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WO-2026092671-A1 - HYDROPHILIC LINKER AND CONJUGATE THEREOF, AND RELATED PREPARATION METHOD AND APPLICATION

WO2026092671A1WO 2026092671 A1WO2026092671 A1WO 2026092671A1WO-2026092671-A1

Abstract

A class of compounds containing a hydrophilic group, a preparation method therefor and an application thereof. Specifically, the present invention relates to compounds represented by formulas (I) and (IV) or pharmaceutically acceptable forms thereof, pharmaceutical compositions thereof, preparation methods therefor, and uses thereof. The compounds can be prepared as a biologically active conjugate to treat diseases associated with abnormal cell proliferation.

Inventors

  • TIAN, QIANG
  • YE, JIAN
  • YANG, YU
  • ZHOU, QIN
  • SONG, Hongmei
  • YU, WENSHENG
  • GE, Junyou

Assignees

  • 四川科伦博泰生物医药股份有限公司

Dates

Publication Date
20260507
Application Date
20251031
Priority Date
20241101

Claims (15)

  1. The compound or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite, and prodrug, wherein the compound has the following structure: in, Each time XG appears, it is independently selected from H, C1-6 alkyl, or substituents and their derivatives containing hydrophilic hydroxyl, glycosyl, amino, quaternary ammonium salt, sulfonyl and carboxylic acid segments; Y is selected from the segment connecting XG and the benzene ring; Z is selected from the portion of a biologically active compound; CM is selected from structures that can react with specific functional groups in the target structure (such as an antibody); L1 is selected from the fragment connecting CM and the aniline moiety; a can be 1, 2, or 3.
  2. The compound of claim 1 or the pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitride, isotope label, metabolite, and prodrug thereof, wherein XG, each time it appears, is independently selected from the following structural fragments: H, C1-6 alkyl (e.g., methyl), (For example: ), (For example: ), (For example: ), (For example: ), (For example: ), (For example: ), (For example: ), (For example: ), Where m is selected from integers from 1 to 30; for example, m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30; Alternatively, XG can be selected from the following structures: (For example: ), (For example: ), (For example: ), (For example: ), (For example: ), (For example: ), (For example: ), (For example: ) (For example: (Specifically: )) (For example: (Specifically: )) (For example: (specifically) )) (For example: ), (For example: ), (For example: ), (For example: ), (For example: ), (For example: ), (For example: ), (For example: ), (For example: ); where m is independently selected from integers from 1 to 30 each time it appears; for example, m is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 each time it appears; preferably, m is 3, 4, or 5; Preferably, Y is selected from chemical bonds, or from a group consisting of one or more C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkylene, C2-6 alkenyl, C2-6 alkynyl , -O- , -NR1- , quaternary ammonium salt, carbonyl, sulfonyl, sulfinyl, phosphoryl (phosphonyl), aryl, heteroaryl, heterocyclic, and/or cycloalkyl; R1 is selected from a structure consisting of one or more hydrogens, C1-6 alkyl, C1-6 alkylene, hydroxyl, -O-, carbonyl, carboxyl, and/or sulfonic acid groups; preferably, R1 is a C1-6 alkyl group; Preferably, the bioactive compound is