CN118681035A - A ligand-drug conjugate and its preparation method and use - Google Patents

Abstract

The present invention discloses a class of ligand drug conjugates and preparation methods and uses thereof. The present invention provides a compound of formula I, a pharmaceutically acceptable salt, stereoisomer, solvate or a solvate of a pharmaceutically acceptable salt thereof. The antibody drug conjugate of the present invention has one or more of the following advantages: (1) The antibody drug conjugate of the present invention has high stability in circulation, reducing the shedding of non-target drugs in non-target cells; (2) The antibody drug conjugate of the present invention can increase the effective release of bioactive molecules in cells, achieving the purpose of increasing efficacy and reducing toxicity; (3) The antibody drug conjugate of the present invention has good tumor tissue targeting; (4) The antibody drug conjugate of the present invention has good therapeutic effects on tumor animal models.

Description

A ligand-drug conjugate and its preparation method and use

Technical Field

The present invention belongs to the field of medical technology and relates to a class of ligand-drug conjugates, and a preparation method thereof and use thereof in preventing and/or treating tumor-related diseases.

Background Art

Nucleoside antimetabolites are important drugs in cancer chemotherapy. Currently, the nucleoside drugs used in clinical practice, such as 5-fluorouracil (5-FU), 1-(2-deoxy-2-methylene-β-D-erythrofuranosyl) cytosine (DMDC), 2'-deoxy-2', 2'-difluorocytosine (gemcitabine), and 1-(2-C-cyano-2-deoxy-D-arabinosyl-furanosyl) cytosine (CNDAC), mainly act on the S phase of tumor cell DNA synthesis. However, chemotherapy drugs that only act on the S phase are not very effective in inhibiting some slow-growing solid tumors. One of the reasons is that this type of drug rarely has the opportunity to bind to non-replicating DNA (i.e., non-S phase). Therefore, it is not enough for nucleoside anti-tumor drugs to only inhibit tumor cell DNA synthesis. TAS-106 (ECyd, 3'-C-ethynylcytidine) is a nucleoside analog (WO199618636; J.Med.Chem.1996,39,5005-5011) that inhibits RNA synthesis in the entire cell cycle except the M phase by blocking RNA polymerase. In vitro and in vivo studies have shown that TAS-106 has strong antiproliferative activity against a variety of human tumor cells and tumor xenografts (Cancer Letters.116(1997),225-231; Oncology2013;85:356–363). The structural formula of TAS-106 is as follows:

Antibody-drug-conjugate (ADC) connects monoclonal antibodies or antibody fragments to biologically active cytotoxic drugs through stable chemical linker compounds, making full use of the specificity of antibodies binding to surface antigens of normal cells and tumor cells and the high efficiency of cytotoxic drugs, while avoiding the defects of low efficacy of the former and excessive toxic side effects of the latter. This means that compared with traditional chemotherapy drugs, antibody-drug conjugates can accurately bind to tumor cells and reduce the impact on normal cells (Mullard A, (2013) Nature Reviews Drug Discovery, 12: 329-332; DiJoseph JF, Armellino DC, (2004) Blood, 103: 1807-1814).

Commonly used toxins for ADCs are tubulin-interfering drugs and DNA-damaging drugs, including camptothecins, MMAEs, and T-DM1s, which mainly act on the S and G2 phases of DNA synthesis. However, these two types of toxins have their own limitations in use (e.g., DNA-damaging drugs have weak inhibitory effects on slowly proliferating tumor cells, and tubulin-interfering drugs have greater toxicity, etc.); in addition, some tumors that are primarily insensitive or secondarily resistant to these two types of toxins are also in urgent need of drugs with new mechanisms as the effective load of ADCs. ADCs with RNA polymerase inhibitor Amatoxin as the effective load have now entered clinical trials (HDP-101), but preclinical toxicology data show that the hematotoxicity and hepato-renal toxicity of Amatoxin result in a low maximum non-severe toxic dose (HNSTD) of its ADCs. Therefore, it is urgent to develop new toxins with new mechanisms, expand the types of toxins, and address unmet clinical needs.

The present invention designs and synthesizes a series of TAS-106 bioconjugates with significant anti-tumor activity for treating tumor-related diseases.

Summary of the invention

The present invention aims to provide a bioconjugate comprising a biological targeting portion and a TAS-106 portion as a cytotoxic agent, which has good inhibitory ability on tumor cells.

In a first aspect, the present invention provides a compound of formula I, a pharmaceutically acceptable salt, stereoisomer, solvate or a solvate of a pharmaceutically acceptable salt thereof:

Ab is a ligand that binds to the target (e.g., a small molecule ligand, a protein, an antibody or an antigen-binding fragment thereof, a peptide, a non-protein agent (e.g., a sugar, RNA, or DNA));

q is an integer or decimal from 1 to 16 (q is the drug loading amount);

L ¹ (L ¹ is a linker moiety, which reacts with any amino group, sulfhydryl group or other chemical functional group on the ligand to covalently connect the entire linker-payload to the ligand) is

^L2 ( ^L2 is a connecting unit) is -(C(R ^L21 R ^L22 ) _n -,

Where n is a natural number,

Any -C(R ^{L21 RL22} )- in L ² is each independently optionally replaced by the following structural units: -Cyr-, -N(R ^L23 )C(O)-, -C(O)N(R ^L23 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR ^L23 -, -O-, -S-, -SO-, -SO ₂ -, -P(R ^L23 )-, -P(＝O)(R ^L23 )-, -N(R ^L23 )SO ₂ -, -SO ₂ N(R ^L23 )-, -C(＝S)-, -C(＝NR ^L23 )-, -N＝N-, -C＝N-, -N＝C-, Instead,

-Cyr- is phenylene, 5- to 8-membered heteroarylene, 3- to 10-membered heterocyclylene or 3- to 10-membered cycloalkylene, wherein the -Cyr- is optionally substituted by 1 or more R ^cx ,

each of ^RL21 , ^RL22 , ^RL23 and ^Rcx is independently hydrogen, deuterium, halogen, _-NO2 , -CN, -OR ^L2a , -SR ^L2a , -N( ^RL2a ) ₂ , -C(O) ^RL2a , -CO2RL2a ^, -C(O)C( _O ) ^RL2a , -C(O) _CH2C (O) ^RL2a , -S(O) ^RL2a , -S(O) ^2RL2a , -C(O)N( ^RL2a ) ₂ , _-SO2N ( ^RL2a ) ₂ , -OC ₍ O) ^RL2a , -N( ^RL2a ) ^SO2RL2b , -N( ^RL2a )COR ^L2b , - _{( CH2} ) _y -CO-(N(Me) _CH2 C(O)) _m -OR ^L2a , -(CH ₂ ) _y -CO-(N(Me)CH ₂ C(O)) _m -NHR ^L2a , -(CH ₂ ) _y -CO-(N(Me)CH ₂ C(O)) _m -N ⁺ (R ^L2a ) ₃ , -(CH ₂ ) _y -NHCOCH ₂ (OCH ₂ CH ₂ )OR ^L2a , -(CH ₂ ) _y -NH (COCH ₂ (N(Me)) _m -R ^L2a , -(CH ₂ ) _y -CONH-(CH ₂ CH ₂ O) _m -R ^L2a , -(CH ₂ ) _y -NHCO-(CH ₂ CH ₂ O) _m -R ^L2a , -(CH ₂ CH ₂ O) _m -R ^L2a , -(COCH ₂ N(Me)) _m -R ^L2a , -COCH ₂ (OCH ₂ CH ₂ ) _m -OR ^L2a , -CO-(CH ₂ CH ₂ O) _m -R ^L2a , -CO-(CH ₂ ) _y -CONH-(CH ₂ CH ₂ O) _m -R ^L2a , -CO-(CH ₂ ) _y -NHCO-(CH ₂ CH ₂ ^O ) _m -R ^L2a , -C _1-6 alkyl, -C _2-6 alkenyl, -C 2-6 alkynyl, _3-8 membered cycloalkyl, 4-10 membered heterocycloalkyl, 6-10 membered aryl or 3-10 membered heteroaryl which is unsubstituted or substituted with one or more R L2a ,

Each m and y is independently a natural number from 0 to 40,

each ^RL2a and ^RL2b is independently hydrogen, deuterium, halogen, _-NO2 , -CN, -OH, -SH, _-NH2 , -N(Me) ₂ , _-CO2H , -S(O) _2Me , -S( _O ) _2OH , -C(O)NH2, _{-SO2NH2 , -C1-6alkyl} , _-C2-6alkenyl , -C2-6alkynyl, _3-8 membered cycloalkyl, 4-10 membered heterocycloalkyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

L ³ is a chemical bond or a short peptide consisting of 1 amino acid residue, 2-10 amino acid residues, One or more of, wherein the amino acid residue is a natural amino acid residue or a non-natural amino acid residue;

Tr is a chemical bond,

Each of R ^Tr , R ^Tr1 and R ^Tr2 is each independently hydrogen, deuterium, halogen, -NO ₂ , -CN, -OH, -SH, -NH ₂ , -CO ₂ H, -S(O) ₂ OH, -C(O)NH ₂ , -SO ₂ NH ₂ , -OC(O)NH ₂ , -CH ₂ CO-(N(Me)CH ₂ C(O)) _z -OR ^Tra , -CH ₂ CO-(N(Me)CH ₂ C(O)) _z -NHR ^Tra , -(CH 2 CH ₂ O) _z -R ^Tra , -CONH-(CH ₂ CH ₂ O) _z -R ^Tra , -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, 3-8 membered cycloalkyl, 4-10 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl _, the -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, 3-8 membered cycloalkyl, 4-10 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl. _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, 3-8 membered cycloalkyl, 4-10 membered heterocycloalkyl, 6-10 membered aryl and 5-10 membered heteroaryl are optionally substituted with one or more R ^Tra ;

R ^Tra is hydrogen, deuterium, halogen, -NO ₂ , -CN, -OH, -SH, -NH ₂ , -N(Me) ₂ , -S(O) ₂ Me, -CO ₂ H, -S(O) ₂ OH, -C(O)NH ₂ , -SO ₂ NH ₂ , -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, 3-8 membered cycloalkyl, 4-10 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl,

z is a natural number 0 or greater;

The heteroatoms in the 5- to 8-membered heteroarylene group, the 3- to 10-membered heterocyclylene group, the 5- to 10-membered heterocyclylene group and the 4- to 10-membered heterocycloalkyl group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4.

In some embodiments, in the compound of Formula I, its pharmaceutically acceptable salt, stereoisomer solvate or pharmaceutically acceptable salt solvate, certain groups have the following definitions, and the definitions of the unmentioned groups are as described in any scheme of the present invention (this paragraph is hereinafter referred to as "in some embodiments").

