ether (200 ml) were added to allow the mixture to settle, and the supernatant was decanted. This process was repeated three times, and the solid product was filtered to obtain a solid. The solid was washed with a 4% methanol / dichloromethane mixture, filtered, collected, and dried in a vacuum oven to yield 0.5 g of the product. 1H-NMR(600MHz,DMSO-d6)δ8.19-8.00(m,100H),7.89-7.88(m,20H),7.51-7.49(m,20H),7. 23-7.16(m,104H),4.57-4.56(m,20H),4.37-4.36(m,20H),4.21-4.19(m,14H),4.05-3.97 (m,40H),3.69-3.59(m,126H),3.19-3.06(m,112H),2.88-2.85(m,8H),2.42(s,56H),2.31-2.24(m,115H ),1.88(s,40H),1.77(s,40H),1.67-1.45(m,128H),1.35(s,72H),1.24-1.22(m,8H),0.89-0.83(m,96H)

[0262] 1.34 Preparation of 71-86

[0263] To a flask containing 71-82 (0.25 g, 0.0145 mmol) was added TFA (0.2 ml, 2.3315 mmol), and dissolution was assisted by ultrasound. The reaction was stirred in a 50°C water bath overnight. After the reaction was completed, the reaction solution was concentrated and evaporated to dryness, then precipitated with methyl tert-butyl ether (300 ml) to precipitate a solid product, which was then filtered. The filter cake was dissolved in DMF (10 ml), and then methyl tert-butyl ether (300 ml) was added to precipitate a solid product, which was then filtered. This process was repeated 6 times. The filter cake was washed with methyl tert-butyl ether (40 ml x 3), and the filter cake was collected and dried under vacuum to obtain 0.2 g of the product.

[0264] 1.35 Preparation of 71-91

[0265] 71-86 (0.13 g, 0.0083 mmol) was placed in a 250 ml flask, dissolved in NMP (20 ml), and stirred in a 50°C water bath for 30 minutes. DIEA (0.2 ml, 0.996 mmol) was then slowly added dropwise. Stirring was continued for 30 minutes, followed by the addition of M-SCM-10K (0.3825 g, 0.0366 mmol, purchased from Jenki, Lot Number: ZZ390P163). The reaction mixture was then placed in a 40°C water bath with slow stirring for one week in the dark. After completion of the reaction, methyl tert-butyl ether (200 ml) and n-hexane (70 ml) were added to precipitate a solid, which was filtered. The filter cake was washed with methyl tert-butyl ether (40 ml x 3) and dried in a vacuum oven to yield 0.47 g of the product.

[0266] 1.36 Preparation of 71-215

[0267] 71-91 (0.47 g, 0.0083 mmol), 71-95 (0.10 g, 0.0496 mmol), HBTU (0.0188 g, 0.0496 mmol), and HOBT (0.0067 g, 0.0496 mmol) were added to a 1 L round-bottom flask and dissolved in DMF (30 ml). The mixture was stirred at room temperature for approximately 20 minutes, and then DIEA (0.1 ml, 0.1489 mmol) was slowly added dropwise. After the addition was complete, the reaction flask was left to react at room temperature with stirring. After the reaction was complete, n-hexane (30 ml) and methyl tert-butyl ether (100 ml) were added to allow sedimentation, and the supernatant was decanted. This process was repeated twice. The solid product was filtered and dissolved in a 4 / 1 dichloromethane / methanol mixture. 100-200 mesh silica gel powder was added and evaporated to dryness. Dry-load the sample and perform column chromatography using a 1% triethylamine / 5-10% methanol / dichloromethane mixture as the eluent. The product fractions were collected and concentrated and evaporated to dryness. The solid product was dissolved in a 4 / 1 anhydrous ethanol / dichloromethane mixture, methyl tert-butyl ether (200 ml) was added to allow precipitation, and filtered to obtain a powdered solid. This process was repeated three times. The filter cake was collected and dried in a vacuum oven to obtain 0.3 g of the product. 1 H-NMR(600MHz,DMSO-d6)δ8.23-8.01(m,156H),7.89-7.88(m,68H),7.39-7.23(m,164H),5.37-5.2 8(m,32H),4.61-4.52(m,52H),4.36-4.35(m,24H),4.03-3.99(m,46H),3.63-3.62(m,134H),3.51-3 .50(m,3748H),3.08-3.05(m,136H),2.79-2.76(m,32H),2.45-2.40(m,96H),2.31-2.23(m,155H),1 .93-1.84(m,64H),1.82-1.73(m,72H),1.59-1.51(m,184H),1.25-1.24(m,112H),0.9-0.89(m,96H)

[0268] Example 2 Synthesis of Compounds 59-126

[0269] 2.1 Preparation of 59-108

[0270] Cyclotrimethylenetetramine (3.4454 g, 20 mmol) was placed in a 250 ml flask, anhydrous ethanol was added and dissolved with ultrasonication, and the mixture was stirred at room temperature. Acrylic acid (28.1034 g, 390 mmol) was then dissolved in anhydrous ethanol and added dropwise to the reaction solution. Stirring was continued at room temperature for 1 hour. The reaction solution was then placed at 85°C and refluxed for 2 hours. The liquid became turbid and was refluxed for another 2 hours. Heating was then stopped and the mixture was cooled to room temperature. After the reaction was completed, the product was adsorbed on the wall of the flask. The liquid was poured out, a small amount of anhydrous ethanol was added, and the mixture was ultrasonically treated for 10 minutes. The filter cake was collected by suction and this operation was repeated three times. The solid product was collected and oven-dried to obtain 1.79 g of the product. 1 H-NMR (600MHz, DMSO-d6) δ11.0(s,4H),2.90(t,J=7.0Hz,8H),2.76(d,J=25.8Hz,16H),2.42(t,J=7.1Hz,8H)

[0271] 2.2a Preparation of 68-54

[0272] 2-Chloro-4,6-dimethoxy-1,3,5-triazine (22.1 g, 125.9 mmol, purchased from Accela) was added to a 1 L flask. THF (300 ml) was added and dissolved by sonication. N-methylmorpholine (12 mL, 114.4 mmol) was then slowly added dropwise. After addition, the mixture was stirred at room temperature for 30 min. A large amount of white solid precipitated, which was collected by filtration and dried to obtain the product.

[0273] 2.2 Preparation of 59-97

[0274] Fmoc-Glu(OH)2 (6.5 g, 17.66 mmol, purchased from Adamas) and Glu(OtBu)2 (10.08 g, 38.87 mmol, purchased from Innochem) were added to a 500 ml flask, dissolved in DMF (150 ml), and stirred at room temperature for approximately 10 minutes. 68-54 (10.76 g, 38.87 mmol) was then added, followed by the slow dropwise addition of N-methylmorpholine (3.58 ml, 155.48 mmol). After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was transferred to a 1 L separatory funnel containing 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 twice with pure water, concentrated, and evaporated to dryness to yield 10 g of the product.

[0275] 2.3 Preparation of 59-99

[0276] To a flask containing 59-97 (10 g, 11.7368 mmol) was added DMF, followed by ultrasonic dissolution and the addition of morpholine (20 ml, 229.7576 mmol). The reaction was stirred at room temperature for 2 h. After completion of the reaction, the reaction solution was poured into a saturated sodium bicarbonate solution (200 ml) and ethyl acetate (200 ml) for extraction. After 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, 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 solid was dry-loaded and subjected to column chromatography using a 0-5% methanol / dichloromethane mixture as the eluent. The product was collected, concentrated, and dried in a vacuum oven to yield 7 g (94.72% yield).

[0277] 2.4 Preparation of 59-106

[0278] 59-99 (7 ​​g, 11.274 mmol), HOBT (2.1 g, 15.374 mmol), and HBTU (5.8 g, 15.374 mmol) were weighed and added to a flask containing 64-124 (3.6 g, 10.25 mmol). An appropriate amount of DMA (40 ml) was added to dissolve the mixture. The mixture was stirred at room temperature for approximately 10 minutes, and DIEA (7.6 ml, 46.125 mmol) was slowly added dropwise. After the addition was complete, the reaction mixture was stirred for another 3 hours. Upon completion of the reaction, the reaction mixture was transferred to a 1 L separatory funnel containing ethyl acetate (200 ml) and saturated sodium bicarbonate solution (150 ml) for extraction. The extraction was performed using the same ethyl acetate (150 ml x 2). The combined organic phases were concentrated to 150 ml, washed with pure water (150 ml × 2), the ethyl acetate phase was collected and evaporated to dryness to a solid, then dissolved with 1 / 4 methanol / dichloromethane mixed solution (100 ml), silica gel powder (100 ml) was added and evaporated to dryness to a powdery solid, dry-loaded, column chromatography was performed using 0.5-5% methanol / dichloromethane mixed solution as eluent, collected, concentrated, and dried in a vacuum oven to obtain 10 g of the product.

[0279] 2.5 Preparation of 38-224

[0280] To a 250ml round-bottom flask, 59-106 (10g, 10.3607mmol) was added an appropriate amount of DMF. Morpholine (9ml, 103.3607mmol) was added after ultrasonic dissolution, and the mixture was stirred at room temperature for 2h. After completion of the reaction, ethyl acetate (200ml) and saturated sodium bicarbonate solution (200ml) were added for extraction. After stratification, the organic phase was collected, and the aqueous phase was extracted again with ethyl acetate (200ml x 3). The combined organic phases were evaporated to dryness to a solid, then dissolved in a 1 / 4 methanol / dichloromethane mixture (100ml). Silica gel powder (60ml) was added and evaporated to dryness, resulting in a powdery solid. The solid was dry-loaded and subjected to column chromatography using a mixture of 1% aqueous ammonia / 5-10% methanol / dichloromethane as the eluent. The product was collected, concentrated, and dried in a vacuum oven to yield 6.9g, with a yield of 89.65%.

[0281] 2.6 Preparation of 38-200

[0282] Fmoc-Gly-OH (8 g, 26.91 mmol, purchased from Accela), Glu(OtBu)2 (7.676 g, 29.601 mmol), HOBT (5.45 g, 40.365 mmol), and HBTU (15.308 g, 40.365 mmol) were added to a 500 mL flask and dissolved in DMF (80 mL). The mixture was stirred at room temperature. DIEA (20 mL, 121.095 mmol) was slowly added dropwise, and the reaction was allowed to stir at room temperature for 3 hours. After the reaction, the reaction solution was transferred to a 1 L separatory funnel filled with deionized water (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 saturated brine (150 mL x 2), concentrated, and evaporated to dryness to yield 12 g of the product.

[0283] 2.7 Preparation of 38-204

[0284] 38-200 (12 g, 22.279 mmol) was placed in a 250 ml round-bottom flask and dissolved in dichloromethane (5 ml) and TFA (60 ml, 891.16 mmol). The mixture was stirred at room temperature overnight. After completion of the reaction, the reaction solution was evaporated to dryness, then dissolved in dichloromethane (5 ml), followed by n-hexane (100 ml) for precipitation. The supernatant was discarded. This process was repeated twice, and the precipitate was evaporated to dryness to yield 9 g of product, with a yield of 94.7%.

[0285] 2.8 Preparation of 38-205

[0286] 38-204 (9 g, 21.106 mmol) and Boc-ethylenediamine (7.3 ml, 46.4332 mmol, purchased from Aladdin) were added to a 500 ml flask, dissolved in DMF (150 ml), and stirred at room temperature for approximately 10 minutes. 68-54 (12.85 g, 46.4332 mmol) was then added, followed by slow dropwise addition of N-methylmorpholine (20.6 ml, 185.7328 mmol). Stirring was continued at room temperature for 3 hours. After the reaction was complete, the reaction solution was transferred to a 1 L separatory funnel filled with deionized water (200 ml) and ethyl acetate (300 ml) for extraction. 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 saturated brine (150 ml x 2), concentrated, added with silica gel powder and evaporated to dryness, dry-loaded, and subjected to column chromatography using 3-5% methanol / dichloromethane solution as the eluent. The product (12.5 g) was collected, concentrated, and dried.

[0287] 2.9 Preparation of 38-217

[0288] To a flask containing 38-205 (10 g, 10.36 mmol) was added an appropriate amount of DMF. Morpholine (20 ml, 229.7576 mmol) was added after ultrasonic dissolution, and the reaction was stirred at room temperature for 2 h. After completion of the reaction, the reaction solution was transferred to a 1 L separatory funnel filled with deionized water (200 ml) and ethyl acetate (300 ml) for extraction. 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 saturated brine (150 ml x 2), concentrated, and evaporated to dryness after adding silica gel powder. The dry sample was then subjected to column chromatography using 0-5% methanol / dichloromethane solution and then 1% ammonia / 5-8% methanol / dichloromethane solution as eluents. The product was collected, concentrated, and dried in a vacuum oven to obtain 12.5 g of the product, with a yield of 83.33%. 1 H-NMR (600MHz, DMSO-d6) δ8.02(t,J=5.5Hz,2H),7.81(t,J=5.4Hz,1H),6.80(dd,J=13.6,5.7Hz,2H),4.22(s,1H),3.12(d,J=1.8H z,2H),3.09-3.06(m,2H),3.04-2.94(m,6H),2.04(t,J=7.9Hz,2H),1.92-1.87(m,1H),1.73(dd,J=13.7,7.8Hz,1H),1.37(s,20H)

[0289] 2.10 Preparation of 59-107

[0290] 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 dichloromethane and DMA (24 ml) was added. Ultrasonication was used to dissolve the mixture and the mixture was stirred overnight at room temperature. After the reaction, the mixture was spin-dried to dryness and dissolved in ethyl acetate (100 ml). The reaction mixture was transferred to a 500 ml separatory funnel and washed with dilute hydrochloric acid (35 ml x 3). The ethyl acetate phase was collected and then washed with purified water (40 ml x 3). The organic phase was collected. The organic phase was dried over anhydrous sodium sulfate and filtered. Finally, the product was concentrated and dried to obtain 3.13 g, with a yield of 71.5%. 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)

[0291] 2.11 59-121

[0292] 59-107 (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 (30 ml). The mixture was stirred and reacted overnight at room temperature. After the reaction was complete, the mixture was filtered and the filtrate was added with silica gel powder and evaporated to dryness. Column chromatography was performed using a 0-2% methanol / dichloromethane mixture as the eluent. The product was collected, concentrated, and dried to yield 2.47 g.

[0293] 2.12 Preparation of 38-227

[0294] 38-224 (3.5 g, 4.711 mmol), N'-Fmoc-N-benzyloxycarbonyl-L-lysine (2.15 g, 4.283 mmol), HOBT (0.87 g, 6.4245 mmol), and HBTU (2.436 g, 6.4245 mmol) were added to a 250 ml flask and dissolved in DMF (20 ml). The mixture was stirred at room temperature for 10 minutes, and DIEA (1.1 ml, 12.849 mmol) was slowly added dropwise. After the addition was complete, stirring was continued at room temperature for 3 hours. After the reaction was complete, the mixture was poured into a separatory funnel filled with ethyl acetate (200 ml) and saturated sodium bicarbonate solution (200 ml) 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 combined organic phases were evaporated to dryness and dried in a vacuum oven to obtain 5.3 g of the product, with a yield of 100%.

[0295] 2.13 Preparation of 38-230

[0296] To a flask containing 38-227 (5.3 g, 4.283 mmol) was added DMF (20 ml), followed by ultrasonic dissolution and the addition of morpholine (7.5 ml, 85.66 mmol). The reaction was stirred at room temperature for 2 h. After the reaction was complete, the mixture was poured into a separatory funnel containing ethyl acetate (200 ml) and saturated sodium bicarbonate solution (200 ml) 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, then dissolved in a 1 / 4 methanol / dichloromethane mixture (100 ml). Silica gel powder (60 ml) was added and evaporated to dryness to a powdery solid. The solid was dry-loaded and subjected to column chromatography using a 1% ammonia solution / 1-10% methanol / dichloromethane mixture as the eluent. The product was collected, concentrated, and dried in a vacuum oven to obtain 3.9 g of the product with a yield of 90.7%. 1 H-NMR(600MHz,DMSO-d6)δ8.17-8.16(m,1H),8.09-8.08(m,1H),7.93-7.92(m,1H),7 .79-7.76(m,1H),7.36-7.31(m,5H),7.23-7.21(m,1H),5.12-5.09(m,2H),5.00(s,2 H),4.29-4.25(m,1H),4.13-4.10(m,2H),3.06-2.95(m,5H),2.26-2.07(m,8H),1.94 -1.87(m,3H),1.78-1.69(m,5H),1.51-1.46(m,4H),1.39(s,36H),1.32-1.21(m,6H)

[0297] 2.14 Preparation of 38-234

[0298] 59-108 (0.1125 g, 0.2475 mmol), 38-230 (1.5 g, 1.4925 mmol), HOBT (0.2025 g, 1.4925 mmol), and HBTU (0.5625 g, 1.4925 mmol) were added to a 250 ml flask and dissolved in DMF (8 ml). The mixture was stirred at room temperature for approximately 10 minutes. DIEA (0.75 ml, 4.4775 mmol) was then slowly added dropwise. After the addition was complete, stirring was continued at room temperature for 3 hours. After the reaction was complete, the mixture was poured into a separatory funnel containing ethyl acetate (100 ml) and saturated sodium bicarbonate solution (100 ml) for extraction. After standing and separating, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (50 ml x 3). The combined organic phases were evaporated to dryness to a solid, and then dissolved in 1 / 4 methanol / dichloromethane mixed solution (50 ml), silica gel powder (30 ml) was added and evaporated to dryness, and the sample was dry loaded and column chromatography was performed using 3-8% methanol / dichloromethane mixed solution as eluent. The product was collected, concentrated, and dried in a vacuum oven to obtain 1.02 g of the product with a yield of 93.58%. 1 H-NMR(600MHz,DMSO-d6)δ8.21-8.17 (m,8H),8.08(d,J=7.6Hz,4H),7.92(d,J=8.1Hz,4H),7.54(d,J=7.1Hz,4H),7 .38-7.32(m,20H),7.27(t,J=5.6Hz,4H),5.01(s,8H),4.28-4.25(m,4H),4.14 -4.10(m,8H),3.12-2.92(m,44H),2.31-2.08(m,40H),1.92-1.87(m,12H),1.7 6-1.68(m,20H),1.52-1.44(m,16H),1.39-1.384(m,144H),1.35-1.20(m,24H)

[0299] 2.15 Preparation of 38-258

[0300] 38-234 (0.52 g, 0.118 mmol) and 10% Pd / C catalyst (0.3 g) were placed in a hydrogenation reactor. DMF (30 ml) was added to dissolve the mixture. The hydrogenation reactor was sealed, evacuated with a water pump, and then filled with hydrogen. This process was repeated three times. The pressure in the hydrogenation reactor was adjusted to 2 MPa, and the reaction was stirred at room temperature overnight. After the reaction, the reaction solution was filtered through diatomaceous earth and washed with DMF (20 ml x 3). The DMF filtrates were combined and repeatedly precipitated with n-hexane and methyl tert-butyl ether until the reaction solution became a solid oil. Drying gave 0.29 g of the product, with a yield of 63.04%.

[0301] 2.16 Preparation of 59-111

[0302] 38-258 (0.1686 g, 0.0436 mmol) was placed in a 250 ml round-bottom flask and dissolved in DMF (20 ml). The mixture was stirred at -5°C for 30 minutes, followed by the slow addition of DIEA (0.3 ml, 1.8152 mol). After the addition was complete, the mixture was stirred at low temperature for 10 minutes, then transferred to room temperature and slowly stirred. M-SCM-10K (2.00 g, 0.19166 mmol, purchased from Jenka, Lot Number: ZZ390P163) was added, and sonication was used to assist dissolution. The reaction was then continued at room temperature with slow stirring in the dark for 4 days. After the reaction, methyl tert-butyl ether and n-hexane were added to precipitate, and the solid product was filtered. The solid product was dissolved in a 1 / 4 methanol / dichloromethane mixed solution, and silica gel powder (30 ml) was added and evaporated to dryness. The sample was dry-loaded and column chromatography was performed using a 1% ammonia water / 5-7% methanol / dichloromethane mixed solution as an eluent. The product was collected, concentrated, and dried in a vacuum oven to obtain 0.93 g of the product with a yield of 62%. 1 H-NMR(600MHz,DMSO-d6)δ8.32-8.15(m,16H),8.09-8.07(m,4H),7.94-7.90(m,4H),4.28-4.25(m,4H),4.20-4.14(m,8H),3.51-3.50(m,3748H ),3.21-3.05(m,44H),2.48-1.95(m,40H),1.93-1.85(m,12H),1.83-1. 53(m,20H),1.50-1.42(m,16H),1.40-1.38(m,144H),1.37-1.28(m,24H)

[0303] 2.17 Preparation of 59-116

[0304] 59-111 (0.93 g, 0.0206 mmol) was placed in a 250 ml round-bottom flask and dissolved with TFA (0.4 ml, 5.056 mmol). The reaction mixture was stirred and allowed to react overnight at room temperature. After the reaction, the reaction solution was evaporated to dryness, then dissolved in dichloromethane (5 ml), and spun down to dryness. This process was repeated three times. Methyl tert-butyl ether was added to allow the solution to settle, ultrasonicated for 10 minutes, allowed to stand, and the supernatant was discarded. This process was repeated two more times. The solution was dissolved in dichloromethane, and methyl tert-butyl ether was added to allow the solution to settle, spun down, and then methyl tert-butyl ether was added to allow the solution to settle. The solution was ultrasonicated, filtered, and the filter cake collected. The filter cake was then dissolved in dichloromethane, and DIEA was added dropwise until the reaction solution was neutral or weakly alkaline. The solution was concentrated and dried to obtain 0.76 g of the product in an 83.4% yield.

[0305] 2.18 Preparation of 59-118

[0306] 59-116 (0.76 g, 0.0171 mmol) and 38-217 (0.2 g, 0.4104 mmol) were added to a 500 ml flask, dissolved in DMF (50 ml), and stirred at room temperature for about 10 minutes. Then, 68-54 (0.10 g, 0.4104 mmol) was added, and N-methylmorpholine (0.17 ml, 1.6416 mmol) was slowly added dropwise. After the addition was complete, stirring was continued at room temperature for 3 hours. After the reaction is completed, methyl tert-butyl ether (100 ml) and n-hexane (200 ml) are added for precipitation, allowed to stand, the supernatant is poured out, and n-hexane and methyl tert-butyl ether are added for precipitation. This process is repeated twice, and a solid product is obtained by filtration. The obtained solid product is dissolved in a 1 / 4 methanol / dichloromethane mixed solution, and silica gel powder (30 ml) is added and evaporated to dryness. The sample is dry-loaded and column chromatography is performed using a 1% ammonia water / 4-10% methanol / dichloromethane mixed solution as an eluent. The product is collected, concentrated, and dried in a vacuum oven to obtain 0.33 g of the product with a yield of 37.29%. 1H-NMR(600MHz,DMSO-d6)δ8.33-8.23(m,8H),8.15-8.01(m,32H),7.99-7.92(m,22H),7.82-7.77( m,16H),7.7-7.64(m,4H),6.83-6.74(m,32H),6.51-6.38(m,4H),4.205-4.150(m,28H),3.51-3.50 (m,3748H),3.44-3.38(m,44H),3.13-2.93(m,162H),2.25-2.04(m,72H),1.935-1.840(m,32H),1 .81-1.68(m,32H),1.53-1.46(m,16H),1.45-1.41(m,16H),1.38-1.36(m,288H),1.34-1.33(m,8H)

[0307] 2.19 Preparation of 59-122

[0308] To a flask containing 59-118 (0.33 g, 0.00637 mmol) was added TFA (3.5 ml, 46.543 mmol), dissolution was assisted by ultrasonication, and the reaction was stirred at room temperature overnight. After completion of the reaction, the reaction solution was evaporated to dryness, then dissolved in dichloromethane (10 ml), and neutralized with excess DIEA. The solid product was then precipitated with methyl tert-butyl ether (300 ml). 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 yield 0.29 g of the product, with a yield of 93.54%.

[0309] 2.20 Preparation of 59-126

[0310] 59-122 (0.29 g, 0.00597 mmol) was dissolved in DMF (5 ml), and DIEA (0.06 ml, 0.38208 mmol) was added dropwise. Then, 59-121 (0.403 g, 0.38208 mmol) was added. Ultrasonication was used to dissolve the mixture, and the mixture was allowed to react at room temperature for 2 days. After the reaction, the mixture was repeatedly precipitated with n-hexane and tert-butyl ether until a solid was obtained. The mixture was then dissolved in a small amount of a 2% methanol / dichloromethane mixture, and methyl tert-butyl ether was added to allow the mixture to settle. The mixture was allowed to stand, and the supernatant was discarded. This process was repeated several times until all impurities in the reaction mixture were removed. The mixture was then dissolved in dichloromethane, and methyl tert-butyl ether was added to allow the mixture to settle. The mixture was allowed to stand, and the supernatant was discarded. This process was repeated three times. The product was dried on a rotary evaporator to yield 0.28 g, with a yield of 59.57%. 1H-NMR(600MHz,DMSO-d6)δ8.26-8.21(m,8H),8.152-8.146(m,32H),8.10-8.03(m,32H),7.994 -7.792(m,64H),7.92-7.90(m,22H),7.876-7.827(m,84H),7.746-7.712(m,32H),7.68-7.644 (m,64H),7.56-7.43(m,256H),7.203-7.166(m,32H),6.315-6.273(m,32H),6.099-5.982(m,4 H),5.85-5.79(m,32H),5.565-5.520(m,32H),4.94-4.88(m,64H),4.66-4.61(m,32H),4.20-4. 14(m,28H),4.127-4.093(m,32H),4.07-3.93(m,96H),3.630-3.618(m,32H),3.51-3.50(m,37 58H),3.444-3.428(m,44H),3.09-2.99(m,162H),2.63-2.595(m,64H),2.58-2.55(m,32H),2. 395-2.358(m,64H),2.27-2.20(m,132H),2.13-2.07(m,132H),1.91-1.85(m,32H),1.786-1.7 57(m,96H),1.663-1.630(m,32H),1.55-1.45(m,160H),1.40-1.37(m,8H),1.30-0.82(m,288H)

[0311] Example 3 Synthesis of Compound 67-228

[0312] 3.1 Preparation of 67-144

[0313] H-Phe(4-I)-OH (5.00 g, 17.176 mmol) was placed in a 500 ml round-bottom flask and dissolved in a THF / H₂O solution (150 ml). The mixture was stirred in a 0°C reaction bath for 1 hour. Anhydrous sodium carbonate (3.64 g, 34.353 mmol) was then added, dissolving the mixture with ultrasonication. The reaction flask was stirred in a 0°C reaction bath for 30 minutes. Di-tert-butyl dicarbonate (7.49 g, 34.353 mmol) was then dissolved in THF (30 ml) and slowly added dropwise to the reaction flask. After the addition was complete, the flask was removed from the 0°C reaction bath and stirred at room temperature for 3 hours. After the reaction, the THF was evaporated to dryness, and extraction with methyl tert-butyl ether (150 ml x 3) was performed. The organic and aqueous phases were separated, and 1N aqueous hydrochloric acid (70 ml) was added dropwise to the aqueous phase to adjust its pH to 2.0. Ethyl acetate (150 ml x 3) was added to the mixture for extraction, and the aqueous and organic phases were separated. The organic phases were combined, concentrated under reduced pressure, and evaporated to dryness. Dichloromethane (100 ml) was then added for dissolution. Silica gel powder (30 ml) was then added and evaporated to dryness. The mixture was dry-loaded and subjected to column chromatography using 20-50% ethyl acetate / petroleum ether as the eluent. The mixture was collected, concentrated, and dried to obtain 6.0 g of the product, with a yield of 89.41%.

[0314] 3.2 Preparation of 67-145

[0315] DMAP (0.37 g, 3.067 mmol) and ethanol (0.7 ml, 15.337 mmol) were added to a 500 ml round-bottom flask containing 67-144 (6.0 g, 15.337 mmol). Dichloromethane (200 ml) was then added and dissolved using ultrasonication. Stirring was performed at -5°C for 30 min. DCC (15.822 g, 76.685 mmol) was then added in three portions, with 5-min intervals between additions. The reaction was continued for 3 h. The reaction progress was monitored by TLC. After completion, the filtrate was filtered and collected. The filtrate was concentrated and added to a 4 / 1 mixture of n-hexane and petroleum ether. The crude solid product was filtered and collected. This process was repeated three times. After evaporation to dryness, methanol / dichloromethane mixed solvent was added for dissolution, and 200-300 mesh silica gel powder (40 ml) was added and evaporated to dryness. The sample was loaded by dry method and column chromatography was performed with 10% ethyl acetate / petroleum ether as eluent. The product was collected, concentrated and dried to obtain 6.1 g.

[0316] 3.3 Preparation of 67-147

[0317] 67-145 (6.1 g, 14.549 mmol) and diboronic acid pinacol ester (8.12 g, 32.009 mmol) were dissolved in DMSO (60 ml), and Pd(dppf)Cl2 solution (1.06 g, 1.454 mmol) and potassium acetate (5.99 g, 61.109 mmol) were added. The mixture was stirred at 80°C under nitrogen for 5 h. After the reaction, ethyl acetate (300 ml×3) was added for extraction. The combined organic phases were washed with pure water (200 ml) and saturated brine (200×2), dried over anhydrous sodium sulfate, filtered and concentrated, and then dissolved in a methanol / dichloromethane mixed solvent. 200-300 mesh silica gel powder (60 ml) was added and evaporated to dryness. The sample was dry-loaded and subjected to column chromatography using 30-50% ethyl acetate / petroleum ether as eluent. The product was collected, concentrated, and dried to obtain 5.56 g with a yield of 91.14%.

