CN114053426A - Double-drug linked assembly unit and double-drug targeting joint-drug conjugate - Google Patents

Double-drug linked assembly unit and double-drug targeting joint-drug conjugate Download PDF

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CN114053426A
CN114053426A CN202110866925.4A CN202110866925A CN114053426A CN 114053426 A CN114053426 A CN 114053426A CN 202110866925 A CN202110866925 A CN 202110866925A CN 114053426 A CN114053426 A CN 114053426A
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drug
dual
drug conjugate
double
targeting linker
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黄金昆
吴成龙
冯超阳
鲁岳
耿嘉豪
李磊
徐鑫
刘俊强
张伟
陈方
谢德建
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Chengdu Scimount Pharmatech Co ltd
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    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
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Abstract

The invention discloses a double-drug linked assembly unit and a double-drug targeting joint-drug conjugate. In particular to a formula VIThe indicated double drug-linked building blocks, or stereoisomers thereof, or optical isomers thereof. The double-drug linking assembly unit can be connected with a targeting joint to obtain a double-drug targeting joint-drug conjugate molecule shown in a formula I. The double-drug targeting joint-drug conjugate can be targeted on tumor cells, reduce the toxic and side effects on normal cells, and simultaneously can effectively overcome the drug resistance of drugs. And ADC already on the market: compared with DS-8201a, the ADC provided by the invention has obviously improved inhibiting effect on breast adenocarcinoma cells and gastric cancer cells. The double-drug linked assembly unit and the double-drug targeting joint-drug conjugate have wide application prospect in preparing anti-tumor drugs for prevention and/or treatment.

Description

Double-drug linked assembly unit and double-drug targeting joint-drug conjugate
Technical Field
The invention belongs to the field of medicines, and particularly relates to a double-medicine link assembly unit and a corresponding double-medicine targeting joint-medicine conjugate thereof.
Background
Antibody-Drug conjugates (ADC) are capable of selectively delivering drugs to and killing cancer cells, but have less impact on normal cells, opening a new era in tumor therapy. As ADC, there are several drugs that have been approved by FDA, for example, antibody CD33 linked to calicheamicin, CD30 antibody linked to auristatin E, and Adcetris for Hodgkin lymphoma and undifferentiated large cell lymphoma patients, and Her2 antibody linked to camptothecin derivative Dxd, and DS-8201 for HER2 positive breast cancer patients and for Sacituzumab govitecan targeting TROP-2 antigen (also called epithelial glycoprotein 1, EGP-1).
The drugs contained in ADCs that have been approved by the FDA to date have primarily targeted DNA or tubulin. The marketed ADCs are respectively connected by an antibody and a targeting DNA or a tubulin drug, at present, no ADC which simultaneously connects the antibody and the targeting DNA and the tubulin drug is marketed, and it is not clear whether the simultaneous connection of the targeting DNA and the tubulin drug to the antibody can kill tumors through two different anti-tumor action mechanisms and can effectively play a role.
Camptothecin derivatives, such as SN-38, Dxd, and Dx-8951, which are compounds known as antitumor small molecule compounds that inhibit DNA topoisomerase I to achieve antitumor effects, have been confirmed to have killing effects on various cancer cells both in vivo and in vitro, and exhibit strong antitumor effects. As compounds for inhibiting tubulin to achieve the anti-tumor effect, such as Eribulin, MMAE, MMAF, maytansine and the like, the compounds have killing effect on various cancer cells in vivo and in vitro, and show strong anti-tumor effect. The two antitumor drugs with different mechanisms are connected to the same antibody, so that the antitumor activity can be synergistic, the antitumor activity can be antagonistic, and the actual effect cannot be expected.
Therefore, it is urgently needed to research an efficient and safe ADC with a multi-drug and multi-target action mechanism, which is very important for developing antitumor drugs with excellent antitumor effect and safety.
Disclosure of Invention
The invention aims to provide a double-drug linked assembly unit and a corresponding double-drug targeting joint-drug conjugate thereof.
The invention provides a double-drug linked assembly unit shown as a formula VI, or a stereoisomer or an optical isomer thereof:
Figure BDA0003187619010000011
wherein T is a tether group capable of attachment to a targeting linker; the targeting joint is a substance capable of targeting and combining with a lesion part;
u is a three-prong linker moiety;
l1 and L2 are cleavable or non-cleavable linking groups;
D1、D2respectively a first drug unit and a second drug unit.
Further, the T can be reacted and connected with a sulfhydryl group on the targeting linker.
Further, the structure of the dual drug linked assembly unit is shown as formula VI-1:
Figure BDA0003187619010000021
wherein, K1、K2Each independently selected from the group consisting ofaKbKc；KaIs phenyl, KbSelected from O, S or none, KcSelected from 0-2 methylene;
n and p are respectively independent integers selected from 0-10;
u is substituted or unsubstituted aryl, heteroaryl, alkanyl, cycloalkyl or heterocycloalkylA group; the substituent is selected from deuterium, halogen, cyano, hydroxyl and C1～6Alkyl or C1～6An alkoxy group;
X1、X2each independently selected from
Figure BDA0003187619010000022
Wherein a, b, c and d are respectively and independently selected from 0 or 1, K3Selected from the group consisting of no, no substitution or by R1Substituted C1～4Alkylene radical, K4Selected from the group consisting of no, no substitution or by R2Substituted C1～4Alkylene radical, K5Selected from the group consisting of no, no substitution or by R3Substituted C1～4Alkylene radical, K6Selected from the group consisting of no, no substitution or by R4Substituted C1～4Alkylene radical, R1、R2、R3、R4Each independently selected from H, C1～5Alkyl, substituted or unsubstituted benzyl, -L1aNHCONH2、-L1aNHCOCR5NH2，L1aIs 0 to 4 methylene groups, R5Is C1～3An alkyl group; the substituent on the benzyl is selected from deuterium, halogen, cyano, hydroxyl and C1～6Alkyl or C1～6An alkoxy group;
B1，B2，C1，C2，E1，E2each independently selected from the group consisting of substituted or unsubstituted:
Figure BDA0003187619010000023
L2aCONHL3、L4OL5CO or none; the substituents are each independently selected from
Figure BDA0003187619010000024
C1～5An alkyl group; wherein L is2a、L3、L4、L5、L6Each independently selected from 0-2 methylene groups;
D1、D2each independently selected from cytotoxic drugs, drugs for treating autoimmune diseases or anti-inflammatory drugs；
T is as defined above.
Further, the structure of the dual drug linked assembly unit is shown in formula VII:
Figure BDA0003187619010000031
wherein n and p are respectively and independently selected from integers of 0-10;
u is substituted or unsubstituted aryl, heteroaryl, alkanyl, cycloalkyl or heterocycloalkyl; the substituent is selected from deuterium, halogen, cyano, hydroxyl and C1～6Alkyl or C1～6An alkoxy group;
X1、X2each independently selected from
Figure BDA0003187619010000032
Wherein a, b, c and d are respectively and independently selected from 0 or 1, R1、R2、R3、R4Each independently selected from H, C1～5Alkyl, substituted or unsubstituted benzyl, -L1aNHCONH2，L1aIs 0 to 3 methylene groups; the substituent on the benzyl is selected from deuterium, halogen, cyano, hydroxyl and C1～6Alkyl or C1～6An alkoxy group;
B1，B2，C1，C2，E1，E2each independently selected from the group consisting of substituted or unsubstituted:
Figure BDA0003187619010000033
L2aCONHL3、L4OL5CO or none; the substituents are each independently selected from
Figure BDA0003187619010000034
C1～5An alkyl group; wherein L is2a、L3、L4、L5、L6Each independently selected from 0-2 methylene groups;
D1、D2each independently selected from cytotoxic drugs, drugs for treating autoimmune diseases or anti-inflammatory drugs;
t is as defined above.
Further, the structure of the dual drug linked assembly unit is shown as formula VII-1:
Figure BDA0003187619010000035
wherein A is1、A2Each is independently selected from 0-10 methylene, O, S, CO, NH, CONH, NHCO or nothing;
m，n，p，U，X1，X2，B1，B2，C1，C2，E1，E2，D1、D2as described above.
Further, the structure of the dual drug linked assembly unit is shown as formula VIIIa or VIIIb:
Figure BDA0003187619010000041
wherein A is1、A2、m、n、p、X1、X2、B1、B2、C1、C2、E1、E2、D1、D2As described above;
m is hydrogen, deuterium, halogen, cyano, hydroxy, C1～6Alkyl or C1～6An alkoxy group.
Further, the structure of the dual drug linked assembly unit is selected from one of the following structures:
Figure BDA0003187619010000042
Figure BDA0003187619010000051
Figure BDA0003187619010000061
wherein D is1、D2As described above, n and p are integers of 0 to 4; preferably, n ═ p.
Further, the structure of the dual drug linked assembly unit is one of the following structures:
Figure BDA0003187619010000062
Figure BDA0003187619010000071
wherein D is1、D2As described above.
Further, said D1、D2Each independently selected from a drug unit targeting DNA or a drug unit targeting tubulin; the drug unit targeting DNA is preferably SN-38, Dxd, Dx-8951 or derivatives thereof, and/or the drug unit targeting tubulin is preferably Eribulin, MMAE, MMAF, maytansine or derivatives thereof.
Further, the dual drug linked assembly unit is one of the following structures:
Figure BDA0003187619010000081
Figure BDA0003187619010000091
Figure BDA0003187619010000101
Figure BDA0003187619010000111
Figure BDA0003187619010000121
Figure BDA0003187619010000131
Figure BDA0003187619010000141
Figure BDA0003187619010000151
Figure BDA0003187619010000161
the invention also provides a double-drug targeting joint-drug conjugate molecule, or a stereoisomer or an optical isomer thereof, wherein the double-drug targeting joint-drug conjugate molecule is obtained by connecting a targeting joint and q double-drug linking and assembling units; the targeting joint is a substance capable of targeting and combining with a lesion part; the structure of the double-drug targeting joint-drug conjugate molecule is shown as formula I:
Figure BDA0003187619010000162
wherein Ab is a targeting linker, q is an integer of 1-20, T, U, L1, L2 and D1、D2As described above.