In some embodiments, Ab is a target-binding polypeptide, antibody, or antigen-binding fragment thereof.

In some embodiments, Ab is an antibody or an antigen-binding fragment thereof.

In some embodiments, the antibody is a fully human antibody, a humanized antibody, a chimeric antibody, a probody, a bispecific antibody, a multispecific antibody, a monoclonal antibody or a polyclonal antibody.

In some embodiments, the antigen-binding fragment is Fab, Fab', F(ab')2, Fv, scFv, diabody, Fd, dAb, VHH, single antibody or complementarity determining region (CDR) fragment.

In some embodiments, Ab is a monoclonal antibody.

In some embodiments, the Ab specifically binds to an antigen selected from the group consisting of 5T4, AGS-16, ANGPTL4, ApoE, CD19, CTGF, CXCR5, FGF2, MCPT8, MFI2, MS4A7, NCA, Sema5b, SLITRK6, STC2, TGF, 0772P, 5T4, ACTA2, ADGRE1, AG-7, AIF1, AKR1C1, AKR1C2, ASLG659, Axl, B7H3, BAFF-R, BCMA, BMPR1B, BNIP3, C1QA, C1QB, CA6, CADM1, CCD79b, CCL5, CCR5, CCR7, CD1lc, CD123, CD138, CD142, CD147, CD166, CD19, CD19, CD22, CD21, CD20, CD205, CD22 ,CD223, CD228, CD25, CD30, CD33, CD37, CD38, CD40, CD45, CD45(PTPRC), CD46, CD47, CD49D(ITGA4), CD56, CD66e, CD70, CD71, CD72, CD74, CD79a, CD79b, CD80, CDCP1, CDH11, CDllb, CEA, CEACAM5, c-Me t, COL6A3, COL7A1, CRIPTO, CSF1R, CTSD, CTSS, CXCL11, CXCL10, DDIT4, DLL3, DLL4, DR5, E16, EFNA4, EGFR, EGFRvIII, EGLN, EGLN3, EMR2, ENPP3, EpCAM, EphA2, EphB2R, ETBR, FcRH2, FcRHl, FGFR2, FGFR3 , FLT3, FOLR-α, GD2, GEDA, GPC-1, GPNMB, GPR20, GZMB, HER2, HER3, HLA-DOB, HMOX1, IFI6, IFNG, IGF-1R, IGFBP3, IL10RA1, IL-13R, IL-2, IL20Ra, IL-3, IL-4, IL-6, IRTA2, KISS1R, KRT33A, LIV-1, L OX, LRP-1, LRRC15, LUM, LY64, LY6E, Ly86, LYPD3, MDP, MMP10, MMP14, MMP16, MPF, MSG783, MSLN, MUC-1, NaPi2b, Napi3b, Nectin-4, Nectin-4, NOG, P2X5, pCAD, P-Cadherin, PDGFRA, PDK1, PD-L1, PF KFB3, PGF, PGK1, PIK3AP1, PIK3CD, PLOD2, PSCA, PSCAhlg, PSMA, PSMA, PTK7, P-cadherin, RNF43, NaPi2b, ROR1, ROR2, SERPINE1, SLC39A6, SLTRK6, STAT1, STEAP1, STEAP2, TCF4, TENB2, TGFB1, TGFB2, TGFBR1, TNFRSF21, TNFSF9, Trop-2, TrpM4, Tyro7, UPK1B, VEGFA, WNT5A, epidermal growth factor, brevican, mesothelin, sodium phosphate cotransporter 2B, Claudin18.2, endotenin receptor, mucins (such as mucin 1 and mucin 16), guanylate cyclase C, integrin a4p7, integrin a5p6, trophoblast glycoprotein, or tissue factor.

In some embodiments, the Ab specifically binds to an antigen selected from the group consisting of 5T4, AGS-16, ANGPTL4, ApoE, CD19, CTGF, CXCR5, FGF2, MCPT8, MFI2, MS4A7, NCA, Sema5b, SLITRK6, STC2, TGF, 0772P, 5T4, ACTA2, ADGRE1, AG-7, AIF1, AKR1C1, AKR1C2, ASLG659, Axl, B7H3, BAFF-R, BCMA, BMPR1B, BNIP3, C1QA, C1QB, CA6, CADM1, CCD79b, CCL5, CCR5, CCR7, CD1lc, CD123, CD138, CD142, CD147, CD166, CD19, CD19, CD22, CD21, CD20, CD205, CD22 ,CD223,C D228, CD25, CD30, CD33, CD37, CD38, CD40, CD45, CD45(PTPRC), CD46, CD47, CD49D(ITGA4), CD56, CD66e, CD70, CD71, CD72, CD74, CD79a, CD79b, CD80, CDCP1, CDH11, CDllb, CEA, CEACAM5, c- Met, COL6A3, COL7A1, CRIPTO, CSF1R, CTSD, CTSS, CXCL11, CXCL10, DDIT4, DLL3, DLL4, DR5, E16, EFNA4, EGFR, EGFRvIII, EGLN, EGLN3, EMR2, ENPP3, EpCAM, EphA2, EphB2R, ETBR, FcRH2, FcRHl, FGFR2, FGFR3 , FL T3, FOLR-α, GD2, GEDA, GPC-1, GPC-3, GPNMB, GPR20, GZMB, HER2, HER3, HLA-DOB, HMOX1, IFI6, IFNG, IGF-1R, IGFBP3, IL10RA1, IL-13R, IL-2, IL20Ra, IL-3, IL-4, IL-6, IRTA2, KISS1R, KRT33A, LIV- 1, LOX, LRP-1, LRRC15, LUM, LY64, LY6E, Ly86, LYPD3, MDP, MMP10, MMP14, MMP16, MPF, MSG783, MSLN, MUC-1, NaPi2b, Napi3b, Nectin-4, Nectin-4, NOG, P2X5, pCAD, P-Cadherin, PDGFRA, PDK1, PD- L1, PFKFB3, PGF, PGK1, PIK3AP1, PIK3CD, PLOD2, PSCA, PSCAhlg, PSMA, PSMA, PTK7, P-cadherin, RNF43, NaPi2b, ROR1, ROR2, SERPINE1, SLC39A6, SLTRK6, STAT1, STEAP1, STEAP2, TCF4, TENB2, TGFB1, TGFB2, TGFBR1, TNFRSF21, TNFSF9, Trop-2, TrpM4, Tyro7, UPK1B, VEGFA, WNT5A, epidermal growth factor, brevican, mesothelin, sodium phosphate cotransporter 2B, Claudin18.2, endotenin receptor, mucins (such as mucin 1 and mucin 16), guanylate cyclase C, integrin a4p7, integrin a5p6, trophoblast glycoprotein, or tissue factor.

In some preferred embodiments, the Ab specifically binds to an antigen selected from the group consisting of HER2, HER3, B7H3, TROP2, Claudin18.2, CD30, CD33, CD70, or EGFR.

In some preferred embodiments, the Ab specifically binds to an antigen selected from the group consisting of HER2, HER3, B7H3, TROP2, Claudin18.2, CD30, CD33, CD70, EGFR, or GPC-3.

In some embodiments, the antibody is an anti-HER2 antibody (eg, Trastuzumab or Pertuzumab or variants thereof, or a Trop-2 antibody (eg, Sacituzumab, M1, M2 or M3) or variants thereof.

In some embodiments, the antibody is an anti-HER2 antibody (e.g., Trastuzumab or Pertuzumab or variants thereof, or a Trop-2 antibody (e.g., Sacituzumab, M1, M2 or M3) or variants thereof, or an anti-GPC-3 antibody (Codrituzumab) or variants thereof. Preferably, the antibody is an anti-HER2 antibody (e.g., Trastuzumab or Pertuzumab) or variants thereof, or an anti-GPC-3 antibody (e.g., Codrituzumab) or variants thereof.

In some embodiments, the antibody is trastuzumab.

In some embodiments, the antibody is trastuzumab or codrituzumab.

In some embodiments, q is an integer or decimal from 2 to 8, preferably an integer or decimal from 7 to 8, for example 7.8 or 7.9.

In some embodiments, q is 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9 or 7.96, for example 7.9 or 7.96.

In some embodiments, ^L1 is

Preferably, ^L1 is More preferably, ^L1 is

In some embodiments, ^L1 is Preferably,

In some embodiments, ^L1 is Among them, a is connected to the antibody and b is connected to ^L2 .

In some embodiments, ^L1 is Wherein, a is connected to the antibody, b is connected to ^L2 ; preferably, ^L1 is Wherein, a is connected to the antibody, b is connected to ^L2 ; preferably, Among them, a is connected to the antibody and b is connected to ^L2 .

In some embodiments, L ² is -(CHR ^L21 ) _n -;

Where n is a natural number from 0 to 20;

Any -CHR ^L21 - in ^L2 can be independently replaced by the following structural units: -Cyr-, -N(R ^L23 )C(O)-, -C(O)N(R ^L23 )-, -C(O)-, -NR ^L23 -, -O-, Replacement;

-Cyr- is phenylene, 5- to 6-membered heteroarylene, 4- to 10-membered heterocyclylene, or 3- to 6-membered cycloalkylene, wherein said -Cyr- is optionally substituted with 1 to 3 R ^cx ;

each of ^RL21 , ^RL23 and ^Rcx is independently hydrogen, halogen, -OR ^L2a , -N( ^RL2a ) ₂ , _-C (O) ^RL2a , -S(O) ^2RL2a , -C(O)N( ^RL2a ) ₂ , _-SO2N ( ^RL2a ) ₂ , -N( ^RL2a ) _SO2RL2b , -N( ^{RL2a )COR L2b ,} -( _CH2 ) _y -CO-(N(Me) _CH2C (O)) _m -OR ^L2a , -( _CH2 ) _y -CO-(N(Me) _CH2C (O)) _m -NHR ^L2a , -( _CH2 ) _y -CONH-( _CH2CH2O ) _m ^-RL2a _, -( _CH2 ) _y -NHCO-(CH ₂ CH ₂ O) _m -R ^L2a , -(CH ₂ ) _y -NHCOCH ₂ (OCH ₂ CH ₂ )OR ^L2a , -(CH ₂ ) _y -NH(COCH ₂ (N(Me)) _m -R ^L2a , -(CH ₂ ) _y -NHCO-(CH ₂ CH ₂ O) _m -R ^L2a , -(CH ₂ CH ₂ O) _m -R ^{L2 a} , -(COCH ₂ N(Me)) _m -R ^L2a , -COCH ₂ (OCH ₂ CH ₂ ) _m -OR ^L2a , -CO-(CH ₂ CH ₂ O) _m -R ^L2a , -C _1-6 alkyl, -C _2-6 alkenyl, -C R t R ; -C _1-6 alkyl, -C 2-6 alkenyl, -C _2-6 alkynyl, 3-8 cycloalkyl, 4-10 heterocycloalkyl, 6-10 aryl or 5-10 heteroaryl; the -C _1-6 alkyl, -C 2-6 alkenyl, -C _2-6 alkynyl, 3-8 cycloalkyl, 4-10 heterocycloalkyl, 6-10 aryl and 5-10 heteroaryl are optionally substituted with one or more R ^{t R} ;

m is a natural number from 0 to 8;

y is 0, 1, 2, 3, 4;

Each ^RL2a , ^RL2b is independently selected from hydrogen, halogen, -CN, -OH, _-NH2 , -N(Me) ₂ , _-CO2H , -C(O) _NH2 or _-C1-6alkyl ;

The heteroatoms in the 5- to 6-membered heteroarylene group, the 4- to 10-membered heterocyclylene group and the 4- to 10-membered heterocycloalkyl group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4.