[0318] 3.4 Preparation of 67-154

[0319] Dissolve 67-147 (5.56 g, 13.259 mmol) in 4M 1,4-dioxane hydrochloride (66.2 ml, 265.18 mmol) and stir for 2 hours. After the reaction, add dichloromethane (30 ml) and evaporate to dryness. When the rotary evaporation stops, add more dichloromethane (30 ml) to dissolve the mixture and evaporate to dryness. Repeat this process 8 times to obtain 4.12 g of the product.

[0320] 3.5 Preparation of 67-155

[0321] To a 500 ml flask containing 67-154 (4.12 g, 12.907 mmol), DIEA (8.53 ml, 51.629 mmol), and acetonitrile (20 ml) was added succinic anhydride (3.87 g, 38.721 mmol, purchased from Innochem) and stirred for 12 hours. The reaction progress was monitored by TLC. After completion, the acetonitrile was evaporated to dryness and then dissolved in a methanol / dichloromethane mixture. 200-300 mesh silica gel powder (40 ml) was added and evaporated to dryness. The sample was dry-applied and subjected to column chromatography using 2-5% methanol / dichloromethane as the eluent. The product was collected, concentrated, and dried to yield 4.9 g. 1H-NMR (600MHz, DMSO-d6) δ12.09(s,1H),8.33(d,J=7.7Hz,1H),7.59(d,J=8.0Hz,2H),7.23(d,J=8.0Hz,2H),4.42(td,J=8.3 ,6.0Hz,1H),4.06-4.01(m,2H),2.96(ddd,J=22.6,13.7,7.4Hz,2H),2.37-2.30(m,4H),1.29(s,12H),1.11(t,J=7.1Hz,3H)

[0322] 3.6 Preparation of 67-34

[0323] Tert-butyl acrylate (10.7242 g, 83.672 mmol) was added to a reaction flask and dissolved in 20 ml of methanol. The reaction mixture was placed in the dark and cooled to 0°C. Tetraethylenepentamine (1.98 g, 10.459 mmol) was then dissolved in 5 ml of methanol and slowly added dropwise to the reaction flask. The reaction was allowed to react overnight at 1°C, then allowed to warm to room temperature and continue at room temperature for 24 hours. After completion of the reaction, the reaction solution was evaporated to dryness, dissolved in a dichloromethane / methanol mixture, and then added with 200-300 mesh silica gel powder and evaporated to dryness. The sample was dry-loaded and subjected to column chromatography using a 0-4% methanol / dichloromethane mixture as the eluent. The product was collected, concentrated, and dried to yield 8.9 g, with a yield of 78.34%. 1 H-NMR (600MHz, DMSO-d6) δ2.67-2.60(m,14H),2.43-2.42(d,J=3.8Hz,16H),2.28-2.26(t,J=6.8Hz,14H),1.39(d,J=1.3Hz,63H)

[0324] 3.7 Preparation of 67-53

[0325] 67-34 (2.4 g, 2.208 mmol) was added to a 100 ml flask, and a drop of water and TFA (22 ml, 309.255 mmol) were added to dissolve the mixture. The mixture was then stirred at room temperature. After completion of the reaction, most of the TFA was evaporated using a rotary evaporator to obtain a viscous oily liquid. This oily liquid was dissolved in methanol (10 ml) and evaporated using a rotary evaporator six times. The mixture was then added with n-hexane and methyl tert-butyl ether to allow precipitation, resulting in a white solid. The solid was filtered and dried in an oven to obtain 1.53 g of the product. 1H-NMR(600MHz,DMSO-d6)δ11.0(s,7H),3.33-3.07(m,18H),2.89(dd,J=29.8,5.2Hz,10H),2.72(s,8H),2.51(s,8H)

[0326] 3.8 Preparation of 67-82

[0327] 1,2-Bis(2-aminoethoxy)ethane (20.2 g, 136.2931 mmol) was weighed into a 500 ml flask and dissolved in dichloromethane (100 ml). Triethylamine (40 ml) was added and the mixture was placed in a 0°C constant temperature reaction bath. A solution of Boc2O (17.85 g, 81.7758 mmol) in dichloromethane (100 ml) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction solution was concentrated under reduced pressure and dissolved in a mixture of methanol and dichloromethane. The sample was dry loaded and subjected to column chromatography using 0.5% aqueous ammonia / 1-3% methanol / dichloromethane as the eluent. The product was collected, concentrated, and dried to yield 12.4 g, a yield of 36.64%.

[0328] 3.9 Preparation of 67-54

[0329] Fmoc-5-tert-butyl L-glutamate (10 g, 23.514 mmol), HBTU (13.376 g, 35.271 mmol), and HOBT (4.765 g, 35.271 mmol) were weighed and added to a flask containing tert-butyl glycine hydrochloride (3.94 g, 23.514 mmol). DMF (300 ml) was then added to dissolve the mixture. DIEA (17.5 ml, 105.813 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 (300 ml) and ethyl acetate (300 ml) were added for extraction. After standing for 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 and dried in a vacuum oven to obtain the product.

[0330] 3.10 Preparation of 67-55

[0331] 67-54 (12.66 g, 23.514 mmol) was placed in a 500 ml round-bottom flask and dissolved in DMF (150 ml). Morpholine (40.97 ml, 470.28 mmol) was then added and stirred at room temperature for 2 hours. After the reaction, saturated NaCl solution (300 ml) and ethyl acetate (300 ml) were added for extraction. After standing and separating the layers, 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 and dried in a vacuum oven to obtain the product.

[0332] 3.11 Preparation of 67-56

[0333] Fmoc-5-tert-butyl L-glutamate (9.68 g, 22.756 mmol), HBTU (12.945 g, 34.135 mmol), and HOBT (4.61 g, 34.135 mmol) were weighed and added to a flask containing 67-55 (7.2 g, 22.756 mmol). DMF (300 ml) was then added to dissolve the mixture. DIEA (8.2 ml, 50.063 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 (300 ml) and EA (300 ml) were added for extraction. After standing and separating, 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 and dried in a vacuum oven to obtain the product.

[0334] 3.12 Preparation of 67-57

[0335] 67-56 (16.47 g, 22.756 mmol) was placed in a 500 ml round-bottom flask and dissolved in DMF (200 ml). Morpholine (39.65 ml, 455.12 mmol) was then added and stirred at room temperature for 2 hours. After the reaction, saturated NaCl solution (300 ml) and ethyl acetate (300 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 until solid and dried in a vacuum oven to obtain the product.

[0336] 3.13 Preparation of 67-58

[0337] 67-57 (5.71 g, 11.378 mmol), HBTU (6.47 g, 17.067 mmol), and HOBT (2.31 g, 17.067 mmol) were weighed and added to a flask containing 64-152 (3.02 g, 11.378 mmol). DMF (200 ml) was then added to dissolve the mixture. DIEA (5.64 ml, 34.134 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 (300 ml) and ethyl acetate (300 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 collected and combined, evaporated to dryness, and then dissolved in a 1 / 4 methanol / dichloromethane mixed solvent. The sample was dry loaded and column chromatography was performed using 40-60% ethyl acetate / petroleum ether as eluent. The target product was collected, concentrated, and dried in a vacuum oven to obtain 4.5 g of the product with a yield of 52.94%.

[0338] 3.14 Preparation of 67-69

[0339] To a flask containing 67-58 (4.5 g, 6.008 mmol) was added dichloromethane (20 ml), and after ultrasonic dissolution, TFA (26.77 ml, 360.52 mmol) was added. The mixture was stirred at room temperature overnight. After completion of the reaction, the reaction solution was concentrated under reduced pressure to remove dichloromethane and most of the TFA. Then, n-hexane (50 ml) and methyl tert-butyl ether (200 ml) were added to allow the mixture to settle, resulting in an oily solid. The supernatant was discarded, and methyl tert-butyl ether (200 ml) was added to allow the mixture to settle. This process was repeated three times, resulting in the precipitation of a powdery solid. The solid was filtered, and the filter cake was washed three times with methyl tert-butyl ether (60 ml). The filter cake was collected and dried under vacuum to give 1.6 g of the product in a yield of 45.98%.

[0340] 3.15 Preparation of 67-96

[0341] 67-69 (1.6 g, 2.392 mmol), HOBT (1.454 g, 10.764 mmol), and HBTU (4.082 g, 10.764 mmol) were weighed and added to a flask containing di-tert-butyl glutamate (2.22 g, 7.534 mmol, purchased from Adamas). DMF (150 ml) was added to dissolve the mixture. The mixture was then placed at -5°C and DIEA (3.5 ml, 21.528 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, saturated NaCl solution (300 ml) and ethyl acetate (300 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 combined organic phases were evaporated to dryness and dried in a vacuum oven to yield 3.6 g of the product.

[0342] 3.16 Preparation of 67-99

[0343] 67-96 (3.2 g, 2.297 mmol) was placed in a hydrogenation reactor, followed by the addition of 10% Pd / C catalyst (0.04 g) and DMF (30 ml). The reaction was evacuated with a water pump and then introduced with hydrogen. This process was repeated three times. The hydrogenation apparatus was adjusted to a reading of 2 MPa and stirred overnight at room temperature. After completion of the reaction, the reaction mixture was filtered through celite, the filter cake was washed with DMF (5 ml x 3), and the filtrate was transferred to a 500 ml round-bottom flask for use as the starting material in the next step.

[0344] 3.17 Preparation of 67-101

[0345] 67-99 (2.5 g, 2.135 mmol, converted), HOBT (0.43 g, 3.203 mmol) and HBTU (1.21 g, 3.203 mmol) were weighed and added to a flask containing N'-fluorenylmethyloxycarbonyl-N-benzyloxycarbonyl-L-lysine (1.07 g, 2.135 mmol, purchased from Adamas). DMF (100 ml) was then added to dissolve the mixture. The mixture was placed at -5°C and DIEA (1.0 ml, 6.405 mmol) was slowly added dropwise. After the dropwise addition, the mixture was reacted for half an hour and then removed from the flask and stirred at room temperature for overnight. After the reaction, n-hexane (50 ml) and methyl tert-butyl ether (200 ml) were added to precipitate the oily solid. The supernatant was discarded, and methyl tert-butyl ether (200 ml) was added to precipitate. This was repeated three times, and a powdery solid precipitated. The filter cake was filtered and washed three times with methyl tert-butyl ether (60 ml). The filter cake was collected and dissolved in a methanol / dichloromethane mixed solvent. The sample was dry-loaded and subjected to column chromatography with 1-5% methanol / dichloromethane as eluent. The target product was collected, concentrated, and dried in a vacuum oven to obtain 2.3 g of the product with a yield of 64.61%.

[0346] 3.18 Preparation of 67-112

[0347] 67-101 (1.1 g, 0.647 mmol) was placed in a 500 ml round-bottom flask and dissolved in DMF (50 ml). Morpholine (1.2 ml, 12.948 mmol) was then added and stirred at room temperature for 2 hours. After the reaction, saturated NaCl solution (300 ml) and ethyl acetate (300 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 until solid and dried in a vacuum oven to obtain the product.

[0348] 3.19 Preparation of 67-113

[0349] 67-112 (0.936 g, 0.647 mmol), HOBT (0.087 g, 0.647 mmol), and HBTU (0.245 g, 0.647 mmol) were weighed and added to a flask containing 67-53 (0.042 g, 0.0616 mmol). DMF (50 ml) was then added to dissolve the mixture. The mixture was then placed at -5°C and DIEA (0.3 ml, 1.941 mmol) was slowly added dropwise. After a half-hour reaction, the mixture was removed and stirred at room temperature overnight. After the reaction, n-hexane (50 ml) and methyl tert-butyl ether (200 ml) were added to allow the mixture to settle, resulting in an oily solid. The supernatant was discarded, and methyl tert-butyl ether (200 ml) was added to allow the mixture to settle. This process was repeated three times, resulting in the precipitation of a powdery solid. The filter cake was then filtered, washed three times with methyl tert-butyl ether (60 ml), and dried in a vacuum oven to yield 0.6 g of the product.

[0350] 3.20 Preparation of 67-114

[0351] 67-113 (0.6 g, 0.0566 mmol) was placed in a hydrogenation reactor, and 10% Pd / C catalyst (0.05 g) was added. DMF (10 ml) was added to dissolve the mixture, and the mixture was evacuated with a water pump and then introduced with hydrogen. This process was repeated three times. The hydrogenation apparatus was adjusted to 2 MPa and the reaction was stirred at room temperature overnight. After the reaction, the reaction solution was filtered through diatomaceous earth, the filter cake was washed with DMF (10 ml x 3), and the filtrate was collected. N-hexane (50 ml) and methyl tert-butyl ether (200 ml) were added to allow the mixture to settle, resulting in an oily solid. The supernatant was discarded, and methyl tert-butyl ether (200 ml) was added to allow the mixture to settle. This process was repeated three times, resulting in the precipitation of a powdery solid. The mixture was filtered, and the filter cake was washed three times with methyl tert-butyl ether (60 ml). The filter cake was collected and dried in a vacuum oven to yield 0.19 g of the product.1 H-NMR(600MHz,DMSO-d6)δ8.30-7.79(m,55H),5.11(s,14H),4.25-4.09(m,39H),3. 89-3.77(m,10H),3.73-3.65(m,8H),3.63-3.55(m,7H),3.48-3.42(m,14H),2.97-2 .92(m,7H),2.80-2.71(m,28H),2.31-2.07(m,48H),2.19-2.06(m,46H),1.96-1.82 (m,40H),1.81-1.66(m,44H),1.53-1.45(m,34H),1.39(s,378H),1.28-1.15(m,42H)

[0352] 3.21 Preparation of 67-116

[0353] 67-114 (0.19 g, 0.0196 mmol) was dissolved in anhydrous DMF (20 ml) in a 250 ml round-bottom flask. DIEA (0.9 ml, 5.4488 mmol) was added dropwise and stirred for 30 minutes. M-SCM-5K (0.8 g, 0.151 mmol, purchased from Jenka, Lot Number: ZZ363P139) was then added. Dissolution was assisted by ultrasonication, and the mixture was stirred at low speed at room temperature in the dark for 4 days. After the reaction, n-hexane (50 ml) and methyl tert-butyl ether (200 ml) were added to precipitate, and an oily solid was obtained. The supernatant was discarded, and methyl tert-butyl ether (200 ml) was added to precipitate. This was repeated three times, and a powdery solid was precipitated. The solid was filtered and dissolved in a methanol / dichloromethane mixed solvent. Silica gel powder was added for drying, and the sample was dry-loaded. Column chromatography was performed using 1% ammonia water / 5-10% methanol / dichloromethane as an eluent. The product was collected, concentrated, and dried in a vacuum oven to obtain 0.45 g. 1 H-NMR(600MHz,DMSO-d6)δ8.27-7.85(m,63H),4.26-4.09(m,56H),3.75-3.72(m,14H),3.52-3.50(m,3269H),3.24-3.20(m,28H),2.90-2.6 9(m,30H),2.32-2.30(m,84H),2.16-2.10(m,56H),1.795-1.757(m,1 4H),1.517-1.471(m,28H),1.402-1.378(s,378H),1.25-1.23(m,56H)

[0354] 3.22 Preparation of 67-210

[0355] 67-116 (2.69 g, 0.0588 mmol) was dissolved in dichloromethane (4 ml), and TFA (3.6 ml, 49.405 mmol) was added. The mixture was stirred at room temperature for two days. After the reaction, the reaction solution was concentrated under reduced pressure to remove dichloromethane and most of the TFA. Then, n-hexane (50 ml) and methyl tert-butyl ether (200 ml) were added to allow the mixture to settle, resulting in an oily solid. The supernatant was discarded, and methyl tert-butyl ether (200 ml) was added to allow the mixture to settle. This process was repeated three times, resulting in the precipitation of a powdery solid. The solid was filtered, and the filter cake was washed three times with methyl tert-butyl ether (60 ml). The filter cake was collected and dried under vacuum to yield 2.27 g of the product, with a yield of 89.01%. 1 H-NMR(600MHz,DMSO-d6)δ12.84-11.70(m,42H),8.31-8.02(m,63H),4.25-4.16(m,56H),3.85-3.80(m,14H),3.735-3.687(m,14H),3.52-3 .50(m,3269H),2.60-2.53(m,14H),2.37-2.34(m,16H),2.31-2.08(m ,154H),1.792-1.770(m,14H),1.52-1.47(m,28H),1.25-1.23(m,56H)

[0356] 3.23 Preparation of 67-213

[0357] 67-210 (2.27 g, 0.052 mmol), 67-82 (0.81 g, 3.293 mmol), HBTU (1.24 g, 3.293 mmol), and HBTU (0.44 g, 3.293 mmol) were mixed in a 250 ml round-bottom flask, dissolved in DMF (50 ml), and then added with DIEA (1.6 ml, 9.879 mmol). The mixture was stirred and reacted at room temperature overnight. After the reaction, n-hexane (50 ml) and methyl tert-butyl ether (200 ml) were added to allow the mixture to settle, resulting in an oily solid. The supernatant was discarded, and dichloromethane (10 ml) was added to dissolve the mixture. MTBE (200 ml) was then added to allow the mixture to settle. This process was repeated three times, resulting in the precipitation of a powdery solid. The solid was filtered, and the filter cake was washed three times with MTBE (60 ml). The filter cake was collected and dried under vacuum to obtain the product. 1H-NMR(600MHz,DMSO-d6)δ8.03-7.91(m,147H),4.18-4.15(m,49H),3.63-3.55 (m,350H),3.52-3.50(m,3269H),3.37-3.32(m,49H),3.28-3.19(m,42H),3.24 -3.23(m,14H),3.07-3.04(m,84H),2.89-2.86(m,154H),2.64-2.53(m,44H),1 .83-1.80(m,14H),1.46-1.40(m,28H),1.40-1.34(m,378H),1.25-1.22(m,42H)

[0358] 3.24 Preparation of 67-216

[0359] Compound 67-213 (1.01 g, 0.019 mmol) was weighed and placed in a 250 ml flask. TFA (11 ml, 159.66 mmol) was added, along with a stirrer. The mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and dissolved in dichloromethane (10 ml). The mixture was neutralized with excess DIEA (0.5 ml). Methyl tert-butyl ether (100 ml) and n-hexane (50 ml) were added to allow the mixture to settle. The oily product was dissolved in a methanol / dichloromethane mixture, and then methyl tert-butyl ether (100 ml) and n-hexane (50 ml) were added to allow the mixture to settle. This process was repeated five times to obtain the product as an oil. 1 H-NMR(600MHz,DMSO-d6)δ8.05-7.98(m,105H),5.11-4.99(m,84H),4.18 -4.12(m,49H),3.62-3.59(m,350H),3.52-3.50(m,3269H),3.47-3.37(m, 49H),3.39-3.34(m,56H),3.24-3.19(m,84H),2.97-2.90(m,14H),2.09-2 .00(m,184H),1.76-1.72(m,14H),1.55-1.45(m,28H),1.25-1.22(m,42H)

[0360] 3.25 Preparation of 67-228

[0361] 67-216 (0.5 g, 0.0101 mmol), 67-155 (0.26 g, 0.6397 mmol), HOBT (0.086 g, 0.6397 mmol) and HBTU (0.24 g, 0.6397 mmol) were mixed in a 100 ml flask, dissolved in DMF (20 ml), and then DIEA (0.3 ml, 1.9191 mmol) was added dropwise. The reaction was stirred at room temperature overnight. After the reaction, n-hexane (50 ml) and methyl tert-butyl ether (200 ml) were added to precipitate the oily solid. The supernatant was poured off, and methyl tert-butyl ether (200 ml) was added to precipitate. This was repeated three times until a powdery solid precipitated. The filter cake was collected by suction and dissolved in a methanol / dichloromethane mixed solvent. Silica gel powder was added to dry the sample, and column chromatography was performed using 1% ammonia water / 8-12% methanol / dichloromethane as the eluent. The product was collected, concentrated, and dried in a vacuum oven to obtain 0.24 g. 1 H-NMR(600MHz,DMSO-d6)δ8.24-8.15(m,189H),7.14-7.05(m,84H),6.68-6.60(m,84H),4.61-4 .47(m,84H),4.09-4.03(m,91H),3.64-3.59(m,350H),3.53-3.49(m,3269H),3.437-3.375(m,4 9H),3.28-3.26(m,84H),3.24-3.20(m,28H),3.16-3.09(m,84H),2.94-2.85(m,42H),2.75-2.7 1(m,114H),2.40-2.31(m,84H),2.00-1.96(m,154H),1.52-1.43(m,42H),1.295-1.287(m,42H), 1.25-1.20(m,504H),1.215-1.187(m,126H)

[0362] Example 4 Synthesis of Compounds 81-118

[0363] 4.1 Preparation of 62-13

[0364] Hexaminocaproic 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. The mixture was then brought to room temperature and stirred overnight. After completion of the reaction, the reaction mixture was transferred to a 2 L separatory funnel, purified water (300 ml) and ethyl acetate (350 ml) were added, and extraction was performed. 36% 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.

[0365] 4.2 Preparation of 65-104

[0366] 71-85 (8.45 g, 17.16 mmol), Niraparib (3.93 g, 12.25 mmol, purchased from PharmaBlock, NPB), HBTU (6.97 g, 18.38 mmol), and HOBT (2.5 g, 18.38 mmol) were added to a 500 ml round-bottom flask. DMF (50 ml) was then added and sonication was used to assist dissolution. The mixture was stirred at -5°C for 3 minutes, and then DIEA (8.1 ml, 49.03 mmol) was slowly added dropwise to continue the reaction. After the addition was complete, stirring was continued at -5°C for 1 hour, then the mixture was brought to room temperature and stirred overnight. After the reaction was completed, the reaction mixture was transferred to a 2 L separatory funnel and extracted with purified water (300 ml) and ethyl acetate (350 ml). 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 brine (250 ml x 2), collected, concentrated under reduced pressure, and evaporated to dryness after adding 200-300 mesh silica gel powder. Dry-load the sample and perform column chromatography using 2% methanol / dichloromethane as the eluent to collect the desired product, concentrate, and evaporate to dryness to obtain 10.51 g of the product.

[0367] 4.3 Preparation of 62-174

[0368] Compound 65-104 (2.5 g, 3.14 mmol) was added to a 500 ml round-bottom flask containing dichloromethane (5 ml). Dissolution was assisted by ultrasonication, followed by the addition of TFA (5.37 ml, 47.17 mmol). The reaction was stirred at room temperature. After completion of the reaction, the dichloromethane and most of the TFA were removed by rotary evaporation, and methyl tert-butyl ether (200 ml) was added to allow precipitation. A solid precipitated and was filtered to obtain 2.08 g of the product.

[0369] 4.4 Preparation of 62-1

[0370] Boc-Glu-OH (3 g, 12.1 mmol), L-glutamic acid dibenzyl ester p-toluenesulfonate (13.29 g, 26.62 mmol), HBTU (13.76 g, 36.3 mmol), and HOBT (4.79 g, 36.3 mmol) were added to a 500 ml round-bottom flask. DMF (100 ml) was then added and dissolved using ultrasound. DIEA (17.99 ml, 108.9 mmol) was added dropwise in an ice-water bath. After the addition was complete, the mixture was removed and stirred at room temperature. Upon completion of the reaction, the reaction mixture was transferred to a 2 L separatory funnel filled with purified water (600 ml) and ethyl acetate (600 ml). 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 bicarbonate solution (30 ml x 2), concentrated under reduced pressure, and 200-300 mesh silica gel powder (25 g) was added and evaporated to dryness. The sample was loaded by dry method and subjected to column chromatography using 1% methanol / dichloromethane as eluent. The target product was collected, concentrated and evaporated to dryness to obtain 10.47 g of the product.

[0371] 4.5 Preparation of 62-2

[0372] Compound 62-1 (10.47 g, 12.1 mmol) was placed in a 500 ml round-bottom flask and dissolved in dichloromethane (15 ml) using ultrasonication. TFA (13.47 ml, 181.5 mmol) was then added and stirred at room temperature. After the reaction, the dichloromethane was rotary evaporated to remove most of the TFA. Methyl tert-butyl ether (200 ml) was then added to allow precipitation. A solid precipitated, which was then filtered and dried to yield 9.2 g of the product.

[0373] 4.6 Preparation of 61-213

[0374] Compound 62-13 (2.716 g, 11.75 mmol) and compound 62-2 (9 g, 11.75 mmol) were added to a 500 ml round-bottom flask, followed by the addition of DMF (50 ml) and sonication-assisted dissolution. After stirring at room temperature for 1 min, compound 68-54 (3.57 g, 12.925 mmol) and N-methylmorpholine (3.8 ml, 35.25 mmol) were added, and the reaction was continued by stirring at room temperature. Upon completion of the reaction, the reaction solution was transferred to a 2 L separatory funnel filled with purified water (300 ml) and ethyl acetate (350 ml) for extraction. The organic phase was collected and the aqueous phase was further extracted with ethyl acetate (200 ml x 3). The combined organic phases were washed with saturated sodium bicarbonate solution (250 ml x 2), collected, concentrated under reduced pressure, and 200-300 mesh silica gel powder (25 g) was added and evaporated to dryness. The sample was loaded by dry method and subjected to column chromatography using 2.5% methanol / dichloromethane as eluent. The target product was collected, concentrated and evaporated to dryness to obtain 10.38 g of the product.

[0375] 4.7 Preparation of 62-156

[0376] 61-213 (0.77 g, 0.786 mmol) and 10% Pd / C catalyst (0.12 g) were added to a hydrogenation reactor. DMF (15 ml) was added, the reactor was sealed, and a water pump was used to evacuate the reactor. Hydrogen was then introduced three times. The hydrogen pressure was then adjusted to 300 psi, and the mixture was stirred overnight at room temperature. After the reaction, the reaction mixture was filtered through celite, and the celite was rinsed with DMF (3 ml x 3). The filtrate was collected and used as the starting material for the next reaction.

[0377] 4.8 Preparation of 62-180

[0378] 62-174 (1.2 g, 1.72 mmol) and 62-156 (0.236 g, 0.38 mmol) were added to a 250 ml round-bottom flask, followed by DMF (10 ml) and sonication-assisted dissolution. After stirring at 0°C for 2 min, 68-54 (0.47 g, 1.72 mmol) and N-methylmorpholine (0.38 ml, 3.45 mmol) were added, and the reaction continued to stir at room temperature. After the reaction, n-hexane (50 ml) and methyl tert-butyl ether (450 ml) were added to allow precipitation. The solid precipitated and was filtered. The filter cake was transferred to a 2 L round-bottom flask and a 1 / 1 methanol / dichloromethane mixture (100 ml) was added. After sonication-assisted dissolution, n-hexane (50 ml) and methyl tert-butyl ether (900 ml) were added to allow precipitation. The solid was then filtered. This mixed solvent dissolution / methyl tert-butyl ether precipitation process was repeated three times. After the final filtration, the product was transferred to a 250 ml round-bottom flask, ethyl acetate (50 ml) was added, ultrasonicated for 10 min, and filtered. This ethyl acetate addition / ultrasonication / filtration process was repeated three times. After the final filtration, the filter cake was dried to obtain 1.18 g of the product.

[0379] 4.9 Preparation of 81-43

[0380] 62-180 (1.7 g, 0.51 mmol) was added to a 250 ml round-bottom flask, and dichloromethane (10 ml) was added. Dissolution was assisted by ultrasonication, followed by the addition of TFA (5.7 ml, 76.6 mmol). The reaction was stirred at room temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove dichloromethane and most of the TFA. Then, n-hexane (50 ml) and methyl tert-butyl ether (200 ml) were added to the solution to allow precipitation, resulting in an oily solid. The supernatant was discarded, and methyl tert-butyl ether (200 ml) was added to the solution to allow precipitation. This was repeated three times, resulting in the precipitation of a powdery solid. The filter cake was collected by filtration and dissolved in 1 / 4 of a methanol / dichloromethane mixture. The sample was dry-loaded and subjected to column chromatography using 1% ammonia water / 8% methanol / dichloromethane as the eluent. The desired product was collected, concentrated, and evaporated to dryness to obtain 1.2 g of the product. 1H-NMR(600MHz,DMSO-d6)δ9.34-9.23(m,4H),8.63-8.51(m,4H),8.28-8.15(m,6H),8.14-7.92(m,24H), 7.93-7.79(m,7H),7.64-7.45(m,11H),7.31-7.06(m,23H),4.63-4.51(m,4H),4.49-4.31(m,8H),4.26- 4.12(m,3H),4.10-3.88(m,8H),3.88-3.77(m,4H),3.76-3.55(m,7H),3.19-3.10(m,2H),3.10-2.97(m, 5H),2.87-2.57(m,18H),2.22-2.02(m,8H),1.99-1.66(m,20H),1.65-1.33(m,20H),0.94-0.65(m,24H)

[0381] 4.10 Preparation of 62-150

[0382] 7-Ethyl-10-hydroxycamptothecin (2 g, 5.1 mmol, referred to as SN38) was added to a 500 ml round-bottom flask, followed by dichloromethane (100 ml). After ultrasonic dissolution, TBDPS-Cl (5.2 ml, 20.39 mmol) and triethylamine (3.2 ml, 22.93 mmol) were added and stirred in a 30° oil bath overnight. After completion of the reaction, the reaction solution was transferred to a 1 L separatory funnel and washed sequentially with 0.2 N HCl solution (150 ml × 2), saturated sodium bicarbonate solution (300 ml), and saturated brine (300 ml). The resulting dichloromethane organic phase was dried over anhydrous magnesium sulfate and concentrated to dryness to obtain 3 g of the product.

[0383] 4.11 Preparation of 62-153

[0384] 62-150 (3 g, 4.75 mmol) and Boc-Gly-OH (1.249 g, 7.13 mmol) were added to a 500 ml round-bottom flask, followed by the addition of dichloromethane (100 ml). Ultrasonication was used to dissolve the mixture, and the mixture was stirred at 0°C for 5 minutes. EDCI (1.36 g, 7.13 mmol) and DMAP (0.26 g, 2.13 mmol) were then added, and the reaction was continued by stirring at 0°C. After the reaction was complete, the reaction solution was transferred to a 1 L separatory funnel and washed sequentially with 0.5% sodium bicarbonate solution (150 ml), purified water (150 ml), 0.1 N HCl solution (150 ml), and saturated brine (150 ml). The resulting dichloromethane organic phase was dried over anhydrous magnesium sulfate, and 200-300 mesh silica gel powder (30 g) was added and evaporated to dryness. The sample was loaded by dry method and column chromatography was performed using 1.5% methanol / dichloromethane as eluent to collect the target product, which was concentrated and evaporated to dryness to obtain 2.9 g of the product.

