Linker-bioactive molecule conjugate and pharmaceutical use thereof

Abstract

A linker-bioactive molecule conjugate and the pharmaceutical use thereof, and specifically provided are compounds of general formulas (I) and (III) or a stereoisomer, racemate, tautomer or pharmaceutically acceptable salt thereof, and an intermediate thereof and a preparation method therefor, and the use thereof in the preparation of a drug for treating tumors or cancer diseases. L-L0-L1-L2-(L3)p1-(L4)p2-L5-D (I) Tb-[L'-D]q (III).

Description

A connector-bioactive molecular conjugate and its application in medicine Technical Field

[0001] This invention relates to a compound of general formula (I) or its stereoisomers, racemates, tautomers, pharmaceutically acceptable salts, intermediates and preparation methods thereof, and its use in the preparation of medicaments for treating tumors or cancer. Background Technology

[0002] Antibodies can be linked to bioactive molecules to form antibody-drug conjugates (ADCs). ADCs combine the targeting ability of antibodies with the activity of bioactive molecules, fully utilizing the specificity of antibodies in binding to antigens on the surface of normal and tumor cells and the high efficiency of cytotoxic substances, thus exhibiting anti-tumor effects and becoming a kind of "biological missile".

[0003] Among currently marketed and clinically investigated antibody-drug conjugates (ADCs), thiol-maleimide conjugation is a widely used core technology. Its advantages of mild reaction conditions and high yield effectively improve the product quality uniformity problem caused by traditional conjugation methods—of the 15 commercially available ADCs containing potent and toxic payloads globally, 10 and most clinical-stage ADCs utilize this conjugation technology. However, this technology has a key drawback: the addition reaction between maleimide and thiol exhibits reversible reverse Michael addition. When the ADC enters the bloodstream, proteins rich in free thiol groups (such as albumin) can exchange thiol groups with the conjugation product, causing premature detachment of the drug payload. This phenomenon not only leads to off-target toxicity due to the non-targeted distribution of free drug molecules but also directly weakens the targeted therapeutic effect of the ADC, ultimately resulting in the current widespread problems of poor plasma stability and limited efficacy and safety for marketed ADCs. ADCs with poor water solubility are prone to degradation due to aggregation (such as protein denaturation and payload shedding), shortening product shelf life. Good water solubility can maintain the molecular conformational stability of ADCs during storage and transportation, reducing the risk of degradation, extending shelf life, and reducing drug waste. Therefore, developing novel linkers with no reverse Michael addition effect, better plasma stability, and better water solubility, or innovative conjugation strategies that can reduce the toxicity and enhance the efficacy of ADCs, has become a key direction that urgently needs breakthroughs in the current ADC field. Summary of the Invention

[0004] The purpose of this invention is, on the one hand, to provide a new linker with better plasma stability and better water solubility after conjugation with an antibody, and on the other hand, to provide a linker-drug conjugate or its stereoisomers, racemates, tautomers, pharmaceutically acceptable salts, intermediates and preparation methods thereof, as well as its application in the preparation of drugs for treating tumors or cancer.

[0005] The linker-drug conjugates and their antibody conjugates of the present invention have one or more effects selected from the group consisting of: (1) having inhibitory activity against the in vitro proliferation of tumor cells; (2) having plasma stability; (3) having in vivo tumor-suppressing effects; (4) having in vivo tumor-targeting capabilities; and (5) having good in vivo safety.

[0006] This invention provides a compound of general formula (I) or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, wherein,

[0007] L-L0-L1-L2-(L3) p1 -(L4) p2 -L5-D(I)

[0008] In some implementations, L is a leaving group that reacts with the target portion;

[0009] In some embodiments, L is selected from halogen, sulfone, or tertiary amine salt (Me3N). + Et3N + ), diazonium salts, -OMs, MeSO2-, CF3SO3-, p-toluenesulfonyl groups;

[0010] In some implementations, L0 is a connector unit, which is selected from... Its left end is connected to L; in some implementations, L0 is selected from... Its left end is connected to L;

[0011] In some implementations, L1 is selected from Its right side connects to L2;

[0012] In some implementations, L1 is selected from Its right side connects to L2;

[0013] In some implementations, m1 is selected from integers 1-12; m3 is selected from 1, 2, 3, 4, 5; m4 is selected from integers 1-12; and m5 is selected from 0, 1, 2, 3, 4, 5.

[0014] In some implementations, G1 is selected from -C(=O)-NH2, -C(=O)-OH, -P(=O)(OH)2,

[0015] In some implementations, L1 is selected from Its right side connects to L2;

[0016] In some implementations, L1 is selected from Its right side is connected to L2; m1 is selected from integers from 2 to 10; m4 is selected from integers from 1 to 10; m5 is selected from 0, 1, 2, 3; in some implementations, m5 is selected from 1, 2;

[0017] In some implementation schemes, m4 is selected from 4, 5, 6, 7, 8; m1 is selected from 3, 4, 5, 6, 7, 8, 9;

[0018] In some implementations, L2 is selected from -Z1-Z2-; in some implementations, L2 is selected from bond or -C(=O)-;

[0019] In some implementations, L2 is selected from key, -Z1-Z2-, -Z1-, -Z2-; in some implementations, Z1 is selected from key, -C 1-6 alkylene-, -C 2-6 -, -C ethynyl 2-6 alkenyl-, wherein the Z1 is optionally divided by 1 to 4 R s Replaced; in some implementations, -L1-L2- is selected from Its right side connects to L3;

[0020] In some implementations, Z1 is selected from -C 1-4 alkylene-, -C 2-4 -, -C ethynyl 2-4 alkenyl-, wherein the Z1 is optionally divided by 1 to 4 R s Replaced;

[0021] In some implementations, Z1 is selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -C≡C-, -C≡C-CH2CH2-, wherein Z1 is optionally divided by 1 to 2 R s Replaced;

[0022] In some implementations, M1 is selected from -O-, -C(=O)-, -NH-, -NH-S(=O)2-NH-, -C 0-4 alkylene-4-8-membered heterocyclic group-, wherein the alkylene group or heterocyclic group is optionally surrounded by 1 to 4 R groups. s Replaced;

[0023] In some implementations, M1 is selected from -O-, -C(=O)-, -NH-, -NH-S(=O)2-NH-, -C 0-2alkylene-5-6-membered nitrogen-containing heteroaryl-, wherein the alkylene or heterocyclic group is optionally surrounded by 1 to 4 R- groups. s Replaced;

[0024] In some embodiments, M1 is selected from -O-, -C(=O)-, -NH-, triazole, and pyrazolyl, wherein the triazole or pyrazolyl group is optionally surrounded by 1 to 4 R groups. s Replaced;

[0025] In some implementations, M2 is selected from -C(=O)-, -C 1-4 Alkylene -C(=O)-, -C 1-4 Alkylene -NH-C(=O)-, -C 1-4 Alkylene-NH-C(=O)-C 1-4 Alkylene -C(=O)-, -C 1-4 Alkylene-NH-C(=O)-C 1-4 Alkylene-OC 1-4 Alkylene-C(=O)-, wherein the alkylene is optionally surrounded by 1 to 4 R- atoms. s Replaced;

[0026] In some embodiments, M2 is selected from -C(=O)-, -CH2-C(=O)-, -CH2CH2-C(=O)-, -CH2CH2-NH-C(=O)CH2-C(=O)-, -CH2CH2-NH-C(=O)CH2OCH2-C(=O)-, wherein the CH2 is optionally surrounded by 1 to 2 R s Replaced;

[0027] In some implementations, M3 is selected from -O-, -S-, and -CR. m1 R m2 -、-NR m3 -;

[0028] In some implementations, M3 is selected from -O-, -CR m1 R m2 -、-NR m3 -; M3 is preferably selected from -CH2-, -O-, and -NH-;

[0029] In some implementations, Z2 is selected from bond, -C (=O)-, -M4-C 0-6 Alkylene -C(=O)-, -M3-C 1-6 Alkylene-M4-, wherein the alkylene is optionally surrounded by 1 to 4 R... s Replaced;

[0030] In some implementations, Z2 is selected from -C(=O)-, -M4-C 0-4 Alkylene -C(=O)-, -M3-C1-4 Alkylene-M4-, wherein the alkylene is optionally surrounded by 1 to 4 R... s Replaced;

[0031] In some embodiments, Z2 is selected from -C(=O)-, -NH-C(=O)-, -O-CH2-C(=O)-, -NH-CH2-C(=O)-, -NHC(=O)-CH2CH2CH2CH2-C(=O)-, -NH-CH2CH2CH2CH2-NH-, -NH-CH2CH2-NH-, -NH-CH2-NH-, and -NH-CH2-NH-, wherein the CH2 is optionally surrounded by 1 to 2 R-molecules. s Replaced;

[0032] In some implementations, M4 is selected from -O-, -S-, and -NR. m4 -; M4 is preferentially selected from -NH-;

[0033] In some implementations, L2 is selected from key, -C (=O)-,

[0034] In some implementations, s2 is selected from integers from 2 to 12; in some implementations, s2 is selected from 2, 3, 4, 5, 6, 7; in some implementations, s2 is selected from 3, 5, 7, 9.

[0035] In some implementation schemes, s3 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8;

[0036] In some implementations, s3 is selected from 0, 1, and 2;

[0037] In some embodiments, L3 is selected from amino acids, peptides consisting of 2-5 amino acids, preferably dipeptides, tripeptides or tetrapeptides;

[0038] In some embodiments, the amino acid is selected from amino acid AA or amino acid AA1; wherein the N-terminus of the amino acid is connected to L2 and the C-terminus is connected to L5.

[0039] In some implementation schemes, the amino acids A and B are each independently selected from valine, glycine, alanine, glutamic acid, phenylalanine, lysine, citrulline, serine, glutamic acid, and aspartic acid.

[0040] In some implementations, amino acid AA1 is selected from...

[0041] In some embodiments, L3 is selected from -AA-, -AA1-, -AA-AA-, -AA-AA-AA-, -AA-AA-AA-AA-, -AA-AA1-, -AA1-AA-, -AA-AA1-AA-, -AA-AA-AA1-, -AA1-AA-AA-AA-, -AA1-AA-AA-AA-AA-;

[0042] In some embodiments, L3 is selected from -Val-Gly-, -Val-Cit-, -Phe-Lys-Gly-, -Gly-Val-Lys-Gly-, -Val-Lys-Gly-Gly-, -Val-Lys-Gly-, -Val-Lys-Ala-, -Gly-Gly-Phe-Gly-, -Val-AA1 -, -Val-AA1-Val-, -Val-AA1-Gly-, -AA1-AA1-, -AA1-AA1-Gly-, -AA1-Val-Cit-, -Val-Ala-, -Ala-Ala-, -Ala-Ala-Ala-, AA1-Gly-Gly-Phe-Gly-, -AA1-Val-Ala-;

[0043] In some implementation schemes, R L0 Each element is independently selected from H, deuterium, and C. 1-6 Alkyl, C 3-8 cycloalkyl, 4-8 membered heterocyclic groups The alkyl, cycloalkyl, or heterocyclic groups are optionally surrounded by 1 to 4 R groups. s Replaced;

[0044] In some implementation schemes, R L0 Each element is independently selected from H, deuterium, and C. 1-4 Alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclic groups The alkyl, cycloalkyl, or heterocyclic group is optionally surrounded by 1 to 4 R groups. s Replaced;

[0045] In some implementations, HG is selected from

[0046] In some implementation schemes, R L0 Each is independently selected from H, deuterium, methyl, ethyl, propyl, isopropyl, The methyl, ethyl, propyl, and isopropyl groups are optionally surrounded by 1 to 4 R groups. s Replaced;

[0047] In some implementation schemes, R L0 Each independently selected

[0048] In some implementation schemes, s5 and s6 are each independently selected from 0, 1, 2, 3, 4, 5, or 6;

[0049] In some implementation schemes, s5 is independently selected from 0, 1, 2, 3, and 4;

[0050] In some implementations, two R L0 Direct connection forms C 3-6 Cycloalkyl or 4-6 membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. s Replaced;

[0051] In some implementations, two R L0 Direct connection forms C 3-8 cycloalkyl or 4-8 membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. s Replaced;

[0052] In some implementations, two R L0 Direct linkage to form cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups, wherein the cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups are optionally bounded by 1 to 4 R groups. s Replaced;

[0053] In some implementation schemes, R L1 R L2 Each element is independently selected from H, deuterium, and C. 1-4 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. s Replaced;

[0054] In some implementation schemes, R L1 R L2 Each is independently selected from H, deuterium, methyl, ethyl, propyl, and isopropyl, wherein the methyl, ethyl, propyl, and isopropyl groups are optionally surrounded by 1 to 4 R groups. s Replaced;

[0055] In some implementation schemes, R L1 R L2 The nitrogen atom attached to it forms a 4-8 membered heterocyclic group, which is optionally surrounded by 1 to 4 R atoms. s Replaced;

[0056] In some implementation schemes, R L1 R L2 The nitrogen atom attached to it forms a 4-7 membered heterocyclic group, which is optionally surrounded by 1 to 4 R atoms. s Replaced;

[0057] In some implementation schemes, R L1 R L2 The nitrogen atom attached thereto forms an azircyclic butyl group, a pyrrolidinyl group, a piperidinyl group, or a piperazine group, wherein the azircyclic butyl group, a pyrrolidinyl group, a piperidinyl group, or a piperazine group is optionally surrounded by 1 to 4 R atoms. s Replaced;

[0058] In some implementations, AA1 is selected from

[0059] In some implementations, AA1 is selected from

[0060] In some implementations, L4 is selected from Its right side connects to L5;

[0061] In some implementations, X is selected from -CH-, -CR L3 -、-N-;

[0062] In some implementations, X is preferably derived from -CH- or -N-;

[0063] In some implementations, Y1 is selected from -N(R L5 -, -C(=O)-; In some implementations, Y1 is selected from -NH-, -C(=O)-;

[0064] In some implementations, Y2 is selected from -N(R L5 )-、-N(R L5 )-C 1-6 alkylene-5-6-membered nitrogen-containing heteroaryl-,-N(R) L5 )-C 1-4 Alkylene-N(R) L5 )-, wherein the alkylene or heteroaryl group is optionally surrounded by 1 to 4 R s Replaced;

[0065] In some implementations, Y2 is selected from -N(R L5 )-、-N(R L5 )-C 1-4 alkylene-5-6-membered nitrogen-containing heteroaryl-,-N(R) L5 )-C 1-2 Alkylene-N(R) L5 )-, wherein the alkylene or heteroaryl group is optionally surrounded by 1 to 4 R s Replaced;

[0066] In some implementations, Y2 is selected from -N(R L5)-、-N(R L5 )-Ethylene-triazolyl-,-N(R L5 )-methylene-triazolyl-,-N(R L5 )-Ethylene-N(R L5 The methylene, ethylene, and triazolyl groups are optionally surrounded by 1 to 4 R groups. s Replaced;

[0067] In some implementations, Y3 is selected from

[0068] In some implementations, Y3 is selected from

[0069] In some implementation schemes, R L8 Each component is independently selected from the amino acid side chain, H, C 1-6 Alkyl-C 1-4 Alkylene C 6-10 Aryl, -C 1-4 alkylene 4-10-membered heterocyclic groups, wherein R L8 Choose from 1 to 4 Rs s Replaced;

[0070] In some implementation schemes, R L8 Each component is independently selected from the amino acid side chain, H, C 1-4 Alkyl, -C 1-4 alkylenephenyl, -C 1-4 alkylene 4-6 membered heterocyclic groups, -C 1-4 alkylene 8-10-membered heteroaryl, wherein R L8 Choose from 1 to 4 Rs s Replaced;

[0071] In some implementation schemes, R L8 Each of the following is independently selected from -CH2CH2CH2-NH-C(=NH)-NH2, -CH2CH2CH2-NH-C(=O)-NH2, -CH2C(=O)OH, -CH2C(=O)NH2, -CH2CH2C(=O)OH, -CH2CH2C(=O)NH2, -CH2SH, -CH2CH2SCH3, H, methyl, ethyl, isopropyl, butyl, -CH2-imidazolyl, -CH2-phenyl, -CH2-indoleyl, wherein R L8 Choose from 1 to 4 Rs s Replaced;

[0072] In some implementation schemes, R L8Each is independently selected from -CH2CH2CH2-NH-C(=NH)-NH2, -CH2CH2CH2-NH-C(=O)-NH2, -CH2C(=O)OH, -CH2C(=O)NH2, -CH2CH2C(=O)OH, -CH2CH2C(=O)NH2, -CH2SH, -CH2CH2SCH3, H, methyl, ethyl, isopropyl, -CH2CH2CH2CH2NH2, -CH2NH2, -CH2OH, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2-imidazolyl, -CH2-phenyl, -CH2-indoleyl;

[0073] In some implementation schemes, R L8 Each is independently selected from α-amino acids, alanine, and valine residues;

[0074] In some implementations, m2 is selected from 2, 3, 4, and 5; in other implementations, m2 is selected from 2 and 3.

[0075] In some implementations, Y4 is selected from -C(=O)-C 1-6 alkyl, The Y4 is arbitrarily divided by 1 to 4 Rs s Replaced;

[0076] In some implementations, Y4 is selected from -C(=O)-C 1-4 alkyl, The Y4 is arbitrarily divided by 1 to 4 Rs s Replaced; in some embodiments, s7 is selected from integers from 1 to 10; in some embodiments, s7 is selected from integers from 1 to 8;

[0077] In some embodiments, Y4 is selected from -C(=O)-methyl, -C(=O)-ethyl, -C(=O)-propyl, -C(=O)-isopropyl, The Y4 is arbitrarily divided by 1 to 2 Rs s Replaced;

[0078] In some implementations, L4 is selected from Its right side connects to L5;

[0079] In some implementations, L5 is selected from spacer units;

[0080] In some implementations, L5 is selected from -Z3-Z4-, and Z3 and Z4 are not both selected from the key;

[0081] In some implementations, L5 is selected from -Z3-Z4-, -Z3-, and -Z4-.

[0082] In some implementations, Z3 is selected from key, Its right side is connected to Z4;

[0083] In some implementations, Z3 is selected from key, Its right side is connected to Z4;

[0084] In some implementations, s1 is selected from 0, 1, 2, 3 or 4;

[0085] In some implementations, s1 is selected from 0, 1, and 2;

[0086] In some implementations, Z4 is selected from the bond, -N(R L5 )-C(R L6 )2-、-OC(R L6 )2-、-M4-C 0-4 Alkylene -C(=O)-, -N(R) L5 )-C 1-4 Alkylene-N(R) L7 )-C(=O)-, wherein the alkylene group is optionally surrounded by 1 to 4 R s It is replaced, and its right side is connected to D;

[0087] In some implementations, Z4 is selected from -N(R L5 )-C(R L6 )2-、-OC(R L6 )2-, -OC(=O)-, -O-CH2CH2-C(=O)-, -N(R L5 )-CH2CH2-N(R L7 )-C(=O)-, its right side is connected to D;

[0088] In some implementations, Z4 is selected from Its right side is connected to D;

[0089] In some implementations, L5 is selected from Its right side is connected to D;

[0090] In some implementation schemes, R L R m1 R m2 R m3 R m4 Each element is independently selected from H, deuterium, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 7-membered heterocyclic groups, wherein the alkyl group, C2-4 alkenyl, C 2-4 Alkyne, cycloalkyl, or heterocyclic groups are optionally surrounded by 1 to 4 R groups. s Replaced;

[0091] In some implementation schemes, R L R m1 R m2 R m3 R m4 Each of the following is independently selected from H, deuterium, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, and cyclobutyl groups are optionally separated by 1 to 4 R groups. s Replaced;

[0092] In some implementation schemes, R L R m1 R m2 R m3 Each is independently selected from H, deuterium, methyl, ethyl, propyl, isopropyl, and cyclopropyl, wherein the methyl, ethyl, propyl, isopropyl, and cyclopropyl groups are optionally surrounded by 1 to 4 R groups. s Replaced;

[0093] In some implementation schemes, R L3 R L4 Each element is independently selected from deuterium, halogens, OH, NH2, CN, NO2, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl or 4-8 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. s Replaced;

[0094] In some implementation schemes, R L3 R L4 Each of the following is independently selected from deuterium, F, Cl, Br, OH, NH2, CN, NO2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl groups are optionally prefixed with 1 to 4 R groups. s Replaced;

[0095] In some implementation schemes, R L3 R L4 Each of the following is independently selected from deuterium, F, Cl, Br, OH, NH2, CN, NO2, methyl, ethyl, isopropyl, methoxy, and cyclopropyl, wherein the methyl, ethyl, isopropyl, methoxy, and cyclopropyl groups are optionally prefixed with 1 to 4 R groups. s Replaced;

[0096] In some implementation schemes, RL6 Each of the following is independently selected from H, deuterium, F, Cl, Br, OH, NH2, CN, NO2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl groups are optionally prefixed with 1 to 4 R groups. s Replaced;

[0097] In some implementation schemes, R L6 Each is independently selected from H, deuterium, F, Cl, Br, OH, NH2, CN, NO2, methyl, ethyl, propyl, isopropyl, CHF2, CH2F, CF3, CD3, OCF3, OCD3, methoxy, ethoxy, and cyclopropyl.

[0098] In some implementation schemes, R L5 Each independently selected from H and C 1-4 Alkyl, C 3-8 Cycloalkyl or 4-8 membered heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. s Replaced;

[0099] In some implementation schemes, R L5 Each is independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, and cyclobutyl groups are optionally prefixed with 1 to 4 R groups. s Replaced;

[0100] In some implementation schemes, R L5 and R L6 Two Rs L6 The atoms bonded to it together form C 3-6 Cycloalkyl or 4-6 membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. s Replaced;

[0101] In some implementation schemes, R L5 and R L6 Two Rs L6 The atoms bonded to it are directly connected to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolyl, piperidinyl, and piperazine, wherein the aziridine, pyrrolyl, piperidinyl, and piperazine groups are optionally surrounded by 1 to 4 R atoms. s Replaced;

[0102] In some implementation schemes, R L7 Each independently selected from H and C 1-4 Alkyl, -C1-4 Alkylene-S(=O)2-C 1-4 Alkyl, C 3-8 Cycloalkyl or 4-8 membered heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. s Replaced;

[0103] In some implementation schemes, R L7 Each is independently selected from H, methyl, ethyl, propyl, isopropyl, -methylene-S(=O)2-methyl, -ethylidene-S(=O)2-C 1-2 Ethyl, -propylidene-S(=O)2-methyl, cyclopropyl, cyclobutyl, wherein the methyl, ethyl, propyl, isopropyl, methylene, ethylidene, propylidene, cyclopropyl, or cyclobutyl is optionally surrounded by 1 to 4 R... s Replaced;

[0104] In some implementation schemes, p1 and p2 are each independently selected from 0 and 1, respectively, and p1 + p2 = 1;

[0105] In some implementation schemes, R s Each element is independently selected from deuterium, halogens, OH, NH2, CN, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 acetylinyl, OC 1-4 Alkyl, SC 1-4 Alkyl, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, wherein the alkyl, alkenyl, or alkynyl groups are optionally substituted with 1 to 4 substituents of deuterium, halogen, OH, NH2, or CN;

[0106] In some implementation schemes, R s Each element is independently selected from deuterium, halogens, OH, NH2, CN, and C. 1-2 Alkyl, C 2-3 alkenyl, C 2-3 acetylinyl, OC 1-2 Alkyl, SC 1-2 Alkyl, NHC 1-2 Alkyl, N(C) 1-2 Alkyl)2, wherein the alkyl, alkenyl, or alkynyl groups are optionally substituted with 1 to 4 substituents of deuterium, F, Cl, Br, OH, NH2, or CN;

[0107] In some implementation schemes, R s Each is independently selected from deuterium, F, Cl, Br, OH, NH2, CN, CHF2, CH2F, CF3, CD3, OCF3, OCD3, methyl, methoxy, methylthio, and ethoxy.

[0108] In some implementations, -L2-(L3) p1 -(L4) p2 -L5- is selected from -Z1-Z2-L3-Z3-Z4-, -Z1-Z2-L3-Z4-, -Z1-L3-Z3-Z4-, -Z1-L3-Z4-, -Z1-L3-Z3-Z4-, -Z1-L3-Z4-, -Z1-L3-Z4-, -Z1-Z2-L4-Z3-Z4-, -Z1-Z2-L4-Z4-, -Z1-L4-Z3-Z4-, -Z1-L4-Z4-, -Z1-L4-Z4-, -L3-L5-, -L4-L5-, -Z2-L3-L5-, -Z2-L3-Z4-, -Z2-L4-L5-, and its right side is connected to D;

[0109] In some implementations, -(L3) p1 -(L4) p2 -L5- Selected from Its right side is connected to D;

[0110] In some implementations, -L2-(L3) p1 -(L4) p2 -L5- Selected from Its right side is connected to D;

[0111] In some embodiments, D is selected from bioactive molecular fragments, preferably from auristatin derivatives, maystasionoids derivatives, DNA destroyers, amanitins, topoisomerase inhibitors, camptothecin derivatives, selective or non-selective kinase inhibitors, Bcl-xl inhibitors and Bcl-2 / Bcl-xl inhibitors, and protein degraders.

[0112] In some implementations, D is selected from oxaliplatin, bleomycin or bleomycin, camptothecin, hydroxycamptothecin, 9-aminocamptothecin, SN-38, irinotecan, ixotecan, topotecan, belotetan or rubotecan, actinomycin D, doxorubicin, docalimicin, daunorubicin, mitoxantrone, podophyllotoxin or etoposide, methotrexate, 5-fluorouracil, cytarabine, gemcitabine, mercaptopurine, pentostatin, fludarabine, cladribine or nerabine, vinca alkaloids, vincristine, vinca alkaloids, paclitaxel, docetaxel or cabazitaxel, serine / threonine kinase inhibitors, tyrosine kinase inhibitors, aspartate kinase inhibitors or histidine kinase inhibitors;

[0113] In some implementations, D is selected from one of the following structures: Indicates an optional connection position, when connected to a certain position of D. When connecting, another location For H;

[0114] In some implementation schemes, R 3 Selected from C 1-6 Alkyl, -C 1-6 Alkylene-NR 3a -S(=O)2C 1-6 Alkyl, -C 1-6 Alkylene-NR 3a -C(=O)C 1-6 Alkyl, wherein the alkylene or alkyl group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0115] In some implementation schemes, R 3 Selected from methyl, ethyl, propyl, isopropyl, -ethylidene-N(R) 3a )-S(=O)2methyl, -ethylidene-N(R 3a )-C(=O)methyl, wherein the methyl, ethyl, ethylidene, propyl, and isopropyl groups are optionally surrounded by 1 to 4 R groups. k Replaced;

[0116] In some implementation schemes, R 3a Selected from H, C 1-6 Alkyl groups, wherein the alkyl group is optionally composed of 1 to 4 elements selected from deuterium, halogens, CN, OH, NH2, C. 1-6 Alkyl, C 1-6 The alkoxy group is substituted; in some embodiments, R 3a The group is selected from H, methyl, ethyl, and isopropyl, wherein the methyl, ethyl, and isopropyl groups are optionally replaced by 1 to 4 groups selected from deuterium, F, Cl, Br, CN, OH, NH2, and methyl.

[0117] In some implementation schemes, R 4 Selected from R 2a Its left end is connected to NH; in some implementations, R 4 Selected from -C(=O)CH2O-, -C(=O)C(R) 2b )2NH-, -C(=O)C(H)(D)O-, -C(=O)CD2O-, -C(=O)CH(R 2b )O-、-C(=O)C(CH3)(R 2b )O-、 Its left end is connected to NH;

[0118] In some implementation schemes, R 5 Selected from S or O;

[0119] In some implementation schemes, R 6 Selected from -C 1-6 alkylene-, -C 3-6 Cycloalkylene-, wherein the alkylene or cycloalkylene group is optionally surrounded by 1 to 6 R groups. k Replaced;

[0120] In some implementation schemes, R 6 Selected from methylene-, ethylene-, propylene-, cyclopropylene, and cyclobutylene, wherein the methylene, ethylene, propylene, cyclopropylene, and cyclobutylene are optionally surrounded by 1 to 4 R groups. k Replaced; in some implementations, R 6 The derivative is selected from -methylene-, -ethylene-, and -propylene-, wherein the methylene-, -ethylene-, and -propylene- are optionally substituted by 1 to 4 derivatives selected from deuterium, F, Cl, Br, CN, OH, NH2, methyl, and methoxy.

[0121] In some implementation schemes, R 7 Selected from OH, -C(=O)OH; in some embodiments, D is selected from one of the structures shown in Table A-1 and Table A-4;

[0122] In some implementations, D is selected from

[0123] In some implementations, ring B is selected from one of the following structures that can be optionally substituted: When replaced, by 1 to 4 R b It has been replaced, and its left side is directly connected to X1;

[0124] In some implementations, ring B is selected from 1 to 3 Rs. b One of the following structures is replaced: Its left side is connected to X1;

[0125] In some implementations, D1 and D2 are each independently selected from O, S, NH, or NR. b In some implementation schemes, D1 and D2 are each independently selected from O, S, and NH.

[0126] In some implementations, D3 and D4 are each independently selected from O, S, N, NH, or NR. bIn some implementations, one of D3 and D4 is selected from N, and the other is selected from O, S, NH, or NR. b ;

[0127] In some implementation schemes, E2, E3, E4, and E5 are each independently selected from CR. b CH or N; in some implementations, one of E2, E3, E4, and E5 is selected from N, and the other three are each independently selected from CR. b CH; In some implementations, two of E2, E3, E4, and E5 are selected from N, and the remaining two are each independently selected from CR. b CH; In some implementations, E2, E3, E4, and E5 are each independently selected from CR. b CH; In some implementation schemes, E2, E3, E4, and E5 are each independently selected from CH;

[0128] In some implementations, E1 is selected from C(R) b 2. CHR b ,CH2,C(=O),CH2CH2,CHR b CHR b , In some implementations, E1 is selected from C(R) b 2. CHR b CH2, C (=O); in some implementations, E1 is selected from CH2, C (CH3), C (=O);

[0129] In some implementation schemes, R b Each element is independently selected from deuterium, halogen, OH, cyano, NH2, NO2, N(C) 1-6 Alkyl)2, NH(C) 1-6 Alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, -C(=O)R 1a -S(=O)2R 1a -P(=O)R 1a R 1b C 3-10 Carbocyclic groups, 4- to 10-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally selected from 1 to 4 R k Replaced;

[0130] In some implementation schemes, R bEach element is independently selected from deuterium, halogen, OH, cyano, NH2, NO2, N(C) 1-4 Alkyl)2, NH(C) 1-4 Alkyl), C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, -C(=O)R 1a -S(=O)2R 1a -P(=O)R 1a R 1b C 3-6 Carbocyclic groups, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0131] In some implementation schemes, R b Each element is independently selected from deuterium, halogen, OH, cyano, NH2, NO2, N(C) 1-4 Alkyl)2, NH(C) 1-4 Alkyl), C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, -C(=O)R 1a -S(=O)2R 1a -P(=O)R 1a R 1b C 3-6 Carbocyclic groups, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0132] In some implementation schemes, R bEach of the following groups is independently selected from deuterium, F, Cl, Br, I, OH, cyano, NH2, NO2, NHCH3, N(CH3)2, COOH, CONH2, -C(=O)-methyl, -C(=O)-ethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole, or thiophene, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole, or thiophene is optionally surrounded by 1 to 4 R groups. k Replaced;

[0133] In some implementation schemes, R 1 Each element is independently selected from H, deuterium, and C. 1-6 Alkyl, -C(=O)R 1a -S(=O)2R 1a -P(=O)R 1a R 1b C 3-8 A carbocyclic or 3- to 10-membered heterocyclic group, wherein the alkyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0134] In some implementation schemes, R 1 Each element is independently selected from H, deuterium, and C. 1-6 Alkyl, C 3-8 A carbocyclic or 3- to 10-membered heterocyclic group, wherein the alkyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0135] In some implementation schemes, R 1 Each element is independently selected from H, deuterium, and C. 1-4 Alkyl, -C(=O)R 1a -S(=O)2R 1a -P(=O)R 1a R 1b C 3-6 A carbocyclic or 3- to 8-membered heterocyclic group, wherein the alkyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0136] In some implementation schemes, R 1 Each is independently selected from H, deuterium, methyl, ethyl, propyl, isopropyl, -C(=O)R 1a -S(=O)2R 1a -P(=O)R1a R 1b Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxetidine, pyrrolidinyl, piperidinyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxetidine, pyrrolidinyl, piperidinyl, or morpholinyl group is optionally surrounded by 1 to 4 R groups. k Replaced; in some implementations, R 1 Selected from H;

[0137] In some implementation schemes, R 1a R 1b Each element is independently selected from H, OH, NH2, and C. 1-6 Alkyl, C 1-6 Alkoxy, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 3-8 Carbocyclic groups, 4- to 10-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the alkyl, alkoxy, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0138] In some implementation schemes, R 1a R 1b Each element is independently selected from H, OH, NH2, and C. 1-4 Alkyl, C 1-4 Alkoxy, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 3-6 Carbocyclic groups, 4- to 8-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the alkyl, alkoxy, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0139] In some implementation schemes, R 1a R 1b Each of the following is independently selected from H, OH, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole, or thiophene, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole, or thiophene is optionally surrounded by 1 to 3 Rs. k Replaced;

[0140] In some implementation schemes, R a Each element is independently selected from deuterium, halogens, OH, NH2, CN, NO2, COOH, CONH2, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0141] In some implementation schemes, R a Each element is independently selected from deuterium, halogens, OH, NH2, CN, NO2, COOH, CONH2, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or 3-8 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0142] In some implementation schemes, R a Each of the following is independently selected from deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, CONH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, and pyrrolidinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, and pyrrolidinyl groups are optionally prefixed with 1 to 4 R. k Replaced;

[0143] In some implementation schemes, Selected from

[0144] In some implementations, m is selected from 0, 1, 2, 3; in other implementations, m is selected from 0, 1, 2.

[0145] In some implementations, p is independently selected from 0, 1, 2, 3, 4, 5, or 6; in other implementations, p is independently selected from 0, 1, 2, or 3.

[0146] In some implementations, Y is selected from O, S, NH, N-CN; in some implementations, Y is selected from O or S.

[0147] In some implementations, X2 is selected from -NR x2 -、-CR x R x -、-O-; In some implementations, X2 is selected from -NH-、-CF2-;

[0148] In some implementation schemes, R x Each is independently selected from halogens; in some implementation schemes, R x Each element is independently selected from F, Cl, and Br;

[0149] In some implementations, X1 is selected from -NR x1 -C 1-4 Alkylene-, -OC 1-4 Alkylene-, -SC 1-4 Alkylene-, C 3-10 Cycloalkyl or 4-10 membered heterocyclic group, wherein the alkylene, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 6 R groups. k Replaced;

[0150] In some implementations, X1 is selected from -NR x1 -C 1-2 Alkylene-, -OC 1-2 Alkylene-, -SC 1-2 Alkylene-, C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups, wherein the alkylene, cycloalkyl, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0151] In some implementations, X1 is selected from -NHCH2-, -NHCH2CH2-, -OCH2-, -SCH2-, -O-CH2CH2-, -S-CH2CH2-, X a The CH2 is optionally converted by 1 to 2 R k Replaced;

[0152] In some implementation schemes, ring X a Selected from C 3-8 Cycloalkyl or 4-10 membered heterocyclic groups, wherein the bonds connecting the left-terminal -C (=Y)- and the right-terminal ring B are attached to the ring X. a On different atoms, the cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R atoms. k Replaced;

[0153] In some implementation schemes, ring X a Selected from 1 to 4 Rs k The following structures are substituted: cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, cyclobutylspirocyclobutyl, aziridinespirocyclobutyl, aziridinespiroaziridine, piperidinylspirocyclobutyl, cyclohexylspirocyclobutyl, cyclopropylcyclopentyl, cyclopentylcyclopentyl, pyrrolidinylcycloalkyl, pyrrolidinylcyclopentyl

[0154] In some implementations, ring Xa is selected from 1 to 3 R. c One of the following structures is replaced:

[0155] In some implementation schemes, C1, C2, C3, and C4 are each independently selected from CR. c CH or N; in some implementations, one of C1, C2, C3, and C4 is selected from N, and the other three are selected from CR. c CH; In some implementation schemes, one of C1, C2, C3, and C4 is selected from CR. c The other three items are selected from CH;

[0156] In some implementation schemes, Selected from Its left side and R 2 Connected;

[0157] In some implementation schemes, R c Each is independently selected from deuterium, halogens, OH, COOH, CN, NO2, NH2, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 acetylinyl, OC 1-6 Alkyl, SC 1-6 Alkyl, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, -C 0-4 Alkylene-C 3-10 carbonyl group, -C 0-4 Alkylene-4 to 10-membered heterocyclic group, wherein the alkyl, alkenyl, alkynylene, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0158] In some implementation schemes, R c Each independently selected from R c1 ;

[0159] In some implementation schemes, R c Each is independently selected from deuterium, halogens, OH, COOH, CN, NO2, NH2, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 acetylinyl, OC 1-6 Alkyl, SC 1-4 Alkyl, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, -C0-2 Alkylene-C 3-6 carbonyl group, -C 0-2 Alkylene-4 to 6-membered heterocyclic group, wherein the alkyl, alkenyl, alkynylene, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0160] In some implementation schemes, R c Each is independently selected from deuterium, F, Cl, Br, I, OH, COOH, CN, NO2, NH2, NHCH3, N(CH3)2, or optionally coated by 1 to 4 R. k The following groups are substituted: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl;

[0161] In some implementations, two R a Two Rs c Together with the atoms or framework attached to it, they form C 3-10 A carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0162] In some implementations, two R a Two Rs c Together with the atoms bonded to it, they form C 3-8 A carbocyclic group or a 4- to 8-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0163] In some implementations, two R a Two Rs c Together with the atoms or skeleton attached thereto, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, oxacyclopentyl, pyrrolyl, piperidinyl, or 1,3-dioxopentyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, oxacyclopentyl, pyrrolyl, piperidinyl, or 1,3-dioxopentyl are optionally surrounded by 1 to 4 R atoms. k Replaced

[0164] In some implementation schemes, R 2 Selected from -C 1-6 Alkylene-VC 1-6 Alkylene-WR 2a -、-C 2-6 Alkylene-WR 2a -、-C 2-6 Alkylene-WR 2c -、-C 2-6 Alkylene-WR2c -R 2a - The alkylene group is optionally surrounded by 1 to 8 elements selected from deuterium, halogen, CN, OH, NH2, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Substituted with cycloalkyl or 3-8 membered heterocyclic groups, with its right end connected to L5;

[0165] In some implementation schemes, R 2 Selected from -C 1-4 Alkylene-VC 1-4 Alkylene-WR 2a -、-C 2-4 Alkylene-WR 2a -、-C 2-4 Alkylene-WR 2c -、-C 2-4 Alkylene-WR 2c -R 2a - The alkylene group is optionally surrounded by 1 to 8 elements selected from deuterium, halogen, CN, OH, NH2, C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 The alkoxy group is substituted, and its right end is connected to L5;

[0166] In some implementation schemes, R 2 Selected from -methylene-V-methylene-WR 2a -、-Ethylene-V-Ethylene-WR 2a -、-Ethylene-V-methylene-WR 2a -、-methylene-V-ethylidene-WR 2a -,-Ethylene-V-Propylene-WR 2a -、-methylene-V-propylene-WR 2a -,-Ethylene-WR 2a -,-Ethylene-WR 2c -,-Propylene-WR 2c -,-Ethylene-WR 2c -R 2a -,-Propylene-WR 2c -R 2a -,-Propylene-WR 2a -, -Butyl-WR 2a - Its right end is connected to L5, wherein the methylene, ethylene, propylene, and butylene are optionally selected from 1 to 8 elements selected from deuterium, F, Cl, Br, I, CN, OH, NH2, and C. 1-4 Alkyl, Halogenated C 1-4Alkyl, C 1-4 Substituents of alkoxy groups;

[0167] In some implementation schemes, R 2 Selected from -CH2CH2-O-CH2CH2-NR w -R 2a -、-CH2-O-CH2CH2-NR w -R 2a -、-CH2CH2-O-CH2CH2-OR 2a -、-CH2CH2-NR v -CH2CH2-OR 2a -CH2CH2-S-CH2CH2-NR w -R 2a -、-CH2CH2-O-CH2CH2-SR 2a -、-CH2CH2-NR v -CH2CH2-NR w -R 2a -、-CH2CH2-NR w -R 2a -、-CH2CH2CH2-NR w -R 2a -、-CH2CH2CH2-OR 2a -、-CH2CH2CH2-OR 2c -、-CH2CH2CH2-OR 2c -R 2a -、-CH2CH2CH2CH2-NR w -R 2a -、-CH2CH2-O-CH2CH2-NR w -C(=O)CH2O-, -CH2CH2-O-CH2CH2-NR w -C(=O)C(H)(D)O-、-CH2CH2-O-CH2CH2-NR w -C(=O)CD2O-, -CH2CH2-O-CH2CH2-NR w -C(=O)CHR 2b O-、-CH2CH2-O-CH2CH2-NR w -C(=O)C(CH3)R 2b O-、-CH2-O-CH2CH2-NR w -C(=O)CHR 2b O-、-CH2-O-CH2CH2-NR w -C(=O)C(CH3)(R 2b)O-, whose right end is connected to L5, wherein the CH2 is optionally replaced by one or two substituents selected from deuterium, F, Cl, Br, CN, OH, NH2, CHF2, CH2F, CF3, methyl, methoxy;

[0168] In some implementation schemes, R 2 Selected from -CH2CH2-O-CH2CH2-NR w -C(=O)CH2O-, -CH2CH2-O-CH2CH2-NR w -C(=O)C(H)(D)O-、-CH2CH2-O-CH2CH2-NR w -C(=O)CD2O-, -CH2CH2-O-CH2CH2-NR w -C(=O)CHR 2b O-、-CH2CH2-O-CH2CH2-NR w -C(=O)C(CH3)R 2b O-、-CH2CH2-O-CH2CH2-NR w -methylene-、-CH2CH2-O-CH2CH2-NR w -Ethylene-, -CH2CH2-O-CH2CH2-NR w -Propylene-, -CH2CH2-O-CH2CH2-NR w -Isopropylidene-,-CH2-O-CH2CH2-NR w -C(=O)CH2O-, -CH2-O-CH2CH2-NR w -C(=O)C(H)(D)O-, -CH2-O-CH2CH2-NR w -C(=O)CD2O-, -CH2-O-CH2CH2-NR w -C(=O)CHR 2b O-、-CH2-O-CH2CH2-NR w -C(=O)C(CH3)(R 2b )O-、 Its right end is connected to L5, and the CH2, methylene, ethylene, propylene, and isopropylene are optionally replaced by 1 to 3 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, CHF2, CH2F, CF3, methyl, methoxy, and cyclopropyl.