In some embodiments, L ² is -(CH ₂ ) _n -;

Where n is a natural number from 0 to 14;

Any -CH ₂ - in L ² may be independently replaced by the following structural units: phenylene, 5- to 6-membered heteroarylene, 4- to 6-membered heterocyclylene, 3- to 6-membered cycloalkylene, -N(R ^L23 )C(O)-, -C(O)N(R ^L23 )-, -C(O)-, -NR ^L23 -, -O-, Replacement;

Each R ^L23 is independently hydrogen, -OR ^L2a , -C(O)R ^L2a , -S(O) ₂ R ^L2a , -C(O)N(R ^L2a ) ₂ , -SO ₂ N(R ^L2a ) ₂ , -(CH ₂ ) _y -CO-(N(Me)CH ₂ C(O)) _m -OR ^L2a , -(CH ₂ ) _y -CO-(N(Me)CH ₂ C(O)) _m -NHR ^L2a , -(CH ₂ ) _y -CONH-(CH ₂ CH ₂ O) _m -R ^L2a , -(CH ₂ ) _y -NHCOCH ₂ (OCH ₂ CH ₂ )OR ^L2a , -(CH ₂ CH ₂ O) _m -R ^L2a , -(COCH ₂ N(Me)) _m -R ^L2a , -COCH ₂ (OCH ₂ CH ₂ ) _m -OR ^L2a , -CO-(CH ₂ CH ₂ O) _m -R ^L2a , or -C _1-6 alkyl; the -C _1-6 alkyl is optionally substituted by one or more Several were replaced by R ^L2a ;

m is a natural number from 0 to 8;

y is 0, 1, 2, 3, or 4;

Each ^RL2a is independently selected from hydrogen, halogen, -CN, -OH, _-NH2 , -N(Me) ₂ , _-CO2H , -C(O) _NH2 or _-C1-6alkyl ;

The heteroatoms of the 5- to 6-membered heteroarylene group and the 4- to 6-membered heterocyclylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3.

In some embodiments, L ² is -(CHR ^L21 ) _n -;

Where n is a natural number from 1 to 10;

Any -CHR ^L21 - in L ² may be independently replaced by the following structural units: -Cyr-, -N(R ^L23 )C(O)-, -C(O)N(R ^L23 )-, -C(O)-, -NR ^L23 - or -O-;

-Cyr- is a 4- to 6-membered heterocyclylene group or a 3- to 6-membered cycloalkylene group;

Each of ^RL21 and ^RL23 is independently hydrogen or -( _CH2CH2O ) _m - ^RL2a _;

m is a natural number from 0 to 4;

Each R ^L2a is hydrogen;

The heteroatoms in the 4- to 6-membered heterocyclylene group are selected from one or more of N, O and S, and the number of the heteroatoms is 1, 2, 3 or 4.

In some embodiments, L ² is -(CHR ^L21 ) _n -;

wherein n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

Any -CHR ^L21 - in L ² may be independently replaced by the following structural units: -Cyr-, -C(O)-, -NR ^L23 - or -O-;

-Cyr- is a 4- to 6-membered heterocyclylene group or a 3- to 6-membered cycloalkylene group; the heteroatom in the 4- to 6-membered heterocyclylene group is N, and the number of heteroatoms is 1 or 2;

Each of ^RL21 and ^RL23 is independently hydrogen or -( _CH2CH2O ) _m - ^RL2a _;

m is 0, 1, 2, 3 or 4;

Each R ^L2a is hydrogen.

In some embodiments, any -CHR ^L21 - in L ² can be independently replaced by the following structural units: -Cyr-, -N(R ^L23 )C(O)-, -C(O)N(R ^L23 )-, -C(O)-, -NR ^L23 - or -O-.

In some embodiments, any -CHR ^L21 - in L ² can be independently replaced by the following structural units: -Cyr-, -C(O)-, -NR ^L23 - or -O-.

In some embodiments, -Cyr- is a 4- to 6-membered heterocyclylene or a 3- to 6-membered cycloalkylene.

In some embodiments, -Cyr- is a 4- to 6-membered heterocyclylene group or a 3- to 6-membered cycloalkylene group, wherein the heteroatom in the 4- to 6-membered heterocyclylene group is N, and the number of heteroatoms is 1 or 2.

In some embodiments, _each of ^RL21 , ^RL23 , and ^Rcx is independently hydrogen or -( _CH2CH2O ) _m - ^RL2a .

In some embodiments, ^L2 is

Each of t1, t2, t3, t4 and m is independently an integer from 0 to 8;

Each t5 and t6 is independently 0 or 1;

-Cyr- is a 4- to 6-membered heterocyclylene group or a 3- to 6-membered cycloalkylene group; preferably, -Cyr- is Further preferably, -Cyr- is

In some embodiments, Cyr- is Further preferably, -Cyr- is

In some embodiments, ^L2 is (the left side of the group reading sequence is connected to L ¹ , and the right side of the reading sequence is connected to L ³ );

Each of t1, t3 and m is independently 0, 1, 2 or 3;

Each t2 is independently 0 or 1;

Each t5 is independently 0 or 1;

1 for every t6;

-Cyr- is a 4- to 6-membered heterocyclylene group or a 3- to 6-membered cycloalkylene group; the heteroatom in the 4- to 6-membered heterocyclylene group is N, and the number of the heteroatoms is 1 or 2.

In some embodiments, ^L2 is (the left side of the group reading sequence is connected to L ¹ , and the right side of the reading sequence is connected to L ³ );

Each of t1 and t3 is independently 0, 1, 2 or 3;

Each t2 is independently 0 or 1;

Each t5 is independently 0 or 1;

Every t6 is 1;

-Cyr- is a 4- to 6-membered heterocyclylene group or a 3- to 6-membered cycloalkylene group; the heteroatom in the 4- to 6-membered heterocyclylene group is N, and the number of the heteroatoms is 1 or 2.

In some embodiments, ^L2 is (the left side of the group reading sequence is connected to L ¹ , and the right side of the reading sequence is connected to L ³ );

Each of t1 and t3 is independently 0, 1, 2 or 3;

Each t2 is independently 0 or 1;

Each t5 is independently 0 or 1;

Every t6 is 1.

In some preferred embodiments, for

In some preferred embodiments, for Preferably, More preferably,

In some preferred embodiments, for Among them, c is connected to _L1 and d is connected to ^L3 .

In some preferred embodiments, for Wherein, c is connected to _L1 , d is connected to ^L3 ; preferably, Wherein, c is connected to _L1 , d is connected to ^L3 ; more preferably, Among them, c is connected to _L1 and d is connected to ^L3 .

In some preferred embodiments, for

Each of t1, t2, t3, t4 and m is independently an integer from 0 to 8;

Each t5 and t6 is independently 0 or 1;

-Cyr- is a 4- to 6-membered heterocyclylene group or a 3- to 6-membered cycloalkylene group; preferably, -Cyr- is Further preferably, -Cyr- is In some preferred embodiments, for

(the left side of the group reading sequence is connected to Ab, and the right side of the reading sequence is connected to ^L3 );

Each of t1, t2, t3, t4 and m is independently an integer from 0 to 8;

Each t5 and t6 is independently 0 or 1;

-Cyr- is a 4- to 6-membered heterocyclylene group or a 3- to 6-membered cycloalkylene group.

In some preferred embodiments, for (The left side of the group reading sequence is connected to Ab, and the right side of the reading sequence is connected to ^L3 )

Each of t1, t3 and m is independently 0, 1, 2 or 3;

Each t2 is independently 0 or 1;

Each t5 is independently 0 or 1;

Every t6 is 1;

-Cyr- is a 4- to 6-membered heterocyclylene group or a 3- to 6-membered cycloalkylene group; the heteroatom in the 4- to 6-membered heterocyclylene group is N, and the number of the heteroatoms is 1 or 2.

In some preferred embodiments, for

(the left side of the group reading sequence is connected to Ab, and the right side of the reading sequence is connected to ^L3 );

Each of t1, t3 and m is independently 0, 1, 2 or 3;

Each t2 is independently 0 or 1;

Each t5 is independently 0 or 1;

Every t6 is 1;

-Cyr- is a 4- to 6-membered heterocyclylene group or a 3- to 6-membered cycloalkylene group; the heteroatom in the 4- to 6-membered heterocyclylene group is N, and the number of the heteroatoms is 1 or 2.

In some preferred embodiments, for (the left side of the group reading sequence is connected to Ab, and the right side of the reading sequence is connected to ^L3 );

Each of t1 and t3 is independently 0, 1, 2 or 3;

Each t2 is independently 0 or 1;

Each t5 is independently 0 or 1;

Every t6 is 1.

In some preferred embodiments, for More preferably, for

In some preferred embodiments, for

Among them, position "1" is connected to Ab, and position "2" is connected to L ³ ;

Preferably, for Wherein, position "1" is connected to Ab, and position "2" is connected to L ³ ; further preferably, for Among them, the "1" position is connected to Ab, and the "2" position is connected to ^L3 .