selected from topoisomerase I inhibitors, topoisomerase II inhibitors, tubulin polymerization inhibitors, tubulin depolymerization inhibitors, DNA interference agents, DNA alkylating agents, DNA cross-linking agents, DNA polymerase inhibitors, DNA damage repair inhibitors, RNA polymerase inhibitors, thymidine synthase inhibitors, poly-ADP-ribose polymerase inhibitors, apoptosis promoters, cell cycle arrestors, protein degrading agents, synthetic lethal agents, kinase inhibitors, and glucocorticoid receptor modulators. Preferably, the bioactive compound is selected from camptothecin compounds, olritatin compounds, maytansine compounds, eribulin compounds, hammetrine compounds, epothilone compounds, kazimycin compounds, anthracycline compounds, benzodiazepine compounds, α-amaminoid compounds, sucrose compounds, alkaloid compounds, tripterygium compounds, nucleoside compounds, glucocorticoid compounds, rapamycin compounds, and lipolytamine compounds; Preferably, CM is selected from functional groups or structural fragments that can react with cysteine, lysine, glutamic acid, glutamine, aspartic acid, asparagine, tyrosine, serine, threonine, methionine, histidine, arginine, non-natural amino acids, glycosyl groups and their derivatives or analogs contained in the target structure. Preferably, CM is selected from halogenated acetyl groups, substituted or unsubstituted maleimide groups, alkyl sulfonyl heteroaryl groups, and fluorophenolic ester groups; Preferably, CM is selected from iodoacetyl, maleimide, bromomaleimide, thiomaleimide, alkylsulfonylpyrimidinyl, and fluorophenol ester. More preferably, CM is selected from the following substituted or unsubstituted structural segments: Preferably, L1 is selected from fragments composed of one or more of the following structures, including but not limited to C1-6 alkylene, C2-6 alkenylene, C2-6 alkyneene, carbonyl, sulfonyl, amino, hydroxyl, -O-, heterocyclic, heteroaryl, aryl, natural or non-natural amino acids and their polypeptides, polyethylene glycol, polysarcosine, carboxylic acid, glycosyl and their derivatives or quaternary ammonium salts; Preferably, L1 is selected from one or more of the following substituted or unsubstituted structural fragments: C1-6 alkylene, 6-10 aryl, 5-6 heteroaryl, substituted or unsubstituted 9-12 nitrogen-containing heterocyclic group (e.g., substituted by one or more R'), -N(R')-, -NH(R'), -N(R') 2 , carbonyl, -O-, natural or non-natural amino acids and their analogues (e.g., Ala, Arg, Asn, Asp, Cit, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, D-Val, D-Leu, D-Ala, Lys(R'), Glu( R '), Lys( COCH2CH2 ( OCH2CH2 ) rOCH3) () and short peptides composed of amino acids (such as Gly-Lys, Asp-Gly-Gly-Phe-Gly (DGGFG), Glu-Gly-Gly-Phe-Gly (EGGFG), Ala-Ala, Ala-Lys, Ala-Lys (Ac), Ala-Pro, Gly-Glu, Gly-Gly, Phe-Lys, Phe-Lys (Ac), Val-Ala, Val-Cit, Val-Lys, Val-Lys (Ac), Ala-Ala-Ala, Ala-D-Ala-Ala, Ala-Ala-Asn, Ala-Ala-Gly, D-Leu-Al) a-Glu, Gly-Gly-Arg, Gly-Glu-Gly, Gly-Gly-Gly, Gly-Ser-Lys, Glu-Val-Ala, Glu-Val-Cit, Ser-D-Ala-Pro, Val-Leu-Lys, Val-Lys-Ala, Val-Ly s-Gly, Gly-Gly-Phe-Gly(GGFG), Gly-Gly-Val-Ala(GGVA), Gly-Phe-Leu-Gly(GFLG), Glu-Ala-Ala-Ala(EAAA), Gly-Gly-Gly-Gly-Gly(GGGGG)), Wherein R' is composed of one or more of the following groups, including but not limited to hydrogen, C1-6 alkyl, C1-6 alkylene, amino, hydroxyl, carboxyl, acyl, -O-, -C1-6 alkylene CO2H , -C1-6 alkylene SO3H , -SO3H , -PO3H2 , -C1-6 alkylene -NHC1-6 alkyl, -C1-6 alkylene -N( C1-6 alkyl) 2 , -CH2N ( C1-6 alkyl)-C(=O) C1-6 alkylene-heterocyclic, -C1-6 alkylene-heterocyclic, -NHC1-6 alkylene- SO3H , -CH₂NH - SO₃H , -CH₂N (C₁ - 6alkyl )-SO₃H, -CH₂NHC₁- 6alkylene -SO₃H, -CH₂N ( C₁ - 6alkyl) C₁- 6alkylene-SO₃H, -CH₂N (C₁-6alkylene-SO₃H) ₂ , -CH₂N ( C₁- 6alkylene -SO₃H) ₃ , -CH₂N( C₁ - 6alkyl ) ₂ - C₁ -6alkylene-SO₃H, -CH₂N (C₁ - 6alkyl) -C ( ＝O) C₁- 6alkylene -N(C₁ - 6alkylene- SO₃H ) ₃ , -CH₂NH -C(＝O)C₁ - 6alkylene-N(C₁ - 6alkylene- SO₃H ) ₃ , -CH₂N (C₁ - 6alkylene- SO₃H )₃ 1-6 alkyl)-C(＝O)C 1-6 alkylene-N(C 1-6 alkyl) 3 , -CH 2 NH-C(＝O)C 1-6 alkylene-N(C 1-6 alkyl) 3 , -CH 2 N(C 1-6 alkyl)-C(＝O)OC 2-6 alkylene-N(C 1-6 alkyl) 3 , -CH 2 N(C 1-6 alkyl)-C(＝O)OC 2-6 alkylene-N(C 1-6 alkyl) 2 -CH 2 CO 2 H, -CH 2 N(C 1-6 alkyl)-C 1-6 alkylene-CO 2 H, -CH 2 N(C 1-6 alkyl) 2 -C 1-6 alkylene-CO 2 H, glucosyl, galactosyl, glucuronic acid, galacturonic acid, -CH 2 N(C 1-6 alkyl)-C(＝O)-(CH 2 CH 2 O)rC 1-6 alkyl, -CH 2 N(C 1-6 alkyl)-C(＝O)-(OCH 2 CH 2 )r-OC 1-6 alkyl, -(CH 2 N(Me)-C(＝O))rC 1-6 alkyl, polyethylene glycol fragments containing 1-10 EO units (i.e. -(CH 2 CH 2 O)r'-C 1-6 alkyl, r' = 1-10), DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid residue), DOTAGA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, α-propionyl), NOTA (1,4,7-triazacyclononane-N,N',N”-triacetic acid residue), EDTA (ethylenediaminetetraacetic acid residue), -C 1-6 alkylene-N(C 1-6 alkyl )-DOTA, -C 1-6 alkyl-N(C 1-6 alkyl)-DOTAGA, -C 1-6 alkyl-N(C 1-6 alkyl)-NOTA or -C 1-6 alkyl-N(C 1-6 alkyl )-EDTA, where r is selected from integers 1-20; s is selected from integers 1-20.
  3. The compound or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite, and prodrug, wherein the compound has a structure as shown in formula (II-a) or (II-b): in, XG, L1 , and CM are each independently as described in claim 1 or 2.
  4. A compound or its salt, ester, stereoisomer, or isotope label, wherein the compound has the following structure: Wherein, XG is as described in any one of claims 1 to 3.
  5. According to any one of claims 1-4, the compound has the following structure:
  6. A compound or its salt, ester, stereoisomer, or isotope label, wherein the compound has the following structure: in, XG is selected from fragments containing hydrophilic hydroxyl groups, glycosyl groups, amino groups, and carboxylic acid groups and their derivatives; Z is selected from the biologically active compound portion; E is selected from the segment connecting L2 and Z; CM is selected from structures that can react with specific functional groups in the target structure (such as an antibody); L2 is selected from the segment connecting parts CM, XG, and E; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; preferably, n is 1; Preferably, XG is selected from the following structural segments: Where m is selected from integers from 1 to 30; Alternatively, XG is selected from the following structural fragments: (For example: ), (For example: ); Preferably, the bioactive compound is selected from topoisomerase I inhibitors, topoisomerase II inhibitors, tubulin polymerization inhibitors, tubulin depolymerization inhibitors, DNA interference agents, DNA alkylating agents, DNA cross-linking agents, DNA polymerase inhibitors, DNA damage repair inhibitors, RNA polymerase inhibitors, thymidine synthase inhibitors, poly-ADP-ribose