[0169] In some implementation schemes, R 2a Selected from -C 1-6 Alkylene-, -C(=O)C(R) 2b)2O-、-C(=O)C(R 2b )2NH-、-C(=O)C(R 2b )2C(R 2b )2O-、-C(=O)C(R 2b )2C(R 2b )2C(R 2b )2O-、-C(=O)-R 2c -O-, its right end is connected to L5, and the alkylene group is optionally surrounded by 1 to 6 elements selected from deuterium, halogen, CN, OH, NH2, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Substituted by cycloalkyl or 3-8 membered heterocyclic groups;

[0170] In some implementation schemes, R 2a Selected from -C 1-4 Alkylene-, -C(=O)C(R) 2b )2O-、-C(=O)C(R 2b )2NH-、-C(=O)C(R 2b )2C(R 2b )2O-、-C(=O)C(R 2b )2C(R 2b )2C(R 2b )2O-、-C(=O)-R 2c -O-, its right end is connected to L5, wherein the alkylene group is optionally surrounded by 1 to 5 elements selected from deuterium, halogen, CN, OH, NH2, C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Substituted by cycloalkyl or 3-6 membered heterocyclic groups;

[0171] In some implementation schemes, R 2a Selected from methylene, ethylene, propylene, isopropylene, butylene, -C(=O)C(R) 2b )2O-、-C(=O)C(R 2b )2NH-、-C(=O)C(R 2b )2C(R 2b )2O-、-C(=O)C(R 2b )2C(R 2b )2C(R 2b )2O-、-C(=O)-R 2c-O-, its right end is connected to L5, wherein the methylene, ethylene, propylene, isopropylene, and butylene are optionally selected from 1 to 4 of the following: deuterium, F, Cl, Br, I, CN, OH, NH2, C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Substituted by cycloalkyl or 3-6 membered heterocyclic groups;

[0172] In some implementation schemes, R 2a Selected from methylene, ethylene, propylene, isopropylene, -C(=O)CH2O-, -C(=O)C(R) 2b )2NH-, -C(=O)C(H)(D)O-, -C(=O)CD2O-, -C(=O)CH(R 2b )O-、-C(=O)C(CH3)(R 2b )O-、 Its right end is connected to L5, wherein the methylene, ethylene, propylene, and isopropylene are optionally replaced by 1 to 3 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, methyl, methoxy, and cyclopropyl.

[0173] In some implementation schemes, R 2b Each element is independently selected from H, deuterium, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 The alkyl, carbocyclic, or heterocyclic group may be selected from 1 to 6 elements chosen from deuterium, halogen, CN, OH, NH2, C. 1-6 Alkyl, C 1-6 Alkoxy, The substituents are replaced;

[0174] In some implementation schemes, R 2b Each element is independently selected from H, deuterium, halogens, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 The alkyl, carbocyclic, or heterocyclic group may be selected from 1 to 5 elements chosen from deuterium, halogen, CN, OH, NH2, C. 1-4 Alkyl, C 1-4 Alkoxy, The substituents are replaced;

[0175] In some implementation schemes, R 2bEach of the following elements is independently selected from H, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolyl, piperidinyl, morpholinyl, piperazine, oxacyclobutyl, tetrahydrofuranyl, and phenyl, wherein methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolyl, piperidinyl, morpholinyl, piperazine, oxacyclobutyl, tetrahydrofuranyl, and phenyl are optionally selected from 1 to 4 elements selected from deuterium, halogen, CN, OH, NH2, and C. 1-4 Alkyl, C 1-4 Alkoxy, The substituents are replaced;

[0176] In some implementation schemes, R 2b Each of these elements is independently selected from H, deuterium, F, Cl, Br, CHF2, CH2F, CF3, CD3, OCD3, CH2OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolyl, piperidinyl, morpholinyl, piperazine, oxacyclobutyl, tetrahydrofuranyl, phenyl.

[0177] In some implementation schemes, R ka R kb Each is independently selected from H, CN, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocyclic groups, C 1-2 Alkylene-C 3-6 carbon cyclo group, C 1-2 Alkylene-4 to 6-membered heterocyclic group, wherein the alkylene, alkyl, cycloalkyl, carbocyclic or heterocyclic group is optionally composed of 1 to 4 groups selected from deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The substituents on the carbon ring are replaced;

[0178] In some implementation schemes, R ka R kb The following groups are selected independently from H, CN, F, Cl, Br or optionally replaced by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, methyl, methoxy, and cyclopropyl: methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, oxecyclobutyl, azacyclobutyl, CH2-cyclopropyl, CH2-cyclobutyl;

[0179] In some implementation schemes, Selected from

[0180] In some implementations, 2 R 2b Direct connection forms C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0181] In some implementations, 2 R 2b Direct connection forms C 3-6 cycloalkyl or 3-7 membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0182] In some implementations, 2 R 2b Direct connection forms an optional 1 to 4 R k The following structures are replaced: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxacyclobutyl, tetrahydrofuranyl, and cyclobutylspirocyclobutyl.

[0183] In some implementation schemes, R 2c Selected from C 3-10 Cycloalkyl or 4-10 membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally surrounded by 1 to 6 R groups. k Replaced;

[0184] In some implementation schemes, R 2c Selected from C 3-8 Cycloalkyl or 4-8 membered heterocyclic groups, wherein the cycloalkyl or heterocyclic group is optionally surrounded by 1 to 6 R groups. k Replaced;

[0185] In some implementation schemes, R 2c Selected from 1 to 4 Rs k The following structures are replaced: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutylspirocyclobutyl, cyclopropylcyclopentyl,

[0186] In some implementation schemes, R 2c Selected from 1 to 4 Rs k The following structures are replaced: aziridine, pyrrolidinyl, piperidinyl, morpholinyl;

[0187] In some implementations, V is selected from O, S, NR v ;

[0188] In some implementation schemes, W is selected from O, S, NR w ;

[0189] In some implementation schemes, R vR w R x1 R x2 Each is independently selected from H, deuterium, and C. 1-4 Alkyl, C 3-6 Carbocyclic, 4- to 6-membered heterocyclic, wherein the alkyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0190] In some implementation schemes, R v R w R x1 R x2 Each is independently selected from H, deuterium, and C. 1-4 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0191] In some implementation schemes, R v R w Each is independently selected from H, deuterium, CHF2, CH2F, CF3, CD3, CH2OH, methyl, ethyl, propyl, isopropyl; in some embodiments, R w Each is independently selected from H and deuterium;

[0192] In some implementation schemes, R x1 R x2 Each is independently selected from H;

[0193] In some implementation schemes, R k Each element is independently selected from deuterium, halogens, OH, =O, CN, NH2, NO2, COOH, CONH2, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, -OC 3-6 Carbocyclic rings, -O-3 to 7-membered heterocycles, -NH-C 3-6 Carbon rings, -NH-3 to 7-membered heterocycles, -SC 3-6 Carbon rings, -S-3 to 7-membered heterocycles, -C 0-4 Alkylene-C 3-6 Carbon ring, -C 0-4 Alkylene-3 to 7-membered heterocycles, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic group is optionally selected from 1 to 4 deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Substituents of alkoxy groups;

[0194] In some implementation schemes, R k Each element is independently selected from deuterium, halogens, OH, CN, NO2, NH2, COOH, CONH2, and C. 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, -OC 3-6 Carbocyclic rings, -O-3 to 7-membered heterocycles, -NH-C 3-6 Carbon rings, -NH-3 to 7-membered heterocycles, -SC 3-6 Carbon rings, -S-3 to 7-membered heterocycles, -C 0-2 Alkylene-C 3-6 Carbon ring, -C 0-2 Alkylene-3 to 7-membered heterocycles, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic group is optionally selected from 1 to 4 deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0195] In some implementation schemes, R k Each of the following groups is independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, NO2, COOH, CONH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, aziridine, oxacyclobutyl, pyrrolylyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, aziridine, oxacyclobutyl, pyrrolylyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl is optionally selected from deuterium, F, Cl, Br, I, CN, OH, NH2, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0196] In some implementation schemes, R k Each is independently selected from deuterium, F, Cl, Br, OH, CN, NH2, NO2, COOH, CONH2, NHCH3, N(CH3)2, CHF2, CH2F, CF3, CD3, CH2OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propynyl, cyclopropyl;

[0197] In some implementations, D is selected from

[0198] The present invention also provides a compound of formula (IV) or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, wherein,

[0199] L-L0-L1-L2-(L3) p1 -(L4) p2 -L5-H (IV);

[0200] In some implementations, D is selected from one of the structures shown in Table A-1;

[0201] In some implementations, general formula (I) is selected from one of the structures shown in Table A-2;

[0202] This invention also relates to a compound of general formula (III) or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, wherein,

[0203] Tb-[L'-D]q(III);

[0204] In some implementations, L' is selected from connectors; preferably, L' is selected from -L0-L1-L2-(L3). p1 -(L4) p2 -L5-;

[0205] In some implementations, the definitions of L0, L1, L2, L3, L4, and L5 are consistent with those described in any of the general formulas (I);

[0206] In some implementations, the definition of D is consistent with that described in any of the general formulas (II);

[0207] In some implementation schemes, q represents the drug-antibody conjugate ratio;

[0208] In some implementations, q is selected from any value between 0.1 and 16.0; in a preferred implementation, q is selected from any integer between 0.1 and 16.0.

[0209] In some embodiments, q is selected from any value between 0.1 and 8.0; in preferred embodiments, q is selected from any integer between 0.1 and 8.0; in some embodiments, q is selected from any value between 1.0 and 10.0.

[0210] In some implementations, q is selected from any value between 2 and 8; in some implementations, q is selected from any value between 3 and 8.

[0211] In some implementations, q is selected from any value between 4 and 8; in some implementations, q is selected from any value between 6 and 8.

[0212] In some implementations, q is selected from any integer between 2 and 8; in some implementations, q is selected from any integer between 3 and 8.

[0213] In some implementations, q is selected from any integer between 4 and 8; in some implementations, q is selected from any integer between 6 and 8.

[0214] In some implementations, q is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12;

[0215] In some implementations, q is selected from 2, 4, 6, and 8;

[0216] In some embodiments, the Tb is a targeting moiety; in some embodiments, the targeting moiety is capable of specifically binding to cell surface receptors or antigens; for example, antibodies and their antigen-binding fragments, ligands, proteins, peptides, non-protein reagents (e.g., sugars, RNA or DNA), antibody analogs, etc.

[0217] In some implementations, Tb is an antibody or its antigen-binding fragment;

[0218] In some implementations, Tb is an antibody or its antigen-binding fragment that has endocytic activity;

[0219] In some implementations, Tb is an antibody or its antigen-binding fragment that has the activity of binding to tumor cell surface antigens;

[0220] In some embodiments, the antibody or its antigen-binding fragment is an antibody or its antigen-binding fragment that has tumor cell surface antigen-binding activity and tumor cell endocytosis activity;

[0221] In some embodiments, the antibody or its antigen-binding fragment is an antibody or its antigen-binding fragment that has antigen-binding activity and little or no tumor cell endocytic activity;

[0222] In some embodiments, the antibody or its antigen-binding fragment is an antibody or its antigen-binding fragment that binds to non-endocytic antigens on the surface of tumor cells;

[0223] In some embodiments, the antibody or its antigen-binding fragment is an antibody or its antigen-binding fragment that does not have tumor cell endocytosis activity;

[0224] In some preferred embodiments, the antibody or its antigen-binding fragment is an antibody or its antigen-binding fragment that has activity in binding to tumor cell surface antigens and has tumor cell endocytosis activity;

[0225] In some implementations, Tb is a ligand or target moiety that binds to the target.

[0226] In some implementations, the target of Tb is selected from targets expressed in tumor cells at a higher rate than in normal cells;

[0227] In some implementations, the target of Tb is selected from targets that are highly expressed in tumor cells but lowly expressed in normal cells;

[0228] In some implementations, the target of Tb is selected from: B7H3, CD20, CD19, CD30, CD33, GPNMB, Her2, Trop-2, EGFR, Her3, GD-2, CD79b, DLL3, CDH6, CDH17, CEACAM5, and BCMA, etc.;

[0229] In some embodiments, the antibody or its antigen-binding fragment includes Fab, Fab', F(ab')2, Fd, Fv, dAb, complementarity-determining region fragment, single-chain antibody (e.g., scFv), non-human antibody, humanized antibody, chimeric antibody, fully human antibody, probody, bispecific antibody, or multispecific antibody.

[0230] In some embodiments, the antibody or its antigen-binding fragment is a non-human antibody, a humanized antibody, a chimeric antibody, or a fully human antibody;

[0231] In some embodiments, the antibody or its antigen-binding fragment is a probody, a bispecific antibody, or a multispecific antibody;

[0232] In some embodiments, the antibody or its antigen-binding fragment includes Fab, Fab', F(ab')2, Fd, Fv, dAb, complementarity-determining region fragment, and single-chain antibody (e.g., scFv);

[0233] In some embodiments, the antigen is B7H3, B7-H4, CCL11, CCR5, CD123, CD133, CD138, CD18, CD19, CD33, CD40, HER2, HER3, CD20, CD38, CD33, BCMA, CD138, EGFR, FGFR4, GD2, PDGFR, TEM1 / CD248, TROP-2, DLL3, CDH6, CDH17, CEACAM5, or a combination thereof; in some embodiments, the antibody is anti-CD33, rituximab, trastuzumab, pertuzumab, OR000213 (huMy9-6IgG4S228P), lintuzumab or gemtuzumab, anti-DLL3, anti-CDH6, anti-CDH17, anti-CEACAM5;

[0234] In some implementations, Tb is CD33Ab1, CD33Ab2, trastuzumab, Raludotatug, anti-CDH17, or CEACAM5Ab1.

[0235] As a first embodiment of the present invention, the compound represented by the aforementioned general formula (I), or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, are used.

[0236] L represents the leaving group that reacts with the target portion;

[0237] L0 is a connector unit, which is selected from... Its left end is connected to L; preferably, L0 is selected from Its left end is connected to L;

[0238] L1 is selected from Its right side is connected to L2; preferably, L1 is selected from Its right side is connected to L2; more preferably, L1 is selected from Its right side connects to L2;

[0239] m1 is selected from integers from 1 to 12; m4 is selected from integers from 1 to 12;

[0240] m3 is selected from 1, 2, 3, 4, 5; m5 is selected from 0, 1, 2, 3, 4, 5; preferably, m5 is selected from 1, 2;

[0241] G1 is selected from -C(=O)-NH2, -C(=O)-OH, and -P(=O)(OH)2. Preferably, G1 is selected from -C(=O)-OH, More preferably, G1 is selected from -C(=O)-OH;

[0242] L2 is selected from -Z1-Z2-; preferably, -L1-L2- is selected from Its right side is connected to L3; more preferably, -L1-L2- is selected from Its right side connects to L3;

[0243] Z1 is selected from key, -C 1-6 alkylene-, -C 2-6 -, -C ethynyl 2-6 alkenyl-, wherein the Z1 is optionally divided by 1 to 4 R s Replaced;

[0244] Z2 is selected from bond, -C(=O)-, -M4-C 0-6 Alkylene -C(=O)-, -M3-C 1-6 Alkylene-M4-, wherein the alkylene is optionally surrounded by 1 to 4 R... s Replaced;

[0245] M1 is selected from -O-, -C(=O)-, -NH-, -NH-S(=O)2-NH-, -C 0-4 alkylene-4-8-membered heterocyclic group-, wherein the alkylene group or heterocyclic group is optionally surrounded by 1 to 4 R groups. s Replaced;

[0246] M2 is selected from -C(=O)-, -C 1-4 Alkylene -C(=O)-, -C 1-4 Alkylene -NH-C(=O)-, -C 1-4 Alkylene-NH-C(=O)-C 1-4 Alkylene -C(=O)-, -C 1-4 Alkylene-NH-C(=O)-C 1-4 Alkylene-OC 1-4 Alkylene-C(=O)-, wherein the alkylene is optionally surrounded by 1 to 4 R- atoms. s Replaced;

[0247] M3 is selected from -O-, -S-, -CR m1 R m2 -、-NR m3 -;

[0248] M4 is selected from -O-, -S-, -NR m4 -;

[0249] R L Rm1 R m2 R m3 R m4 Each element is independently selected from H, deuterium, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 7-membered heterocyclic groups, wherein the alkyl group, C 2-4 alkenyl, C 2-4 Alkyne, cycloalkyl, or heterocyclic groups are optionally surrounded by 1 to 4 R groups. s Replaced;

[0250] s2 is selected from integers from 2 to 12; s3 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8;

[0251] L3 is selected from amino acids, specifically peptides composed of 2-5 amino acids;

[0252] L4 is selected from Its right side connects to L5;

[0253] X is selected from -CH-, -CR L3 -、-N-;

[0254] Y1 is selected from -N(R) L5 )-、-C(=O)-;

[0255] Y2 is selected from -N(R) L5 )-、-N(R L5 )-C 1-6 alkylene-5-6-membered nitrogen-containing heteroaryl-,-N(R) L5 )-C 1-4 Alkylene-N(R) L5 )-, wherein the alkylene or heteroaryl group is optionally surrounded by 1 to 4 R s Replaced;

[0256] Y3 is selected from

[0257] R L8 Each component is independently selected from the amino acid side chain, H, C 1-6 Alkyl, -C 1-4 Alkylene C 6-10 Aryl, -C 1-4 alkylene 4-10-membered heterocyclic groups, wherein R L8 Choose from 1 to 4 Rs s Replaced;

[0258] m2 is selected from 2, 3, 4, and 5;

[0259] Y4 is selected from -C(=O)-C 1-6 alkyl, The Y4 is arbitrarily divided by 1 to 4 Rs s Replaced;

[0260] s7 is selected from integers from 1 to 10;

[0261] R L3 R L4 Each element is independently selected from deuterium, halogens, OH, NH2, CN, NO2, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl or 4-8 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. s Replaced;

[0262] R L5 Each independently selected from H and C 1-4 Alkyl, C 3-8 Cycloalkyl or 4-8 membered heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. s Replaced;

[0263] R s Each element is independently selected from deuterium, halogens, OH, NH2, CN, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 acetylinyl, OC 1-4 Alkyl, SC 1-4 Alkyl, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, wherein the alkyl, alkenyl, or alkynyl groups are optionally substituted with 1 to 4 substituents of deuterium, halogen, OH, NH2, or CN;

[0264] s1 is selected from 0, 1, 2, 3 or 4;

[0265] L5 is selected from the spacer unit;

[0266] p1 and p2 are each independently selected from 0 and 1, and p1 + p2 = 1;

[0267] D is selected from bioactive molecular fragments, preferably from auristatin derivatives, maystasionoids derivatives, DNA destroyers, amanitins, topoisomerase inhibitors, camptothecin derivatives, selective or non-selective kinase inhibitors, Bcl-xl inhibitors and Bcl-2 / Bcl-xl inhibitors, and protein degraders; more preferably, D is selected from topoisomerase inhibitors.

[0268] As a second embodiment of the present invention, the compound represented by the aforementioned general formula (I), or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, are used.

[0269] The amino acid is selected from amino acid AA or amino acid AA1; wherein the N-terminus of the amino acid is connected to L2 and the C-terminus is connected to L5.

[0270] The amino acids A and B are each independently selected from valine, glycine, alanine, glutamic acid, phenylalanine, lysine, citrulline, serine, glutamic acid, and aspartic acid;

[0271] Amino acid AA1 is selected from Preferably, amino acid AA1 is selected from

[0272] R L0 Each element is independently selected from H, deuterium, and C. 1-6 Alkyl, C 3-8 cycloalkyl, 4-8 membered heterocyclic groups The alkyl, cycloalkyl, or heterocyclic groups are optionally surrounded by 1 to 4 R groups. s Replaced; preferably, R L0 Each independently selected More preferably, R L0 Each independently selected

[0273] Or two Rs L0 Direct connection forms C 3-8 cycloalkyl or 4-8 membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. s Replaced;

[0274] s5 and s6 are each independently selected from 0, 1, 2, 3, 4, 5 or 6; preferably, s6 is each independently selected from 4;

[0275] R L1 R L2 Each element is independently selected from H, deuterium, and C. 1-4 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. s Replaced;

[0276] Or R L1 R L2 The nitrogen atom attached to it forms a 4-8 membered heterocyclic group, which is optionally surrounded by 1 to 4 R atoms. s Replaced;

[0277] HG is selected from Preferably, HG is selected from More preferably, HG is selected from

[0278] L5 is selected from -Z3-Z4-, where Z3 and Z4 are not both selected from the key;

[0279] Z3 is selected from key, Its right side is connected to Z4;

[0280] Z4 is selected from the bond, -N(R) L5 )-C(R L6 )2-、-OC(R L6 )2-、-M4-C 0-4 Alkylene -C(=O)-, -N(R) L5 )-C 1-4 Alkylene-N(R) L7 )-C(=O)-, wherein the alkylene group is optionally surrounded by 1 to 4 R s It is replaced, and its right side is connected to D;

[0281] R L6 Each element is independently selected from H, deuterium, halogens, OH, NH2, CN, NO2, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl or 4-8 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. s Replaced;

[0282] Or R L5 and R L6 Two Rs L6 Together with the carbon atoms attached to it, they form C 3-8 cycloalkyl or 4-8 membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. s Replaced;

[0283] R L7 Each independently selected from H and C 1-4 Alkyl, -C 1-4 Alkylene-S(=O)2-C 1-4 Alkyl, C 3-8 Cycloalkyl or 4-8 membered heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. s Replaced;

[0284] The definitions of the remaining substituents are consistent with those described in Schemes 1 and 2 of this invention.

[0285] As a third embodiment of the present invention, the compound represented by the aforementioned general formula (I), or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, are used.

[0286] L is selected from halogen, sulfone, and tertiary amine salt (Me3N). + Et3N +), diazonium salts, -OMs, MeSO2-, CF3SO3-, p-toluenesulfonyl groups;

[0287] L3 is selected from -AA-, -AA1-, -AA-AA-, -AA-AA-AA-, -AA-AA-AA-AA-, -AA-AA1-, -AA1-AA-, -AA-AA1-AA-, -AA-AA-AA1-, -AA1-AA- AA-AA-, -AA1-AA-AA-AA-AA-, -AA1-AA-AA-AA-, -AA1-AA-AA-AA-AA-; preferably, L3 is selected from -AA-AA-, -AA-AA-AA-, -AA-AA-AA-AA-;

[0288] R L0 Each element is independently selected from H, deuterium, and C. 1-4 Alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclic groups The alkyl, cycloalkyl, or heterocyclic group is optionally surrounded by 1 to 4 R groups. s Replaced;

[0289] Each s5 is independently selected from 0, 1, 2, 3, and 4;

[0290] Or two Rs L0 Direct connection forms C 3-6 Cycloalkyl or 4-6 membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. s Replaced;

[0291] R L1 R L2 Each element is independently selected from H, deuterium, and C. 1-4 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. s Replaced;

[0292] Or R L1 R L2 The nitrogen atom attached to it forms a 4-7 membered heterocyclic group, which is optionally surrounded by 1 to 4 R atoms. s Replaced;

[0293] L2 is selected from key, -Z1-Z2-, -Z1-, -Z2;

[0294] Z1 is selected from -C 1-4 alkylene-, -C 2-4 -, -C ethynyl 2-4 alkenyl-, wherein the Z1 is optionally divided by 1 to 4 R s Replaced;

[0295] Z2 is selected from -C(=O)- and -M4-C. 0-4 Alkylene -C(=O)-, -M3-C 1-4 Alkylene-M4-, wherein the alkylene is optionally surrounded by 1 to 4 R... s Replaced;

[0296] M1 is selected from -O-, -C(=O)-, -NH-, -NH-S(=O)2-NH-, -C 0-2 alkylene-5-6-membered nitrogen-containing heteroaryl-, wherein the alkylene or heterocyclic group is optionally surrounded by 1 to 4 R- groups. s Replaced;

[0297] M2 is selected from -C(=O)-, -C 1-4 Alkylene -C(=O)-, -C 1-4 Alkylene -NH-C(=O)-, -C 1-4 Alkylene-NH-C(=O)-C 1-4 Alkylene -C(=O)-, -C 1-4 Alkylene-NH-C(=O)-C 1-4 Alkylene-OC 1-4 Alkylene-C(=O)-, wherein the alkylene is optionally surrounded by 1 to 4 R- atoms. s Replaced;

[0298] R L R m1 R m2 R m3 R m4 Each of the following is independently selected from H, deuterium, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, and cyclobutyl groups are optionally separated by 1 to 4 R groups. s Replaced;

[0299] Y2 is selected from -N(R) L5 )-、-N(R L5 )-C 1-4 alkylene-5-6-membered nitrogen-containing heteroaryl-,-N(R) L5 )-C 1-2 Alkylene-N(R) L5 )-, wherein the alkylene or heteroaryl group is optionally surrounded by 1 to 4 R s Replaced;

[0300] R L8 Each component is independently selected from the amino acid side chain, H, C 1-4 Alkyl, -C 1-4 alkylenephenyl, -C 1-4 alkylene 4-6 membered heterocyclic groups, -C 1-4alkylene 8-10-membered heteroaryl, wherein R L8 Choose from 1 to 4 Rs s Replaced;

[0301] Y4 is selected from -C(=O)-C 1-4 alkyl, The Y4 is arbitrarily divided by 1 to 4 Rs s Replaced; s7 is selected from integers from 1 to 8;

[0302] R L3 R L4 Each of the following is independently selected from deuterium, F, Cl, Br, OH, NH2, CN, NO2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl groups are optionally prefixed with 1 to 4 R groups. s Replaced;

[0303] R L5 Each is independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, and cyclobutyl groups are optionally prefixed with 1 to 4 R groups. s Replaced;

[0304] L5 is selected from -Z3-Z4-, -Z3-, and -Z4-; preferably, L5 is selected from -Z3- and -Z4-; more preferably, L5 is selected from -Z4-.

[0305] Z3 is selected from Its right side is connected to Z4; preferably, Z3 is selected from... Its right side is connected to Z4;

[0306] Z4 is selected from -N(R) L5 )-C(R L6 )2-、-OC(R L6 )2-、-M4-C 0-4 Alkylene -C(=O)-, -N(R) L5 )-C 1-4 Alkylene-N(R) L7 )-C(=O)-, wherein the alkylene group is optionally surrounded by 1 to 4 R s It is replaced, and its right side is connected to D;

[0307] Or R L5 and R L6 Two Rs L6 The atoms bonded to it together form C 3-6 Cycloalkyl or 4-6 membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. s Replaced;

[0308] R L6 Each of the following is independently selected from H, deuterium, F, Cl, Br, OH, NH2, CN, NO2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl groups are optionally prefixed with 1 to 4 R groups. s Replaced;

[0309] R L7 Each is independently selected from H, methyl, ethyl, propyl, isopropyl, -methylene-S(=O)2-C 1-2 Alkyl, -Ethylene-S(=O)2-C 1-2 Alkyl, -propylidene-S(=O)2-C 1-2 Alkyl, C 3-8 Cycloalkyl or 4-8 membered heterocyclic group, wherein the methylene, ethylene, propylene, methyl, ethyl, propyl, isopropyl, alkyl, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. s Replaced;

[0310] R s Each element is independently selected from deuterium, halogens, OH, NH2, CN, and C. 1-2 Alkyl, C 2-3 alkenyl, C 2-3 acetylinyl, OC 1-2 Alkyl, SC 1-2 Alkyl, NHC 1-2 Alkyl, N(C) 1-2 Alkyl)2, wherein the alkyl, alkenyl, or alkynyl groups are optionally substituted with 1 to 4 substituents of deuterium, F, Cl, Br, OH, NH2, or CN;

[0311] The definitions of the remaining substituents are consistent with those described in Schemes 1 and 2 of this invention.

[0312] As a fourth embodiment of the present invention, the compound represented by the aforementioned general formula (I), or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, are used.

[0313] R s Each is independently selected from deuterium, F, Cl, Br, OH, NH2, CN, CHF2, CH2F, CF3, CD3, OCF3, OCD3, methyl, methoxy, methylthio, and ethoxy.

[0314] R L0 Each is independently selected from H, deuterium, methyl, ethyl, propyl, isopropyl, The methyl, ethyl, propyl, and isopropyl groups are optionally surrounded by 1 to 4 R groups. s Replaced;

[0315] Or RL0 Each independently selected

[0316] Or two Rs L0 Direct linkage to form cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups, wherein the cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups are optionally bounded by 1 to 4 R groups. s Replaced;

[0317] R L1 R L2 Each is independently selected from H, deuterium, methyl, ethyl, propyl, and isopropyl, wherein the methyl, ethyl, propyl, and isopropyl groups are optionally surrounded by 1 to 4 R groups. s Replaced;

[0318] Or R L1 R L2 The nitrogen atom attached thereto forms an azircyclic butyl group, a pyrrolidinyl group, a piperidinyl group, or a piperazine group, wherein the azircyclic butyl group, a pyrrolidinyl group, a piperidinyl group, or a piperazine group is optionally surrounded by 1 to 4 R atoms. s Replaced;

[0319] Z1 is selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -C≡C-, -C≡C-CH2CH2, wherein Z1 is optionally divided by 1 to 2 R s Replaced;

[0320] Z2 is selected from -C(=O)-, -NH-C(=O)-, -O-CH2-C(=O)-, -NH-CH2-C(=O)-, -NHC(=O)-CH2CH2CH2CH2-C(=O)-, -NH-CH2CH2CH2CH2-NH-, -NH-CH2CH2-NH-, -NH-CH2-NH-, and -NH-CH2-NH-, wherein the CH2 is optionally surrounded by 1 to 2 R s Replaced;

[0321] M1 is selected from -O-, -C(=O)-, -NH-, triazole, and pyrazolyl, wherein the triazole or pyrazolyl group is optionally surrounded by 1 to 4 R groups. s Replaced;

[0322] M2 is selected from -C(=O)-, -CH2-C(=O)-, -CH2CH2-C(=O)-, -CH2CH2-NH-C(=O)CH2-C(=O)-, -CH2CH2-NH-C(=O)CH2OCH2-C(=O)-, wherein the CH2 is optionally surrounded by 1 to 2 R s Replaced;

[0323] M3 is selected from -O-, -CR m1 R m2 -、-NR m3 -;

[0324] R L R m1 R m2 R m3 Each is independently selected from H, deuterium, methyl, ethyl, propyl, isopropyl, and cyclopropyl, wherein the methyl, ethyl, propyl, isopropyl, and cyclopropyl groups are optionally surrounded by 1 to 4 R groups. s Replaced;

[0325] Y2 is selected from -N(R) L5 )-、-N(R L5 )-Ethylene-triazolyl-,-N(R L5 )-methylene-triazolyl-,-N(R L5 )-Ethylene-N(R L5 The ethylene or triazole group is optionally surrounded by 1 to 4 R groups. s Replaced;

[0326] R L8 Each of the following is independently selected from -CH2CH2CH2-NH-C(=NH)-NH2, -CH2CH2CH2-NH-C(=O)-NH2, -CH2C(=O)OH, -CH2C(=O)NH2, -CH2CH2C(=O)OH, -CH2CH2C(=O)NH2, -CH2SH, -CH2CH2SCH3, H, methyl, ethyl, isopropyl, butyl, -CH2-imidazolyl, -CH2-phenyl, -CH2-indoleyl, wherein R L8 Choose from 1 to 4 Rs s Replaced;

[0327] Y4 is selected from -C(=O)-methyl, -C(=O)-ethyl, -C(=O)-propyl, -C(=O)-isopropyl, The Y4 is arbitrarily divided by 1 to 2 Rs s Replaced;

[0328] Z4 is selected from -N(R) L5 )-C(R L6 )2-、-OC(R L6 )2-、-OC(=O)-、-N(R L5 )-CH2CH2-N(R L7 Z4 is selected from -N(R)-C(=O)-, and its right side is connected to D; preferably, Z4 is selected from -N(R)-C(=O)-. L5 )-C(R L6 )2-, whose right side is connected to D; more preferably, Z4 is selected from Its right side is connected to D;

[0329] R L3 R L4 Each of the following is independently selected from deuterium, F, Cl, Br, OH, NH2, CN, NO2, methyl, ethyl, isopropyl, methoxy, and cyclopropyl, wherein the methyl, ethyl, isopropyl, methoxy, and cyclopropyl groups are optionally prefixed with 1 to 4 R groups. s Replaced;

[0330] R L6 Each is independently selected from H, deuterium, F, Cl, Br, OH, NH2, CN, NO2, methyl, ethyl, propyl, isopropyl, CHF2, CH2F, CF3, CD3, OCF3, OCD3, methoxy, ethoxy, and cyclopropyl.

[0331] As an option, R L5 and R L6 Two Rs L6 The atoms bonded to it are directly connected to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolyl, piperidinyl, and piperazine, wherein the aziridine, pyrrolyl, piperidinyl, and piperazine groups are optionally surrounded by 1 to 4 R atoms. s Replaced;

[0332] R L7 Each is independently selected from H, methyl, ethyl, propyl, isopropyl, -methylene-S(=O)2-methyl, -ethylidene-S(=O)2-C 1-2 Ethyl, -propylidene-S(=O)2-methyl, cyclopropyl, cyclobutyl, wherein the methyl, ethyl, propyl, isopropyl, methylene, ethylidene, propylidene, cyclopropyl, or cyclobutyl is optionally surrounded by 1 to 4 R... s Replaced;

[0333] The definitions of the remaining substituents are consistent with those described in Schemes 1, 2, 3, and 4 of this invention.

[0334] As a fifth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts thereof...

[0335] L2 is selected from bond, -C(=O)-, Preferably, L2 is selected from the bond;

[0336] s2 is selected from 2, 3, 4, 5, 6, and 7;

[0337] L3 is selected from -Val-Gly-, -Val-Cit-, -Phe-Lys-Gly-, -Gly-Val-Lys-Gly-, -Val-Lys-Gly-Gly-, -Val-Lys-Gly -, -Val-Lys-Ala-, -Gly-Gly-Phe-Gly-, -Val-AA1-, -Val-AA1-Val-, -Val-AA1-Gly-, -AA1-AA1-, -AA1- AA1-Gly-, -AA1-Val-Cit-, -Val-Ala-, -Ala-Ala-, -Ala-Ala-Ala-, AA1-Gly-Gly-Phe-Gly-, -AA1-Val -Ala-; Preferably, L3 is selected from -Val-Cit-, -Gly-Gly-Phe-Gly-, -Val-Ala-, -Ala-Ala-Ala-, AA1-Gly-Gly-Phe-Gly-;

[0338] AA1 is selected from Preferably, AA1 is selected from More preferably, AA1 is selected from

[0339] L4 is selected from Its right side is connected to L5; preferably, L4 is selected from Its right side connects to L5;

[0340] R L8 Each is independently selected from -CH2CH2CH2-NH-C(=NH)-NH2, -CH2CH2CH2-NH-C(=O)-NH2, -CH2C(=O)OH, -CH2C(=O)NH2, -CH2CH2C(=O)OH, -CH2CH2C(=O)NH2, -CH2SH, -CH2CH2SCH3, H, methyl, ethyl, isopropyl, -CH2CH2CH2CH2NH2, -CH2NH2, -CH2OH, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2-imidazolyl, -CH2-phenyl, -CH2-indoleyl;

[0341] m2 is selected from 2 and 3;

[0342] L5 is selected from Its right side is connected to D; preferably, L5 is selected from Its right side is connected to D; more preferably, L5 is selected from Its right side is connected to D;

[0343] s1 is selected from 0, 1, and 2;

[0344] The definitions of the remaining substituents are consistent with those described in Schemes 1, 2, 3, and 4 of this invention.

[0345] As a sixth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, wherein...

[0346] L1 is selected from Its right side is connected to L2; m1 is selected from integers from 2 to 10; preferably, L1 is selected from... Its right side connects to L2;

[0347] Or -L1-L2- selected from Its right side connects to L3;

[0348] m4 is selected from integers from 1 to 10; preferably, m4 is selected from 4, 6, or 8; m5 is selected from 0, 1, 2, or 3.