Further, the targeting linker is an antibody, an antibody fragment, a protein or an aptamer, preferably an antibody directed against a cell surface receptor and a tumor associated antigen;
and/or q is an integer of 1-8.
Further, the structure of the dual-drug targeting linker-drug conjugate molecule is selected from one of the following structures:
Figure BDA0003187619010000171
Figure BDA0003187619010000181
Figure BDA0003187619010000191
Figure BDA0003187619010000201
Figure BDA0003187619010000211
Figure BDA0003187619010000221
Figure BDA0003187619010000231
Figure BDA0003187619010000241
Figure BDA0003187619010000251
the invention also provides a double-drug targeting linker-drug conjugate, or a stereoisomer or an optical isomer thereof, wherein the double-drug targeting linker-drug conjugate is obtained by connecting a targeting linker and the double-drug linking assembly unit; the targeting joint is a substance capable of targeting and combining with a pathological part, and is preferably an antibody, an antibody fragment, a protein or a nucleic acid aptamer; the antibody is preferably an antibody directed against a cell surface receptor and a tumor associated antigen.
Further, the double-drug targeting joint-drug conjugate consists of two or more than two of molecules of the double-drug targeting joint-drug conjugate shown in the formula IIa, and the DAR value of the double-drug targeting joint-drug conjugate is 6.00-7.00, preferably 6.41;
or the double-drug targeting joint-drug conjugate consists of two or more than two of molecules of the double-drug targeting joint-drug conjugate shown in formula IIb, wherein the DAR value of the double-drug targeting joint-drug conjugate is 1.50-2.50, and is preferably 2.03;
or the double-drug targeting joint-drug conjugate consists of two or more than two of molecules of the double-drug targeting joint-drug conjugate shown in formula IIc, wherein the DAR value of the double-drug targeting joint-drug conjugate is 4.00-5.00, and is preferably 4.38;
or the double-drug targeting joint-drug conjugate consists of two or more than two of molecules of the double-drug targeting joint-drug conjugate shown in formula IId, and the DAR value of the double-drug targeting joint-drug conjugate is 1.50-2.50, preferably 1.99;
or the double-drug targeting joint-drug conjugate consists of two or more than two of the molecules of the double-drug targeting joint-drug conjugate shown in the formula IIe, wherein the DAR value of the double-drug targeting joint-drug conjugate is 3.00-4.00, and is preferably 3.35;
or the double-drug targeting joint-drug conjugate consists of two or more than two of molecules of the double-drug targeting joint-drug conjugate shown in formula IIf, wherein the DAR value of the double-drug targeting joint-drug conjugate is 2.00-3.00, and is preferably 2.31;
or the double-drug targeting joint-drug conjugate consists of two or more than two of molecules of the double-drug targeting joint-drug conjugate shown in formula IIg, and the DAR value of the double-drug targeting joint-drug conjugate is 3.00-4.00, preferably 3.47;
or the double-drug targeting joint-drug conjugate consists of two or more than two of double-drug targeting joint-drug conjugate molecules shown in a formula II SMP-52581, and the DAR value of the double-drug targeting joint-drug conjugate is 1.50-2.50, preferably 1.93;
or the double-drug targeting joint-drug conjugate consists of two or more than two of double-drug targeting joint-drug conjugate molecules shown in a formula II SMP-96745, and the DAR value of the double-drug targeting joint-drug conjugate is 4.00-5.00, preferably 4.27;
or the double-drug targeting joint-drug conjugate consists of two or more than two of double-drug targeting joint-drug conjugate molecules shown in a formula II SMP-39545, and the DAR value of the double-drug targeting joint-drug conjugate is 5.00-6.00, preferably 5.24;
or the double-drug targeting joint-drug conjugate consists of two or more than two of double-drug targeting joint-drug conjugate molecules shown in a formula II SMP-93954, and the DAR value of the double-drug targeting joint-drug conjugate is 4.00-5.00, preferably 4.32;
or the double-drug targeting joint-drug conjugate consists of two or more than two of double-drug targeting joint-drug conjugate molecules shown in a formula II SMP-11115, and the DAR value of the double-drug targeting joint-drug conjugate is 7.00-8.00, preferably 7.71;
or the double-drug targeting joint-drug conjugate consists of two or more than two of double-drug targeting joint-drug conjugate molecules shown in a formula II SMP-04404, and the DAR value of the double-drug targeting joint-drug conjugate is 4.00-5.00, preferably 4.67;
or the double-drug targeting joint-drug conjugate consists of two or more than two of double-drug targeting joint-drug conjugate molecules shown in a formula II SMP-37241, and the DAR value of the double-drug targeting joint-drug conjugate is 6.00-7.00, preferably 6.39;
or the double-drug targeting joint-drug conjugate consists of two or more than two of double-drug targeting joint-drug conjugate molecules shown in a formula II SMP13432, and the DAR value of the double-drug targeting joint-drug conjugate is 4.00-5.00, preferably 4.26;
or the double-drug targeting joint-drug conjugate consists of two or more than two of double-drug targeting joint-drug conjugate molecules shown in a formula II SMP-84984, and the DAR value of the double-drug targeting joint-drug conjugate is 5.00-6.00, preferably 5.69;
or the double-drug targeting joint-drug conjugate consists of two or more than two of double-drug targeting joint-drug conjugate molecules shown in a formula II SMP-04140, and the DAR value of the double-drug targeting joint-drug conjugate is 2.00-3.00, preferably 2.47;
or the double-drug targeting joint-drug conjugate consists of two or more than two of double-drug targeting joint-drug conjugate molecules shown in a formula II SMP-76794, and the DAR value of the double-drug targeting joint-drug conjugate is 2.00-3.00, preferably 2.58;
or the double-drug targeting joint-drug conjugate consists of two or more than two of double-drug targeting joint-drug conjugate molecules shown in a formula II SMP-99767, and the DAR value of the double-drug targeting joint-drug conjugate is 6.50-7.50, preferably 7.14;
or the double-drug targeting joint-drug conjugate consists of two or more than two of double-drug targeting joint-drug conjugate molecules shown in a formula II SMP-86145, and the DAR value of the double-drug targeting joint-drug conjugate is 6.00-7.00, preferably 6.45;
or the double-drug targeting joint-drug conjugate consists of two or more than two of double-drug targeting joint-drug conjugate molecules shown in a formula II SMP-54418, and the DAR value of the double-drug targeting joint-drug conjugate is 7.00-8.00, preferably 7.26;
or the double-drug targeting joint-drug conjugate consists of two or more than two of double-drug targeting joint-drug conjugate molecules shown in a formula II SMP-44708, and the DAR value of the double-drug targeting joint-drug conjugate is 1.50-2.50, preferably 2.07.
The invention also provides a preparation method of the dual-drug targeting linker-drug conjugate molecule or the dual-drug targeting linker-drug conjugate, which comprises the following steps: coupling the targeting joint with the double-drug linkage assembly unit, and purifying to obtain the target; preferably, the purification means is dialysis.
The invention also provides a medicine for preventing and/or treating tumors, which is a preparation prepared by taking the double-medicine targeting joint-medicine conjugate molecule, or the stereoisomer or the optical isomer thereof, or the double-medicine targeting joint-medicine conjugate, or the stereoisomer or the optical isomer thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
The invention also provides the application of the dual-drug targeting linker-drug conjugate molecule, or the stereoisomer or the optical isomer thereof, or the dual-drug targeting linker-drug conjugate, or the stereoisomer or the optical isomer thereof in preparing drugs for preventing and/or treating tumors.
Further, the tumor is selected from lung cancer, urinary tract cancer, large intestine cancer, prostate adenocarcinoma, ovarian cancer, pancreatic cancer, breast cancer, bladder cancer, stomach cancer, gastrointestinal stromal tumor, cervical cancer, esophageal cancer, squamous cell cancer, peritoneal cancer, liver cancer, colon cancer, rectal cancer, colorectal cancer, uterine cancer, salivary gland cancer, kidney cancer, vulval cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, or sarcoma.
Definitions of terms used in connection with the present invention: the initial definitions provided herein for a group or term apply to that group or term throughout the specification unless otherwise indicated; for terms not specifically defined herein, the meanings that would be given to them by a person skilled in the art are to be given in light of the disclosure and the context.
An "antibody" or "antibody unit" is within the scope thereof, including any portion to which an antibody binds. This unit may bind, reactively associate or complex with a receptor, antigen, or other receptor unit present in the targeted cell population. The antibody may be any protein or intraproteinaceous molecule that can bind, complex or otherwise react with a portion of a cell population to be treated or biologically engineered.
The antibodies of the present invention are capable of specifically binding to an antigen. Designed antigens include: tumor Associated Antigens (TAAs), cell surface receptor proteins and other cell surface molecules, cell survival regulators, cell proliferation regulators, molecules associated with tissue growth or differentiation (e.g., known or predicted to be functional), lymphokines, cytokines, factors involved in the regulation of cell circulation, molecules involved in angiogenesis, and molecules associated with angiogenesis. The tumor-associated factor may be a cluster differentiation factor (e.g., a CD protein). The antigen to which the antibody of the invention binds may be one or a subset of the above categories, the other subset comprising other molecules/antigens having specific properties.
Antibodies useful in the dual drug linked building blocks and dual drug targeting linker-drug conjugates of the invention include, but are not limited to, antibodies directed against tumor associated antigens of cell surface receptors. Tumor associated antigens include, but are not limited to, those listed below, including names and gene bank accession numbers. The antibodies target the corresponding tumor-associated antigens including all amino acid sequence variants and homologues, having at least 70%, 80%, 85%, 90% or 95% homology with the sequences identified in the references, or having biological properties and characteristics that are fully identical to the tumor-associated antigen sequences in the cited documents.