In some preferred embodiments, L ³ is a chemical bond, 1 amino acid residue, a short peptide consisting of 2 to 7 amino acid residues, The amino acid residue is Val, D-Val, Nva, Phe, Lys, Leu, Ile, Gly, Ala, D-Ala, Cit, Asp, Asn, Glu, Gln, Pro, Arg, Lys(Ac), Lys(Me), Lys(Et), Lys(nPr), Nva or AA;

AA

In some preferred embodiments, ^L3 is a chemical bond, Val, D-Val, Phe, Lys, Leu, Ile, Gly, Ala, D-Ala, Cit, Asp, Asn, Glu, Gln, AA, Val-Cit, Val-Ala, Val-Lys, Val-Lys(Ac), Phe-Lys, Phe-Lys(Ac), Leu-Lys, Leu-Lys(Ac), Ala-Ala, D-Ala-Ala, Gly-Glu, Gly-Asp, Gly-Asn, Val-Glu, Val-Asp, Val-Asn, Asn-Asn, Val-AA, Ala-AA, Phe-AA, Glu-Val-Cit, Ala-Ala-Ala, Ala-(D-Ala)-Ala, Ala-Ala -Asn, Ala-(D-Ala)-Asn, Ala-Ala-Asp, Val-Lys-Gly, D-Val-Leu-Lys, Gly-Gly-Arg, Gly-Gly-Gly, Gly-Glu-Gly, Lys-Ala-Asn, Gly-Phe-Gly, Gly-Gly-Phe, Asn-Pro-Val, Val-AA-Gly, Ala-AA-Gly, Gly -AA-Gly, Gly-Gly-Gly-Gly, Gly-Gly-Phe-Gly, Gly-Gly-Glu-Gly, Lys-Ala-Ala-Asn, Lys-Ala-Ala-Asp, Ala-Ala-Pro-Val, Ala-Ala-Pro-Nva,

AA

In some preferred embodiments, ^L3 is a chemical bond, Val, D-Val, Phe, Lys, Leu, Ile, Gly, Ala, D-Ala, Cit, Asp, Asn, Glu, Gln, AA, Val-Cit, Val-Ala, Val-Lys, Val-Lys(Ac), Phe-Lys, Phe-Lys(Ac), Leu-Lys, Leu-Lys(Ac), Ala-Ala, D-Ala-Ala, Gly-Glu, Gly-Asp, Gly-Asn, Val-Glu, Glu-Gly, Val-Asp, Val-Asn, Asn-Asn, Val-AA, Ala-AA, Phe-AA, Glu-Val-Cit, Ala-Ala-Ala, Ala-(D-Ala)-Ala, Ala -Ala-Asn, Ala-(D-Ala)-Asn, Ala-Ala-Asp, Val-Lys-Gly, D-Val-Leu-Lys, Gly-Gly-Arg, Gly-Gly-Gly, Gly-Glu-Gly, Lys-Ala-Asn, Gly-Phe-Gly, Gly-Gly-Phe, Asn-Pro-Val, Val-AA-Gly, Ala-AA-Gly , Gly-AA-Gly, Gly-Gly-Gly-Gly, Gly-Gly-Phe-Gly, Gly-Gly-Glu-Gly, Lys-Ala-Ala-Asn, Lys-Ala-Ala-Asp, Ala-Ala-Pro-Val, Ala-Ala-Pro-Nva,

AA

In some preferred embodiments, ^L3 is a chemical bond, Lys, Cit, Asp, Asn, Glu, Gln, Val-Cit, Val-Ala, Ala-Ala, Gly-Glu, Gly-Asp, Gly-Asn, Asn-Asn, Gly-Glu-Gly, Gly-Gly-Phe-Gly, Val-Lys-Gly, Gly-Gly-Gly-Gly or Gly-Gly-Glu-Gly.

In some preferred embodiments, ^L3 is a chemical bond, Lys, Cit, Asp, Asn, Glu, Gln, Val-Cit, Val-Ala, Ala-Ala, Gly-Glu, Glu-Gly, Gly-Asp, Gly-Asn, Asn-Asn, Gly-Glu-Gly, Gly-Phe-Gly, Gly-Gly-Phe-Gly, Val-Lys-Gly, Gly-Gly-Gly-Gly or Gly-Gly-Glu-Gly.

In some preferred embodiments, ^L3 is a chemical bond, Val-Ala, Ala-Ala, Gly-Glu, Gly-Asn, Gly-Asp, Gly-Glu-Gly, Gly-Gly-Glu-Gly, or Gly-Gly-Phe-Gly.

In some preferred embodiments, ^L3 is a chemical bond, Val-Ala, Ala-Ala, Gly-Glu, Glu-Gly, Gly-Asn, Gly-Asp, Gly-Glu-Gly, Gly-Phe-Gly, Gly-Gly-Glu-Gly, or Gly-Gly-Phe-Gly.

In some preferred embodiments, ^L3 is a chemical bond, Val-Ala, Ala-Ala, Gly-Glu, Gly-Asn, Gly-Asp, Gly-Glu-Gly, Gly-Gly-Glu-Gly or Gly-Gly-Phe-Gly.

In some preferred embodiments, ^L3 is a chemical bond, Val-Ala, Ala-Ala, Gly-Glu, Glu-Gly, Gly-Asn, Gly-Asp, Gly-Glu-Gly, Gly-Phe-Gly, Gly-Gly-Glu-Gly or Gly-Gly-Phe-Gly; preferably, ^L3 is Glu-Gly, Val-Ala, Ala-Ala, Gly-Glu-Gly, Gly-Phe-Gly, Gly-Gly-Glu-Gly or Gly-Gly-Phe-Gly; more preferably, it is Glu-Gly, Val-Ala, Gly-Phe-Gly, Ala-Ala, Gly-Glu-Gly, Gly-Gly-Glu-Gly or Gly-Gly-Phe-Gly; most preferably, it is Gly-Gly-Phe-Gly.

In some preferred embodiments, for

In some preferred embodiments, for

In some preferred embodiments, for

The "1" position is connected to Ab, and the "2" position is connected to Tr;

Preferably,

The "1" position is connected to Ab, and the "2" position is connected to Tr;

More preferably, The "1" position is connected to Ab, and the "2" position is connected to Tr.

In some preferred embodiments, Tr is a chemical bond,

Each of R ^Tr , R ^Tr1 and R ^Tr2 is independently hydrogen, halogen, -NO ₂ , -CN, -OH, -NH ₂ , -CO ₂ H, -S(O) ₂ H, -C(O)NH ₂ , -SO ₂ NH ₂ , _-OC (O) _NH2 , _-CH2CO- (N(Me)CH2C(O)) _z - ^ORTra , _-CH2CO- (N(Me) _CH2C (O)) _z - ^NHRTra , -( _CH2CH2O ) _z - ^RTra , -CONH-( _CH2CH2O ) _z - ^RTra , or _{-C1-6alkyl ;} said _C1-6alkyl is optionally substituted with _one or more ^R3a ;

R ^3a is hydrogen, deuterium, halogen, -NO ₂ , -CN, -OH, -NH ₂ , -N(Me) ₂ , -S(O) ₂ Me, -CO ₂ H, -S(O) ₂ OH, -C(O)NH ₂ , -SO ₂ NH ₂ , or -C _1-6 alkyl;

z is an integer of 0 or greater.

In some preferred embodiments, Tr is a chemical bond or The "1" position is connected to ^L3 , and the "2" position is connected to TAS-106; each of R ^Tr1 and R ^Tr2 is independently hydrogen, deuterium, halogen or -C _1-6 alkyl; more preferably, R ^Tr1 and R ^Tr2 are hydrogen or deuterium.

In some preferred embodiments, Tr is The "1" position is connected to ^L3 , the "2" position is connected to TAS-106, and R ^Tr1 and R ^Tr2 are hydrogen or deuterium.

In some preferred embodiments, Tr is a chemical bond,

In some preferred embodiments, Tr is a chemical bond or More preferably,

In some preferred embodiments, Tr is a chemical bond, Among them, e is connected to L ³ and f is connected to TAS-106.

In some preferred embodiments, Tr is a chemical bond or wherein, e is connected to L ³ , and f is connected to TAS-106; more preferably, Among them, e is connected to L ³ and f is connected to TAS-106.

In some preferred embodiments, -TAS-106 is Preferably

In some preferred embodiments, Tr is a chemical bond,

In some embodiments, the compound represented by Formula I is a compound represented by Formula (Ia) or Formula (Ib):

in,

Ab, L ¹ , L ² , L ³ , q and Tr are defined as in any one of the schemes of formula (I).

In some preferred embodiments, the Ab is a target-binding polypeptide, an antibody or an antigen-binding fragment thereof; preferably, the Ab is an antibody or an antigen-binding fragment thereof; more preferably, the Ab is trastuzumab or Trop-2 antibody (Sacituzumab);

q is an integer or decimal from 1 to 16; preferably, q is an integer or decimal from 2 to 8; for example, q is an integer or decimal from 7 to 8;

^L1 is

^L2 is -(CHR ^L21 ) _n -;

Where n is a natural number from 1 to 10;

Any -CHR ^L21 - in L ² may be independently replaced by the following structural units: -Cyr-, -N(R ^L23 )C(O)-, -C(O)N(R ^L23 )-, -C(O)-, -NR ^L23 - or -O-;

-Cyr- is a 4- to 6-membered heterocyclylene group or a 3- to 6-membered cycloalkylene group; the heteroatom of the heterocycloalkyl group is N, and the number of heteroatoms is 1 or 2;

Each of ^RL21 and ^RL23 is independently hydrogen or -(CH ₂ CH ₂ O) _m ^-RL2a ; m is a natural number from 0 to 4; each ^RL2a is hydrogen;

L ³ is a chemical bond, Val-Ala, Ala-Ala, Gly-Glu, Gly-Asn, Gly-Asp, Gly-Glu-Gly, Gly-Gly-Glu-Gly or Gly-Gly-Phe-Gly;

Tr is a chemical bond,

In some preferred embodiments, the Ab is an anti-HER2 antibody or a variant thereof, or an anti-GPC-3 antibody or a variant thereof;

q is an integer or decimal between 7 and 8;

^L1 is

^L2 is

Each of t1, t3 and m is independently 0, 1, 2 or 3;

Each t2 is independently 0 or 1;

Each t5 is independently 0 or 1;

Every t6 is 1;

-Cyr- is a 4- to 6-membered heterocyclylene group or a 3- to 6-membered cycloalkylene group; the heteroatom in the 4- to 6-membered heterocyclylene group is N, and the number of heteroatoms is 1 or 2;

L ³ is Glu-Gly, Val-Ala, Ala-Ala, Gly-Glu-Gly, Gly-Phe-Gly, Gly-Gly-Glu-Gly or Gly-Gly-Phe-Gly;

Tr is a chemical bond or wherein the "1" position is connected to L ³ , and the "2" position is connected to TAS-106; each of R ^Tr1 and R ^Tr2 is independently hydrogen, deuterium, halogen or -C _1-6 alkyl;

-TAS-106

In some preferred embodiments, the Ab is an anti-HER2 antibody or a variant thereof, or an anti-GPC-3 antibody or a variant thereof;

q is an integer or decimal between 7 and 8;

for

Each of t1, t3 and m is independently 0, 1, 2 or 3;

Each t2 is independently 0 or 1;

Each t5 is independently 0 or 1;

1 for every t6;

-Cyr- is a 4- to 6-membered heterocyclylene group or a 3- to 6-membered cycloalkylene group; the heteroatom in the 4- to 6-membered heterocyclylene group is N, and the number of heteroatoms is 1 or 2;

L ³ is Glu-Gly, Val-Ala, Ala-Ala, Gly-Glu-Gly, Gly-Phe-Gly, Gly-Gly-Glu-Gly or Gly-Gly-Phe-Gly;

Tr is a chemical bond or The "1" position is connected to ^L3 , and the "2" position is connected to TAS-106; each R ^Tr1 and R ^Tr2 is independently hydrogen or deuterium;

-TAS-106

In some preferred embodiments, the Ab is trastuzumab or codrituzumab;

q is an integer or decimal between 7 and 8;

for

Each of t1 and t3 is independently 0, 1, 2 or 3;

Each t2 is independently 0 or 1;

Each t5 is independently 0 or 1;

Every t6 is 1;

L3 is Gly-Gly-Phe-Gly;

Tr is The "1" position is connected to L ³ , the "2" position is connected to TAS-106, and R ^Tr1 and R ^Tr2 are hydrogen or deuterium;

-TAS-106

In the present invention, -S- in the compound is a sulfhydryl sulfur atom generated by reduction of disulfide bonds in the antibody or a sulfhydryl sulfur atom generated by antibody modification; -NH- in the compound is a part of the amino group in the lysine residue of the antibody.