[0349] -L2-(L3) p1 -(L4) p2 -L5- Selected from Its right side is connected to D;

[0350] s2 is selected from 3, 5, 7, and 9;

[0351] Or -(L3) p1 -(L4) p2 -L5- Selected from Its right side is connected to D; preferably, -(L3) p1 -(L4) p2 -L5- Selected from Its right side is connected to D;

[0352] The definitions of the remaining substituents are consistent with those described in Schemes 1, 2, 3, 4 or 5 of this invention.

[0353] As a seventh embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, wherein...

[0354] D is selected from Preferably, D is selected from

[0355] Alternatively, D can be selected from one of the following structures:

[0356] Preferably, D is selected from More preferably, D is selected from

[0357] Indicates an optional connection position, when connected to a certain position of D. When connecting, another location For H;

[0358] R 3 Selected from C 1-6 Alkyl, -C 1-6 Alkylene-NR 3a -S(=O)2C 1-6 Alkyl, -C 1-6 Alkylene-NR 3a -C(=O)C 1-6 Alkyl, wherein the alkylene or alkyl group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0359] R 3a Selected from H, C 1-6 Alkyl groups, wherein the alkyl group is optionally composed of 1 to 4 elements selected from deuterium, halogens, CN, OH, NH2, C. 1-6 Alkyl, C 1-6 Substituents of alkoxy groups;

[0360] R 4 Selected from R 2a Its left end is connected to NH;

[0361] R 5 Selected from S or O; preferably, R 5 Selected from O;

[0362] R 6 Selected from -C 1-6 alkylene-, -C 3-6 Cycloalkylene-, wherein the alkylene or cycloalkylene group is optionally surrounded by 1 to 6 R groups. k Replaced;

[0363] R 7 Selected from OH and -C(=O)OH;

[0364] R 1 Each element is independently selected from H, deuterium, and C. 1-6 Alkyl, -C(=O)R 1a -S(=O)2R 1a -P(=O)R 1a R 1b C 3-8 A carbocyclic or 3- to 10-membered heterocyclic group, wherein the alkyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0365] R k Each element is independently selected from deuterium, halogens, OH, =O, CN, NH2, NO2, COOH, CONH2, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, -OC 3-6 Carbocyclic rings, -O-3 to 7-membered heterocycles, -NH-C 3-6 Carbon rings, -NH-3 to 7-membered heterocycles, -SC 3-6 Carbon rings, -S-3 to 7-membered heterocycles, -C 0-4 Alkylene-C 3-6 Carbon ring, -C 0-4 Alkylene-3 to 7-membered heterocycles, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic group is optionally selected from 1 to 4 deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 The alkoxy group is substituted; preferably, R k Each element is independently selected from deuterium, halogens, OH, CN, and C. 1-4 Alkyl, OC 1-4 Alkyl groups, wherein the alkyl group is optionally composed of 1 to 4 elements selected from deuterium, halogens, CN, OH, NH2, C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0366] R 2 Selected from -C 1-6 Alkylene-VC 1-6 Alkylene-WR 2a -、-C 2-6 Alkylene-WR 2a -、-C2-6 Alkylene-WR 2c -、-C 2-6 Alkylene-WR 2c -R 2a - The alkylene group is optionally surrounded by 1 to 8 elements selected from deuterium, halogen, CN, OH, NH2, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Substituted with cycloalkyl or 3-8 membered heterocyclic groups, with its right end connected to L5;

[0367] V is selected from O, S, NR v Preferably, V is selected from O;

[0368] W is selected from O, S, NR w Preferably, W is selected from NR. w ;

[0369] R 2a Selected from -C 1-6 Alkylene-, -C(=O)C(R) 2b )2O-、-C(=O)C(R 2b )2NH-、-C(=O)C(R 2b )2C(R 2b )2O-、-C(=O)C(R 2b )2C(R 2b )2C(R 2b )2O-、-C(=O)-R 2c -O-, its right end is connected to L5, and the alkylene group is optionally surrounded by 1 to 6 elements selected from deuterium, halogen, CN, OH, NH2, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Substituents of cycloalkyl or 3-8 membered heterocyclic groups; preferably, R 2a Selected from -C(=O)C(R) 2b )2O-、-C(=O)C(R 2b )2NH-、-C(=O)C(R 2b )2C(R 2b )2O-、-C(=O)-R 2c -O-, its right end is connected to L5;

[0370] R 2b Each element is independently selected from H, deuterium, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8The alkyl, carbocyclic, or heterocyclic group may be selected from 1 to 6 elements chosen from deuterium, halogen, CN, OH, NH2, C. 1-6 Alkyl, C 1-6 Alkoxy, The substituent is replaced by; preferably, R 2b Each element is independently selected from H, deuterium, halogens, and C. 1-4 Alkyl, C 3-6 The carbocyclic group, wherein the alkyl group or carbocyclic group is optionally composed of 1 to 4 radicals selected from deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 Alkoxy, The substituents are replaced;

[0371] R ka R kb Each is independently selected from H, CN, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocyclic groups, C 1-2 Alkylene-C 3-6 carbon cyclo group, C 1-2 Alkylene-4 to 6-membered heterocyclic group, wherein the alkylene, alkyl, cycloalkyl, carbocyclic or heterocyclic group is optionally composed of 1 to 4 groups selected from deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The substituents on the carbon ring are replaced;

[0372] As an option, 2 R 2b Direct connection forms C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. k Replaced; preferably, 2 R 2b Direct connection forms C 3-6 cycloalkyl group, wherein the cycloalkyl group is optionally surrounded by 1 to 4 R groups k Replaced;

[0373] R 2c Selected from C 3-10 Cycloalkyl or 4-10 membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally surrounded by 1 to 6 R groups. k Replaced; preferably, R 2c Selected from C 3-6 cycloalkyl groups, wherein the cycloalkyl group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0374] R a Each element is independently selected from deuterium, halogens, OH, NH2, CN, NO2, COOH, CONH2, and C. 1-6 Alkyl, C1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0375] m is selected from 0, 1, 2, and 3;

[0376] p is independently selected from 0, 1, 2, 3, 4, 5 or 6; preferably, p is independently selected from 0 or 1;

[0377] Y is selected from O, S, NH, N-CN;

[0378] X1 is selected from -NR x1 -C 1-4 Alkylene-, -OC 1-4 Alkylene-, -SC 1-4 Alkylene-, C 3-10 Cycloalkyl or 4-10 membered heterocyclic group, wherein the alkylene, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 6 R groups. k Replaced; preferably, X1 is selected from -NR x1 -C 1-4 Alkylene-, -OC 1-4 Alkylene-, wherein the alkylene is optionally surrounded by 1 to 4 R k Replaced;

[0379] X2 is selected from -NR x2 -、-CR x R x -、-O-; Preferably, X2 is selected from -NR x2 -;

[0380] R x Each is independently selected from halogens;

[0381] R v R w R x1 R x2 Each is independently selected from H, deuterium, and C. 1-4 Alkyl, C 3-6 Carbocyclic, 4- to 6-membered heterocyclic, wherein the alkyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k Replaced; preferably, R v R w R x1 R x2 Each is independently selected from H, deuterium, and C. 1-4 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0382] Ring B is selected from one of the following structures with optional substitution: When replaced, by 1 to 4 R b The ring B is replaced by a structure whose left side is directly connected to X1; preferably, ring B is selected from one of the following optional structures: When replaced, by 1 to 4 R b It has been replaced, and its left side is directly connected to X1;

[0383] D1 and D2 are each independently selected from O, S, NH, or NR. b ;

[0384] D3 and D4 are each independently selected from O, S, N, NH, or NR. b ;

[0385] E2, E3, E4, and E5 are each independently selected from CR. b CH or N;

[0386] E1 is selected from C(R) b 2. CHR b ,CH2,C(=O),CH2CH2,CHR b CHR b , Preferably, E1 is selected from C(R) b 2. CHR b CH2, C (=O);

[0387] R b Each element is independently selected from deuterium, halogen, OH, cyano, NH2, NO2, N(C) 1-6 Alkyl)2, NH(C) 1-6 Alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, -C(=O)R 1a -S(=O)2R 1a -P(=O)R 1a R 1b C 3-10 Carbocyclic groups, 4- to 10-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally selected from 1 to 4 R k Replaced;

[0388] C1, C2, C3, and C4 are each independently selected from CR c CH or N;

[0389] R c Each is independently selected from deuterium, halogens, OH, COOH, CN, NO2, NH2, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 acetylinyl, OC 1-6 Alkyl, SC 1-6 Alkyl, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, -C 0-4 Alkylene-C 3-10 carbonyl group, -C 0-4 Alkylene-4 to 10-membered heterocyclic group, wherein the alkyl, alkenyl, alkynylene, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R groups. k Replaced; preferably, R c Each is independently selected from deuterium, halogens, OH, CN, and C. 1-4 Alkyl, OC 1-4 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0390] R 1a R 1b Each element is independently selected from H, OH, NH2, and C. 1-6 Alkyl, C 1-6 Alkoxy, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 3-8 Carbocyclic groups, 4- to 10-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the alkyl, alkoxy, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0391] As an option, two R a Two Rs c Together with the atoms or framework attached to it, they form C 3-10 A carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k What it replaced.

[0392] As an eighth embodiment of the present invention, the compound represented by the aforementioned general formula (II) or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts thereof...

[0393] R v R w Each is independently selected from H, deuterium, CHF2, CH2F, CF3, CD3, CH2OH, methyl, ethyl, propyl, and isopropyl.

[0394] X1 is selected from -NHCH2-, -NHCH2CH2-, -OCH2-, -SCH2-, -O-CH2CH2-, -S-CH2CH2-, X a The CH2 is optionally converted by 1 to 2 R k The CH2 group is replaced by one or two substituents selected from deuterium, F, Cl, Br, CHF2, CH2F, CF3, CD3, methyl, and methoxy.

[0395] X2 is selected from -NH- and -CF2-; preferably, X2 is selected from -NH-.

[0396] X a Selected from 1 to 4 Rs k The following structures are substituted: cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, cyclobutylspirocyclobutyl, aziridinespirocyclobutyl, aziridinespiroaziridine, piperidinylspirocyclobutyl, cyclohexylspirocyclobutyl, cyclopropylcyclopentyl, cyclopentylcyclopentyl, pyrrolidinylcycloalkyl, pyrrolidinylcyclopentyl The bond connecting the left end -C (=Y)- and the right end ring B is linked in ring X. a On different atoms;

[0397] R 2 Selected from -methylene-V-methylene-WR 2a -、-Ethylene-V-Ethylene-WR 2a -、-Ethylene-V-methylene-WR 2a -、-methylene-V-ethylidene-WR 2a -,-Ethylene-V-Propylene-WR 2a -、-methylene-V-propylene-WR 2a -,-Ethylene-WR 2a -,-Ethylene-WR 2c -,-Propylene-WR 2c -,-Ethylene-WR 2c -R 2a -,-Propylene-WR 2c -R 2a -,-Propylene-WR 2a -, -Butyl-WR 2a - Its right end is connected to L5, wherein the methylene, ethylene, propylene, and butylene are optionally selected from 1 to 8 elements selected from deuterium, F, Cl, Br, I, CN, OH, NH2, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C1-4 The alkoxy group is substituted; preferably, R 2 Selected from -Ethylene-O-Ethylene-NR w -R 2a - Its right end is connected to L5, wherein the methylene, ethylene, propylene, and butylene are optionally selected from 1 to 8 elements selected from deuterium, F, Cl, Br, I, CN, OH, NH2, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0398] R 2a Selected from methylene, ethylene, propylene, isopropylene, butylene, -C(=O)C(R) 2b )2O-、-C(=O)C(R 2b )2NH-、-C(=O)C(R 2b )2C(R 2b )2O-、-C(=O)C(R 2b )2C(R 2b )2C(R 2b )2O-、-C(=O)-R 2c -O-, its right end is connected to L5, wherein the methylene, ethylene, propylene, isopropylene, and butylene are optionally selected from 1 to 4 of the following: deuterium, F, Cl, Br, I, CN, OH, NH2, C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Substituents of cycloalkyl or 3-6 membered heterocyclic groups; preferably, R 2a Selected from -C(=O)C(R) 2b )2O-、-C(=O)-R 2c -O-, its right end is connected to L5;

[0399] R 2b Each of the following elements is independently selected from H, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolyl, piperidinyl, morpholinyl, piperazine, oxacyclobutyl, tetrahydrofuranyl, and phenyl, wherein methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolyl, piperidinyl, morpholinyl, piperazine, oxacyclobutyl, tetrahydrofuranyl, and phenyl are optionally selected from 1 to 4 elements selected from deuterium, halogen, CN, OH, NH2, and C. 1-4 Alkyl, C 1-4 Alkoxy, The substituent is replaced by; preferably, R2b Each of the following is independently selected from H, deuterium, F, Cl, Br, I, methyl, cyclopropyl, and cyclobutyl, wherein the methyl, cyclopropyl, and cyclobutyl groups are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, methyl, and methoxy.

[0400] R ka R kb The following groups are selected independently from H, CN, F, Cl, Br or optionally replaced by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, methyl, methoxy, and cyclopropyl: methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, oxecyclobutyl, azacyclobutyl, CH2-cyclopropyl, CH2-cyclobutyl;

[0401] As an option, 2 R 2b Direct connection forms an optional 1 to 4 R k The following structures are replaced: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxacyclobutyl, tetrahydrofuranyl, and cyclobutylspirocyclobutyl.

[0402] R 2c Selected from 1 to 4 Rs k The following structures are replaced: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutylspirocyclobutyl, cyclopropyl-cyclopentyl, aziridine, pyrrolidinyl, piperidinyl, morpholinyl. Preferably, R 2c The cyclopropyl or cyclobutyl group is selected from cyclopropyl or cyclobutyl, wherein the cyclopropyl or cyclobutyl group is optionally replaced by 1 to 4 substituents selected from deuterium, F, Cl, Br, CHF2, CH2F, CF3, CD3, methyl, or methoxy.

[0403] R k Each of the following groups is independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, NO2, COOH, CONH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, aziridine, oxacyclobutyl, pyrrolylyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, aziridine, oxacyclobutyl, pyrrolylyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl is optionally selected from deuterium, F, Cl, Br, I, CN, OH, NH2, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0404] R 1 Each is independently selected from its own H, deuterium, methyl, ethyl, propyl, isopropyl, -C(=O)R 1a -S(=O)2R 1a -P(=O)R 1a R 1b Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxetidine, pyrrolidinyl, piperidinyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxetidine, pyrrolidinyl, piperidinyl, or morpholinyl group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0405] R 1a R 1b Each of the following is independently selected from H, OH, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole, or thiophene, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole, or thiophene is optionally surrounded by 1 to 3 Rs. k Replaced;

[0406] R a Each of the following is independently selected from deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, CONH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, and pyrrolidinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, and pyrrolidinyl groups are optionally prefixed with 1 to 4 R. k Replaced;

[0407] R bEach of the following groups is independently selected from deuterium, F, Cl, Br, I, OH, cyano, NH2, NO2, NHCH3, N(CH3)2, COOH, CONH2, -C(=O)-methyl, -C(=O)-ethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole, or thiophene, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole, or thiophene is optionally surrounded by 1 to 4 R groups. k Replaced;

[0408] R c Each is independently selected from deuterium, F, Cl, Br, I, OH, COOH, CN, NO2, NH2, NHCH3, N(CH3)2, or optionally coated by 1 to 4 R. k The substituted groups include: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, and cyclopentyl; preferably, R c Each is independently selected from deuterium, F, Cl, Br, I, CHF2, CH2F, CF3, CD3, and methyl;

[0409] As an option, two R a Two Rs c Together with the atoms or skeleton attached thereto, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, oxacyclopentyl, pyrrolyl, piperidinyl, or 1,3-dioxopentyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, oxacyclopentyl, pyrrolyl, piperidinyl, or 1,3-dioxopentyl are optionally surrounded by 1 to 4 R atoms. k Replaced;

[0410] The definitions of the remaining substituents are consistent with those described in Scheme 7 of this invention.

[0411] As a ninth embodiment of the present invention, the compound represented by the aforementioned general formula (II) or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts thereof...

[0412] R kEach of the following is independently selected from deuterium, F, Cl, Br, OH, CN, NH2, NO2, COOH, CONH2, NHCH3, N(CH3)2, CHF2, CH2F, CF3, CD3, CH2OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl; preferably, R k Each is independently selected from deuterium, F, Cl, Br, CHF2, CH2F, CF3, CD3, and methyl;

[0413] R 4 Selected from -C(=O)CH2O-, -C(=O)C(R) 2b )2NH-, -C(=O)C(H)(D)O-, -C(=O)CD2O-, -C(=O)CH(R 2b )O-、-C(=O)C(CH3)(R 2b )O-、 Its left end is connected to NH; preferably, R 4 Selected from -C(=O)CH2O-, -C(=O)C(H)(D)O-, -C(=O)CD2O-, -C(=O)CH(R) 2b )O-、-C(=O)C(CH3)(R 2b )O-、 Its left end is connected to NH; p is independently selected from 0, 1, 2, and 3;

[0414] Y is selected from O or S; preferably, Y is selected from O;

[0415] R 2 Selected from -CH2CH2-O-CH2CH2-NR w -R 2a -、-CH2-O-CH2CH2-NR w -R 2a -、-CH2CH2-O-CH2CH2-OR 2a -、-CH2CH2-NR v -CH2CH2-OR 2a -CH2CH2-S-CH2CH2-NR w -R 2a -、-CH2CH2-O-CH2CH2-SR 2a -、-CH2CH2-NR v -CH2CH2-NR w -R 2a -、-CH2CH2-NR w -R 2a-、-CH2CH2CH2-NR w -R 2a -、-CH2CH2CH2-OR 2a -、-CH2CH2CH2-OR 2c -、-CH2CH2CH2-OR 2c -R 2a -、-CH2CH2CH2CH2-NR w -R 2a -、-CH2CH2-O-CH2CH2-NR w -C(=O)CH2O-, -CH2CH2-O-CH2CH2-NR w -C(=O)C(H)(D)O-、-CH2CH2-O-CH2CH2-NR w -C(=O)CD2O-, -CH2CH2-O-CH2CH2-NR w -C(=O)CHR 2b O-、-CH2CH2-O-CH2CH2-NR w -C(=O)C(CH3)R 2b O-、-CH2-O-CH2CH2-NR w -C(=O)CHR 2b O-、-CH2-O-CH2CH2-NR w -C(=O)C(CH3)(R 2b O-, whose right end is connected to L5, wherein the CH2 is optionally replaced by one or two substituents selected from deuterium, F, Cl, Br, CN, OH, NH2, CHF2, CH2F, CF3, methyl, methoxy; preferably, R 2 Selected from -CH2CH2-O-CH2CH2-NR w -C(=O)CH2O-, -CH2CH2-O-CH2CH2-NR w -C(=O)C(H)(D)O-、-CH2CH2-O-CH2CH2-NR w -C(=O)CD2O-, -CH2CH2-O-CH2CH2-NR w -C(=O)CHR 2b O-、-CH2CH2-O-CH2CH2-NR w -C(=O)C(CH3)R 2b O-、-CH2CH2-O-CH2CH2-NR w -C(=O)-R 2c -O-、-CH2CH2CH2-OR 2c -R2a - Its right end is connected to L5, wherein the CH2 is optionally replaced by one or two substituents selected from deuterium, F, Cl, Br, CN, OH, NH2, CHF2, CH2F, CF3, methyl, methoxy;

[0416] R 2a Selected from methylene, ethylene, propylene, isopropylene, -C(=O)CH2O-, -C(=O)CH2NH-, -C(=O)C(H)(D)O-, -C(=O)CD2O-, -C(=O)CH(R) 2b )O-、-C(=O)C(CH3)(R 2b )O-、 Its right end is connected to L5, wherein the methylene, ethylene, propylene, and isopropylene are optionally replaced by 1 to 3 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, methyl, methoxy, and cyclopropyl; preferably, R 2a Selected from -C(=O)CH2O-, -C(=O)C(H)(D)O-, -C(=O)CD2O-, -C(=O)CH(R) 2b )O-、-C(=O)C(CH3)(R 2b )O-、 Its right end is connected to L5, wherein the methylene, ethylene, propylene, and isopropylene are optionally replaced by 1 to 3 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, methyl, methoxy, and cyclopropyl.

[0417] R 2b Each of the following elements is independently selected from H, deuterium, F, Cl, Br, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolyl, piperidinyl, morpholinyl, piperazine, oxacyclobutyl, tetrahydrofuranyl, and phenyl, wherein methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolyl, piperidinyl, morpholinyl, piperazine, oxacyclobutyl, tetrahydrofuranyl, and phenyl are optionally replaced by 1 to 4 elements selected from deuterium, F, Cl, Br, I, CN, OH, NH2, methyl, methoxy, The substituent is replaced by; preferably, R 2b Each of the following is independently selected from F, Cl, Br, methyl, ethyl, propyl, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, propyl, cyclopropyl, and cyclobutyl groups are optionally selected by 1 to 4 of the following: deuterium, F, Cl, Br, I, CN, OH, NH2, methyl, methoxy. The substituents are replaced;

[0418] Selected from Preferably, Selected from Selected from Its left side and R 2 Connected; preferably, Selected from Its left side and R 2 Connected;

[0419] Ring B is selected from any 1 to 3 Rs. b One of the following structures is replaced: Its left side is connected to X1; preferably, ring B is selected from 1 to 3 R. b One of the following structures is replaced: Its left side is connected to X1;

[0420] Ring Xa is selected from 1 to 3 R's by choice. c One of the following structures is replaced:

[0421] Selected from Preferably, Selected from

[0422] The definitions of the remaining substituents are consistent with those described in Schemes 7 and 8 of this invention.

[0423] As a tenth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, wherein...

[0424] D is selected from one of the following structures:

[0425] Indicates an optional connection position, when connected to a certain position of D. When connecting, another location For H;

[0426] R 3 Selected from C 1-6 Alkyl, -C 1-6 Alkylene-NR 3a -S(=O)2C 1-6 Alkyl, -C 1-6 Alkylene-NR3a -C(=O)C 1-6 Alkyl groups, wherein the alkylene group or alkyl group is optionally composed of 1 to 4 elements selected from deuterium, halogens, CN, OH, NH2, C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Substituents of cycloalkyl groups; preferably, R 3 The group is selected from methyl, ethyl, -ethylidene-N(isopropyl)-S(=O)2methyl, -ethylidene-N(isopropyl)-C(=O)methyl, wherein the methyl, ethyl, ethylidene, and isopropyl groups are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, CN, OH, NH2, methyl, and methoxy groups;

[0427] R 3a Selected from H, C 1-6 Alkyl groups, wherein the alkyl group is optionally composed of 1 to 4 elements selected from deuterium, halogens, CN, OH, NH2, C. 1-6 Alkyl, C 1-6 The alkoxy group is substituted; preferably, R 3a Selected from methyl, ethyl, and isopropyl;

[0428] R 4 Selected from H, deuterium, halogens, C 1-6 Alkyl, C 3-6 Cycloalkyl groups, wherein the alkyl group or cycloalkyl group is optionally composed of 1 to 4 elements selected from deuterium, halogen, CN, OH, NH2, C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Substituents of cycloalkyl groups; preferably, R 4 The group is selected from H, deuterium, F, Cl, Br, methyl, ethyl, isopropyl, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, isopropyl, cyclopropyl, and cyclobutyl groups are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, CN, OH, NH2, methyl, and methoxy groups;

[0429] R 5 Selected from S or O;

[0430] R 6 Selected from -C 1-6 Alkylene, wherein the alkylene is optionally surrounded by 1 to 6 elements selected from deuterium, halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Substituents of cycloalkyl groups; preferably, R 6 The group is selected from -methylene-, -ethylene-, and -propylene-, wherein the methylene-, -ethylene-, and -propylene- are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, CN, OH, NH2, methyl, and methoxy;

[0431] R 7 Selected from OH and -C(=O)OH;

[0432] The definitions of the remaining substituents are consistent with those described in Schemes 1, 2, 3, 4, 5, and 6 of this invention.

[0433] As an eleventh embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, wherein D is selected from one of the structures shown in Table A-1 and Table A-4.

[0434] As a twelfth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, wherein the compound is selected from one of the structures shown in Table A-2.

[0435] As a thirteenth embodiment of the present invention, the compound represented by the following general formula (III), or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, are used.

[0436] Tb-[L'-D]q(III)

[0437] Tb is the target region; preferably, the target region is selected from antibody or antigen-binding fragments; the target region can specifically bind to cell surface receptors or antigens; the antigen is B7H3, B7-H4, CCL11, CCR5, CD123, CD133, CD138, CD18, CD19, CD33, CD40, HER2, HER3, CD20, CD38, CD33, BCMA, CD138, EGFR, FGFR4, GD2, PDGFR, TEM1 / CD248, TROP-2, DLL3, CDH6, CDH17, CEACAM5. Or a combination thereof; the antibody is anti-CD33, rituximab, trastuzumab, pertuzumab, OR000213(huMy9-6IgG4S228P), lintuzumab, anti-DLL3, anti-CDH6, anti-CDH17, anti-CEACAM5, or gemtuzumab; more preferably, Tb is CD33Ab1, CD33Ab2, trastuzumab, Raludotatug, anti-CDH17, or CEACAM5Ab1;

[0438] L' is selected from connectors; preferably, L' is selected from -L0-L1-L2-(L3). p1 -(L4) p2-L5-; more preferably, L' is selected from -L0-L1-L2-L3-L5-, -L0-L1-L3-L5-, L0-L1-L2-L4-L5-; even more preferably, L' is selected from -L0-L1-L3-L5-;

[0439] q is selected from any value between 1 and 20. For example, q is any value between 1-10, 1-8, 2-8, 4-8 or 6-8. Preferably, q is 2±0.4, 4±0.4, 6±0.4 or 8±0.4. More preferably, q is any value between 6 and 8.

[0440] The definitions of L0, L1, L2, L3, L4, L5, and D are consistent with any one of the embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 of this invention.

[0441] As a fourteenth embodiment of the present invention, the compound represented by the following general formula (IV), or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, wherein,

[0442] L-L0-L1-L2-(L3) p1 -(L4) p2 -L5-H(IV);

[0443] The definitions of L, L0, L1, L2, L3, L4, L5, p1, and p2 are consistent with those of any one of the embodiments 1, 2, 3, 4, 5, and 6 of this invention.

[0444] As a fifteenth embodiment of the present invention, the compound represented by the following general formula (IA), or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, wherein,

[0445] L-L0-L1-L3-L5-D(IA)

[0446] L is selected from halogen, sulfone, and tertiary amine salt (Me3N). + Et3N + ), diazonium salts, -OMs, MeSO2-, CF3SO3-, p-toluenesulfonyl groups;

[0447] L0 is selected from Its left end is connected to L;

[0448] L1 is selected from Its right side is connected to L3; m5 is selected from 1 and 2; preferably, -L1- is selected from Its right side connects to L3;

[0449] L3 is selected from -AA-, -AA1-, -AA-AA-, -AA-AA-AA-, -AA-AA-AA-AA-, -AA-AA1-, -AA1-AA-, -AA-AA1-AA-, -AA-AA-AA1-, -AA1-AA-AA-AA-, -AA1-AA-AA- AA-AA-; preferably, L3 is selected from -Val-Gly-, -Val-Cit-, -Phe-Lys-Gly-, -Gly-Val-Lys-Gly-, -Val-Lys-Gly-Gly-, -Val-Lys-Gly-, -Val-Lys-Ala-, -Gl y-Gly-Phe-Gly-, -Val-AA1-, -Val-AA1-Val-, -Val-AA1-Gly-, -AA1-AA1-, -AA1-AA1-Gly-, -AA1-Val-Cit-, -Val-Ala-, -Ala-Ala-Ala-, A A1-Gly-Gly-Phe-Gly-, -AA1-Val-Ala-; more preferably, L3 is selected from -Val-Cit-, -Gly-Gly-Phe-Gly-, -Val-Ala-, -Ala-Ala-Ala-, AA1-Gly-Gly-Phe-Gly-;

[0450] AA1 is selected from Preferably, AA1 is selected from

[0451] L5 is selected from -Z4-;

[0452] Z4 is selected from -N(R) L5 )-C(R L6 )2-、-OC(R L6 )2-、-OC(=O)-、-N(R L5 )-CH2CH2-N(R L7 Z4 is selected from -N(R)-C(=O)-, and its right side is connected to D; preferably, Z4 is selected from -N(R)-C(=O)-. L5 )-C(R L6 )2-, whose right side is connected to D; more preferably, Z4 is selected from Its right side is connected to D; more preferably, Z4 is selected from Its right side is connected to D;

[0453] D is selected from Preferably, D is selected from

[0454] More preferably, D is selected from

[0455] X1 is selected from -NR x1 -C 1-4 Alkylene-, -OC 1-4 Alkylene-, wherein the alkylene is optionally surrounded by 1 to 4 R k The CH2 group is replaced by one or two substituents selected from deuterium, F, Cl, Br, CHF2, CH2F, CF3, CD3, methyl, and methoxy.

[0456] R 2 Selected from -Ethylene-O-Ethylene-NR w -R 2a - Its right end is connected to L5, wherein the methylene, ethylene, propylene, and butylene are optionally selected from 1 to 8 elements selected from deuterium, F, Cl, Br, I, CN, OH, NH2, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 The alkoxy group is substituted; preferably, R 2 Selected from -CH2CH2-O-CH2CH2-NR w -C(=O)CH2O-, -CH2CH2-O-CH2CH2-NR w -C(=O)C(H)(D)O-、-CH2CH2-O-CH2CH2-NR w -C(=O)CD2O-, -CH2CH2-O-CH2CH2-NR w -C(=O)CHR 2b O-、-CH2CH2-O-CH2CH2-NR w -C(=O)C(CH3)R 2b O-、-CH2CH2-O-CH2CH2-NR w -C(=O)-R 2c -O-, its right end is connected to L5, wherein the CH2 is optionally replaced by one or two substituents selected from deuterium, F, Cl, Br, CN, OH, NH2, CHF2, CH2F, CF3, methyl, methoxy; more preferably, R 2 Selected from Its right end connects to L5;

[0457] R c Each is independently selected from deuterium, F, Cl, Br, I, or arbitrarily selected by 1 to 4 R. kThe substituted groups include: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, methylthio, and cyclopropyl; preferably, R c Each is independently selected from deuterium, F, Cl, and Br;

[0458] R 5 Selected from S or O; preferably, R 5 Selected from O;

[0459] R 4 Selected from R 2a Its left end is connected to NH; preferably, R 4 Selected from -C(=O)CH2O-, -C(=O)C(H)(D)O-, -C(=O)CD2O-, -C(=O)C(H)(CH3)O-, Its left end is connected to NH;

[0460] R 2a Selected from -C(=O)C(R) 2b )2O-、-C(=O)-R 2c -O-, its right end is connected to L5; preferably, R 2a Selected from -C(=O)CH2O-, -C(=O)C(H)(D)O-, -C(=O)CD2O-, -C(=O)CH(R) 2b )O-、-C(=O)C(CH3)(R 2b )O-、 Its right end is connected to L5, wherein the methylene, ethylene, propylene, and isopropylene are optionally replaced by 1 to 3 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, methyl, methoxy, and cyclopropyl.

[0461] R 2b Each element is independently selected from H, deuterium, halogens, and C. 1-4 Alkyl, C 3-6 The carbocyclic group, wherein the alkyl group or carbocyclic group is optionally composed of 1 to 4 radicals selected from deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 Alkoxy, The substituent is replaced by; preferably, R 2b Each of the following is independently selected from H, deuterium, F, Cl, Br, I, methyl, cyclopropyl, and cyclobutyl, wherein the methyl, cyclopropyl, and cyclobutyl groups are optionally replaced by 1 to 4 groups selected from deuterium, F, Cl, Br, methyl, methoxy, The substituents are replaced;

[0462] R ka R kbThe following groups are selected independently from H, CN, F, Cl, Br or optionally replaced by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, methyl, methoxy, and cyclopropyl: methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, oxecyclobutyl, azacyclobutyl, CH2-cyclopropyl, CH2-cyclobutyl;

[0463] Preferably, Selected from

[0464] R 2c Selected from C 3-6 cycloalkyl groups, wherein the cycloalkyl group is optionally surrounded by 1 to 4 R groups. k Replaced; preferably, R 2c The cyclopropyl or cyclobutyl group is selected from cyclopropyl or cyclobutyl, wherein the cyclopropyl or cyclobutyl group is optionally replaced by 1 to 4 substituents selected from deuterium, F, Cl, Br, CHF2, CH2F, CF3, CD3, methyl, or methoxy.

[0465] R k Each is independently selected from deuterium, F, Cl, Br, CHF2, CH2F, CF3, CD3, and methyl.

[0466] The definitions of the remaining substituents are consistent with those described in Schemes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 of this invention.

[0467] As a sixteenth embodiment of the present invention, the compound represented by the following general formulas (I-Aa) and (I-Ab), or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, wherein...

[0468] R 4 Selected from -C(=O)CH2O-, -C(=O)C(H)(D)O-, -C(=O)CD2O-, -C(=O)C(H)(CH3)O-, Its left end is connected to NH;

[0469] R 5 Selected from S or O; preferably, R 5 Selected from O;

[0470] X1 is selected from -NHCH2- and -OCH2-, wherein the CH2 is optionally substituted with one or two substituents selected from deuterium, F, Cl, Br, CHF2, CH2F, CF3, CD3, methyl, and methoxy; preferably, X1 is selected from -NHCH2-, wherein the CH2 is optionally substituted with one or two substituents selected from deuterium, F, Cl, Br, CHF2, CH2F, CF3, CD3, methyl, and methoxy.

[0471] R 2 Selected from Its right end connects to L5;

[0472] R c Each is independently selected from deuterium, F, Cl, Br, I, methyl, CHF2, CH2F, CF3; preferably, R c Each is independently selected from deuterium, F, Cl, and Br;

[0473] L3 is selected from -Gly-Gly-Phe-Gly-, Preferably, L3 is selected from -Gly-Gly-Phe-Gly-;

[0474] L5 is selected from Its right side is connected to D; preferably, L5 is selected from Its right side is connected to D.

[0475] As the seventeenth embodiment of the present invention, the ligand-drug conjugate or its stereoisomer, racemate, tautomer, or pharmaceutically acceptable salt represented by the following general formula (III-A) is used.

[0476] Tb-[L-L0-L1-L3-L5-D]q(III-A)

[0477] The definition of substituents is consistent with that described in Scheme 14, Scheme 15 and Scheme 16 of this invention.

[0478] This invention relates to a compound or its stereoisomer, racemate, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the structures shown in Table A-2.

[0479] This invention relates to a ligand-drug conjugate or its stereoisomer, racemate, tautomer, or pharmaceutically acceptable salt thereof, wherein the conjugate is selected from one of the structures in Table A-3 below.

[0480] Table A-1

[0481] Table A-2

[0482] This invention relates to a pharmaceutical composition comprising the compound described herein or its ligand-drug conjugate or its stereoisomer, racemate, tautomer, pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition contains 1-1500 mg of the compound described herein or its stereoisomer, racemate, tautomer, or pharmaceutically acceptable salt.

[0483] This invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the above-described compound of the invention or its ligand-drug conjugate or its stereoisomer, racemate, tautomer, pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

[0484] This invention relates to the use of a compound of the present invention or its ligand-drug conjugate or its stereoisomer, racemate, tautomer, or pharmaceutically acceptable salt in the preparation of a drug for treating tumors or cancer.

[0485] In some embodiments, the pharmaceutical composition of the present invention may be in unit dosage form (the amount of the active pharmaceutical ingredient in a unit dosage form is also referred to as a "dosage strength").

[0486] The term "effective amount" or "therapeutic effective amount" as used in this application means that administering a sufficient amount of the compound disclosed in this application will alleviate, to some extent, one or more symptoms of the disease or condition (e.g., tumor) being treated. In some embodiments, the result is a reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of the compound disclosed in this application required to provide a clinically significant reduction in disease symptoms.Examples of therapeutically effective doses include, but are not limited to, 1-1500 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-600 mg, 90-600 mg, 100-600 mg, 200-600 mg, and 1-500 mg. 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg , 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-40 0mg, 30-400mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90-400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 250- 400mg, 300-400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg , 80-300mg, 90-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg, 80-1000mg, 80-800mg.

[0487] In some embodiments, the pharmaceutical composition includes, but is not limited to, 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, The compounds of the present invention, or their stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts thereof, in doses of 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, or 840 mg.

[0488] A method for treating a disease in mammals, the method comprising administering to a subject a therapeutically effective amount of the compound of the present invention or its ligand-drug conjugate or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, preferably 1-1500 mg, wherein the disease is preferably a tumor or cancer.

[0489] A method for treating a disease in mammals, the method comprising administering a drug, a compound of the present invention or a ligand-drug conjugate thereof or a stereoisomer, racemate, tautomer, or pharmaceutically acceptable salt thereof, to a subject at a daily dose of 1-1000 mg / day, said daily dose being a single dose or multiple doses. In some embodiments, the daily dose includes, but is not limited to, 10-1500 mg / day, 10-1000 mg / day, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, and 200-800 mg / day. The daily doses are 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, and 200-400 mg / day. In some embodiments, the daily doses include, but are not limited to, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 80 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 160 mg / day, 200 mg / day, 300 mg / day, 320 mg / day, 400 mg / day, 480 mg / day, 600 mg / day, 640 mg / day, 800 mg / day, and 1000 mg / day.

[0490] This invention relates to a kit that may include a single-dose or multi-dose composition, the kit containing the compound of the present invention or its ligand-drug conjugate or its stereoisomer, racemate, tautomer, or pharmaceutically acceptable salt, wherein the amount of the compound of the present invention or its ligand-drug conjugate or its stereoisomer, racemate, tautomer, or pharmaceutically acceptable salt is the same as that in the above-described pharmaceutical composition.

[0491] This invention relates to the use of the above-described compound or its ligand-drug conjugate or its stereoisomer, racemate, tautomer, pharmaceutically acceptable salt, or the above-described pharmaceutical composition in the preparation of a medicament for treating tumors or cancer-related diseases.

[0492] The amounts of the compounds of the present invention or their ligand-drug conjugates or their stereoisomers, racemates, tautomers, and pharmaceutically acceptable salts are, in each case, converted to the form of free base.

[0493] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0494] The term "ligand-drug conjugate" refers to a substance obtained by linking a bioactive molecule (drug molecule) to a target moiety. In some embodiments of the present invention, the bioactive molecule and the target moiety are linked via a linker. The linker is capable of cleavage under specific conditions (e.g., hydrolytic enzymes and / or low pH environments within tumors) or specific actions (e.g., the action of lysosomal proteases), thereby separating the bioactive molecule from the target moiety. In some embodiments of the present invention, the linker comprises cleavable or cleavable units, such as peptides or disulfide bonds. In some embodiments of the present invention, the bioactive molecule and the target moiety are directly linked by a covalent bond, which is capable of cleavage under specific conditions or actions, thereby separating the bioactive molecule from the target moiety. In some embodiments of the present invention, the ligand-drug conjugate comprises a target moiety, a linker, and fragments of compounds of formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Iaa, and Ibb of the present invention. In this invention, the "ligand-drug conjugate" is preferably an antibody-drug conjugate (ADC), which refers to a monoclonal antibody or antibody fragment linked to a bioactive molecule through a stable linker.

[0495] The terms “bioactive substance,” “bioactive molecule,” “drug,” or “drug molecule” refer to substances that inhibit or prevent cell function and / or cause cell death or damage. In some embodiments of the present invention, the bioactive substance, bioactive molecule, or drug molecule in the conjugate is a molecule with antitumor biological activity.