Tumor-associated antigens: BMPR1B (Genbank accession No.: NM-001203), E16(Genbank accession No.: NM-003486), STEAP1(Genbank accession No.: NM-012449),0772P (Genbank accession No.: AF361486), MPF (Genbank accession No.: NM-005823), Napi3b (Genbank accession No.: NM-006424), Sema 5b (Genbank accession No.: AB040878), PSCA hlg (Genbank accession No.: AY358628), ETBR (Genbank accession No.: AY275463), CRIP 783(Genbank accession No.: NM-017763), STEAP2(Genbank accession No.: FcR 5138), TrpM4(Genbank accession No.: NM 7676760136), CRIP 003203 or NM-003212), CRIP 21(Genbank accession No.: BCA-225826), HER accession No. (Genbank accession No.: BCA accession No. M-709723), CRI-accession No. (Genbank accession No.: BCA-accession No.: BCH-accession No. M-accession No. (Genbank accession No.: Bruna-639723), Genbank accession No.: BCH-accession No. (Genbank accession No.: BCH-accession No.: 01 000626 3), EphB2R (Genbank accession No.: NM-004442), GEDA (Genbank accession No.: AY260763), BAFF-R (Genbank accession No.: AF1164546), CD22(Genbank accession No.: AK026467), CD79a (Genbank accession No.: NP-001774.1), CXCR5(Genbank accession No.: NP-001701.1), HLA-DOB (Genbank accession No.: NP-002111.1), P2X5(Genbank accession No.: NP-002552.2), CD72(Genbank accession No.: NP-001773.1), LY64(Genbank accession No.: NP-005573.1), FcRH1(Genbank accession No.: NP-443170.1), IRTA2(Genbank accession No.: NP-112571.1), TENB2(Genbank accession No.: AF 179274).
As used herein, "drug," "drug unit," or the code "D" refers broadly to any compound having a desired biological activity and having reactive functional groups to prepare a conjugate described herein. Further, the drug includes a cytotoxic compound for cancer therapy, a biologically active protein or polypeptide, including but not limited to camptothecin derivatives such as SN-38, Dxd, Dx-8951, tubulin acting compounds such as Eribulin, MMAE, MMAF, maytansine, etc. (structures shown below).
Figure BDA0003187619010000291
The "linker" or "antibody drug conjugate linker" described herein can be divided into two classes according to the intracellular drug release mechanism: non-cleavable linkers and cleavable linkers.
For the double-drug antibody drug conjugate containing the non-cleavable linker, the drug release mechanism is as follows: after the conjugate is combined with the antigen and is endocytosed by cells, the antibody is subjected to enzymolysis in lysosomes, so that small molecular drugs are released, and active small molecules consisting of the linker and the amino acid residues of the antibody are formed.
Cleavable linkers that cleave within the target cell and release the active drug (small molecule drug itself) can be divided into two main categories: chemically labile linkers and enzyme labile linkers.
Chemically labile linkers can be selectively cleaved due to differences in plasma and cytoplasmic properties, including pH, glutathione concentration, etc. Enzyme-labile linkers, such as peptide linkers, allow for better control of drug release. The peptide linker can be cleaved efficiently by an endolytic protease, such as cathepsin-active plasmin. This peptide linkage is considered to be very stable in plasma because extracellular undesirable pH values and serum protease inhibitors result in proteases which are generally not active extracellularly. In view of higher plasma stability and good intracellular cleavage selectivity and effectiveness, enzyme-labile linkers are widely used as cleavable linkers for antibody drug conjugates.
In the invention, "q" represents the number of coupled double-drug linked assembly units on one targeting joint in a double-drug targeting joint-drug conjugate molecule, and q is an integer.
However, dual-drug targeting linker-drug conjugates used in the art are typically mixtures of multiple dual-drug targeting linker-drug conjugate molecules with different q values.
"DAR value" means the average number of coupled double-drug linked building blocks on one targeting linker in a double-drug targeting linker-drug conjugate, which is equivalent to the average of q values. The DAR value may not be an integer.
The invention provides a double-drug linked assembly unit, which can be connected with a targeting joint to obtain a corresponding double-drug targeting joint-drug conjugate, wherein the double-drug targeting joint-drug conjugate can act on tumor cells in a targeting way, so that the toxic and side effects on normal cells are reduced, and meanwhile, the drug resistance of a drug can be effectively overcome. And ADC already on the market: compared with DS-8201a, the ADC provided by the invention has obviously improved inhibiting effect on breast adenocarcinoma cells and gastric cancer cells. The double-drug linked assembly unit and the double-drug targeting joint-drug conjugate have wide application prospect in preparing anti-tumor drugs for prevention and/or treatment.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The raw materials and equipment used in the invention are known products and are obtained by purchasing commercial products.
Examples 1-22 are specific examples of the preparation of dual drug linked building blocks of the present invention.
Example 1, synthesis of compound XIe:
step 1: preparation of intermediate 4-2:
Figure BDA0003187619010000301
a15 mL reaction flask was charged with starting material L-2(300mg), DCM (5mL), and oxalyl chloride (0.3mL) was added dropwise slowly at 0 deg.C and the reaction stirred at room temperature for 30 min. DCM was removed by concentration under reduced pressure and DCM (20mL) was added to the residue; 5-Aminoisophthalic acid (350mg) was dissolved in DMF (2mL), DIPEA (320mg) was added thereto, and the above DCM solution was slowly added dropwise at 0 ℃ and the reaction was stirred at room temperature for 2 hours. HPLC purification (H)2O: ACN 10-90%), to obtain 4-2 pure product, which weighs 200 mg. MS (EI) m/s: 375.1(M + H).
Step 2: preparation of intermediate 4-3:
Figure BDA0003187619010000311
to a 50mL reaction flask were added the starting materials 4-2(53mg), DMF (2.5mL), HATU (54mg), and DIPEA (18mg) in this order, and the reaction was stirred at room temperature for 5 minutes. The starting material A (40mg) was dissolved in DMF (1mL) and the solution was slowly added dropwise to the above reaction mixture, followed by reaction at room temperature for 20 minutes. HPLC purification (H)2O: ACN 10-90%) to give 4-3 pure product, weighing 20 mg. MS (EI) m/s: 740.5(M/2+ H).
And step 3: preparation of target product XIe:
Figure BDA0003187619010000312
a25 mL reaction flask was charged with 4-3(15mg) of each raw material, DMF (1.5mL), HATU (5.7mg) and DIPEA (2.5mg) in this order, stirred at room temperature for 1 minute, charged with C (11.5mg) of each raw material, and reacted at room temperature for 20 minutes. HPLC purification (H)2O: 10-90%) to obtain XIe pure product, weighing 17.7 mg. MS (EI) m/s: 1299.3(M/2+ H).1H NMR(400MHz,DMSO-d6)δ9.87(m,3H),8.29–8.13(m,5H),7.78(m,2H),7.57–7.44(m,5H),7.42–7.24(m,10H),6.81–6.66(m,3H),6.16(m,2H),5.41–5.31(m,4H),5.19(qm,1H),5.17–5.09(m,5H),5.07–5.00(m,3H),4.91(m,1H),4.49–3.68(m,28H),3.68–3.50(m,3H),3.44–3.36(m,1H),3.35–3.19(m,11H),3.18–3.01(m,4H),2.91(d,J＝7.8Hz,6H),2.68(m,1H),2.62–2.25(m,13H),2.25–1.46(m,40H),1.45–1.22(m,4H),1.18(m,3H),1.09(d,J＝7.0Hz,3H),1.02(d,J＝8.0Hz,3H),0.98–0.90(m,15H),0.90–0.77(m,15H).
Example 2, synthesis of compound XIc:
Figure BDA0003187619010000321
step 1: preparation of target product XIc:
a25 mL reaction flask was charged with 4-3(15mg) of the starting materials, DMF (1.5mL), HATU (5.7mg) and DIPEA (2.5mg) in this order, stirred at room temperature for 1 minute, charged with the starting material B (8.5mg), and reacted at room temperature for 20 minutes. HPLC purification (H2O: ACN 10-90%) gave pure XIc weighing 9.8 mg. MS (EI) m/s: 1016.5(M/2+ H).
Example 3 synthesis of compound SMP-52581:
step 1: preparation of intermediate 4-2-B:
Figure BDA0003187619010000322
50mL reaction bottles are added in sequenceStarting materials 4-2(89mg), DMF (2.5mL), HATU (90mg), DIPEA (30mg) were stirred at room temperature for 5 minutes. The starting material B (50mg) was dissolved in DMF (1mL) and the solution was slowly added dropwise to the above reaction mixture, followed by reaction at room temperature for 20 minutes. HPLC purification (H)2O: ACN 10-90%) to give pure 4-2-B, weighing 35 mg. MS (EI) m/s: 1197.2(M + H).
Step 2: preparation of a target product SMP-52581:
Figure BDA0003187619010000331
a15 mL reaction flask was charged with the starting material 4-2-B (15mg), DMF (1.5mL), HATU (7.1mg), and DIPEA (3.2mg) in that order, and the reaction was stirred at room temperature for 5 minutes. The starting material C (14mg) was dissolved in DMF (0.5mL) and the solution was slowly added dropwise to the above reaction mixture, followed by reaction at room temperature for 20 minutes. HPLC purification (H)2O: ACN 10-90%) to give a pure product, weighing 6.9 mg. MS (EI) m/s: 1157.5(M + H).
Example 4 synthesis of compound SMP-96745:
Figure BDA0003187619010000332
step 1: preparation of target product SPM-96745:
to a 50mL reaction flask were added the starting materials 4-2(4.4mg), DMF (1.0mL), HATU (4.4mg) and DIPEA (2mg) in this order, and the reaction was stirred at room temperature for 1 minute. The starting material B (20mg) was added to the above reaction mixture all at once, and reacted at room temperature for 20 minutes. HPLC purification (H)2O: ACN 10-90%) to give a pure product, weighing 10.5 mg. MS (EI) m/s: 1010.2(M + H).
Example 5, synthesis of compound XIf:
step 1: preparation of intermediate X-1:
Figure BDA0003187619010000341
a25 mL reaction flask was charged with intermediate X (27mg), DMF (1.5mL), HATU (30mg), and DIPEA (31mg) in this order, and the mixture was stirred at room temperature for 5 minutes to react, whereupon the intermediate was addedA (30mg) was dissolved in DMF (0.5mL) and the solution was clarified, and then the solution was added dropwise to the reaction mixture and reacted at room temperature for 30 minutes. The intermediate A was completely reacted. HPLC purification (H)2O: ACN ═ 10-90%), to give pure intermediate X-1, weighing 18 mg. MS (EI) m/s: 723.4(M/2+ H).