In some preferred embodiments, the compound of formula I is any of the following compounds:

In some preferred embodiments, the compound of formula I is any of the following compounds:

q is an integer or decimal from 1 to 16, preferably an integer or decimal from 2 to 8, for example an integer or decimal from 7 to 8. In some preferred embodiments, the compound of formula I is any of the following compounds:

In a second aspect, the present invention further provides a compound of formula II, or a salt or stereoisomer, solvate or solvate of a salt thereof:

^L1a - ^L2 - ^L3 -Tr-(TAS-106)

Formula II

Wherein, (L ^1a reacts with any amino group, thiol group or other chemical functional group on the ligand to covalently connect the entire linker-payload to the ligand), L ^1a is Wherein Lg ¹ is a leaving group, preferably, Lg ¹ is but not limited to halogen, OTf, sulfone group (eg, MeSO ₂ -) or tertiary amine salt group (eg, Me ₃ N ⁺ , Et ₃ N ⁺ ), diazonium salt group, -OMs, );

L ² , L ³ , and Tr are as defined above.

In some preferred embodiments, L ² is -(CHR ^L21 ) _n -;

Where n is a natural number from 0 to 20;

Any -CHR ^L21 - in ^L2 can be independently replaced by the following structural units: -Cyr-, -N(R ^L23 )C(O)-, -C(O)N(R ^L23 )-, -C(O)-, -NR ^L23 -, -O-, Replacement;

-Cyr- is phenylene, 5- to 6-membered heteroarylene, 4- to 10-membered heterocyclylene, or 3- to 6-membered cycloalkylene, wherein said -Cyr- is optionally substituted with 1 to 3 R ^cx ;

each of ^RL21 , ^RL23 and ^Rcx is independently hydrogen, halogen, -OR ^L2a , -N( ^RL2a ) ₂ , _-C (O) ^RL2a , -S(O) ^2RL2a , -C(O)N( ^RL2a ) ₂ , _-SO2N ( ^RL2a ) ₂ , -N( ^RL2a ) _SO2RL2b , -N( ^{RL2a )COR L2b ,} -( _CH2 ) _y -CO-(N(Me) _CH2C (O)) _m -OR ^L2a , -( _CH2 ) _y -CO-(N(Me) _CH2C (O)) _m -NHR ^L2a , -( _CH2 ) _y -CONH-( _CH2CH2O ) _m ^-RL2a _, -( _CH2 ) _y -NHCO-(CH ₂ CH ₂ O) _m -R ^L2a , -(CH ₂ ) _y -NHCOCH ₂ (OCH ₂ CH ₂ )OR ^L2a , -(CH ₂ ) _y -NH(COCH ₂ (N(Me)) _m -R ^L2a , -(CH ₂ ) _y -NHCO-(CH ₂ CH ₂ O) _m -R ^L2a , -(CH ₂ CH ₂ O) _m -R ^{L2 a} , -(COCH ₂ N(Me)) _m -R ^L2a , -COCH ₂ (OCH ₂ CH ₂ ) _m -OR ^L2a , -CO-(CH ₂ CH ₂ O) _m -R ^L2a , -C _1-6 alkyl, -C _2-6 alkenyl, -C The -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, _3-8 membered cycloalkyl, 4-10 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more R ^Tra ;

m is a natural number from 0 to 8;

y is 0, 1, 2, 3, 4;

Each ^RL2a , ^RL2b is independently selected from hydrogen, halogen, -CN, -OH, _-NH2 , -N(Me) ₂ , _-CO2H , -C(O) _NH2 or _-C1-6alkyl ;

The heteroatoms in the 5- to 6-membered heteroarylene group, the 4- to 10-membered heterocyclylene group and the 4- to 10-membered heterocycloalkyl group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4;

Preferably,

^L2 is -( _CH2 ) _n- ;

Where n is a natural number from 0 to 14;

Any -CH ₂ - in L ² may be independently replaced by the following structural units: phenylene, 5- to 6-membered heteroarylene, 4- to 6-membered heterocyclylene, 3- to 6-membered cycloalkylene, -N(R ^L23 )C(O)-, -C(O)N(R ^L23 )-, -C(O)-, -NR ^L23 -, -O-, Replacement;

Each R ^L23 is independently hydrogen, -OR ^L2a , -C(O)R ^L2a , -S(O) ₂ R ^L2a , -C(O)N(R ^L2a ) ₂ , -SO ₂ N(R ^L2a ) ₂ , -(CH ₂ ) _y -CO-(N(Me)CH ₂ C(O)) _m -OR ^L2a , -(CH ₂ ) _y -CO-(N(Me)CH ₂ C(O)) _m -NHR ^L2a , -(CH ₂ ) _y -CONH-(CH ₂ CH ₂ O) _m -R ^L2a , -(CH ₂ ) _y -NHCOCH ₂ (OCH ₂ CH ₂ )OR ^L2a , -(CH ₂ CH ₂ O) _m -R ^L2a , -(COCH ₂ N(Me)) _m -R ^L2a , -COCH ₂ (OCH ₂ CH ₂ ) _m -OR ^L2a , -CO-(CH ₂ CH ₂ O) _m -R ^L2a , or -C _1-6 alkyl; the -C _1-6 alkyl is optionally substituted by one or more Several were replaced by R ^L2a ;

m is a natural number from 0 to 8;

y is 0, 1, 2, 3, or 4;

Each ^RL2a is independently selected from hydrogen, halogen, -CN, -OH, _-NH2 , -N(Me) ₂ , _-CO2H , -C(O) _NH2 or _-C1-6alkyl ;

The heteroatoms of the 5- to 6-membered heteroarylene group and the 4- to 6-membered heterocyclylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3;

More preferably,

^L2 is -(CHR ^L21 ) _n -;

Where n is a natural number from 1 to 10;

Any -CHR ^L21 - in L ² may be independently replaced by the following structural units: -Cyr-, -N(R ^L23 )C(O)-, -C(O)N(R ^L23 )-, -C(O)-, -NR ^L23 - or -O-;

-Cyr- is a 4- to 6-membered heterocyclylene group or a 3- to 6-membered cycloalkylene group;

Each of ^RL21 and ^RL23 is independently hydrogen or -( _CH2CH2O ) _m - ^RL2a _;

m is a natural number from 0 to 4;

Each R ^L2a is hydrogen;

The heteroatoms in the 4- to 6-membered heterocyclylene group are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4;

Further preferably,

^L2 is

Each of t1, t2, t3, t4 and m is independently an integer from 0 to 8;

Each t5 and t6 is independently 0 or 1;

-Cyr- is a 4- to 6-membered heterocyclylene group or a 3- to 6-membered cycloalkylene group; preferably, -Cyr- is Further preferably, -Cyr- is

Further preferably,

Further preferably,

for Among them, c is connected to _L1 and d is connected to ^L3 .

In some preferred embodiments, L ³ is a chemical bond, 1 amino acid residue, a short peptide consisting of 2 to 7 amino acid residues, The amino acid residue is Val, D-Val, Nva, Phe, Lys, Leu, Ile, Gly, Ala, D-Ala, Cit, Asp, Asn, Glu, Gln, Pro, Arg, Lys(Ac), Lys(Me), Lys(Et), Lys(nPr), Nva or AA;

AA

Preferably, L ³ is chemical bond, Val, D-Val, Phe, Lys, Leu, Ile, Gly, Ala, D-Ala, Cit, Asp, Asn, Glu, Gln, AA, Val-Cit, Val-Ala , Val-Lys, Val-Lys(Ac), Phe-Lys, Phe-Lys(Ac), Leu-Lys, Leu-Lys(Ac), Ala-Ala, D-Ala-Ala, Gly-Glu, Gly- Asp, Gly-Asn, Val-Glu, Val-Asp, Val-Asn, Asn-Asn, Val-AA, Ala-AA, Phe-AA, Glu-Val-Cit, Ala-Ala-Ala, Ala-(D -Ala)-Ala、Ala-Ala -Asn, Ala-(D-Ala)-Asn, Ala-Ala-Asp, Val-Lys-Gly, D-Val-Leu-Lys, Gly-Gly-Arg, Gly-Gly-Gly, Gly-Glu-Gly , Lys-Ala-Asn, Gly-Phe-Gly, Gly-Gly-Phe, Asn-Pro-Val, Val-AA-Gly, Ala-AA-Gly, Gly-AA-Gly, Gly-Gly-Gly-Gly , Gly-Gly-Phe-Gly, Gly-Gly-Glu-Gly, Lys-Ala-Ala-Asn, Lys-Ala-Ala-Asp, Ala-Ala-Pro-Val, Ala-Ala-Pro-Nva,

AA

More preferably, L ³ is chemical bond, Lys, Cit, Asp, Asn, Glu, Gln, Val-Cit, Val-Ala, Ala-Ala, Gly-Glu, Gly-Asp, Gly-Asn, Asn-Asn, Gly -Glu-Gly, Gly-Gly-Phe-Gly, Gly-Gly-Gly-Gly or Gly-Gly-Glu-Gly;

Preferably, ^L3 is a chemical bond, Val-Ala, Ala-Ala, Gly-Glu, Gly-Asn, Gly-Asp, Gly-Glu-Gly, Gly-Gly-Glu-Gly, or Gly-Gly-Phe-Gly;

For example

Still preferably, ^L3 is a chemical bond, Val-Ala, Ala-Ala, Gly-Glu, Gly-Asn, Gly-Asp, Gly-Glu-Gly, Gly-Gly-Glu-Gly or Gly-Gly-Phe-Gly.