[0385] 4.12 Preparation of 62-155

[0386] Compound 62-153 (2.9 g, 3.68 mmol) was added to a 500 ml round-bottom flask, followed by 1,4-dioxane (10 ml). The mixture was dissolved using ultrasonication. Then, 4 M HCl-dioxane (10 ml) was added and stirred at room temperature for 5 h. After completion of the reaction, the HCl-dioxane was removed by rotary evaporation under reduced pressure. Methyl tert-butyl ether (300 ml) was added to allow precipitation. The solid precipitated and was filtered. The filter cake was dried to yield 2.08 g of the product. 1 H-NMR(600MHz,DMSO-d6)δ8.67-8.64(m,1H),8.06(d, J=8.9Hz,1H),7.80-7.64(m,4H),7.56-7.42(m,6H),7.26(s,1H),7.14(s,1H),5.59-5.44(m,2H),5.30-5.13(m,2H),4.48-4.40(m,2H) ,4.33-4.22(m,1H),4.08-3.94(m,1H),2.72-2.56(m,2H),2.22-2.06(m,2H),1.11(s,9H),0.93(t,J=7.0Hz,3H),0.83(t,J=7.2Hz,3H)

[0387] 4.13 Preparation of 65-131

[0388] 62-155 (0.5 g, 0.72 mmol) was added to a 500 ml round-bottom flask, followed by THF (15 ml). After sonication, the mixture was stirred at 25°C for 5 min, followed by the addition of succinic anhydride (0.18 g, 1.81 mmol). Triethylamine (0.25 ml, 1.74 mmol) was then slowly added dropwise. The mixture was stirred at room temperature for 12 h. After completion, methyl tert-butyl ether (350 ml) was added to allow precipitation. A solid precipitated and was filtered. The filter cake was dissolved in dichloromethane (200 ml), 200-300 mesh silica gel powder (25 g) was added, and the mixture was evaporated to dryness. The sample was dry-applied and subjected to column chromatography using 0.5% formic acid / 3-6% methanol / dichloromethane as the eluent. The desired product was collected, concentrated, and evaporated to dryness to yield 0.1 g. 1 H-NMR (600MHz, DMSO-d6) δ12.03 (s, 1H), 8.44-8.37 (m, 1H), 8.06 (d, J = 8.9Hz, 1H), 7.79-7.71 (m,4H),7.61-7.55(m,1H),7.56-7.44(m,6H),7.12(s,1H),7.03(s,1H),5.47-5.44(m,2H),5. 24-5.14(m,2H),4.17-4.10(m,1H),4.02-3.95(m,1H),2.66-2.58(m,2H),2.45-2.4(m,2H),2 .39-2.31(m,2H),2.17-2.09(m,2H),1.11(s,9H),0.93(t,J=7.0Hz,3H),0.83(t,J=7.2Hz,3H)

[0389] 4.14 Preparation of 69-33

[0390] Fmoc-Glu(OtBu)-OH (10 g, 23.50 mmol) and β-alanine benzyl ester p-toluenesulfonate (7.86 g, 22.38 mmol) were added to a 500 ml round-bottom flask. DMF (50 ml) was then added and sonicated. The mixture was stirred at -5°C for 3 minutes. 68-54 (6.813 g, 24.62 mmol) and N-methylmorpholine (3.71 ml, 33.57 mmol) were then added and allowed to react at room temperature. Upon completion of the reaction, the reaction mixture was transferred to a 2 L separatory funnel filled with purified water (300 ml) and ethyl acetate (350 ml). 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 bicarbonate solution (250 ml x 2). The organic phases were collected, 200-300 mesh silica gel powder (50 g) was added, and the mixture was evaporated to dryness. The sample was loaded by dry method and subjected to column chromatography using 0.5% methanol / dichloromethane as eluent. The target product was collected, concentrated and evaporated to dryness to obtain 11.64 g of the product.

[0391] 4.15 Preparation of 69-34

[0392] Compound 69-33 (11.64 g, 19.84 mmol) was added to a 500 ml round-bottom flask, followed by dichloromethane (20 ml) and ultrasonic dissolution. TFA (39.58 ml, 347.13 mmol) was then added and stirred at room temperature. After completion of the reaction, TFA was removed by rotary evaporation. The reaction solution was transferred with ethyl acetate to a 2 L separatory funnel filled with purified water (300 ml) and ethyl acetate (350 ml) for extraction. The organic phase was collected and the aqueous phase was washed with ethyl acetate (200 ml x 3). The combined organic phases were washed with saturated brine (250 ml x 2). The organic phases were collected, concentrated, and evaporated to dryness to yield 8.95 g of the product.

[0393] 4.16 Preparation of 69-36

[0394] 69-34 (7.05 g, 13.31 mmol) and 38-224 (9.89 g, 13.375 mmol) were added to a 500 ml round-bottom flask, followed by DMF (15 ml) and sonication-assisted dissolution. After stirring at room temperature for 2 min, 68-54 (4.05 g, 14.64 mmol) and N-methylmorpholine (2.94 ml, 26.63 mmol) were added, and the reaction continued to stir at room temperature. After completion of the reaction, methyl tert-butyl ether (420 ml) was added to allow precipitation. The solid precipitated and was filtered. The filter cake was dissolved in a 1 / 1 methanol / dichloromethane mixture (300 ml), and 200-300 mesh silica gel powder (30 g) was added and evaporated to dryness. The sample was dry-loaded and subjected to column chromatography using 5% methanol / dichloromethane as the eluent. The desired product was collected, concentrated, and evaporated to dryness to yield 14.97 g.

[0395] 4.17 Preparation of 69-37

[0396] Compound 69-36 (10 g, 7.965 mmol) was added to a 500 ml round-bottom flask, followed by DMF (10 ml) and sonication-assisted dissolution. Morpholine (15 ml) was then added and stirred at room temperature. After completion, methyl tert-butyl ether (400 ml) was added to allow precipitation. The solid precipitated and was filtered. The filter cake was washed with petroleum ether (200 ml) and dried to yield 8.27 g of the product.

[0397] 4.18 Preparation of 69-39

[0398] 69-37 (8.22 g, 7.965 mmol), N'-fluorenylmethyloxycarbonyl-N-benzyloxycarbonyl-L-lysine (4.20 g, 8.36 mmol), HBTU (3.32 g, 8.76 mmol) and HOBT (1.18 g, 8.76 mmol) were added to a 500 ml round-bottom flask, and DMF (20 ml) was added. The mixture was dissolved with ultrasonic assistance and stirred at 0°C for 3 min. DIEA (1.97 ml, 11.94 mmol) was added and the reaction was stirred at room temperature. After the reaction is completed, methyl tert-butyl ether (400 ml) is added to precipitate the solid, which is filtered off with suction. The filter cake is dissolved with a 1 / 1 methanol / dichloromethane mixed solvent (300 ml), and 200-300 mesh silica gel powder (35 g) is added and evaporated to dryness. The sample is dry-loaded and column chromatography is performed using 8% methanol / dichloromethane as an eluent. The target product is collected, concentrated, and evaporated to dryness to obtain 10.85 g of the product. 1H-NMR(600MHz,DMSO-d6)δ8.16(d,J=7.5Hz,1H),8.08(d,J=7.6Hz,1H),8.01-7.94(m,2H),7. 93-7.85(m,3H),7.75-7.66(m,3H),7.52-7.45(m,1H),7.43-7.27(m,14H),7.23(t,J=5.7Hz, 1H),5.15-4.94(m,4H),4.34-4.06(m,7H),3.97(td,J=4.5,8.5Hz,1H),3.39-3.22(m,2H),3. 03-2.91(m,4H),2.53-2.47(m,2H),2.31-2.00(m,10H),1.95-1.57(m,9H),1.57-1.13(m,47H)

[0399] 4.19 Preparation of 69-45

[0400] 69-39 (3.0 g, 1.926 mmol) was added to a 500 ml round-bottom flask, followed by DMF (20 ml) and sonication-assisted dissolution. Morpholine (8.44 ml, 96.8 mmol) was then added and stirred at room temperature. After completion, methyl tert-butyl ether (400 ml) was added to allow precipitation. The solid precipitated and was filtered. The filter cake was dissolved in a 1 / 1 methanol / dichloromethane mixture (300 ml). 200-300 mesh silica gel powder (30 g) was added and evaporated to dryness. The sample was dry-applied and subjected to column chromatography using 1% aqueous ammonia / 5% methanol / dichloromethane as the eluent to collect the desired product, concentrate, and evaporate to dryness to obtain 2.3 g of the product. 1 H-NMR(600 MHz, DMSO-d6)δ8.16(d,J=7.5Hz,1H),8.08(d,J=7.6Hz,1H),8.01-7.94(m,2H),7.93-7.8 5(m,1H),7.75-7.66(m,1H),7.52-7.45(m,1H),7.43-7.27(m,9H),7.23(t,J=5.7Hz,1H),5 .15-4.94(m,4H),4.34-4.06(m,4H),3.97(td,J=4.5,8.5Hz,1H),3.39-3.22(m,2H),3.03- 2.91(m,4H),2.53-2.47(m,4H),2.31-2.00(m,10H),1.95-1.57(m,9H),1.57-1.13(m,47H)

[0401] 4.20 Preparation of 81-22

[0402] 69-45 (1.5 g, 1.157 mmol), triethylenetetraaminehexaacetic acid (0.063 g, 0.1256 mmol, purchased from TCI), HBTU (0.438 g, 1.157 mmol), and HOBT (0.156 g, 1.157 mmol) were added to a 100 ml round-bottom flask. DMF (15 ml) was then added and dissolved with ultrasonication. After stirring at 0°C for 5 min, DIEA (1.13 ml, 6.864 mmol) was added and the reaction was stirred at room temperature. After completion of the reaction, ethyl acetate (300 ml) and purified water (300 ml) were added for extraction. The organic phase was collected, and the aqueous phase was further extracted with ethyl acetate (200 ml). The organic phases were combined and concentrated, and 1 / 4 of a methanol / dichloromethane mixed solvent (50 ml) was added. The mixture was dissolved with ultrasonic assistance, and 200-300 mesh silica gel powder (10 g) was added and evaporated to dryness. The sample was dry-loaded and column chromatography was performed using 4% methanol / dichloromethane as the eluent. The target product was collected, concentrated, and evaporated to dryness to obtain 0.49 g of the product with a yield of 74%.

[0403] 4.21 Preparation of 81-30

[0404] 81-22 (1 g, 0.122 mmol) and 10% Pd / C catalyst (250 mg) were added to a hydrogenation reactor. DMF (10 ml) and acetic acid (0.5 ml) were added. The hydrogenation reactor was sealed, evacuated with a water pump, and then refilled with hydrogen. This process was repeated three times, with the hydrogen pressure adjusted to 2 MPa. The reaction was then allowed to react at 35°C for 72 h. After completion of the reaction, the filtrate was collected by suction filtration using a Buchner funnel containing filter paper. Methyl tert-butyl ether (100 ml) and n-hexane (100 ml) were added, shaken, allowed to stand, and the supernatant decanted. This process was repeated multiple times until the product became a viscous oil. 0.57 g of the product was obtained by drying. 1 H-NMR(600MHz,DMSO-d6)δ8.54-8.45(m,3H),8.23-7.90(m,33H),7.90-7.68(m,6H),4.27 -4.23(m,6H),4.20-4.17(m,5H),4.13-4.07(m,14H),4.05-3.99(m,6H),3.89-3.43(m,8H) ,3.31-3.23(m,5H),3.23-3.15(m,6H),3.11-3.03(m,12H),3.03-2.92(m,20H),2.87-2.7 5(m,20H),2.51-2.44(m,4H),2.29-1.98(m,74H),1.93-1.65(m,57H),1.51-1.13(m,279H)

[0405] 4.22 Preparation of 81-68

[0406] 81-30 (0.59 g, 0.0865 mmol) was added to a round-bottom flask, followed by ultra-dry DMF (15 ml). Dissolution was assisted by ultrasonication, and the mixture was stirred at -5°C for 5 minutes. DIEA (0.85 ml, 5.19 mmol) was then slowly added dropwise. The reaction was continued with stirring for 2 minutes, then removed and M-SCM-5000 (2.87 g, 0.545 mmol, purchased from JianKai, batch number: ZZ403P152) was added. The reaction was stirred at low speed at 35°C in the dark for 48 hours. After the reaction is completed, methyl tert-butyl ether (500 ml) is added to precipitate, and the solid precipitates and is filtered. The filter cake is dissolved with 1 / 4 methanol / dichloromethane mixed solvent (30 ml) under ultrasonic assistance, and 100-200 mesh silica gel powder (10 g) is added and evaporated to dryness. The sample is dry loaded and column chromatography is performed with 5% methanol / dichloromethane to 1% ammonia water / 15% methanol / dichloromethane as eluents. The target product is collected, concentrated, and evaporated to dryness to obtain 0.37 g of the product. 1 H-NMR(600MHz,DMSO-d6)δ8.79-7.48(m,48H),4.27-4.23(m,6H),4.20-4.17(m,5 H),4.13-4.07(m,14H),4.05-3.99(m,6H),3.89-3.43(m,2798H),3.31-3.23(m,5 H),3.23-3.15(m,6H),3.11-3.03(m,12H),3.03-2.92(m,14H),2.87-2.75(m,14H ),2.51-2.44(m,4H),2.29-1.98(m,74H),1.93-1.65(m,57H),1.51-1.13(m,279H)

[0407] 4.23 Preparation of 81-48

[0408] 81-68 (0.6 g, 0.0158 mmol), 81-43 (0.46 g, 0.143 mmol), HBTU (0.054 g, 0.143 mmol) and HOBT (0.019 g, 0.143 mmol) were added to a 50 ml round-bottom flask, and then NMP (7 ml) was added. Dissolution was assisted by ultrasonic wave. After stirring at 0° for 10 min, DIEA (0.14 ml, 0.8532 mmol) was added dropwise. After continuing to stir and react at 0° for 5 min, the mixture was taken out and stirred at room temperature. After the reaction is completed, methyl tert-butyl ether (500 ml) is added to settle the solid, which is precipitated and filtered. A 1 / 1 methanol / dichloromethane mixed solvent (100 ml) is added to the filter cake and dissolved with ultrasonic assistance. 100-200 mesh silica gel powder (10 g) is added and evaporated to dryness. The sample is dry-loaded and column chromatography is performed using 0-1% ammonia water / 5-10% methanol / dichloromethane as eluent. The target product is collected, concentrated, and evaporated to dryness to obtain 0.4 g of the product. 1 H-NMR(600MHz,DMSO-d6)δ9.34-9.23(m,24H),8.79-7.48(m,360H),7.31-7.06(m,138H) ,4.63-4.51(m,24H),4.49-4.31(m,48H),4.27-4.12(m,29H),4.13-3.88(m,68H),3.88-3 .43(m,2864H),3.31-3.23(m,5H),3.23-3.10(m,18H),3.10-2.92(m,56H),2.87-2.75(m, 110H),2.51-2.44(m,4H),2.29-1.65(m,299H),1.65-1.13(m,399H),0.94-0.65(m,144H)

[0409] 4.24 Preparation of 81-106

[0410] 81-48 (1.5 g, 0.026 mmol) was added to a 50 ml round-bottom flask, followed by TFA (10 ml, 134.6 mmol). The reaction was stirred at room temperature. After completion of the reaction, an appropriate amount of dichloromethane was added, and the TFA and dichloromethane were removed by rotary evaporation. An appropriate amount of methyl tert-butyl ether was then added and removed by rotary evaporation. MTBE (100 ml) was then added and ultrasonicated. The mixture was allowed to stand and the supernatant was decanted. This process was repeated several times, followed by concentration and drying to obtain 1.38 g of a solid product. 1H-NMR(600MHz,DMSO-d6)δ9.34-9.23(m,24H),8.79-7.48(m,360H),7.31-7.06(m,138H),4.63-4 .51(m,24H),4.49-4.31(m,48H),4.27-4.12(m,29H),4.13-3.88(m,68H),3.88-3.43(m,2888H), 3.31-3.10(m,23H),3.10-2.92(m,56H),2.87-2.75(m,110H),2.52-2.4 3(m,4H),2.29-1.66(m,299H),1.66-1.13(m,183H),0.94-0.64(m,144H)

[0411] 4.25 Preparation of 81-110

[0412] 81-106 (0.87 g, 0.0156 mmol), N-Boc-ethylenediamine hydrochloride (0.12 g, 0.75 mmol), HBTU (0.28 g, 0.75 mmol) and HOBT (0.1 g, 0.75 mmol) were added to a 50 ml round-bottom flask, and then DMF (7 ml) was added. The mixture was dissolved with ultrasonic assistance. After stirring at 0° for 1 min, DIEA (0.3 ml, 1.872 mmol) was added dropwise and the reaction was stirred at 35°C. After the reaction is completed, methyl tert-butyl ether (500 ml) is added to precipitate, and the solid precipitates and is filtered. The filter cake is dissolved with 1 / 4 methanol / dichloromethane mixed solvent (50 ml), and 100-200 mesh silica gel powder (10 g) is added and evaporated to dryness. The sample is dry loaded and column chromatography is performed with 1% ammonia water / 2-10% methanol / dichloromethane as eluent. The target product is collected, concentrated, and evaporated to dryness to obtain 0.9 g of the product. 1 H-NMR(600MHz,DMSO-d6)δ9.34-9.22(m,24H),8.79-7.45(m,384H),7.31-7.06 (m,162H),4.63-4.51(m,24H),4.49-4.30(m,48H),4.27-4.12(m,29H),4.13-3. 88(m,68H),3.88-3.43(m,2960H),3.31-3.10(m,23H),3.10-2.92(m,56H),2.87 -2.73(m,110H),2.52-1.66(m,303H),1.66-1.13(m,399H),0.94-0.64(m,144H)

[0413] 4.26 Preparation of 81-113

[0414] 81-110 (0.9 g, 0.015 mmol) was added to a 50 ml round-bottom flask, and TFA (5 ml, 67.3 mmol) was added. The reaction was stirred at room temperature. After the reaction was completed, TFA was removed by rotary evaporation, and methyl tert-butyl ether (500 ml) was added to precipitate. A solid precipitated, which was treated with ultrasound and removed by rotary evaporation. 1 / 4 of a methanol / dichloromethane mixed solvent (50 ml) was added to dissolve the product, and methyl tert-butyl ether (200 ml) was added to precipitate a solid. The product was allowed to stand, the supernatant was poured out, and the residual solvent was removed by rotary evaporation. This dissolution, precipitation, and vacuum rotary evaporation process was repeated three times. The solid was dried to obtain a solid. The solid was then dissolved in an appropriate amount of dichloromethane, DIEA was added to adjust the pH to a weak alkaline state, and the product was evaporated to dryness and dried to obtain 0.44 g of the product.

[0415] 4.27 Preparation of 81-116

[0416] 81-113 (0.44 g, 0.0077 mmol), 65-131 (0.44 g, 0.559 mmol), HBTU (0.21 g, 0.559 mmol) and HOBT (0.075 g, 0.559 mmol) were added to a 500 ml round-bottom flask, and DMF (10 ml) was added. The mixture was dissolved with ultrasonic assistance and stirred at 0°C for 30 min. DIEA (0.28 ml, 1.677 mmol) was then slowly added dropwise. After the addition was complete, the reaction was stirred at room temperature overnight. After the reaction, n-hexane (50 ml) and methyl tert-butyl ether (200 ml) were added to precipitate the oily solid. The supernatant was discarded, and methyl tert-butyl ether (200 ml) was added to precipitate. This was repeated three times until a powdery solid precipitated. The filter cake was collected by filtration and dissolved in 1 / 4 of a methanol / dichloromethane mixed solvent. The sample was dry-loaded and subjected to column chromatography using 1% triethylamine / 8-10% methanol / dichloromethane as an eluent. The target product was collected, concentrated, and evaporated to dryness to obtain 0.18 g of the product. 1H-NMR(600MHz,DMSO-d6)δ9.34-9.22(m,24H),8.79-7.37(m,720H),7.31-7.03(m,186H),5.50 -5.42(m,48H),5.31-5.12(m,48H),4.63-4.51(m,24H),4.49-4.30(m,48H),4.27-4.12(m,53H) ,4.13-3.87(m,92H),3.87-3.43(m,2960H),3.31-3.10(m,23H),3.10-2.92(m,56H),2.87-2.7 3(m,110H),2.73-2.55(m,48H),2.52-1.64(m,447H),1.64-0.99(m,399H),0.94-0.64(m,288H)

[0417] 4.28 Preparation of 81-118

[0418] 81-116 (0.08 g, 0.00106 mmol) was added to a 50 ml round-bottom flask, THF (7 ml) was added, and ultrasonic wave-assisted dissolution was added. TBAF (0.032 g, 0.102 mmol) and 0.1 N dilute hydrochloric acid (0.1 ml) were added, and the reaction was continued at room temperature with stirring for 12 h. After the reaction was completed, THF was removed by rotary evaporation, and methyl tert-butyl ether (50 ml) was added to settle. A solid was precipitated and filtered with suction. An appropriate amount of DMF was added to the filter cake to dissolve it, and methyl tert-butyl ether (200 ml) was added to precipitate a solid. This process of dissolving the product with DMF and adding methyl tert-butyl ether to separate the product was repeated four times. The product was then filtered with suction and dried to give 0.028 g of the product. 1 H-NMR(600MHz,DMSO-d6)δ9.34-9.22(m,24H),8.79-7.45(m,504H),7.31-7.03(m,186H),5.50 -5.42(m,48H),5.31-5.12(m,48H),4.63-4.51(m,24H),4.49-4.30(m,48H),4.27-4.12(m,53H) ,4.13-3.87(m,92H),3.87-3.43(m,2960H),3.31-3.10(m,23H),3.10-2.92(m,56H),2.87-2.7 3(m,110H),2.73-2.55(m,48H),2.55-1.64(m,447H),1.64-0.99(m,183H),0.94-0.64(m,288H)

[0419] Example 5 Synthesis of Compound 50-221

[0420] 5.1 Preparation of 50-185

[0421] 38-230 (6.23 g, 6.23 mmol), 67-53 (0.474 g, 0.684 mmol), HBTU (2.72 g, 7.182 mmol), HOBT (0.97 g, 7.182 mmol), and DMF (30 ml) were placed in a 500 ml flask and dissolved with ultrasonication. The mixture was stirred at 0°C for 10 min, followed by the dropwise addition of DIEA (3.56 ml, 21.546 mmol). The mixture was stirred at room temperature for 30 h. After completion of the reaction, the reaction mixture was transferred to a 2 L separatory funnel containing ethyl acetate (300 ml) and saturated sodium bicarbonate solution (500 ml). The aqueous phase was further extracted with ethyl acetate (300 ml). The combined organic phases were concentrated, added to 200-300 mesh silica gel powder, and evaporated to dryness. The sample was dry-applied and subjected to column chromatography using 4-6% methanol / dichloromethane as the eluent to collect the desired product. The product was concentrated and evaporated to dryness to yield 5.25 g. 1 H-NMR(600MHz,DMSO-d6)δ8.23-8.14(m,14H),8.12-8.04(m,7H),7.98-7.89(m,7H),7.58-7.51(m,7H) ,7.40-7.29(m,35H),7.29-7.21(m,7H),5.07-4.97(m,14H),4.32-4.22(m,7H),4.16-4.08(m,14H),3.9 0-3.82(m,5H),3.27-3.13(m,9H),3.13-3.05(m,11H),3.05-2.89(m,33H),2.89-2.66(m,22H),2.32-2 .20(m,28H),2.20-2.05(m,27H),1.96-1.84(m,21H),1.81-1.64(m,34H),1.63-1.16(m,323H);ESI[M+H + ]7601.33,[M+Na + ]7624.07,[M+K + ]7638.58

[0422] 5.2 Preparation of 50-196

[0423] 50-185 (0.65 g, 0.0855 mmol) was placed in a hydrogenation reactor, followed by the addition of 10% Pd / C catalyst (0.6 g) and DMF (30 ml) to dissolve the mixture. The reactor was sealed, evacuated with a water pump, and then filled with hydrogen. This process was repeated three times, with the hydrogen pressure adjusted to 1.8 MPa. The reaction mixture was stirred overnight at room temperature. After the reaction, the reaction solution was filtered through diatomaceous earth, which was then rinsed with DMF (15 ml). The DMF solutions were combined and settled with n-hexane (200 ml). The supernatant was decanted and the mixture was then settled with methyl tert-butyl ether (150 ml x 3). Finally, the mixture was dried in a vacuum oven to yield 0.4 g of the product. 1 H-NMR(600MHz,DMSO-d6)δ8.25-8.15(m,7H),8.14-8.05(m,7H),8.02-7.90(m,14H),7 .82-7.24(m,7H),7.24-7.12(m,7H),4.32-4.22(m,7H),4.16-4.08(m,14H),3.90-3.82 (m,5H),3.56-3.13(m,3264H),3.13-2.88(m,15H),2.88-2.64(m,22H),2.32-2.20(m, 28H),2.20-2.06(m,56H),1.96-1.84(m,21H),1.81-1.64(m,34H),1.63-1.16(m,323H)

[0424] 5.3 Preparation of 50-205

[0425] 50-196 (0.291 g, 0.0437 mmol) and M-SCM-5K (1.95 g, 0.3667 mmol, Lot Number: ZZ363P139, purchased from Tianjin Jiankai) were placed in a 100 ml round-bottom flask and dissolved in DMF (10 ml). The mixture was stirred at -5°C for 30 minutes. DIEA (1.5 ml, 9.177 mmol) was then slowly added dropwise. After the addition was complete, the mixture was reacted at low temperature for 2 hours, then slowly stirred at room temperature and monitored by TLC. After completion of the reaction, methyl tert-butyl ether (150 ml) was added to the reaction solution for precipitation. The supernatant was decanted and then precipitated with n-hexane (150 ml). This process was repeated three times, drained, dissolved in dichloromethane, and 100-200 mesh silica gel powder was added and evaporated to dryness. , dry loading, column chromatography with 1% ammonia / 4-6% methanol / dichloromethane as eluent, collect the target product, concentrate, and evaporate to dryness to obtain 1.207 g of the product. 1H-NMR(600MHz,DMSO-d6)δ8.22-7.92(m,42H),7.66-7.12(m,42H),4.57(s,12H) ,4.11(s,13H),3.74-3.62(m,18H),3.51(s,3269H),3.22-3.08(m,16H),3.07(t, 15H),3.01-2.96(t,22H),2.26-2.20(q,18H),2.11-2.07(d,10H),1.93-1.88(m,10H ),1.67-1.63(m,26H),1.57(s,22H),1.49(s,22H),1.39(s,252H),1.36-1.32(m,29H)

[0426] 5.4 Preparation of 50-215

[0427] 50-205 (0.4 g, 0.0093 mmol) was placed in a 100 ml round-bottom flask and dissolved in TFA (0.4 ml, 5.208 mmol). The reaction was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure and evaporated to dryness. Dichloromethane (5 ml) was then added to dissolve the solution, followed by n-hexane (100 ml) to allow precipitation. The supernatant was discarded. This process was repeated twice. The sediment was evaporated to dryness, dissolved in dichloromethane, and DIEA (0.3 ml) was added to make the solution weakly alkaline. The product (0.38 g) was dried by rotary evaporation. 1 H-NMR(600MHz,DMSO-d6)δ12.12-11.98(m,28H),8.25-8.15(m,7H),8.14-8.05(m,7H) ,8.02-7.90(m,14H),7.82-7.24(m,7H),7.24-7.12(m,7H),4.32-4.22(m,7H),4.16-4. 08(m,14H),3.90-3.82(m,5H),3.56-3.13(m,3264H),3.13-2.88(m,15H),2.88-2.64(m ,22H),2.32-2.06(m,84H),1.96-1.84(m,21H),1.81-1.64(m,34H),1.63-1.16(m,71H)

[0428] 5.5 Preparation of 50-217

[0429] 50-215 (0.38 g, 0.0093 mmol), N-Boc-ethylenediamine (0.063 g, 0.3906 mmol), HBTU (0.15 g, 0.3906 mmol), HOBT (0.05 g, 0.3906 mmol), and DMF (10 ml) were placed in a 250 ml flask and dissolved with ultrasound. The mixture was stirred at 0°C for 10 min, followed by the dropwise addition of DIEA (0.2 ml, 1.1718 mmol). The reaction mixture was stirred at room temperature until complete. Methyl tert-butyl ether (50 ml) and n-hexane (100 ml) were added to the reaction mixture for precipitation. The supernatant was decanted and drained, then dissolved in dichloromethane. 100-200 mesh silica gel powder was added and evaporated to dryness. The sample was dry-applied and subjected to column chromatography using 1% ammonia / 4-5% methanol / dichloromethane as the eluent. The desired product was collected, concentrated, and dried to yield 0.21 g. 1 H-NMR(600MHz,DMSO-d6)δ8.26-8.14(m,7H),8.14-8.05(m,7H),8.05-7.24( m,49H),7.24-6.95(m,35H),4.32-4.20(m,7H),4.16-4.08(m,14H),3.90-3.8 2(m,5H),3.56-3.13(m,3376H),3.13-2.88(m,15H),2.88-2.64(m,22H),2.3 2-2.06(m,84H),1.96-1.84(m,21H),1.81-1.64(m,34H),1.64-1.14(m,323H)

[0430] 5.6 Preparation of 50-219

[0431] 50-217 (0.21 g, 0.0046 mmol) was dissolved in a 100 ml round-bottom flask with TFA (0.5 ml, 6.44 mmol). The mixture was stirred and reacted overnight at room temperature. After completion of the reaction, the solution was concentrated and evaporated to dryness. Dichloromethane (30 ml) was then added for dissolution and neutralized with excess DIEA. The solution was then precipitated with n-hexane (100 ml), and the supernatant was discarded. This process was repeated twice, and the precipitate was evaporated to dryness to yield 0.196 g of the product. 1H-NMR(600MHz,DMSO-d6)δ8.26-8.12(m,7H),8.12-8.05(m,7H),8.05-7.22( m,49H),7.22-6.95(m,7H),4.32-4.18(m,8H),4.16-4.07(m,13H),3.90-3.8 2(m,5H),3.56-3.13(m,3432H),3.13-2.87(m,15H),2.87-2.64(m,22H),2.3 4-2.06(m,84H),1.96-1.84(m,21H),1.82-1.64(m,34H),1.64-1.14(m,71H)

[0432] 5.7 Preparation of 50-220

[0433] 50-219 (0.15 g, 0.0035 mmol), 65-131 (0.129 g, 0.1459 mmol), HBTU (0.055 g, 0.1459 mmol), HOBT (0.02 g, 0.1459 mmol), and DMF (3 ml) were placed in a 50 ml flask and dissolved with ultrasonication. The mixture was stirred at 0°C for 10 min, and then DIEA (0.03 ml, 0.196 mmol) was added. The reaction mixture was stirred at room temperature until the reaction was complete. Methyl tert-butyl ether (50 ml) and n-hexane (50 ml) were added to the reaction solution for precipitation, and the precipitate was evaporated to dryness to obtain 0.1 g of the product. 1 H-NMR(600MHz,DMSO-d6)δ8.44-8.37(m,28H),8.26-8.05(m,70H),8.05-7.22(m,317H), 7.22-6.95(m,63H),5.47-5.44(m,56H),5.30-5.10(m,56H),4.32-4.07(m,49H),4.02-3. 82(m,33H),3.56-3.13(m,3404H),3.13-2.64(m,37H),2.64-2.58(m,56H),2.45-2.40(m ,56H),2.39-2.06(m,196H),1.96-1.64(m,55H),1.64-1.10(m,323H),0.95-0.83(m,84H)

[0434] 5.8 Preparation of 50-221

[0435] 50-220 (0.1 g, 0.0016 mmol), TBAF (0.044 g, 0.1792 mmol), THF (1 ml), and 1N dilute HCl solution (1 ml) were placed in a 50 ml flask, dissolved with ultrasound, and stirred at room temperature. After the reaction, the THF was removed by rotary evaporation. Anhydrous ethanol (20 ml) was added to dissolve the mixture, and then rotary evaporated to dryness. This process was repeated three times. DMF (3 ml) was then added to dissolve the mixture, isopropanol was added to allow the mixture to settle, and the mixture was filtered. This process was repeated twice. CH2Cl2 (4 ml) was added to dissolve the mixture, methyl tert-butyl ether (30 ml) was added to allow the mixture to settle, and the mixture was filtered and dried to obtain 0.05 g of the product. 1 H-NMR(600MHz,DMSO-d6)δ8.44-8.37(m,56H),8.26-8.05(m,70H),8.05-7.22(m,37H), 7.22-6.95(m,63H),5.47-5.44(m,56H),5.30-5.10(m,56H),4.32-4.07(m,49H),4.02-3 .82(m,33H),3.56-3.13(m,3404H),3.13-2.64(m,37H),2.64-2.58(m,56H),2.45-2.4(m ,56H),2.39-2.06(m,196H),1.96-1.64(m,55H),1.64-1.10(m,71H),0.95-0.82(m,84H)

[0436] Example 6 Synthesis of Compounds 69-113

[0437] 6.1 Preparation of 69-42

[0438] Boc-Glu-OH (0.683 g, 2.317 mmol, purchased from Ark Pharm) and 64-135 (5 g, 4.866 mmol) were added to a 500 ml flask, dissolved in DMF (30 ml), and stirred at room temperature for approximately 10 minutes. 68-54 (1.606 g, 5.80 mmol) was then added, and N-methylmorpholine (1.2 ml, 11.05 mmol, purchased from Aladdin) was slowly added dropwise. After the addition was complete, stirring was continued at room temperature for 3 hours. After the reaction was completed, the reaction solution was added with methyl tert-butyl ether (150 ml) and n-hexane (100 ml) for precipitation. The solid product was precipitated, filtered, and vacuum dried to obtain 3.9 g of the product.