Step 2: preparation of target product XIf:
Figure BDA0003187619010000342
a15 mL reaction flask was charged with the starting materials X-1(15mg), DMF (1.5mL), HATU (3.9mg) and DIPEA (2.6mg) in that order, and the reaction was stirred at room temperature for 5 minutes. The starting material C (12mg) was dissolved in DMF (0.5mL) and slowly added dropwise to the above reaction mixture, followed by reaction at room temperature for 20 minutes. HPLC purification (H)2O: ACN 10-90%) to give a pure product, weighing 4.6 mg. MS (EI) m/s: 1281.7(M/2+ H).1H NMR(400MHz,DMSO-d6)δ9.87(s,2H),8.45(d,J＝8.9Hz,1H),7.87(m,2H),7.75(m,2H),7.59–7.43(m,5H),7.43–7.23(m,10H),6.81–6.67(m,3H),6.16(m,2H),5.43–5.26(m,4H),5.23–5.09(m,6H),5.09–4.97(m,3H),4.96–4.87(m,1H),4.43–4.22(m,12H),4.22–4.09(m,4H),4.09–3.70(m,13H),3.64(t,J＝5.9Hz,2H),3.55(m,1H),3.43–3.35(m,1H),3.34–3.20(m,11H),3.19–3.00(m,4H),2.91(d,J＝7.8Hz,6H),2.68(m,1H),2.62–2.24(m,15H),2.22–1.44(m,42H),1.42–1.23(m,4H),1.18(m,3H),1.09(d,J＝7.0Hz,3H),1.02(d,J＝8.0Hz,3H),0.95(d,J＝7.6Hz,3H),0.92–0.78(m,27H).
Example 6, synthesis of compound XIb:
Figure BDA0003187619010000351
a15 mL reaction flask was charged with the starting materials X-1(15mg), DMF (1.5mL), HATU (3.9mg) and DIPEA (2.6mg) in that order, and the reaction was stirred at room temperature for 5 minutes. The starting material B (12mg) was dissolved in DMF (0.5mL) and slowly added dropwise to the above reaction mixture, followed by reaction at room temperature for 20 minutes. HPLC purification (H)2O: ACN 10-90%) to give a pure product, weighing 5.6 mg. MS (EI) m/s: 1275.5(M/2+ H).
Example 7 Synthesis of Compound SMP-39545:
Figure BDA0003187619010000352
step 1: preparation of a target product SMP-39545:
a15 mL reaction flask was charged with the starting material X (2.3mg), DMF (1.5mL), HATU (2.3mg) and DIPEA (2mg) in this order, and the reaction was stirred at room temperature for 1 minute. The starting material A (15mg) was dissolved in DMF (0.5mL) and slowly added dropwise to the above reaction mixture, followed by reaction at room temperature for 20 minutes. HPLC purification (H)2O: 10-90%) to obtain pure SMP-39545 (4.5 mg in weight). MS (EI) m/s: 1272.5(M/2+ H).
Example 8 Synthesis of Compound SMP-93954:
step 1: preparation of intermediate X-2:
Figure BDA0003187619010000361
after intermediate X (45mg), DMF (1.5mL), HATU (50mg) and DIPEA (22.7mg) were added to a 25mL reaction flask in this order and stirred at room temperature for 5 minutes, intermediate A (30mg) was dissolved in DMF (0.5mL) and clarified, and then added dropwise to the reaction mixture and reacted at room temperature for 30 minutes. The intermediate was completely reacted after spotting. HPLC purification (H)2O: ACN ═ 10-90%), purified intermediate X-2, weighed 13 mg. MS (EI) m/s: 729.0(M/2+ H).
Step 2: preparation of a target product SMP-93954:
Figure BDA0003187619010000362
a15 mL reaction flask was charged with the starting materials X-2(15mg), DMF (1.5mL), HATU (3.9mg) and DIPEA (2.6mg) in that order, and the reaction was stirred at room temperature for 5 minutes. The starting material B (8.6mg) was dissolved in DMF (0.5mL) and slowly added dropwise to the above reaction mixture, followed by reaction at room temperature for 20 minutes. HPLC purification (H)2O: ACN 10-90%) to give a pure product, weighing 9.6 mg. MS (EI) m/s: 1141.0(M/2+ H).1H NMR(400MHz,DMSO-d6)δ9.87(s,1H),8.45(d,J＝8.9Hz,1H),8.15–8.02(m,4H),7.88(m,2H),7.75(d,J＝8.9Hz,1H),7.54–7.46(m,2H),7.39–7.29(m,4H),7.29–7.18(m,6H),6.75(t,J＝7.4Hz,1H),6.70(s,2H),6.16(t,J＝4.8Hz,1H),5.87(s,1H),5.43–5.29(m,2H),5.24–5.17(m,2H),5.17–5.09(m,4H),5.09–4.99(m,4H),4.69(dd,J＝12.3,1.0Hz,1H),4.60–4.49(m,2H),4.42–4.35(m,2H),4.35–4.29(m,3H),4.29–4.21(m,4H),4.21–4.14(m,2H),4.13(m,2H),4.10–3.99(m,4H),3.99–3.86(m,3H),3.83–3.68(m,8H),3.64(m,3H),3.40–3.18(m,5H),3.18–3.01(m,2H),3.01–2.76(m,4H),2.61–2.26(m,13H),2.23(s,3H),2.20–2.09(m,3H),2.09–1.96(m,4H),1.96–1.80(m,7H),1.80–1.63(m,10H),1.63–1.45(m,9H),1.43–1.31(m,2H),1.02(d,J＝8.0Hz,3H),0.96(t,J＝8.1Hz,3H),0.85(t,J＝1.6Hz,3H),0.84(t,J＝1.6Hz,3H).
Example 9 Synthesis of the Compound SMP-11115:
Figure BDA0003187619010000371
step 1: preparation of target product SMP-11115:
a15 mL reaction flask was charged with the starting material X (2.3mg), DMF (1.5mL), HATU (2.3mg) and DIPEA (2mg) in this order, and the reaction was stirred at room temperature for 1 minute. The starting material C (25mg) was dissolved in DMF (0.5mL) and slowly added dropwise to the above reaction mixture, followed by reaction at room temperature for 20 minutes. HPLC purification (H)2O: 10-90 percent of ACN) to obtain pure SMP-11115 with the weight of 18 mg. MS (EI) m/s: 1287.5(M/2+ H).
Example 10, Synthesis of Compound SMP-04404:
Figure BDA0003187619010000372
step 1: preparation of target product SMP-04404:
a15 mL reaction flask was charged with the starting material X (2.0mg), DMF (1.5mL), HATU (13mg), and DIPEA (5.3mg) in this order, and the reaction was stirred at room temperature for 1 minute. The starting material B (10mg) was dissolved in DMF (0.5mL) and slowly added dropwise to the above reaction mixture, followed by reaction at room temperature for 20 minutes. HPLC purification (H)2O: ACN 10-90%), to obtainPure SMP-04404 weighing 3.4 mg. MS (EI) m/s: 1493(M/2+ H).
Example 11, Synthesis of Compound SMP-37241:
step 1: preparation of intermediate Y:
Figure BDA0003187619010000381
a50 mL reaction flask was charged first with H2THF (2: 1) is added into the solution, and then NaHCO is added into the solution in sequence3(148mg) and Y (200mg), stirred at room temperature until the solution was clear, and L-3(460mg) was added to the above reaction solution in one portion in DME (6mL) and reacted at room temperature for 12 hours. And (3) post-treatment: the reaction mixture was extracted three times with EA: MeOH 30: 1: 25 × 3(mL), and the organic phase was dried over anhydrous sodium sulfate and then distilled under reduced pressure to give a crude product of L-3-1. Purification by HPLC (H)2O: ACN ═ 10-90%), purified intermediate L-3-1 (45mg in weight). MS (EI) m/s: 327.1(M + H)
Step 2: preparation of intermediate Y-1:
Figure BDA0003187619010000382
after intermediate Y (51mg), DMF (2.5mL), HATU (60.4mg) and DIPEA (23mg) were added to a 25mL reaction flask in this order and stirred at room temperature for 5 minutes, intermediate C starting material (60mg) was dissolved in DMF (1.0mL) and clarified, and then added dropwise to the reaction mixture and reacted at room temperature for 30 minutes. The intermediate was completely reacted after spotting. HPLC purification (H)2O: ACN ═ 10-90%), to give pure intermediate Y-1, weighing 40 mg. MS (EI) m/s: 1443.1(M + H).1H NMR(400MHz,DMSO-d6)δ9.87(s,1H),8.59(d,J＝8.9Hz,1H),7.76(m,2H),7.54–7.45(m,2H),7.34(m,2H),6.78–6.68(m,3H),6.16(t,J＝4.8Hz,1H),5.41–5.30(m,2H),5.19(m,1H),5.14(m,3H),5.04(m,2H),4.49–4.36(m,2H),4.36–4.29(m,3H),4.29–4.21(m,4H),4.21–4.13(m,2H),4.10–3.99(m,4H),3.96–3.86(m,2H),3.83–3.69(m,2H),3.64(m,3H),3.32(s,3H),3.27(m,2H),3.16–3.02(m,2H),2.71–2.57(m,2H),2.57–2.27(m,9H),2.21–2.14(m,2H),2.11–1.95(m,4H),1.93–1.45(m,24H),1.36(m,2H),1.02(d,J＝8.0Hz,3H),0.85(t,J＝1.6Hz,3H),0.84(t,J＝1.6Hz,3H).