polymerase inhibitors, apoptosis promoters, cell cycle arrestors, protein degrading agents, synthetic lethal agents, kinase inhibitors, and glucocorticoid receptor modulators. Preferably, the bioactive compound is selected from camptothecin compounds, olritatin compounds, maytansine compounds, eribulin compounds, hammetrine compounds, epothilone compounds, kazimycin compounds, anthracycline compounds, benzodiazepine compounds, α-amaminoid compounds, sucrose compounds, alkaloid compounds, tripterygium compounds, nucleoside compounds, glucocorticoid compounds, rapamycin compounds, and lipolytamine compounds; Preferably, CM is selected from functional groups or structural fragments that can react with cysteine, lysine, glutamic acid, glutamine, aspartic acid, asparagine, tyrosine, serine, threonine, methionine, histidine, arginine, non-natural amino acids, glycosyl groups and their derivatives or analogs contained in the target structure. Preferably, CM is selected from the following substituted or unsubstituted structural segments: Preferably, L2 is selected from fragments composed of one or more of the following structures, including but not limited to C1-6 alkylene, C2-6 alkenylene, C2-6 alkyneene, carbonyl, sulfonyl, amino, hydroxyl, -O-, heterocyclic, heteroaryl, aryl, natural or non-natural amino acids and their polypeptides, polyethylene glycol, polysarcosine, carboxylic acid, glycosyl and their derivatives or quaternary ammonium salts; Preferably, L2 is selected from one or more of the following substituted or unsubstituted structural segments: C1-6 alkylene, 6-10 aryl, 5-6 heteroaryl, substituted or unsubstituted 9-12 nitrogen-containing heterocyclic group (e.g., substituted by one or more R'), -N(R')-, -NH(R'), -N(R') 2 , carbonyl, -O-, natural or non-natural amino acids and their analogues (e.g., Ala, Arg, Asn, Asp, Cit, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, D-Val, D-Leu, D-Ala, Lys(R'), Glu( R '), Lys( COCH2CH2 ( OCH2CH2 ) rOCH3) () and short peptides composed of amino acids (such as Gly-Lys, Asp-Gly-Gly-Phe-Gly (DGGFG), Glu-Gly-Gly-Phe-Gly (EGGFG), Ala-Ala, Ala-Lys, Ala-Lys (Ac), Ala-Pro, Gly-Glu, Gly-Gly, Phe-Lys, Phe-Lys (Ac), Val-Ala, Val-Cit, Val-Lys, Val-Lys (Ac), Ala-Ala-Ala, Ala-D-Ala-Ala, Ala-Ala-Asn, Ala-Ala-Gly, D-Leu-Al) a-Glu, Gly-Gly-Arg, Gly-Glu-Gly, Gly-Gly-Gly, Gly-Ser-Lys, Glu-Val-Ala, Glu-Val-Cit, Ser-D-Ala-Pro, Val-Leu-Lys, Val-Lys-Ala, Val-Ly s-Gly, Gly-Gly-Phe-Gly(GGFG), Gly-Gly-Val-Ala(GGVA), Gly-Phe-Leu-Gly(GFLG), Glu-Ala-Ala-Ala(EAAA), Gly-Gly-Gly-Gly-Gly(GGGGG)), Wherein R' is composed of one or more of the following groups, including but not limited to hydrogen, C1-6 alkyl, C1-6 alkylene, amino, hydroxyl, carboxyl, acyl, -O-, -C1-6 alkylene CO2H , -C1-6 alkylene SO3H , -SO3H , -PO3H2 , -C1-6 alkylene -NHC1-6 alkyl, -C1-6 alkylene -N( C1-6 alkyl) 2 , -CH2N ( C1-6 alkyl)-C(=O) C1-6 alkylene-heterocyclic, -C1-6 alkylene-heterocyclic, -NHC1-6 alkylene- SO3H , -CH₂NH - SO₃H , -CH₂N (C₁ - 6alkyl)-SO₃H, -CH₂NHC₁- 6alkylene -SO₃H, -CH₂N ( C₁ - 6alkyl) C₁ -6alkylene-SO₃H, -CH₂N (C₁-6alkylene-SO₃H) ₂ , -CH₂N (C₁ - 6alkylene -SO₃H) ₃ , -CH₂N( C₁- 6alkyl ) ₂ -C₁ -6alkylene-SO₃H, -CH₂N ( C₁ - 6alkyl) -C (＝O) C₁ - 6alkylene -N(C₁ - 6alkylene- SO₃H ) ₃ , -CH₂NH -C(＝O)C₁ - 6alkylene-N(C₁ - 6alkylene-SO₃H) ₃ , -CH₂N ( C₁- 6alkylene- SO₃H )₃ 1-6 alkyl)-C(＝O)C 1-6 alkylene-N(C 1-6 alkyl) 3 , -CH 2 NH-C(＝O)C 1-6 alkylene-N(C 1-6 alkyl) 3 , -CH 2 N(C 1-6 alkyl)-C(＝O)OC 2-6 alkylene-N(C 1-6 alkyl) 3 , -CH 2 N(C 1-6 alkyl)-C(＝O)OC 2-6 alkylene-N(C 1-6 alkyl) 2 -CH 2 CO 2 H, -CH 2 N(C 1-6 alkyl)-C 1-6 alkylene-CO 2 H, -CH 2 N(C 1-6 alkyl) 2 -C 1-6 alkylene-CO 2 H, glucosyl, galactosyl, glucuronic acid, galacturonic acid, -CH 2 N(C 1-6 alkyl)-C(＝O)-(CH 2 CH 2 O)rC 1-6 alkyl, -CH 2 N(C 1-6 alkyl)-C(＝O)-(OCH 2 CH 2 )r-OC 1-6 alkyl, -(CH 2 N(Me)-C(＝O))rC 1-6 alkyl, polyethylene glycol fragments containing 1-10 EO units (i.e. -(CH 2 CH 2 O)r'-C 1-6 alkyl, r' = 1-10), DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid residue), DOTAGA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, α-propionyl), NOTA (1,4,7-triazacyclononane-N,N',N”-triacetic acid residue), EDTA (ethylenediaminetetraacetic acid residue), -C 1-6 alkylene-N(C 1-6 alkyl)-DOTA, -C 1-6 alkyl-N(C 1-6 alkyl)-DOTAGA, -C 1-6 alkyl-N(C 1-6 alkyl)-NOTA or -C 1-6 alkyl-N(C 1-6 alkyl)-EDTA, where r is selected from integers 1-20; s is selected from integers 1-20; Preferably, E is selected from self-eliminating structures; Preferably, E is selected from single bonds, -NHCH 2 -, and -NHBn-O(＝O)-.
  7. According to claim 6, the compound has the following structure:
  8. A biologically active conjugate having the structure shown in any one of formulas (IA) to (IV-A): Alternatively, the coupling structure is as follows: Alternatively, the coupling structure is as follows: Alternatively, the coupling structure is as follows: in, CM' is selected from the structure that connects A; A is selected from antibodies or their antigen-binding fragments, peptides or small molecule fragments that have a targeting effect; x is between 1 and 10; Z, E, L1 , L2 , XG, Y, a, and n are as described in any one of claims 1 to 6; Preferably, CM' is selected from functional groups or structural fragments that have reacted with cysteine, lysine, glutamic acid, glutamine, aspartic acid, asparagine, tyrosine, serine, threonine, methionine, histidine, arginine, non-natural amino acids, glycosyl groups and their derivatives or analogs contained in the Ab structure. Preferably, CM' is selected from C1-6 alkylene-substituted acyl groups, substituted or unsubstituted succinimide groups, substituted or unsubstituted heteroaryl groups, and 3-6 membered heterocyclic acyl groups; Preferably, CM' is selected from acyl, succinimide, substituted or unsubstituted pyrimidinyl, and piperidinyl. Preferably, CM' is selected from the following substituted or unsubstituted structural segments: Preferably, the Ab is selected from antibodies that target tumor antigens, such as monoclonal or bispecific antibodies targeting Her2, Her3, EGFR, TROP2, B7H3, c-Met, CEACAM5, CLDN18.2, FRa, CDH6, CDH3, PTK7, DLL3, GPC3, etc. Preferably, A is selected from antibodies that target tumor antigens, such as trastuzumab antibody, patocilizumab antibody, etc. Preferably, A is selected from polypeptides that target tumor antigens, such as somatostatin analogs, GnRH/LHRH analogs, angiotensin-2, Heptaarginine, TAT47-57, DPV1047 Vectocell peptide, polypeptides that target EphA2, GPC3 or Nectin-4, etc. Preferably, A is selected from small molecule fragments that target tumor antigens, such as N-acetylgalactosamine (GalNAc) fragments, bisphosphonate fragments with bone targeting, fragments that selectively bind to prostate-specific membrane antigen (PSMA), fragments that selectively bind to somatostatin receptors, etc.