[0496] The term "camptothecin derivatives" refers to camptothecin and its derivatives that are cytotoxic, such as camptothecin, 10-hydroxycamptothecin, SN38 (7-ethyl-10-hydroxycamptothecin), topotecan, ixotecan, irinotecan, 9-nitro-10-hydroxycamptothecin, and compounds or pharmaceutically acceptable salts of general formula (II-A).

[0497] The term "targeting moiety" refers to the portion of a conjugate that specifically binds to a target (or a portion of the target) on the cell surface. Through the interaction between the targeting moiety and the target, the conjugate can be delivered to a specific cell population. When the targeting moiety in a conjugate is an antibody, the conjugate can be called a "drug-antibody conjugate".

[0498] The term "bioactive molecular fragment" refers to a portion (fragment or group) of a ligand-drug conjugate (e.g., antibody-drug conjugate (ADC)) known in the art, which, after the linker breaks in tumor tissues or tumor cells, can form a bioactive drug (e.g., a small molecule cytotoxic drug, which includes a group after losing an atom or group of atoms) or its derivative (e.g., its precursor).

[0499] The term "ligand" refers to a macromolecular compound that recognizes and binds to antigens or receptors associated with target cells. The role of ligands is to deliver drugs to the target cell population that has bound to them. These ligands include, but are not limited to, protein hormones, lectins, growth factors, antibodies, or other molecules that can bind to cells. In embodiments of this invention, the ligand is designated as Tb. The ligand can form a linker bond through the reaction of heteroatoms on the ligand with a linker, preferably an antibody or its antigen-binding fragment. The antibody is selected from chimeric antibodies, humanized antibodies, fully human antibodies, or murine antibodies; preferably, a monoclonal antibody.

[0500] In one embodiment, the ligand has a thiol functional group, such that the ligand unit is bonded to the linker via the sulfur atom of the thiol functional group.

[0501] In another embodiment, the ligand has a lysine residue that can react with an activated ester (including but not limited to N-hydroxysuccinimide, pentafluorophenyl, and p-nitrophenyl ester) of the linker unit of the drug linker compound, thereby generating an amide bond between the nitrogen atom from the ligand and the C=O functional group of the linker unit from the drug linker compound.

[0502] In one embodiment, the ligand is an antibody, and the thiol group is generated by reducing the interchain disulfide bonds of the antibody. Therefore, in some embodiments, the linker is conjugated to the cysteine ​​residues of the reduced interchain disulfide of the ligand.

[0503] In another embodiment, the ligand is derived from the antibody, and the thiol functional group is introduced into the antibody chemically, for example, by introducing a cysteine ​​residue. Therefore, in some embodiments, the linker binds to the drug unit via the introduced cysteine ​​residue of the ligand.

[0504] The terms “antibody-drug conjugate”, “antibody-protein degrader conjugate”, “antibody-drug conjugate”, and “ADC” are used interchangeably here.

[0505] The terms "conjugating" and "linking" are used interchangeably. "Conjugating" and "linking" refer to the covalent or non-covalent attachment of a bioactive molecular fragment to a ligand (preferably an antibody).

[0506] The terms "drug-ligand conjugation ratio," "drug-antibody conjugation ratio," "DAR," or "drug-antibody ratio" refer to the ratio of bioactive molecules to ligands or antibodies in a conjugate, i.e., the average number of bioactive molecules linked to each ligand or antibody. In some embodiments, the DAR of the conjugate is a value from 1 to 10. In some embodiments, the DAR of the conjugate is a value of 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, the DAR of the conjugate is 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, or 3. 9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.

[0507] The term "antibody" refers to an immunoglobulin molecule typically composed of two pairs of polypeptide chains (each pair consisting of one light chain (LC) and one heavy chain (HC)). Antibody light chains can be classified as κ (kappa) and λ (lambda) light chains. Heavy chains can be classified as μ, δ, γ, α, or ε, and antibody isotypes are defined as IgM, IgD, IgG, IgA, and IgE, respectively. Within both light and heavy chains, variable and constant regions are linked by a "J" region of approximately 12 or more amino acids, and the heavy chain also contains a "D" region of approximately 3 or more amino acids. Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region (CH). The heavy chain constant region consists of three domains (CH1, CH2, and CH3). Each light chain consists of a light chain variable region (VL) and a light chain constant region (CL). The light chain constant region consists of one domain, CL. Constant domains do not directly participate in antibody-antigen binding but exhibit various effector functions, such as mediating the binding of immunoglobulins to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. The VH and VL regions can be further subdivided into highly degenerated regions (called complementarity-determining regions (CDRs)) interspersed with more conserved regions called framework regions (FRs). Each VH and VL consists of three CDRs and four FRs arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions (VH and VL) of each heavy / light chain pair form antigen-binding sites. The amino acid distribution in each region or domain can follow various numbering systems known in the art.The antibodies described in this invention are preferably specific antibodies against cell surface antigens on target cells. Non-limiting examples include one or more of the following antibodies: anti-B7H3 antibody, anti-B7-H4 antibody, anti-CCL11 antibody, anti-CCR5 antibody, anti-CD123 antibody, anti-CD133 antibody, anti-CD138 antibody, anti-CD18 antibody, anti-CD19 antibody, anti-CD33 antibody, anti-CD40 antibody, anti-HER2 antibody, anti-HER3 antibody, anti-CD20 antibody, anti-CD38 antibody, anti-CD33 antibody, anti-BCMA antibody, anti-CD138 antibody, anti-EGFR antibody, anti-FGFR4 antibody, anti-GD2 antibody, anti-PDGFR antibody, anti-TEM1 / CD248 antibody, anti-CDH17 antibody, anti-CEACAM5 antibody, and anti-TROP-2 antibody; preferably trastux. Trastuzumab (trastuzumab, brand name Herceptin), Pertuzumab (also known as 2C4, brand name Perjeta), Nimotuzumab (Nimotuzumab, brand name Taixinsheng), Enoblituzumab, Emibetuzumab, Inotuzumab, rituximab, OR000213 (huMy9-6IgG4S228P), lintuzumab, Pinatuzumab, Brentuximab, Gemtuzumab, Bivatuzumab, Lorvotuzumab, cBR96, anti-CDH17, anti-CEACAM5, and Glematumamab.

[0508] The term "complementarity-determining region" or "CDR" refers to the amino acid residues in the variable region of an antibody that are responsible for antigen binding. Each of the heavy and light chain variable regions contains three CDRs, named CDR1, CDR2, and CDR3. The precise boundaries of these CDRs can be defined according to various numbering systems known in the art, such as the Kabat numbering system (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991), the Chothia numbering system (Chothia & Lesk (1987) J. Mol. Biol. 196: 901-917; Chothia et al. (1989) Nature 342: 878-883), the IMGT numbering system (Lefranc et al., Dev. Comparat. Immunol. 27: 55-77, 2003), or the AbM numbering system (Martin ACR, Cheetham JC, Rees AR (1989) Modelling antibody hypervariable loops: A combined algorithm. Proc Natl Acad Sci USA 86: 9268-9272). For a given antibody, those skilled in the art will readily identify the CDR as defined by each numbering system. Furthermore, the correspondence between different numbering systems is well known to those skilled in the art (see, for example, Lefranc et al., Dev. Comparat. Immunol. 27:55-77, 2003).

[0509] The CDRs contained in the antibodies or antigen-binding fragments of the present invention can be determined according to various numbering systems known in the art. In some embodiments, the CDRs contained in the antibodies or antigen-binding fragments of the present invention are preferably determined by the Kabat, Chothia, or AbM or IMGT numbering systems. As used herein, the terms "framework residue region" or "FR residue" refer to those amino acid residues in the variable region of the antibody other than the CDR residues as defined above.

[0510] The term "antigen-binding fragment" in antibody refers to a fragment of the antibody polypeptide, such as a fragment of the full-length antibody polypeptide, which retains the ability to specifically bind to the same antigen bound by the full-length antibody, and / or competes with the full-length antibody for specific binding to the antigen; it is also referred to as the "antigen-binding moiety". See Fundamental Immunology, Ch. 7 (Paul, W., ed., 2nd ed., Raven Press, NY (1989), which is incorporated herein by reference in its entirety for all purposes. Antigen-binding fragments of antibodies can be generated by recombinant DNA technology or by enzymatic or chemical cleavage of intact antibodies. Non-limiting examples of antigen-binding fragments include Fab fragments, Fab' fragments, F(ab)'2 fragments, F(ab)'3 fragments, Fd, Fv, scFv, di-scFv, (scFv)2, disulfide-stabilized Fv proteins (“dsFv”), single-domain antibodies (sdAb, nanobodies), and peptides containing at least a portion of an antibody sufficient to confer specific antigen-binding ability to the peptide. Engineered antibody variants are reviewed in Holliger et al., 2005; Nat In Biotechnol, 23:1126-1136, the term "Fd" refers to an antibody fragment composed of VH and CH1 domains; the term "dAb fragment" refers to an antibody fragment composed of VH domains (Ward et al., Nature 341:544-546 (1989)); the term "Fab fragment" refers to an antibody fragment composed of VL, VH, CL, and CH1 domains; the term "F(ab')2 fragment" refers to an antibody fragment containing two Fab fragments connected by disulfide bridges on the hinge region; the term "Fab' fragment" refers to the fragment obtained by reducing the disulfide bonds connecting the two heavy chain fragments in the F(ab')2 fragment, which consists of a complete light chain and heavy chain Fd fragment (composed of VH and CH1 domains).

[0511] The term "Fv" refers to an antibody fragment consisting of the VL and VH domains of a single arm of the antibody. Fv fragments are generally considered to be the smallest antibody fragment capable of forming a complete antigen-binding site. It is generally believed that six CDRs confer antigen-binding specificity to the antibody. However, even a variable region (such as the Fd fragment, which contains only three antigen-specific CDRs) can recognize and bind to the antigen, although its affinity may be lower than that of a complete binding site.

[0512] The term "Fc" refers to an antibody fragment formed by disulfide bonds connecting the second and third constant regions of the first heavy chain to the second and third constant regions of the second heavy chain. The Fc fragment of an antibody has various functions but does not participate in antigen binding.

[0513] The term "scFv" refers to a single polypeptide chain containing VL and VH domains, wherein the VL and VH are linked by a linker or directly (see, for example, Bird et al., Science 242:423-426 (1988); Huston et al., Proc. Natl. Acad. Sci. USA 85:5879-5883 (1988); and Pluckthun, The Pharmacology of Monoclonal Antibodies, Vol. 113, edited by Roseburg and Moore, Springer-Verlag, New York, pp. 269-315 (1994)). Such scFv molecules may have a general structure: NH2-VL-linker-VH-COOH or NH2-VH-linker-VL-COOH. Suitable prior art linkers consist of repeating GGGGS amino acid sequences or variants thereof. For example, a linker having the amino acid sequence (GGGGS)4 can be used, but variants thereof can also be used (Holliger et al. (1993), Proc. Natl. Acad. Sci. USA 90:6444-6448). Other linkers that can be used in this invention are described by Alfthan et al. (1995), Protein Eng. 8:725-731, Choi et al. (2001), Eur. J. Immunol. 31:94-106, Hu et al. (1996), Cancer Res. 56:3055-3061, Kipriyanov et al. (1999), J. Mol. Biol. 293:41-56, and Roovers et al. (2001), Cancer Immunol. In some cases, a disulfide bond may also exist between the VH and VL domains of the scFv. In some embodiments, the VH and VL domains can be positioned relative to each other in any suitable arrangement. For example, containing NH2-VH-VH-COOH, NH 2- VL-VL-COOH of scFv.

[0514] Each of the above antibody fragments retains the ability to specifically bind to the same antigen bound by the full-length antibody, and / or competes with the full-length antibody for specific binding to the antigen.

[0515] In this document, unless the context clearly indicates otherwise, when the term "antibody" is used, it includes not only the complete antibody but also the antigen-binding fragment of the antibody. Antigen-binding fragments (e.g., the antibody fragments described above) of a given antibody (e.g., the antibody provided in this invention) can be obtained using conventional techniques known to those skilled in the art (e.g., recombinant DNA technology or enzymatic or chemical fragmentation methods), and the antigen-binding fragments of the antibody can be screened for specificity in the same manner as those used for complete antibodies.

[0516] In this invention, the term "antibody" is used in its broadest sense, including complete monoclonal antibodies, polyclonal antibodies, and multispecific antibodies (e.g., bispecific antibodies) formed from at least two complete antibodies, as long as they have the desired biological activity.

[0517] The term "monoclonal antibody" refers to an antibody derived from a largely homogeneous group of antibodies, meaning that the antibodies constituting this cluster are identical, except for a small number of possible natural mutations. Monoclonal antibodies possess high specificity against a single determinant (epitope) of an antigen, while polyclonal antibodies, in contrast, contain different antibodies targeting different determinants (epitopes). Besides specificity, a key advantage of monoclonal antibodies is that their synthesis is unaffected by contamination from other antibodies. The modifier "monoclonal" here indicates that the antibody is characterized by originating from a largely homogeneous group of antibodies, and should not be interpreted as requiring a special method of preparation.

[0518] In some embodiments of the invention, monoclonal antibodies further include chimeric antibodies, i.e., a portion of the heavy chain and / or light chain is identical or homologous to one, a class, or a subclass of antibody, while the remainder is identical or homologous to another, a different class, or a different subclass of antibody, provided they possess the desired biological activity (see, for example, US 4,816,567; and Morrison et al., 1984, PNAS, 81:6851-6855). Chimeric antibodies that can be used in the present invention include primatized antibodies, which comprise a variable region antigen-binding sequence from a non-human primate (e.g., ancient monkey, chimpanzee, etc.) and a human constant region sequence.

[0519] The term "bispecific antibody," also known as "bifunctional antibody-drug conjugate," refers to a conjugate formed by a first antibody (fragment) and a second antibody (fragment) through a conjugate arm. This conjugate retains the activity of each antibody and thus has both bifunctionality and bispecificity.

[0520] The term "multispecific antibody" includes, for example, trispecific antibodies and tetraspecific antibodies. The former is an antibody that has the binding specificity of three different antigens, while the latter is an antibody that has the binding specificity of four different antigens.

[0521] The term "intact antibody" or "full-length antibody" refers to an antibody that contains an antigen-binding variable region and a light chain constant region (CL), and heavy chain constant regions (CH1, CH2, and CH3). The constant regions can be natural sequences (e.g., human natural constant region sequences) or amino acid sequence variants thereof. Intact antibodies are preferably intact antibodies with one or more effector functions. Intact antibodies can be classified into different "classes" based on the amino acid sequence of their heavy chain constant regions. The five main classes are IgA, IgD, IgE, IgG, and IgM, some of which can be further divided into different "subclasses" (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant regions of different antibody classes are referred to as α, β, ε, γ, and μ, respectively. The subunit structures and three-dimensional conformations of different immunoglobulin classes are well known in the art.

[0522] The term "probody" is a modified antibody, including an antibody or antibody fragment that is specifically designed to bind to its target and can be coupled with a masking group, wherein the masking group is defined as having a cleavage constant for the binding ability of the antibody or antibody fragment to its target that is at least 100 times, 1000 times, or 10000 times greater than the cleavage constant for the binding ability of an antibody or antibody fragment without a coupled masking group to its target.

[0523] The antibodies of the present invention include murine antibodies, chimeric antibodies, humanized antibodies, and fully human antibodies, with humanized antibodies and fully human antibodies being preferred.

[0524] The term "mouse antibody" refers to antibodies obtained by fusing B cells from immunized mice with myeloma cells, screening for mouse hybrid fusion cells that can proliferate indefinitely and secrete antibodies, and then screening, preparing and purifying the antibodies; or it refers to antibodies secreted by plasma cells formed by the differentiation and proliferation of B cells after the antigen enters the mouse body.

[0525] The term "chimeric antibody" refers to an antibody formed by fusing the variable region of a murine antibody with the constant region of a human antibody. It can reduce the immune response induced by murine antibodies. To create a chimeric antibody, a hybridoma that secretes murine-specific monoclonal antibodies must first be established. Then, the variable region gene is cloned from the murine hybridoma cells. Next, the constant region gene of the human antibody is cloned as needed. The murine variable region gene and the human constant region gene are then linked to form a chimeric gene, which is inserted into an expression vector. Finally, the chimeric antibody molecule is expressed in a eukaryotic or prokaryotic system.

[0526] The term "humanized antibody," also known as a CDR-grafted antibody, refers to a genetically engineered non-human antibody whose amino acid sequence is modified to increase homology with that of a human antibody. Typically, all or part of the CDR region of a humanized antibody is derived from a non-human antibody (donor antibody), while all or part of the non-CDR region (e.g., the variable region FR and / or constant region) is derived from a human immunoglobulin (receptor antibody). Humanized antibodies generally retain the intended properties of the donor antibody, including but not limited to antigen specificity, affinity, reactivity, the ability to enhance immune cell activity, and the ability to enhance the immune response. The donor antibody can be a mouse, rat, rabbit, or non-human primate (e.g., cynomolgus monkey) antibody with the intended properties (e.g., antigen specificity, affinity, reactivity, the ability to enhance immune cell activity, and / or the ability to enhance the immune response).

[0527] The term "fully human antibody," also known as a "fully human monoclonal antibody," refers to an antibody whose variable and constant regions are both human-derived, eliminating immunogenicity and toxicity. The development of monoclonal antibodies has gone through four stages: murine monoclonal antibodies, chimeric monoclonal antibodies, humanized monoclonal antibodies, and fully human monoclonal antibodies. Related technologies for the preparation of fully human antibodies mainly include: human hybridoma technology, EBV-transformed B lymphocyte technology, phage display technology, transgenic mouse antibody preparation technology, and single B cell antibody preparation technology.

[0528] The term "linker" or "connector" refers to a fragment that links a bioactive molecule (drug molecule) to a target moiety; it may also connect to other linkers before being linked to the drug. A preferred embodiment of the invention is denoted as L', for example, L... 0 To L 5 L 0 The end is connected to the ligand, L 5 The end is connected to the drug (D). The linker of the present invention may have multiple components (e.g., in some embodiments, a linker unit responsible for antibody coupling; a degradable peptide unit; and optionally an extension unit or a spacer unit).

[0529] The term "connector unit" refers to a component of a ligand-drug conjugate or drug-linker conjugate or linker that serves to connect the target portion to the remainder of the ligand-drug conjugate. A connector unit can connect a Tb unit to L1, and specific examples include, but are not limited to (where its left end is connected to L and its right end is connected to L1):

[0530] The term "spacer unit" refers to a component of a ligand-drug conjugate or drug-linker conjugate or linker. The spacer unit, in its presence, enables the linker of drug (D) to link to drug (L3) or drug (L4). The spacer unit is typically embedded between the breakable linker and the active drug, or is itself part of the breakable linker. The mechanism of action of the spacer unit is that when the breakable linker breaks under suitable conditions, the spacer unit spontaneously rearranges its structure, thereby releasing the attached active drug. In some embodiments, the spacer unit includes p-aminobenzyloxycarbonyl (PABC), substituted or unsubstituted ethylenediamine, etc. In some embodiments, the spacer unit is L5.

[0531] The term "amino acid" refers to natural, non-natural, standard, non-standard, proteogenous, non-proteogenous, L-type, or D-type amino acids; in some embodiments, the amino acid is selected from alanine, valine, leucine, isoleucine, methionine, tryptophan, phenylalanine, proline, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, or citrulline, or derivatives thereof, or combinations thereof.

[0532] The term "peptide" refers to a compound fragment that lies between amino acids and proteins. It is composed of two or more amino acid molecules linked together by peptide bonds. It is a structural and functional fragment of proteins, such as hormones and enzymes, which are essentially peptides.

[0533] The term "amino acid side chain" refers to a monovalent hydrogen or non-hydrogen substituent bonded to the α-carbon of an α-amino acid. Exemplary amino acid side chains include, but are not limited to, α-carbon substituents of glycine, alanine, valine, leucine, isoleucine, methionine, tryptophan, phenylalanine, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, and citrulline.

[0534] The twenty common amino acids involved in this invention are written in accordance with conventional usage. See, for example, Immunology-ASynthesis (2nd Edition, E.S. Golub and D.G. Ren, Eds., Sinauer Associates, Sunderland, Mass. (1991)), which is incorporated herein by reference. In this invention, the terms “peptide” and “protein” have the same meaning and are used interchangeably. Furthermore, in this invention, amino acids are generally represented by single-letter and three-letter abbreviations known in the art. For example, alanine may be represented by A or Ala; arginine by R or Arg; glycine by G or Gly; and glutamine by Q or Gln.

[0535] The compounds of this invention include their racemic, stereoisomer, tautomer, isotopic compounds, and pharmaceutically acceptable salts.

[0536] The carbon, hydrogen, oxygen, sulfur, nitrogen, phosphorus, F, Cl, Br, I, etc. involved in the groups and compounds described in this invention include their isotopic forms. That is, the carbon, hydrogen, oxygen, sulfur, nitrogen, phosphorus, F, Cl, Br, I, etc. involved in the groups and compounds described in this invention may be optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 11 C 12 C 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called superheavy hydrogen), and the isotopes of oxygen include 15 O、 16 O、 17 O and 18 O, isotopes of sulfur include 32 S, 33 S, 34 S, 35 S and 36 S, nitrogen isotopes include 13 N、 14 N and 15 N, isotopes of fluorine include 17 F, 18 F and 19 F, isotopes of chlorine include 35 Cl、 36 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br, an isotope of iodine, includes 123 I, 125 I, phosphorus isotopes include 31 P, 32 P.

[0537] “CN” refers to cyano.

[0538] "Halogen" refers to F, Cl, Br or I.

[0539] "Halogen-substituted" refers to substitution with F, Cl, Br, or I, including but not limited to 1 to 10 substituents selected from F, Cl, Br, or I, 1 to 6 substituents selected from F, Cl, Br, or I, and 1 to 4 substituents selected from F, Cl, Br, or I. "Halogen-substituted" is abbreviated as "halogenated".

[0540] "alkyl" refers to a substituted or unsubstituted straight-chain or branched saturated aliphatic hydrocarbon group, including but not limited to alkyl groups with 1 to 20 carbon atoms, alkyl groups with 1 to 8 carbon atoms, alkyl groups with 1 to 6 carbon atoms, and alkyl groups with 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and their various branched isomers; the alkyl group can be monovalent, divalent, trivalent, or tetravalent.

[0541] "Alkylene" refers to substituted or unsubstituted straight-chain and branched divalent saturated hydrocarbon groups, including -(CH2). v - (v is an integer from 1 to 10), alkylene examples include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0542] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, typically having 3 to 12 carbon atoms. Cycloalkyl groups can be monocyclic, fused, bridged, or spirocyclic. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-cyclobutyl, cyclobutyl-spirobutyl, adamantane, etc. Cycloalkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0543] "Alkenyl" refers to a substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon group having at least one, typically one, two, or three, carbon-carbon double bonds. The main chain has, but is not limited to, 2 to 10, 2 to 6, or 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2... -Methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene, etc.; the alkenyl group can be monovalent, divalent, trivalent, or tetravalent.

[0544] "Alynyl" refers to a substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon group having at least one, typically one, two, or three, carbon-carbon triple bonds. The main chain comprises 2 to 10 carbon atoms, including but not limited to having 2 to 6 carbon atoms on the main chain, or 2 to 4 carbon atoms on the main chain. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, and 4-pentynyl. The alkynyl group can be monovalent, divalent, trivalent, or tetravalent.

[0545] "Alkoxy" refers to a substituted or unsubstituted -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy.

[0546] "Carbocyclic group" or "carbocyclic ring" refers to a substituted or unsubstituted aromatic or non-aromatic ring. The aromatic or non-aromatic ring can be a 3- to 8-membered monocyclic ring or a 4- to 12-membered bicyclic ring. The carbocyclic group can be attached to the aromatic or non-aromatic ring, and the ring can be optionally a monocyclic, fused, bridged, or spirocyclic ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring, etc. "Carbocyclic group" or "carbon ring" can be monovalent, divalent, trivalent or tetravalent.

[0547] "Heterocyclic group" or "heterocyclic" refers to a substituted or unsubstituted aromatic or non-aromatic ring. The aromatic or non-aromatic ring can be a 3- to 8-membered monocyclic ring or a 4- to 12-membered bicyclic ring, and contains one or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O, S or Se. The selectively substituted C, N, S or Se in the ring of the heterocyclic group can be oxidized to various oxidation states. The heterocyclic group can be attached to a heteroatom or a carbon atom, and can be attached to an aromatic ring or a non-aromatic ring. The heterocyclic group is optionally a monocyclic, bridged, fused, or spirocyclic ring. Non-limiting examples include epoxyethyl, aziridinepropyl, oxacyclobutyl, aziridinebutyl, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxahexane, aziridineheptyl, pyridinyl, furanyl, thiophene, pyranyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithioyl, dihydrofuranyl, dihydropyranyl, dithiapentylcycloyl. Tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophene, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzooxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptyl, "Heterocyclic group" or "heterocyclic" can be monovalent, divalent, trivalent or tetravalent.

[0548] A "spirocyclic" or "spirocyclic group" refers to a polycyclic group in which substituted or unsubstituted rings share a single atom (called a spiro atom). The number of ring atoms in a spirocyclic system includes, but is not limited to, 5 to 20, 6 to 14, 6 to 12, or 6 to 10. One or more rings may contain zero or more (including but not limited to 1, 2, 3, or 4) double bonds, and optionally, may contain 0 to 5 double bonds selected from N, O, or S (=O). n Heteroatoms (n is 0, 1, or 2). Non-limiting embodiments include:

[0549] "Spirocyclic" or "spirocyclic group" can be monovalent, divalent, trivalent or tetravalent.

[0550] "Circular fused" or "circular fused group" refers to a polycyclic group in which each ring in a system shares a pair of adjacent atoms with other rings in the system. One or more rings may contain zero or more (including but not limited to 1, 2, 3 or 4) double bonds and may be substituted or unsubstituted. Each ring in a circular fused system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to those selected from N, S (=O)). n Or O, where n is 0, 1, or 2). The number of ring atoms in a cyclic system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include:

[0551] "Cyclone" or "cyclone base" can be monovalent, divalent, trivalent, or tetravalent.

[0552] A “bridged ring” or “bridged ring group” refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, and may contain zero or more double bonds. Any ring in a bridged ring system may contain 0 to 5 groups selected from heteroatoms or containing heteroatoms (including but not limited to N, S(=O)n, or O, where n is 0, 1, or 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include: Cubicane, adamantane. "Bridged ring" or "bridged ring group" can be monovalent, divalent, trivalent, or tetravalent.

[0553] "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a monocyclic or fused ring, wherein the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring can be fused to a saturated or unsaturated carbon ring, wherein the ring connected to the parent structure is the aryl ring. Non-limiting embodiments include benzene rings, naphthalene rings, etc. The "aryl" or "aryl ring" can be monovalent, divalent, trivalent, or tetravalent. When it is divalent, trivalent, or tetravalent, the linking site is located on the aryl ring.

[0554] "Heteroaryl" or "heteroary ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or a group containing heteroatoms (including but not limited to N, O, S(=O)n or Se(=O)n, where n is 0, 1, or 2). The number of ring atoms in the heteroaryl ring includes, but is not limited to, 5 to 15, 5 to 10, or 5 to 6. The atoms C, N, and S on the ring may be optionally oxidized (i.e., C(=O), NO, S(=O)n, Se(=O)n, where n is 1 or 2). Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furanyl, thiophenyl, selenyl, pyridyl, pyranyl, N-alkylpyrrolithyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazoleyl, benzopyrazolyl, benzimidazoleyl, benzopyridyl, pyrrolopyridyl, pyridinoneyl, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbon ring or heterocycle, wherein the ring connected to the parent structure is an aryl ring. Non-limiting embodiments include: The heteroaryl groups mentioned in this article are defined in accordance with this definition. Heteroaryl groups can be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent, or tetravalent, the linkage site is located on an aromatic ring.

[0555] "Substituted" or "substituted" means substituted by one or more (including but not limited to 2, 3, 4, or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged cyclic, spirocyclic, fused cyclic, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, and -(CH2). m -C(=O)-R a -O-(CH2) m -C(=O)-R a -(CH2) m -C(=O)-NR b R c -(CH2) m S(=O) n R a -(CH2) m -Alkenyl-R a OR d Or -(CH2) m -alkynyl-R a (where m and n are 0, 1, or 2), arylthio, thiocarbonyl, silyl, or -NR b R c Groups, wherein R b With R cIndependently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, R b With R c It can form five- or six-membered cycloalkyl or heterocyclic groups, R a With R d Each group is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic, carbonyl, ester, bridged cyclic, spirocyclic, or fused cyclic groups.

[0556] "1 to X substituents selected from..." means substituted by 1, 2, 3...X substituents selected from..., where X is any integer between 1 and 10. For example, "1 to 4 R..." k "Replace" refers to being replaced by 1, 2, 3, or 4 Rs. k Substitution. For example, "1 to 5 substituents selected from ..." means that the ring is substituted by 1, 2, 3, 4 or 5 substituents selected from ... . For example, "the heterobridged ring is optionally substituted by 1 to 4 substituents selected from H or F" means that the heterobridged ring is optionally substituted by 1, 2, 3 or 4 substituents selected from H or F.

[0557] The XY-membered rings (where X and Y are integers, and 3 ≤ X < Y, X < Y ≤ 20, selected from any integer between 4 and 20) include rings of the X, X+1, X+2, X+3, X+4…Y-membered elements. These rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterofused rings, heterospirocyclic rings, or heterobridged rings. For example, "4-7-membered heteromonocyclic rings" refers to heteromonocyclic rings of 4, 5, 6, or 7 members, and "5-10-membered heterofused rings" refers to heterofused rings of 5, 6, 7, 8, 9, or 10 members.

[0558] C x-y Carbocyclic rings (including aryl, cycloalkyl, monocyclic, spirocyclic, fused, or bridged carbocyclic rings) include C x C x+1 C x+2 C x+3 C x+4 ….C y A ring of elements (x is an integer, and 3 ≤ x < y, where y is any integer between 4 and 20), for example, C. 3-6 "Cycloalkyl" refers to C3, C4, C5, or C6 cycloalkyl groups.

[0559] When a functional group has one or more connectable sites, any one or more of these sites can be linked to other functional groups via chemical bonds. When the chemical bond connection is non-directional and a hydrogen atom is present at the connectable site, the number of hydrogen atoms at that site decreases accordingly with the number of bonds being formed, resulting in a functional group with a corresponding valence. For example... This indicates that any connectable site on the piperidinyl group can be linked to other groups via a single chemical bond, including at least... These four connection methods, even if an H atom is drawn on -N-, This also includes For example This indicates that the R group on the piperidinyl group can be located on C or N, and at least includes [missing information]. For example, the general formula segment is: When X is selected from CH2 or NH, it means that the R group on the general formula fragment can be located on C or X. When X is selected from CH2, the general formula fragment can be... When X is selected from NH, the general formula fragment can be:

[0560] When the listed linking groups do not specify their linking direction, the linking direction includes the direction of the reading order from left to right and from right to left. For example, when ALB is selected from -MW-, it includes AMWB and AWMB.

[0561] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or possibility that the event or environment may or may not occur. For example, "optionally substituted F alkyl" means that the alkyl group may but does not have to be substituted with F, and the description includes the case where the alkyl group is substituted with F and the case where the alkyl group is not substituted with F.

[0562] "Pharmaceutically acceptable salt" or "its pharmaceutically acceptable salt" means that the compound of the present invention retains the bioavailability and properties of a free acid or a free base, and that the free acid is obtained by reacting with a non-toxic inorganic or organic base, and the free base is obtained by reacting with a non-toxic inorganic or organic acid.

[0563] "Pharmaceutical composition" refers to a mixture of one or more compounds described in this invention, or stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic agents.

[0564] "Product specification" refers to the weight of the active pharmaceutical ingredient contained in each vial, tablet, or other unit of preparation.

[0565] "Carrier" refers to a material that does not cause significant stimulation to an organism and does not eliminate the biological activity and properties of the compound given.

[0566] "Animals" refers to mammals, such as humans, companion animals, zoo animals, and livestock, with humans, horses, or dogs being preferred.

[0567] "Stereoisomers" are isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0568] "Tautomers" refer to functional group isomers that are produced by the rapid movement of an atom in two positions within a molecule, such as keto-enol isomers and amide-imine alcohol isomers. Detailed Implementation

[0569] The following embodiments illustrate the technical solution of the present invention in detail, but the scope of protection of the present invention includes, but is not limited to, these embodiments.

[0570] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ increments. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0571] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0572] HPLC determinations were performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM).

[0573] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) are 0.15mm-0.20mm in diameter, and the silica gel plates used for thin-layer chromatography separation and purification are 0.4mm-0.5mm in diameter.

[0574] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0575] The known starting materials of this invention can be synthesized using or according to methods known in the art, or can be purchased from companies such as Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0576] THF: Tetrahydrofuran; DMF: N,N-Dimethylformamide; DIPEA: N,N-Diisopropylethylamine; DBU: CAS No.: 6674-22-2; NBS: CAS No.: 128-08-5;

[0577] Example 1.1

[0578] Intermediate 1: Preparation of Intermediate 1

[0579] Step 1: Preparation of 1b

[0580] At 0 °C, N-methylmorpholine (24.13 g, 238.56 mmol) was added to a solution of 1a (40.00 g, 119.28 mmol), glycine tert-butyl ester (23.47 g, 178.92 mmol), 1-hydroxybenzotriazole (19.34 g, 143.14 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (27.44 g, 143.14 mmol) in 500 mL of dichloromethane and reacted at room temperature for 16 h. Then, 500 mL of dichloromethane was added, and the mixture was washed successively with 10% citric acid aqueous solution (100 mL), saturated sodium bicarbonate aqueous solution (100 mL × 2), and saturated saline solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate (v / v) = 5:1) to obtain 1b (50.00 g, yield: 93%).

[0581] LCMS m / z = 393.0 [M-55] +

[0582] Step 2: Preparation of 1c

[0583] Diethylamine (22.02 g, 301.00 mmol) was added to acetonitrile (80 mL) solution (27.00 g, 60.20 mmol) of product 1b, and the reaction was carried out at room temperature for 4 h. The reaction solution was concentrated under reduced pressure to obtain product 1c (crude product).

[0584] LCMS m / z = 171.0 [M-55] +

[0585] Step 3: Preparation of 1 day

[0586] N,N-diisopropylethylamine (20.32 g, 157.26 mmol) and 1f (13.74 g, 47.18 mmol) were added to a 50 mL solution of tetrahydrofuran (crude product) in 1c, and the reaction was carried out at 60 °C for 16 h. After cooling to room temperature, water (100 mL) and ethyl acetate (100 mL x 3) were added for extraction. The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:tetrahydrofuran (v / v) = 10:1) to give 1d (16.00 g, two-step yield: 61%).

[0587] LCMS m / z = 437.1 [M+H] +

[0588] Step 4: Preparation of Intermediate 1

[0589] N,N-diisopropylethylamine (3.55 g, 27.49 mmol) was added to a 1d (4.00 g, 9.16 mmol) solution of tetrahydrofuran (21 mL), and the mixture was microwaved at 150 °C for 6 h. After cooling to room temperature, water (100 mL) and ethyl acetate (100 mL x 3) were added for extraction. The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:tetrahydrofuran (v / v) = 10:1) to give intermediate 1 (2.50 g, yield: 70%).

[0590] LCMS m / z = 391.2[M+H] + .

[0591] Intermediate 2: Preparation of Intermediate 2

[0592] Intermediate 2 is obtained by referring to the synthesis method of intermediate 1, using 2a as the starting material.

[0593] LCMS m / z = 391.0 [M+H] + .

[0594] Example 1.2:

[0595] Example 1: Preparation of Compound 1

[0596] Step 1: Preparation of 1C

[0597] 1A (1.3 g, 3.95 mmol) (synthesized according to patent WO2021198965), 1B (0.68 g, 4.35 mmol) and diisopropylethylamine (1.53 g, 11.85 mmol) were added to anhydrous tetrahydrofuran (50 mL), reacted at room temperature for 1 h, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 100 / 1-5 / 1) to give 1C (1.6 g, yield: 90%).

[0598] LCMS m / z = 393.2 [M-55] +

[0599] Step 2: Preparation of 1E

[0600] 1D (synthesized according to patent WO2023 / 116835) (1.8 g, 6.66 mmol), Raney nickel (1.2 g, 20.45 mmol), and di-tert-butyl dicarbonate (2.9 g, 13.29 mmol) were added to tetrahydrofuran (30 mL) and stirred overnight at room temperature under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered and concentrated under reduced pressure to give compound 1E (1.7 g, yield: 68%).

[0601] LCMS m / z = 375.1 [M+H] +

[0602] Step 3: Preparation of compound 1F

[0603] 1E (500 mg, 1.34 mmol) and trifluoroacetic acid (5 mL) were added to dichloromethane (5 mL), and the reaction was carried out at room temperature for 0.5 h. The mixture was concentrated under reduced pressure, and N,N-dimethylformamide (10 mL), DIPEA (1.11 mL), and 1C (662 mg, 1.47 mmol) were added to the concentrate. The mixture was then reacted at 50 °C for 4 h. After cooling to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: methanol / dichloromethane (V / V) = 0-5%) to give 1F (650 mg, yield: 77%).

[0604] LCMS m / z = 627.3 [M-1] -

[0605] Step 4: Preparation of Compound 1

[0606] Dissolve 1F (60 mg, 0.095 mmol) in dichloromethane (1 mL), add trifluoroacetic acid (1 mL), react at room temperature for 1 h, concentrate, redissolve in a mixed solvent DCM / MeOH (20:1; 5 mL), then add sodium bicarbonate (50 mg), and stir at room temperature for 0.5 h. The mixture was filtered under reduced pressure, and the filter cake was washed with a mixed solvent DCM / MeOH (20:1; 5 mL). The filtrate was concentrated, and N,N-dimethylformamide (3 mL), 1g (15 mg, 0.15 mmol), diisopropylethylamine (49 mg, 0.38 mmol), and HATU (72 mg, 0.19 mmol) were added to the concentrate. The mixture was reacted overnight at room temperature. The reaction solution was purified by preparative liquid chromatography (instrument: Waters 2767 preparative column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: acetonitrile / water (containing 0.1% trifluoroacetic acid)). After lyophilization, compound 1 (25 mg) was obtained.

[0607] LCMS m / z = 613.1 [M+1] +

[0608] H 1 -NMR(400MHz,CD3OD)δ8.17(d,1H),7.62-7.53(m,2H),7.19(s,2H),5.20(dd,1H),4.67-4.46(m,4H),3.86-3.65(m,1H),3.48-3.38(m ,1H),3.28-3.22(m,1H),3.00-2.60(m,6H),2.52(qd,1H),2.25-2.14(m,1H),2.09-1.71(m,2H),1.05-0.98(m,2H),0.94-0.78(m,2H).

[0609] Example 2: Preparation of Compound 2

[0610] Compound 2 was obtained by referring to the synthesis method in Example 1.

[0611] LCMS m / z = 627.2 [M+H] +

[0612] H 1 -NMR(400MHz,CD3OD)δ8.20(d,1H),7.64-7.53(m,2H),7.24-7.14(m,2H),5.20(dd,1H),4.70-4.49(m,4H),4.36-4.26(m,1H), 3.44(t,1H),3.29-3.12(m,2H),3.00-2.73(m,5H),2.73-2.61(m,2H),2.59-2.37(m,3H),2.26-2.02(m,3H),1.90-1.75(m,2H).