And step 3: preparation of a target product SMP-37241:
Figure BDA0003187619010000391
after intermediate Y-1(10mg), DMF (1.5mL), HATU (3.1mg) and DIPEA (1.3mg) were added to a 25mL reaction flask in this order and stirred at room temperature for 1 minute, intermediate B starting material (5.8mg) was dissolved in DMF (0.5mL) and clarified, and then slowly dropped into the reaction mixture and reacted at room temperature for 30 minutes. The intermediate was completely reacted after spotting. HPLC purification (H)2O: 10-90 percent of ACN) to obtain the pure SMP-37241 product with the weight of 2.1 mg. MS (EI) m/s: 1133.5(M/2+ H).1H NMR(400MHz,DMSO-d6)δ9.87(s,1H),8.60(d,J＝8.7Hz,1H),8.19–7.99(m,4H),7.90(d,J＝9.1Hz,1H),7.77(m,2H),7.54–7.46(m,2H),7.41–7.29(m,4H),7.30–7.17(m,6H),6.75(t,J＝7.4Hz,1H),6.70(s,2H),6.16(t,J＝4.8Hz,1H),5.87(s,1H),5.41–5.29(m,2H),5.24–5.17(m,2H),5.17–5.10(m,4H),5.09–5.00(m,4H),4.69(dd,J＝12.3,1.0Hz,1H),4.60–4.50(m,3H),4.42–4.36(m,2H),4.36–4.29(m,4H),4.29–4.21(m,4H),4.21–4.14(m,2H),4.13(m,2H),4.10–3.97(m,4H),3.97–3.86(m,2H),3.83–3.68(m,8H),3.64(m,3H),3.36–3.20(m,5H),3.16–3.01(m,2H),2.99–2.78(m,4H),2.61–2.44(m,6H),2.43–2.27(m,5H),2.26–2.10(m,6H),2.09–1.95(m,4H),1.95–1.44(m,27H),1.36(m,2H),1.02(d,J＝8.0Hz,3H),0.96(t,J＝8.1Hz,3H),0.85(t,J＝1.6Hz,3H),0.84(t,J＝1.6Hz,3H).
Example 12 synthesis of compound SMP-13432:
Figure BDA0003187619010000401
step 1: preparation of a target product SMP-13432:
after intermediate Y-1(10mg), DMF (1.5mL), HATU (3.6mg) and DIPEA (1.2mg) were added to a 25mL reaction flask in this order and stirred at room temperature for 1 minute, intermediate A starting material (7.2mg) was dissolved in DMF (0.5mL) and clarifiedSlowly added dropwise to the above reaction solution, and reacted at room temperature for 30 minutes. The intermediate was completely reacted after spotting. HPLC purification (H)2O: 10-90 percent of ACN) to obtain the pure product SMP-13432 with the weight of 2.6 mg. MS (EI) m/s: 1274.5(M/2+ H).
Example 13 Synthesis of Compound SMP-84984:
Figure BDA0003187619010000402
step 1: preparation of a target product SMP-84984:
after intermediate Y (1.5mg), DMF (1.5mL), HATU (5.4mg) and DIPEA (2.4mg) were added to a 25mL reaction flask in this order and stirred at room temperature for 1 minute, intermediate B starting material (8mg) was dissolved in DMF (0.5mL) and clarified, and then slowly added dropwise to the reaction mixture, followed by reaction at room temperature for 30 minutes. The intermediate was completely reacted after spotting. HPLC purification (H)2O: ACN ═ 10-90%), purified intermediate SMP-84984, weighing 2.5 mg. MS (EI) m/s: 986.1(M/2+ H).
Example 14, synthesis of compound XIa:
Figure BDA0003187619010000411
step 1: preparation of intermediate Y-A:
after intermediate Y (26mg), DMF (2.5mL), HATU (31mg) and DIPEA (12mg) were added to a 25mL reaction flask in this order and stirred at room temperature for 5 minutes, the intermediate A starting material (30mg) was dissolved in DMF (1.0mL) and clarified, and then the mixture was added dropwise to the reaction mixture and allowed to react at room temperature for 30 minutes. The intermediate was completely reacted after spotting. HPLC purification (H)2O: ACN ═ 10-90%), to give pure intermediate Y-a weighing 20 mg. MS (EI) m/s: 1431.1
Step 2: preparation of target product XIa:
Figure BDA0003187619010000412
a25 mL reaction flask was charged with intermediate Y-A (10mg), DMF (1.5mL)HATU (2.5mg) and DIPEA (1.2mg) were reacted with stirring at room temperature for 1 minute, and then the intermediate B starting material (5.8mg) was dissolved in DMF (0.5mL) and clarified, and then the resulting solution was added dropwise to the reaction mixture and reacted at room temperature for 30 minutes. The intermediate was completely reacted after spotting. HPLC purification (H)2O: ACN 10-90%) to give pure product XIa, weighing 2.5 mg. MS (EI) m/s: 1127.5(M/2+ H).
Example 15 Synthesis of Compound SMP-04140:
step 1: preparation of intermediate Z:
Figure BDA0003187619010000421
a50 mL reaction flask was charged first with H2THF (2: 1) is added into the solution, and then NaHCO is added into the solution in sequence3(1.05g) and SM1(500mg), and after stirring at room temperature until the solution was clear, L-3(1.9g) was dissolved in DME (18mL) and added to the above reaction solution in one portion, and reacted at room temperature for 12 hours. And (3) post-treatment: the reaction mixture was extracted three times with EA: MeOH 30: 1: 35 × 3(mL), and the organic phase was dried over anhydrous sodium sulfate and distilled under reduced pressure to give crude Z. Purification by HPLC (H)2O: ACN ═ 10-90%), to give pure intermediate Z weighing 300 mg. MS (EI) m/s: 313.1(M + H)
Step 2: preparation of intermediate Z-1:
Figure BDA0003187619010000422
after intermediate Z (22mg), DMF (1.5mL), HATU (26.6mg) and DIPEA (9.0mg) were added to a 25mL reaction flask in this order and stirred at room temperature for 5 minutes, intermediate C starting material (20mg) was dissolved in DMF (1.0mL) and clarified, and then added dropwise to the reaction mixture slowly and reacted at room temperature for 30 minutes. The intermediate was completely reacted after spotting. HPLC purification (H)2O: ACN ═ 10-90%), to give pure intermediate Z-1, weighing 15 mg. MS (EI) m/s: 715(M/2+ H).
And step 3: preparation of a target product SMP-04140:
Figure BDA0003187619010000431
after intermediate Z-1(10mg), DMF (1.5mL), HATU (4mg) and DIPEA (1.8mg) were added to a 25mL reaction flask in this order and stirred at room temperature for 1 minute, intermediate B starting material (5.8mg) was dissolved in DMF (0.5mL) and clarified, and then slowly dropped into the reaction mixture and reacted at room temperature for 30 minutes. The intermediate was completely reacted after spotting. HPLC purification (H)2O: 10-90 percent of ACN) to obtain the pure SMP-04140 product with the weight of 1.7 mg. MS (EI) m/s: 1126.5(M/2+ H).
Example 16, Synthesis of Compound SMP-76794:
Figure BDA0003187619010000432
step 1: preparation of target product SMP-76794:
after intermediate Z-1(10mg), DMF (1.5mL), HATU (4mg) and DIPEA (1.8mg) were added to a 25mL reaction flask in this order and stirred at room temperature for 1 minute, the intermediate A starting material (8.1mg) was dissolved in DMF (0.5mL) and clarified, and then slowly added dropwise to the reaction mixture, followed by reaction at room temperature for 30 minutes. The intermediate was completely reacted after spotting. HPLC purification (H)2O: 10-90 percent of ACN) to obtain the pure product SMP-76794 with the weight of 1.8 mg. MS (EI) m/s: 1126.5(M/2+ H).
Example 17 Synthesis of Compound SMP-99767:
Figure BDA0003187619010000441
step 1: preparation of a target product SMP-99767:
after intermediate Z (1.5mg), DMF (1.5mL), HATU (5.4mg) and DIPEA (2.5mg) were added to a 25mL reaction flask in this order and stirred at room temperature for 1 minute, intermediate B starting material (8mg) was dissolved in DMF (1.0mL) and clarified, and then slowly added dropwise to the reaction mixture, followed by reaction at room temperature for 30 minutes. The intermediate was completely reacted after spotting. HPLC purification (H)2O: 10-90 percent of ACN) to obtain the pure SMP-99767 product with the weight of 3 mg. MS (EI) m/s: 979.3(M/2+ H).
Example 18 Synthesis of Compound SMP-86145:
step 1: preparation of intermediate Z-A:
Figure BDA0003187619010000442
after intermediate Z (21mg), DMF (1.5mL), HATU (25mg) and DIPEA (8.6mg) were added to a 25mL reaction flask in this order and stirred at room temperature for 5 minutes, intermediate A as a starting material (25mg) was dissolved in DMF (1.0mL) and clarified, and then the mixture was added dropwise to the reaction mixture and allowed to react at room temperature for 30 minutes. The intermediate was completely reacted after spotting. HPLC purification (H)2O: ACN ═ 10-90%), to give pure intermediate Z-A weighing 20 mg. MS (EI) m/s: 708(M/2+ H).
Step 2: preparation of a target product SMP-86145:
Figure BDA0003187619010000451
after intermediate Z-A (10mg), DMF (1.5mL), HATU (4.0mg) and DIPEA (1.8mg) were added toA 25mL reaction flask in this order and stirred at room temperature for 1 minute, intermediate B starting material (5.9mg) was dissolved in DMF (0.5mL) and clarified, and then the mixture was added dropwise to the reaction mixture slowly and reacted at room temperature for 30 minutes. The intermediate was completely reacted after spotting. HPLC purification (H)2O: 10-90 percent of ACN) to obtain the pure SMP-86145 product with the weight of 1.8 mg. MS (EI) m/s: 1120(M/2+ H).
Example 19 Synthesis of the Compound SMP-54418:
step 1: preparation of intermediate V-2:
Figure BDA0003187619010000452
a25 mL reaction flask was charged with intermediate V-3(1g), DMF (20mL), K2CO3(1.16g), bromoacetic acid (593mg), and nitrogen atmosphere for 12h at room temperature. And (3) post-treatment: after distilling DMF under reduced pressure at 55 deg.C, the remaining solid was dissolved in H2O (10mL), pH 3 was adjusted at 0 deg.C, and the mixture was extracted three to five times with ethyl acetate and saturated brine, and the organic phase was extracted with anhydrous sodium sulfateDrying, and distilling under reduced pressure to obtain a crude product of V-2. HPLC purification (H)2O: ACN ═ 10-90%), to give pure intermediate V-2, weighing 400 mg. MS (EI) m/s: 340(M + H).