[0439] 6.2 Preparation of 69-73

[0440] 69-42 (3.7 g, 1.994 mmol) was weighed and placed in a 250 ml round-bottom flask. The mixture was dissolved in dichloromethane (5 ml) and trifluoroacetic acid (2.222 ml, 29.916 mmol) and stirred at room temperature overnight. After the reaction, the reaction solution was concentrated under reduced pressure and evaporated to dryness. Dichloromethane (10 ml) and methanol (3 ml) were then added for dissolution. Methyl tert-butyl ether (150 ml) and n-hexane (100 ml) were then added for precipitation. The solid product was filtered and dried under vacuum to obtain 3.5 g of the product.

[0441] 6.3 Preparation of 69-74

[0442] Compound 69-73 (3.50 g, 1.99 mmol), DMF (20 ml), and DIEA (1.32 ml, 7.97 mmol) were placed in a 250 ml flask and stirred at room temperature for 30 min. Succinic anhydride (0.598 g, 5.98 mmol, purchased from Innochem) was then added and the reaction was continued with stirring. After the reaction was completed, the reaction solution was added with methyl tert-butyl ether (150 ml) and n-hexane (100 ml) to allow precipitation. The solid product was filtered and dried to yield 3.58 g.

[0443] 6.4 Preparation of 69-108

[0444] Compound 69-74 (4.6 g, 2.48 mmol) and Boc-ethylenediamine (0.372 g, 2.361 mmol) were weighed and placed in a 250 ml flask. NMP (30 ml) was added and dissolved with ultrasound. After stirring at room temperature for 10 min, compound 68-54 (0.563 g, 0.598 mmol) was added. N-methylmorpholine (0.611 ml, 4.722 mmol, purchased from Aladdin) was slowly added dropwise. After the addition was complete, the reaction was stirred at room temperature for 5 hours. The reaction progress was monitored by TLC. After completion of the reaction, methyl tert-butyl ether (100 ml) and n-hexane (200 ml) were added to the reaction solution for sedimentation. A solid product precipitated, which was filtered and dried under vacuum to obtain 4.98 g of the product.

[0445] 6.5 Preparation of 69-109

[0446] 69-108 (4.983 g, 2.48 mmol) was weighed into a 250 ml round-bottom flask and dissolved in dichloromethane (5 ml) and TFA (2.787 ml, 37.2 mmol). The mixture was stirred and reacted at room temperature overnight. After the reaction, the reaction solution was concentrated under reduced pressure and evaporated to dryness. Dichloromethane (10 ml) and methanol (3 ml) were then added for dissolution. Methyl tert-butyl ether (150 ml) and n-hexane (100 ml) were added for precipitation. The solid product was precipitated and filtered. The crude product was dissolved in a 1 / 4 methanol / dichloromethane mixture, and 100-200 mesh silica gel powder (20 g) was added and evaporated to dryness. The sample was dry-applied and subjected to column chromatography using 1% ammonia water / 8% methanol / dichloromethane as the eluent. The desired product was collected, concentrated, and evaporated to dryness to obtain 2.75 g of the product. 1 H-NMR(600MHz,DMSO-d6)δ10.41-9.88(m,2H),9.07-8.78(m,2H),8.25-8.11(m,4H),8.11-8.04(m,2H),8.04-7.98(m,2 H),7.93-7.80(m,6H),7.56-7.46(m,2H),7.31-7.07(m,10H),5.89-5.77(m,2H),4.59-4.52(m,2H),4.40-4.31(m,2H),4 .18-4.09(m,1H),4.08-3.94(m,4H),3.76-3.52(m,13H),3.24-2.99(m,14H),2.88-2.70(m,2H),2.67-2.57(m,1H),2.44 -2.41(m,6H),2.40-2.32(m,4H),2.32-2.29(m,6H),2.28-2.18(m,4H),2.18-2.10(m,2H),1.95-1.83(m,5H),1.83-1.68 (m,5H),1.67-1.44(m,10H),0.92-0.79(m,12H)

[0447] 6.6 Preparation of 69-57

[0448] Axitinib (5 g, 12.938 mmol, 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. 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 for precipitation. The solid product was filtered and dried under vacuum to obtain 7.13 g of the product.

[0449] 6.7 Preparation of 69-58

[0450] To 69-57 (7.136 g, 12.938 mmol), Boc-ethylenediamine (2.04 ml, 12.938 mmol, purchased from Aladdin) and triethylamine (5.4095 ml, 38.814 mmol) were added. The mixture was dissolved in DMF (30 ml) and stirred at room temperature. After completion of the reaction, deionized water (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 combined organic phases were concentrated to a solid and dried in a vacuum oven to yield 7.4 g of the product.

[0451] 6.8 Preparation of 69-59

[0452] Weigh 69-58 (7.409 g, 12.938 mmol), add dichloromethane (10 ml) and trifluoroacetic acid (9.61 ml, 129.38 mmol), and stir at room temperature to react. After the reaction is completed, concentrate the reaction solution, add methyl tert-butyl ether (150 ml) and n-hexane (100 ml) to precipitate the solid product, and filter it. After dissolving the solid in a 1 / 5 methanol / dichloromethane mixed solvent, add 200-300 mesh silica gel powder (20 g) and evaporate to dryness. Column chromatography is performed using 1% ammonia water / 5% methanol / dichloromethane as the eluent for dry loading. The target product is collected, concentrated, and evaporated to dryness to obtain 5.1 g of the product. 1 H-NMR(600MHz,DMSO-d6)δ8.67-8.59(m,1H),8.46-8.18(m,3H),8.01-7.30(m,1H),7.89-7.55(m, 4H),7.53-7.48(m,1H),7.40-7.02(m,5H),6.28-5.96(m,1H),3.44-3.12(m,4H),2.81-2.73(m,4H)

[0453] 6.9 Preparation of 69-9

[0454] Diethylenetriamine (2g, 19.385mmol) was weighed into a 500ml flask and methanol (20ml) was added. After sonication, tert-butyl acrylate (18.6g, 145.38mmol) was added dropwise. After complete addition, the mixture was removed from the flask and allowed to react in the dark at room temperature for 24h. After completion of the reaction, the methanol was removed by rotary evaporation. The reaction solution was transferred to a 1L separatory funnel filled with deionized water (200ml) and ethyl acetate (300ml) for extraction. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (100ml x 3). The combined organic phases were washed with saturated brine (150ml x 2), concentrated, and evaporated to dryness. The crude solid product was dissolved in a 1 / 4 methanol / dichloromethane mixture, added with 200-300 mesh silica gel powder (30g), and evaporated to dryness. The sample was dry-loaded and subjected to column chromatography using 40% ethyl acetate / petroleum ether as the eluent. The desired product was collected, concentrated, and evaporated to dryness to obtain 7.76g.

[0455] 6.10 Preparation of 69-38

[0456] Compound 69-9 (7.76 g, 12.98 mmol) was weighed and added to dichloromethane (10 ml). After sonication, trifluoroacetic acid (21.8 ml, 194.7 mmol) was added and the reaction was stirred at room temperature. After completion of the reaction, the dichloromethane and most of the trifluoroacetic acid were removed by rotary evaporation. Dichloromethane (20 ml) was added and sonication was assisted, followed by rotary evaporation to remove the dichloromethane. This process was repeated three times, and finally, the product (4.86 g) was dried. 1 H-NMR(600MHz,DMSO-d6)δ12.74-11.64(m,5H),3.09-2.83(m,18H),2.64-2.48(m,10H)

[0457] 6.11 Preparation of 69-54

[0458] Weigh 69-45 (2.5 g, 1.929 mmol), 69-38 (0.12 g, 0.257 mmol), HBTU (0.732 g, 1.929 mmol) and HOBT (0.26 g, 1.929 mmol) into a 500 ml flask, add DMF (15 ml), dissolve with ultrasonic assistance, stir at room temperature for 2 min, and then slowly add DIEA (0.85 ml, 5.14 mmol, purchased from Aladdin). After the addition is complete, continue stirring the reaction at room temperature for 24 hours. After the reaction, methyl tert-butyl ether (100 ml) and n-hexane (200 ml) were added to the reaction solution for precipitation. A solid product was precipitated and filtered. The solid was dissolved with a 1 / 4 methanol / dichloromethane mixed solvent (100 ml). 200-300 mesh silica gel powder (35 g) was added and evaporated to dryness. The sample was dry-loaded and column chromatography was performed with 3% methanol / dichloromethane as eluent to collect the target product. The product was concentrated to obtain 1.58 g. 1 H-NMR(600MHz,DMSO-d6)δ8.48-8.39(m,5H),8.21-8.10(m,10H),8.10-8.04(m,5H),7.95-7.86(m,5H),7.81- 7.73(m,5H),7.59-7.51(m,5H),7.42-7.29(m,50H),7.28-7.21(m,5H),5.11-4.97(m,20H),4.30-4.24(m,5H), 4.24-4.17(m,5H),4.15-4.07(m,10H),4.06-3.97(m,5H),3.41-3.24(m,10H),3.09-2.69(m,44H),2.57-2.46 (m,10H),2.32-2.06(m,43H),2.06-1.98(m,11H),1.97-1.85(m,16H),1.85-1.62(m,37H),1.51-1.14(m,227H)

[0459] 6.12 Preparation of 69-60

[0460] Compound 69-54 (0.25 g, 0.0364 mmol) was placed in a hydrogenation reactor, followed by the addition of a 10% Pd / C catalyst (0.1 g). DMF (4 ml) was then added to dissolve the catalyst. The hydrogenation reactor was sealed, evacuated with a water pump, and then filled with hydrogen. This process was repeated three times. The pressure on the hydrogenation reactor was adjusted to 2 MPa, and the reaction was allowed to proceed overnight at room temperature. After the reaction, the reaction solution was filtered through celite, and the celite was rinsed with DMF (3 ml x 3). The combined DMF solutions were used as the starting material for the next reaction.

[0461] 6.13 Preparation of 69-61

[0462] 69-60 (0.208 g, 0.0364 mmol) was weighed and added to a 50 ml round-bottom flask. Dry DMF was added for dissolution. The mixture was stirred at -5°C for 2 minutes. DIEA (0.146 ml, 0.887 mol) was slowly added dropwise and allowed to react for another 2 minutes. M-SCM-5K (1.034 g, 0.182 mmol, purchased from Jiankai, Lot Number: ZZ363P139) was then added. 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 allow the solid to settle. The solid was filtered and the filter cake dried to yield 0.86 g of the product. 1 H-NMR(600MHz,DMSO-d6)δ12.05-11.89(m,5H),8.47-8.35(m,5H),8.22-8.04(m,20H),7.9 5-7.86(m,5H),7.81-7.72(m,5H),7.59-7.51(m,5H),4.30-4.24(m,5H),4.24-4.17(m,5H), 4.15-4.07(m,10H),4.06-3.96(m,5H),3.60-3.24(m,2350H),3.11-2.68(m,44H),2.57-2.4 6(m,10H),2.32-2.06(m,43H),2.06-1.98(m,11H),1.97-1.62(m,53H),1.51-1.12(m,227H)

[0463] 6.14 Preparation of 69-99

[0464] 69-61 (2.48 g, 0.088 mmol), 69-59 (0.2295 g, 0.4856 mmol), HBTU (0.184 g, 0.4856 mmol) and HOBT (0.065 g, 0.4856 mmol) were weighed into a 500 ml flask, and DMF (30 ml) was added. The mixture was dissolved with ultrasonic assistance and stirred at room temperature for 10 min. DIEA (0.327 ml, 1.98 mmol, purchased from Aladdin) was slowly added dropwise. After the addition was complete, the reaction was continued by stirring at room temperature for 5 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, methyl tert-butyl ether (100 ml) and n-hexane (200 ml) were added to the reaction solution for precipitation. A solid product precipitated and was filtered. The filter cake was added with a 1 / 1 methanol / dichloromethane mixed solvent (200 ml) and dissolved with the aid of ultrasound. 100-200 mesh silica gel powder (10 g) was added and evaporated to dryness. The sample was dry-loaded and subjected to column chromatography using 1% ammonia water / 6% methanol / dichloromethane as eluent to collect the target product. The product was concentrated to obtain 2.41 g.

[0465] 6.15 Preparation of 69-101

[0466] 69-99 (2.41 g, 0.072 mmol) was weighed and added to dichloromethane (5 ml), followed by trifluoroacetic acid (5 ml, 67 mmol). The mixture was stirred at room temperature. After completion of the reaction, the reaction solution was concentrated and methyl tert-butyl ether (150 ml) and n-hexane (100 ml) were added for precipitation. The solid product was precipitated and filtered, and the filter cake was dried to obtain 2.05 g of the product.

[0467] 6.16 Preparation of 69-113

[0468] 69-101 (0.239 g, 0.00714 mmol), 69-109 (0.322 g, 0.171 mmol), HBTU (0.064 g, 0.171 mmol) and HOBT (0.023 g, 0.171 mmol) were weighed and placed in a 500 ml flask. NMP (15 ml) was added and dissolved with ultrasonic assistance. After stirring at room temperature for 10 min, DIEA (0.1061 ml, 0.641 mmol, purchased from Aladdin) was slowly added dropwise. The progress of the reaction was monitored by TLC. After the reaction was completed, methyl tert-butyl ether (100 ml) and n-hexane (200 ml) were added to the reaction solution for precipitation. Solid precipitated and was filtered. A 1 / 1 methanol / dichloromethane mixed solvent (200 ml) was added to the filter cake and dissolved with the aid of ultrasound. 100-200 mesh silica gel powder (10 g) was added and evaporated to dryness. The sample was dry-loaded and column chromatography was performed using 1% ammonia water / 10% methanol / dichloromethane as eluent. The target product was collected, concentrated, and dried in vacuo to obtain 0.32 g of the product.1 H-NMR(600MHz,DMSO-d6)δ10.45-9.86(m,40H),9.07-8.78(m,40H),8.67-8.59(m,5H),8.47-8.30(m,10H),8.25-7.86(m ,316H),7.81-7.48(m,77H),7.44-7.07(m,225H),6.28-5.96(m,5H),5.89-5.77(m,40H),4.59-4.52(m,40H),4.40-4.24 (m, 45H), 4.24-4.07 (m, 35H), 4.07-3.94 (m, 76H), 3.76-3.24 (m, 2630H), 3.24-2.68 (m, 375H), 2.68-2.46 (m, 30H), 2.44-2.41 (m, 120H), 2.40-2.32 (m, 80H), 2.32-2.06 (m, 283H), 2.06-1.62 (m, 264H), 1.62-1.12 (m, 247H), 0.92-0.79 (m, 240H) Example 7 Synthesis of Compounds 71-246

[0469] 7.1 Preparation of 71-161

[0470] 71-85 (4.7631 g, 9.6699 mmol), SB-743921 (5.0 g, 9.6699 mmol, referred to as SB7, purchased from Tianjin Famoxi), HBTU (5.5008 g, 14.5049 mmol) and HOBT (1.9599 g, 14.5049 mmol) were added to a 500 ml round-bottom flask, DMF (60 ml) was added to dissolve, stirred at -5 ° C for about 20 minutes, then DIEA (7.2 ml, 43.5145 mmol) was slowly added dropwise, and the reaction was continued at -5 ° C for 1 hour, and then transferred to room temperature and stirred for reaction. After the reaction was completed, the reaction solution was transferred to a 1 L separatory funnel filled with saturated brine (250 ml) and ethyl acetate (200 ml) for extraction, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (200 ml). The combined organic phases were washed with deionized water (200 ml), concentrated and evaporated to dryness. 1 / 4 of a methanol / dichloromethane mixture was added to the crude product to dissolve it, and silica gel powder was added and evaporated to dryness. The product was dry loaded and subjected to column chromatography using 1-4% methanol / dichloromethane as the eluent. The target product was collected, concentrated, and dried to obtain 8.62 g of the product with a yield of 90.0%.

[0471] 7.2 Preparation of 71-162

[0472] To a flask containing 71-161 (8.62 g, 8.6929 mmol) was added dichloromethane (20 ml), and dissolution was assisted by ultrasonication. TFA (6.5 ml, 86.929 mmol) was then added, and the mixture was stirred and reacted at room temperature overnight. After the reaction, the reaction solution was concentrated and evaporated to dryness to remove dichloromethane and most of the TFA. The solid product was then precipitated with methyl tert-butyl ether (300 ml). The solid product was filtered, and the filter cake was washed with methyl tert-butyl ether (40 ml x 3). The filter cake was collected and dried under vacuum to yield 7.74 g of the product.

[0473] 7.3 Preparation of 71-166

[0474] 71-48 (1.2 g, 3.9513 mmol), 71-162 (7.74 g, 8.6929 mmol), HBTU (3.59 g, 9.4831 mmol), and HOBT (1.28 g, 9.4831 mmol) were placed in a 500 ml solution and dissolved in DMF (30 ml). The mixture was stirred at -5°C for approximately 20 minutes, followed by the slow dropwise addition of DIEA (6.5 ml, 39.513 mmol). The reaction was continued at -5°C for 1 hour, then the mixture was transferred to room temperature and stirred. After completion of the reaction, n-hexane (250 ml) and methyl tert-butyl ether (70 ml) were added to allow sedimentation, and the supernatant was decanted. This process was repeated five times. The solid product was obtained by filtration and dissolved in a 4 / 1 dichloromethane / methanol mixed solvent. 200-300 mesh silica gel powder was added and evaporated to dryness. The product was dry loaded and subjected to column chromatography using a 2-5% methanol / dichloromethane mixed solution as the eluent. The target product was collected, concentrated, and dried in a vacuum oven to obtain 8.10 g of the product. 1 H-NMR(600MHz,DMSO-d6)δ8.15-8.04(m,12H),8.00-7.93(m,4H),7.70-7.65(m,2H ),7.26-7.20(m,28H),4.53-4.51(m,2H),4.27-4.19(m,5H),3.66-3.55(m,10H),3 .53-3.47(m,4H),3.44-3.39(m,4H),2.34-2.28(m,8H),2.17-2.15(m,4H),1.90-1 .80(m,2H),1.75-1.67(m,2H),1.61-1.42(m,14H),1.34(s,9H),0.89-0.79(m,24H)

[0475] 7.4 Preparation of 71-167

[0476] To a flask containing 71-166 (8.1 g, 3.9513 mmol) was added dichloromethane (15 ml), which was dissolved using ultrasound. TFA (2.9 ml, 39.513 mmol) was then added and stirred at room temperature overnight. After completion of the reaction, the reaction solution was concentrated and evaporated to dryness to remove dichloromethane and most of the TFA. The solution was then precipitated with methyl tert-butyl ether (300 ml) to precipitate a solid product. The solid product was filtered, and the filter cake was washed with methyl tert-butyl ether (40 ml x 3). The filter cake was collected and dried under vacuum to yield 7.71 g of the product.

[0477] 7.5 Preparation of 71-225

[0478] 62-156 (0.3159 g, 0.5107 mmol), 71-167 (4.3843 g, 2.2471 mmol), HBTU (1.1621 g, 3.0642 mmol), and HOBT (0.4140 g, 3.0642 mmol) were added to a 500 ml round-bottom flask. DMF (70 ml) was added to dissolve the mixture. The mixture was stirred at -5°C for approximately 20 minutes, followed by the slow dropwise addition of DIEA (1.0 ml, 6.1284 mmol). After the addition was complete, the reaction flask was stirred at -5°C for 1 hour, and finally transferred to room temperature and stirred. After the reaction was complete, n-hexane (30 ml) and methyl tert-butyl ether (200 ml) were added to allow sedimentation, and the supernatant was decanted. This process was repeated three times. The solid product was obtained by filtration and dissolved in a 4 / 1 dichloromethane / methanol mixed solvent. The solid product was dry-loaded and subjected to column chromatography using a mixed solution of 1% ammonia water / 4-5% methanol / dichloromethane as the eluent. The target product was collected, evaporated to dryness, and dried in a vacuum oven to obtain 3.8 g of the product with a yield of 89.1%.

[0479] 7.6 Preparation of 71-226

[0480] To a flask containing 71-225 (1.0 g, 0.1197 mmol) was added dichloromethane (5 ml), which was dissolved using ultrasound. TFA (0.2 ml, 2.394 mmol) was then added and stirred at room temperature overnight. After the reaction, the reaction solution was concentrated and evaporated to dryness to remove dichloromethane and most of the TFA. The solution was then precipitated with methyl tert-butyl ether (300 ml) to precipitate the solid product. The solid product was filtered and the filter cake was washed with methyl tert-butyl ether (40 ml x 3). The filter cake was collected and dried under vacuum to yield 0.9 g of the product. 1 H-NMR (600 MHz, DMSO-d 6)δ8.18-8.06(m,52H),7.81-7.80(m,8H),7.54-7.49(m,16H),7.24-7.20(m,112H),4.5 4-4.53(m,8H),4.25-4.14(m,24H),3.90-3.88(m,10H),3.75-3.61(m,32H),3.55-3.3 8(m,32H),3.01-2.99(m,10H),2.76-2.75(m,12H),2.39-2.27(m,32H),2.21-2.06(m, 20H),1.89-1.68(m,18H),1.55-1.46(m,34H),1.36-1.23(m,14H),0.91-0.80(m,96H)

[0481] 7.7 Preparation of 71-228

[0482] 81-68 (0.15 g, 0.004 mmol), 71-226 (0.3 g, 0.0363 mmol), HBTU (0.0137 g, 0.0363 mmol), and HOBT (0.0049 g, 0.0363 mmol) were placed in a 250 ml solution 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 (0.1 ml, 0.552 mmol). After the addition was complete, the reaction mixture was stirred at room temperature. 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 this process was repeated five times. The solid product was then filtered. The obtained solid product was dissolved in a 4 / 1 dichloromethane / methanol mixed solvent, dry-loaded, and subjected to column chromatography using a 1% ammonia solution / 4-7% methanol / dichloromethane mixed solution as the eluent. The target product was collected, concentrated, and dried in a vacuum oven to obtain 0.22 g of the product with a yield of 64.7%. 1H-NMR(600MHz,DMSO-d6)δ8.16-8.06(m,312H),7.83-7.785(m,48H),7.54-7.49(m,96H),7.24-7.20(m,672H),4.55-4.53 (m,68H),4.25-4.09(m,226H),3.90-3.86(m,90H),3.66-3.63(m,148H),3.53-3.49(m,2802H),3.44-3.42(m,24H),3.40-3 .38(m,52H),3.01-2.99(m,106H),2.83-2.69(m,200H),2.66-2.57(m,90H),2.31-2.30(m,150H),2.18-2.10(m,140H),1.9 1-1.63(m,198H),1.60-1.52(m,84H),1.49-1.47(m,164H),1.387-1.363(s,216H),1.24-1.23(m,60H),0.91-0.8(m,576H)

[0483] 7.8 Preparation of 71-230

[0484] TFA (10 ml) was added to a flask containing 71-228 (0.22 g, 0.0025 mmol). The mixture was dissolved with ultrasound and stirred in a 37°C water bath overnight. After the reaction, dichloromethane was added to the reaction solution, which was then 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 with methyl tert-butyl ether (40 ml x 8) and then collected and dried under vacuum to obtain 0.2 g of the product. 1H-NMR(600MHz,DMSO-d6)δ10.01-9.89(m,24H),8.18-8.05(m,312H),7.82-7.81(m,48H),7.54-7.49(m,96H),7. 24-7.29(m,672H),4.54-4.53(m,68H),4.24-4.14(m,226H),3.90-3.85(m,90H),3.66-3.62(m,224H),3.520-3. 495(m,2802H),3.03-2.97(m,106H),2.84-2.72(m,200H),2.64-2.61(m,90H),2.33-2.27(s,150H),2.18-2.10( m,140H),1.93-1.67(m,198H),1.58-1.51(m,84H),1.50-1.43(m,164H),1.17-1.11(m,60H),0.91-0.80(m,576H)

[0485] 7.9 Preparation of 71-231

[0486] 71-230 (0.2 g, 0.0023 mmol), N-Boc-ethylenediamine (0.0132 g, 0.0828 mmol), HBTU (0.031 g, 0.0828 mmol), and HOBT (0.011 g, 0.0828 mmol) were added to a 250 ml round-bottom flask. DMF (40 ml) was added to dissolve the mixture and stirred at room temperature for approximately 20 minutes. DIEA (0.1 ml, 0.6 mmol) was then slowly added dropwise. After the addition was complete, the reaction flask was allowed to stir at room temperature. After completion of the reaction, n-hexane (100 ml) and methyl tert-butyl ether (40 ml) were added to allow the mixture to settle, and the supernatant was decanted. This process was repeated four times. The solid product was obtained by filtration and dissolved in a 4 / 1 dichloromethane / methanol mixture. Silica gel powder was added and evaporated to dryness. The product was dry loaded and subjected to column chromatography using a 1% ammonia solution / 5-7% methanol / dichloromethane mixture as the eluent. The target product was collected, concentrated, and dried to obtain 0.10 g of the product with a yield of 50.0%.

[0487] 7.10 Preparation of 71-240

[0488] To a flask containing 71-231 (0.1 g, 0.0011 mmol) was added TFA (0.4 ml, 5.28 mmol). Dissolution was assisted by ultrasonication, and the reaction was stirred in a 35°C water bath overnight. After completion of the reaction, the reaction solution was concentrated and evaporated to dryness, dissolved in DMF (5 ml), and neutralized by adding excess DIEA. The solution was then precipitated with methyl tert-butyl ether (100 ml) and n-hexane (100 ml), and the supernatant was decanted. This process was repeated twice. The filter cake was then washed with methyl tert-butyl ether (40 ml x 8), collected, and dried under vacuum to yield 0.097 g of the product.