  9. According to claim 8, the coupling structure is as follows: Wherein, Ab-(S-) represents the antibody or its antigen-binding fragment, This indicates the specific linkage between the thiol group and the pyrimidine group in the antibody or its antigen-binding fragment.
  10. The composition comprising one or more conjugates as described in claim 8 or 9, wherein the DAR value (drug-antibody conjugate ratio) of the composition is 1-10, for example: 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 2-3, 2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, 3-4, 3-5, 3 ~6, 3~7, 3~8, 3~9, 3~10, 4~5, 4~6, 4~7, 4~8, 4~9, 4~10, 5~6, 5~7, 5~8, 5~9, 5~10, 6~7, 6~8, 6~9, 6~10, 7~8, 7~9, 7~10, 8~9, 8~10, or 9~10, preferably 3~8, for example, 3.0~3.5, 3.0~4.0. 3.0–4.5, 3.0–5.0, 6.0–6.5, 6.0–7.0, 6.0–7.5, 6.0–8.0, 6.0–8.5, 6.5–7.0, 6.5–7.5, 6.5–8.0, 6.5–8.5, 7.0–7.5, 7.0–8.0 or 7.5–8.0; or, the DAR of the composition is about 6.0 to 9.0, preferably. Approximately 6.0-8.0, for example, approximately 6.0, approximately 6.01, approximately 6.02, approximately 6.03, approximately 6.04, approximately 6.05, approximately 6.06, approximately 6.07, approximately 6.08, approximately 6.09, approximately 6.1, approximately 6.11, approximately 6.12, approximately 6.13, approximately 6.14, approximately 6.15, approximately 6.16, approximately 6.17, approximately 6.18, approximately 6.19, approximately 6.2, approximately 6.2 1. Approximately 6.22, 6.23, 6.24, 6.25, 6.26, 6.27, 6.28, 6.29, 6.3, 6.31, 6.32, 6.33, 6.34, 6.35, 6.36, 6.37, 6.38, 6.39, 6.4, 6.41, 6.42, 6.43, 6.44 Approximately 6.45, 6.46, 6.47, 6.48, 6.49, 6.5, 6.51, 6.52, 6.53, 6.54, 6.55, 6.56, 6.57, 6.58, 6.59, 6.6, 6.61, 6.62, 6.63, 6.64, 6.65, 6.66, 6.67. Approximately 6.68, 6.69, 6.7, 6.71, 6.72, 6.73, 6.74, 6.75, 6.76, 6.77, 6.78, 6.79, 6.8, 6.81, 6.82, 6.83, 6.84, 6.85, 6.86, 6.87, 6.88, 6.89, 6.9, 6 .91, approximately 6.92, approximately 6.93, approximately 6.94, approximately 6.95, approximately 6.96, approximately 6.97, approximately 6.98, approximately 6.99, approximately 7.0, approximately 7.01, approximately 7.02, approximately 7.03, approximately 7.04, approximately 7.05, approximately 7.06, approximately 7.07, approximately 7.08, approximately 7.09, approximately 7.1, approximately 7.11, approximately 7.12, approximately 7.13, approximately 7.1 4. Approximately 7.15, 7.16, 7.17, 7.18, 7.19, 7.2, 7.21, 7.22, 7.23, 7.24, 7.25, 7.26, 7.27, 7.28, 7.29, 7.3, 7.31, 7.32, 7.33, 7.34, 7.35, 7.36, 7.37 Approximately 7.38, approximately 7.39, approximately 7.4, approximately 7.41, approximately 7.42, approximately 7.43, approximately 7.44, approximately 7.45, approximately 7.46, approximately 7.47, approximately 7.48, approximately 7.49, approximately 7.5, approximately 7.51, approximately 7.52, approximately 7.53, approximately 7.54, approximately 7.55, approximately 7.56, approximately 7.57, approximately 7.58, approximately 7.59, approximately 7.6, approximately 7.61, approximately 7.62, approximately 7.63, approximately 7.64, approximately 7.65, approximately 7.66, approximately 7.67, approximately 7.68, approximately 7.69, approximately 7.7, approximately 7.71, approximately 7.72, approximately 7.73, approximately 7.74, approximately 7.75, approximately 7.76, approximately 