In some preferred embodiments, Tr is a chemical bond,

Each of R ^Tr , R ^Tr1 and R ^Tr2 is independently hydrogen, halogen, -NO ₂ , -CN, -OH, -NH ₂ , -CO ₂ H, -S(O) ₂ H, -C(O)NH ₂ , -SO ₂ NH ₂ , _-OC (O) _NH2 , _-CH2CO- (N(Me)CH2C(O)) _z - ^ORTra , _-CH2CO- (N(Me) _CH2C (O)) _z - ^NHRTra , -( _CH2CH2O ) _z - ^RTra , -CONH-( _CH2CH2O ) _z - ^RTra , or _{-C1-6alkyl ;} said _C1-6alkyl is optionally substituted with _one or more ^R3a ;

R ^3a is hydrogen, deuterium, halogen, -NO ₂ , -CN, -OH, -NH ₂ , -N(Me) ₂ , -S(O) ₂ Me, -CO ₂ H, -S(O) ₂ OH, -C(O)NH ₂ , -SO ₂ NH ₂ , or -C _1-6 alkyl;

z is an integer of 0 or greater;

Preferably, Tr is a chemical bond,

More preferably, Tr is a chemical bond,

Wherein, e is connected to L ³ , f is connected to TAS-106; Tr is preferably a chemical bond,

In some preferred embodiments, the compound of formula II is represented by formula IIa or formula IIb

The remaining groups are as defined in formula (Ia) and formula (Ib).

In some preferred embodiments, the compound of formula II is represented by formula IIa or formula IIb

The remaining groups are as defined in formula (I) and formula (II).

In some preferred embodiments, L ^1a is

Preferably, ^L1 is More preferably, ^L1 is

In some preferred embodiments, for

Each of t1, t2, t3, t4 and m is independently selected from an integer from 0 to 8;

Each t5 and t6 is independently 0 or 1;

-Cyr- is a 4- to 6-membered heterocyclylene group or a 3- to 6-membered cycloalkylene group; preferably, -Cyr- is Further preferably, -Cyr- is

In some preferred embodiments, the compound of the structure represented by formula (IIa) is: for More preferably, for

In some preferred embodiments, the compound of formula II is any of the following compounds:

In a third aspect, the present invention further provides a compound having a structure shown in Formula III, or a salt, stereoisomer, solvate or solvate of a salt thereof:

Wherein, L ¹ , L ² , Tr and L ³ are defined as above, and L ¹ is used to directly or indirectly connect to the ligand that binds to the target.

In some preferred embodiments, the structure shown in Formula III is shown in Formula IIIa or Formula IIIb

Each group is defined as in any one of formula (Ia) and formula (Ib).

In some preferred embodiments, the compound represented by formula III, formula IIIa or formula IIIb, wherein,

^L1 is

^L2 is -(CHR ^L21 ) _n -;

Where n is a natural number from 1 to 10;

Any -CHR ^L21 - in L ² may be independently replaced by the following structural units: -Cyr-, -N(R ^L23 )C(O)-, -C(O)N(R ^L23 )-, -C(O)-, -NR ^L23 - or -O-;

-Cyr- is a 4- to 6-membered heterocyclylene group or a 3- to 6-membered cycloalkylene group; the heteroatom of the heterocycloalkyl group is N, and the number of heteroatoms is 1 or 2;

Each of ^RL21 and ^RL23 is independently hydrogen or -(CH ₂ CH ₂ O) _m ^-RL2a ; m is a natural number from 0 to 4; each ^RL2a is hydrogen;

L ³ is a chemical bond, Val-Ala, Ala-Ala, Gly-Glu, Gly-Asn, Gly-Asp, Gly-Glu-Gly, Gly-Gly-Glu-Gly or Gly-Gly-Phe-Gly;

Tr is a chemical bond,

The present invention also provides a pharmaceutical composition, which comprises the compound of the structure shown in the above-mentioned formula I, II or formula III, or a pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a pharmaceutically acceptable salt thereof.

The present invention also provides a pharmaceutical preparation, which comprises the compound of the structure shown in the above-mentioned formula I, II or formula III, or a pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a pharmaceutically acceptable salt thereof.

The present invention also provides a use of a substance S in the preparation of a drug for preventing or treating cancer; the substance S is the above-mentioned formula I, II or a compound having a structure shown in formula III or a pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a pharmaceutically acceptable salt, the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical preparation. The cancer is a solid tumor or a non-solid tumor. For example, it is selected from esophageal cancer (such as esophageal adenocarcinoma and esophageal squamous cell carcinoma), brain tumor, lung cancer (such as small cell lung cancer and non-small cell lung cancer), squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colorectal cancer, liver cancer, kidney cancer, non-Hodgkin's lymphoma, central nervous system tumors (such as glioma, glioblastoma multiforme, glioma or sarcoma), prostate cancer or thyroid cancer.

The present invention also provides a use of a substance S in the preparation of a drug for preventing or treating a disease associated with abnormal cell activity; the substance S is a compound of the above-mentioned formula I, II or a compound having a structure shown in formula III or a pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a pharmaceutically acceptable salt, the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical preparation. The disease associated with abnormal cell activity may be cancer. The definition of cancer is as described above.

The present invention also provides a use of a substance S in the preparation of a drug; the substance S is the compound of the above-mentioned formula I, II or a compound having a structure shown in formula III or a pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a pharmaceutically acceptable salt, the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical preparation; the drug is used to treat a disease associated with target A; the target A is the target corresponding to the antibody in the substance S. The disease associated with target A used to treat by the drug is cancer. The definition of cancer is as described above.

The present invention also provides a method for preventing or treating a disease associated with abnormal cell activity; the method comprises administering a therapeutically effective amount of a substance S to a patient in need thereof, wherein the substance S is a compound of the above-mentioned formula I, II or a compound having a structure shown in formula III or a pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a pharmaceutically acceptable salt, the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical preparation. The disease associated with abnormal cell activity may be cancer. The definition of cancer is as described above.

The present invention also provides a method for preventing or treating cancer; the method comprises administering a therapeutically effective amount of a substance S to a patient in need thereof, wherein the substance S is a compound of the above-mentioned formula I, II or a compound having a structure shown in formula III, or a pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a pharmaceutically acceptable salt, or the above-mentioned pharmaceutical preparation. The cancer is defined as described above.

In this application, unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. In addition, the cell culture, molecular genetics, nucleic acid chemistry, and immunology laboratory operation procedures used herein are conventional procedures widely used in the corresponding fields. At the same time, in order to better understand the present disclosure, the definitions and explanations of the relevant terms are provided below.

In this application, when the connecting groups listed do not specify their connecting direction, their connecting direction is connected in the same direction as the reading order from left to right. For example, the groups in ^L The reading order of the group is from left to right, the left side of the group is L ¹ , and the right side of the group is L ^3. The group is connected to L ¹ and L ³ in the same direction as the reading order from left to right, that is,

In this application, the term "pharmaceutical excipients" refers to excipients and additives used in the production of drugs and the preparation of prescriptions. It refers to substances that have been reasonably evaluated in terms of safety and are included in drug preparations in addition to active ingredients. In addition to excipients, acting as carriers, and improving stability, pharmaceutical excipients also have important functions such as solubilization, solubilization, and sustained and controlled release. They are important ingredients that may affect the quality, safety, and effectiveness of drugs. According to their sources, they can be divided into natural products, semi-synthetic substances, and fully synthetic substances. According to their functions and uses, they can be divided into: solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, adhesives, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, antioxidants, chelating agents, penetration enhancers, pH regulators, buffers, plasticizers, surfactants, foaming agents, defoamers, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculating agents, filter aids, release retardants, etc.; according to their route of administration, they can be divided into oral, injection, mucosal, transdermal or topical administration, nasal or oral inhalation administration and ocular administration, etc. The same pharmaceutical excipients can be used in drug preparations with different routes of administration and have different functions and uses.

In the present application, the term "pharmaceutical composition" refers to various suitable dosage forms that can be prepared according to the route of administration, such as tablets, capsules, granules, oral solutions, oral suspensions, oral emulsions, powders, tinctures, syrups, injections, suppositories, ointments, creams, pastes, ophthalmic preparations, pills, implants, aerosols, powder sprays, sprays, etc.

In the present application, the term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" generally refers to a salt of the compound or ligand-drug conjugate of the present application, or a salt of the compound described in the present application. Such salts may be safe and/or effective when used in mammals, and may have the desired biological activity. The antibody-antibody drug conjugate compound of the present application may form a salt with an acid. Non-limiting examples of pharmaceutically acceptable salts include: hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, citrate, acetate, succinate, ascorbate, oxalate, nitrate, sorbate, hydrogen phosphate, dihydrogen phosphate, salicylate, hydrogen citrate, tartrate, maleate, fumarate, formate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, and p-toluenesulfonate.

In the present application, the term "solvate" or "solvate compound" generally refers to a pharmaceutically acceptable solvate formed by the ligand-drug conjugate compound of the present application and one or more solvent molecules, and non-limiting examples of solvent molecules include water, ethanol, acetonitrile, isopropanol, DMSO, and ethyl acetate.

The term "drug loading" generally refers to the average number of cytotoxic drugs loaded on each ligand, and can also be expressed as the ratio of the amount of cytotoxic drugs to the amount of antibodies. The range of cytotoxic drug loading can be 0-16, for example 1-10 cytotoxic drugs connected to each ligand (Ab). In an embodiment of the present application, the drug loading is expressed as q, which can be exemplified as an integer or decimal of 1 to 2, 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, 7 to 8, 8 to 9, 9 to 10. For example, the drug loading q is 7.8 or 7.9. The drug loading of each ADC molecule after the coupling reaction can be identified by conventional methods such as UV/visible light spectroscopy, mass spectrometry, HIC, ELISA test and HPLC characteristics.

In the present application, the term "ligand-drug conjugate" generally refers to a ligand connected to a biologically active cytotoxic drug via a stable linker. In the present application, a "ligand-drug conjugate" may be an antibody-drug conjugate (ADC), and the ADC may refer to a monoclonal antibody or antibody fragment connected to a biologically active cytotoxic drug via a stable linker.