[0489] 7.11 Preparation of 71-241

[0490] 71-240 (0.097 g, 0.0011 mmol), N-acetyl-L-cysteine ​​(0.0064 g, 0.0396 mmol purchased from Psaitong), HBTU (0.015 g, 0.0396 mmol) and HOBT (0.005 g, 0.0396 mmol) were added to a 250 ml round-bottom flask, dissolved in DMF (3 ml), and stirred at room temperature for about 20 minutes. DIEA (0.1 ml, 0.65 mmol) was then slowly added dropwise. After the addition was complete, stirring was continued at room temperature. After the reaction is completed, n-hexane and methyl tert-butyl ether are added to precipitate to form a viscous solid. The supernatant is poured off and the crude product is evaporated to dryness by rotary evaporation. It is dissolved with a 4 / 1 dichloromethane / methanol mixture and 100-200 mesh silica gel powder is added and evaporated to dryness. The sample is dry loaded and column chromatography is performed using a mixed solution of 1% ammonia water / 5-8% methanol / dichloromethane as an eluent. The target product is collected, concentrated, and dried to obtain 0.09 g of the product.

[0491] 7.12 Preparation of 71-246

[0492] 71-241 (0.9 g, 0.0011 mmol) and MI-AH-PLGLAG-iRGD (0.052 g, 0.0316 mmol, purchased from Dangang Biotechnology) were added to a 500 ml flask, and an appropriate amount of DMSO was added to dissolve the mixture. The mixture was stirred and reacted at room temperature overnight. After the reaction, n-hexane (30 ml) and methyl tert-butyl ether (100 ml) were added to allow precipitation. The supernatant was decanted, and this process was repeated seven times. The solid product was filtered to obtain the product. The solid product was dissolved in a 4 / 1 dichloromethane / methanol mixture, added with 100-200 mesh silica gel powder, evaporated to dryness, and dry-loaded. Column chromatography was performed using a mixture of 1% ammonia water and 5-9% methanol / dichloromethane as the eluent. The desired product was collected, concentrated, and dried in a vacuum oven to obtain 0.04 g of the product. 1H-NMR(600MHz,DMSO-d6)δ11.43-10.91(m,72H),8.92-8.68(m,48H),8.29-8.01(m,750H),7.84-7.80(m,180H),7.37-7.05(m,63 6H),4.62-4.49(m,210H),4.39-4.14(m,672H),3.79-3.71(m,184H),3.69-3.66(m,140H),3.62-3.61(m,108H),3.54-3.47(m,280 2H),3.01-2.97(m,222H),2.91-2.87(m,176H),2.80-2.75(m,236H),2.32-2.22(m,224H),2.18-2.07(m,206H),2.02-1.99(m,64H ),1.91-1.84(m,380H),1.79-1.70(m,280H),1.64-1.56(m,254H),1.48-1.46(m,370H),1.20-1.28(m,156H),0.87-0.82(m,864H)

[0493] Example 8 Synthesis of Compounds 70-92

[0494] 8.1 Preparation of 70-2

[0495] Triethylenetetramine (1 ml, 7 mmol) and tert-butyl acrylate (12.2 ml, 84 mmol) were added to a 250 ml flask and purged with nitrogen. Methanol (10 ml) was added to dissolve the mixture and allowed to react at room temperature with stirring. The reaction was monitored by TLC. After completion of the reaction, the reaction solution was concentrated under reduced pressure and extracted with ethyl acetate (100 ml) and saturated sodium bicarbonate solution (100 ml). The organic phase was collected and the aqueous phase was extracted with saturated sodium chloride solution (100 ml x 2). The organic phases were combined, concentrated, and dried in a vacuum oven to obtain the product. 1 H-NMR (600MHz, DMSO-d6) δ2.744-2.569(m,12H),2.464-2.368(m,12H),2.340-2.174(m,12H),1.478-1.308(m,54H); ESI[M+H + ]916.004

[0496] 8.2 Preparation of 70-70

[0497] To a flask containing 70-2 (1 g, 1.1 mmol), dichloromethane (30 ml) was added and dissolved using ultrasound. TFA (29 ml, 120 mmol) was then added and 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. Solid precipitated from the reaction solution and 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 the product.

[0498] 8.3 Preparation of 70-77

[0499] Reactants 69-34 (13.2 g, 23.6 mmol), 67-55 (7.5 g, 23.6 mmol), HOBT (3.8 g, 28.3 mmol), and HBTU (10.7 g, 28.3 mmol) were placed in a reaction flask. DMF (200 ml) was added and dissolved with ultrasonication. The mixture was stirred at 0°C. DIEA (8.6 mmol, 51.9 mmol) was added dropwise. After complete addition, the mixture was transferred to room temperature and stirred for 1 hour. The reaction progress was monitored by TLC. After completion of the reaction, the reaction solution was poured into a separatory funnel filled with saturated brine (300 ml) and ethyl acetate (300 ml). The organic phase was collected, and the aqueous phase was further extracted with ethyl acetate (200 ml x 2). The combined organic phases were evaporated to dryness, dissolved in 1 / 4 of a methanol / dichloromethane mixture, and silica gel powder was added and evaporated to dryness. The mixture was then eluted with 1-2.5% methanol / dichloromethane for column chromatography. The target product was collected, concentrated, and evaporated to dryness to obtain 17.8 g of the product with a yield of 90.8%.

[0500] 8.4 Preparation of 70-78

[0501] Reactant 70-77 (6.1 g, 7.5 mmol) was placed in a reaction flask and dissolved in DMF (50 ml). Morpholine (13 ml, 150 mmol) was then added and stirred at room temperature. The reaction progress was monitored by TLC. After completion of the reaction, the mixture was extracted with ethyl acetate (150 ml) and saturated brine (100 ml). The organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate (100 ml). The combined organic phases were washed with deionized water, and the separated aqueous phase was extracted twice with ethyl acetate. The combined organic phases were concentrated and evaporated to dryness to yield 5.9 g of the product.

[0502] 8.5 Preparation of 70-79

[0503] 70-78 (5.9 g, 7.5 mmol), Fmoc-Lys(Boc)-OH (3.5 g, 7.5 mmol), HOBT (1.2 g, 9.0 mmol), and HBTU (3.4 g, 9.0 mmol) were placed in a reaction flask. DMF (200 ml) was added and dissolved with ultrasound. The mixture was then stirred at 0°C for 10 minutes. DIEA (3 mmol, 16.5 mmol) was then added dropwise. The mixture was then stirred at room temperature overnight and the reaction progress was monitored by TLC. After the reaction, n-hexane (50 ml) and methyl tert-butyl ether (200 ml) were added to allow the reaction to settle, resulting in an oily solid. The supernatant was discarded, and methyl tert-butyl ether (200 ml) was added to allow the reaction to settle. This process was repeated three times, resulting in the precipitation of a powdery solid. The filter cake was collected by filtration and dried in a vacuum oven to yield 7.5 g of the product (94.6% yield). 1 H-NMR(600MHz,DMSO-d6)δ8.00-7.95(m,3H),7.92-7.87(m,2H),7.74-7.71(m,3H),7.59-7.53(m,2H),7.50- 7.45(m,1H),7.44-7.39(m,4H),7.37-7.35(m,2H),7.33-7.31(m,2H),5.08(s,2H),4.32-4.21(m,3H),4.19- 4.13(m,2H),4.03-3.91(m,3H),3.80-3.57(m,4H),3.31-3.25(m,2H),3.19-3.11(m,2H),2.95-2.83(m,2H), 2.53(s,1H),2.29-2.18(m,2H),2.16-2.12(m,1H),1.92-1.66(m,4H),1.66-1.45(m,2H),1.39-1.33(m,27H)

[0504] 8.6 Preparation of 70-80

[0505] 70-79 (2 g, 1.9 mmol) was weighed and placed in a reaction flask. DMF (20 ml) was added to dissolve the mixture. Morpholine (3.3 ml, 38 mmol) was then added and stirred at room temperature. The reaction progress was monitored by TLC. After the reaction was completed, n-hexane (50 ml) and methyl tert-butyl ether (200 ml) were added to allow the mixture to settle, resulting in an oily solid. The supernatant was discarded, and methyl tert-butyl ether (200 ml) was added to allow the mixture to settle. This process was repeated three times until a solid precipitated. The filter cake was collected by filtration and dried in a vacuum oven to yield 0.88 g of the product (55.5% yield).

[0506] 8.7 Preparation of 70-81

[0507] Reactants 70-80 (0.79 g, 0.94 mmol), 70-70 (76 mg, 0.13 mmol), HOBT (0.2 g, 1.4 mmol), and HBTU (0.5 g, 1.4 mmol) were placed in a reaction flask. DMF ( ) was added and dissolved with ultrasonication. The mixture was stirred at 0°C and DIEA (0.3 mmol, 1.5 mmol) was added dropwise. After complete addition, the mixture was transferred to room temperature and stirred for 1 hour. The reaction progress was monitored by TLC. After completion of the reaction, the mixture was extracted with ethyl acetate ( ) and deionized water ( ). The organic phase was washed twice with pure water and evaporated to dryness to obtain a crude solid product. The crude solid product was dissolved in 1 / 4 methanol / dichloromethane mixture, added with silica gel powder, evaporated to dryness, and dry-applied to a column chromatography column using 0-5% methanol / dichloromethane as the eluent. The desired product was collected, concentrated, and dried to obtain 0.36 g of the product with a yield of 56.8%. 1 H-NMR(600MHz,DMSO-d6)δ8.47-8.37(m,6H),8.31-8.25(m,6H),8.19-8.11(m,6H),8.04-7.97 (m,6H),7.53-7.52(m,6H),7.40-7.27(m,32H),6.87-6.70(m,6H),5.11-5.02(m,12H),4.31-4 .25(m,6H),4.22-4.16(m,6H),4.05-4.00(m,6H),3.77-3.75(m,2H),3.75-3.72(m,4H),3.67- 3.65(m,4H),3.65-3.63(m,2H),3.40-3.36(m,10H),3.32-3.26(m,12H),2.98(s,32H),2.93-2 .88(m,18H),2.87-2.75(m,36H),2.60-2.52(m,18H),2.42-2.36(m,2H),2.26-2.22(m,12H),2 .14-2.07(m,12H),1.91-1.86(m,6H),1.82-1.78(m,6H),1.74-1.72(m,6H),1.72-1.67(m,12H ),1.51-1.48(m,2H),1.40-1.39(m,1H),1.39-1.38(m,54H),1.37-1.36(s,54H),1.35-1.34(m ,6H),1.33-1.30(m,6H),1.30-1.28(m,2H),1.28-1.26(m,3H),1.25-1.23(m,4H),1.23(s,2H)

[0508] 8.8 Preparation of 70-84

[0509] Weigh 70-81 (0.36 g, 0.067 mmol) and add it to a microhydrogenation reactor. Dissolve it in DMF (30 ml), then add 10% Pd / C catalyst (30 mg). Seal the reactor. Evacuate with a water pump and then refill with hydrogen. Repeat this process three times, adjusting the hydrogenation pressure to 2 MPa. Stir overnight and monitor the reaction progress by TLC. After completion, filter through celite and set aside the filtrate.

[0510] 8.9 Preparation of 70-87

[0511] Compounds 70-84 (0.067 mmol), 64-135 (0.5 g, 0.6 mmol), HOBT (0.081 g, 0.6 mmol), and HBTU (0.23 g, 0.6 mmol) were placed in a reaction flask. DMF (20 ml) was added and dissolved with ultrasonication. The mixture was stirred at 0°C. DIEA (0.2 mmol, 1.0 mmol) was then added dropwise. After complete addition, the mixture was transferred to room temperature and stirred for 2 h. The reaction progress was monitored by TLC. After completion of the reaction, the mixture was settled with methyl tert-butyl ether (100 ml) and n-hexane (20 ml). The mixture was filtered using a fritted funnel, and the filter cake was collected and washed with methyl tert-butyl ether (100 ml x 2). The filter cake was then transferred to a flask and dried to yield 0.54 g of the product, with a yield of 83.07%. 1H-NMR(600MHz, DMSO-d6) δ 8.45 - 8.40 (m, 6H), 8.31 - 8.25 (m, 6H), 8.21 - 8.15 (m, 6H), 8.13 - 8.09 (m, 6H), 8.09 - 8.08 (m, 6H), 8.06 (s, 6H), 8.03 - 8.00 (m, 6H), 8.00 - 8.98 (m, 6H), 7.94 - 7.91 (m, 6H), 7.90 - 7.88 (m 6H), 7.75 - 7.70 (m, 6H), 7.59 - 7.53 (m, 12H), 7.44 - 7.40 (m, 6H), 7.27 - 7.22 (m, 24H), 7.19 - 7.16 (m, 6H), 4.66 - 4.60 (m, 2H), 4.59 - 4.53 (m, 6H), 4.40 - 4.34 (m, 6H), 4.30 - 4.24 (m, 6H), 4.24 - 4.17 (m, 6H), 4.08 - 3.96 (m, 20H), 3.74 - 3.72 (m, 6H), 3.71 - 3.69 (m, 6H), 3.69 - 3.65 (m, 6H), 3.65 - 3.54 (m, 38H), 3.24 - 3.17 (m, 20H), 3.16 - 3.10 (m, 18H), 3.09 - 3.02 (m, 12H), 3.01 - 2.95 (m, 22H), 2.93 - 2.87 (m, 26H), 2.78 - 2.76 (m, 4H), 2.67 - 2.61 (m, 12H), 2.43 (s, 20H), 2.31 (s, 22H), 2.27 - 2.21 (m, 26H), 2.13 - 2.07 (m, 10H), 1.91 - 1.86 (m, 18H), 1.81 - 1.75 (m, 24H), 1.73 - 1.66 (m, 18H), 1.61 - 1.56 (m, 14H), 1.54 - 1.48 (m, 16H), 1.4 (s, 54H), 1.38 (s, 54H), 1.36 (s, 54H), 1.34 (s, 12H), 0.913 - 0.890 (m, 18H), 0.860 - 0.843 (m, 18H)

[0512] Preparation of 8. 10 70 - 88

[0513] Compound 70-87 (0.54 g, 0.056 mmol) was dissolved in dichloromethane (13 ml) and TFA (1.5 ml, 20 mmol) was added. The reaction mixture was stirred at room temperature and the reaction progress was monitored by TLC. After the reaction, the reaction solution was concentrated under reduced pressure to remove dichloromethane and most of the TFA. Methyl tert-butyl ether (100 ml) and n-hexane (10 ml) were then added to allow sedimentation. The solution was filtered using a sand core funnel, and the filter cake was collected. The filter cake was washed twice with methyl tert-butyl ether (50 ml) and transferred to a flask and dried to obtain 0.5 g of the product.

[0514] 8.11 Preparation of 70-90

[0515] Reactant 70-88 (0.5 g, 0.056 mmol) was placed in a reaction flask, and ultra-dry DMF (20 ml) was added. Dissolution was assisted by ultrasound and stirred at 0°C for 10 minutes. DIEA (0.2 mmol, 1 mmol) was then added dropwise. After the mixture was transferred to room temperature and stirred for 0.5 hours, M-SCM-5K (1.8 g, 0.36 mmol) was added. The mixture was stirred at low speed in the dark, and the reaction progress was monitored by TLC. After the reaction was completed, n-hexane (50 ml) and methyl tert-butyl ether (200 ml) were added to allow the mixture to settle, resulting in an oily solid. The supernatant was discarded, and methyl tert-butyl ether (200 ml) was added to allow the mixture to settle. This process was repeated three times, resulting in the precipitation of a solid. The filter cake was collected by filtration and dried in a vacuum oven to yield 2.3 g of the product.

[0516] 8.12 Preparation of 68-86

[0517] 71-85 (51.0 mmol), lapatinib (24.7 g, 42.8 mmol, purchased from Shanghai Hengxin, abbreviated as LPT), HOBT (6.3 g, 46.7 mmol), and HBTU (17.7 g, 46.7 mmol) were placed in a reaction flask. DMF (500 ml) was added and dissolved with ultrasonication. Stirring was performed at 0°C. DIEA (15.4 mmol, 93.4 mmol) was added dropwise. After the mixture was transferred to room temperature and stirred for 2 hours, the reaction progress was monitored by TLC. After completion of the reaction, the mixture was extracted with ethyl acetate (400 ml) and deionized water (300 ml). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (200 ml x 2). The combined organic phases were concentrated appropriately, washed with saturated brine, and the organic phase was separated. The aqueous phase was extracted twice with ethyl acetate (200 ml). The combined organic phases were concentrated, and the aqueous phase was extracted twice with ethyl acetate (200 ml). The combined organic phases were concentrated, and dried in a vacuum oven to yield 45.0 g of the product.

[0518] 8.13 Preparation of 68-69

[0519] Reactant 68-86 (45.0 g, 42.8 mmol) was added to a reaction flask containing dichloromethane (100 ml). TFA (31.5 ml, 424.8 mmol) was then added and stirred at room temperature. The reaction progress was monitored by TLC. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the dichloromethane and most of the TFA. MTBE (500 ml) and n-hexane (100 ml) were then added to allow sedimentation. The product was filtered using a fritted funnel, and the filter cake was collected and rinsed with MTBE (300 ml x 3). The filter cake was transferred to a flask and dried to yield 41 g of the product.

[0520] 8.14 Preparation of 71-59

[0521] Reactants 71-48 (0.45 g, 1.48 mmol), 68-69 (3.26 mmol), HOBT (1.7 g, 4.44 mmol), and HBTU (0.6 g, 4.44 mmol) were placed in a reaction flask. DMF (20 ml) was added and dissolved with ultrasound. The mixture was stirred at 0°C, and DIEA (2.2 mmol, 13.32 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 (100 ml) and n-hexane (20 ml). The filter cake was collected by suction filtration using a fritted funnel and rinsed twice with methyl tert-butyl ether (100 ml). The filter cake was transferred to a flask and dried to yield 2.81 g of the product, with a yield of 87.8%.

[0522] 8.15 Preparation of 70-60

[0523] 71-59 (2.81 g, 1.29 mmol) was added to a reaction flask containing dichloromethane (20 ml) and dissolved. TFA (1.9 ml, 25.8 mmol) was then added and stirred at room temperature. The reaction progress was monitored by TLC. After the reaction, the mixture was precipitated with methyl tert-butyl ether (100 ml) and n-hexane (20 ml). The mixture was filtered using a fritted funnel to collect the filter cake. The cake was rinsed twice with methyl tert-butyl ether (80 ml) and transferred to a flask for drying. The mixture was dissolved in 1 / 4 methanol / dichloromethane mixture and silica gel powder was added for evaporation to dryness. The mixture was dry-loaded and subjected to column chromatography using 1% ammonia / 8% methanol / dichloromethane as the eluent. The mixture was collected, concentrated, and dried to obtain 1.7 g of the product in a 63.4% yield.

[0524] 8.16 Preparation of 70-92

[0525] 70-60 (1.54 g, 1.8 mmol), 70-90 (2.3 g, 0.056 mmol), HOBT (0.14 g, 1.1 mmol) and HBTU (0.38 g, 1.1 mmol) were placed in a reaction flask, DMF (30 ml) was added, and dissolution was assisted by ultrasonication. The mixture was stirred at 0°C, and DIEA (0.6 mm1, 56 mmol) was added dropwise. After the reaction was transferred to room temperature and stirred for 2 hours, the reaction progress was monitored by TLC. After the reaction, methyl tert-butyl ether (100 ml) and n-hexane (20 ml) were used for precipitation, and the mixture was filtered with a sand core funnel to collect the filter cake, which was washed with methyl tert-butyl ether (100 ml × 2). The filter cake was transferred to a flask and dissolved with a 1 / 4 methanol / dichloromethane mixed solvent. Silica gel powder was added and evaporated to dryness. The sample was dry loaded and column chromatography was performed with 1% ammonia water / 8% methanol / dichloromethane as eluent. The product was collected, concentrated, and dried to obtain 1.6 g with a yield of 55.17%. 1H-NMR(600MHz,DMSO-d6)δ8.75-8.72(m,12H),8.56-8.54(m,12H),8.24-8.14(m,60H),8.09-8.04 (m,42H),8.03-8.00(m,30H),7.82-7.77(m,16H),7.76-7.69(m,22H),7.51-7.44(m,22H),7.39-7. 17(m,108H),7.14-7.09(m,28H),7.06-7.03(m,6H),6.705-6.662(m,10H),6.555-6.525(m,4H),5 .268-5.252(m,24H),4.79-4.67(m,28H),4.60-4.53(m,20H),4.40-4.33(m,20H),4.295-4.170(m, 40H),4.13-3.94(m,24H),3.880-3.846(m,18H),3.807-3.740(m,42H),3.627-3.602(m,74H),3.5 20-3.497(m,2789H),3.17-3.19(m,58H),3.08-3.05(m,30H),2.98-2.93(m,36H),2.83-2.79(m,30 H),2.637-2.600(m,18H),2.403-2.381(m,10H),2.32-2.27(m,32H),2.14-2.08(m,30H),1.79-1.7 0(m,40H),1.65-1.56(m,48H),1.528-1.460(m,44H),1.307-1.290(m,12H),0.895-0.830(m,108H)

[0526] Example 9 Synthesis of Compound 77-231

[0527] 9.1 Preparation of 68-138

[0528] Fmoc-L-glutamic acid-1-tert-butyl ester (3.34 g, 7.8528 mmol, purchased from Inochem), HBTU (3.28 g, 8.6380 mmol), and HOBT (1.17 g, 8.6380 mmol) were weighed and added to a flask containing 67-82 (1.95 g, 7.8528 mmol). DMF (40 ml) was then added to dissolve the mixture. The mixture was placed at -5°C and DIEA (2.86 ml, 17.2760 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, saturated brine (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, concentrated, evaporated to dryness, and dried in a vacuum oven to obtain the product.

[0529] 9.2 Preparation of 68-145

[0530] To a flask containing 68-138 (7.8528 mmol), add DMF (50 ml) and dissolve it with ultrasound. Then add morpholine (6.84 ml, 78.528 mmol) and stir at room temperature for 2 h. After the reaction, add saturated brine (200 ml) and ethyl acetate (200 ml) for extraction. After standing and separating, the organic phase is collected and the aqueous phase is extracted with ethyl acetate (200 ml x 3). The combined organic phases are concentrated, evaporated to dryness, and dried in a vacuum oven to obtain the product.

[0531] 9.3 Preparation of 68-149

[0532] Weigh pteroic acid (0.98g, 3.1382mmol, purchased from Inokai), HBTU (2.98g, 4.7073mmol) and HOBT (1.06g, 4.7073mmol) into a flask containing 68-145 (4.7073mmol), add DMF (50ml) to dissolve it, stir at -5°C for 5 minutes, slowly add DIEA (1.55ml, 9.4147mmol), dropwise, react for half an hour, take out, stir at room temperature and react overnight. After the reaction is completed, add saturated brine (200ml) and ethyl acetate (200ml) for extraction, let stand and separate, collect the organic phase, and extract the aqueous phase with ethyl acetate (200ml×3). The combined organic phases are concentrated, evaporated to dryness, and dried in a vacuum oven to obtain 0.75g of the product with a yield of 33%.

[0533] 9.4 Preparation of 68-153

[0534] To a flask containing 68-149 (0.75 g, 1.0305 mmol) was added dichloromethane (10 ml). Ultrasonication was used to dissolve the mixture, followed by the addition of TFA (0.77 ml, 10.305 mmol). The mixture was stirred and allowed to react overnight at room temperature. After the reaction, n-hexane (100 ml) and methyl tert-butyl ether (600 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 collected by filtration and dried to yield 0.55 g of the product, with a yield of 93.22%.

[0535] 9.5 Preparation of 77-12

[0536] Fmoc-glycine (5 g, 16.817 mmol, purchased from Inochem), HBTU (10.5 g, 27.6635 mmol), and HOBT (3.74 g, 27.6635 mmol) were weighed and added to a flask containing tert-butyloxyformylhydrazide (2.89 g, 21.8621 mmol, purchased from Inochem). DMF (300 ml) was then added to dissolve the mixture. The mixture was stirred at -5°C for several minutes, and DIEA (9.15 ml, 55.3269 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, saturated brine (200 ml) and ethyl acetate (200 ml) were added for extraction. After standing and demixing, the organic phase was collected and the aqueous phase was extracted with ethyl acetate (200 ml x 3). The combined organic phases were concentrated, evaporated to dryness, and dried in a vacuum oven to obtain the product.

[0537] 9.6 Preparation of 77-11

[0538] Acetonitrile (50 ml) was added to a flask containing 77-12 (7.17 g, 16.817 mmol). Ultrasonication was used to dissolve the product, followed by diethylamine (25.98 ml, 252.255 mmol). The mixture was stirred at room temperature for 2 h. After completion of the reaction, saturated brine (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 combined organic phases were evaporated to dryness and dried in a vacuum oven to yield 2.6 g of the product, with a yield of 81.7%.

[0539] 9.7 Preparation of 80-26

[0540] 1,4,7-Triazacyclononane (0.5 g, 3.8699 mmol) was weighed and added to a 500 ml flask. Methanol (100 ml) was added to dissolve the mixture. Tert-butyl acrylate (2.25 ml, 15.4799 mmol) was added under nitrogen and stirred at room temperature overnight. After the reaction, saturated brine (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 combined organic phases were evaporated to dryness until solid and then dissolved in a 1 / 4 methanol / dichloromethane mixture. Silica gel powder was added and evaporated to dryness to obtain a powdered solid. The solid was dry-loaded and subjected to column chromatography using a 2-4% methanol / dichloromethane mixture as the eluent. The product was collected, concentrated, and dried in a vacuum oven to obtain 1.35 g of the product with a yield of 68.18%. ESI [M+Na + ]514.705

[0541] 9.8 Preparation of 80-27

[0542] To a flask containing 80-26 (1.35 g, 2.5 mmol) was added dichloromethane (10 ml). Ultrasonication was used to dissolve the product, followed by the addition of TFA (0.2 ml). The mixture was stirred and reacted overnight 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 to allow precipitation. Solid precipitated in the reaction solution, which 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 obtain the product. 1 H-NMR(600MHz,DMSO-d6)δ3.03-3.00(m,6H),2.87-2.78(m,12H),2.56-2.50(m,6H)

[0543] 9.9 Preparation of 68-178

[0544] 77-11 (1.33 g, 3.6054 mmol), HBTU (3.0 g, 7.9319 mmol) and HOBT (1.07 g, 7.9319 mmol) were added to a flask containing 38-204 (1.5 g, 7.9319 mmol), and DMF (100 ml) was added to dissolve it. The mixture was placed at -5°C and DIEA (11.12 ml, 67.2700 mmol) was slowly added dropwise. After the addition was completed, 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 the solid product is obtained by filtration. It is dissolved with dichloromethane and methanol, and silica gel powder is added and evaporated to dryness. The product is dry-loaded and subjected to column chromatography using 5-12% methanol / dichloromethane as the eluent. The product is collected, concentrated, and dried to obtain the product.

[0545] 9.10 Preparation of 68-179

[0546] To a flask containing 68-178 (3.8309 mmol) was added DMF (20 ml). After ultrasonic dissolution, morpholine (3.3 ml, 38.309 mmol) was added and stirred at room temperature for 2 h. After completion of the reaction, n-hexane (25 ml) and methyl tert-butyl ether (200 ml) were added to allow the solution to settle. The supernatant was decanted, and n-hexane and methyl tert-butyl ether were added to allow the solution to settle. This process was repeated three times. The solid product was filtered and dried in a vacuum oven to yield 1.45 g of the product, with a yield of 69.38%.

[0547] 9.11 Preparation of 68-127

[0548] 69-45 (1.33 g, 0.9883 mmol), HBTU (0.38 g, 0.9883 mmol), and HOBT (0.14 g, 0.9883 mmol) were weighed and added to a flask containing 80-27 (0.1 g, 0.2895 mmol). DMF (20 ml) was then added to dissolve the mixture. The mixture was placed at -5°C and DIEA (0.33 ml, 1.9766 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 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 off, dissolved in dichloromethane and methanol, added with silica gel powder and evaporated to dryness, dry-loaded, and subjected to column chromatography using 8-12% methanol / dichloromethane as eluent. The product was collected, concentrated, and dried to obtain 0.46 g, with a yield of 38.05%. 1H-NMR(600MHz,DMSO-d6)δ8.48-8.40(m,3H),8.21-8.13(m,6H),8.11-8.05(m,3H),7.94-7.88(m,3H),7.81-7.74(m,3H),7.58-7.53 (m,3H),7.42-7.29(m,33H),7.28-7.22(m,3H),5.09(s,6H),5.02-4.97(m,6H),4.31-4.19(m,6H),4.13-4.09(m,6H),4.05-3.98(m, 3H),3.30-3.25(m,3H),3.03-2.94(m,27H),2.82(s,15H),2.28-2.22(m,12H),2.19-2.14(m,6H),2.13-2.08(m,6H),2.04-1.99(m,6 H),1.93-1.87(m,9H),1.76-1.66(m,18H),1.50-1.44(m,9H),1.40-1.38(m,108H),1.36-1.31(m,12H),1.28-1.19(m,15H); ESI[M+Na + ]4183.41

[0549] 9.12 Preparation of 68-130

[0550] 68-127 (0.25 g, 0.0598 mmol) and 10% Pd / C catalyst (0.01 g) were placed in a hydrogenation reactor. DMF (30 ml) was added to dissolve the product. The hydrogenation reactor was sealed and evacuated with a water pump, followed by the introduction of hydrogen. This process was repeated three times. The pressure on the hydrogenation reactor was adjusted to 1.8 MPa. 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 yielded a DMF solution of the product, which served as the starting material for the next reaction.