7.77, approximately 7.78, approximately 7.79, approximately 7.8, approximately 7.81, approximately 7.82, approximately 7.83, approximately 7 .84, approximately 7.85, approximately 7.86, approximately 7.87, approximately 7.88, approximately 7.89, approximately 7.9, approximately 7.91, approximately 7.92, approximately 7.93, approximately 7.94, approximately 7.95, approximately 7.96, approximately 7.97, approximately 7.98, approximately 7.99, approximately 8.0, approximately 8.01, approximately 8.02, approximately 8.03, approximately 8.04, approximately 8.05, approximately 8.06, approximately 8.0 7, approximately 8.08, approximately 8.09, approximately 8.1, approximately 8.11, approximately 8.12, approximately 8.13, approximately 8.14, approximately 8.15, approximately 8.16, approximately 8.17, approximately 8.18, approximately 8.19, approximately 8.2, approximately 8.21, approximately 8.22, approximately 8.23, approximately 8.24, approximately 8.25, approximately 8.26, approximately 8.27, approximately 8.28, approximately 8.29, approximately 8.3, Approximately 8.31, 8.32, 8.33, 8.34, 8.35, 8.36, 8.37, 8.38, 8.39, 8.4, 8.41, 8.42, 8.43, 8.44, 8.45, 8.46, 8.47, 8.48, 8.49, 8.5, 8.51, 8.52, 8.53, 8 .54, approximately 8.55, approximately 8.56, approximately 8.57, approximately 8.58, approximately 8.59, approximately 8.6, approximately 8.61, approximately 8.62, approximately 8.63, approximately 8.64, approximately 8.65, approximately 8.66, approximately 8.67, approximately 8.68, approximately 8.69, approximately 8.7, approximately 8.71, approximately 8.72, approximately 8.73, approximately 8.74, approximately 8.75, approximately 8.76, approximately 8. 77, approximately 8.78, approximately 8.79, approximately 8.8, approximately 8.81, approximately 8.82, approximately 8.83, approximately 8.84, approximately 8.85, approximately 8.86, approximately 8.87, approximately 8.88, approximately 8.89, approximately 8.9, approximately 8.91, approximately 8.92, approximately 8.93, approximately 8.94, approximately 8.95, approximately 8.96, approximately 8.97, approximately 8.98, approximately 8.99, approximately 9.0.
  11. A pharmaceutical composition comprising the antibody-drug conjugate of claim 8 or 9 or the composition of claim 10, and one or more pharmaceutical excipients.
  12. Use of the antibody-drug conjugate of claim 8 or 9, the composition of claim 10, or the pharmaceutical composition of claim 11 in the preparation of a medicament for treating cancer.
  13. The use according to claim 12, wherein the cancer is selected from solid tumors or hematologic malignancies; for example, selected from gastric cancer, breast cancer, lung cancer (e.g., non-small cell lung cancer, specifically lung adenocarcinoma) and urothelial carcinoma.
  14. The antibody-drug conjugate of claim 8 or 9, the composition of claim 10, or the pharmaceutical composition of claim 11, for the treatment of Her2-expressing cancers.
  15. The antibody-drug conjugate of claim 8 or 9, the composition of claim 10, or the pharmaceutical composition of claim 11 are for the treatment of solid tumors or hematologic malignancies, such as gastric cancer, breast cancer, lung cancer (e.g., non-small cell lung cancer, specifically lung adenocarcinoma) or urothelial carcinoma.