In the present application, the term "ligand" generally refers to small molecules, polypeptides, RNA, DNA, carbohydrates and macromolecular compounds that can recognize and bind to antigens or receptors associated with target cells. The role of the ligand can be to present the drug to the target cell population bound to the ligand. These ligands include but are not limited to protein hormones, lectins, growth factors, antibodies or other molecules that can bind to cells, receptors and/or antigens. In the present application, the ligand can be expressed as Ab, and the ligand antigen forms a connection bond with the connecting unit through the heteroatom on the ligand, which can be an antibody or an antigen-binding fragment thereof. The antibody can be selected from a chimeric antibody, a humanized antibody, a fully human antibody or a mouse antibody; the antibody can be a monoclonal antibody. For example, the antibody can be an antibody targeting the following targets: HER2, HER3, B7H3, TROP2, Claudin18.2, CD30, CD33, CD70 or EGFR. For example, the antibody can be an antibody targeting the following targets: 5T4, AGS-16, ANGPTL4, ApoE, CD19, CTGF, CXCR5, FGF2, MCPT8, MFI2, MS4A7, NCA, Sema5b, SLITRK6, STC2, TGF, 0772P, 5T4, ACTA2, ADGRE1, AG-7, AIF1, AKR1C1, AKR1C2, ASLG 659, Axl, B7H3, BAFF-R, BCMA, BMPR1B, BNIP3, C1QA, C1QB, CA6, CADM1, CCD79b, CCL5, CCR5, CCR7, CD1lc, CD123, CD138, CD142, CD147, CD166, CD19, CD19, CD22, CD21, CD20, CD205, CD22, CD223, CD2 28，CD25，CD30，CD33，CD37，CD38，CD40，CD45，CD45(PTPRC)，CD46，CD47，CD49D(ITGA4)，CD56，CD66e，CD70，CD71，CD72，CD74，CD79a，CD79b，CD80，CDCP1，CDH11，CDllb，CEA，CEACAM5，c-Met，COL6A3，COL7A1，CRIPTO，CSF1R，CTSD，CTSS，CXCL11，CXCL10，DDIT4，DLL3，DLL4，DR5，E16，EFNA4，EGFR，EGFRvIII，EGLN，EGLN3，EMR2，ENPP3，EpCAM，EphA2，EphB2R，ETBR，FcRH2，FcRHl，FGFR2，FGFR3， FLT3，FOLR-α，GD2，GEDA，GPC-1，GPNMB，GPR20，GZMB，HER2，HER3，HLA-DOB，HMOX1，IFI6，IFNG，IGF-1R，IGFBP3，IL10RA1，IL-13R，IL-2，IL20Ra，IL-3，IL-4，IL-6，IRTA2，KISS1R，KRT33A，LIV-1，LOX，LRP-1，LRRC15，LUM，LY64，LY6E，Ly86，LYPD3，MDP，MMP10，MMP14，MMP16，MPF，MSG783，MSLN，MUC-1，NaPi2b，Napi3b，Nectin-4，Nectin-4，NOG，P2X5，pCAD，P-Cadherin，PDGFRA，PDK1，PD-L1，P FKFB3, PGF, PGK1, PIK3AP1, PIK3CD, PLOD2, PSCA, PSCAhlg, PSMA, PSMA, PTK7, P-cadherin, RNF43, NaPi2b, ROR1, ROR2, SERPINE1, SLC39A6, SLTRK6, STAT1, STEAP1, STEAP2, TCF4, TENB2, TGFB1, TGFB2, TGFBR1, TNFRSF21, TNFSF9, Trop-2, TrpM4, Tyro7, UPK1B, VEGFA, WNT5A, epidermal growth factor, brevican, mesothelin, sodium phosphate cotransporter 2B, claudin 18.2, endotenin receptor, mucins (such as mucin 1 and mucin 16), guanylate cyclase C, integrin a4p7, integrin a5p6, trophoblast glycoprotein, or tissue factor.

In the present application, the term "antibody or antigen-binding fragment thereof" generally refers to immunological binding agents extending to all antibodies from all species, including dimers, trimers and multimers; bispecific antibodies; chimeric antibodies; fully human antibodies; humanized antibodies; recombinant and remodeled antibodies and fragments thereof. The term "antibody or fragment thereof" may refer to any antibody-like molecule having an antigen-binding region, and the term includes small molecule fragments such as Fab', Fab, F(ab') ₂ , single domain antibodies (DABs), Fv, scFv (single chain Fv), linear antibodies, diabodies, etc. The term "antigen-binding fragment" may refer to one or more fragments of an antibody that retain the ability to specifically bind to an antigen. For example, a fragment of a full-length antibody may be used to perform the antigen-binding function of an antibody. The techniques for preparing and using various antibody-based constructs and fragments are well known in the art. The antibodies may include: anti-HER2 (ErbB2) antibody, anti-EGFR antibody, anti-B7-H3 antibody, anti-c-Met antibody, anti-HER3 (ErbB3) antibody, anti-HER4 (ErbB4) antibody, anti-CD20 antibody, anti-CD22 antibody, anti-CD30 antibody, anti-CD33 antibody, anti-CD44 antibody, anti-CD56 antibody, anti-CD70 antibody, anti-CD73 antibody, anti-CD105 antibody, anti-CEA antibody, anti-A33 antibody, anti-Cripto antibody, anti-EphA2 antibody, anti-G250 antibody, anti-MUCl antibody, anti-Lewis Y antibody, anti-TROP2 antibody, anti-Claudin One or more of 18.2 antibody, anti-VEGFR antibody, anti-GPNMB antibody, anti-Integrin antibody, anti-PSMA antibody, anti-Tenascin-C antibody, anti-SLC44A4 antibody or anti-Mesothelin antibody, for example, may be Trastuzumab or Pertuzumab.

In this application, the term "chimeric antibody" generally refers to an antibody formed by fusing the variable region of a mouse antibody with the constant region of a human antibody, which can reduce the immune response induced by the mouse antibody. To establish a chimeric antibody, a hybridoma that secretes mouse-specific monoclonal antibodies can be established, and then the variable region gene can be cloned from the mouse hybridoma cells. The constant region gene of the human antibody can be cloned as needed, and the mouse variable region gene and the human constant region gene can be connected to form a chimeric gene and then inserted into an expression vector, and the chimeric antibody molecule can be expressed in a eukaryotic system or a prokaryotic system.

In the present application, the term "humanized antibody", also known as CDR-grafted antibody, generally refers to an antibody produced by transplanting a mouse CDR sequence into a human antibody variable region framework, i.e., different types of human germline antibody framework sequences. The heterologous reaction induced by chimeric antibodies due to carrying a large amount of mouse protein components can be overcome. Such framework sequences can be obtained from public DNA databases including germline antibody gene sequences or published references. For example, the germline DNA sequences of human heavy chain and light chain variable region genes can be found in the "VBase" human germline sequence database.

In the present application, the terms "fully human antibody", "fully human antibody" or "completely human antibody", also known as "fully human monoclonal antibody", the variable region and constant region of the antibody can be both human, eliminating immunogenicity and toxic side effects. The development of monoclonal antibodies has gone through four stages, namely: murine monoclonal antibodies, chimeric monoclonal antibodies, humanized monoclonal antibodies and fully human monoclonal antibodies. The antibody or ligand described in the present application can be a fully human monoclonal antibody. The relevant technologies for the preparation of fully human antibodies can be: human hybridoma technology, EBV transformed B lymphocyte technology, phage display technology (phagedisplay), transgenic mouse antibody preparation technology (transgenic mouse) and single B cell antibody preparation technology, etc.

In this application, the term "CDR" generally refers to one of the six hypervariable regions within the variable domain of an antibody that primarily contribute to antigen binding. One of the most commonly used definitions of the six CDRs is provided by Kabat E.A. et al., (1991) Sequences of proteins of immunological interest. NIH Publication 91-3242), Chothia et al., "Canonical Structures For the Hypervariable Regions of Immunoglobulins," J. Mol. Biol. 196: 901 (1987); and MacCallum et al., "Antibody-Antigen Interactions: Contact Analysis and Binding Site Topography," J. Mol. Biol. 262: 732 (1996)). As used in this application, the Kabat definition of CDRs can be applied to CDR1, CDR2 and CDR3 (CDRL1, CDRL2, CDRL3 or L1, L2, L3) of the light chain variable domain, and CDR1, CDR2 and CDR3 (CDR H1, CDRH2, CDRH3 or H1, H2, H3) of the heavy chain variable domain.

In the present application, the term "methylene" generally refers to a residue derived from a group of 1 carbon atom by removing two hydrogen atoms. The methylene group may be substituted or unsubstituted, substituted or unsubstituted.

In the present application, the term "alkyl" refers to a saturated straight or branched hydrocarbon group. As used herein, the term "C _1-6 alkyl" refers to a saturated straight or branched hydrocarbon group having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5 or 6 carbon atoms). "C _1-6 alkyl" is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl, etc.

In the present application, the term "alkylene" refers to a saturated straight or branched divalent hydrocarbon group. As used herein, the term "C _1-6 alkylene" refers to a saturated straight or branched divalent hydrocarbon group having 1 to 6 carbon atoms. "C _1-6 alkylene" includes, for example, but is not limited to, methylene, ethylene, propylene or butylene.

In the present application, the term "alkenyl" refers to a straight or branched aliphatic hydrocarbon group with one or more carbon-carbon double bonds. For example, the term " _C2-6 alkenyl" as used herein refers to an alkenyl group (such as vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, etc.) having 2-6 carbon atoms and one, two or three (preferably one) carbon-carbon double bonds.

In the present application, the term "alkenylene" refers to a straight or branched divalent aliphatic hydrocarbon group having one or more carbon-carbon double bonds, and the two groups (or fragments) connected thereto may be connected to the same carbon atom or to different carbon atoms. For example, the term " _C2-6 alkenylene" as used herein refers to an alkenylene group having 2 to 6 carbon atoms (e.g. wait).

In the present application, the term "alkynyl" refers to a straight or branched aliphatic hydrocarbon group with one or more carbon-carbon triple bonds. For example, the term " _C2-6alkynyl " as used herein refers to an alkynyl group (such as ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc.) with 2-6 carbon atoms and one, two or three (preferably one) carbon-carbon triple bonds.

In the present application, the term "alkynylene" refers to a straight or branched divalent aliphatic hydrocarbon group having one or more carbon-carbon triple bonds, wherein the two groups (or fragments) connected thereto are respectively connected to different carbon atoms. For example, the term " _C2-6 alkynylene" as used herein refers to an alkynylene group having 2 to 6 carbon atoms (e.g. wait).

In the present application, the term "aryl" refers to a monocyclic or condensed aromatic hydrocarbon group having a conjugated π electron system. For example, the term "C _6-12 aryl" used herein refers to an aryl group having 6-12 carbon atoms (such as phenyl, naphthyl, etc.).