[0551] 9.13 Preparation of 68-131

[0552] 68-130 (0.21 g, 0.0598 mmol) was placed in a 250 ml flask and dissolved in DMF (20 ml). DIEA (0.13 ml, 0.0873 mmol) was slowly added dropwise at -5 degrees Celsius. After stirring for 30 minutes, the mixture was taken out and Y-SCM-10K (2.0 g, 0.1975 mmol, purchased from Jiankai) was added. The mixture 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 mixture to settle. The supernatant was decanted, and n-hexane (20 ml) and methyl tert-butyl ether (100 ml) were added to allow the mixture to settle. This was repeated three times. The solid product was filtered to obtain a solid product. MTBE (100 ml x 3) was then added for washing. The solid was collected and dried in a vacuum oven to obtain 2.1 g of the product.

[0553] 9.14 Preparation of 68-156

[0554] 68-131 (1 g, 0.0294 mmol), HBTU (0.066 g, 0.1763 mmol) and HOBT (0.024 g, 0.1763 mmol) were weighed and added into a flask containing 68-153 (0.10 g, 0.1763 mmol). DMF (20 ml) was then added to dissolve the mixture. The mixture was placed at -5°C and DIEA (0.058 ml, 0.3526 mmol) was slowly added dropwise. 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 the solid product is filtered to obtain the solid product. It is dissolved with dichloromethane and methanol, and silica gel powder is added and evaporated to dryness. The solid product is loaded by dry method and subjected to column chromatography with 8-12% methanol / dichloromethane as eluent. The solid product is collected, concentrated, and dried to obtain 0.43 g of the product with a yield of 40.99%. 1H-NMR(600MHz,DMSO-d6)δ8.51-8.38(m,3H),8.20-8.11(m,6H),8.11-7.95(m,9H),7.95-7.89(m,5H),7.81-7.75(m,7H) ,7.56-7.52(m,3H),7.38-7.30(m,2H),7.21-7.17(m,3H),7.11-7.01(m,16H),4.29-4.20(m,14H),4.13-4.09(m,14H),3 .99-3.87(m,9H),3.56-3.49(m,3191H),3.02-2.94(m,38H),2.88-2.78(m,27H),2.40-2.38(m,6H),2.30-2.21(m,18H), 2.18-2.11(m,21H),2.06-2.01(m,8H),1.98-1.89(m,16H),1.78-1.70(m,25H),1.45-1.36(m,108H),1.26-1.21(m,28H)

[0555] 9.15 Preparation of 68-175

[0556] To a flask containing 68-156 (0.43 g, 0.0120 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 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 to allow precipitation. A powdery solid precipitated, which 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 obtain the product.

[0557] 9.16 Preparation of 68-180

[0558] 68-175 (0.0120 mmol), HBTU (0.1 g, 0.2647 mmol) and HOBT (0.36 g, 0.2647 mmol) were weighed and added into a flask containing 68-179 (0.088 g, 0.1584 mmol). DMF (10 ml) was then added to dissolve the mixture. The mixture was placed at -5°C and DIEA (0.54 ml, 3.2481 mmol) was slowly added dropwise. After the addition was complete, the mixture was reacted for half an hour and then 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 is repeated 3 times, and the solid product is filtered to obtain the solid product, which is dissolved with dichloromethane and methanol, and silica gel powder is added and evaporated to dryness. The solid product is loaded by dry method and subjected to column chromatography with 5-12% methanol / dichloromethane as eluent. The solid product is collected, concentrated, and dried to obtain 0.32 g of the product.

[0559] 9.17 Preparation of 68-193

[0560] 68-180 (0.32 g, 0.0077 mmol) was added to a 250 ml flask, and dichloromethane (8 ml) and TFA (8 ml) were added to dissolve it. The reaction 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 to allow precipitation. A powdery solid precipitated in the reaction solution, which 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 0.35 g of the product.

[0561] 9.18 Preparation of 77-231

[0562] 68-193 (0.30 g, 0.0077 mmol) was placed in a dry 500 ml round-bottom flask and dissolved in anhydrous methanol (10 ml). TFA (0.27 ml, 3.6 mmol) and doxorubicin hydrochloride (0.16 g, 0.2772 mmol, referred to as DOX-HCl) were then added and stirred at room temperature overnight. After completion, 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, and the solid product was filtered to obtain a solid. The solid product was dissolved in dichloromethane and methanol, added to silica gel powder, evaporated to dryness, and dry-applied. Column chromatography was performed using 6-10% methanol / dichloromethane as the eluent. The product was collected, concentrated, and dried to obtain 0.13 g of the product, with a yield of 32.02%. 1H-NMR(600MHz,DMSO-d6)δ14.10-14.00(m,24H),13.40-13.21(m,24H),8.51-8.38(m,3H),8.20-8.11(m,6H ),8.11-7.95(m,90H),7.96-7.89(m,55H),7.78-7.61(m,33H),7.53-7.34(m,6H),7.10-7.01(m,16H),5.5-5 .21(m,73H),5.01-4.26(m,108H),4.19-4.01(m,84H),3.96-3.75(m,32H),3.58-3.49(m,3524H),3.01-2.95 (m,81H),2.85-2.81(m,27H),2.40-2.14(m,80H),2.06-2.01(m,8H),1.91-1.70(m,42H),1.25-1.19(m,76H)

[0563] Example 10 Synthesis of Compounds 82-183

[0564] 10.1 Preparation of 80-14

[0565] Boc-ethylenediamine (1.65 g, 10.3 mmol), HBTU (5.57 g, 14.7 mmol), and HOBT (1.99 g, 14.7 mmol) were weighed and added to a flask containing 71-71 (4 g, 8.2896 mmol). DMF (200 ml) was then added to dissolve the mixture. The mixture was stirred at -5°C for several minutes, and DIEA (7.3 ml, 44.1 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, saturated brine (200 ml) and ethyl acetate (200 ml) were added for extraction. After standing and demixing, the organic phase was collected and the aqueous phase was extracted with ethyl acetate (200 ml x 3). The combined organic phases were concentrated, evaporated to dryness, and dried in a vacuum oven to yield 3.76 g of the product, an overproduction yield.

[0566] 10.2 Preparation of 80-16

[0567] To a flask containing 80-14 (4.9 mmol) was added DMF (30 ml). Morpholine (5.5 ml, 73.5 mmol) was added after ultrasonic dissolution and allowed to react at room temperature for 2 h. After the reaction, saturated brine (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 combined organic phases were evaporated to dryness to a solid and dried in a vacuum oven to obtain 2.67 g of the product, an overproduction yield.

[0568] 10.3 Preparation of 80-18

[0569] 80-16 (2.67 g, 4.9 mmol), HBTU (2.79 g, 7.35 mmol) and HOBT (0.99 g, 7.35 mmol) were weighed and added into a flask containing N'-fluorenylmethyloxycarbonyl-N-benzyloxycarbonyl-L-lysine (2.46 g, 4.9 mmol, purchased from Inochem), and then DMF (60 ml) was added to dissolve the mixture. The mixture was placed at -5°C and DIEA (2.5 ml, 14.7 mmol) was slowly added dropwise. After the dropwise addition, 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 the solid product is filtered to obtain the solid product. It is dissolved with dichloromethane and methanol, and silica gel powder is added and evaporated to dryness. The solid product is loaded by dry method and subjected to column chromatography with 8-12% methanol / dichloromethane as eluent. The solid product is collected, concentrated, and dried to obtain 3.66 g of the product with a yield of 72%.

[0570] 10.4 Preparation of 80-20

[0571] To a flask containing 80-18 (3.56 mmol), add DMF (60 ml). Dissolve the mixture with ultrasonication, then add morpholine (6.7 ml, 71.2 mmol). Stir and react at room temperature for 2 h. After the reaction, extract with saturated brine (200 ml) and ethyl acetate (200 ml). After stratification, the organic phase is collected and the aqueous phase is extracted with ethyl acetate (200 ml x 3). The combined organic phases are evaporated to dryness and dried in a vacuum oven to yield 2.25 g of the product, with a yield of 78%.

[0572] 10.5 Preparation of 80-28

[0573] 80-20 (0.72 g, 0.8975 mmol), HBTU (0.494 g, 1.302 mmol) and HOBT (0.176 g, 1.302 mmol) were weighed and added into a flask containing 80-27 (0.1 g, 0.2895 mmol), and DMF (20 ml) was added to dissolve the mixture. The mixture was stirred at -5°C for several minutes, and DIEA (0.72 ml, 4.34 mmol) was slowly added dropwise. After the dropwise addition, the mixture was reacted for half an hour, removed from the flask, and stirred at room temperature 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 the solid product is filtered to obtain the solid product, which is dissolved with dichloromethane and methanol, and silica gel powder is added and evaporated to dryness. The solid product is loaded by dry method and subjected to column chromatography with 8-12% methanol / dichloromethane as eluent. The solid product is collected, concentrated, and dried to obtain 0.47 g of the product with a yield of 59%. 1 H-NMR(600MHz,DMSO-d6)δ8.13-7.71(m,15H),7.43-7.15(m,18H),6.94-6.67(m,6 H),5.10-4.90(m,6H),4.36-3.91(m,6H),3.24-2.89(m,48H),2.86-2.77(m,7H),2 .72-2.62(m,9H),2.16-2.01(m,13H),1.89-1.82(m,4H),1.77-1.65(m,4H),1.61- 1.54(m,3H),1.51-1.43(m,12H),1.42-1.31(m,54H),1.29-1.15(m,14H);ESI[M+H + ]2713.99

[0574] 10.6 Preparation of 80-30

[0575] 80-28 (0.47 g, 2.2137 mmol) and 10% Pd / C catalyst (0.04 g) were placed in a hydrogenation reactor. DMF (30 ml) was added to dissolve the product. The hydrogenation reactor was sealed and evacuated with a water pump, followed by the addition of hydrogen. This process was repeated three times. The pressure on the hydrogenation reactor was adjusted to 2 MPa. 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 of the product, which served as the starting material for the next reaction.

[0576] 10.7 Preparation of 80-35

[0577] 80-30 (0.1g, 0.043mmol) is put into a 250ml flask, DMF (20ml) is added to dissolve, DIEA (0.118ml, 0.714mmol) is slowly added dropwise at -5 degrees Celsius, dripped and finished, and taken out after the reaction for 30 minutes. M-SCM-10K (1.49g, 0.143mmol, purchased from Jiankai) is added and the reaction is stirred at low speed in dark place for one week at room temperature. After the reaction is completed, normal hexane (25ml) and methyl tert-butyl ether (200ml) are added to settle, the supernatant is poured out, normal hexane (20ml) and methyl tert-butyl ether (100ml) are added to settle, and this is repeated 3 times. Suction filtration obtains a solid product, and methyl tert-butyl ether (100ml) is added to clean three times. The solid is collected and dried in a vacuum oven to obtain 1.0g of the product, with a yield of 71%.

[0578] 10.8 Preparation of 80-38

[0579] 80-35 (0.5 g, 0.0154 mmol) was added to a 250 ml flask and dissolved in dichloromethane (8 ml) and TFA (10 ml, 26.9 mmol). The reaction 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 to allow precipitation. A powdery solid precipitated from the reaction solution. The filter cake 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 0.5 g of the product, an overproduction yield.

[0580] 10.9 Preparation of 80-5

[0581] Compound 59-106 (6.13 g, 6.35 mmol) was added to a 250 ml flask, and dichloromethane (8 ml) and TFA (43.43 ml, 381 mmol) were added to dissolve the compound. The reaction mixture was stirred at room temperature overnight. 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 to allow precipitation. A powdery solid precipitated from the reaction solution. 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 obtain 5.1 g of the product, an overproduction yield.

[0582] 10.10 Preparation of 80-7

[0583] 80-5 (0.828 g, 1.43 mmol), 68-54 (2.0 g, 7.15 mmol), and NMM (1.6 ml, 14.3 mmol) were weighed and added to a flask containing 68-69 (6.0 g, 6.29 mmol). DMF (50 ml) was then added to dissolve the mixture. The mixture 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 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 6.24 g of the product, which was an overproduction yield.

[0584] 10.11 Preparation of 80-15

[0585] 80-7 (6.24 g, 1.43 mmol) was added to a 250 ml flask, and DMF (20 ml) and morpholine (1.1 ml, 14.3 mmol) were added to dissolve the mixture. The reaction was stirred at room temperature overnight. After the reaction was completed, methyl tert-butyl ether (60 ml) was added to allow precipitation. A powdery solid precipitated in the reaction solution, which 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 obtain 3.8 g of the product with a yield of 62%. ESI [M+Na + ]4291

[0586] 10.12 Preparation of 80-17

[0587] Weigh 80-15 (1.0 g, 0.234 mmol), HBTU (0.13 g, 0.351 mmol), HOBT (0.05 g, 0.351 mmol) and Fmoc-Glu(OtBu)-OH (0.1 g, 0.234 mmol) into a flask, add DMF (15 ml) to dissolve, stir at -5 ° C for several minutes, slowly add DIEA (0.12 ml, 0.702 mmol) dropwise, react for half an hour, take out, and stir the reaction at room temperature 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 the solid product is filtered to obtain the solid product. It is dissolved with dichloromethane and methanol, and silica gel powder is added and evaporated to dryness. The solid product is loaded by dry method and subjected to column chromatography with 6-10% methanol / dichloromethane as eluent. The solid product is collected, concentrated, and dried to obtain 0.9 g of the product with a yield of 82%.

[0588] 10.13 Preparation of 80-19

[0589] To a flask containing 80-17 (0.9 g, 0.19 mmol), DMF (10 ml) was added. After ultrasonic dissolution, morpholine (0.28 ml, 3.85 mmol) was added and 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 solution to settle. The supernatant was decanted, and n-hexane and methyl tert-butyl ether were added to allow the solution to settle. This process was repeated three times. The solid product was filtered and dried in a vacuum oven to yield 0.8 g of the product, with a yield of 94%.

[0590] 10.14 Preparation of 80-22

[0591] 80-19 (0.8 g, 0.18 mmol) was weighed and added to a 250 ml flask. DMF (15 ml) was then added to dissolve the mixture. DIEA (0.13 ml, 0.81 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 1 h, and succinic anhydride (0.1 g, 1.08 mmol) was added. 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 dried in a vacuum oven to yield 0.8 g of the product (97% yield).

[0592] 10.15 Preparation of 80-23

[0593] Weigh 80-22 (0.8 g, 0.175 mmol), HBTU (0.098 g, 0.26 mmol) and HOBT (0.035 g, 0.26 mmol) and add them to a flask containing 64-135 (0.156 g, 0.19 mmol). Then add DMF (20 ml) to dissolve the mixture. Stir for several minutes at -5 ° C. Slowly add DIEA (0.087 ml, 0.53 mmol) dropwise. After the dropwise addition is complete, react for half an hour, remove the mixture, and stir the reaction at room temperature overnight. After the reaction is complete, add n-hexane (25 ml) and methyl tert-butyl ether (200 ml) to precipitate. Pour the supernatant, add n-hexane and methyl tert-butyl ether to precipitate, repeat this process three times, and filter to obtain a solid product. Collect and dry in a vacuum oven to obtain 0.9 g of the product, which is an overproduction. ESI [M+Na + ]5380

[0594] 10.16 Preparation of 80-29

[0595] 80-23 (0.9 g, 0.168 mmol) was added to a 250 ml flask, dissolved in dichloromethane (20 ml) and TFA (5 ml), and the reaction was stirred at room temperature overnight. 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 to allow precipitation. A powdery solid precipitated from the reaction solution, which 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 0.79 g of the product (88%).

[0596] 10.17 Preparation of 82-183

[0597] 80-29 (0.219 g, 0.0414 mmol), HBTU (0.02 g, 0.0565 mmol) and HOBT (0.007 g, 0.0565 mmol) were weighed and added to a flask containing 80-38 (0.2 g, 0.00628 mmol). DMF (20 ml) was then added to dissolve the mixture. The mixture was stirred at -5°C for several minutes, and DIEA (0.003 ml, 0.1695 mmol) was slowly added dropwise. After the addition was complete, the mixture was reacted for half an hour and then removed from the flask and stirred at room temperature 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 the solid product is filtered to obtain the solid product. It is dissolved with dichloromethane and methanol, and silica gel powder is added and evaporated to dryness. The solid product is loaded by dry method and subjected to column chromatography with 6-10% methanol / dichloromethane as eluent. The solid product is collected, concentrated, and dried to obtain 0.2 g of the product with a yield of 51.3%. 1H-NMR(600MHz,DMSO-d6)δ8.82-8.68(m,24H),8.63-8.49(m,24H),8.23-7.96(m,192 H),7.91-7.76(m,36H),7.77-7.64(m,24H),7.55-7.39(m,48H),7.36-7.28(m,48H),7 .25-7.17(m,102H),7.12-7.05(m,18H),6.72-6.49(m,24H),5.33-5.19(m,48H),4.8 1-4.64(m,48H),4.62-4.50(m,32H),4.43-4.31(m,40H),4.29-4.04(m,96H),3.86-3. 80(m,48H),3.79-3.70(m,96H),3.69-3.58(m,282H),3.53-3.45(m,2849H),3.12-2. 95(m,137H),2.91-2.84(m,12H),2.77-2.67(m,24H),2.44-2.34(m,26H),2.30-2.25( m,15H),2.16-2.02(m,45H),1.95-1.80(m,27H),1.78-1.70(m,22H),1.66-1.57(m,3 6H),1.55-1.43(m,75H),1.36-1.30(m,21H),1.30-1.16(m,92H),0.98-0.67(m,180H)

[0598] Example 11 Synthesis of Compounds 82-87

[0599] 11.1 Preparation of 58-145

[0600] Tris(2-aminoethyl)amine (1 ml, 6.67 mmol, abbreviated as TAEA) was weighed and placed in a 500 ml flask. Methanol (100 ml) was added to dissolve the mixture. Tert-butyl acrylate (7.76 ml, 53.40 mmol) was added under nitrogen and stirred at room temperature overnight. After the reaction, saturated brine (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 combined organic phases were evaporated to dryness to a solid, then dissolved in 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 a 40% ethyl acetate / petroleum ether mixture as the eluent. The product was collected, concentrated, and dried in a vacuum oven to yield 5.91 g (96.7% yield).

[0601] 11.2 Preparation of 58-148

[0602] To a flask containing 58-145 (1.5 g, 1.64 mmol), 1,4-dioxane (10 ml) was added. Ultrasonication was used to dissolve the solution, followed by the addition of 4M hydrochloric acid-1,4-dioxane (49 ml). The mixture was stirred at 70°C for 5 h. After completion of the reaction, solid precipitated in the reaction solution, which 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 0.9 g of the product, with a yield of 75.8%. 1 H-NMR(600MHz,DMSO-d6)δ3.39-3.29(m,18H),3.03-2.97(m,6H),2.93-2.84(m,12H)

[0603] 11.3 Preparation of 58-77

[0604] Fmoc-β-alanine (1.22 g, 3.93 mmol, purchased from Inochem), HBTU (2.24 g, 5.90 mmol), and HOBT (0.80 g, 5.90 mmol) were weighed and added to a flask containing 59-99 (2.50 g, 3.97 mmol). DMF (50 ml) was then added to dissolve the mixture. The mixture was stirred at -5°C for several minutes, and DIEA (2.92 ml, 17.69 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, saturated brine (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 combined organic phases were concentrated, evaporated to dryness, and dried in a vacuum oven to yield 3.63 g of the product.

[0605] 11.4 Preparation of 58-81

[0606] To a flask containing 58-77 (3.63 g, 3.93 mmol), DMF (30 ml) was added. Morpholine (6.85 ml, 78.60 mmol) was added after ultrasonic dissolution, and the mixture was stirred at room temperature for 2 h. After the reaction, saturated brine (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 combined organic phases were concentrated, evaporated to dryness, and dried in a vacuum oven to obtain 3.69 g of the product, an overproduction yield.

[0607] Preparation of 11.58-82

[0608] N'-Fmoc-N-benzyloxycarbonyl-L-lysine (1.87 g, 3.74 mmol, purchased from Inochem), HBTU (2.13 g, 5.61 mmol), and HOBT (0.76 g, 5.61 mmol) were weighed and added to a flask containing 58-81 (3.69 g, 3.93 mmol). DMF (100 ml) was then added to dissolve the mixture. The mixture was stirred at -5°C for several minutes, and DIEA (2.79 ml, 16.84 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, saturated brine (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 1 / 4 methanol / dichloromethane mixed solvent. Silica gel powder (20 ml) was added and evaporated to dryness to obtain a powdery solid. The solid was dry-loaded and subjected to column chromatography using a 3% methanol / dichloromethane mixed solution as the eluent. The product was collected, concentrated, and dried in a vacuum oven to obtain 3.05 g of the product with a yield of 68.8%. 1H-NMR(400MHz,DMSO-d6)δ8.24-8.16(m,1H),8.11-8.02(m,2H),7.94-7.85(m,3H),7.77-7.66( m,2H),7.46-7.38(m,3H),7.37-7.28(m,7H),7.26-7.19(m,1H),5.06-4.96(m,2H),4.32-4.19( m,3H),4.15-4.07(m,2H),3.95-3.83(m,1H),3.29-3.18(m,2H),3.02-2.92(m,2H),2.35-2.13( m,8H),1.96-1.84(m,3H),1.78-1.65(m,3H),1.61-1.48(m,3H),1.37(s,36H),1.33-1.16(m,4H)

[0609] 11.6 Preparation of 58-211

[0610] Compound 58-82 (1.1 g, 0.93 mmol) was added to DMF (10 ml) and dissolved with ultrasonication. Morpholine (1.62 ml, 18.56 mmol) was then added and stirred at room temperature for 2 h. After completion of the reaction, saturated brine (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 combined organic phases were concentrated, evaporated to dryness, and dried in a vacuum oven to yield 0.86 g of the product (97.1% yield).

[0611] 11.7 Preparation of 58-212

[0612] 58-148 (0.10 g, 0.14 mmol), HBTU (0.37 g, 0.97 mmol), and HOBT (0.13 g, 0.97 mmol) were weighed and added to a flask containing 58-211 (0.86 g, 0.89 mmol). DMF (15 ml) was then added to dissolve the mixture. The mixture was stirred at -5°C for several minutes, and DIEA (0.49 ml, 2.92 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 completed, saturated brine (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, dissolved in dichloromethane and methanol, added with silica gel powder and evaporated to dryness, dry-loaded, and subjected to column chromatography using 1% ammonia water / 7% methanol / dichloromethane as eluent. The product was collected, concentrated, and dried to obtain 0.33 g with a yield of 39%. 1H-NMR(600MHz,DMSO-d6)δ8.27-7.89(m,30H),7.38-7.12(m,37H),5.12-5.01(m,12H),4.31-4.06(m,25H),2.95(s,16H),2 .62(s,16H),2.38-2.07(m,66H),1.78-1.69(m,40H),1.64-1.42(m,23H),1.46-1.32(m,216H),1.28-1.11(m,28H); ESI[M+H + ]6246.206

[0613] 11.8 Preparation of 58-214

[0614] 58-212 (0.19 g, 0.0314 mmol) and 10% Pd / C catalyst (0.04 g) were placed in a hydrogenation reactor. DMF (30 ml) was added to dissolve the product. The hydrogenation reactor was sealed and evacuated with a water pump, followed by the addition of hydrogen. This process was repeated three times. The pressure on the hydrogenation reactor was adjusted to 1.8 MPa, and the reaction mixture was stirred overnight at room temperature. After 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.

[0615] 11.9 Preparation of 58-215

[0616] 58-214 (0.17 g, 0.0314 mmol) was placed in a 250 ml flask and dissolved in DMF (20 ml). A DMF solution of M-SCM-5K (1.00 g, 0.1883 mmol, purchased from Jiankai) was then slowly added. The mixture 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 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 in a vacuum oven to yield 1.1 g of the product (95.7% yield).

[0617] 11.10 Preparation of 58-216

[0618] To 58-215 (1.1 g, 0.03 mmol) was added dichloromethane (8 ml) and TFA (8 ml) to dissolve the mixture, and the mixture was 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, and the solid product was filtered and collected and dried in a vacuum oven to yield 1.0 g of the product (90.3% yield).

[0619] 11.11 Preparation of 58-217

[0620] 58-216 (1.0 g, 0.0284 mmol), HBTU (0.39 g, 1.02 mmol), and HOBT (0.14 g, 1.02 mmol) were weighed and added to a flask containing 77-11 (0.14 g, 0.75 mmol). DMF (20 ml) was then added to dissolve the mixture. The mixture was stirred at -5°C for several minutes, and DIEA (0.51 ml, 3.07 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 dried in a vacuum oven to yield 1.23 g of product, an overproduction yield.

[0621] 11.12 Preparation of 58-218

[0622] 58-217 (1.23 g, 0.0325 mmol) was added to a 250 ml flask, dissolved in dichloromethane (8 ml) and TFA (8 ml), and stirred overnight at room temperature. After the reaction, the reaction solution was evaporated to an oil using a rotary evaporator. MTBE (60 ml) was then added to allow precipitation. A powdery solid precipitated from the reaction solution, which was filtered and the filter cake was washed with MTBE (40 ml x 3). The filter cake was collected and dried in a vacuum oven to yield 1.18 g of the product, an overproduction yield.

[0623] 11.13 Preparation of 82-87

[0624] 58-218 (3.1 g, 0.0838 mmol) was placed in a dry 500 ml round-bottom flask and dissolved in anhydrous methanol (30 ml). TFA (0.27 ml, 3.6 mmol) and DOX-HCl (1.16 g, 2.0112 mmol) were then added and stirred at room temperature overnight. After completion, n-hexane (25 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 three times. The solid product was filtered and dissolved in dichloromethane and methanol. Silica gel powder was added and evaporated to dryness. The sample was dry-loaded and subjected to column chromatography using 6-10% methanol / dichloromethane as the eluent. The product was collected, concentrated, and dried to yield 2.3 g, a yield of 55.42%. 1 H-NMR(600MHz,DMSO-d6)δ14.04-14.00(m,24H),9.16-9.07(m,24H),7.96-7.94(m,14H),7.92-7.85(m,97H),7.68-7.59(m,50H) ,7.16-7.10(m,21H),7.02-6.87(m,22H),6.75-6.67(m,21H),5.56-5.50(m,48H),5.47-5.44(m,48H),5.31-5.25(m,48H),4.92-4 .88(m,49H),4.62-4.57(m,81H),4.22-4.17(m,46H),3.98-3.97(m,80H),3.64-3.60(m,68H),3.56-3.46(m,3076H),3.21-3.15( m,49H),3.02-2.96(m,51H),2.76-2.71(m,31H),2.19-2.06(m,101H),1.91-1.84(m,57H),1.73-1.66(m,57H),1.16-1.12(m,73H)

[0625] Example 12 Synthesis of Compound 73-49

[0626] 12.1 Preparation of 61-220

[0627] Fmoc-L-glutamic acid 5-tert-butyl ester (10 g, 23.5 mmol) and β-alanine tert-butyl ester hydrochloride (4.27 g, 23.5 mmol) were weighed and added to a 500 ml round-bottom flask. DMF (25 ml) was then added and dissolved with ultrasonication. The mixture was stirred at -5°C for 2 minutes. 68-54 (7.15 g, 25.85 mmol) was then added, and N-methylmorpholine (7.8 ml, 70.5 mmol) was slowly added dropwise to continue the reaction. After the reaction, the reaction mixture was transferred to a 2 L separatory funnel filled with purified water (300 ml) and ethyl acetate (300 ml) 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 evaporated to dryness to yield 12.98 g of the product.

[0628] 12.2 Preparation of 61-221

[0629] 61-220 (12.98 g, 23.5 mmol) was added to a 500 ml round-bottom flask, followed by DMF (20 ml) and sonication-assisted dissolution. Morpholine (30.7 ml, 352.5 mmol) was then added and the reaction stirred at room temperature. After completion of the reaction, the reaction mixture was poured into a 2 L separatory funnel filled with purified 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 combined organic phases were washed with saturated sodium bicarbonate solution (200 ml x 2), collected, concentrated, and added to 200-300 mesh silica gel powder (90 g). The mixture was evaporated to dryness, and the sample was dry-applied. Column chromatography was performed using 1% ammonia / 7% methanol / dichloromethane as the eluent. The desired product was collected, concentrated, and evaporated to dryness to obtain 6.2 g of the product in an 80% yield.

[0630] 12.3 Preparation of 61-222

[0631] Fmoc-L-glutamic acid (3.15 g, 8.527 mmol) and 61-221 (6.2 g, 18.76 mmol) were weighed and added to a 500 ml round-bottom flask. DMF (15 ml) was then added and sonicated for dissolution. The mixture was stirred at -5°C for 2 minutes. 68-54 (5.19 g, 18.76 mmol) was then added, followed by the slow dropwise addition of N-methylmorpholine (5.6 ml, 51.16 mmol) to continue the reaction. After completion of the reaction, the reaction mixture was transferred to a 2 L separatory funnel filled with purified water (300 ml) and ethyl acetate (300 ml) 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 × 2). The organic phases were collected and concentrated. 200-300 mesh silica gel powder (40 g) was added and evaporated to dryness. The mixture was dry-loaded and column chromatography was performed using 1-3% methanol / dichloromethane as the eluent. The target product was collected, concentrated, and evaporated to dryness to obtain 8.1 g of the product with a yield of 95%.

[0632] 12.4 Preparation of 61-224

[0633] 61-222 (8.1 g, 8.147 mmol) was added to a 500 ml round-bottom flask, followed by DMF (20 ml) and sonication-assisted dissolution. Morpholine (10.65 ml, 122.21 mmol) was then added and the reaction stirred at room temperature. After completion of the reaction, the reaction mixture was removed and poured into a 2 L separatory funnel filled with purified 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 combined organic phases were washed with saturated sodium bicarbonate solution (200 ml x 2). The organic phases were collected, concentrated, and 200-300 mesh silica gel powder (30 g) was added 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 6.2 g of the product in a 98% yield.