[0613] Example 3: Preparation of trifluoroacetate of compound 3

[0614] Step 1: Preparation of 3B

[0615] 3A (1.20 g, 3.21 mmol) and Lawson's reagent (0.71 g, 1.76 mmol) were added to 1,4-dioxane (40 mL) and reacted at 100 °C for 12 h. After cooling to room temperature, the mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (mobile phase: methanol / dichloromethane (V / V) = 0-6%) to give 3B (0.30 g, yield: 24%).

[0616] LCMS m / z = 390.3[M+1] +

[0617] Step 2: Preparation of 3C products

[0618] 3B (300 mg, 0.77 mmol) was added to a solution of 1,4-dioxane-hydrochloride (10 mL, 4 mol / L) and reacted at room temperature for 3 h. The mixture was then concentrated under vacuum. N,N-dimethylformamide (10 mL), 1C (346 mg, 0.77 mmol), and diisopropylethylamine (0.50 g, 3.87 mmol) were added and the mixture was reacted at 50 °C for 3 h. The mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: methanol / dichloromethane (V / V) = 0-5%) to give 3C (200 mg, yield: 40%).

[0619] LCMS m / z = 544.4 [M-99] -

[0620] Preparation of compound 3

[0621] Compound 3 was synthesized using 3C as a substrate according to the method described in Example 1. The crude product was purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; column: Xbridge Prep C18 5um 19*250mm). The mobile phase composition was acetonitrile / water (containing 5 mmol / L ammonium bicarbonate). After lyophilization, compound 3 (30 mg, yield: 42%) was obtained.

[0622] LCMS m / z = 602.3 [M+H] +

[0623] Example 4: Preparation of Compound 4

[0624] Compound 4 was obtained from 4A (synthesized according to patent WO2024169913A1) as a raw material, following the synthesis method of Example 1.

[0625] LCMS m / z = 627.3 [M+H] + .

[0626] Example 4-1: Preparation of compound 4-1

[0627] Compound 4-1 was obtained from 4-1A using the synthesis method described in Example 4.

[0628] LCMS m / z = 627.3 [M+H] + .

[0629] Example 4-2: Preparation of compound 4-2

[0630] Compound 4-2 was obtained from 4-2A using the synthesis method described in Example 4.

[0631] LCMS m / z = 627.3 [M+H] + .

[0632] Example 1.3:

[0633] Example 5: Preparation of Compound 5

[0634] Step 1: Preparation of 5A

[0635] Copper sulfate (2.04 g, 12.81 mmol) and sodium ascorbate (5.08 g, 25.62 mmol) were added to intermediate 1 (5.00 g, 12.81 mmol), a solution of azido-octaethylene glycol-carboxylic acid (5.99 g, 12.81 mmol) in tert-butanol (60 mL) and water (20 mL). The reaction was carried out at room temperature under a nitrogen atmosphere for 16 h. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 6). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (dichloromethane:methanol (v / v) = 10:1) to give 5A (6.50 g, yield: 59%).

[0636] LCMS m / z = 858.4 [M+1] +

[0637] Step 2: Preparation of 5B

[0638] 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (670 mg, 3.51 mmol) and N-hydroxysuccinimide (400 mg, 3.51 mmol) were added to a solution of 5A (1.00 g, 1.17 mmol) in 10 mL of dichloromethane. The reaction was carried out at room temperature for 3 h under a nitrogen atmosphere. Water (20 mL) and dichloromethane (30 mL x 3) were added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 5B (crude product).

[0639] LCMS m / z = 955.7 [M+1] +

[0640] Step 3: Preparation of 5C

[0641] m-chloroperoxybenzoic acid (820 mg, 4.02 mmol) was added in portions to a 10 mL solution of dichloromethane in 5B (crude product). The reaction was carried out at room temperature for 4 h under a nitrogen atmosphere. Water (20 mL) and dichloromethane (30 mL x 3) were added for extraction. The organic phase was washed with saturated sodium thiosulfate aqueous solution, then with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 5C (crude product).

[0642] LCMS m / z = 987.6 [M+1] +

[0643] Step 4: 5D Fabrication

[0644] Trifluoroacetic acid (5 mL) was added to a 5°C solution of crude dichloromethane (5 mL), and the reaction was carried out at room temperature for 4 h. The reaction solution was concentrated under reduced pressure to obtain the crude product, which was then purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC system, XBridge@Prep C18 column, inner diameter x length = 19 mm x 250 mm). Preparation method: The crude product was dissolved in DMF and filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: acetonitrile / water (containing 0.05% trifluoroacetic acid). Gradient elution method: Acetonitrile was used to elute from 30% to 80% (flow rate: 12 mL / min; elution time: 15 min), and the solution was lyophilized to obtain 5D (260 mg, three-step yield: 19%).

[0645] LCMS m / z = 931.6 [M+1] +

[0646] Step 5: Preparation of 5F

[0647] Palladium on carbon (50 mg, Pd / C content: 10%, water content approximately 50%) was added to a methanol (10 mL) solution of 5E (1.00 g, 1.31 mmol, synthesized according to patent WO2024207177). The reaction was carried out at room temperature for 2 h under a hydrogen atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 5F (850 mg, yield: 96%).

[0648] LCMS m / z = 670.2 [M-1] -

[0649] Step 6: 5G Preparation

[0650] Trifluoroacetic acid (3 mL) was added to a 1F solution (280 mg, 0.45 mmol) in 3 mL of dichloromethane. The reaction was carried out at room temperature for 10 min. The crude product was concentrated under reduced pressure and dissolved in 10 mL of dichloromethane:methanol at a ratio of 20:1. Sodium bicarbonate solid (250 mg) was added and the mixture was stirred for 0.5 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the crude product. 5F (300 mg, 0.45 mmol), N,N-diisopropylethylamine (116 mg, 0.90 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (188 mg, 0.50 mmol) were added sequentially to a 2 mL solution of the crude product in N,N-dimethylformamide and the reaction was carried out at room temperature for 12 h. Water (20 mL) and dichloromethane (30 mL x 3) were added for extraction. The organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:(dichloromethane / methanol = 10 / 1)(v:v) = 10:1) to obtain 5g (280mg, yield: 53%).

[0651] LCMS m / z = 1182.7 [M+1] +

[0652] Step 7: Preparation of 5H

[0653] Diethylamine (88 mg, 1.2 mmol) was added to 5 G (280 mg, 0.24 mmol) of acetonitrile (4 mL) solution, and the reaction was carried out at room temperature for 12 h. The crude product was concentrated under reduced pressure and purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC system, XBridge@Prep C18 column, inner diameter x length = 19 mm x 250 mm). Preparation method: The crude product was dissolved in DMF and filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase: Acetonitrile / water (containing 0.05% trifluoroacetic acid). Gradient elution method: Acetonitrile was eluted from 30% to 80% (flow rate: 12 mL / min; elution time: 14 min), and lyophilized to obtain 5H (110 mg, yield: 48%).

[0654] LCMS m / z = 960.3[M+1] +

[0655] Step 8: Preparation of Compound 5

[0656] N,N-diisopropylethylamine (3 mg, 0.02 mmol) was added to a solution of 5H (16 mg, 0.02 mmol) and 5D (20 mg, 0.02 mmol) in 4 mL of N,N-dimethylformamide, and reacted at room temperature for 2 h. The reaction solution was purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, SunFire@Prep C8 column, inner diameter x length = 19 mm × 150 mm). Preparation method: The crude product was dissolved in DMF and filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: acetonitrile / water (containing 0.05% formic acid). Gradient elution method: Acetonitrile was used to elute from 10% to 55% (flow rate: 12 mL / min; elution time: 16 min), and the solution was lyophilized to obtain compound 5 (12 mg, yield: 39%).

[0657] LCMS m / z = 1776.2 [M+1] +

[0658] Example 6: Synthesis of Compound 6

[0659] Step 1: Synthesis of 6A

[0660] 1F (260 mg, 0.41 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The mixture was reacted at room temperature for 3 h, and the residue was concentrated under reduced pressure. The residue was reconstituted with DCM / MeOH (20:1; 5 mL), and sodium bicarbonate (80 mg) was added. The mixture was stirred at room temperature for 15 min, filtered, and the filter cake was washed with DCM / MeOH (20:1; 5 mL). The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by C18 reverse-phase column chromatography and lyophilized to give 6A (118 mg, yield: 53.97%).

[0661] LCMS m / z = 529.3 [M+H] +

[0662] Step 2: Synthesis of 6C

[0663] 6B (2.63 g, 5.02 mmol, synthesis reference patent WO2019192979) was dissolved in acetonitrile (10 mL), followed by the addition of water (3 mL), N-BOC-2-azidoethylamine (0.93 g, 5.02 mmol), and cuprous bromide (0.72 g, 5.02 mmol). The reaction was carried out at room temperature for 16 h under nitrogen protection. Water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain 6C (1.98 g, yield: 55.53%).

[0664] LCMS m / z = 710.2[M+H] +

[0665] Step 3: 6D Synthesis

[0666] 6C (0.5 g, 0.7 mmol) and DIPEA (360 mg, 2.8 mmol) were dissolved in DMF (15 mL). Di(p-nitrobenzene) carbonate (430 mg, 1.4 mmol) was slowly added under ice-water bath conditions, and the reaction was carried out overnight at room temperature. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined. The organic phase was washed with water (100 mL × 2) and saturated sodium chloride solution (100 mL × 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography to give 6D (315 mg, yield 51.11%).

[0667] LCMS m / z = 875.1 [M+H] +

[0668] Step 4: Synthesis of 6F

[0669] 6D (0.3 g, 0.34 mmol) and 6E (81 mg, 0.37 mmol) were dissolved in DMF (6 mL), and DIPEA (130 mg, 1.02 mmol) was added. The mixture was reacted overnight at room temperature. The crude product was concentrated under reduced pressure, purified by a C18 reverse-phase column, and lyophilized to give 6F (100 mg, yield 30.63%).

[0670] LCMS m / z = 952.2[M+H] +

[0671] Step 5: Synthesis of 6G

[0672] 6F (90 mg, 0.095 mmol) and 6A (60 mg, 0.11 mmol) were dissolved in DMF (3 mL), and DIPEA (37 mg, 0.29 mmol) and HATU (43 mg, 0.11 mmol) were added. The mixture was reacted at room temperature for 2 h. The crude product was concentrated under reduced pressure and purified by C18 reversed-phase column chromatography and then lyophilized to give 6G (41 mg, yield: 29.64%).

[0673] LCMS m / z = 1462.2 [M+H] +

[0674] Step 4: Synthesis of 6H

[0675] 6g (41mg, 0.028mmol) was dissolved in THF (2mL), and 6N HCl (2mL) was added at room temperature. The reaction was carried out overnight at 45℃. The crude product was concentrated under reduced pressure and purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, SunFire@Prep C18 column, inner diameter x length = 19mm × 250mm). Preparation method: The crude product was dissolved in DMF and filtered through a 0.45μm filter membrane to prepare the sample solution. Mobile phase system: acetonitrile / water (containing 0.1% trifluoroacetic acid). Gradient elution method: Acetonitrile was eluted from 5% to 40% (flow rate: 12mL / min; elution time 15min), and then lyophilized to obtain 6H (22mg, yield 64.2%).

[0676] LCMS m / z = 1222.1 [M+H] +

[0677] Step 5: Synthesis of Compound 6

[0678] 6H (20 mg, 0.016 mmol) and 5D (15 mg, 0.016 mmol) were dissolved in DMF (2 mL), and DIPEA (6.2 mg, 0.048 mmol) was added at room temperature. The reaction was carried out at room temperature for 3 h. The crude product was concentrated under reduced pressure and purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, SunFire@Prep C8 column, inner diameter x length = 19 mm × 250 mm). Preparation method: The crude product was dissolved in DMF and filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: acetonitrile / water (containing 0.1% trifluoroacetic acid). Gradient elution method: Acetonitrile was used to elute from 5% to 50% (flow rate: 15 mL / min; elution time 25 min), and the solution was lyophilized to obtain compound 6 (6 mg, yield 17.99%).

[0679] LCMS m / z = 2038.5 [M+H] +

[0680] Example 7: Synthesis of Compound 7

[0681] Step 1: Synthesis of 7A

[0682] To a 3 mL solution of dichloromethane (250 mg, 0.29 mmol), m-chloroperoxybenzoic acid (85%, 120 mg, 0.58 mmol) was added, and the mixture was reacted at room temperature for 2 h under nitrogen protection. Then, m-chloroperoxybenzoic acid (120 mg, 0.58 mmol) was added, and the mixture was reacted at room temperature for 3 h. An aqueous solution of sodium thiosulfate was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined. The organic phase was concentrated under reduced pressure to obtain a crude product, which was then purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC system, Atlantis T3 column, inner diameter x length = 19 mm × 250 mm). Preparation method: The crude product was dissolved in DMF and filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: acetonitrile / water (containing 0.1% trifluoroacetic acid). Gradient elution method: Acetonitrile was eluted from 10% to 60% (flow rate: 15 mL / min; elution time: 20 min), and then lyophilized to obtain 7A (126 mg, yield: 48.59%).

[0683] LCMS m / z = 890.6 [M+H] +

[0684] Step 2: Synthesis of 7C

[0685] 6E (230 mg, 1.07 mmol) and DIPEA (0.35 mL, 2.14 mmol) were added to a DMF (6 mL) solution of 7B (730 mg, 1.07 mmol). The reaction was carried out overnight at room temperature under nitrogen protection. The crude product was concentrated under reduced pressure, purified by C18 reverse-phase column chromatography, and lyophilized to give 5C (105 mg, yield 12.92%).

[0686] LCMS m / z = 758.5 ​​[M+H] +

[0687] Step 3: 7D Synthesis

[0688] To a DMF (3 mL) solution of 7C (105 mg, 0.14 mmol), HATU (80 mg, 0.21 mmol), DIPEA (54 mg, 0.42 mmol), and compound 7A (74 mg, 0.14 mmol) were added sequentially. The reaction was carried out under nitrogen protection at room temperature for 3 h. The crude product was concentrated under reduced pressure and purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC system, SunFire@Prep C18 column, inner diameter x length = 19 mm × 250 mm). Preparation method: The crude product was dissolved in DMF and filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: acetonitrile / water (containing 0.1% trifluoroacetic acid). Gradient elution method: Acetonitrile was eluted from 10% to 80% (flow rate: 15 mL / min; elution time: 25 min), and lyophilized to obtain 7D (90 mg, yield: 51.20%).

[0689] LCMS m / z = 1269.0 [M+H] +

[0690] Step 4: Synthesis of 7E

[0691] Piperidine (1 mL, 10.92 mmol) was added to a solution of 7D in acetonitrile (1 mL) and tetrahydrofuran (1 mL), and the reaction was carried out at room temperature for 3 h. The crude product was concentrated under reduced pressure and purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, XBridge Shield RP column, inner diameter x length = 19 mm × 250 mm). Preparation method: The crude product was dissolved in DMF and filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase: Acetonitrile / water (containing 5 mM ammonium bicarbonate). Gradient elution method: Acetonitrile was eluted from 10% to 60% (flow rate: 15 mL / min; elution time: 25 min), and lyophilized to obtain 7E (40 mg, yield 57.05%).

[0692] LCMS m / z = 1046.4 [M+H] +

[0693] Step 5: Synthesis of 7F

[0694] Add 5A (34 mg, 0.038 mmol), HATU (22 mg, 0.057 mmol), and DIPEA (15 mg, 0.11 mmol) to a DMF (3 mL) solution of 7E (40 mg, 0.038 mmol). React at room temperature for 3 h under nitrogen protection. Concentrate under reduced pressure to obtain the crude product, which is then purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC system, Atlantis T3 column, inner diameter x length = 19 mm × 250 mm). Preparation method: Dissolve the crude product in DMF and filter through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase: Acetonitrile / water (containing 0.1% trifluoroacetic acid). Gradient elution method: Elute with acetonitrile from 10% to 60% (flow rate: 15 mL / min; elution time: 20 min), lyophilize to obtain 7E (30 mg, yield: 40.91%).

[0695] LCMS m / z = 959.4 [M / 2 + H] +

[0696] Step 6: Synthesis of Compound 7

[0697] Trifluoroacetic acid (1 mL) was added to a solution of 7E (30 mg, 0.016 mmol) in dichloromethane (2 mL), and the reaction was carried out at room temperature for 5 h. The crude product was concentrated under reduced pressure and purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC system, SunFire@Prep C18 column, inner diameter x length = 19 mm × 250 mm). Preparation method: The crude product was dissolved in DMF and filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase: acetonitrile / water (containing 0.1% trifluoroacetic acid). Gradient elution method: Acetonitrile was used to elute from 5% to 50% (flow rate: 15 mL / min; elution time: 25 min), followed by lyophilization to obtain compound 7 (7 mg, yield: 24.04%).

[0698] LCMS m / z = 931.5[M / 2 + H] +

[0699] Example 8: Preparation of Compound 8

[0700] Compound 8 was obtained using intermediate 1 and 5H as substrates, following the synthetic method described in Example 5.

[0701] LCMS m / z = 1600.1[M+1] + .

[0702] Example 9: Preparation of Compound 9

[0703] Step 1: Preparation of 9B

[0704] 1f (10.69 g, 36.72 mmol) was added to a tetrahydrofuran (100 mL) solution of 9A (7.98 g, 36.72 mmol) and N,N-diisopropylethylamine (18.98 g, 146.88 mmol) and reacted at 60 °C for 16 h. After cooling to room temperature, water (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:tetrahydrofuran (v / v) = 85:15) to obtain 9B (12.00 g).

[0705] LCMS m / z = 428.2 [M+H] +

[0706] Step 2: Preparation of 9C

[0707] N,N-diisopropylethylamine (10.88 g, 84.21 mmol) was added to a solution of 9B (12 g, 28.07 mmol) in tetrahydrofuran (48 mL), and the mixture was microwaved at 150 °C for 6 h. After cooling to room temperature, water (100 mL) and ethyl acetate (100 mL x 3) were added for extraction. The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:tetrahydrofuran (v / v) = 83:17) to give 9C (8.30 g, yield: 78%).

[0708] LCMS m / z = 382.2[M+H] +

[0709] Step 3: Preparation of 9D

[0710] At 0°C, an aqueous solution (6 mL) of lithium hydroxide monohydrate (220 mg, 5.24 mmol) was added to a tetrahydrofuran solution (30 mL) containing 9C (2.00 g, 5.24 mmol), and the reaction was carried out at room temperature for 1 h. The pH was adjusted to approximately 3 with 1N hydrogen chloride aqueous solution, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol (v / v) = 10:1) to obtain 9D (1.80 g, yield: 93%).

[0711] LCMS m / z = 368.1 [M+H] +

[0712] Step 4: Preparation of 9E

[0713] At 0 °C, a mixture of N,N'-dicyclohexylcarbodiimide (1.52 g, 7.35 mmol) and acetonitrile (5 mL) was slowly added to a solution of 9D (1.80 g, 4.90 mmol) and N-hydroxysuccinimide (0.85 g, 7.35 mmol) in acetonitrile (50 mL). The reaction was carried out at room temperature for 16 h. The mixture was filtered, and the filter cake was washed with acetonitrile (15 mL x 3). The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (dichloromethane:tetrahydrofuran (v / v) = 93:7) to obtain 9E (2.00 g, yield: 88%).

[0714] LCMS m / z = 465.2[M+H] +

[0715] Step 5: Preparation of 9F

[0716] At 0 °C, m-chloroperoxybenzoic acid (912 mg, 5.28 mmol) was added to a solution of 9E (800 mg, 1.72 mmol) in dichloromethane (30 mL), and the reaction was carried out at room temperature for 16 h. The mixture was then cooled to -70 °C, and a solid precipitated. The solid was filtered, and the filtrate was concentrated under reduced pressure to obtain 9F (854 mg, crude product).

[0717] Step 6: Preparation of 9G

[0718] 10 mL of trifluoroacetic acid was added to a 20 mL solution of dichloromethane containing 9F (854 mg, crude product), and the reaction was carried out at room temperature for 3 h. After concentration under reduced pressure, 9 G (757 mg, crude product) was obtained.

[0719] Step 7: Preparation of Compound 9

[0720] At 0°C, N,N-diisopropylethylamine (8 mg, 0.06 mmol) and 5H (30 mg, 0.03 mmol) were added sequentially to a 9 g (23.78 mg, crude) solution of N,N-dimethylformamide (3 mL), and the reaction was allowed to proceed at room temperature for 0.5 h. At 0°C, N,N-diisopropylethylamine (4 mg, 0.03 mmol) was added again, and the reaction was allowed to proceed at room temperature for another 0.5 h. The reaction solution was purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC system, SunFire@Prep C8 column, inner diameter x length = 19 mm × 150 mm). Preparation method: The reaction solution was filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: acetonitrile / water (containing 0.05% formic acid). Gradient elution method: Acetonitrile was eluted from 5% to 45% (flow rate: 12 mL / min; elution time: 16 min), and after lyophilization, compound 9 (10 mg, yield: 14%) was obtained.

[0721] LCMS m / z = 1285.3 [M+1] +

[0722] Example 10: Preparation of Compound 10

[0723] Step 1: Preparation of 10B

[0724] At 0 °C, p-toluenesulfonic acid (90.06 mg, 0.52 mmol) was added to a solution of 10A (2.00 g, 5.23 mmol) and benzyl 1-hydroxycyclopropane-1-carboxylic acid ester (2.00 g, 10.41 mmol) in tetrahydrofuran (20 mL), and the reaction was carried out at room temperature for 6 h. The reaction solution was poured into ice water and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:tetrahydrofuran (v / v) = 3:1) to obtain 10B (1.70 g, yield: 63%).

[0725] Step 2: Preparation of 10C

[0726] Diethylamine (0.72 g, 9.90 mmol) was added to a solution of 10B (1.7 g, 3.30 mmol) in acetonitrile (40 mL), and the reaction was carried out at room temperature for 4 h. After concentration under reduced pressure, 10C (1.44 g, crude product) was obtained.

[0727] LCMS m / z = 293.1 [M+1] +

[0728] Step 3: Preparation of 10D

[0729] A solution of sodium carbonate (1.40 g, 13.24 mmol) in water (10 mL) was added to a solution of 10C (1.44 g, crude product), (S)-2,5-dioxopyrrolidone-1-yl 2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-methylbutyrate (1.40 g, 3.21 mmol) in tetrahydrofuran (40 mL) and water (30 mL). The reaction was carried out at room temperature for 4 h. The mixture was extracted with ethyl acetate (40 mL x 3), and the organic phases were combined. The organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:tetrahydrofuran (v / v) = 89:11) to give 10D (2.0 g, two-step yield: 99%).

[0730] Step 4: Preparation of 10E

[0731] Palladium on carbon (400 mg, 10% wt) was added to a 50 mL solution of 10D (2.00 g, 3.26 mmol) in tetrahydrofuran. The reaction was carried out at room temperature for 4 h under a hydrogen atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 10E (1.2 g, yield: 70%).

[0732] LCMS m / z = 522.0 [M-1] -

[0733] Step 5: Preparation of 10F

[0734] At 0 °C, N,N-diisopropylethylamine (558 mg, 4.32 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (410 mg, 1.08 mmol) were added sequentially to solutions of 10E (567 mg, 1.08 mmol) and 6A (571 mg, 1.08 mmol) in N,N-dimethylformamide (8 mL), and the reaction was carried out at room temperature for 16 h. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol (v / v) = 9:1) to give 10F (811 mg, yield: 72%).

[0735] LCMS m / z = 1034.3 [M+1] +

[0736] Step 6: Preparation of 10G

[0737] Diethylamine (0.29 g, 3.96 mmol) was added to 10F (811 mg, 0.78 mmol) of acetonitrile (150 mL) solution, and the reaction was carried out at room temperature for 16 h. The crude product was obtained by concentration under reduced pressure and purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC system, SunFire@Prep C8 column, inner diameter x length = 19 mm × 150 mm). Preparation method: The crude product was dissolved in DMF and filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase: acetonitrile / water (containing 0.05% trifluoroacetic acid). Gradient elution method: Acetonitrile was used to elute from 5% to 45% (flow rate: 12 mL / min; elution time: 16 min), and the solution was lyophilized to obtain compound 10 G (400 mg, yield: 63%).

[0738] LCMS m / z = 812.3[M+1] +

[0739] Step 7: Preparation of Compound 10

[0740] At 0°C, N,N-diisopropylethylamine (10 mg, 0.08 mmol) and 10 g (30 mg, 0.04 mmol) were added to a 9 g (23.78 mg, crude) solution of N,N-dimethylformamide (3 mL), and the reaction was carried out at room temperature for 0.5 h. At 0°C, N,N-diisopropylethylamine (5 mg, 0.04 mmol) was added again, and the reaction was carried out at room temperature for 0.5 h. The reaction solution was purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, SunFire@Prep C8 column, inner diameter x length = 19 mm × 150 mm). Preparation method: The reaction solution was filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: acetonitrile / water (containing 0.05% formic acid). Gradient elution method: Acetonitrile was eluted from 5% to 45% (flow rate: 12 mL / min; elution time: 16 min), and after lyophilization, compound 10 (6 mg, yield: 10%) was obtained.

[0741] LCMS m / z = 1137.3 [M+1] +

[0742] Example 11: Preparation of Compound 11

[0743] Step 1: Synthesis of 11B

[0744] Diethylamine (0.72 g, 9.90 mmol) was added to a 40 mL solution of acetonitrile containing 10B (1.7 g, 3.30 mmol), and the reaction was carried out at room temperature for 4 h. After concentration under reduced pressure, 10C (crude product) was obtained. At 0 °C, 11A (1.50 g, 3.92 mmol), 1-hydroxybenzotriazole (1.50 g, 3.95 mmol), N-methylmorpholine (1.0 g, 9.89 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (757 mg, 3.95 mmol) were added sequentially to a 10 mL solution of 10C containing N,N-dimethylformamide, and the reaction was carried out at room temperature for 16 h. The reaction solution was slowly added to water (100 mL), and a solid precipitated out. The mixture was filtered, and the filter cake was washed with water (20 mL x 3). After drying the filter cake, the crude product was obtained. The crude product was purified by column chromatography (dichloromethane:methanol (v / v) = 9:1) to obtain 11B (1.22 g, two-step yield: 56%).

[0745] Step 2: Synthesis of 11C

[0746] 11B (1.22 g, 1.86 mmol) was dissolved in tetrahydrofuran (25 mL) and ethanol (25 mL), and palladium on carbon (300 mg, 10% wt) was added. The reaction was carried out at room temperature for 4 h under a hydrogen atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 11C (1.0 g, yield: 95%).

[0747] LCMS m / z = 565.2 [M-1] -

[0748] Step 3: Preparation of 11D

[0749] At 0 °C, N,N-diisopropylethylamine (496 mg, 3.84 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (365 mg, 0.96 mmol) were added sequentially to a solution of 11C (544 mg, 0.96 mmol) and 6A (508 mg, 0.96 mmol) in N,N-dimethylformamide (10 mL), and the reaction was carried out at room temperature for 16 h. The reaction solution was slowly added to water (100 mL), and a solid precipitated out. The mixture was filtered, and the filter cake was washed with water (20 mL x 3). After drying, 11D (1.03 g, crude product) was obtained.

[0750] LCMS m / z = 1077.4 [M+1] +

[0751] Step 4: Preparation of 11E

[0752] Diethylamine (351 mg, 4.8 mmol) was added to a solution of 11D (1.03 g, crude) in acetonitrile (150 mL), and the reaction was carried out at room temperature for 16 h. The crude product was concentrated under reduced pressure and purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC system, SunFire@Prep C8 column, inner diameter x length = 19 mm × 150 mm). Preparation method: The crude product was dissolved in DMF and filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase: acetonitrile / water (containing 0.05% trifluoroacetic acid). Gradient elution method: Acetonitrile was used to elute from 5% to 45% (flow rate: 12 mL / min; elution time: 16 min), and the solution was lyophilized to obtain 11E (375 mg, two-step yield: 46%).

[0753] LCMS m / z = 855.6 [M+1] +

[0754] Step 5: Preparation of Compound 11

[0755] At 0°C, N,N-diisopropylethylamine (10 mg, 0.08 mmol) and 11E (30 mg, 0.04 mmol) were added to a 9 g (23.78 mg, crude) solution of N,N-dimethylformamide (3 mL), and the reaction was allowed to proceed at room temperature for 0.5 h. At 0°C, N,N-diisopropylethylamine (5 mg, 0.04 mmol) was added again, and the reaction was allowed to proceed at room temperature for 0.5 h. The reaction solution was purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC system, SunFire@Prep C8 column, inner diameter x length = 19 mm × 150 mm). Preparation method: The reaction solution was filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: acetonitrile / water (containing 0.05% trifluoroacetic acid). Gradient elution method: Acetonitrile was eluted from 5% to 45% (flow rate: 12 mL / min; elution time: 16 min), and after lyophilization, compound 11 was obtained (5 mg, yield: 8%).

[0756] LCMS m / z = 1180.6 [M+1] +

[0757] Example 12: Preparation of Compound 12

[0758] Compound 12 was obtained using 10A and benzyl trans-3-hydroxycyclobutanecarboxylate as starting materials, following the synthesis method described in Example 10.

[0759] LCMS m / z = 1151.3[M+1] +

[0760] Example 13: Preparation of Compound 13

[0761] Step 1: Preparation of 13B

[0762] Trifluoroacetic acid (10 mL) was added to a solution of 13A (900 mg, 2.36 mmol, prepared from (R)-5-tert-butyl-1-methyl-2-aminoglutarate as the starting material, according to the synthesis method of 9C) in 10 mL of dichloromethane. The reaction was carried out at room temperature for 3 h, and the residue was concentrated under reduced pressure. Water (20 mL) was added, and the pH of the system was adjusted to 5-6 with saturated sodium bicarbonate aqueous solution. The mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol (v / v) = 10:1) to obtain 13B (686 mg, yield: 89%).

[0763] LCMS m / z = 326.1 [M+1] +

[0764] Step 2: Preparation of 13C

[0765] At 0 °C, N-methylmorpholine (587 mg, 5.80 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (447 mg, 2.33 mmol) were added sequentially to a solution of 13B (638 mg, 1.96 mmol), glycine (4-methoxyphenyl) methyl ester hydrochloride (638 mg, 2.38 mmol), and 1-hydroxybenzotriazole (315 mg, 2.33 mmol) in N,N-dimethylformamide (15 mL). The reaction was carried out at room temperature for 16 h. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:tetrahydrofuran (v / v) = 82:18) to give 13C (835 mg, yield: 85%).

[0766] LCMS m / z = 503.1 [M+1] +

[0767] Step 3: Preparation of 13D

[0768] At 0°C, 236 mg (1.70 mmol) of 1,5,7-triazabicyclo[4.4.0]decen-5-ene was slowly added to a 13C solution of 30 mL tetrahydrofuran (855 mg, 1.70 mmol) and 9 mL water, and the reaction was carried out at 0°C for 20 min. At 0°C, 0.3 mL of 1N dilute hydrochloric acid was added, followed by 30 mL of water and extraction with 30 mL x 3 ethyl acetate. The organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:tetrahydrofuran (v / v) = 10:1). The crude product was purified by Pre-HPLC (instrument and preparative column: Waters AutoP preparative HPLC, SunFire@PrepC18 column, inner diameter x length = 19 mm × 250 mm). Preparation method: The crude product was dissolved in DMF and filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile / water (containing 0.1% trifluoroacetic acid). Gradient elution method: Acetonitrile was used to elute from 10% to 70% (flow rate: 15 mL / min; elution time: 25 min), and after lyophilization, 13D (5 mg, yield: 17%) was obtained.

[0769] LCMS m / z = 489.1 [M+1] +

[0770] Compound 13 was obtained using 13D and 5H as raw materials according to the synthesis method described in Example 9.

[0771] LCMS m / z = 1342.3 [M+1] +

[0772] Example 14: Preparation of Compound 14

[0773] Compound 14 was obtained using 14A and 1f as starting materials, following the synthesis method described in Example 9.

[0774] LCMS m / z = 1285.3 [M+1] +

[0775] Example 15: Preparation of Compound 15

[0776] Compound 15 was obtained using 14g and 10g as starting materials, following the synthesis method described in Example 10.

[0777] LCMS m / z = 1137.5 [M+1] +

[0778] Example 16: Preparation of Compound 16

[0779] Step 1: Preparation of 16A

[0780] Trifluoroacetic acid (10 mL) was added to a solution of 14E (670 mg, 1.44 mmol) in dichloromethane (10 mL), and the reaction was carried out at room temperature for 1 h. After concentration under reduced pressure, 16A (600 mg, crude product) was obtained.

[0781] Step 2: Preparation of 16b

[0782] At 0°C, N,N-diisopropylethylamine (760 mg, 5.88 mmol) was added to a solution of 16A (600 mg, crude product) and 2,5,8,11,14,17,20-heptaoxadecano-22-amine (600 mg, 1.76 mmol) in N,N-dimethylformamide (5 mL), and the reaction was carried out at room temperature for 16 h. The reaction solution was purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, SunFire@Prep C8 column, inner diameter x length = 19 mm × 150 mm). Preparation method: The reaction solution was filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: acetonitrile / water (containing 0.05% TFA). Gradient elution method: Acetonitrile was eluted from 10% to 60% (flow rate: 12 mL / min; elution time: 16 min), and lyophilized to obtain 16B (500 mg, two-step yield: 55%).

[0783] LCMS m / z = 633.3[M+1] +

[0784] Step 3: Preparation of 16C

[0785] At 0 °C, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (340 mg, 1.77 mmol) was added to a solution of 16B (376 mg, 0.59 mmol) and N-hydroxysuccinimide (204 mg, 1.77 mmol) in dichloromethane (10 mL), and the reaction was carried out at room temperature for 2 h. Dichloromethane (100 mL) was added, and the mixture was washed with water (20 mL x 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:tetrahydrofuran (v / v) = 10:1) to give 16C (230 mg, yield: 53%).

[0786] LCMS m / z = 730.2[M+1] +

[0787] Step 4: Preparation of 16D

[0788] At 0°C, m-chloroperoxybenzoic acid (195 mg, 0.96 mmol) was added to a solution of 16C (230 mg, 0.32 mmol) in dichloromethane (10 mL), and the reaction was carried out at room temperature for 8 h. The mixture was then cooled to -50°C, and a solid precipitated. The solid was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC system, XBridge@Prep C18 column, inner diameter x length = 19 mm x 250 mm). Preparation method: The crude product was dissolved in DMF and filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: acetonitrile / water (containing 0.05% trifluoroacetic acid). Gradient elution method: Acetonitrile was used to elute from 30% to 80% (flow rate: 12 mL / min; elution time: 15 min), and the solution was lyophilized to obtain 16D (230 mg, yield: 96%).

[0789] LCMS m / z = 762.2[M+1] +

[0790] Step 5: Preparation of Compound 16

[0791] At 0°C, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (8 mg, 0.02 mmol) was added to a solution of 16D (17 mg, 0.03 mmol), N,N-diisopropylethylamine (3 mg, 0.02 mmol), and N,N-dimethylformamide (2 mL), and reacted at room temperature for 1 h. At 0°C, 5H (20 mg, 0.02 mmol) was added to the reaction solution, and reacted at room temperature for 1 h. The reaction solution was purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, SunFire@Prep C8 column, inner diameter x length = 19 mm × 150 mm). Preparation method: The reaction solution was filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: acetonitrile / water (containing 0.05% formic acid). Gradient elution method: Acetonitrile was eluted from 10% to 55% (flow rate: 12 mL / min; elution time: 16 min), and after lyophilization, compound 16 (12 mg, yield: 39%) was obtained.

[0792] LCMS m / z = 1607.0 [M+1] +

[0793] Example 17: Preparation of Compound 17

[0794] Step 1: Preparation of 17B

[0795] At 0 °C, N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (209 mg, 0.55 mmol) was added to a solution of 17A (340 mg, 0.50 mmol), 6A (291 mg, 0.55 mmol), and N,N-diisopropylethylamine (258 mg, 2.00 mmol) in N,N-dimethylformamide (4 mL), and reacted at room temperature for 16 h. The reaction solution was purified by C18 reverse-phase column chromatography (the reaction solution was filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase: acetonitrile / water (containing 0.05% formic acid). Gradient elution method: acetonitrile was used to elute from 5% to 80% (flow rate: 65 mL / min; elution time: 20 min), and lyophilized to obtain 17B (376 mg, yield: 63%).

[0796] LCMS m / z = 1196.4 [M+H] +

[0797] Step 2: Preparation of 17C

[0798] Diethylamine (113 mg, 1.55 mmol) was added to a 10 mL solution of 17B (376 mg, 0.31 mmol) in acetonitrile, and the reaction was carried out at room temperature for 16 h. The reaction solution was concentrated, and the residue was purified by C18 reverse-phase column chromatography (the residue was dissolved in DMF and filtered through a 0.45 μm filter membrane to prepare the sample solution). The mobile phase system was acetonitrile / water (containing 0.05% formic acid). Gradient elution method: acetonitrile was used to elute from 5% to 80% (flow rate: 65 mL / min; elution time: 20 min), and the sample was lyophilized to obtain 17C (200 mg, yield: 65%).

[0799] LCMS m / z = 974.3 [M+H] +

[0800] Step 3: Preparation of Compound 17

[0801] At 0°C, N,N-diisopropylethylamine (5.10 mg, 0.04 mmol) was added to a solution of 17C (30 mg, 0.03 mmol) and 9G (17 mg, 0.04 mmol) of N,N-dimethylformamide (3 mL), and the reaction was carried out at 0°C for 1 h. The reaction solution was purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, SunFire@Prep C18 column, inner diameter x length = 19 mm × 150 mm). Preparation method: The reaction solution was filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: acetonitrile / water (containing 0.05% formic acid). Gradient elution method: Acetonitrile was used to elute from 10% to 80% (flow rate: 12 mL / min; elution time 16 min), and after lyophilization, compound 17 (10 mg, yield: 24%) was obtained.

[0802] LCMS m / z = 1299.7 [M+1] +

[0803] Example 18: Preparation of Compound 18

[0804] Step 1: Preparation of 18B

[0805] 18A (4.5 g, 21.82 mmol) and N,N-diisopropylethylamine (5.64 g, 43.64 mmol) were dissolved in N,N-dimethylformamide (150 mL). Di(p-nitrobenzene) carbonate (9.96 g, 32.73 mmol) was slowly added under ice-water bath, and the reaction was carried out overnight at room temperature. The mixture was extracted with water (500 mL) and ethyl acetate (500 mL × 3), and the organic phases were combined. The organic phase was washed with water (500 mL × 2) and saturated sodium chloride solution (500 mL × 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to give 18B (13.2 g, yield: 78%).

[0806] Step 2: Preparation of 18C

[0807] 18B (6.12 g, 16.47 mmol) and tert-butyl methyl (2-(methylamino)ethyl)carbamate (3.10 g, 16.47 mmol) were dissolved in N,N-dimethylformamide (50 mL), and N,N-diisopropylethylamine (4.26 g, 32.94 mmol) was added. The mixture was reacted overnight at room temperature. The crude product was concentrated under reduced pressure and purified by a C18 reverse-phase column (mobile phase: acetonitrile / water (containing 0.05% trifluoroacetic acid), gradient elution method: acetonitrile from 35% to 70% (flow rate: 50 mL / min; elution time: 20 min). After lyophilization, 18C (6.1 g, yield: 93.8%) was obtained.