Step 2: preparation of intermediate V-1:
Figure BDA0003187619010000453
a25 mL reaction flask was charged with intermediate V-2(400mg), TFA, under nitrogen, and reacted at room temperature for 20 min. Vacuum distillation at 55 ℃ to obtain a crude product of V-1. HPLC purification (H)2O: ACN ═ 10-90%), to give pure intermediate V-2, weighing 140 mg. MS (EI) m/s: 240(M + H). And step 3: preparation of intermediate V:
Figure BDA0003187619010000461
a15 mL reaction flask was charged with starting material L-2(123mg), DCM (2mL), and oxalyl chloride (0.1mL) was added dropwise slowly at 0 deg.C and the reaction stirred at room temperature for 30 min. DCM was removed by concentration under reduced pressure and DCM (20mL) was added to the residue; after V-1(140mg) was dissolved in DCM (2mL), DIPEA (140mg) was added, and the above DCM solution was slowly added dropwise at 0 ℃ and the reaction was stirred at room temperature for 2 hours. HPLC purification (H)2O: 10-90%) to obtain pure product V, weighing 50 mg. MS (EI) m/s: 433(M + H).
And 4, step 4: preparation of intermediate 065-1:
Figure BDA0003187619010000462
after intermediate V (30mg), DMF (1.5mL), HATU (25mg) and DIPEA (8.6mg) were added to a 25mL reaction flask in this order and stirred at room temperature for 5 minutes, intermediate A (21mg) was dissolved in DMF (0.5mL) and clarified, and then added dropwise to the reaction mixture and reacted at room temperature for 30 minutes. The intermediate A was completely reacted. HPLC purification (H)2O: ACN 10-90%) to give pure intermediate 065-1(8mg in weight). MS (EI) m/s: 769(M/2+ H).
And 5: preparation of target product SMP-54418:
Figure BDA0003187619010000463
after sequentially adding the intermediate 065-1(8mg), DMF (1.5mL), DIPEA (1.3mg) and HATU (2.9mg) to a 25mL reaction flask, the starting material B (4.3mg) was added in one portion and reacted at room temperature for 20 minutes. The intermediate was completely reacted after spotting. HPLC purification (H)2O: 10-90 percent of ACN) to obtain the pure SMP-54418 product with the weight of 7 mg. MS (EI) m/s: 1181(M/2+ H).
Example 20 Synthesis of the Compound SMP-44708:
step 1: preparation of intermediate 066-1:
Figure BDA0003187619010000471
after intermediate V (15mg), DMF (1.5mL), HATU (16mg) and DIPEA (6.9mg) were added to a 25mL reaction flask in this order and stirred at room temperature for 5 minutes, intermediate B (30mg) was dissolved in DMF (0.5mL) and clarified, and then added dropwise to the reaction mixture and reacted at room temperature for 30 minutes. The intermediate B was reacted completely. HPLC purification (H)2O: ACN 10-90%) to give pure intermediate 066-1, weighing 8.4 mg. MS (EI) m/s: 1255.5(M + H).
Step 2: preparation of a target product SMP-44708:
Figure BDA0003187619010000472
a25 mL reaction flask was charged with the intermediate 066-1(8.4mg), DMF (1.5mL), DIPEA (1.2mg), and HATU (3.0mg) in this order, and then the C starting material (7.5mg) was added all at once to the flask and reacted at room temperature for 20 minutes. The intermediate was completely reacted after spotting. HPLC purification (H)2O: 10-90 percent of ACN) to obtain the pure product SMP-44708, which weighs 7 mg. MS (EI) m/s: 1185.5(M/2+ H).1H NMR(400MHz,DMSO-d6)δ9.87(s,1H),8.15–8.02(m,4H),8.01–7.87(m,3H),7.75(d,J＝8.9Hz,1H),7.53–7.46(m,2H),7.38–7.29(m,4H),7.29–7.18(m,6H),7.12(dt,J＝8.8,1.0Hz,2H),6.89–6.84(m,2H),6.75(t,J＝7.4Hz,1H),6.70(s,2H),6.16(t,J＝4.8Hz,1H),5.87(s,1H),5.42–5.30(m,2H),5.24–5.17(m,2H),5.17–5.09(m,4H),5.09–4.99(m,4H),4.69(m,1H),4.61–4.51(m,2H),4.49(m,2H),4.43–3.98(m,18H),3.96–3.85(m,2H),3.83–3.70(m,8H),3.64(m,3H),3.36–3.19(m,5H),3.19–3.02(m,2H),3.02–2.79(m,6H),2.58–1.96(m,19H),1.96–1.43(m,28H),1.36(m,2H),1.02(d,J＝8.0Hz,3H),0.96(t,J＝8.1Hz,3H),0.85(t,J＝1.6Hz,3H),0.84(t,J＝1.6Hz,3H).
Example 21, synthesis of compound XId:
Figure BDA0003187619010000481
after the intermediates 4 to 3(12mg) in example 1, DMF (1.5mL), DIPEA (1.5mg) and HATU (3.5mg) were added in this order to a 25mL reaction flask, the starting material D (8.0mg) was added in one portion and reacted at room temperature for 20 minutes. The intermediate was completely reacted after spotting. HPLC purification (H)2O: ACN 10-90%) to give pure XId, which weighed 7.3 mg. MS (EI) m/s: 1299.9(M/2+ H).
Example 22, synthesis of compound XIg:
Figure BDA0003187619010000482
a25 mL reaction flask was charged with the intermediates x-1(8.0mg) of example 5, DMF (1.5mL), DIPEA (1.0mg) and HATU (3.0mg) in this order, and then charged with the starting material D (7.0mg) in one portion to react at room temperature for 20 minutes. The intermediate was completely reacted after spotting. HPLC purification (H)2O: ACN 10-90%) to give pure XId, weighing 6.7 mg. MS (EI) m/s: 1282.5(M/2+ H).1H NMR(400MHz,DMSO-d6)δ9.87(m,2H),8.45(d,J＝8.9Hz,1H),7.87(m,2H),7.73(m,3H),7.57–7.46(m,5H),7.41–7.27(m,11H),7.27–7.15(m,5H),6.70(s,2H),6.16(m,2H),5.42–5.29(m,4H),5.11(m,4H),5.04(m,1H),4.95–4.86(m,1H),4.42–4.20(m,9H),4.18–4.08(m,4H),4.01–3.79(m,6H),3.64(t,J＝5.9Hz,2H),3.55(m,2H),3.44–3.36(m,2H),3.24(s,12H),3.18–3.01(m,4H),3.01–2.86(m,14H),2.65(m,2H),2.58–2.46(m,4H),2.40(s,4H),2.20–1.63(m,24H),1.62–1.44(m,6H),1.42–1.22(m,6H),1.18(m,3H),1.09(m,6H),0.95(d,J＝7.6Hz,6H),0.91–0.79(m,42H).
Example 23 is a specific example of the preparation of an antibody-drug conjugate (ADC) of the present invention.
Example 23 preparation of ADC
The two-drug linked assembly units prepared in examples 1 to 22 and the antibody were used as raw materials to prepare corresponding ADCs, respectively. The general method is as follows:
step 1: antibody reduction
Trastuzumab was prepared into a 10mg/mL solution (3.0mL) with PBS6.0/EDTA, and 10mM aqueous tris (2-carboxyethyl) phosphine hydrochloride (TCEP) solution (0.0934mL) and 1M aqueous dipotassium hydrogen phosphate solution (0.150mL) were added thereto to ensure that the pH of the reaction solution was between 7.3 and 7.5, followed by stirring for 1 minute and incubation at 37 ℃ for 1 hour.
Step 2: antibody-drug conjugation
The temperature of the solution was lowered to 10 ℃, and DMSO solutions (0.0374mL) containing 10mM of one of the double drug linked assembly units of examples 1 to 22 were added thereto, respectively, and the mixture was stirred for 1 minute and then incubated for 2 hours.
And step 3: purification of
Dialyzing the reaction solution obtained in the step 2 by using a 10KD semipermeable membrane at the dialysis temperature of 25 ℃, 4L of dialysis solvent for 4 times, dialyzing for 4 hours for 4 times, centrifuging and concentrating the obtained dialysate by using a 10KD ultrafiltration centrifugal tube until the concentration of ADC is about 5mg/mL, and storing at the temperature of-20-30 ℃ for later use.
The prepared ADCs were named example 1-ADC to example 22-ADC, respectively, and the structures thereof were as follows:
1. example 14-ADC:
Figure BDA0003187619010000501
2. example 6-ADC:
Figure BDA0003187619010000502
3. example 2-ADC:
Figure BDA0003187619010000511
4. example 21-ADC:
Figure BDA0003187619010000512
5. example 1-ADC:
Figure BDA0003187619010000513
6. example 5-ADC:
Figure BDA0003187619010000521
7. example 22-ADC:
Figure BDA0003187619010000522
8. example 3-ADC:
Figure BDA0003187619010000523
Figure BDA0003187619010000531
9. example 4-ADC:
Figure BDA0003187619010000532
10. example 7-ADC:
Figure BDA0003187619010000533
11. example 8-ADC:
Figure BDA0003187619010000541
12. example 9-ADC:
Figure BDA0003187619010000542
13. example 10-ADC:
Figure BDA0003187619010000551
14. example 11-ADC:
Figure BDA0003187619010000552
15. example 12-ADC:
Figure BDA0003187619010000561
16. example 13-ADC:
Figure BDA0003187619010000562
17. example 15-ADC:
Figure BDA0003187619010000571
18. example 16-ADC:
Figure BDA0003187619010000572
19. example 17-ADC:
Figure BDA0003187619010000581
20. example 18-ADC:
Figure BDA0003187619010000582
21. example 19-ADC:
Figure BDA0003187619010000583
22. example 20-ADC:
Figure BDA0003187619010000591
EXAMPLE 24 DAR value determination of ADCs of the invention
Step 1: ADC reduction
Each ADC sample prepared in example 23 was diluted to 1mg/ml with 50mmol/L Tris buffer solution (pH8.0), and then freshly prepared DTT stock solution (1mol/L) was added to make the final concentration of Dithiothreitol (DTT) 50mmol/L, and incubation was carried out at 37 ℃ for 20-30 min for reduction reaction.