[0634] 12.5 Preparation of 61-227

[0635] 61-224 (6.2 g, 8.03 mmol), 64-124 (2.83 g, 8.03 mmol), HBTU (4.56 g, 12.04 mmol) and HOBT (1.62 g, 12.04 mmol) were placed in a 500 ml flask, and DMF (15 ml) was added to dissolve with ultrasonic assistance. After stirring at room temperature for 2 min, DIEA (4.64 ml, 28.105 mmol, purchased from Aladdin) was slowly added dropwise. After the addition was complete, the reaction was continued to stir at room temperature. After the reaction, methyl tert-butyl ether (100 ml) and n-hexane (200 ml) were added to the reaction solution for precipitation. A solid product was precipitated and filtered. The solid was dissolved with 1 / 4 methanol / dichloromethane mixed solvent, and 200-300 mesh silica gel powder (35 g) was added and evaporated to dryness. The sample was dry loaded and column chromatography was performed with 3% methanol / dichloromethane as eluent. The product was collected, concentrated, and evaporated to dryness to obtain 7.48 g of the product with a yield of 83%.

[0636] 12.6 Preparation of 61-229

[0637] 61-227 (7.4 g, 6.68 mmol) was added to a 500 ml round-bottom flask, followed by DMF (20 ml) and sonication-assisted dissolution. Morpholine (8.73 ml, 100.24 mmol) was then added and stirred at room temperature. After completion of the reaction, the mixture was extracted with ethyl acetate (200 ml) and water (300 ml). The organic phase was collected, and the aqueous phase was extracted again with ethyl acetate (150 ml x 2). The combined organic phases were washed with saturated sodium bicarbonate solution (200 ml x 2), the organic phases were collected, dehydrated with anhydrous magnesium sulfate, filtered, and the filtrate was collected, concentrated, and dried to yield 5.91 g of the product.

[0638] 12.7 Preparation of 61-231

[0639] 61-229 (5.91 g, 6.68 mmol), N'-Fmoc-N-benzyloxycarbonyl-L-lysine (3.35 g, 6.68 mmol), HBTU (3.8 g, 10.02 mmol), and HOBT (1.354 g, 10.02 mmol) were placed in a 500 ml flask. DMF (15 ml) was added and dissolved with ultrasound. After stirring at room temperature for 10 min, DIEA (3.86 ml, 23.38 mmol, purchased from Aladdin) was slowly added dropwise. After the addition was complete, the reaction was continued with stirring at room temperature. After the reaction was completed, n-hexane (50 ml) and methyl tert-butyl ether (450 ml) were added to allow precipitation. A solid precipitated and was filtered. The filter cake was dissolved in DMF (20 ml), and then n-hexane (50 ml) and methyl tert-butyl ether (450 ml) were added to allow precipitation. This process was repeated three times. The crude solid product was dissolved in a 1 / 4 methanol / dichloromethane mixed solvent, and 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 3% methanol / dichloromethane as the eluent. The product was collected, concentrated, and evaporated to dryness to obtain 6.3 g of the product with a yield of 68.8%. 1 H-NMR(600MHz, DMSO-d6)δ8.19(d,J=8.1Hz,1H),8.14(d,J=8.0Hz,1H),8.09(q,J=5.2Hz,2H),7.94(d,J=7.5Hz,1H),7.89(d ,J=7.6Hz,2H),7.83(t,J=5.7Hz,1H),7.73(dd,J=3.2,7.8Hz,2H),7.45-7.26(m,10H),7.23(t,J=5.8Hz,1H) ,5.00(s,2H),4.32-4.16(m,5H),4.09(q,J=7.5Hz,1H),3.91(td,J=5.1,8.7Hz,1H),3.47-3.24(m,2H),3.21 -3.11(m,2H),3.10-2.91(m,4H),2.42-2.30(m,4H),2.26-2.03(m,8H),1.89-1.65(m,6H),1.62-1.16(m,48H)

[0640] 12.8 Preparation of 61-232

[0641] 61-231 (3 g, 2.19 mmol) was added to a 250 ml round-bottom flask, followed by DMF (10 ml) and sonication-assisted dissolution. Morpholine (2.86 ml, 32.85 mmol) was then added and allowed to react at room temperature with stirring. After the reaction, n-hexane (50 ml) and methyl tert-butyl ether (450 ml) were added to allow the solid to precipitate, which was filtered. The filter cake was re-dissolved in DMF (20 ml) and then precipitated with methyl tert-butyl ether (500 ml). This process was repeated three times. The filter cake was collected and dissolved in a 1 / 1 methanol / dichloromethane mixture (100 ml). 200-300 mesh silica gel powder (30 g) was added and evaporated to dryness. The sample was dry-applied and subjected to column chromatography using 1% ammonia / 4% methanol / dichloromethane as the eluent. The desired product was collected, concentrated, and evaporated to dryness to obtain 2.2 g of the product in an 88% yield. 1 H-NMR (600MHz, DMSO-d6) δ8.19(d,J=8.2Hz,1H),8.14(d,J=8.0Hz,1H),8.10(q,J=5.9Hz,2H),7.95(d,J= 7.4Hz,1H),7.80(t,J=5.8Hz,1H),7.40-7.28(m,5H),7.22(t,J=5.7Hz,1H),5.00(s,2H),4.27-4.16(m,2H ),4.15-4.01(m,3H),3.38-3.27(m,1H),3.21-3.12(m,1H),3.08(dd,J=5.3,7.5Hz,1H),3.06-3.00(m,2H) ,2.99-2.93(q,J=6.7Hz,2H),2.42-2.30(m,5H),2.26-2.05(m,9H),1.90-1.66(m,6H),1.57-1.18(m,48H)

[0642] 12.9 Preparation of 73-5

[0643] 61-232 (1 g, 0.8715 mmol), 67-53 (0.066 g, 0.095 mmol), HBTU (0.3814 g, 1.00 mmol), and HOBT (0.135 g, 1.00 mmol) were placed in a 500 ml flask. DMF (10 ml) was added and dissolved with ultrasound. After stirring at room temperature for 2 min, DIEA (0.63 ml, 3.83 mmol, purchased from Aladdin) was slowly added dropwise. After the addition was complete, the reaction was continued with stirring at room temperature. After the reaction was completed, n-hexane (50 ml) and methyl tert-butyl ether (450 ml) were added to allow the reaction to settle. A solid precipitated and was filtered. The filter cake was redissolved in DMF (10 ml), and methyl tert-butyl ether (500 ml) was added to allow the reaction to settle. The solid was then filtered. This process was repeated three times. The filter cake was collected and dissolved in a 1 / 1 methanol / dichloromethane mixed solvent (100 ml). 200-300 mesh silica gel powder (30 g) was added and evaporated to dryness. The mixture was dry-loaded and subjected to column chromatography using 1% ammonia water / 3-16% methanol / dichloromethane as eluent. The target product was collected, concentrated, and evaporated to dryness to obtain 0.12 g of the product with a yield of 18%. 1 H-NMR(600MHz,DMSO-d6)δ8.22-8.05(m,35H),7.99-7.92(m,14H),7.40-7.27(m,35H), 7.25-7.19(m,7H),5.08-4.94(m,14H),4.26-4.16(m,14H),4.13-4.04(m,14H),3.89-3 .80(m,7H),3.56-3.38(m,18H),3.38-3.10(m,14H),3.07-2.85(m,35H),2.81-2.69(m, 26H),2.44-2.27(m,28H),2.27-2.04(m,56H),1.91-1.62(m,42H),1.61-1.10(m,336H)

[0644] 12.10 Preparation of 73-14

[0645] Raw material 73-5 (0.60 g, 0.0703 mmol) and 10% Pd / C catalyst (130 mg) were added to a hydrogenation reactor. DMF (10 ml) was then added to dissolve the mixture. The hydrogenation reactor was sealed, evacuated with a water pump, and then filled with hydrogen. This process was repeated three times, with the hydrogen pressure adjusted to 2 MPa. The reaction was then allowed to proceed at room temperature for 72 h. After completion of the reaction, the mixture was filtered through a Büchner funnel containing filter paper. The reactor was rinsed with DMF (5 ml x 3). The filtrate was collected and used as the starting material for the next reaction.

[0646] 12.11 Preparation of 73-17

[0647] The 73-14 solution (0.0703 mol) was first added to a 500 ml round-bottom flask, then diluted with DMF (10 ml) and stirred at -5°C for 2 minutes. DIEA (0.32 ml, 1.96 mmol) was then slowly added dropwise, and the reaction was continued with stirring for 3 minutes. M-SCM-5000 (2.9 g, 0.54 mmol, batch number ZZ348P126, purchased from Tianjin Jiankai) was added, and the reaction was stirred at low speed in the dark for 72 hours. After the reaction, n-hexane (50 ml) and methyl tert-butyl ether (450 ml) were added to the mixture for precipitation. Solid precipitated and was filtered. The filter cake was added with a 1 / 1 methanol / dichloromethane mixed solvent (20 ml) and dissolved with the assistance of ultrasound. 100-200 mesh silica gel powder (20 g) was added and evaporated to dryness. The sample was dry-loaded and column chromatography was performed using 1% ammonia water / 5% methanol / dichloromethane as eluent. The target product was collected, concentrated, and evaporated to dryness to obtain 1.51 g of the product with a yield of 53%. 1 H-NMR(600MHz,DMSO-d6)δ8.23-7.99(m,42H),7.99-7.92(m,14H),4.26- 4.16(m,14H),4.13-4.04(m,14H),3.89-3.80(m,7H),3.63-3.38(m,3301 H),3.38-3.10(m,14H),3.10-2.85(m,35H),2.81-2.68(m,26H),2.44-2. 27(m,28H),2.27-2.04(m,56H),1.91-1.62(m,42H),1.61-1.09(m,336H)

[0648] 12.12 Preparation of 73-47

[0649] 73-17 (0.35 g, 0.0081 mmol) was added to a 50 ml round-bottom flask, and TFA (5.2 ml) was added. The reaction was stirred at room temperature. After the reaction was completed, most of the TFA was removed using a rotary evaporator, and methyl tert-butyl ether (50 ml) was added to allow the solution to settle. A solid precipitated, which was filtered. The filter cake was redissolved in DMF (5 ml) and then added to methyl tert-butyl ether (45 ml) to allow the solution to settle. This process was repeated three times. The filter cake was redissolved in DMF (5 ml) and DIEA (0.165 ml, 1 mmol) was slowly added dropwise with stirring to neutralize the product. MTBE (45 ml) was then added to allow the solution to settle. A solid precipitated, which was filtered and dried to obtain 0.19 g of the product (57% yield). 1H-NMR(600MHz,DMSO-d6)δ12.1-11.89(m,28H),8.23-7.99(m,42H),7.99-7.9 2(m,14H),4.26-4.16(m,14H),4.13-4.04(m,14H),3.89-3.80(m,7H),3.63-3 .38(m,3301H),3.38-3.10(m,14H),3.10-2.85(m,35H),2.82-2.68(m,26H),2 .44-2.24(m,28H),2.24-2.03(m,56H),1.91-1.62(m,42H),1.61-1.09(m,84H)

[0650] 12.13 Preparation of 73-49

[0651] 73-47 (0.1 g, 0.0023 mmol), HBTU (0.0376 g, 0.099 mmol), HOBT (0.013 g, 0.099 mmol), and 67-154 (0.0317 g, 0.099 mmol) were added to a 50 ml round-bottom flask. DMF (7 ml) was then added and dissolved with ultrasound. After stirring at room temperature for 1 min, DIEA (0.05 ml, 0.298 mmol) was slowly added dropwise to continue the reaction. After completion of the reaction, methyl tert-butyl ether (45 ml) was added to allow precipitation. A solid precipitated and was filtered. The filter cake was redissolved in a 1 / 1 mixture of anhydrous ethanol and dichloromethane (10 ml), and methyl tert-butyl ether (45 ml) was added to allow precipitation. The solid precipitated and was filtered. This process was repeated three times. The filter cake was dried to yield 0.034 g of the product. 1 H-NMR(600MHz,DMSO-d6)δ8.23-7.99(m,70H),7.99-7.92(m,14H),7.70-7.52 (m,56H),7.33-7.20(m,56H),4.26-4.04(m,84H),3.89-3.80(m,7H),3.63-3. 38(m,3301H),3.38-3.10(m,14H),3.10-2.85(m,91H),2.85-2.68(m,26H),2. 44-2.22(m,28H),2.22-2.03(m,56H),1.90-1.62(m,42H),1.62-1.09(m,504H)

[0652] Example 13 Synthesis of Compound 82-226

[0653] 13.1 Preparation of 66-135

[0654] Ethylenediamine (1g, 12.8041mmol) was added to a reaction flask containing dichloromethane (10ml) and stirred at low temperature. Acrylic acid (10g, 138.7732mmol) was then dissolved in dichloromethane (20ml) and slowly added dropwise to the reaction flask. After the addition was complete, the mixture was purged with nitrogen and transferred to an oil bath at 55°C. Stirring and reacting under reflux for three days allowed a white solid to precipitate. After the reaction was complete, the filter cake was filtered to obtain a white solid. The solid was washed three times with dichloromethane (100ml) and dried to yield 2.4434g of the crude product, a 55% yield. 1 H-NMR(600MHz,DMSO-d6)δ12.01(s,4H),2.80-2.68(m,8H),2.57-2.53(m,4H),2.36-2.31(m,8H)

[0655] 13.2 Preparation of 66-148

[0656] 66-135 (0.8 g, 2.2965 mmol), Boc-ethylenediamine (2.9434 ml, 18.3723 mmol), HOBT (5.2255 g, 13.7790 mmol), and HBTU (1.8618 g, 13.7790 mmol) were placed in a reaction flask. DMF (100 ml) was added and dissolved with ultrasound. The mixture was stirred at 0°C. DIEA (6.0 mmol, 36.744 mmol) was slowly added dropwise. After the reaction was complete, the mixture was brought to room temperature and continued to stir. The reaction progress was monitored by TLC. After the reaction was completed, n-hexane (50 ml) and methyl tert-butyl ether (200 ml) were added to allow the mixture to settle, resulting in an oily solid. The supernatant was discarded, and methyl tert-butyl ether (200 ml) was added to allow the mixture to settle. This process was repeated five times. The crude product was dissolved in ethyl acetate (15 ml) and refrigerated at 2-8 degrees Celsius overnight. A powdery solid precipitated and was filtered. The filter cake was washed three times with methyl tert-butyl ether (60 ml). The filter cake was collected and dissolved in a methanol / dichloromethane mixed solvent. The sample was dry-loaded and column chromatography was performed using 1-8% methanol / dichloromethane as the eluent. The target product was collected, concentrated, and dried in a vacuum oven to obtain 0.6488 g of the product with a yield of 30.89%. 1H-NMR(600MHz,DMSO-d6)δ8.02-7.94(m,4H),7.19-7.04(m,1H),6.94-6.55(m,3H),3.12-3.03(m,8H),3 .01-2.92(m,8H),2.63-2.57(m,4H),2.49-2.45(m,8H),2.28-2.16(m,8H),1.45-1.30(m,36H);ESI[M+H + ]917.106

[0657] 13.3 Preparation of 66-168

[0658] 66-148 (1.1 g, 1.1994 mmol) was placed in a 250 ml round-bottom flask, and dichloromethane (20 ml) was added. Dissolution was assisted by ultrasound, and TFA (5.3 ml, 71.9628 mmol) was added. Finally, the reaction flask was placed in a stirring reaction at room temperature overnight, and the reaction progress was monitored by TLC. After the reaction was completed, the reaction solution was first concentrated under reduced pressure to remove dichloromethane and most of the TFA, and then n-hexane (50 ml) and methyl tert-butyl ether (200 ml) were added to precipitate the oily solid. The supernatant was discarded, and methyl tert-butyl ether (200 ml) was added to precipitate the oily solid. This was repeated three times, and a powdery solid was precipitated. The filter cake was collected by filtration and dried in a vacuum oven to obtain 0.6197 g of the product.

[0659] 13.4 Preparation of 66-171

[0660] 66-168 (0.6197 g, 1.1994 mmol) was dissolved in anhydrous ethanol (20 ml). DIEA (3.2 ml, 19.1904 mmol) was slowly added dropwise at -5°C. After 10 minutes, tert-butyl acrylate (2.4596 g, 19.1904 mmol) was added. The mixture was purged with nitrogen and stirred at 40°C for two days. The reaction progress was monitored by TLC. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and then 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 resulting product was dissolved in a mixture of dichloromethane and methanol, added to silica gel powder, evaporated to dryness, and dry-applied. Column chromatography was performed using 3-10% methanol / dichloromethane as the eluent. The product was collected, concentrated, and dried to yield 1.14 g. 1H-NMR(600MHz,DMSO-d6)δ7.93-7.62(m,4H),3.16-2.92(m,16H),2.69-2.61(m,19 H),2.46-2.38(m,13H),2.35-2.27(m,17H),2.23-2.13(m,4H),1.43-1.36(m,72H)

[0661] 13.5 Preparation of 58-179

[0662] 66-171 (1.14 g, 0.739 mmol) was placed in a 250 ml round-bottom flask and dissolved in 4 M 1,4-dioxane hydrochloride (45 ml, 88.68 mmol). The reaction flask was heated in a 70°C oil bath under reflux with stirring for 24 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and n-hexane (25 ml) and methyl tert-butyl ether (200 ml) were added to allow precipitation. The supernatant was decanted, and n-hexane (25 ml) and methyl tert-butyl ether (200 ml) were added to allow precipitation. This process was repeated three times. The solid product was filtered, added toluene (2 ml) and dichloromethane (10 ml), dissolved with ultrasonication, and evaporated to dryness. The product was dried in a vacuum oven to yield 0.8078 g, an overproduction yield. 1 H-NMR(600MHz,DMSO-d6)δ12.18-12.11(m,4H),8.44-8.41(m,4H),3.69-3.65(m,12H),3.47- 3.40(m,12H),3.38-3.34(m,14H),3.14-3.09(m,10H),2.86-2.82(m,6H),2.78-2.70(m,14H)

[0663] 13.6 Preparation of 66-136

[0664] N'-Fmoc-N-benzyloxycarbonyl-L-lysine (5.5329 g, 11.0096 mmol), tert-butyl alanine (2.0 g, 11.0096 mmol), HOBT (1.6364 g, 12.1105 mmol), and HBTU (4.5927 g, 12.1105 mmol) were placed in a reaction flask. DMF (30 ml) was added and sonication was used to dissolve the mixture. DIEA (4 ml, 24.2211 mmol) was then added dropwise at 0°C. After the mixture was cooled to room temperature and stirred overnight, the reaction was monitored by TLC. After the reaction, the mixture was extracted into a separatory funnel containing saturated NaCl solution (300 ml) and ethyl acetate (300 ml). 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 and dried in a vacuum oven to yield 6.9332 g of the product (overproduction yield).

[0665] 13.7 Preparation of 66-195

[0666] Reactant 66-136 (6.9332 g, 11.0096 mmol) was dissolved in DMF (30 ml). Morpholine (14.4 ml, 165.144 mmol) was then added and stirred at room temperature for 3 hours. The reaction progress was monitored by TLC. After completion of the reaction, the mixture was poured into a separatory funnel filled with saturated NaCl solution (100 ml) and ethyl acetate (150 ml) for extraction. After standing and stratification, the organic phase was collected and the aqueous phase was extracted with ethyl acetate (100 ml x 3). The combined organic phases were concentrated, evaporated to dryness, and dried in a vacuum oven to obtain 3.9 g of the product, with a yield of 86.92%. 1 H-NMR(600MHz,DMSO-d6)δ8.01-7.90(m,1H),7.43-7.27(m,5H),7.26-7.16(m,1H),5.10-4.49(m,2H),3.30-3.20(m,2H), 3.14-3.07(m,1H),3.00-2.93(m,2H),2.45-2.22(m,3H),1.58-1.48(m,1H),1.42-1.39(m,9H),1.38-1.21(m,5H); ESI[M+H + ]409.30

[0667] 13.8 Preparation of 66-200

[0668] 58-179 (0.1156 g, 0.1057 mmol), 66-195 (0.656 g, 1.6099 mmol), and PyOxim (0.9727 g, 1.9022 mmol, purchased from Inochem) were placed in a reaction flask. DMF (30 ml) was added and dissolved with ultrasound. The mixture was stirred at 0°C. DIEA (1 ml, 5.8545 mmol) was added dropwise. After addition, the mixture was brought to room temperature and continued to stir. 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 (30 ml) and methyl tert-butyl ether (100 ml) were added to allow sedimentation. This process was repeated three times. The crude product was dissolved in a mixed solvent of dichloromethane and methanol, silica gel powder was added and evaporated to dryness, dry-loaded, and column chromatography was performed using 1% ammonia water / 5-15% methanol / dichloromethane as eluent. The product was collected, concentrated, and dried in a vacuum oven to obtain 0.1868 g of the product with a yield of 42%. 1 H-NMR(600MHz,DMSO-d6)δ8.10-8.04(m,6H),8.03-8.01(m,3H),8.00-7.93(m,9H),7.85-7.71(m,4H),7.39-7.26(m,4 0H),7.22-7.15(m,7H),5.05-4.97(m,16H),4.20-4.14(m,7H),4.11-4.09(m,1H),3.58-3.55(m,8H),3.18-3.16(m,8H) ,3.11-3.06(m,8H),2.97-2.92(m,16H),2.69-2.62(m,24H),2.45-2.40(m,16H),2.35-2.32(m,16H),2.28-2.22(m,12H ),2.20-2.16(m,6H),1.62-1.51(m,9H),1.50-1.42(m,11H),1.39-1.36(m,72H),1.36-1.32(m,8H),1.29-1.14(m,20H)

[0669] 13.9 Preparation of 66-201

[0670] Weigh 66-200 (0.1868 g, 0.0443 mmol) into a microhydrogenation reactor and dissolve it in DMF (30 ml). Add 10% Pd / C catalyst (30 mg) and place a magnetic stirrer. Seal the reactor, evacuate with a water pump, and then refill with hydrogen. Repeat this process three times. Adjust the hydrogen pressure in the reactor to 2 MPa. Stir overnight and monitor the reaction progress by TLC. After completion, filter through celite and set aside the filtrate.

[0671] 13.10 Preparation of 66-202

[0672] Reactant 66-201 (0.0695 g, 0.0222 mmol) was placed in a reaction flask, and DMF (30 ml) was added with ultrasonication to dissolve the mixture. The mixture was stirred at 0°C, and DIEA (0.12 mmol, 0.7088 mmol) was added. After complete dropwise addition, the mixture was brought to room temperature and stirred for 0.5 hours. M-SCM-5K (1.0350 g, 0.1949 mmol, purchased from Jiankai) was added, and the reaction progress was monitored by TLC. After the reaction was completed, n-hexane (50 ml) and methyl tert-butyl ether (200 ml) were added to allow the mixture to settle, resulting in an oily solid. The supernatant was discarded, and methyl tert-butyl ether (200 ml) was added to allow the mixture to settle. This process was repeated three times, resulting in the precipitation of a powdery solid. The filter cake was then washed three times with methyl tert-butyl ether (60 ml), collected, and dried to yield 0.99 g of the product, an overproduction yield.

[0673] 13.11 Preparation of 66-212

[0674] Reactant 66-202 (0.99 g, 0.0245 mmol) was dissolved in dichloromethane (10 ml), followed by the addition of TFA (2.7 ml, 3.675 mmol). The mixture was stirred and heated under reflux at 50°C. Reaction progress was monitored by TLC. After completion of the reaction, the reaction solution was concentrated under reduced pressure to remove the dichloromethane and most of the TFA. Then, n-hexane (50 ml) and methyl tert-butyl ether (200 ml) were added to allow the solution to settle, resulting in an oily solid. The supernatant was discarded, and methyl tert-butyl ether (200 ml) was added to allow the solution to settle. This process was repeated three times, resulting in the precipitation of a powdery solid. The filter cake was collected by filtration and dried in a vacuum oven to yield 1.33 g of the product.

[0675] 13.12 Preparation of 66-155

[0676] Reactants 80-15 (1.4 g, 0.3279 mmol), Boc-Lys(Fmoc)-OH (0.1613 g, 0.3607 mmol), HOBT (0.0487 g, 0.3607 mmol), and HBTU (0.1368 g, 0.3607 mmol) were placed in a reaction flask. DMF (20 ml) was added and ultrasonically assisted for dissolution. The mixture was stirred at 0°C and DIEA (0.5 mmol, 2.8112 mmol) was added dropwise. After the addition was complete, the mixture was brought to room temperature and the reaction was continued with stirring. The reaction progress was monitored by TLC. After the reaction, n-hexane (50 ml) and methyl tert-butyl ether (200 ml) were added to precipitate the oily solid. The supernatant was discarded, and methyl tert-butyl ether (200 ml) was added to precipitate. This process was repeated three times to precipitate a powdery solid. The filter cake was collected by filtration and dried in a vacuum oven to obtain 1.5 g of the product with a yield of 96.94%.

[0677] 13.13 Preparation of 66-157

[0678] Reactant 66-155 (1.5 g, 0.3179 mmol) was dissolved in DMF (30 ml), and morpholine (0.4 ml, 4.7680 mmol) was added. The mixture was stirred at room temperature and the reaction progress was monitored by TLC. After the reaction was completed, n-hexane (30 ml) and methyl tert-butyl ether (150 ml) were added to allow the mixture to settle, resulting in an oily solid. The supernatant was discarded, and methyl tert-butyl ether (100 ml) was added to allow the mixture to settle. This process was repeated three times, resulting in the precipitation of a powdery solid. The filter cake was collected by filtration and dried in a vacuum oven to obtain 0.4772 g of the product with a yield of 34%. ESI [M+H + ]4498.78

[0679] 13.14 Preparation of 66-162

[0680] 66-157 (0.4772 g, 0.1061 mmol) was weighed and added to a 250 ml flask. DMF (30 ml) was then added to dissolve the mixture. DIEA (0.1 ml, 0.5306 mmol) was slowly added dropwise. After stirring for 1 hour, succinic anhydride (0.03 g, 0.3183 mmol) was added. The mixture was stirred and reacted overnight at room temperature. After the reaction was completed, n-hexane (30 ml) and methyl tert-butyl ether (150 ml) were added to allow the mixture to settle, resulting in an oily solid. The supernatant was discarded, and methyl tert-butyl ether (100 ml) was added to allow the mixture to settle. This process was repeated three times, resulting in the precipitation of a powdery solid. The filter cake was collected by filtration and dried in a vacuum oven to yield 0.3951 g of the product with a yield of 81.01%. ESI [M+Na + ]4618.63

[0681] 13.15 Preparation of 66-163

[0682] 66-162 (0.3951 g, 0.0859 mmol), 64-135 (0.0742 g, 0.0902 mmol), HOBT (0.0128 g, 0.0945 mmol), and HBTU (0.0359 g, 0.0945 mmol) were placed in a reaction flask. DMF (20 ml) was added and dissolved with ultrasound. The mixture was stirred at 0°C. DIEA (0.03 ml, 0.1891 mmol) was added dropwise. After complete addition, the mixture was brought to room temperature and continued to stir. The reaction progress was monitored by TLC. After completion of the reaction, n-hexane (30 ml) and methyl tert-butyl ether (150 ml) were added to allow the reaction to settle, resulting in an oily solid. The supernatant was discarded, and methyl tert-butyl ether (100 ml) was added to allow the reaction to settle. This process was repeated three times, resulting in the precipitation of a powdery solid. The filter cake was collected by filtration and dried in a vacuum oven to yield 0.3975 g of the product, with a yield of 85.68%.