[0808] LCMS m / z = 321.2[M+H] +

[0809] Step 3: Preparation of 18D

[0810] 18C (6.40 g, 15.22 mmol) was dissolved in methanol (100 mL), and Pd / C (640 mg, 10% water content) was added. The mixture was reacted overnight at room temperature. The solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, SunFire@Prep C8 column, inner diameter x length = 19 mm × 250 mm). Preparation method: The crude product was dissolved in N,N-dimethylformamide and filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: acetonitrile / water (containing 0.1% trifluoroacetic acid). Gradient elution method: Acetonitrile was used to elute from 18% to 55% (flow rate: 14 mL / min; elution time: 16 min), and the solution was lyophilized to obtain 18D (4.1 g, yield: 82%).

[0811] LCMS m / z = 231.1 [M+H] +

[0812] Step 4: Preparation of 18E

[0813] 6A (840 mg, 1.59 mmol) and 18D (525 mg, 1.59 mmol) were dissolved in N,N-dimethylformamide (15 mL), and N,N-diisopropylethylamine (620 mg, 4.77 mmol) and HATU (730 mg, 1.91 mmol) were added. The reaction was carried out at room temperature for 2 h. The crude product was concentrated under reduced pressure and purified by C18 reversed-phase column chromatography (mobile phase: acetonitrile / water (containing 0.05% trifluoroacetic acid), gradient elution method: acetonitrile from 25% to 65% (flow rate: 45 mL / min; elution time: 20 min), lyophilized to obtain 18E (850 mg, yield: 64%).

[0814] LCMS m / z = 841.5 [M+H] +

[0815] Step 5: Preparation of 18F

[0816] 18E (0.85 g, 1.01 mmol) was dissolved in 6 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The reaction was carried out at room temperature for 2 hours. The residue was concentrated under reduced pressure and purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC system, SunFire@Prep C8 column, inner diameter x length = 19 mm × 250 mm). Preparation method: The residue was dissolved in N,N-dimethylformamide and filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase: acetonitrile / water (containing 0.1% trifluoroacetic acid). Gradient elution method: Acetonitrile was used to elute from 15% to 50% (flow rate: 15 mL / min; elution time: 15 min). After lyophilization, 18F (430 mg, yield: 57%) was obtained.

[0817] LCMS m / z = 741.3 [M+H] +

[0818] Step 6: Preparation of 18H

[0819] 18F (82 mg, 0.11 mmol) and 18G (90 mg, 0.11 mmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (28 mg, 0.22 mmol) was added. The reaction mixture was reacted at room temperature for 16 h. The reaction solution was purified by C18 chromatography (mobile phase: acetonitrile / water (containing 0.05% trifluoroacetic acid). Gradient elution method: acetonitrile was used to elute from 30% to 80% (flow rate: 60 mL / min; elution time: 20 min). After lyophilization, 18H (150 mg, yield: 95%) was obtained.

[0820] LCMS m / z = 1393.4 [M+H] +

[0821] Step 7: Synthesis of Compound 16J

[0822] 18H (80 mg, 0.05 mmol) was dissolved in THF (2 mL), and 6N HCl (2 mL) was added at room temperature. The reaction was carried out at 45 °C for 4 h. The reaction solution was purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, SunFire@Prep C18 column, inner diameter x length = 19 mm × 250 mm). Preparation method: The crude product was dissolved in N,N-dimethylformamide and filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: acetonitrile / water (containing 0.1% trifluoroacetic acid). Gradient elution method: Acetonitrile was eluted from 5% to 37% (flow rate: 15 mL / min; elution time 16 min), and then lyophilized to obtain 16J (20 mg, yield: 30%).

[0823] LCMS m / z = 1153.4 [M+H] +

[0824] Step 8: Synthesis of Compound 18

[0825] 16 J (20 mg, 0.02 mmol) and 9 G (9 mg, 0.02 mmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (3 mg, 0.03 mmol) was added at room temperature. The reaction mixture was reacted at room temperature for 1 h. The reaction solution was purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, SunFire@Prep C8 column, inner diameter x length = 19 mm × 250 mm). Preparation method: The reaction solution was diluted with N,N-dimethylformamide and filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: acetonitrile / water (containing 0.1% trifluoroacetic acid). Gradient elution method: Acetonitrile was used to elute from 10% to 52.5% (flow rate: 15 mL / min; elution time: 17 min), and the solution was lyophilized to obtain compound 18 (5 mg, yield: 20%).

[0826] LCMS m / z = 1478.3 [M+H] +

[0827] Example 19: Preparation of Compound 19

[0828] At 0 °C, N,N-diisopropylethylamine (3.26 mg, 0.03 mmol) was added to a 2 mL solution of N,N-dimethylformamide (17C, 20 mg, 0.02 mmol) and 14G (10 mg, 0.02 mmol), and reacted at 0 °C for 1 h. The reaction solution was purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, SunFire@Prep C18 column, inner diameter x length = 19 mm × 150 mm). Preparation method: The reaction solution was filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: acetonitrile / water (containing 0.05% formic acid). Gradient elution method: Acetonitrile was used to elute from 10% to 80% (flow rate: 12 mL / min; elution time 16 min), and after lyophilization, compound 19 (5 mg, yield: 9%) was obtained.

[0829] LCMS m / z = 1299.4 [M+1] +

[0830] Example 20: Preparation of Compound 20

[0831] Compound 20 was obtained using 10A and benzoyl glycolate as starting materials, following the synthesis method described in Example 10.

[0832] LCMS m / z = 1151.4 [M+1] +

[0833] Example 21: Preparation of compound 21

[0834] Compound 21 was obtained using 21A as the starting material and synthesized according to the method described in Example 10.

[0835] LCMS m / z = 1299.3 [M+1] +

[0836] Example 22: Preparation of compound 22

[0837] Compound 22 was obtained using 20B and FMOC-alanylalanine as starting materials, following the synthesis method described in Example 10.

[0838] LCMS m / z = 1194.3 [M+1] +

[0839] Example 23: Preparation of compound 23

[0840] Compound 23 was obtained by using 12B and (((9H-fluorene-9-yl)methoxy)carbonyl)-L-alanyl-L-alanine as starting materials, following the synthesis method of Example 12.

[0841] LCMS m / z = 1194.6 [M+1] +

[0842] Example 24: Preparation of compound 24

[0843] Compound 24 was obtained using 21A and 9G as starting materials, following the synthesis method described in Example 21.

[0844] LCMS m / z = 1299.7 [M+1] +

[0845] Example 25: Preparation of Compound 25

[0846] Compound 25 was obtained using 24B and 14G as starting materials, following the synthesis method described in Example 24.

[0847] LCMS m / z = 1299.4 [M+1] +

[0848] Example 26: Preparation of Compound 26

[0849] Compound 26 was obtained using 20D and 9G as starting materials, following the synthesis method described in Example 20.

[0850] LCMS m / z = 1151.3[M+1] +

[0851] Example 27: Preparation of Compound 27

[0852] Compound 27 was obtained by using 22B and 9G as starting materials, following the synthesis method described in Example 22.

[0853] LCMS m / z = 1194.3 [M+1] +

[0854] Example 28: Preparation of Compound 28

[0855] Step 1: Preparation of 28A

[0856] Trifluoroacetic acid (10 mL) was added to a solution of 9C (2.3 g, 6.03 mmol) in dichloromethane (10 mL), and the reaction was carried out at room temperature for 3 h. The residue was concentrated under reduced pressure and extracted with dichloromethane (30 mL x 3) in ice water. The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (dichloromethane:methanol (v / v) = 95:5) to give 28A (1.10 g, yield: 56%).

[0857] LCMS m / z = 326.2[M+1] +

[0858] Step 2: Preparation of 28B

[0859] At 0 °C, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (325 mg, 1.69 mmol) was added to a solution of 28A (500 mg, 1.54 mmol), D-glucosamine (335 mg, 1.85 mmol), and 1-hydroxybenzotriazole (229 mg, 1.69 mmol) in N,N-dimethylformamide (8 mL), and the reaction was carried out at room temperature for 3 h. The reaction solution was purified by reverse-phase column chromatography (mobile phase: acetonitrile / water (containing 0.05% trifluoroacetic acid), and lyophilized to give 28B (737 mg, yield: 98%).

[0860] LCMS m / z = 489.2[M+1] +

[0861] Step 3: Preparation of 28C

[0862] At 0°C, 5 mL of an aqueous solution of lithium hydroxide monohydrate (737 mg, 1.51 mmol) was slowly added to 5 mL of a tetrahydrofuran solution of 28B (737 mg, 1.51 mmol), and the reaction was allowed to proceed at room temperature for 3 h. At 0°C, the pH of the system was adjusted to approximately 3-4 using 1 N hydrochloric acid solution. The solution was concentrated under reduced pressure to obtain a residue, which was then purified by reverse-phase column chromatography (mobile phase: acetonitrile / water (containing 0.05% trifluoroacetic acid), and lyophilized to obtain 28C (355 mg, yield: 50%).

[0863] LCMS m / z = 475.2[M+1] +

[0864] Step 4: Preparation of 28D

[0865] 28C (100 mg, 0.21 mmol) was dissolved in acetonitrile (3 mL) and water (2 mL). At 0 °C, an aqueous solution of potassium peroxide monosulfonate (258 mg, 0.42 mmol) (1 mL) was slowly added to the reaction solution, and the reaction was carried out at room temperature for 16 h. The residue was concentrated under reduced pressure and purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, SunFire@Prep C8 column, inner diameter x length = 19 mm × 150 mm). Preparation method: The residue was filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: acetonitrile / water (containing 0.05% formic acid). Gradient elution method: Acetonitrile was used to elute from 5% to 45% (flow rate: 12 mL / min; elution time: 16 min), and the solution was lyophilized to obtain 28D (8.35 mg, yield: 8%).

[0866] LCMS m / z = 507.0 [M+1] +

[0867] Step 5: Preparation of Compound 28

[0868] At 0°C, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (5.7 mg, 0.02 mmol) was added to N,N-dimethylformamide (3 mL) containing 28D (8.35 mg, 0.02 mmol), 17C (15 mg, 0.02 mmol), and N,N-diisopropylethylamine (5 mg, 0.04 mmol), and the reaction was allowed to proceed at room temperature for 0.5 h. Then, N,N-diisopropylethylamine (20 mg, 0.16 mmol) was added at 0°C, and the reaction was allowed to proceed at room temperature for another 0.5 h. The reaction solution was purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC system, SunFire@Prep C8 column, inner diameter x length = 19 mm × 150 mm). Preparation method: The reaction solution was filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase: acetonitrile / water (containing 0.05% formic acid). Gradient elution method: acetonitrile was used to elute from 5% to 45% (flow rate: 12 mL / min; elution time: 16 min), and after lyophilization, compound 28 was obtained (3 mg, yield: 22%).

[0869] LCMS m / z = 1462.4 [M+1] +

[0870] Example 29: Preparation of compound 29

[0871] Compound 29 was obtained by using 29A as the starting material and following the synthesis method of Example 28.

[0872] LCMS m / z = 1448.8 [M+1] +

[0873] Example 30: Synthesis of Compound 30

[0874] Step 1: Synthesis of 30B

[0875] 30A (1.8 g, 2.55 mmol) and di(p-nitrobenzene) carbonate (1.16 g, 3.82 mmol) were dissolved in N,N-dimethylformamide (6 mL), and N,N-diisopropylethylamine (990 mg, 7.65 mmol) was added. The reaction mixture was allowed to react overnight at room temperature. The reaction solution was purified by a C18 reversed-phase column (mobile phase: acetonitrile / water (containing 0.5% trifluoroacetic acid), gradient elution method: acetonitrile was used to elute from 30% to 75% (flow rate: 45 mL / min; elution time: 20 min). After lyophilization, 30C (160 mg, yield 94.77%) was obtained.

[0876] Step 2: Synthesis of 30C

[0877] 30B (100 mg, 0.11 mmol) and 18F (81.5 mg, 0.11 mmol) were dissolved in N,N-dimethylformamide (6 mL), and N,N-diisopropylethylamine (28 mg, 0.22 mmol) was added. The mixture was reacted overnight at room temperature. The crude product was concentrated under reduced pressure and purified by a C18 reversed-phase column (mobile phase: acetonitrile / water (containing 0.5% trifluoroacetic acid), gradient elution method: acetonitrile was used to elute from 28% to 68% (flow rate: 50 mL / min; elution time: 20 min). After lyophilization, 30C (160 mg, yield 94.77%) was obtained.

[0878] LCMS m / z = 1476.9 [M+H] +

[0879] Step 3: 30D Synthesis

[0880] 30C (80 mg, 0.054 mmol) was dissolved in THF (2 mL), and 6N HCl (2 mL) was added at room temperature. The reaction was carried out overnight at 45 °C. The crude product was concentrated under reduced pressure and purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, SunFire@Prep C18 column, inner diameter x length = 19 mm × 250 mm). Preparation method: The crude product was dissolved in N,N-dimethylformamide and filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: acetonitrile / water (containing 0.1% trifluoroacetic acid). Gradient elution method: Acetonitrile was used to elute from 5% to 37% (flow rate: 15 mL / min; elution time 16 min), and then lyophilized to obtain 30D (22 mg, yield 32.84%).

[0881] LCMS m / z = 1236.7 [M+H] +

[0882] Step 4: Synthesis of Compound 30

[0883] 30D (27 mg, 0.022 mmol) and 9G (11.89 mg, 0.024 mmol crude product) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (8.9 mg, 0.088 mmol) was added at room temperature. The reaction was carried out at room temperature for 2 h. The crude product was concentrated under reduced pressure and purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, SunFire@Prep C8 column, inner diameter x length = 19 mm × 250 mm). Preparation method: The crude product was dissolved in N,N-dimethylformamide and filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: acetonitrile / water (containing 0.1% formic acid). Gradient elution method: Acetonitrile was eluted from 10% to 52.5% (flow rate: 15 mL / min; elution time: 17 min), and after lyophilization, compound 30 (4 mg, yield 11.64%) was obtained.

[0884] LCMS m / z = 1561.9 [M+H] +

[0885] Example 31: Synthesis of Compound 31

[0886] Step 1: Synthesis of 31B

[0887] 31A (55 mg, 0.072 mmol) and 18F (53.37 mg, 0.072 mmol) were dissolved in N,N-dimethylformamide (5 mL). N,N-diisopropylethylamine (27 mg, 0.22 mmol) was slowly added under ice-water bath, and the reaction was allowed to proceed overnight at room temperature. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined. The organic phases were washed successively with water (100 mL × 2) and saturated NaCl aqueous solution (100 mL × 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified using a C18 reversed-phase column (additional purification method). The mobile phase was acetonitrile / water (containing 0.5% trifluoroacetic acid), and the gradient elution method was acetonitrile from 35% to 75% (flow rate: 50 mL / min; elution time: 20 min). After lyophilization, compound 31B (81 mg, yield 82.49%) was obtained.

[0888] LCMS m / z = 1368.8 [M+H] +

[0889] Step 2: Synthesis of 31C

[0890] Diethylamine (22 mg, 0.29 mmol) was added to a solution of 31C (81 mg, 0.059 mmol) and tetrahydrofuran (5 mL), and the reaction was carried out at room temperature for 3 h. The crude product was concentrated under reduced pressure and purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC system, SunFire@PrepC18 column, inner diameter x length = 19 mm × 250 mm). Preparation method: The crude product was dissolved in N,N-dimethylformamide and filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase: acetonitrile / water (containing 0.5% ammonium bicarbonate). Gradient elution method: Acetonitrile was used to elute from 20% to 50% (flow rate: 12 mL / min; elution time: 15 min), and the solution was lyophilized to obtain 31C (41 mg, yield 60.43%).

[0891] LCMS m / z = 1146.7 [M+H] +

[0892] Step 3: Synthesis of Compound 31

[0893] 31C (20 mg, 0.017 mmol) and 9G (7.49 mg, 0.017 mmol) were dissolved in N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine (4.4 mg, 0.034 mmol) was added under ice-water bath conditions, and the reaction was carried out at 10 °C for 1 h. The reaction solution was purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, SunFire@PrepC18 column, inner diameter x length = 19 mm × 250 mm). Preparation method: The sample solution was prepared by filtration through a 0.45 μm filter membrane. Mobile phase: Acetonitrile / water (containing 0.1% FA). Gradient elution method: Acetonitrile was used to elute from 15% to 47.5% (flow rate: 12 mL / min; elution time: 15 min). After lyophilization, compound 31 (5 mg, yield 19.48%) was obtained.

[0894] LCMS m / z = 1471.8 [M+H] +

[0895] Example 32: Synthesis of Compound 32

[0896] Step 1: Synthesis of 32A

[0897] 1f (5 g, 17.17 mmol) and R-propargyl glycine methyl ester (2.18 g, 17.17 mmol) were dissolved in THF (50 mL), and N,N-diisopropylethylamine (2.63 g, 8.64 mmol) was slowly added. The reaction was carried out overnight at 60 °C. After cooling to room temperature, water (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined. The organic phase was washed with water (100 mL × 2) and saturated NaCl aqueous solution (100 mL × 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the residue, which was purified by column chromatography (mobile phase: acetonitrile / water (containing 0.05% trifluoroacetic acid), gradient elution method: acetonitrile was eluted from 30% to 65% (flow rate: 50 mL / min; elution time: 20 min) to obtain 32A (4.5 g, yield 77.67%).

[0898] LCMS m / z = 338.1 [M+H] +

[0899] Step 2: Synthesis of 32B

[0900] Compound 32A (4.5 g, 13.34 mmol) was dissolved in THF (25 mL) and water (5 mL). Lithium hydroxide monohydrate (0.96 g, 40.02 mmol) was slowly added at room temperature, and the reaction was allowed to proceed for 2 h at room temperature. The residue was concentrated under reduced pressure and purified using a C18 reversed-phase column (mobile phase: acetonitrile / water (containing 0.05% trifluoroacetic acid), gradient elution method: acetonitrile eluted from 20% to 55% (flow rate: 50 mL / min; elution time: 20 min) to give 32B (3.1 g, yield: 78.71%).

[0901] LCMS m / z = 296.0 [M+H] +

[0902] Step 3: Synthesis of 32C

[0903] 32B (1 g, 3.39 mmol), EDCI (0.78 g, 4.07 mmol), and HOBt (0.55 g, 4.07 mmol) were dissolved in N,N-dimethylformamide (15 mL), and N,N-diisopropylethylamine (1.31 g, 10.17 mmol) was slowly added at room temperature. The reaction was carried out at room temperature for 12 hours. The residue was concentrated under reduced pressure and purified by a C18 reversed-phase column (mobile phase: acetonitrile / water (containing 0.05% trifluoroacetic acid), gradient elution method: acetonitrile was eluted from 30% to 75% (flow rate: 45 mL / min; elution time: 20 min) to give 32C (0.31 g, yield: 33.01%).

[0904] LCMS m / z = 278.0 [M+H] +

[0905] Step 4: 32D compositing

[0906] 32C (0.25 g, 0.90 mmol) and MPEG6-AZIDE (0.29 g, 0.90 mmol) were dissolved in N,N-dimethylformamide (25 mL) and water (5 mL). Anhydrous copper sulfate (0.14 g, 0.90 mmol) and sodium vitamin C (0.36 g, 1.8 mmol) were slowly added at room temperature, and the reaction was carried out overnight at room temperature. The residue was concentrated under reduced pressure and purified by a C18 reversed-phase column (mobile phase: acetonitrile / water (containing 0.05% trifluoroacetic acid), gradient elution method: acetonitrile was eluted from 30% to 60% (flow rate: 45 mL / min; elution time: 20 min) to give 32D (0.45 g, yield: 83.37%).

[0907] LCMS m / z = 599.3 [M+H] +

[0908] Step 5: Synthesis of 32E

[0909] 32D (0.2 g, 0.33 mmol) was dissolved in acetonitrile (5 mL) and water (1 mL), and potassium peroxide monosulfonate (0.41 g, 0.66 mmol) was slowly added at room temperature. The reaction was allowed to proceed for 2 h at room temperature. After the reaction, the reaction solution was purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, SunFire@PrepC18 column, inner diameter x length = 19 mm × 250 mm). Preparation method: The crude product was dissolved in N,N-dimethylformamide and filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: acetonitrile / water (containing 0.1% TFA). Gradient elution method: Acetonitrile was used to elute from 10% to 35% (flow rate: 12 mL / min; elution time: 14 min) to obtain 32E (0.1 g, yield: 47.46%).

[0910] LCMS m / z = 631.3 [M+H] +

[0911] Step 6: Synthesis of Compound 32

[0912] 32E (20 mg, 0.032 mmol) and 5H (30.73 mg, 0.032 mmol) were dissolved in 3 mL of N,N-dimethylformamide. N,N-diisopropylethylamine (12 mg, 0.096 mmol) and HATU (15 mg, 0.038 mmol) were added sequentially at room temperature, and the reaction was allowed to proceed for 2 h at room temperature. The reaction solution was purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC system, SunFire@PrepC18 column, inner diameter x length = 19 mm × 250 mm). Preparation method: The sample solution was prepared by filtration through a 0.45 μm filter membrane. Mobile phase system: acetonitrile / water (containing 0.1% FA). Gradient elution method: Acetonitrile was eluted from 15% to 47.5% (flow rate: 12 mL / min; elution time: 15 min), and after lyophilization, compound 32 (5 mg, yield: 10.02%) was obtained.

[0913] LCMS m / z = 1572.9 [M+H] +

[0914] Example 33: Preparation of compound 33

[0915] Compound 33 was obtained by using 14C as the starting material and following the synthesis method of Example 28.

[0916] LCMS m / z = 1462.4 [M+1] +

[0917] Example 34: Preparation of compound 34

[0918] Step 1: Preparation of 34B

[0919] N-methylmorpholine (20 mg, 0.20 mmol), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (48 mg, 0.20 mmol) were added to a solution of 34A (95 mg, 0.20 mmol) (synthesized in the reference Assembly of Glycopeptides in Living Cells Resembling Viral Infection for Cargo Delivery) and 17C (150 mg, 0.15 mmol) in 20 mL of dichloromethane. The reaction was carried out at room temperature for 6 h. The crude product was concentrated and purified by a C18 reversed-phase column (mobile phase: acetonitrile / water (containing 0.05% trifluoroacetic acid), gradient elution method: acetonitrile was eluted from 35% to 70% (flow rate: 50 mL / min; elution time: 20 min). After lyophilization, 34B (120 mg, yield: 54%) was obtained.

[0920] LCMS m / z = 1445.9 [M+H] +

[0921] Step 2: Preparation of 34C

[0922] Diethylamine (30 mg, 0.42 mmol) was added to a 5 mL solution of acetonitrile containing 120 mg (0.08 mmol) of 34B, and the reaction was carried out at room temperature for 3 h. The crude product was concentrated under reduced pressure and purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC system, SunFire@PrepC18 column, inner diameter x length = 19 mm × 250 mm). Preparation method: The crude product was dissolved in N,N-dimethylformamide and filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase: Acetonitrile / water (containing 0.5% trifluoroacetic acid). Gradient elution method: Acetonitrile was used to elute from 20% to 50% (flow rate: 12 mL / min; elution time: 15 min), and the solution was lyophilized to obtain 34C (60 mg, yield 59%).

[0923] LCMS m / z = 1223.7 [M+H] +

[0924] Step 3: Synthesis of Compound 34

[0925] 34C (30 mg, 0.03 mmol) and 14G (50 mg, 0.1 mmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (4 mg, 0.03 mmol) was added at room temperature. The reaction mixture was reacted at room temperature for 1 h. The reaction solution was purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, SunFire@Prep C8 column, inner diameter x length = 19 mm × 250 mm). Preparation method: The reaction solution was diluted with N,N-dimethylformamide and filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: acetonitrile / water (containing 0.1% formic acid). Gradient elution method: Acetonitrile was used to elute from 10% to 52.5% (flow rate: 15 mL / min; elution time: 17 min), and the solution was lyophilized to obtain compound 34 (8 mg, yield: 21%).

[0926] LCMS m / z = 1548.0 [M+H] +

[0927] Example 35: Preparation of compound 35

[0928] Compound 35 was obtained using compounds 34C and 9G as substrates, following the synthetic method described in Example 34.

[0929] LCMS m / z = 1548.0 [M+H] +

[0930] Example 36: Preparation of compound 36

[0931] At 0 °C, N,N-diisopropylethylamine (18.61 mg, 0.14 mmol) was added to a solution of 36a (100 mg, 0.12 mmol) and 9G (176 mg, crude product) in 4 mL of N,N-dimethylformamide, and reacted at 0 °C for 1 h. The reaction solution was purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, SunFire@Prep C18 column, inner diameter x length = 19 mm × 150 mm). Preparation method: The reaction solution was filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: acetonitrile / water (containing 0.05% formic acid). Gradient elution method: Acetonitrile was used to elute from 10% to 80% (flow rate: 12 mL / min; elution time: 16 min), and after lyophilization, compound 36 (35 mg, yield: 25%) was obtained.

[0932] LCMS m / z = 1166.7 [M+H] +

[0933] Example 37: Preparation of compound 37

[0934] At 0 °C, N,N-diisopropylethylamine (18.61 mg, 0.14 mmol) was added to a solution of 36a (100 mg, 0.12 mmol) and 14G (180 mg, crude product) in 4 mL of N,N-dimethylformamide, and reacted at 0 °C for 1 h. The reaction solution was purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, SunFire@Prep C18 column, inner diameter x length = 19 mm × 150 mm). Preparation method: The reaction solution was filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: acetonitrile / water (containing 0.05% formic acid). Gradient elution method: Acetonitrile was used to elute from 10% to 80% (flow rate: 12 mL / min; elution time 16 min), and after lyophilization, compound 37 (25 mg, yield: 18%) was obtained.

[0935] LCMS m / z = 1166.3 [M+H] +

[0936] Example 2.1: Preparation of antibody-drug conjugates and DAR assay method:

[0937] Preparation of CD33-ADC:

[0938] General method:

[0939] The antibody sample was diluted to approximately 6 mg / mL with conjugation buffer (50 mM PB, pH 7.0), and TCEP was added as a reducing agent. The molar equivalent of TCEP was adjusted according to the target DAR: 8 equivalents were added when the target DAR was 8, and 2-3 equivalents were added when the target DAR was 4. Reduction was carried out at 22°C for 16 h, and the degree of antibody reduction was monitored by LC-MS. After the antibody was fully reduced, Tris buffer was added to adjust the pH of the reaction system to 7.0-7.4. Then, an excess of linker-drug solution dissolved in DMA was added, controlling the molar equivalent ratio of linker-drug to antibody to be 7-12. Conjugation was carried out at 22°C for 1 h. After the reaction, the conjugation product was purified using a Zeba desalting column with a molecular weight cutoff of 40 kDa to remove free linker-drug and other small molecule impurities. Simultaneously, the product was replaced with final product storage buffer (20 mM histidine, 8% sucrose, pH 6.0) to obtain the final product. After purification, the DAR of the sample was determined by LC-MS, the monomer purity was detected by SEC-HPLC, and the concentration was determined by UV-Vis method.

[0940] Example 2.1.1: Preparation of CD33-ADC-01

[0941] Add 1 mg of CD33 antibody (CD33Ab1) to a 1.5 mL EP tube, followed by conjugation buffer (50 mM PB, pH 7.0) and 5 mM TCEP solution (TCEP / antibody molar ratio of 8.0) to achieve an antibody concentration of 6 mg / mL. Mix the reaction solution thoroughly and incubate at 22°C for 16 h at 60 rpm in a shaker. Adjust the pH to approximately 7.4 by adding 1 M Tris-HCl (pH 8.5), then add DMA and 10 mM of Compound 9 stock solution dissolved in DMA (Compound 9 / antibody molar ratio of 12), bringing the total organic solvent content to 10%. Mix the reaction solution thoroughly and incubate at 22°C for another 1 h at 60 rpm in a shaker. Purify the conjugated sample using a Zeba desalting column (40 K molecular weight cutoff) and transfer the solution to the final ADC storage buffer to obtain the final product. The DAR value determined by mass spectrometry was 8.02. The storage buffer was 20 mM histidine, 8% sucrose, pH 6.0.

[0942] Example 2.1.2: Preparation of CD33-ADC-02

[0943] By replacing compound 9 in Example 2.1.1 with compound 8, the conjugate product CD33-ADC-02 of compound 8 and CD33 antibody was obtained. The DAR value was determined to be 7.8 by mass spectrometry.

[0944] Example 2.1.3: Preparation of CD33-ADC-03

[0945] By replacing compound 9 in Example 2.1.1 with compound 10, the conjugate product CD33-ADC-03 of compound 10 and CD33 antibody (CD33Ab1) was obtained. The DAR value was determined to be 8.03 by mass spectrometry.

[0946] Example 2.1.4: Preparation of CD33-ADC-04

[0947] By replacing compound 9 in Example 2.1.1 with compound 13, the conjugate product CD33-ADC-04 of compound 13 and CD33 antibody (CD33Ab1) was obtained. The DAR value was determined by mass spectrometry to be 7.98.

[0948] Example 2.1.5: Preparation of CD33-ADC-05

[0949] By replacing compound 9 in Example 2.1.1 with compound 14, the conjugate product CD33-ADC-05 of compound 14 and CD33 antibody (CD33Ab1) was obtained. The DAR value was determined by mass spectrometry to be 8.23.

[0950] Example 2.1.6: Preparation of CD33-ADC-06

[0951] By replacing compound 9 in Example 2.1.1 with compound 15, the conjugate product CD33-ADC-06 of compound 15 and CD33 antibody (CD33Ab1) was obtained. The DAR value was determined to be 8.11 by mass spectrometry.

[0952] Example 2.1.7: Preparation of CD33-ADC-07

[0953] By replacing compound 9 in Example 2.1.1 with compound 16, the conjugate product CD33-ADC-07 of compound 16 and CD33 antibody (CD33Ab1) was obtained. The DAR value was determined by mass spectrometry to be 8.31.

[0954] Example 2.1.8: Preparation of CD33-ADC-08

[0955] Using compound 17 as the linker drug, a universal conjugation method was employed to obtain the conjugation product CD33-ADC-08 of compound 17 and CD33 antibody (CD33Ab1). The DAR value was determined by mass spectrometry to be 3.39.

[0956] Example 2.1.9: Preparation of CD33-ADC-09

[0957] Add 1 mg of CD33 antibody (CD33Ab1) to a 1.5 mL EP tube, followed by conjugation buffer (50 mM PB, pH 7.0) and 5 mM TCEP solution (TCEP / antibody molar ratio of 8.0) to achieve an antibody concentration of 6 mg / mL. Mix the reaction solution thoroughly and incubate at 22°C for 16 h at 60 rpm in a shaker. Adjust the pH to approximately 7.4 by adding 1 M Tris-HCl (pH 8.5), then add DMA and 10 mM of Compound 17 stock solution dissolved in DMA (Compound 17 / antibody molar ratio of 12), bringing the total organic solvent content to 10%. Mix the reaction solution thoroughly and incubate at 22°C for another 1 h at 60 rpm in a shaker. Purify the conjugated sample using a Zeba desalting column (40 K molecular weight cutoff) and transfer the solution to the final ADC storage buffer to obtain the final product. The DAR value determined by mass spectrometry was 7.92. The storage buffer was 20 mM histidine, 8% sucrose, pH 6.0.

[0958] Example 2.1.10: Preparation of CD33-ADC-10

[0959] By replacing compound 9 in Example 2.1.1 with compound 19, the conjugate product CD33-ADC-10 of compound 19 and CD33 antibody (CD33Ab1) was obtained. The DAR value was determined to be 8.0 by mass spectrometry.

[0960] Example 2.1.11: Preparation of CD33-ADC-11

[0961] By replacing compound 9 in Example 2.1.1 with compound 12, the conjugate product CD33-ADC-11 of compound 12 and CD33 antibody (CD33Ab1) was obtained. The DAR value was determined to be 8.1 by mass spectrometry.

[0962] Example 2.1.12: Preparation of CD33-ADC-12

[0963] By replacing compound 9 in Example 2.1.1 with compound 23, the conjugate product CD33-ADC-12 of compound 23 and CD33 antibody (CD33Ab1) was obtained. The DAR value was determined to be 8.0 by mass spectrometry.

[0964] Example 2.1.13: Preparation of CD33-ADC-13

[0965] By replacing compound 9 in Example 2.1.1 with compound 24, the conjugate product CD33-ADC-13 of compound 24 and CD33 antibody (CD33Ab1) was obtained. The DAR value was determined to be 8.1 by mass spectrometry.

[0966] Example 2.1.14: Preparation of CD33-ADC-14

[0967] By replacing compound 9 in Example 2.1.1 with compound 21, the conjugate product CD33-ADC-14 of compound 21 and CD33 antibody (CD33Ab1) was obtained. The DAR value was determined by mass spectrometry to be 8.01.

[0968] Example 2.1.15: Preparation of CD33-ADC-15

[0969] By replacing compound 9 in Example 2.1.1 with compound 28, the conjugate product CD33-ADC-15 of compound 28 and CD33 antibody (CD33Ab1) was obtained. The DAR value was determined by mass spectrometry to be 7.89.

[0970] Example 2.1.16: Preparation of CD33-ADC-16

[0971] By replacing compound 9 in Example 2.1.1 with compound 33, the conjugate product CD33-ADC-16 of compound 33 and CD33 antibody (CD33Ab1) was obtained. The DAR value was determined by mass spectrometry to be 7.80.

[0972] Example 2.1.17: Preparation of CD33-ADC-17

[0973] By replacing compound 9 in Example 2.1.1 with compound 34, the conjugate product CD33-ADC-17 of compound 34 and CD33 antibody (CD33Ab1) was obtained. The DAR value was determined to be 7.99 by mass spectrometry.

[0974] Example 2.1.18: Preparation of CD33-ADC-18

[0975] By replacing compound 9 in Example 2.1.1 with compound 35, the conjugate product CD33-ADC-18 of compound 35 and CD33 antibody (CD33Ab1) was obtained. The DAR value was determined to be 7.97 by mass spectrometry.

[0976] Example 2.1.19: Preparation of CD33-ADC-19

[0977] Compound 36 was used instead of compound 9 in Example 2.1.1, and CD33Ab2 antibody was used instead of CD33Ab1 antibody in Example 2.1.1 to obtain the conjugate product CD33-ADC-19 of compound 36 and CD33Ab2 antibody. The DAR value was determined to be 7.0 by mass spectrometry.

[0978] Example 2.1.20: Preparation of CD33-ADC-20

[0979] Compound 37 was used instead of compound 9 in Example 2.1.1, and CD33Ab2 antibody was used instead of CD33Ab1 antibody in Example 2.1.1 to obtain the conjugate product CD33-ADC-19 of compound 37 and CD33Ab2 antibody. The DAR value was determined to be 7.1 by mass spectrometry.

[0980] Example 2.1.21: Preparation of CD33-ADC-21

[0981] Compound 17 was used instead of compound 9 in Example 2.1.1, and CD33Ab2 antibody was used instead of CD33Ab1 antibody in Example 2.1.1 to obtain the conjugate product CD33-ADC-21 of compound 17 and CD33Ab2 antibody. The DAR value was determined to be 6.3 by mass spectrometry.

[0982] Example 2.1.22: Preparation of CD33-ADC-22

[0983] Add 1 mg of CD33 antibody (CD33Ab2) to a 1.5 mL EP tube, followed by conjugation buffer (50 mM PB, pH 7.0) and 5 mM TCEP solution (TCEP / antibody molar ratio of 8.0) to achieve an antibody concentration of 6 mg / mL. Mix the reaction solution thoroughly and incubate at 22°C for 16 h at 60 rpm in a shaker. Adjust the pH to approximately 7.4 by adding 1 M Tris-HCl (pH 8.5), then add DMA and 10 mM of Compound 19 stock solution dissolved in DMA (Compound 19 / antibody molar ratio of 12), bringing the total organic solvent content to 10%. Mix the reaction solution thoroughly and incubate at 22°C for another 1 h at 60 rpm in a shaker. Purify the conjugated sample using a Zeba desalting column (40 K molecular weight cutoff) and transfer the solution to the final ADC storage buffer to obtain the final product. The DAR value determined by mass spectrometry was 6.7. The storage buffer was 20 mM histidine, 8% sucrose, pH 6.0.

[0984] The amino acid sequence of the antibody used for conjugation is as follows:

[0985] CD33

[0986] CD33Ab1

[0987] CD33Ab1_HC

[0988] SEQ ID NO:1:

[0989] CD33Ab1_LC

[0990] SEQ ID NO:2:

[0991] CD33Ab2

[0992] CD33Ab2_HC

[0993] SEQ ID NO:3:

[0994] CD33Ab2_LC

[0995] SEQ ID NO:4:

[0996] Preparation of HER2-ADC:

[0997] Example 2.1.23: Preparation of HER2-ADC-1

[0998] Add 1 mg of HER2 antibody (Trastuzumab) to a 1.5 mL EP tube, followed by conjugation buffer (50 mM PB, pH 7.0) and 5 mM TCEP solution (TCEP / antibody molar ratio of 8.0) to achieve an antibody concentration of 6 mg / mL. Mix the reaction solution thoroughly and incubate at 22°C for 16 h at 60 rpm in a shaker. Adjust the pH to approximately 7.4 by adding 1 M Tris-HCl (pH 8.5), then add DMA and 10 mM of Compound 36 stock solution dissolved in DMA (Compound 36 / antibody molar ratio of 12), bringing the total organic solvent content to 10%. Mix the reaction solution thoroughly and incubate at 22°C for another 1 h at 60 rpm in a shaker. Purify the conjugated sample using a Zeba desalting column (40 K molecular weight cutoff) and transfer the solution to the final ADC storage buffer to obtain the final product. The DAR value determined by mass spectrometry was 7.91. The storage buffer was 20 mM histidine, 8% sucrose, pH 6.0.

[0999] Example 2.1.24: Preparation of HER2-ADC-2

[1000] Add 1 mg of HER2 antibody (Trastuzumab) to a 1.5 mL EP tube, followed by conjugation buffer (50 mM PB, pH 7.0) and 5 mM TCEP solution (TCEP / antibody molar ratio of 8.0) to achieve an antibody concentration of 6 mg / mL. Mix the reaction solution thoroughly and incubate at 22°C for 16 h at 60 rpm in a shaker. Adjust the pH to approximately 7.4 by adding 1 M Tris-HCl (pH 8.5), then add DMA and 10 mM of Compound 37 stock solution dissolved in DMA (Compound 37 / antibody molar ratio of 12), bringing the total organic solvent content to 10%. Mix the reaction solution thoroughly and incubate at 22°C for another 1 h at 60 rpm in a shaker. Purify the conjugated sample using a Zeba desalting column (40 K molecular weight cutoff) and transfer the solution to the final ADC storage buffer to obtain the final product. The DAR value determined by mass spectrometry was 8.17. The storage buffer was 20 mM histidine, 8% sucrose, pH 6.0.