Step 2: determination of DAR value
Injecting the sample obtained in the step 1 into LC-MS for detection, obtaining HPLC peak areas of L +0, L +1, H +0, H +1, H +2, H +3 and H +4 after deconvolution treatment, and obtaining a DAR value through calculation.
The DAR value here represents the average number of conjugated dual drug linked building blocks on one antibody in the ADC sample to be tested.
The results are shown in table 1 below.
TABLE 1 measurement of DAR value of ADC
Figure BDA0003187619010000592
Figure BDA0003187619010000601
The following test examples demonstrate the advantageous effects of the present invention.
Test example 1: cell experiment procedure
(1) Test method
The cells were plated in 96-well cell plates at a density of 3000 SK-BR-3 cells (human breast adenocarcinoma cells) per well and 1500N 87 cells (human gastric carcinoma cells) per well, and cultured overnight.
The following day, each ADC to be tested (i.e., ADC in example 1-ADC to ADC in example 22) and Trastuzumab-GGFG-Dxd (DS-8201a, a known ADC) as a positive control were prepared, and the samples were diluted in a 1:5 ratio gradient to prepare 9 concentration gradient points with the highest concentration of 500nM as the final concentration of the drug. Positive control Cisplatin (Cisplatin) was diluted in a 1:3 gradient to prepare 9 concentration gradient points with a final dosing concentration of 100. mu.M as the highest concentration.
The prepared ADCs to be detected and positive controls are added into cells, and the wells with only the culture medium added are used as negative controls. After adding the drug, the cell is cultured for 144 hours, then the cell viability is detected by using a CTG (CELL TITER-GLO) method, and the IC50 value of each tested drug on SK-BR-3 cells and N87 cells is respectively calculated. The results are shown in table 2 below.
(2) Test results
TABLE 2 IC of each drug pair SK-BR-3 cells and N87 cells50Value of
Figure BDA0003187619010000602
Figure BDA0003187619010000611
The experimental results show that compared with a chemotherapeutic drug Cisplatin (Cisplatin), the ADC provided by the invention can obviously improve the inhibition effect on breast adenocarcinoma cells and gastric cancer cells. And ADC already on the market: compared with DS-8201a, the ADC provided by the invention has obviously improved inhibiting effect on breast adenocarcinoma cells and gastric cancer cells.
In summary, the present invention provides a dual-drug linked assembly unit, which can be connected to a targeting linker to obtain a corresponding dual-drug targeting linker-drug conjugate, and the dual-drug targeting linker-drug conjugate can act on tumor cells in a targeted manner, thereby reducing toxic and side effects on normal cells, and simultaneously effectively overcoming drug resistance of drugs. And ADC already on the market: compared with DS-8201a, the ADC provided by the invention has obviously improved inhibiting effect on breast adenocarcinoma cells and gastric cancer cells. The double-drug linked assembly unit and the double-drug targeting joint-drug conjugate have wide application prospect in preparing anti-tumor drugs for prevention and/or treatment.

Claims (19)

1. A dual drug linked building block of formula VI, or a stereoisomer, or an optical isomer thereof:
Figure FDA0003187618000000011
wherein T is a tether group capable of attachment to a targeting linker; the targeting joint is a substance capable of targeting and combining with a lesion part;
u is a three-prong linker moiety;
l1 and L2 are cleavable or non-cleavable linking groups;
D1、D2respectively a first drug unit and a second drug unit.
2. The dual drug linked building block of claim 1, or a stereoisomer thereof, or an optical isomer thereof, wherein: the T can be connected with a sulfhydryl group on the targeting joint in a reaction way.
3. The dual drug linked assembly unit of claim 1 or 2, or a stereoisomer thereof, or an optical isomer thereof, wherein: the structure of the double-medicine link assembly unit is shown as a formula VI-1:
Figure FDA0003187618000000012
wherein, K1、K2Each independently selected from the group consisting ofaKbKc；KaIs phenyl, KbSelected from O, S or none, KcSelected from 0-2 methylene;
n and p are respectively independent integers selected from 0-10;
u is substituted or unsubstituted aryl, heteroaryl, alkanyl, cycloalkyl or heterocycloalkyl; the substituent is selected from deuterium, halogen, cyano, hydroxyl and C1～6Alkyl or C1～6An alkoxy group;
X1、X2each independently selected from
Figure FDA0003187618000000013
Wherein a, b, c and d are respectively and independently selected from 0 or 1, K3Selected from the group consisting of no, no substitution or by R1Substituted C1～4Alkylene radical, K4Selected from the group consisting of no, no substitution or by R2Substituted C1～4Alkylene radical, K5Selected from the group consisting of no, no substitution or by R3Substituted C1～4Alkylene radical, K6Selected from the group consisting of no, no substitution or by R4Substituted C1～4Alkylene radical, R1、R2、R3、R4Each independently selected from H, C1～5Alkyl, substituted or unsubstituted benzyl, -L1aNHCONH2、-L1aNHCOCR5NH2，L1aIs 0 to 4 methylene groups, R5Is C1～3An alkyl group; the substituent on the benzyl is selected from deuterium, halogen, cyano, hydroxyl and C1～6Alkyl or C1～6An alkoxy group;
B1，B2，C1，C2，E1，E2each independently selected from the group consisting of substituted or unsubstituted:
Figure FDA0003187618000000021
L2aCONHL3、L4OL5CO or none; the substituents are each independently selected from
Figure FDA0003187618000000022
C1～5An alkyl group; wherein L is2a、L3、L4、L5、L6Each independently selected from 0-2 methylene groups;
D1、D2each independently selected from cytotoxic drugs, drugs for treating autoimmune diseases or anti-inflammatory drugs;
t is as defined in claim 1 or 2.
4. The dual drug linked assembly unit of claim 3, or a stereoisomer thereof, or an optical isomer thereof, wherein: the structure of the double-drug linking assembly unit is shown as formula VII:
Figure FDA0003187618000000023
wherein n and p are respectively and independently selected from integers of 0-10;
u is substituted or unsubstituted aryl, heteroaryl, alkanyl, cycloalkyl or heterocycloalkyl; the substituent is selected from deuterium, halogen, cyano, hydroxyl and C1～6Alkyl or C1～6An alkoxy group;
X1、X2each independently selected from
Figure FDA0003187618000000024
Wherein a, b, c, d are eachIndependently selected from 0 or 1, R1、R2、R3、R4Each independently selected from H, C1～5Alkyl, substituted or unsubstituted benzyl, -L1aNHCONH2，L1aIs 0 to 3 methylene groups; the substituent on the benzyl is selected from deuterium, halogen, cyano, hydroxyl and C1～6Alkyl or C1～6An alkoxy group;
B1，B2，C1，C2，E1，E2each independently selected from the group consisting of substituted or unsubstituted:
Figure FDA0003187618000000025
L2aCONHL3、L4OL5CO or none; the substituents are each independently selected from
Figure FDA0003187618000000026
C1～5An alkyl group; wherein L is2a、L3、L4、L5、L6Each independently selected from 0-2 methylene groups;
D1、D2each independently selected from cytotoxic drugs, drugs for treating autoimmune diseases or anti-inflammatory drugs;
t is as claimed in claim 3.
5. The dual drug linked assembly unit of claim 4, or a stereoisomer thereof, or an optical isomer thereof, wherein: the structure of the double-drug linking assembly unit is shown as the formula VII-1:
Figure FDA0003187618000000031
wherein A is1、A2Each is independently selected from 0-10 methylene, O, S, CO, NH, CONH, NHCO or nothing;
m，n，p，U，X1，X2，B1，B2，C1，C2，E1，E2，D1、D2as claimed in claim 4.
6. The dual drug linked assembly unit of claim 5, or a stereoisomer thereof, or an optical isomer thereof, wherein: the structure of the dual-drug linked assembly unit is shown as a formula VIIIa or VIIIb:
Figure FDA0003187618000000032
wherein A is1、A2、m、n、p、X1、X2、B1、B2、C1、C2、E1、E2、D1、D2As claimed in claim 5;
m is hydrogen, deuterium, halogen, cyano, hydroxy, C1～6Alkyl or C1～6An alkoxy group.
7. The dual drug linked assembly unit of claim 6, or a stereoisomer thereof, or an optical isomer thereof, wherein: the structure of the dual drug linked assembly unit is selected from one of the following structures:
Figure FDA0003187618000000041
Figure FDA0003187618000000051
wherein D is1、D2The compound of claim 6, wherein n and p are integers of 0 to 4; preferably, n ═ p.
8. The dual drug linked assembly unit of claim 7, or a stereoisomer thereof, or an optical isomer thereof, wherein: the structure of the double-drug linking assembly unit is one of the following structures:
Figure FDA0003187618000000052
Figure FDA0003187618000000061
Figure FDA0003187618000000071
wherein D is1、D2As claimed in claim 7.
9. The dual drug linked assembly unit according to any one of claims 1 to 8, or a stereoisomer thereof, or an optical isomer thereof, wherein: said D1、D2Each independently selected from a drug unit targeting DNA or a drug unit targeting tubulin; the drug unit targeting DNA is preferably SN-38, Dxd, Dx-8951 or derivatives thereof, and/or the drug unit targeting tubulin is preferably Eribulin, MMAE, MMAF, maytansine or derivatives thereof.