[0683] 13.16 Preparation of 66-213

[0684] 66-163 (0.3975 g, 0.0736 mmol) was added to a 250 ml flask, and dichloromethane (5 ml) and TFA (0.8 ml, 11.04 mmol) were added to dissolve the mixture. The mixture was stirred at room temperature overnight and the reaction progress was monitored by TLC. 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 to allow precipitation. A powdery 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 0.3901 g of the product, an overyield. ESI [M+H + ]5298.104

[0685] 13.17 Preparation of 82-226

[0686] 66-162 (0.37 g, 0.084 mmol), 66-213 (0.39 g, 0.0736 mmol), HOBT (0.01 g, 0.0736 mmol) and HBTU (0.3 g, 0.0736 mmol) were placed in a reaction flask, DMF (30 ml) was added and dissolved with ultrasonic assistance, the mixture was stirred at 0 degrees Celsius, DIEA (0.4 mml, 2.6880 mmol) was added dropwise, and after the addition was complete, the mixture was taken out to room temperature and the reaction was continued with stirring. The reaction progress was monitored by TLC. After the reaction, n-hexane (50 ml) and methyl tert-butyl ether (200 ml) were added to precipitate the oily solid. The supernatant was poured off, and methyl tert-butyl ether (200 ml) was added to precipitate. This was repeated three times, and a powdery solid precipitated. The filter cake was filtered and washed three times with methyl tert-butyl ether (60 ml). The filter cake was collected and dissolved in a methanol / dichloromethane mixed solvent. The sample was dry-loaded and subjected to column chromatography with 1-8% methanol / dichloromethane as eluent. The target product was collected, concentrated, and dried in a vacuum oven to obtain 0.09 g of the product with a yield of 12.4%. 1H-NMR(600MHz,DMSO-d6)δ10.18-10.07(m,8H),9.91-9.85(m,32H),9.05-9.03(m,24H),8.98-8.91(m,8H),8.7 8-8.71(m,40H),8.59-8.53(m,40H),8.24-8.04(m,216H),8.02-8.00(m,56H),7.98-7.95(m,56H),7.90-7.84(m ,16H),7.82-7.78(m,40H),7.74-7.70(m,32H),7.48-7.45(m,32H),7.35-7.32(m,64H),7.22-7.19(m,192H),7 .15-7.08(m,112H),7.07-7.04(m,12H),7.02-6.98(m,48H),6.69-6.68(m,16H),6.68-6.66(m,16H),5.83-5.77 (m,8H),5.27-5.25(m,64H),5.01-5.00(m,2H),4.99-4.97(m,2H),4.95-4 .94(m,2H),4.93-4.92(m,2H),4.76-4.73(m,40H),4.71-4.68(m,24H),4. 59-4.54(m,40H),4.40-4.31(m,64H),4.26-4.16(m,96H),3.80-3.74(m,9 6H),3.72-3.47(m,1864H),3.07-2.99(m,184H),2.91-2.88(m,64H),2.74 -2.73(m,64H),2.63-2.60(m,24H),2.43-2.42(m,16H),2.40-2.37(m,16H ),2.31-2.30(m,16H),2.17-2.06(m,80H),1.51-1.42(m,142H),1.36-1.3 5(m,64H),1.23-1.22(m,196H),1.20-1.19(m,16H),1.19-1.18(m,16H),1 .17-1.16(m,16H),1.07-1.06(m,2H),1.06-1.05(m,4H),1.05-1.04(m,2H)

[0687] Example 14 Synthesis of Compounds 59-169

[0688] 14.1 Preparation of 59-151

[0689] 62-13 (2 g, 8.65 mmol) and N,N-disuccinimidyl carbonate (3.3 g, 13 mmol) were added to a 100 ml round-bottom flask. DMF (10 ml) was added and dissolved with ultrasound. The mixture was stirred at 0°C. Triethylamine (1.8 ml, 13 mmol) was slowly added dropwise. Stirring was continued for 30 minutes, and finally, the reaction was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was transferred to a 1 L separatory funnel and extracted with purified water (200 ml) and ethyl acetate (200 ml) to obtain the organic phase. The aqueous phase was then extracted with ethyl acetate (200 ml). The combined organic phases were washed with deionized water (200 ml × 2) and evaporated to dryness. The obtained solid product was dissolved in a 4 / 1 dichloromethane / methanol mixed solvent, 200-300 mesh silica gel powder was added and evaporated to dryness. The sample was dry loaded and column chromatography was performed using a 30% ethyl acetate / petroleum ether mixed solution as the eluent. The target product was collected, concentrated and evaporated to dryness, and dried in a vacuum oven to obtain 8.9 g of the product. 1 H-NMR (600MHz, DMSO-d6) δ6.77(s,1H),2.90(dd,J=12.9,6.6Hz,2H),2.81(s,4H),2.65(t,J=7.3Hz,2H),1.41-1.30(m,15H)

[0690] 14.2 Preparation of 59-152

[0691] Sodium dodecahydrododecaborate (3.36 g, 0.0179 mol) was added to a 250 ml round-bottom flask and dissolved in distilled water (30 ml). The pH was measured to be approximately 7. O-hydroxylaminesulfonic acid (4.5 g, 0.0398 mol) was added and dissolved using ultrasonication. The reaction mixture was refluxed in an oil bath under nitrogen for 5 hours, then cooled to room temperature. Tetramethylammonium chloride (2 g, 0.0182 mol) was dissolved in distilled water (5 ml) and added to the reaction mixture. The mixture was allowed to stand to precipitate, which was filtered, collected, and dried. The crude product yielded 7 g. Distilled water (35 ml) was added to the crude product filter cake, which was refluxed in an oil bath, then cooled to room temperature overnight for recrystallization. This process was repeated three times. The mixture was filtered, and the filter cake was dried in a vacuum oven to yield 2.46 g of the product, with a yield of 60.0%.

[0692] 14.3 Preparation of 59-158

[0693] NaH (0.278 g, 11.56 mmol, 60% dispersion in mineral oil) was added to a 250 ml flask, followed by anhydrous DMF (10 ml). The mixture was stirred at 0°C under nitrogen. 59-152 (0.5 g, 2.89 mmol) was dissolved in anhydrous DMF (20 ml) and slowly added dropwise to the reaction mixture. Stirring was continued at 0°C for 30 minutes. When no bubbles appeared, the temperature was raised to 50°C and the reaction was allowed to react for 1 hour. The mixture was then cooled to room temperature, and 59-151 (1.23 g, 3.757 mmol) was added. After sonication, the temperature was raised to 50°C and the reaction was stirred 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 the mixture to settle. The supernatant was decanted, and n-hexane (20 ml) and methyl tert-butyl ether (100 ml) were added to allow the mixture to settle. This process was repeated five times. The resulting crude solid product was dissolved in a mixture of methanol and dichloromethane, and the insoluble matter was removed by filtration. The insoluble matter was dissolved again in a mixture of methanol and dichloromethane and filtered twice. The combined filtrates were concentrated to dryness on a rotary evaporator, dissolved in ethyl acetate (10 ml), and then settled in n-hexane (150 ml). The mixture was filtered, the filter cake collected, and dried to obtain 0.808 g of product 59-158, with a yield of 72.4%. 1 H-NMR(600MHz,DMSO-d6)δ6.76(d,J=5.0Hz,2H),2.87(d,J=6.7Hz,2H),2.37-2.34 (m,2H),1.45-1.40(m,4H),1.37(s,9H),1.33(s,2H),1.18(dd,J=8.7,5.5Hz,11H)

[0694] 14.4 Preparation of 59-163

[0695] 59-158 (0.2 g, 0.518 mmol) was placed in a 100 ml flask, and TFA (0.77 ml, 10.36 mmol) was added. The reaction solution was stirred at room temperature. After the reaction was completed, the reaction solution was concentrated by vacuum rotary evaporation, and then methyl tert-butyl ether was added to precipitate, allowed to stand, and the liquid was discarded. This process was repeated three times. The crude solid product was then dissolved in a small amount of 1 / 4 methanol / dichloromethane solution mixed solvent, and then methyl tert-butyl ether was added to precipitate, allowed to stand, and the liquid was discarded. This process was repeated twice. The solid was dried using a rotary evaporator and dried in a vacuum oven to obtain 0.13 g of the product with a yield of 87.84%.

[0696] 14.5 Preparation of 59-169

[0697] 73-47 (0.22 g, 0.00518 mmol), 59-163 (0.06 g, 0.005182 mmol), HOBT (0.0294 g, 0.2176 mmol), and HBTU (0.0825 g, 0.2176 mmol) were placed in a 100 ml round-bottom flask and dissolved in DMF (5 ml). DIEA (0.108 ml, 0.653 mmol) was slowly added dropwise with stirring at room temperature, and 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), the supernatant was decanted, and methyl tert-butyl ether (300 ml) and n-hexane (100 ml) were added again for precipitation. This process was repeated three times to obtain a solid precipitate. Then add 4 / 1 dichloromethane / methanol mixed solvent to dissolve, precipitate with methyl tert-butyl ether (300 ml) and n-hexane (100 ml), pour out the supernatant, repeat this dissolution / precipitation 5 times, and finally dry to obtain 0.039 g of product. 1 H-NMR(600MHz,DMSO-d6)δ8.02-7.926(m,28H),7.898-7.849(m,7H),7.747-7.705(m,7H),7.682-7.641(m,7H),7.419-7.391(m,7H), 7.167-7.116(m,56H),4.64-4.58(m,21H),3.636-3.63(m,28H),3.525-3.501(m,3269H),3.246-3.227(m,28H),3.095-3.075(m,64H), 2.924-2.90(m,16H),2.898-2.897(m,56H),2.756-2.734(m,44H),2.554-2.546(m,8H),2.533-2.512(m,66H),2.209-2.156(m,14H),2 .025-1.977(m,14H),1.68-1.633(m,32H),1.559-1.548(m,14H),1.395-1.370(m,120H),1.355-1.350(m,86H),1.228-1.224(m,308H)

[0698] Example 15 Synthesis of Compound 67-237

[0699] 15.1 Preparation of 67-236

[0700] 67-216 (0.4 g, 0.00812 mmol), 5-maleimidocaproic acid (0.108 g, 0.51178 mmol), HOBT (0.069 g, 0.51178 mmol), and HBTU (0.194 g, 0.51178 mmol) were mixed in a 100 ml flask and dissolved in DMF (10 ml). DIEA (0.25 ml, 1.53535 mmol) was slowly added dropwise at -5°C. After 30 minutes of reaction, the mixture was removed and stirred at room temperature. 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 (20 ml) and methyl tert-butyl ether (100 ml) were added to allow sedimentation. This process was repeated three times. The solid product was filtered off and then washed with methyl tert-butyl ether (100 ml x 3). The product was collected and dried to obtain 0.2 g. 1 H-NMR(600MHz,DMSO-d6)δ8.27-8.13(m,147H),7.01-6.96(m,84H),4.19-4.10(m,42H) ,4.08-4.06(m,14H),3.88-3.78(m,77H),3.62-3.54(m,350H),3.509-3.497(m,3269H) ,3.27-3.23(m,84H),3.145-3.123(m,105H),2.918-2.90(m,72H),2.61-2.58(m,14H), 2.397-2.372(m,16H),2.075-2.014(m,180H),1.55-1.49(m,112H),1.25-1.22(m,224H)

[0701] 15.2 Preparation of 67-237

[0702] Sodium mercaptododecaborate (0.032 g, 0.147 mmol, abbreviated as N-BSH) and 67-236 (0.2 g, 0.0035 mmol) were weighed and mixed in a 100 ml flask. A stirrer was added, and methanol (10 ml) was added to dissolve the reaction. The temperature was maintained at 30°C, and the reaction progress was monitored by TLC. After the reaction was completed, dilution was added with dichloromethane, followed by concentration to obtain an oil. This was then precipitated with methyl tert-butyl ether (30 ml) and n-hexane (20 ml), and the supernatant was decanted. This process was repeated five times, and finally dried to yield 0.2 g of the product. 1H-NMR(600MHz,DMSO-d6)δ8.03-7.88(m,147H),4.110-4.073(m,133H),3.70-3.55 (m,392H),3.520-3.495(m,3269H),3.241-3.233(m,42H),3.052-2.97(m,84H),2.9 5-2.86(m,147H),2.617-2.610(m,42H),2.39-2.38(m,30H),2.09-2.01(m,212H), 1.81-1.78(m,14H),1.48-1.44(m,112H),1.28-1.23(m,208H),1.02-0.70(m,462H)

[0703] Example 16 Synthesis of Compounds 78-139

[0704] 16.1 Preparation of 78-103

[0705] Irinotecan (3 g, 5.11 mmol) was weighed and added to a flask containing succinic anhydride (3.07 g, 30.66 mmol). An appropriate amount of pyridine was added to dissolve the mixture. DMAP (1.25 ml, 10.22 mmol) was slowly added dropwise and stirred at room temperature for 4 hours. 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 decanted, and n-hexane and methyl tert-butyl ether were added to allow the mixture to settle. This process was repeated three times, and the solid product was filtered to obtain a solid product. The solid product was dissolved in a mixed solvent of dichloromethane and methanol, added with silica gel powder, evaporated to dryness, and dry-loaded. Column chromatography was performed using a mixture of 1% formic acid / 5-10% methanol / dichloromethane as the eluent. The product was collected, concentrated, and dried in a vacuum oven to obtain 3.1 g of the product, with a yield of 88%. 1H-NMR(600MHz,DMSO-d6)δ8.24-8.14(m,1H),8.02-7.91(m,1H),7.69-7.62(m,1H),7.14 -7.06(m,1H),5.54-5.45(m,2H),5.38-5.32(m,2H),4.28(s,1H),4.15-4.04(m,1H),3.21 -3.16(m,2H),3.12-3.04(m,1H),2.89(s,1H),2.83-2.69(m,2H),2.52-2.39(m,6H),2.1 5(s,2H),1.81(s,2H),1.56-1.44(m,6H),1.39(s,2H),1.28(s,3H),0.90(s,3H);ESI[M+H + ]687.3

[0706] 16.2 Preparation of 80-234

[0707] 1,4,7,-Triazacyclononane (0.2 g, 1.55 mmol), tert-butyl succinate (0.89 g, 5.1 mmol), HBTU (1.9 g, 5.1 mmol), and HOBT (0.7 g, 5.1 mmol) were placed in a 500 ml flask, dissolved in DMF (15 ml), and stirred at -5°C for approximately 20 minutes. DIEA (1.5 ml, 9.3 mmol) was then slowly added dropwise. The reaction was continued at -5°C for 1 hour. The reaction was then moved to room temperature and stirred overnight. After completion of the reaction, the reaction mixture was transferred to a 1 L separatory funnel and extracted with saturated brine (200 ml) and ethyl acetate (200 ml) to obtain an organic phase. The aqueous phase was then extracted with ethyl acetate (200 ml x 2). The combined organic phases were washed with saturated brine (200 ml x 2) and evaporated to dryness to yield 3.1 g of the product. 1 H-NMR(600MHz,DMSO-d6)δ3.61(s,6H),3.34(s,6H),2.51-2.44(m,6H),2.40(s,6H),1.38(s,27H); ESI[M+Na + ]620.34

[0708] 16.3 Preparation of 78-70

[0709] To a flask containing 80-234 (0.7 g, 1.17 mmol) was added dichloromethane (10 ml). Ultrasonication was used to dissolve the mixture, followed by the addition of TFA (5.2 ml, 70.3 mmol). The mixture was stirred and allowed to react overnight at room temperature. Upon completion of the reaction, the reaction solution was evaporated to an oil using a rotary evaporator. Dichloromethane (30 ml) was then added, and the mixture was ultrasonically treated and concentrated. This process was repeated five times. Methyl tert-butyl ether was then added, ultrasonically treated, and allowed to stand for 20 minutes. The supernatant was then discarded. This process was repeated three times. The resulting solid was evaporated to dryness and dried in a vacuum oven to yield 0.5 g of the product. 1 H-NMR (600MHz, DMSO-d6) δ3.61-3.54(m,6H),3.38-3.26(m,6H),2.50-2.44(m,6H),2.45-2.39(m,6H); ESI[M+Na + ]452

[0710] 16.4 Preparation of 76-126

[0711] To a flask containing 59-106 (3 g, 3.1082 mmol) was added dichloromethane (20 ml), and after ultrasonic dissolution, TFA (15 ml) was added. The mixture was stirred and reacted at room temperature overnight. After the reaction, the reaction solution was concentrated under reduced pressure to remove dichloromethane and most of the TFA. Methyl tert-butyl ether (500 ml) and n-hexane (100 ml) were then added to allow sedimentation. The solution was filtered using a sand core funnel and rinsed with methyl tert-butyl ether (300 ml x 3). The filter cake was collected and dried in a vacuum oven to obtain the product.

[0712] 16.5 Preparation of 80-216

[0713] 67-82 (3.40 g, 13.6761 mmol), HBTU (5.18 g, 13.6761 mmol) and HOBT (1.85 g, 13.6761 mmol) were weighed and added into a flask containing 76-126 (2.30 g, 3.1082 mmol), and DMF (80 ml) was added to dissolve it. The mixture was placed at -5°C and DIEA (0.30 ml, 1.8040 mmol) was slowly added dropwise. After the addition was completed, 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 is repeated 3 times, and the solid product is filtered to obtain the solid product, which is then dissolved with 1 / 4 methanol / dichloromethane mixed solvent, and silica gel powder (100 ml) is added and evaporated to dryness to obtain a powdery solid. The solid is dry-loaded and column chromatography is performed with 3-8% methanol / dichloromethane mixed solvent as eluent. The product is collected, concentrated, and dried in a vacuum oven to obtain 4.56 g.

[0714] 16.6 Preparation of 80-222

[0715] To a flask containing 80-216 (4.56 g, 2.7453 mmol) was added DMF (30 ml). After ultrasonic dissolution, morpholine (2.39 ml, 27.4533 mmol) was added and 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 solution to settle. The supernatant was decanted, and n-hexane (40 ml) and methyl tert-butyl ether (70 ml) were added to allow the solution to settle. This process was repeated three times. The solid product was filtered and dried in a vacuum oven to yield 2.34 g (77% yield).

[0716] 16.7 Preparation of 78-65

[0717] N-Fmoc-5-tert-butyl L-glutamate (1.7 g, 3.9956 mmol), L-alanine benzyl ester p-toluenesulfonate (1.4 g, 3.9956 mmol), HBTU (1.66 g, 4.3958 mmol), HOBT (0.6 g, 4.3958 mmol), and DMF (20 ml) were dissolved in a 250 ml flask. The reaction flask was stirred at -5°C for approximately 20 minutes. DIEA (1.3 ml, 7.9925 mmol) was then slowly added dropwise. After the addition was complete, the reaction was stirred at -5°C for 1 hour, then brought to room temperature and stirred. After completion of the reaction, the reaction solution was transferred to a 1 L separatory funnel and extracted with saturated brine (200 ml) and ethyl acetate (200 ml) to obtain the organic phase. The aqueous phase was then extracted with ethyl acetate (200 ml x 3). The combined organ...

Claims

1. A compound represented by general formula I or a pharmaceutically acceptable salt thereof, in, M is a chain or cyclic structure containing one or more identical or different heteroatoms, and M is connected to L1 through the heteroatoms; Each L1 is independently selected from a bond, A group consisting of 1 or 2 identical or different aforementioned L1 and 1 or more identical or different aforementioned M in the following manner: L1-M-(L1) n 、L1-M-(L1-M-(L1) n ) n or L1-M-(L1-M-(L1-M-(L1) n ) n ) n , end 1 is connected to M, 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; Each L2 is independently a residue of an amino acid whose side chain contains a functional group selected from -NH2, -OH, -SH and -COOH, and L2 is connected to L1, L3 and L4 through the N-terminus, C-terminus and the functional group of the amino acid. 41 Connection, preferably, L2 is connected to L3 via the functional group; Each L3 and L 43 'Independently End 1 is connected to L2, and end 2 is connected to PEG; Each PEG is independently selected from polyethylene glycol, amino-polyethylene glycol, methoxy-polyethylene glycol, carboxyl-polyethylene glycol and cholesterol-polyethylene glycol; Each L 41 Independently End 1 is connected to L2, and end 2 is connected to L 42 Connection, 3 ends with L 42 'Connect, where each L 411 , L 412 and L 413 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, -NH(CH2) x3 C(O)-、-CO(CH2) x3 C(O)-, -NH(CH2) x3 NH- and -NH(CH2)2(OCH2CH2) x3 NH- and any combination thereof, each x3 is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, A 41 is a bond or is selected from an amino acid residue or a derivative thereof or a polypeptide fragment consisting of two or more amino acids or a derivative thereof; Each L 42 and L 42 'Independently for keys or 1 end with L 41 Connection, both ends are the same as L 43 or L 43 'Connect, where each L 421 and L 422 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, -NH(CH2) x4 C(O)-、-CO(CH2) x4 C(O)-、-NH(CH2) x4 NH- and -NH(CH2)2(OCH2CH2) x4 NH- and any combination thereof, each x4 is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, A 42 is a bond or is selected from an amino acid residue or a derivative thereof or a polypeptide fragment consisting of two or more amino acids or a derivative thereof, t1 = n2 or n2'; Each L 43 and L 43 ' are independently selected from a bond, -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(CH2) x5 C(O)-、-NH(CH2) x5 NH-, -NH(CH2)2(OCH2CH2) x5 NH-, -C(O)(CH2) x5 C(O)-, and any combination thereof, wherein each x5 is independently selected 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 drugs are selected from microtubule inhibitors, DNA intercalators, DNA topoisomerase inhibitors and RNA polymerase inhibitors; preferably, the cytotoxic drugs are selected from PTX (paclitaxel), PCB (pabloxilibu), SN38 (7- and -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 dodecahydrogen dodecaborate, PPT-iRGD, disodium 11-hydrogen mercapto dodecaborate, 11-hydrogen mercapto dodecaborate ( 10 B) disodium borax, disodium undecahydroamino dodecaboride, undecahydroamino dodecaboride ( 10 B) disodium chloride, each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; Each n1 and n1' is independently selected from 0, 1, 2, 3, 4, 5, 6, 7 and 8; Each n2 and n2' is independently selected from 1, 2, 3, 4, 5, 6, 7 and 8; Each n3 and n3' is independently selected from 1, 2, 3, 4, 5, 6, 7 and 8.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is characterized by one or more of the following: (1) M is selected from the group obtained by losing one or more (e.g., 1 to 10) hydrogen atoms from the following molecules: in, X and X' are independently selected from -OH, -NRR' and -SH, Z is selected from -C(RR')-, -O- and -N(R)-, R and R' are independently selected from hydrogen, C 1-6 Alkyl, and amino or C 1-6 Alkylamino substituted C 1-6 Alkyl, x7 and x8 are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, and x9 is selected from 1, 2, 3, 4, 5 and 6; (2) L1 is selected from A group consisting of one or more identical or different L1 and one or more identical or different M in the following manner: L1-M-(L1) n , wherein x1 and x2 are each independently selected from 1, 2, 3, 4, 5 and 6; (3) L2 is selected from the following amino acid residues: Lys, Cys, Thr, Ser, Asp or Glu; (4) PEG is methoxy-polyethylene glycol; (5) PEG number average molecular weight is 5k-40k; (6) Each L 411 independently selected from a bond, -NH(CH2) x3 C(O)-、-CO(CH2) x3 C(O)-、-NH(CH2) x3 NH-, -NH(CH2) x3 C(O)NH(CH2) x3 C(O)-、-NH(CH2)2(OCH2CH2) x3 NH- and -NH(CH2)2(OCH2CH2) x3 NH-, x3 is selected from 1, 2, 3, 4, 5 and 6; (7) Each L 412 independently selected from a bond, -NH(CH2) x3 C(O)-、-CO(CH2) x3 C(O)-、-NH(CH2) x3 NH-, -NH(CH2) x3 C(O)-A-, -NH(CH2) x3 C(O)NH(CH2) x3 C(O)-、-NH(CH2)2(OCH2CH2) x3 NH- and -NH(CH2)2(OCH2CH2) x3 NH-, wherein A is selected from an amino acid residue or a derivative thereof or a polypeptide fragment consisting of two or more amino acids or a derivative thereof, the amino acid is selected from Glu and Asp, and each x3 is independently selected from 1, 2, 3, 4, 5 and 6; (8) Each L 413 independently selected from a bond, -NH(CH2) x3 C(O)-、-NH(CH2) x3 NH-, -NH(CH2)2(OCH2CH2) x3 NH-, -CO(CH2) x3 C(O)-、-NH(CH2) x3 C(O)NH(CH2) x3 C(O)- and -NH(CH2) x3 C(O)NH(CH2) x3 NH-, each x3 is independently selected from 1, 2, 3, 4, 5 and 6; (9)A 41 or A 42 wherein the amino acid is selected from the group consisting of Glu, Gly, Asp, Lys, Cys, Thr and Ser; (10) Each L 421 independently selected from a bond, -NH(CH2) x4 C(O)-、-CO(CH2) x4 C(O)-、-NH(CH2) x4 NH-, -NH(CH2)2(OCH2CH2) x4 NH- and any combination thereof, each x4 is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; (11) Each L 422 independently selected from a bond, -NH(CH2) x3 C(O)-A'-, -NH(CH2) x4 C(O)-、-CO(CH2) x4 C(O)-、-NH(CH2) x4 NH- and -NH(CH2)2(OCH2CH2) x4 NH-, wherein A' is selected from an amino acid residue or a derivative thereof or a polypeptide fragment consisting of two or more amino acids or a derivative thereof, and each x4 is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; (12)L 43 and L 43 ' wherein the amino acid is selected from Glu, Gly, Phe, Leu and Cys; (13)L 41 , L 42 , L 42 ', L 43 and L 43 ' wherein the derivative is selected from acylated (eg acetylated) or alkylated (eg methylated) derivatives; (14) Each x5 is independently selected from 1, 2, 3, 4, 5 and 6.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized by one or more of the following: (1) M is selected from the group obtained by losing one or more (e.g., 1-10) hydrogen atoms of the following molecules: EDA, DETA, AMDA, TAEA, TETA, TEPA, DAPO, APDO, APD, glycerol, MPE, TAN and TACD; preferably, M is selected from: (2) L1 is selected from Each x1 and x2 is independently selected from 0, 1, 2, 3, 4 and 5; (3) L2 is selected from the following amino acid residues: Lys, Cys, Thr, or Ser; (4) PEG number average molecular weight is 5k-10k or 10k-40k, for example, 5k or 10k; (5)A 41 and A 42 Independently selected from bond, Glu, Lys, Glu-Asp, Glu-Glu, Glu(Glu)2, Glu(Glu)(Glu(Glu)(GlyGlu)), GluGluGly, GlyGlu; (6) Each L 41 Independently selected from -NH(CH2)2CO-, -NH(CH2)5CO-, (7) Each L 42 and L 42 'Independently selected from a bond, Glu, GlyGlu, -NH(CH2)5CO-, -CO(CH2)2CO-, -NH(CH2)2NH-, -NH(CH2)5CO-Glu, Glu(Glu)2, -NH(CH2)2(OCH2CH2)2NH-, (8)L 43 Select from key, Cys(Ac)、-NH-N=、-GlyPheLeuGly-、-C(O)(CH2) x5 C(O)-、-Gly-NH-N=、Glu(GlyPheLeuGly-)2、GlyGlu(GlyPheLeuGly)2、-Glu(Gly-NHN=)2、-C(O)(CH2) x5 C(O)-Glu(GlyPheLeuGly)(Glu(GlyPheLeuGly)2)、Glu(Glu)2、-NH(CH2) x5 C(O)-、-NH(CH2) x5 C(O)NH-、-NH(CH2)2(OCH2CH2) x5 NH-、 -C(O)(CH2) x5 C(O)-NH(CH2) x5 C(O)-, and Each x5 is independently selected from 1, 2, 3, 4, 5 and 6.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein the compound is characterized by one or more of the following: (1) L2 is selected from a Lys residue; (2)L 43 Select from key, Cys(Ac), -GlyPheLeuGly-, -C(O)(CH2)2C(O)-, Gly-NHN=, -GlyGlu(GlyPheLeuGly-)2, Glu(GlyPheLeuGly-)2, -Glu(Gly-NHN=)2, -C(O)(CH2)2C(O)-Glu(GlyPheLeuGly)(Glu(GlyPheLeuGly)2), Glu(Glu)2, -NH(CH2)5C(O)-, -NH(CH2)5C(O)NH-, -NH(CH2)2(OCH2CH2)2NH-, -C(O)(CH2)2C(O)-NHCH2C(O)-, -C(O)(CH2)2C(O)-NH(CH2)2C(O)-, and 5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following compounds:

6. A compound represented by general formula II or a pharmaceutically acceptable salt thereof, in, Each Pg1 and Pg2 is 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; and the carboxyl protecting group is selected from ester protecting groups, such as Methyl, ethyl, tert-butyl, allyl or benzyl esters; m1 and m2 are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20; The remaining groups are as defined in any one of claims 1 to 5.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following compounds:

8. A compound represented by the general formula III or a pharmaceutically acceptable salt thereof, in, Pg1' is hydrogen or selected from amino protecting groups, such as alkoxycarbonyl protecting groups, such as Boc, Fmoc, Cbz or Teoc; m1, m2, m2', Pg1, Pg2 and Pg2' are as defined in claim 6 or 7; The remaining groups are as defined in any one of claims 1 to 7.

9. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following compounds:

10. A compound represented by the general formula IV or a pharmaceutically acceptable salt thereof, M-[L1-Pg3] n IV in, Each Pg3 is independently hydrogen or selected from a carboxyl protecting group, such as an ester protecting group, preferably a methyl ester, an ethyl ester, a tert-butyl ester, an allyl ester or a benzyl ester; The remaining groups are as defined in any one of claims 1 to 9.

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

12. A compound represented by general formula V or a pharmaceutically acceptable salt thereof, in, Each group is as defined in any one of claims 1 to 11.

13. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

14. A pharmaceutical composition comprising an effective amount of the compound according to any one of claims 1 to 5 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.

15. Use of the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing a disease (eg, 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, 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 gland penile cancer, prostate cancer, urethral cancer, vaginal cancer, vulvar cancer, anal cancer, sarcoma, and metastases of the above cancers.

16. An injection comprising the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 14; Preferably, the injection solution uses physiological saline as a carrier.

17. A method for preparing a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein: When the formula I and L 41 When the connected n1+n1' branches are all the same, it includes the following steps: S1-1: reacting the compound of formula II with PEG having an activated group to obtain intermediate 1-1; S1-2: The intermediate 1-1 is subjected to any of the following reactions to obtain the compound: (1) Direct and provide Precursor reactions of fragments; (2) Sequentially and provide L 42 Fragment, L 43 fragments and precursor reactions of D fragments; (3) Sequentially and provide fragments and precursor reactions of D fragments; (4) Sequentially and provide L 42 Fragment, L 43 Precursor reaction of -n3D fragment Preferably, step S1-1 is performed before or after step S1-2, or, when step S1-2 involves multiple steps, step S1-1 is performed after any step of S1-2 is completed; When the formula I and L 41 Connected Differently, it includes the following steps: S2-1: reacting the compound of formula II with PEG having an activated group to obtain intermediate 2-1; S2-2: The intermediate 2-1 is subjected to any of the following reactions to obtain the compound: (1) Sequentially and provide Precursor reactions of fragments; (2) Sequentially and provide Precursor reactions of fragments; (3) First and provide The precursor reaction of the fragment is then followed by any of the following reactions: 1) Sequentially and provide L 42 Fragment, L 43 - Precursor reaction of n3D fragment; 2) Sequentially and provide L 42 Fragment, L 43 fragment and the precursor reaction of fragment D; 3) sequentially and provide fragments and precursor reactions of D fragments; Preferably, step S2-1 is performed before or after S2-2, or, when S2-2 has multiple steps, step S2-1 is performed after any step of S2-2 is completed; Optionally, before or after any of the above reactions, a step of removing protecting groups and / or activating (e.g., carbonyl or amino group activation) is also included; Preferably, the precursor is a compound that provides the corresponding fragment, either in free or activated form; Preferably, the PEG activating group is Each group is as defined in any one of claims 1 to 13.

18. The method of claim 17, wherein the compound of formula II is obtained by reacting the compound of formula IV with a compound of formula III; Preferably, before carrying out the reaction, a step of removing the protecting group is also included.

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