[1001] The amino acid sequence of the antibody used for conjugation is as follows:

[1002] HER2

[1003] Trastuzumab

[1004] Trastuzumab_HC

[1005] SEQ ID NO:5:

[1006] SEQ ID NO:6:

[1007] Trastuzumab_LC

[1008] Preparation of CDH6-ADC:

[1009] Example 2.1.25: Preparation of CDH6-ADC-1

[1010] Add 1 mg of CDH6 antibody (Raludotatug) to a 1.5 mL EP tube, followed by conjugation buffer (50 mM PB, pH 7.0) and 5 mM TCEP solution (TCEP / antibody molar ratio of 8.0) to achieve an antibody concentration of 6 mg / mL. Mix the reaction solution thoroughly and incubate at 22°C for 16 h at 60 rpm in a shaker. Adjust the pH to approximately 7.4 by adding 1 M Tris-HCl (pH 8.5), then add DMA and 10 mM of Compound 36 stock solution dissolved in DMA (Compound 36 / antibody molar ratio of 12), bringing the total organic solvent content to 10%. Mix the reaction solution thoroughly and incubate at 22°C for another 1 h at 60 rpm in a shaker. Purify the conjugated sample using a Zeba desalting column (40 K molecular weight cutoff) and transfer the solution to the final ADC storage buffer to obtain the final product. The DAR value determined by mass spectrometry was 7.93. The storage buffer was 20 mM histidine, 8% sucrose, pH 6.0.

[1011] Example 2.1.26: Preparation of CDH6-ADC-2

[1012] Add 1 mg of CDH6 antibody (Raludotatug) to a 1.5 mL EP tube, followed by conjugation buffer (50 mM PB, pH 7.0) and 5 mM TCEP solution (TCEP / antibody molar ratio of 8.0) to achieve an antibody concentration of 6 mg / mL. Mix the reaction solution thoroughly and incubate at 22°C for 16 h at 60 rpm in a shaker. Adjust the pH to approximately 7.4 by adding 1 M Tris-HCl (pH 8.5), then add DMA and 10 mM of compound 37 stock solution dissolved in DMA (compound 37 / antibody molar ratio of 12), bringing the total organic solvent content to 10%. Mix the reaction solution thoroughly and incubate at 22°C for another 1 h at 60 rpm in a shaker. Purify the conjugated sample using a Zeba desalting column (40 K molecular weight cutoff) and transfer the solution to the final ADC storage buffer to obtain the final product. The DAR value determined by mass spectrometry was 8.15. The storage buffer was 20 mM histidine, 8% sucrose, pH 6.0.

[1013] The amino acid sequence of the antibody used for conjugation is as follows:

[1014] Raludotatug

[1015] Raludotatug-HC

[1016] SEQ ID NO:7:

[1017] SEQ ID NO:8:

[1018] Raludotatug-LC

[1019] Example 2.1.27: Preparation of CDH17-ADC-1

[1020] Compound 36 was used instead of compound 9 in Example 2.1.1, and CDH17 antibody (CDH17Ab1) was used instead of CD33 antibody (CD33Ab1) in Example 2.1.1 to obtain the conjugate product CDH17-ADC-1 of compound 36 and CDH17 antibody (CDH17Ab1). The DAR value was determined to be 7.94 by mass spectrometry.

[1021] Example 2.1.28: Preparation of CDH17-ADC-2

[1022] Compound 37 was used instead of compound 9 in Example 2.1.1, and CDH17 antibody (CDH17Ab1) was used instead of CD33 antibody (CD33Ab1) in Example 2.1.1 to obtain the conjugate product CDH17-ADC-2 of compound 37 and CDH17 antibody (CDH17Ab1). The DAR value was determined to be 8.15 by mass spectrometry.

[1023] The amino acid sequence of the antibody used for conjugation is as follows:

[1024] CDH17Ab1

[1025] CDH17Ab1-HC

[1026] SEQ ID NO:9:

[1027] CDH17Ab1-LC

[1028] SEQ ID NO:10:

[1029] Example 2.1.29: Preparation of CEACAM5-ADC-1

[1030] Compound 36 was used instead of compound 9 in Example 2.1.1, and CEACAM5 antibody (CEACAM5Ab1) was used instead of CD33 antibody (CD33Ab1) in Example 2.1.1 to obtain the conjugate product CEACAM5-ADC-1 of compound 36 and CEACAM5 antibody (CEACAM5Ab1). The DAR value was determined to be 7.83 by mass spectrometry.

[1031] Example 2.1.30: Preparation of CEACAM5-ADC-2

[1032] Compound 37 was used instead of compound 9 in Example 2.1.1, and CEACAM5 antibody (CEACAM5Ab1) was used instead of CD33 antibody (CD33Ab1) in Example 2.1.1 to obtain the conjugate product CEACAM5-ADC-2 of compound 37 and CEACAM5 antibody (CEACAM5Ab1). The DAR value was determined to be 8.18 by mass spectrometry.

[1033] The amino acid sequence of the antibody used for conjugation is as follows:

[1034] CEACAM5Ab1

[1035] CEACAM5Ab1-HC

[1036] SEQ ID NO:11:

[1037] CEACAM5Ab1-LC

[1038] SEQ ID NO:12:

[1039] Preparation of control ADC:

[1040] Following the method described in US20170035906A1, the following linker drug compounds were first obtained:

[1041] A control ADC-1 was obtained by conjugation with a HER2 antibody (Trastuzumab):

[1042] Conjugation with CDH6 antibody (Raludotatug) yielded a control ADC-2:

[1043] Conjugation with CDH17 antibody (CDH17Ab1) yielded a control ADC-5:

[1044] Conjugation with CEACAM5 antibody (CEACAM5Ab1) yielded a control ADC-6:

[1045] Compound I(a) was prepared by referring to the method of patent WO 2022254376A1:

[1046] Coupling with CD33Ab1 yielded control ADC-3 and control ADC-4:

[1047] Biological Test Example 1: Study on the degradation activity of the compound on GSPT1 protein in U937 cells

[1048] U937 cells (human myeloid leukemia cell line, ATCC, Cat.CRL-1593.2) were cultured in RPMI 1640 medium (supplemented with 10% FBS and 1% penicillin antibiotics) at 37°C in a 5% CO2 incubator. U937 cells in the exponential growth phase were collected and seeded into 6-well plates at a density of 5 × 10⁶ cells / well. 5Cells / well. The test compound was then prepared to the corresponding concentration and added to the cells in the well plate. The cells were then cultured at 37°C and 5% CO2 for 24 hours. After the culture, the cells were collected and RIPA lysis buffer (Beyotime, Cat. P0013B, cocktail: RIPA 1:100) was added. The cells were lysed on ice for 15 minutes, centrifuged at 12000 rpm and 4°C for 10 minutes, and the supernatant protein sample was collected. The protein was quantified using the BCA kit (Beyotime, Cat. P0009). The protein was diluted to 1 mg / mL and the expression of GSPT1 (Abcam, AB234433) and the internal control β-actin (CST, 3700S) was detected using the fully automated protein expression quantification analyzer (Proteinsimple). The expression level of GSPT1 relative to the internal control was calculated using the fully automated protein expression quantification analysis software "Compass for SW" and DC was calculated using GraphPad Prism 8.0 software according to equation (1). 50 Value. Among them, Protein 给药 The relative expression levels of GSPT1 in different dosage groups, Protein 溶媒 The relative expression level of GSPT1 in the solvent control group is shown.

[1049] Conclusion: The compounds of the present invention, such as the compound in the examples (payload), have a good degradation effect on GSPT1 protein in U937 cells.

[1050] Biological Test Example 2: Study on the Killing Activity of Compounds on U937 Cells

[1051] U937 cells (human myeloid leukemia cell line, ATCC, Cat.CRL-1593.2) were cultured in RPMI 1640 medium (with 10% FBS and 1% penicillin antibiotics) at 37°C in a 5% CO2 incubator. U937 cells in the exponential growth phase were collected and seeded into 96-well plates at a density of 1000 cells / well. The test compounds were then prepared to the appropriate concentrations and added sequentially to the seeded wells. The plates were then cultured at 37°C in 5% CO2 for 72 hours. After culture, cell viability assay reagent (Promega, Cat.G7573, 50 μL / well) was added, mixed for 2 minutes, and incubated at room temperature for 10 minutes. The luminescence signal was detected using a multi-mode microplate reader (BMG, PHERAstar FSX). The IC50 values ​​of the compounds inhibiting cell proliferation were calculated using GraphPad Prism 8.1 software according to equations (1) and (2). 50 Value and maximum inhibition rate. Where T is... 给药 The cell signal reading is T after 72 hours of compound incubation. 阴性对照Cell signal readings after 72 hours of incubation with DMSO control. Growth % = (T 给药 / T 阴性对照 ×100)% Formula (1)

[1052] Max inhibition% calculation: The inhibition rate at the highest compound concentration is calculated according to equation (2). Max inhibition % = (100 - Growth) % (Equation (2))

[1053] Table 1. Killing activity of the compounds of this invention against U937 cells. Note: In Table 3, A < 50 nM

[1054] Conclusion: The compounds of the present invention, such as the compound in the examples (payload), have a strong killing effect on U937 cells.

[1055] Biological Test Example 3: CAco-2 Test

[1056] The experiment used monolayers of Caco-2 cells, incubated in triple parallel in 96-well Transwell plates. A transport buffer solution (HBSS, 10 mM HEPES, pH 7.4±0.05) containing either the compound of the present invention (2 μM) or the control compounds digoxin (10 μM), naldolol (2 μM), and metoprolol (2 μM) was added to the dosing well on the apical or basal side. A transport buffer solution containing DMSO was added to the corresponding receiving well. After incubation at 37±1 °C for 2 hours, the cell plate was removed, and appropriate amounts of sample were transferred from both the apical and basal sides to new 96-well plates. Acetonitrile containing an internal standard was then added to precipitate the protein. The samples were analyzed using LC MS / MS to determine the concentrations of the compound of the present invention and the control compounds. The concentration data were used to calculate the apparent permeability coefficients for transport from the apical to the basal side of the monolayer cells, and from the basal side to the apical side, thereby calculating the efflux rate. Leakage of fluorescein was used to evaluate the integrity of the monolayer cells after 2 hours of incubation.

[1057] Conclusion: The payloads of the conjugates of the present invention, such as compound 1 and compound 2, have low efflux.

[1058] Biological Test Example 4. Assay of the cytotoxic activity of antibody-drug conjugates against U937 (CD33 positive), EOL-1 (CD33 positive), and MOL-4 (CD33 negative) cells.

[1059] CD33-positive human myeloid leukemia cell lines U937 (ATCC) and EOL-1 (Nanjing Kebai), and CD33-negative human acute lymphoblastic leukemia cell line MOL-4 (ATCC) were cultured in RPMI 1640 medium (supplemented with 10% FBS and 1% penicillin antibiotics) at 37°C in a 5% CO2 incubator. Cells in the exponential growth phase were collected and plated in 96-well plates, with plating densities of 1000, 4000, and 5000 cells / well for U937, EOL-1, and MOLT-4, respectively. The appropriate concentrations of the test compound or ADC were then added sequentially to the plated cells, and the plates were incubated at 37°C in 5% CO2 for 72 hours. After culture, cell viability assay reagent (Promega, Cat. G7573, 50 μL / well) was added, mixed for 2 minutes, and incubated at room temperature for 10 minutes. The luminescence signal was detected using a multi-functional microplate reader (BMG, PHERAstar FSX). The luminescence readings were calculated using GraphPad Prism 8.1 software according to equations (1) and (2) to determine the IC50 value of the compound inhibiting cell proliferation. 50 Value and maximum inhibition rate. Where T is... 给药 The cell signal reading is T after 72 hours of compound incubation. 阴性对照 Cell signal readings after 72 hours of incubation with DMSO control. Growth% = (T 给药 / T 阴性对照 ×100)% Formula (1)

[1060] Max inhibition% calculation: Calculate the inhibition rate at the highest concentration of the compound according to equation (2). Max inhibition% = (100 - Growth) % Equation (2)

[1061] Table 2. Killing activity of the antibody-drug conjugate of the present invention against U937 (CD33 positive), EOL-1 (CD33 positive), and MOL-4 (CD33 negative) cells. Note: In Table 2, A < 500 pM, 500 pM ≤ B < 5 nM, 5 nM ≤ C < 50 nM, 50 nM ≤ D ≤ 100 nM, and E > 100 nM.

[1062] Conclusion: The antibody-drug conjugate of the present invention, such as the antibody-drug conjugate in the examples, has a strong killing effect on U937 (CD33 positive) and EOL-1 (CD33 positive) cells, but a weak killing effect on MOL-4 (CD33 negative) cells.

[1063] Biological Test Example 5. CD34+HSPC Cell Killing Assay

[1064] CD34 +HSPC (Hematopoietic Stem and Progenitor Cells) were purchased from MILECELL (Cat#hmPB CD34+ cell isolation and cryopreservation service). Culture conditions: StemSpan TM SFEMⅡ(STEMCELL, Cat#09655)+StemSpan TM CD34 + Expansion Supplement (STEMCELL, Cat#02691) was cultured in a 37°C, 5% CO2 incubator. First, cells were removed from the liquid nitrogen tank and revived. After resuspending and counting, cells were seeded at a density of 2000 cells / well in 96-well plates, 90 μL per well. Then, 10 μL of different concentrations of the compound (9 compound gradients, 1 DMSO well, and 1 Blank well; 2 replicates per compound concentration) were added to each well, and the plates were incubated at 37°C, 5% CO2. On day 4 of drug-treated culture, replenishment was performed by adding 10 μL of the diluted compound to 90 μL of culture medium, and then adding an equal volume to the seeded 96-well plates. The plates were then incubated at 37°C, 5% CO2 for another 3 days. After culture, centrifuge at 1000 rpm for 3 minutes, remove 100 μL of culture supernatant from each well, add 50 μL of CellTiter-Glo detection solution, and incubate with gentle shaking at room temperature for 10 minutes. chemiluminescence readings are then detected using a BMG microplate reader (PHERAstar FSX). Results are processed according to equation (3), and the proliferation inhibition rate of each compound concentration is calculated. Using GraphPad Prism software, a four-parameter curve is fitted to calculate the IC50 concentration of the compound when the proliferation inhibition rate is 50%. 50 Value. RLU compound For the drug treatment group, RLU readings control RLU is the average value of the compound solvent control group. Blank This represents the mean value of the blank control group. Inhibition% = (1 - (RLU) compound -RLU Blank ) / (RLU control -RLU Blank Formula (3) is calculated as follows: ()×100%

[1065] Table 3. Killing activity of the antibody-drug conjugate of the present invention against CD34+HSPC cells.

[1066] Conclusion: The antibody-drug conjugates of the present invention, such as those in the examples, exhibit weak killing effect on CD34+HSPC cells, low hematologic toxicity, and good safety. For example, CD33-ADC-01 at 100 nM showed a 46% inhibition rate against CD34+HSPC cells, CD33-ADC-07 at 100 nM showed a 36% inhibition rate, CD33-ADC-12 at 100 nM showed a 44% inhibition rate, and CD33-ADC-10 at 250 nM showed a 41% inhibition rate.

[1067] Biological Test Example 6: Study on the Degradation Activity of GSPT1 Protein by Antibody-Drug Conjugate in U937 Cells

[1068] CD33-positive human myeloid leukemia cell lines U937 (ATCC) and EOL-1 (Nanjing Kebai) were cultured in RPMI 1640 medium (supplemented with 10% FBS and 1% penicillin antibiotics) at 37°C in a 5% CO2 incubator. U937 cells in the exponential growth phase were collected and seeded into 6-well plates at a density of 5 × 10⁶ cells / well. 5 Cells / well. Then, the test compound or ADC was prepared to the corresponding concentration and added to the cells in the well plate. The cells were then cultured at 37°C and 5% CO2 for 24 hours. After the culture, the cells were collected and RIPA lysis buffer (Beyotime, Cat. P0013B, cocktail: RIPA 1:100) was added. The cells were lysed on ice for 15 minutes, centrifuged at 12000 rpm and 4°C for 10 minutes, and the supernatant protein sample was collected. The protein was quantified using the BCA kit (Beyotime, Cat. P0009). The protein was diluted to 1 mg / mL and the expression of GSPT1 (Abcam, AB234433) and the internal control β-actin (CST, 3700S) was detected using the fully automated protein expression quantification analyzer (Proteinsimple). The expression level of GSPT1 relative to the internal control was calculated using the fully automated protein expression quantification analysis software "Compass for SW" and DC was calculated using GraphPad Prism 8.0 software according to equation (1). 50 Value. Among them, Protein 给药 The relative expression levels of GSPT1 in different dosage groups, Protein 溶媒 This represents the relative expression level of GSPT1 in the solvent control group. Protein% = Protein 给药 / Protein 溶媒 ×100% Equation (1)

[1069] Table 4. Antibody-drug conjugate activity against GSPT1 protein degradation in U937 cells. Note: In Table 3, A < 100 pM, 100 pM ≤ B < 1 nM, 1 nM ≤ C < 10 nM, and D ≥ 10 nM are considered valid.

[1070] Conclusion: The antibody-drug conjugate of the present invention, such as the antibody-drug conjugate in the examples, has a good degradation effect on GSPT1 protein in U937 cells.

[1071] Biological Test Example 7: Study on the cytotoxic activity of antibody-drug conjugates in human ovarian cancer cell line OVCAR3, human gastric cancer cell line NCI-N87, human breast ductal carcinoma cell line HCC1954, and human breast cancer cell line BT474

[1072] Human ovarian cancer cell line OVCAR3, human gastric cancer cell line NCI-N87, human breast ductal carcinoma cell line HCC1954, and human breast cancer cell line BT474 were derived from ATCC and cultured in a 37°C, 5% CO2 incubator using complete medium with 10-20% FBS as recommended by the cell bank's website. Once cells reached the exponential growth phase, they were trypsinized and counted. The cell concentration was adjusted to an appropriate density, and 100 μL of cells were seeded into each well of a clear-bottomed 96-well plate (Greiner, 655090). The plates were then transferred to a 37°C, 5% CO2 incubator and cultured overnight. The next day, 50 μL of serially diluted medium containing different concentrations of the test compound was added to each well, with 2-3 replicates per concentration. A DMSO solvent control group and a negative control group were also included. Cells were cultured for another 3-7 days at 37°C, 5% CO2. After incubation, CellTiter- After the test reagent (Promega, G7558) has been brought to room temperature, add 50 μL of CellTiter to each well. The test reagents were prepared by shaking the 96-well plate on a shaker for 10 minutes (the entire process must be performed in the dark). The fluorescence signal value (LUM) of each well was detected using the Luminescence module of the Pherastar FSX multi-microplate reader (BMG LRBTECH). The result was obtained using the formula... Calculate the inhibition rate of the test compound. Perform fitting analysis using statistical analysis software to calculate the IC50 of the test compound. 50 Numerical value.

[1073] Table 5: Killing activity of the antibody-drug conjugate of the present invention against OVCAR3 (CDH6 positive) cells

[1074] Table 6: Antibody-drug conjugates of the present invention against BT474 (HER2 positive), HCC1954 (HER2 positive), and NCI-N87 (HER2 positive)

[1075] Killing activity of positive cells

[1076] Conclusion: The antibody-drug conjugates of the present invention, such as those described in the examples, exhibit good cell killing effects against human ovarian cancer cell line OVCAR3, human gastric cancer cell line NCI-N87, human breast ductal carcinoma cell line HCC1954, and human breast cancer cell line BT474.

[1077] Biological Test Example 8: In Vitro Plasma Stability Test

[1078] Using mixed-sex C57BL6J mice and human plasma, the ADC was prepared to a working concentration of 100 μg / mL and incubated at 37°C for 0, 1, 3, 5, and 7 days. After incubation, the samples were purified using magnetic beads, and the concentrations of antibody-bound drug (acDrug) and free drug (free payload) were measured to reflect the stability of the ADC in mouse and human plasma.

[1079] Table 7-1: Human plasma stability data of the antibody-drug conjugate (ADC) of the present invention

[1080] Table 7-2: Plasma stability data of the antibody-drug conjugate (ADC) of this invention in mice

[1081] Conclusion: The antibody-drug conjugates of this invention, such as those described in the examples, exhibit good stability in mouse and human plasma. The ADCs conjugated with the linker of this invention show good plasma stability, superior to control ADC-1, Enhertu, control ADC-2, and DS-6000a, with a lower payload shedding rate.

[1082] Biological Test Example 9: Mouse Pharmacokinetic Test

[1083] 9.1 Experimental animals: Female C57BL6J mice, 20-30g, 3 mice / compound.

[1084] 9.2 Experimental design: On the day of the experiment, female C57BL6J mice were randomly grouped according to their body weight.

[1085] Table 8. Dosage Information

[1086] Note: Intravenous administration solvent: PBS / NaCl;

[1087] Blood samples of 0.06 mL were collected via the orbital cavity before and after isoflurane anesthesia and placed in EDTAK2 centrifuge tubes. The samples were centrifuged at 5000 rpm for 10 min at 4°C to collect plasma. Blood was collected at different time points for the intravenous group: 0.0833 h, 1 h, 6 h, 24 h, 72 h, 168 h, and 336 h. Before analysis, all samples were stored at -80°C, and the concentrations of antibody-bound drug (acDrug) and free drug (free payload) in the plasma were determined using LC-MS / MS.

[1088] Conclusion: The antibody-drug conjugate of this invention exhibits good PK behavior in mice and has a low concentration of free payload.

[1089] Biological Test Example 10. Rat Pharmacokinetic Test

[1090] 10.1 Experimental animals: Male SD rats, approximately 220g, 6-8 weeks old, 3 rats / compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[1091] 10.2 Experimental Design: On the day of the experiment, SD rats were randomly grouped according to their body weight and administered drugs according to the table below.

[1092] Table 9. Dosage Information Note: Intravenous administration solvent: PBS / NaCl

[1093] Blood samples of 0.15 ml were collected via the orbital cavity before and after isoflurane anesthesia and placed in EDTAK2 centrifuge tubes. The plasma was collected by centrifugation at 5000 rpm and 4°C for 10 min. Blood was collected at different time points for the intravenous group: 0.0833 h, 1 h, 6 h, 24 h, 72 h, 168 h, and 336 h. Before analysis, all samples were stored at -80°C, and the concentrations of antibody-bound drug (acDrug) and free drug (free payload) in the plasma were determined using LC-MS / MS.

[1094] Conclusion: The antibody-drug conjugate of this invention exhibits good PK behavior in rats with low free payload concentration.

[1095] Biological Test Example 11. Pharmacokinetic Test in Beagle Dogs

[1096] 11.1 Experimental animals: Male beagle dogs, weighing approximately 8–11 kg, 3 dogs per compound.

[1097] 11.2 Experimental Methods: On the day of the experiment, beagle dogs were randomly grouped according to their body weight and administered medication as shown in the table below.

[1098] Table 10. Dosage Information Note: Intravenous administration solvent: PBS / NaCl

[1099] Blood samples (1 ml) were collected via jugular or limb veins before and after drug administration and placed in EDTAK2 centrifuge tubes. The plasma was collected by centrifugation at 5000 rpm and 4°C for 10 min. Blood collection time points for the venous group were 0.0833 h, 1 h, 6 h, 24 h, 72 h, 168 h, and 336 h. Before analysis, all samples were stored at -80°C, and the concentrations of antibody-bound drug (acDrug) and free drug (free payload) in the plasma were determined using LC-MS / MS.

[1100] Conclusion: The antibody-drug conjugate of this invention exhibits good PK behavior in beagle dogs with low free payload concentration.

[1101] Biological Test Example 12. Monkey Pharmacokinetic Test

[1102] 12.1 Experimental animals: Male cynomolgus monkeys, 3-5 kg, 3-6 years old, 3 per compound.

[1103] 12.2 Experimental Methods: On the day of the experiment, monkeys were randomly grouped according to their body weight and administered medication as shown in the table below.

[1104] Table 11. Dosage Information Note: Intravenous administration solvent: PBS / NaCl

[1105] Blood samples of 1.0 mL were collected from venous sites in the extremities before and after drug administration and placed in EDTAK2 centrifuge tubes. Plasma was collected by centrifugation at 5000 rpm and 4°C for 10 min. Blood was collected at various time points: 0.0833 h, 1 h, 6 h, 24 h, 72 h, 168 h, and 336 h. Before analysis, all samples were stored at -80°C, and the concentrations of antibody-bound drug (acDrug) and free drug (free payload) in the plasma were determined using LC-MS / MS.

[1106] Conclusion: The antibody-drug conjugate of this invention exhibits good PK behavior in monkeys, with low concentrations of free drug.

[1107] Biological Test Example 13. ADC Bystander Kill Test:

[1108] 293T-CDH6 (Kyinno Bio, KC-3200) and 293T (ATCC) cells were cultured in EMEM at 37°C and 5% CO2 for 48–72 h. Cells were trypsinized and counted, and the cell concentration was adjusted to an appropriate density. 4200 293T-CDH6 cells / well were seeded at 600 μL / well into the lower chamber of a 24-well Transwell plate (Corning, 3421), and 300 293T cells / well were seeded at 100 μL / well into the lower chamber of a 24-well Transwell plate (Corning, 3421). The 24-well Transwell plates (Corning, 3421) were transferred to a 37°C, 5% CO2 incubator and cultured overnight. The next day, 150 μL of serially diluted culture medium containing different concentrations of the test compound was added to the upper chamber, and 100 μL to the lower chamber. Meanwhile, a DMSO solvent control group was set up and cultured for another 4 days in an incubator at 37°C and 5% CO2.

[1109] After the culture is completed, remove CellTiter- The assay reagent (Promega, G7558) was brought to room temperature. A clean 24-well plate (NEST, 702001) was prepared, and the upper chamber was placed into each well. 150 μL of CellTiter was added to each well. Test reagents; discard 400 μL of culture medium from the lower chamber, and add 100 μL of CellTiter to each well. Prepare the test reagents by placing the 24-well plate on a shaker and shaking for 10 minutes (the entire process should be carried out in the dark). After shaking, aspirate 100 μL of cell lysis buffer into each clean, black-bottomed, clear 96-well plate (GREINER, 655090).

[1110] The fluorescence signal value (LUM) of each well was detected using the Luminescence module of the Pherastar FSX multi-functional microplate reader (BMG LRBTECH). The fluorescence signal was determined using the formula... The inhibition rates of the test compounds in the upper and lower chambers were calculated under co-culture conditions and with only negative cells. Graphpad software was used for fitting analysis to calculate the inhibition rates of the test compounds on 293T-CDH6 and 293T cells. The vertical axis represents the percentage inhibition rate, and the horizontal axis represents the sample concentration.

[1111] Conclusion: The antibody-drug conjugates of the present invention, such as the antibody-drug conjugates described in the examples, have a good bystander effect.

[1112] Biological Test Example 14: In vivo pharmacodynamic study of a mouse model of human leukemia MV4-11-luc cell tail vein xenograft tumor.

[1113] plan:

[1114] Cell culture: MV4-11-luc cells were cultured in suspension in vitro under the following conditions: RPMI 1640 medium supplemented with 10% fetal bovine serum and 1% penicillin / streptomycin / amphotericidal B, at 37°C in a 5% CO2 incubator. Cells were passaged twice a week. When cell saturation reached 80%-90% and the desired number was achieved, cells were harvested, counted, and seeded.

[1115] Animals: Female or male NOG mice aged 6-8 weeks were selected for enrollment and cell inoculation.

[1116] Tumor inoculation: A certain number of MV4-11-luc cells were injected into each mouse via the tail vein, and the mice were divided into groups of 5-10 animals approximately 7-10 days after inoculation.

[1117] Animal administration: Weigh the animals before administration and measure tumor volume or signal. Randomize the animals according to tumor volume or signal and administer the drug. Dilute the test substance to the target concentration with solvent and administer via tail vein injection at a volume of 10 L / g based on the mouse's body weight. The dosage is 0.1 mg / kg-10 mg / kg. The administration frequency is once daily, once weekly, once monthly, or as a single dose.

[1118] Experimental indicators: The experimental indicators are to examine whether tumor growth is inhibited, delayed, or cured, and changes in mouse body weight. Intravenous immunoassay (IVIS) was performed once or twice weekly to monitor tumor growth and measure mouse weight.

[1119] The antitumor efficacy of the compound was evaluated using TGI (%) or relative tumor proliferation rate (T / C) (%). TGI (%) reflects the tumor growth inhibition rate. The calculation of TGI (%) is as follows: TGI (%) = [(1 - (mean tumor signal at the end of treatment - mean tumor signal at the start of treatment)) / (mean tumor signal at the end of treatment in the solvent control group - mean tumor signal at the start of treatment in the solvent control group)] × 100%.

[1120] Data Analysis: The t-test is used for comparisons between two groups. One-way ANOVA is used for comparisons between three or more groups. If the F-value shows a significant difference, multiple comparisons should be performed after ANOVA analysis. A p-value < 0.05 is considered statistically significant.

[1121] Table 12. In vivo efficacy results of human leukemia MV4-11-luc cell tail vein xenograft tumor model

[1122] Table 13. In vivo efficacy results of human leukemia MV4-11-luc cell tail vein xenograft tumor model.

[1123] Conclusion: The antibody-drug conjugates of the present invention, such as the antibody-drug conjugates in the examples, specifically CD33-ADC-01, CD33-ADC-05, CD33-ADC-07, CD33-ADC-09, CD33-ADC-16, and CD33-ADC-17, have good in vivo efficacy in a mouse model of human leukemia MV4-11-luc cell tail vein xenograft tumor.

[1124] Biological Test Example 15: Inhibition of Compound Growth on Human Breast Ductal Carcinoma Cell (HCC1954) Xenograft Model in Nude Mice

[1125] Cell inoculation and animal administration:

[1126] HCC1954 cells are a human breast ductal carcinoma cell line purchased from ATCC and cultured in RPMI-1640 + 10% FBS + 1% penicillin-drug antibody incubator at 37°C and 5% CO2. When the cells are in the exponential growth phase, they are collected, counted, and an equal volume of matrix gel is added. The cells are then subcutaneously inoculated into the right side of immunodeficient mice (female, 4-6 weeks old) with 200 μL of HCC1954 cells and 50% matrix gel. Inoculation continues until the tumor reaches 150-200 mm². 3 Mice were randomly assigned to groups based on tumor volume and body weight. ADCs and other test drugs were administered intravenously or orally as a single dose, once weekly (qw), or once daily, with 6-10 mice per group.

[1127] Experimental observations and conclusion:

[1128] Mice were weighed twice weekly after inoculation, and the long diameter (a) and short diameter (b) of the tumor were measured simultaneously. The tumor volume V = ab was calculated. 2 / 2 and tumor growth curves were plotted and tumor inhibition rates were calculated. After the experiment, all mice were euthanized.

[1129] Conclusion: The antibody-drug conjugates of the present invention, such as the antibody-drug conjugates described in the examples, have good in vivo efficacy.

[1130] Biological Test Example 16: Inhibition Experiment of OVCAR3 Subcutaneous Tumor Model Growth

[1131] Experimental reagents: Human ovarian cancer OVCAR3 cells were purchased from ATCC; RPMI-1640 medium was purchased from Gibco (catalog number 22400-089); fetal bovine serum was purchased from HyClone (catalog number SH30406.05); penicillin-streptomycin was purchased from Gibco (catalog number 15140-122); bovine insulin was purchased from MCE (catalog number HY-P1156); 0.5% Trypsin-EDTA was purchased from Gibco (catalog number 15400-054); PBS was purchased from Sangon Biotech (catalog number E607008-0500); and Matrigel was purchased from Corning (catalog number 354234).

[1132] Experimental methods: Animal information: Balb / c nude mice, female, 5-7 weeks old, weighing approximately 15-18 grams, Sichuan Weitonglihua Laboratory Animal Technology Co., Ltd. The mice were housed in an SPF-grade environment with individual air supply and exhaust for each cage. All animals had free access to standard certified commercial laboratory food and water.

[1133] Cell culture: Human ovarian cancer OVCAR3 cell line was cultured in vitro under the following conditions: RPMI-1640 medium supplemented with 20% fetal bovine serum, 1% penicillin-streptomycin, and 10 μg / mL bovine insulin, incubated at 37°C with 5% CO2. When cells adhered and reached 80%–90% confluence, they were passaged at a ratio of 1:2–1:3 every 3 or 4 days, and then cultured in a 37°C, 5% CO2 incubator for approximately 20 days to expand the cell count. When the desired cell number was reached, the cells were harvested and counted.

[1134] Cell seeding: 0.2 mL of OVCAR3 cell suspension (containing 3 x 10⁻⁶ cells) was injected. 6 10 cells (PBS volume ratio 1:1) were subcutaneously inoculated into the axilla of each mouse.

[1135] Grouped administration: When the tumor grows to 100-150mm 3 Tumors were randomly assigned to groups based on tumor volume, with the grouping day designated as Day 0.

[1136] Tumor measurement and experimental parameters: Tumor diameter was measured twice weekly using calipers. Tumor volume was calculated using the formula: V = 0.5a × b, where a and b represent the major and minor diameters of the tumor, respectively. Mouse body weight was measured twice weekly. The tumor-suppressive efficacy of the test drug was evaluated using the tumor growth inhibition rate (TGI) (%).

[1137] The formula for calculating tumor growth inhibition rate is: TGI(%) = [1 - (T Vt -T V0 ) / (C Vt -C V0)]×100%

[1138] T Vt T represents the average tumor volume at the end of a certain treatment group. V0 The mean tumor volume at the time of grouping for this treatment group; C Vt C represents the average tumor volume at the end of the Vehicle group. V0 The average tumor volume when the Vehicle group was grouped. Vt and C Vt Take data from the same day.

[1139] Statistical analysis: Data are expressed as mean and standard error (SEM). Statistical methods used include Two-Way ANOVA and Dunnett's Multiple Comparisons Test. A p-value < 0.05 was considered statistically significant between groups.

[1140] Conclusion: The antibody-drug conjugates of the present invention, such as the antibody-drug conjugates described in the examples, have good in vivo efficacy.

Claims

1. A compound or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, wherein the compound is selected from compounds of general formula (I). L-L0-L1-L2-(L3) p1 -(L4) p2 -L5-D(I) L represents the leaving group that reacts with the target portion; L0 is a connector unit, which is selected from... Its left end is connected to L; L1 is selected from Its right side connects to L2; m1 is selected from integers from 1 to 12; m4 is selected from integers from 1 to 12; m3 is selected from 1, 2, 3, 4, 5; m5 is selected from 0, 1, 2, 3, 4, 5; G1 is selected from -C(=O)-NH2, -C(=O)-OH, and -P(=O)(OH)2. L2 is selected from -Z1-Z2-; Z1 is selected from key, -C 1-6 alkylene-, -C 2-6 -, -C ethynyl 2-6 alkenyl-, wherein the Z1 is optionally divided by 1 to 4 R s Replaced; Z2 is selected from bond, -C(=O)-, -M4-C 0-6 Alkylene -C(=O)-, -M3-C 1-6 Alkylene-M4-, wherein the alkylene is optionally surrounded by 1 to 4 R... s Replaced; M1 is selected from -O-, -C(=O)-, -NH-, -NH-S(=O)2-NH-, -C 0-4 alkylene-4-8-membered heterocyclic group-, wherein the alkylene group or heterocyclic group is optionally surrounded by 1 to 4 R groups. s Replaced; M2 is selected from -C(=O)-, -C 1-4 Alkylene -C(=O)-, -C 1-4 Alkylene -NH-C(=O)-, -C 1-4 Alkylene-NH-C(=O)-C 1-4 Alkylene -C(=O)-, -C 1-4 Alkylene-NH-C(=O)-C 1-4 Alkylene-OC 1-4 Alkylene-C(=O)-, wherein the alkylene is optionally surrounded by 1 to 4 R- atoms. s Replaced; M3 is selected from -O-, -S-, -CR m1 R m2 -、-NR m3 -; M4 is selected from -O-, -S-, -NR m4 -; R L R m1 R m2 R m3 R m4 Each element is independently selected from H, deuterium, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 7-membered heterocyclic groups, wherein the alkyl group, C 2-4 alkenyl, C 2-4 Alkyne, cycloalkyl, or heterocyclic groups are optionally surrounded by 1 to 4 R groups. s Replaced; s2 is selected from integers from 2 to 12; s3 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8; L3 is selected from amino acids, specifically peptides composed of 2-5 amino acids; L4 is selected from Its right side connects to L5; X is selected from -CH-, -CR L3 -、-N-; Y1 is selected from -N(R) L5 )-、-C(=O)-; Y2 is selected from -N(R) L5 )-、-N(R L5 )-C 1-6 alkylene-5-6-membered nitrogen-containing heteroaryl-,-N(R) L5 )-C 1-4 Alkylene-N(R) L5 )-, wherein the alkylene or heteroaryl group is optionally surrounded by 1 to 4 R s Replaced; Y3 is selected from R L8 Each component is independently selected from the amino acid side chain, H, C 1-6 Alkyl, -C 1-4 Alkylene C 6-10 Aryl, -C 1-4 alkylene 4-10-membered heterocyclic groups, wherein R L8 Choose from 1 to 4 Rs s Replaced; m2 is selected from 2, 3, 4, and 5; Y4 is selected from -C(=O)-C 1-6 alkyl, The Y4 is arbitrarily divided by 1 to 4 Rs s Replaced; s7 is selected from integers from 1 to 10; R L3 R L4 Each element is independently selected from deuterium, halogens, OH, NH2, CN, NO2, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl or 4-8 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. s Replaced; R L5 Each independently selected from H and C 1-4 Alkyl, C 3-8 Cycloalkyl or 4-8 membered heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. s Replaced; R s Each element is independently selected from deuterium, halogens, OH, NH2, CN, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 acetylinyl, OC 1-4 Alkyl, SC 1-4 Alkyl, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, wherein the alkyl, alkenyl, or alkynyl groups are optionally substituted with 1 to 4 substituents of deuterium, halogen, OH, NH2, or CN; s1 is selected from 0, 1, 2, 3 or 4; L5 is selected from the spacer unit; p1 and p2 are each independently selected from 0 and 1, and p1 + p2 = 1; D is selected from bioactive molecular fragments, preferably from auristatin derivatives, maystasionoids derivatives, DNA destroyers, amanitins, topoisomerase inhibitors, camptothecin derivatives, selective or non-selective kinase inhibitors, Bcl-xl inhibitors and Bcl-2 / Bcl-xl inhibitors, and protein degraders.

2. The compound according to claim 1, or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, wherein, The amino acid is selected from amino acid AA or amino acid AA1; wherein the N-terminus of the amino acid is connected to L2 and the C-terminus is connected to L5. The amino acids A and B are each independently selected from valine, glycine, alanine, glutamic acid, phenylalanine, lysine, citrulline, serine, glutamic acid, and aspartic acid; Amino acid AA1 is selected from R L0 Each element is independently selected from H, deuterium, and C. 1-6 Alkyl, C 3-8 cycloalkyl, 4-8 membered heterocyclic groups The alkyl, cycloalkyl, or heterocyclic groups are optionally surrounded by 1 to 4 R groups. s Replaced; Or two Rs L0 Direct connection forms C 3-8 cycloalkyl or 4-8 membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. s Replaced; s5 and s6 are each independently selected from 0, 1, 2, 3, 4, 5 or 6; R L1 R L2 Each element is independently selected from H, deuterium, and C. 1-4 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. s Replaced; Or R L1 R L2 The nitrogen atom attached to it forms a 4-8 membered heterocyclic group, which is optionally surrounded by 1 to 4 R atoms. s Replaced; HG is selected from L5 is selected from -Z3-Z4-, where Z3 and Z4 are not both selected from the key; Z3 is selected from key, Its right side is connected to Z4; Z4 is selected from the bond, -N(R) L5 )-C(R L6 )2-、-OC(R L6 )2-、-M4-C 0-4 Alkylene -C(=O)-, -N(R) L5 )-C 1-4 Alkylene-N(R) L7 )-C(=O)-, wherein the alkylene group is optionally surrounded by 1 to 4 R s It is replaced, and its right side is connected to D; R L6 Each element is independently selected from H, deuterium, halogens, OH, NH2, CN, NO2, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl or 4-8 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. s Replaced; Or R L5 and R L6 Two Rs L6 Together with the carbon atoms attached to it, they form C 3-8 cycloalkyl or 4-8 membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. s Replaced; R L7 Each independently selected from H and C 1-4 Alkyl, -C 1-4 Alkylene-S(=O)2-C 1-4 Alkyl, C 3-8 Cycloalkyl or 4-8 membered heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. s What it replaced.