10. The dual drug linked assembly unit according to any one of claims 1 to 3, or a stereoisomer thereof, or an optical isomer thereof, wherein: the double-medicine link assembly unit has one of the following structures:
Figure FDA0003187618000000072
Figure FDA0003187618000000081
Figure FDA0003187618000000091
Figure FDA0003187618000000101
Figure FDA0003187618000000111
Figure FDA0003187618000000121
Figure FDA0003187618000000131
Figure FDA0003187618000000141
Figure FDA0003187618000000151
11. a dual-drug targeting linker-drug conjugate molecule, or a stereoisomer, or an optical isomer thereof, characterized in that: the dual-drug targeting linker-drug conjugate molecule is obtained by connecting a targeting linker and q dual-drug linking assembly units as defined in any one of claims 1 to 10; the targeting joint is a substance capable of targeting and combining with a lesion part; the structure of the double-drug targeting joint-drug conjugate molecule is shown as formula I:
Figure FDA0003187618000000161
wherein Ab is a targeting linker, q is an integer of 1-20, T, U, L1, L2 and D1、D2The method according to any one of claims 1 to 10.
12. The dual-drug targeting linker-drug conjugate molecule of claim 11, or a stereoisomer thereof, or an optical isomer thereof, wherein: the targeting linker is an antibody, an antibody fragment, a protein or a nucleic acid aptamer, and the antibody is preferably an antibody aiming at a cell surface receptor and a tumor-associated antigen;
and/or q is an integer of 1-8.
13. The dual-drug targeting linker-drug conjugate molecule of claim 11 or 12, or a stereoisomer thereof, or an optical isomer thereof, characterized in that: the structure of the dual-drug targeting linker-drug conjugate molecule is selected from one of the following structures:
Figure FDA0003187618000000162
Figure FDA0003187618000000171
Figure FDA0003187618000000181
Figure FDA0003187618000000191
Figure FDA0003187618000000201
Figure FDA0003187618000000211
Figure FDA0003187618000000221
Figure FDA0003187618000000231
Figure FDA0003187618000000241
Figure FDA0003187618000000251
14. a dual-drug targeting linker-drug conjugate, or a stereoisomer, or an optical isomer thereof, characterized in that: the double-drug targeting joint-drug conjugate is obtained by connecting a targeting joint and the double-drug linking assembly unit of any one of claims 1 to 10; the targeting joint is a substance capable of targeting and combining with a pathological part, and is preferably an antibody, an antibody fragment, a protein or a nucleic acid aptamer; the antibody is preferably an antibody directed against a cell surface receptor and a tumor associated antigen.
15. The dual-drug targeting linker-drug conjugate of claim 14, or a stereoisomer thereof, or an optical isomer thereof, wherein: the double-drug targeting linker-drug conjugate consists of two or more than two molecules of the double-drug targeting linker-drug conjugate shown in formula IIa in claim 13, wherein the DAR value of the double-drug targeting linker-drug conjugate is 6.00-7.00, and is preferably 6.41;
or, the double-drug targeting linker-drug conjugate consists of two or more than two of the molecules of the double-drug targeting linker-drug conjugate shown in formula IIb in claim 13, and the DAR value of the double-drug targeting linker-drug conjugate is 1.50-2.50, preferably 2.03;
or, the dual-drug targeting linker-drug conjugate consists of two or more than two of the dual-drug targeting linker-drug conjugate molecules shown in formula IIc in claim 13, and the DAR value of the dual-drug targeting linker-drug conjugate is 4.00-5.00, preferably 4.38;
or, the double-drug targeting linker-drug conjugate consists of two or more than two of the molecules of the double-drug targeting linker-drug conjugate shown in formula IId in claim 13, and the DAR value of the double-drug targeting linker-drug conjugate is 1.50-2.50, preferably 1.99;
or, the double-drug targeting linker-drug conjugate is composed of two or more than two of the molecules of the double-drug targeting linker-drug conjugate shown in formula IIe in claim 13, and the DAR value of the double-drug targeting linker-drug conjugate is 3.00-4.00, preferably 3.35;
or, the double-drug targeting linker-drug conjugate consists of two or more than two of the molecules of the double-drug targeting linker-drug conjugate shown in formula IIf in claim 13, and the DAR value of the double-drug targeting linker-drug conjugate is 2.00-3.00, preferably 2.31;
or, the double-drug targeting linker-drug conjugate is composed of two or more than two of the molecules of the double-drug targeting linker-drug conjugate shown in formula IIg in claim 13, and the DAR value of the double-drug targeting linker-drug conjugate is 3.00-4.00, preferably 3.47;
or, the dual-drug targeting linker-drug conjugate consists of two or more than two of the dual-drug targeting linker-drug conjugate molecules shown in formula II SMP-52581 in claim 13, and the DAR value of the dual-drug targeting linker-drug conjugate is 1.50-2.50, preferably 1.93;
or, the dual-drug targeting linker-drug conjugate consists of two or more than two of the dual-drug targeting linker-drug conjugate molecules shown in formula II SMP-96745 in claim 13, and the DAR value of the dual-drug targeting linker-drug conjugate is 4.00-5.00, preferably 4.27;
or, the dual-drug targeting linker-drug conjugate consists of two or more than two of the dual-drug targeting linker-drug conjugate molecules shown in formula II SMP-39545 in claim 13, and the DAR value of the dual-drug targeting linker-drug conjugate is 5.00-6.00, preferably 5.24;
or, the dual-drug targeting linker-drug conjugate consists of two or more than two of the dual-drug targeting linker-drug conjugate molecules shown in formula II SMP-93954 in claim 13, and the DAR value of the dual-drug targeting linker-drug conjugate is 4.00-5.00, preferably 4.32;
or, the dual-drug targeting linker-drug conjugate consists of two or more than two of the dual-drug targeting linker-drug conjugate molecules shown in formula II SMP-11115 in claim 13, and the DAR value of the dual-drug targeting linker-drug conjugate is 7.00-8.00, preferably 7.71;
or, the dual-drug targeting linker-drug conjugate consists of two or more than two of the dual-drug targeting linker-drug conjugate molecules shown in formula II SMP-04404 in claim 13, and the DAR value of the dual-drug targeting linker-drug conjugate is 4.00-5.00, preferably 4.67;
or, the dual-drug targeting linker-drug conjugate consists of two or more than two of the dual-drug targeting linker-drug conjugate molecules shown in formula II SMP-37241 in claim 13, and the DAR value of the dual-drug targeting linker-drug conjugate is 6.00-7.00, preferably 6.39;
or, the dual-drug targeting linker-drug conjugate consists of two or more than two of the dual-drug targeting linker-drug conjugate molecules shown in formula II SMP13432 in claim 13, and the DAR value of the dual-drug targeting linker-drug conjugate is 4.00-5.00, preferably 4.26;
or, the dual-drug targeting linker-drug conjugate consists of two or more than two of the dual-drug targeting linker-drug conjugate molecules shown in formula II SMP-84984 in claim 13, and the DAR value of the dual-drug targeting linker-drug conjugate is 5.00-6.00, preferably 5.69;
or, the dual-drug targeting linker-drug conjugate consists of two or more than two of the dual-drug targeting linker-drug conjugate molecules shown in formula II SMP-04140 in claim 13, and the DAR value of the dual-drug targeting linker-drug conjugate is 2.00-3.00, preferably 2.47;
or, the dual-drug targeting linker-drug conjugate consists of two or more than two molecules of the dual-drug targeting linker-drug conjugate shown in formula II SMP-76794 in claim 13, and the DAR value of the dual-drug targeting linker-drug conjugate is 2.00-3.00, preferably 2.58;
or, the dual-drug targeting linker-drug conjugate consists of two or more than two of the dual-drug targeting linker-drug conjugate molecules shown in formula II SMP-99767 in claim 13, and the DAR value of the dual-drug targeting linker-drug conjugate is 6.50-7.50, preferably 7.14;
or, the dual-drug targeting linker-drug conjugate consists of two or more than two of the dual-drug targeting linker-drug conjugate molecules shown in formula II SMP-86145 in claim 13, and the DAR value of the dual-drug targeting linker-drug conjugate is 6.00-7.00, preferably 6.45;
or, the dual-drug targeting linker-drug conjugate consists of two or more than two of the dual-drug targeting linker-drug conjugate molecules shown in formula II SMP-54418 in claim 13, and the DAR value of the dual-drug targeting linker-drug conjugate is 7.00-8.00, preferably 7.26;
or, the dual-drug targeting linker-drug conjugate is composed of two or more than two of the dual-drug targeting linker-drug conjugate molecules shown in formula II SMP-44708 in claim 13, and the DAR value of the dual-drug targeting linker-drug conjugate is 1.50-2.50, preferably 2.07.
16. The dual-drug targeting linker-drug conjugate molecule of any one of claims 11 to 13, or the method of preparing the dual-drug targeting linker-drug conjugate of any one of claims 14 to 15, wherein: the method comprises the following steps: coupling the targeting joint with the double-drug linkage assembly unit, and purifying to obtain the target; preferably, the purification means is dialysis.
17. A medicament for preventing and/or treating tumors, which is characterized in that: the double-drug targeting linker-drug conjugate molecule, or a stereoisomer or an optical isomer thereof according to any one of claims 11 to 13, or the double-drug targeting linker-drug conjugate, or a stereoisomer or an optical isomer thereof according to any one of claims 14 to 15 is used as an active ingredient, and is added with pharmaceutically acceptable auxiliary materials to prepare the preparation.
18. Use of the dual-drug targeting linker-drug conjugate molecule of any one of claims 11 to 13, or a stereoisomer or an optical isomer thereof, or the dual-drug targeting linker-drug conjugate of any one of claims 14 to 15, or a stereoisomer or an optical isomer thereof, for the preparation of a medicament for the prevention and/or treatment of a tumor.
19. Use according to claim 18, characterized in that: the tumor is selected from lung cancer, urethra cancer, carcinoma of large intestine, adenocarcinoma of prostate, ovarian cancer, pancreatic cancer, breast cancer, bladder cancer, gastric cancer, gastrointestinal stromal tumor, cervical cancer, esophageal cancer, squamous cell carcinoma, cancer of peritoneum, liver cancer, colon cancer, rectal cancer, colorectal cancer, uterine cancer, salivary gland carcinoma, renal cancer, vulval cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma or sarcoma.
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