Description

Hydrophilic linkers and their conjugates, as well as related preparation methods and applications This application is based on the following applications filed on November 1, 2024: CN application number 202411554776.8; CN application number 202411554395.X; CN application number 202411554571.X; CN application number 202411582899.2; CN application number 202411858078.7; and CN application number 202411859198. Based on and claiming priority to the following applications, the disclosures of the aforementioned applications are incorporated herein by reference in their entirety: .9 Application dated December 17, 2024; PCT application number PCT/CN2025/074725 application dated January 24, 2025; PCT application number PCT/CN2025/074728 application dated January 24, 2025; CN application number 202510163776.3 application dated February 14, 2025; and CN application number 202510784034.2 application dated June 12, 2025. Technical Field This invention relates to a class of hydrophilic linker compounds and their conjugates, as well as their preparation methods and applications in the pharmaceutical field. Background Technology Antibody-drug conjugates (ADCs) are composed of monoclonal antibodies targeting specific antigens and effector molecules linked together by a linker. An ADC consists of three main parts: an antibody responsible for selectively recognizing antigens on the surface of target cells, a payload responsible for killing target cells or regulating their function, and a linker connecting the antibody and the payload. The linker, acting as a bridge for the ADC drug, needs to possess good stability and hydrophilicity to prevent the effector molecule from breaking off or accumulating and being cleared from the bloodstream; simultaneously, the breakable linker must also be capable of specific release at specific sites, such as the tumor microenvironment. To enhance the hydrophilicity of ADCs, sugar, polyethylene glycol, and polysarcosine structures have been introduced into linkers. Among these, β-glucuronic acid is a typical structure of hydrophilic sugar linkers and is also a substrate for β-glucuronidase. Tumor cell lysosomes contain abundant β-glucuronidase, therefore using β-glucuronic acid as a linker is a feasible pathway for releasing effector molecules. Furthermore, due to the hydrophilic properties of β-glucuronic acid, linking it to some hydrophobic effector molecules can improve the hydrophilicity of ADCs. In 2006, Seattle Genetics reported a structure that carries oligristatin effector molecules via a β-glucuronic acid linker and its ADC (Bioconjugate Chem. 2006, 17, 3, 831-840. WO2007011968). In addition, carbohydrate fragments are embedded in the side chains of the structure between the linker coupling head and the enzyme digestion site to enhance the hydrophilicity of the ADC (WO2023280227 A2, WO2023208168 A1). To enhance the shielding or masking effect of the hydrophilic linker on the hydrophobicity of the effector molecule, polysarcosine structures have also been introduced into the linker (WO2019081455 A1, WO2022228493). Summary of the Invention This invention provides a novel drug linker containing hydrophilic hydroxyl, amino, and carboxylic acid fragments, which is expected to be used in research on antibody-drug conjugates, small molecule conjugates, etc. The first aspect of the present invention provides a compound or thereof, a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitride, isotope label, metabolite, and prodrug, wherein the compound has the following structure: in, Each time XG appears, it is independently selected from H, C1-6 alkyl, or substituents and their derivatives containing hydrophilic hydroxyl, glycosyl, amino, quaternary ammonium salt, sulfonyl and carboxylic acid segments; Y is selected from the segment connecting XG and the benzene ring; Z is selected from the portion of a biologically active compound; CM is selected from structures that can react with specific functional groups in the target structure (such as an antibody); L1 is selected from the fragment connecting CM and the aniline moiety; a can be 1, 2, or 3. In some embodiments, the compound has the following structure: in, Each time XG appears, it is independently selected from H, C1-6 alkyl, or substituents and their derivatives containing hydrophilic hydroxyl, glycosyl, amino, quaternary ammonium salt, sulfonyl and carboxylic acid segments; Y is selected from the segment connecting XG and the benzene ring; Z is selected from the portion of a biologically active compound; CM is selected from structures that can react with specific functional groups in the target structure (such as an antibody); L1 is selected from the fragment connecting CM and the aniline moiety; a can be 1, 2, or 3. In some embodiments, the compound has the following structure: in, Each time XG appears, it is independently selected from H, C1-6 alkyl, or substituents and their derivatives containing hydrophilic