3. The compound according to claim 2, or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, wherein, L is selected from halogen, sulfone, and tertiary amine salt (Me3N). + Et3N + ), diazonium salts, -OMs, MeSO2-, CF3SO3-, p-toluenesulfonyl groups; L3 is selected from -AA-, -AA1-, -AA-AA-, -AA-AA-AA-, -AA-AA-AA-AA-, -AA-AA1-, -AA1-AA-, -AA-AA1-AA-, -AA-AA-AA1-; R L0 Each element is independently selected from H, deuterium, and C. 1-4 Alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclic groups The alkyl, cycloalkyl, or heterocyclic group is optionally surrounded by 1 to 4 R groups. s Replaced; Each s5 is independently selected from 0, 1, 2, 3, and 4; Or two Rs L0 Direct connection forms C 3-6 Cycloalkyl or 4-6 membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. s Replaced; R L1 R L2 Each element is independently selected from H, deuterium, and C. 1-4 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. s Replaced; Or R L1 R L2 The nitrogen atom attached to it forms a 4-7 membered heterocyclic group, which is optionally surrounded by 1 to 4 R atoms. s Replaced; L2 is selected from key, -Z1-Z2-, -Z1-, -Z2-; Z1 is selected from -C 1-4 alkylene-, -C 2-4 -, -C ethynyl 2-4 alkenyl-, wherein the Z1 is optionally divided by 1 to 4 R s Replaced; Z2 is selected from -C(=O)- and -M4-C. 0-4 Alkylene -C(=O)-, -M3-C 1-4 Alkylene-M4-, wherein the alkylene is optionally surrounded by 1 to 4 R... s Replaced; M1 is selected from -O-, -C(=O)-, -NH-, -NH-S(=O)2-NH-, -C 0-2 alkylene-5-6-membered nitrogen-containing heteroaryl-, wherein the alkylene or heterocyclic group is optionally surrounded by 1 to 4 R- groups. s Replaced; M2 is selected from -C(=O)-, -C 1-4 Alkylene -C(=O)-, -C 1-4 Alkylene -NH-C(=O)-, -C 1-4 Alkylene-NH-C(=O)-C 1-4 Alkylene -C(=O)-, -C 1-4 Alkylene-NH-C(=O)-C 1-4 Alkylene-OC 1-4 Alkylene-C(=O)-, wherein the alkylene is optionally surrounded by 1 to 4 R- atoms. s Replaced; R L R m1 R m2 R m3 R m4 Each of the following is independently selected from H, deuterium, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, and cyclobutyl groups are optionally separated by 1 to 4 R groups. s Replaced; Y2 is selected from -N(R) L5 )-、-N(R L5 )-C 1-4 alkylene-5-6-membered nitrogen-containing heteroaryl-,-N(R) L5 )-C 1-2 Alkylene-N(R) L5 )-, wherein the alkylene or heteroaryl group is optionally surrounded by 1 to 4 R s Replaced; R L8 Each component is independently selected from the amino acid side chain, H, C 1-4 Alkyl, -C 1-4 alkylenephenyl, -C 1-4 alkylene 4-6 membered heterocyclic groups, -C 1-4 alkylene 8-10-membered heteroaryl, wherein R L8 Choose from 1 to 4 Rs s Replaced; Y4 is selected from -C(=O)-C 1-4 alkyl, The Y4 is arbitrarily divided by 1 to 4 Rs s Replaced; s7 is selected from integers from 1 to 8; R L3 R L4 Each of the following is independently selected from deuterium, F, Cl, Br, OH, NH2, CN, NO2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl groups are optionally prefixed with 1 to 4 R groups. s Replaced; R L5 Each is independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, and cyclobutyl groups are optionally prefixed with 1 to 4 R groups. s Replaced; L5 is selected from -Z3-Z4-, -Z3-, -Z4-; Z3 is selected from Its right side is connected to Z4; Z4 is selected from -N(R) L5 )-C(R L6 )2-、-OC(R L6 )2-、-M4-C 0-4 Alkylene -C(=O)-, -N(R) L5 )-C 1-4 Alkylene-N(R) L7 )-C(=O)-, wherein the alkylene group is optionally surrounded by 1 to 4 R s It is replaced, and its right side is connected to D; Or R L5 and R L6 Two Rs L6 The atoms bonded to it together form C 3-6 Cycloalkyl or 4-6 membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. s Replaced; R L6 Each of the following is independently selected from H, deuterium, F, Cl, Br, OH, NH2, CN, NO2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl groups are optionally prefixed with 1 to 4 R groups. s Replaced; R L7 Each is independently selected from H, methyl, ethyl, propyl, isopropyl, -methylene-S(=O)2-C 1-2 Alkyl, -Ethylene-S(=O)2-C 1-2 Alkyl, -propylidene-S(=O)2-C 1-2 Alkyl, C 3-8 Cycloalkyl or 4-8 membered heterocyclic group, wherein the methylene, ethylene, propylene, methyl, ethyl, propyl, isopropyl, alkyl, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. s Replaced; R s Each element is independently selected from deuterium, halogens, OH, NH2, CN, and C. 1-2 Alkyl, C 2-3 alkenyl, C 2-3 acetylinyl, OC 1-2 Alkyl, SC 1-2 Alkyl, NHC 1-2 Alkyl, N(C) 1-2 Alkyl)2, wherein the alkyl, alkenyl, or alkynyl groups are optionally substituted with 1 to 4 substituents of deuterium, F, Cl, Br, OH, NH2, or CN.

4. The compound according to claim 3, or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, wherein, R s Each is independently selected from deuterium, F, Cl, Br, OH, NH2, CN, CHF2, CH2F, CF3, CD3, OCF3, OCD3, methyl, methoxy, methylthio, and ethoxy. R L0 Each is independently selected from H, deuterium, methyl, ethyl, propyl, isopropyl, The methyl, ethyl, propyl, and isopropyl groups are optionally surrounded by 1 to 4 R groups. s Replaced; Or R L0 Each independently selected Or two Rs L0 Direct linkage to form cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups, wherein the cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups are optionally bounded by 1 to 4 R groups. s Replaced; R L1 R L2 Each is independently selected from H, deuterium, methyl, ethyl, propyl, and isopropyl, wherein the methyl, ethyl, propyl, and isopropyl groups are optionally surrounded by 1 to 4 R groups. s Replaced; Or R L1 R L2 The nitrogen atom attached thereto forms an azircyclic butyl group, a pyrrolidinyl group, a piperidinyl group, or a piperazine group, wherein the azircyclic butyl group, a pyrrolidinyl group, a piperidinyl group, or a piperazine group is optionally surrounded by 1 to 4 R atoms. s Replaced; Z1 is selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -C≡C-, -C≡C-CH2CH2, wherein Z1 is optionally divided by 1 to 2 R s Replaced; Z2 is selected from -C(=O)-, -NH-C(=O)-, -O-CH2-C(=O)-, -NH-CH2-C(=O)-, -NHC(=O)-CH2CH2CH2CH2-C(=O)-, -NH-CH2CH2CH2CH2-NH-, -NH-CH2CH2-NH-, -NH-CH2-NH-, and -NH-CH2-NH-, wherein the CH2 is optionally surrounded by 1 to 2 R s Replaced; M1 is selected from -O-, -C(=O)-, -NH-, triazole, and pyrazolyl, wherein the triazole or pyrazolyl group is optionally surrounded by 1 to 4 R groups. s Replaced; M2 is selected from -C(=O)-, -CH2-C(=O)-, -CH2CH2-C(=O)-, -CH2CH2-NH-C(=O)CH2-C(=O)-, -CH2CH2-NH-C(=O)CH2OCH2-C(=O)-, wherein the CH2 is optionally surrounded by 1 to 2 R s Replaced; M3 is selected from -O-, -CR m1 R m2 -、-NR m3 -; R L R m1 R m2 R m3 Each is independently selected from H, deuterium, methyl, ethyl, propyl, isopropyl, and cyclopropyl, wherein the methyl, ethyl, propyl, isopropyl, and cyclopropyl groups are optionally surrounded by 1 to 4 R groups. s Replaced; Y2 is selected from -N(R) L5 )-、-N(R L5 )-Ethylene-triazolyl-,-N(R L5 )-methylene-triazolyl-,-N(R L5 )-Ethylene-N(R L5 The ethylene or triazole group is optionally surrounded by 1 to 4 R groups. s Replaced; R L8 Each of the following is independently selected from -CH2CH2CH2-NH-C(=NH)-NH2, -CH2CH2CH2-NH-C(=O)-NH2, -CH2C(=O)OH, -CH2C(=O)NH2, -CH2CH2C(=O)OH, -CH2CH2C(=O)NH2, -CH2SH, -CH2CH2SCH3, H, methyl, ethyl, isopropyl, butyl, -CH2-imidazolyl, -CH2-phenyl, -CH2-indoleyl, wherein R L8 Choose from 1 to 4 Rs s Replaced; Y4 is selected from -C(=O)-methyl, -C(=O)-ethyl, -C(=O)-propyl, -C(=O)-isopropyl, The Y4 is arbitrarily divided by 1 to 2 Rs s Replaced; Z4 is selected from -N(R) L5 )-C(R L6 )2-、-OC(R L6 )2-、-OC(=O)-、-N(R L5 )-CH2CH2-N(R L7 )-C(=O)-, its right side is connected to D; R L3 R L4 Each of the following is independently selected from deuterium, F, Cl, Br, OH, NH2, CN, NO2, methyl, ethyl, isopropyl, methoxy, and cyclopropyl, wherein the methyl, ethyl, isopropyl, methoxy, and cyclopropyl groups are optionally prefixed with 1 to 4 R groups. s Replaced; R L6 Each is independently selected from H, deuterium, F, Cl, Br, OH, NH2, CN, NO2, methyl, ethyl, propyl, isopropyl, CHF2, CH2F, CF3, CD3, OCF3, OCD3, methoxy, ethoxy, and cyclopropyl. As an option, R L5 and R L6 Two Rs L6 The atoms bonded to it are directly connected to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolyl, piperidinyl, and piperazine, wherein the aziridine, pyrrolyl, piperidinyl, and piperazine groups are optionally surrounded by 1 to 4 R atoms. s Replaced; R L7 Each is independently selected from H, methyl, ethyl, propyl, isopropyl, -methylene-S(=O)2-methyl, -ethylidene-S(=O)2-C 1-2 Ethyl, -propylidene-S(=O)2-methyl, cyclopropyl, cyclobutyl, wherein the methyl, ethyl, propyl, isopropyl, methylene, ethylidene, propylidene, cyclopropyl, or cyclobutyl is optionally surrounded by 1 to 4 R... s What it replaced.

5. The compound according to claim 4, or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, wherein, L2 is selected from bond, -C(=O)-, s2 is selected from 2, 3, 4, 5, 6, and 7; L3 is selected from -Val-Gly-, -Val-Cit-, -Phe-Lys-Gly-, -Gly-Val-Lys-Gly-, -Val-Lys-Gly-Gly-, -Val-Lys-Gly-, -Val-Lys-Ala-, -Gly-Gly-Phe-Gly-, -Val- AA1-, -Val-AA1-Val-, -Val-AA1-Gly-, -AA1-AA1-, -AA1-AA1-Gly-, -AA1-Val-Cit-, -Val-Ala-, -Ala-Ala-, AA1-Gly-Gly-Phe-Gly-, -AA1-Val-Ala-; AA1 is selected from L4 is selected from Its right side connects to L5; R L8 Each is independently selected from -CH2CH2CH2-NH-C(=NH)-NH2, -CH2CH2CH2-NH-C(=O)-NH2, -CH2C(=O)OH, -CH2C(=O)NH2, -CH2CH2C(=O)OH, -CH2CH2C(=O)NH2, -CH2SH, -CH2CH2SCH3, H, methyl, ethyl, isopropyl, -CH2CH2CH2CH2NH2, -CH2NH2, -CH2OH, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2-imidazolyl, -CH2-phenyl, -CH2-indoleyl; m2 is selected from 2 and 3; L5 is selected from Its right side is connected to D; s1 is selected from 0, 1, and 2.

6. The compound according to claim 5, or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, wherein, L1 is selected from Its right side connects to L2; m1 is selected from integers from 2 to 10; m4 is selected from integers from 1 to 10; m4 is preferably selected from 4, 6, or 8; m5 is selected from 0, 1, 2, or 3. -L2-(L3) p1 -(L4) p2 -L5- Selected from Its right side is connected to D; s2 is selected from 3, 5, 7, and 9; Or -(L3) p1 -(L4) p2 -L5- Selected from Its right side is connected to D.

7. The compound according to claim 1, or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, wherein, D is selected from Alternatively, D can be selected from one of the following structures: Preferably, D is selected from Indicates an optional connection position, when connected to a certain position of D. When connecting, another location For H; R 3 Selected from C 1-6 Alkyl, -C 1-6 Alkylene-NR 3a -S(=O)2C 1-6 Alkyl, -C 1-6 Alkylene-NR 3a -C(=O)C 1-6 Alkyl, wherein the alkylene or alkyl group is optionally surrounded by 1 to 4 R groups. k Replaced; R 3a Selected from H, C 1-6 Alkyl groups, wherein the alkyl group is optionally composed of 1 to 4 elements selected from deuterium, halogens, CN, OH, NH2, C. 1-6 Alkyl, C 1-6 Substituents of alkoxy groups; R 4 Selected from R 2a Its left end is connected to NH; R 5 Selected from S or O; R 6 Selected from -C 1-6 alkylene-, -C 3-6 Cycloalkylene-, wherein the alkylene or cycloalkylene group is optionally surrounded by 1 to 6 R groups. k Replaced; R 7 Selected from OH and -C(=O)OH; R 1 Each element is independently selected from H, deuterium, and C. 1-6 Alkyl, -C(=O)R 1a -S(=O)2R 1a -P(=O)R 1a R 1b C 3-8 A carbocyclic or 3- to 10-membered heterocyclic group, wherein the alkyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k Replaced; R k Each element is independently selected from deuterium, halogens, OH, =O, CN, NH2, NO2, COOH, CONH2, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, -OC 3-6 Carbocyclic rings, -O-3 to 7-membered heterocycles, -NH-C 3-6 Carbon rings, -NH-3 to 7-membered heterocycles, -SC 3-6 Carbon rings, -S-3 to 7-membered heterocycles, -C 0-4 Alkylene-C 3-6 Carbon ring, -C 0-4 Alkylene-3 to 7-membered heterocycles, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic group is optionally selected from 1 to 4 deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Substituents of alkoxy groups; R 2 Selected from -C 1-6 Alkylene-VC 1-6 Alkylene-WR 2a -、-C 2-6 Alkylene-WR 2a -、-C 2-6 Alkylene-WR 2c -、-C 2-6 Alkylene-WR 2c -R 2a - The alkylene group is optionally surrounded by 1 to 8 elements selected from deuterium, halogen, CN, OH, NH2, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Substituted with cycloalkyl or 3-8 membered heterocyclic groups, with its right end connected to L5; V is selected from O, S, NR v ; W is selected from O, S, NR w ; R 2a Selected from -C 1-6 Alkylene-, -C(=O)C(R) 2b )2O-、-C(=O)C(R 2b )2NH-、-C(=O)C(R 2b )2C(R 2b )2O-、-C(=O)C(R 2b )2C(R 2b )2C(R 2b )2O-、-C(=O)-R 2c -O-, its left end is connected to W, and its right end is connected to L5, wherein the alkylene group is optionally surrounded by 1 to 6 elements selected from deuterium, halogen, CN, OH, NH2, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Substituted by cycloalkyl or 3-8 membered heterocyclic groups; R 2b Each element is independently selected from H, deuterium, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 The alkyl, carbocyclic, or heterocyclic group may be selected from 1 to 6 elements chosen from deuterium, halogen, CN, OH, NH2, C. 1-6 Alkyl, C 1-6 Alkoxy, The substituents are replaced; R ka R kb Each is independently selected from H, CN, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocyclic groups, C 1-2 Alkylene-C 3-6 carbon cyclo group, C 1-2 Alkylene-4 to 6-membered heterocyclic group, wherein the alkylene, alkyl, cycloalkyl, carbocyclic or heterocyclic group is optionally composed of 1 to 4 groups selected from deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The substituents on the carbon ring are replaced; As an option, 2 R 2b Direct connection forms C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. k Replaced; R 2c Selected from C 3-10 Cycloalkyl or 4-10 membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally surrounded by 1 to 6 R groups. k Replaced; R a Each element is independently selected from deuterium, halogens, OH, NH2, CN, NO2, COOH, CONH2, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. k Replaced; m is selected from 0, 1, 2, and 3; p can be independently selected from 0, 1, 2, 3, 4, 5 or 6; Y is selected from O, S, NH, N-CN; X1 is selected from -NR x1 -C 1-4 Alkylene-, -OC 1-4 Alkylene-, -SC 1-4 Alkylene-, C 3-10 Cycloalkyl or 4-10 membered heterocyclic group, wherein the alkylene, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 6 R groups. k Replaced; X2 is selected from -NR x2 -、-CR x R x -、-O-; R x Each is independently selected from halogens; R v R w R x1 R x2 Each is independently selected from H, deuterium, and C. 1-4 Alkyl, C 3-6 Carbocyclic, 4- to 6-membered heterocyclic, wherein the alkyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k Replaced; Ring B is selected from one of the following structures with optional substitution: When replaced, by 1 to 4 R b It has been replaced, and its left side is directly connected to X1; D1 and D2 are each independently selected from O, S, NH, or NR. b ; D3 and D4 are each independently selected from O, S, N, NH, or NR. b ; E2, E3, E4, and E5 are each independently selected from CR. b CH or N; E1 is selected from C(R) b 2. CHR b ,CH2,C(=O),CH2CH2,CHR b CHR b , R b Each element is independently selected from deuterium, halogen, OH, cyano, NH2, NO2, N(C) 1-6 Alkyl)2, NH(C) 1-6 Alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, -C(=O)R 1a -S(=O)2R 1a -P(=O)R 1a R 1b C 3-10 Carbocyclic groups, 4- to 10-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally selected from 1 to 4 R k Replaced; C1, C2, C3, and C4 are each independently selected from CR c CH or N; R c Each is independently selected from deuterium, halogens, OH, COOH, CN, NO2, NH2, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 acetylinyl, OC 1-6 Alkyl, SC 1-6 Alkyl, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, -C 0-4 Alkylene-C 3-10 Carbocyclic group, -C 0-4 Alkylene-4 to 10-membered heterocyclic group, wherein the alkyl, alkenyl, alkynylene, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R groups. k Replaced; R 1a R 1b Each element is independently selected from H, OH, NH2, and C. 1-6 Alkyl, C 1-6 Alkoxy, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 3-8 Carbocyclic groups, 4- to 10-membered heterocyclic groups, C 6-10 aryl or 5 to 10-membered heteroaryl, wherein the alkyl, alkoxy, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally surrounded by 1 to 4 R groups. k Replaced; As an option, two R a Two Rs c Together with the atoms or framework attached to it, they form C 3-10 A carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k What it replaced.

8. The compound according to claim 7, or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, wherein, R 3 Selected from methyl, ethyl, propyl, isopropyl, -ethylidene-N(R) 3a )-S(=O)2methyl, -ethylidene-N(R 3a )-C(=O)methyl, wherein the methyl, ethyl, ethylidene, propyl, and isopropyl groups are optionally surrounded by 1 to 4 R groups. k Replaced; R 6 Selected from methylene-, ethylene-, propylene-, cyclopropylene, and cyclobutylene, wherein the methylene, ethylene, propylene, cyclopropylene, and cyclobutylene are optionally surrounded by 1 to 4 R groups. k Replaced; R v R w Each is independently selected from H, deuterium, CHF2, CH2F, CF3, CD3, CH2OH, methyl, ethyl, propyl, and isopropyl. X1 is selected from -NHCH2-, -NHCH2CH2-, -OCH2-, -SCH2-, -O-CH2CH2-, -S-CH2CH2-, X a The CH2 is optionally converted by 1 to 2 R k Replaced; X2 is selected from -NH- and -CF2-; X a Selected from 1 to 4 Rs k The following structures are substituted: cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, cyclobutylspirocyclobutyl, aziridinespirocyclobutyl, aziridinespiroaziridine, piperidinylspirocyclobutyl, cyclohexylspirocyclobutyl, cyclopropylcyclopentyl, cyclopentylcyclopentyl, pyrrolidinylcycloalkyl, pyrrolidinylcyclopentyl The bond connecting the left end -C (=Y)- and the right end ring B is linked in ring X. a On different atoms; R 2 Selected from -methylene-V-methylene-WR 2a -、-Ethylene-V-Ethylene-WR 2a -、-Ethylene-V-methylene-WR 2a -、-methylene-V-ethylidene-WR 2a -,-Ethylene-V-Propylene-WR 2a -、-methylene-V-propylene-WR 2a -,-Ethylene-WR 2a -,-Ethylene-WR 2c -,-Propylene-WR 2c -,-Ethylene-WR 2c -R 2a -,-Propylene-WR 2c -R 2a -,-Propylene-WR 2a -, -Butyl-WR 2a - The methylene, ethylene, propylene, and butylene groups are optionally selected from 1 to 8 elements chosen from deuterium, F, Cl, Br, I, CN, OH, NH2, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups; R 2a Selected from methylene, ethylene, propylene, isopropylene, butylene, -C(=O)C(R) 2b )2O-、-C(=O)C(R 2b )2NH-、-C(=O)C(R 2b )2C(R 2b )2O-、-C(=O)C(R 2b )2C(R 2b )2C(R 2b )2O-、-C(=O)-R 2c -O-, its left end is connected to W, and its right end is connected to L5, wherein the methylene, ethylene, propylene, isopropylene, and butylene are optionally selected from 1 to 4 of deuterium, F, Cl, Br, I, CN, OH, NH2, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Substituted by cycloalkyl or 3-6 membered heterocyclic groups; R 2b Each of the following elements is independently selected from H, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolyl, piperidinyl, morpholinyl, piperazine, oxacyclobutyl, tetrahydrofuranyl, and phenyl, wherein methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolyl, piperidinyl, morpholinyl, piperazine, oxacyclobutyl, tetrahydrofuranyl, and phenyl are optionally selected from 1 to 4 elements selected from deuterium, halogen, CN, OH, NH2, and C. 1-4 Alkyl, C 1-4 Alkoxy, The substituents are replaced; R ka R kb The following groups are selected independently from H, CN, F, Cl, Br or optionally replaced by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, methyl, methoxy, and cyclopropyl: methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, oxecyclobutyl, azacyclobutyl, CH2-cyclopropyl, CH2-cyclobutyl; As an option, 2 R 2b Direct connection forms an optional 1 to 4 R k The following structures are replaced: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxacyclobutyl, tetrahydrofuranyl, and cyclobutylspirocyclobutyl. R 2c Selected from 1 to 4 Rs k The following structures are replaced: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutylspirocyclobutyl, cyclopropyl-cyclopentyl, aziridine, pyrrolidinyl, piperidinyl, morpholinyl. R k Each of the following groups is independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, NO2, COOH, CONH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, aziridine, oxacyclobutyl, pyrrolylyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, aziridine, oxacyclobutyl, pyrrolylyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl is optionally selected from deuterium, F, Cl, Br, I, CN, OH, NH2, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups; R 1 Each is independently selected from H, deuterium, methyl, ethyl, propyl, isopropyl, -C(=O)R 1a -S(=O)2R 1a -P(=O)R 1a R 1b Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxetidine, pyrrolidinyl, piperidinyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxetidine, pyrrolidinyl, piperidinyl, or morpholinyl group is optionally surrounded by 1 to 4 R groups. k Replaced; R 1a R 1b Each of the following is independently selected from H, OH, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole, or thiophene, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole, or thiophene is optionally surrounded by 1 to 3 Rs. k Replaced; R a Each of the following is independently selected from deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, CONH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, and pyrrolidinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, and pyrrolidinyl groups are optionally prefixed with 1 to 4 R. k Replaced; R b Each of the following groups is independently selected from deuterium, F, Cl, Br, I, OH, cyano, NH2, NO2, NHCH3, N(CH3)2, COOH, CONH2, -C(=O)-methyl, -C(=O)-ethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole, or thiophene, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolyl, piperidinyl, morpholinyl, imidazole, pyrazole, pyrrole, or thiophene is optionally surrounded by 1 to 4 R groups. k Replaced; R c Each is independently selected from deuterium, F, Cl, Br, I, OH, COOH, CN, NO2, NH2, NHCH3, N(CH3)2, or optionally coated by 1 to 4 R. k The following groups are substituted: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl; As an option, two R a Two Rs c Together with the atoms or skeleton attached thereto, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, oxacyclopentyl, pyrrolyl, piperidinyl, or 1,3-dioxopentyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, oxacyclopentyl, pyrrolyl, piperidinyl, or 1,3-dioxopentyl are optionally surrounded by 1 to 4 R atoms. k What it replaced.

9. The compound according to claim 8, or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, wherein, R 3a The group is selected from H, methyl, ethyl, and isopropyl, wherein the methyl, ethyl, and isopropyl groups are optionally replaced by 1 to 4 substituents selected from deuterium, F, Cl, Br, CN, OH, NH2, and methyl. R 4 Selected from -C(=O)CH2O-, -C(=O)C(R) 2b )2NH-, -C(=O)C(H)(D)O-, -C(=O)CD2O-, -C(=O)CH(R 2b )O-、-C(=O)C(CH3)(R 2b )O-、 Its left end is connected to NH; p is independently selected from 0, 1, 2, and 3; Y is selected from O or S; R 2 Selected from -CH2CH2-O-CH2CH2-NR w -R 2a -、-CH2-O-CH2CH2-NR w -R 2a -、-CH2CH2-O-CH2CH2-O-R 2a -、-CH2CH2-NR v -CH2CH2-O-R 2a 、-CH2CH2-S-CH2CH2-NR w -R 2a -、-CH2CH2-O-CH2CH2-S-R 2a -、-CH2CH2-NR v -CH2CH2-NR w -R 2a -、-CH2CH2-NR w -R 2a -、-CH2CH2CH2-NR w -R 2a -、-CH2CH2CH2-O-R 2a -、-CH2CH2CH2-O-R 2c -、-CH2CH2CH2-O-R 2c -R 2a -、-CH2CH2CH2CH2-NR w -R 2a -、-CH2CH2-O-CH2CH2-NR w -C(=O)CH2O-、-CH2CH2-O-CH2CH2-NR w -C(=O)C(H)(D)O-、-CH2CH2-O-CH2CH2-NR w -C(=O)CD2O-、-CH2CH2-O-CH2CH2-NR w -C(=O)CHR 2b O-、-CH2CH2-O-CH2CH2-NR w -C(=O)C(CH3)R 2b O-、-CH2-O-CH2CH2-NR w -C(=O)CHR 2b O-、-CH2-O-CH2CH2-NR w -C(=O)C(CH3)(R 2b )O-, whose right end is connected to L5, wherein the CH2 is optionally replaced by one or two substituents selected from deuterium, F, Cl, Br, CN, OH, NH2, CHF2, CH2F, CF3, methyl, methoxy; R 2a Selected from methylene, ethylene, propylene, isopropylene, -C(=O)CH2O-, -C(=O)CH2NH-, -C(=O)C(H)(D)O-, -C(=O)CD2O-, -C(=O)CH(R) 2b )O-、-C(=O)C(CH3)(R 2b )O-、 Its right end is connected to L5, wherein the methylene, ethylene, propylene, and isopropylene are optionally replaced by 1 to 3 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, methyl, methoxy, and cyclopropyl. R 2b Each of the following elements is independently selected from H, deuterium, F, Cl, Br, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolyl, piperidinyl, morpholinyl, piperazine, oxacyclobutyl, tetrahydrofuranyl, and phenyl, wherein methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolyl, piperidinyl, morpholinyl, piperazine, oxacyclobutyl, tetrahydrofuranyl, and phenyl are optionally replaced by 1 to 4 elements selected from deuterium, F, Cl, Br, I, CN, OH, NH2, methyl, methoxy, The substituents are replaced; Selected from Selected from Its left side and R 2 Connected; Ring B is selected from any 1 to 3 Rs. b One of the following structures is replaced: Its left side is connected to X1; Ring Xa is selected from 1 to 3 R's by choice. c One of the following structures is replaced: Selected from 10. The compound according to claim 1, or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, wherein, D is selected from one of the structures shown in Table A-1 and Table A-4.

11. The compound of claim 10 or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, wherein the compound is selected from one of the structures shown in Table A-2.

12. The compound according to claim 1, or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, wherein, The compounds are selected from general formula (IA). L-L0-L1-L3-L5-D(IA) L is selected from halogen, sulfone, and tertiary amine salt (Me3N). + Et3N + ), diazonium salts, -OMs, MeSO2-, CF3SO3-, p-toluenesulfonyl groups; L0 is selected from Its left end is connected to L; L1 is selected from Its right side is connected to L3; m5 is selected from 1 and 2; preferably, -L1- is selected from Its right side connects to L3; L3 is selected from -AA-, -AA1-, -AA-AA-, -AA-AA-AA-, -AA-AA-AA-AA-, -AA-AA1-, -AA1-AA-, -AA-AA1-AA-, -AA-AA-AA1-, -AA1-AA-AA-AA-, -AA1-AA-AA- AA-AA-; preferably, L3 is selected from -Val-Gly-, -Val-Cit-, -Phe-Lys-Gly-, -Gly-Val-Lys-Gly-, -Val-Lys-Gly-Gly-, -Val-Lys-Gly-, -Val-Lys-Ala-, -Gl y-Gly-Phe-Gly-, -Val-AA1-, -Val-AA1-Val-, -Val-AA1-Gly-, -AA1-AA1-, -AA1-AA1-Gly-, -AA1-Val-Cit-, -Val-Ala-, -Ala-Ala-Ala-, A A1-Gly-Gly-Phe-Gly-, -AA1-Val-Ala-; more preferably, L3 is selected from -Val-Cit-, -Gly-Gly-Phe-Gly-, -Val-Ala-, -Ala-Ala-Ala-, AA1-Gly-Gly-Phe-Gly-; AA1 is selected from Preferably, AA1 is selected from L5 is selected from -Z4-; Z4 is selected from -N(R) L5 )-C(R L6 )2-、-OC(R L6 )2-、-OC(=O)-、-N(R L5 )-CH2CH2-N(R L7 Z4 is selected from -N(R)-C(=O)-, and its right side is connected to D; preferably, Z4 is selected from -N(R)-C(=O)-. L5 )-C(R L6 )2-, whose right side is connected to D; more preferably, Z4 is selected from Its right side is connected to D; more preferably, Z4 is selected from Its right side is connected to D; D is selected from Preferably, D is selected from More preferably, D is selected from X1 is selected from -NR x1 -C 1-4 Alkylene-, -OC 1-4 Alkylene-, wherein the alkylene is optionally surrounded by 1 to 4 R k The CH2 group is replaced by one or two substituents selected from deuterium, F, Cl, Br, CHF2, CH2F, CF3, CD3, methyl, and methoxy. R 2 Selected from -Ethylene-O-Ethylene-NR w -R 2a - Its right end is connected to L5, wherein the methylene, ethylene, propylene, and butylene are optionally selected from 1 to 8 elements selected from deuterium, F, Cl, Br, I, CN, OH, NH2, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 The alkoxy group is substituted; preferably, R 2 Selected from -CH2CH2-O-CH2CH2-NR w -C(=O)CH2O-, -CH2CH2-O-CH2CH2-NR w -C(=O)C(H)(D)O-、-CH2CH2-O-CH2CH2-NR w -C(=O)CD2O-, -CH2CH2-O-CH2CH2-NR w -C(=O)CHR 2b O-、-CH2CH2-O-CH2CH2-NR w -C(=O)C(CH3)R 2b O-、-CH2CH2-O-CH2CH2-NR w -C(=O)-R 2c -O-, its right end is connected to L5, wherein the CH2 is optionally replaced by one or two substituents selected from deuterium, F, Cl, Br, CN, OH, NH2, CHF2, CH2F, CF3, methyl, methoxy; more preferably, R 2 Selected from Its right end connects to L5; R c Each is independently selected from deuterium, F, Cl, Br, I, or arbitrarily selected by 1 to 4 R. k The substituted groups include: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, methylthio, and cyclopropyl; preferably, R c Each is independently selected from deuterium, F, Cl, and Br; R 5 Selected from S or O; preferably, R 5 Selected from O; R 4 Selected from R 2a Its left end is connected to NH; preferably, R 4 Selected from -C(=O)CH2O-, -C(=O)C(H)(D)O-, -C(=O)CD2O-, -C(=O)C(H)(CH3)O-, Its left end is connected to NH; R 2a Selected from -C(=O)C(R) 2b )2O-、-C(=O)-R 2c -O-, its right end is connected to L5; preferably, R 2a Selected from -C(=O)CH2O-, -C(=O)C(H)(D)O-, -C(=O)CD2O-, -C(=O)CH(R) 2b )O-、-C(=O)C(CH3)(R 2b )O-、 Its right end is connected to L5, wherein the methylene, ethylene, propylene, and isopropylene are optionally replaced by 1 to 3 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, methyl, methoxy, and cyclopropyl. R 2b Each element is independently selected from H, deuterium, halogens, and C. 1-4 Alkyl, C 3-6 The carbocyclic group, wherein the alkyl group or carbocyclic group is optionally composed of 1 to 4 radicals selected from deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 Alkoxy, The substituent is replaced by; preferably, R 2b Each of the following is independently selected from H, deuterium, F, Cl, Br, I, methyl, cyclopropyl, and cyclobutyl, wherein the methyl, cyclopropyl, and cyclobutyl groups are optionally replaced by 1 to 4 groups selected from deuterium, F, Cl, Br, methyl, methoxy, The substituents are replaced; R ka R kb The following groups are selected independently from H, CN, F, Cl, Br or optionally replaced by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, methyl, methoxy, and cyclopropyl: methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, oxecyclobutyl, azacyclobutyl, CH2-cyclopropyl, CH2-cyclobutyl; Preferably, Selected from R 2c Selected from C 3-6 cycloalkyl groups, wherein the cycloalkyl group is optionally surrounded by 1 to 4 R groups. k Replaced; preferably, R 2c The cyclopropyl or cyclobutyl group is selected from cyclopropyl or cyclobutyl, wherein the cyclopropyl or cyclobutyl group is optionally replaced by 1 to 4 substituents selected from deuterium, F, Cl, Br, CHF2, CH2F, CF3, CD3, methyl, or methoxy. R k Each is independently selected from deuterium, F, Cl, Br, CHF2, CH2F, CF3, CD3, and methyl.

13. The compound according to claim 12, or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, wherein, The compounds are selected from those with the general formulas (I-Aa) and (I-Ab). R 4 Selected from -C(=O)CH2O-, -C(=O)C(H)(D)O-, -C(=O)CD2O-, -C(=O)C(H)(CH3)O-, Its left end is connected to NH; R 5 Selected from S or O; preferably, R 5 Selected from O; X1 is selected from -NHCH2- and -OCH2-, wherein the CH2 is optionally substituted with one or two substituents selected from deuterium, F, Cl, Br, CHF2, CH2F, CF3, CD3, methyl, and methoxy; preferably, X1 is selected from -NHCH2-, wherein the CH2 is optionally substituted with one or two substituents selected from deuterium, F, Cl, Br, CHF2, CH2F, CF3, CD3, methyl, and methoxy. R 2 Selected from Its right end connects to L5; R c Each is independently selected from deuterium, F, Cl, Br, I, methyl, CHF2, CH2F, CF3; preferably, R c Each is independently selected from deuterium, F, Cl, and Br; L3 is selected from -Gly-Gly-Phe-Gly-, Preferably, L3 is selected from -Gly-Gly-Phe-Gly-; L5 is selected from Its right side is connected to D; preferably, L5 is selected from Its right side is connected to D.

14. A ligand-drug conjugate of formula (III) or its stereoisomer, racemate, tautomer, or pharmaceutically acceptable salt, wherein, Tb-[L'-D]q(III) Tb is the target portion; Preferably, the targeting portion is selected from antibody or antigen-binding fragments; the targeting portion is specifically capable of binding to cell surface receptors or antigens; the antigen is B7H3, B7-H4, CCL11, CCR5, CD123, CD133, CD138, CD18, CD19, CD33, CD40, HER2, HER3, CD20, CD38, CD33, BCMA, CD138, EGFR, FGFR4, GD2, PDGFR, TEM1 / CD248, TROP-2, DLL3, CDH6, CDH17, CEACAM5, or a combination thereof; the antibody is anti-CD33, rituximab, trastuzumab, pertuzumab, OR000213(huMy9-6IgG4S228P), lintuzumab, anti-DLL3, anti-CDH6, anti-CDH17, anti-CEACAM5, or gemtuzumab; L' is selected from connectors; preferably, L' is selected from -L0-L1-L2-(L3). p1 -(L4) p2 -L5-; more preferably, L' is selected from -L0-L1-L2-L3-L5-, -L0-L1-L3-L5-, L0-L1-L2-L4-L5-; even more preferably, L' is selected from -L0-L1-L3-L5-; The definitions of L0, L1, L2, L3, L4, and L5 are as described in any one of claims 1-6, 12, and 13; The definition of D is as described in any one of claims 7-10, 12, and 13; q is selected from any value between 1 and 20. For example, q is any value between 1-10, 1-8, 2-8, 4-8 or 6-8. Preferably, q is 2±0.4, 4±0.4, 6±0.4 or 8±0.

4. More preferably, q is any value between 6 and 8.

15. The ligand-drug conjugate or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts according to claim 14, wherein, The coupling agents are selected from general formulas (III-A), (III-Aa), and (III-Ab). Tb-[L-L0-L1-L3-L5-D]q(III-A) The remaining substituents are defined as described in any one of claims 12 or 13.

16. The ligand-drug conjugate according to claim 14, or its stereoisomer, racemate, tautomer, or pharmaceutically acceptable salt, wherein the conjugate is selected from one of the structures shown in Table A-3.

17. A pharmaceutical composition comprising the compound of any one of claims 1-16 or its ligand-drug conjugate or its stereoisomer, racemate, tautomer, pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, preferably, the pharmaceutical composition comprising 1-1500 mg of the compound of any one of claims 1-16 or its conjugate or its stereoisomer, racemate, tautomer, or pharmaceutically acceptable salt.

18. The use of the compound or its ligand-drug conjugate or its stereoisomer, racemate, tautomer, pharmaceutically acceptable salt or composition according to any one of claims 1-16 in the preparation of a medicament for treating tumors or cancer.

19. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of the compound of any one of claims 1-16 or a ligand-drug conjugate thereof or a stereoisomer, racemate, tautomer, or pharmaceutically acceptable salt thereof, preferably 1-1500 mg, wherein the disease is preferably a tumor or cancer.

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