In the present application, the term "arylene" refers to a monocyclic or condensed divalent aromatic hydrocarbon group having a conjugated π electron system. For example, the term "C _6-10 arylene" used herein refers to an arylene group having 6 to 10 carbon atoms.

In the present application, the term "heteroaryl" or "heteroaromatic ring" refers to a monocyclic and fused heterocyclic ring system containing one or more conjugated π-electron systems, wherein one or more (e.g., 1, 2 or 3) ring atoms are heteroatoms selected from N, O, P and S, and the remaining ring atoms are C. A heteroaryl or heteroaromatic ring can be characterized by the number of ring atoms. For example, a 5-12 membered heteroaryl can contain 5-12 (e.g., 5, 6, 7, 8, 9, 10, 11 or 12) ring atoms, in particular 5, 6, 9, 10 ring atoms. Examples of heteroaryl include thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, indolyl, and the like.

In the present application, the term "heteroarylene" refers to a monocyclic or condensed divalent aromatic group containing a conjugated π-electron system, which has one or more carbon atoms (such as 1, 2, 3, 4, 5, 6, 9 or 10 carbon atoms) and one or more (such as 1, 2, 3 or 4) heteroatoms independently selected from N, O, P and S in the ring, for example, a total of 5-12 (preferably 5-10, more preferably 5, 6, 9 or 10) ring atoms.

In the present application, the term "cycloalkyl" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic hydrocarbon group. For example, "C _3-12 cycloalkyl" or "3-12 membered cycloalkyl" refers to a cycloalkyl group having 3-12 ring carbon atoms (such as 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12). Common cycloalkyl groups include (but are not limited to) monocyclic cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutene, cyclopentene, cyclohexene, etc.; or bicyclic cycloalkyl groups, including fused rings, bridged rings or spiro rings, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, decahydronaphthyl, etc.

In the present application, the term "cycloalkylene" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic divalent cyclic group. For example, "C _3-12 cycloalkylene" or "3-12 membered cycloalkylene" refers to a cycloalkylene having 3-12 ring carbon atoms (such as 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12). Common cycloalkylenes include (but are not limited to) monocyclic cycloalkylenes, such as cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclobutene, cyclopentene, cyclohexene, etc.; or bicyclic cycloalkylenes, including fused rings, bridged rings or spiro rings, such as bicyclo[1.1.1]pentylene, bicyclo[2.2.1]heptylene, bicyclo[3.2.1]octylene, bicyclo[5.2.0]nonylene, decahydronaphthylene, etc.

The term "heterocycloalkyl" refers to a saturated or partially saturated non-aromatic cyclic group containing at least one ring member selected from N, O, P and S as a heteroatom, preferably, the number of the heteroatoms is 1, 2, 3 or 4. For example, 3-8-membered or 3-6-membered heterocycloalkyl. Specific examples include, but are not limited to, oxirane, oxocyclobutane, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, homopiperazinyl, etc.

The term "heterocycloalkylene" refers to a saturated or partially saturated non-aromatic divalent cyclic group containing at least one ring member being a heteroatom selected from N, O, P and S, preferably, the number of the heteroatoms is 1, 2, 3 or 4. For example, 3-8-membered or 3-6-membered heterocycloalkylene. Specific examples include, but are not limited to, oxiranediylene, oxocyclobutanediylene, pyrrolidinylene, tetrahydrofuranylene, piperidinylene, piperazinylene, tetrahydropyranylene, homopiperazinylene, etc.

The term "condensed ring (condensed ring system)" refers to a polycyclic structure formed by two or more (e.g., 3, 4, or 5) carbocyclic rings or heterocyclic rings with a common ring edge, wherein the carbocyclic ring includes a cycloalkyl group and an aryl group, and the heterocyclic ring includes a heteroaromatic ring and a heterocycloalkyl group. The condensed ring system includes, but is not limited to, a condensed ring system formed by a cycloalkyl group and a cycloalkyl group, a condensed ring system formed by a cycloalkyl group and a heterocycloalkyl group, a condensed ring system formed by a cycloalkyl group and an aromatic ring, a condensed ring system formed by a cycloalkyl group and a heteroaromatic ring, a condensed ring system formed by a heterocycloalkyl group and a heteroaromatic ring, a condensed ring system formed by a heterocycloalkyl group and an aromatic ring, a condensed ring system formed by a heteroaromatic ring and a heteroaromatic ring, a condensed ring system formed by a heteroaromatic ring and an aromatic ring, and the like.

In the present application, the term "halogen" generally refers to fluorine, chlorine, bromine, iodine, for example, it can be fluorine, chlorine.

In the present application, the term "each independently" means that at least two groups (or fragments) with the same or similar value ranges in the structure may have the same or different meanings under certain circumstances. For example, substituent X and substituent Y are each independently hydrogen, halogen, hydroxyl, cyano, alkyl or aryl. When substituent X is hydrogen, substituent Y may be hydrogen, halogen, hydroxyl, cyano, alkyl or aryl; similarly, when substituent Y is hydrogen, substituent X may be hydrogen, halogen, hydroxyl, cyano, alkyl or aryl.

In this application, the term "optional" or "optionally" generally means that the subsequently described event or circumstance may but need not occur, and the description includes occasions where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and the description may include situations where the heterocyclic group is substituted with an alkyl group and situations where the heterocyclic group is not substituted with an alkyl group.

In the present application, the term "substituted" generally refers to one or more hydrogen atoms in a group, for example up to 5, for example 1 to 3 hydrogen atoms, which are replaced independently of one another by a corresponding number of substituents. The substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g. olefinic) bond.

In the present application, the term 0 or more (e.g., 0 or more than 1, 0 or 1, 0) methylene units are "replaced" generally means that when the structure contains 1 or more methylene units, the one or more methylene units may be unsubstituted or replaced with one or more groups other than methylene (e.g., -NHC(O)-, -C(O)NH-, -C(O)-, -OC(O)-, -C(O)O-, -NH-, -O-, -S-, -SO-, -SO ₂ -, -PH-, -P(＝O)H-, -NHSO ₂ -, -SO ₂ NH-, -C(＝S)-, -C(＝NH)-, -N＝N-, -C＝N-, -N＝C-, or -C(＝N ₂ )-).

In the present application, one or more hydrogen atoms, for example up to 5, for example 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. The substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g. olefinic) bond.

In the present application, the term "amino acid" refers to natural amino acids and non-natural amino acids, and the writing of conventional amino acids follows conventional usage. See, for example, Immunology-A Synthesis (2nd Edition, E.S.Golub and D.R.Gren, Eds., Sinauer Associates, Sunderland, Mass. (1991)), which is incorporated herein by reference. In this article, the terms "polypeptide" and "protein" have the same meaning and can be used interchangeably. And in the present application, amino acids are generally represented by single-letter and three-letter abbreviations known in the art. For example, alanine can be represented by A or Ala; arginine can be represented by R or Arg; glycine can be represented by G or Gly; glutamine can be represented by Q or Gln;

In this application, the term "unnatural amino acid" has the following structure: wherein r is selected from 0, ₁ , ₂ , 3, 4, and ₅ ; wherein ^Ra and ^Rb are each independently selected from -C1-6alkyl- _NH2 , _-C1-6alkyl -NH- _C1-6alkyl , _-C1-6alkyl -N( _C1-6alkyl ) ₂ , _-C1-6alkyl -NH-C3-10cycloalkyl, -C1-6alkyl-N(3-10-memberedcycloalkyl)(C1-6alkyl), -C1-6alkyl- _{C3-10cycloalkyl, -C1-6alkyl-(3-10-memberedheterocycloalkyl), -C1-6alkyl-NHCOC1-6alkyl , -C1-6alkyl - NHCOOC1-6alkyl , -C1-6alkyl} -NHS(O) _2C1-6alkyl , _-C1-6alkyl -S(O) _{2 - C1-6alkyl , -C1-6alkyl} -NH-C3-10cycloalkyl, -C _1-6 alkyl-S(O) ₂ -C _3-10 cycloalkyl, -C _1-6 alkyl-S(O) ₂ -NH ₂ , -C _1-6 alkyl-COOH, -C _1-6 alkyl-CONH ₂ , -C _1-6 alkyl-CONHC _1-6 alkyl, -C _1-6 alkyl-CO(3-10 membered heterocycloalkyl), The alkyl, cycloalkyl and heterocycloalkyl groups are each optionally substituted by one or more substituents selected from H, halogen, -OH, -NH ₂ , -SH, -NO ₂ , CN, -COOH and oxo groups; or any ^Ra , ^Rb and the atoms to which they are connected together form a 3-10 membered heterocycloalkyl or 3-10 membered cycloalkyl group; the cycloalkyl and heterocycloalkyl groups are each optionally substituted by one or more substituents selected from H, halogen, -OH, -NH ₂ , -SH, -NO ₂ , CN, -COOH and oxo groups;

In the present application, the term "compound" generally refers to a substance with two or more different elements. For example, the compound of the present application may be an organic compound, for example, the compound of the present application may be a compound with a molecular weight of less than 500, a compound with a molecular weight of less than 1000, a compound with a molecular weight of more than 1000, or a compound with a molecular weight of more than 10000 or more than 100000. In the present application, a compound may also refer to a compound connected by chemical bonds, for example, a compound in which one or more molecules with a molecular weight of less than 1000 are connected to a biomacromolecule by chemical bonds, and the biomacromolecule may be a high polysaccharide, protein, nucleic acid, polypeptide, etc. For example, the compound of the present application may include a compound in which a protein is connected to one or more molecules with a molecular weight of less than 1000, a compound in which a protein is connected to one or more molecules with a molecular weight of less than 10000, or a compound in which a protein is connected to one or more molecules with a molecular weight of less than 10000.

In the present application, the term "stereoisomer" means an isomer formed by at least one asymmetric center. In compounds with one or more (e.g., one, two, three, or four) asymmetric centers, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers may be produced. Specific individual molecules may also exist as geometric isomers (cis/trans).

As used herein, the term "tautomer" means that a compound can exist as a mixture of two or more structurally distinct forms (generally referred to as tautomers) that are in rapid equilibrium.

Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of the present application encompasses all such isomers in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) or mixtures thereof.

In this article, solid lines can be used Solid wedge Virtual wedge Carbon-carbon bonds of the compounds of the invention are depicted. The use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.). The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomer shown is present. When present in a racemic mixture, the solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise indicated, the compounds of the invention are intended to exist in the form of stereoisomers, which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

This article uses wavy lines The bonds in the structural formula represented are intended to indicate that the structure represents either a cis or trans isomer, or a mixture of cis and trans isomers in any ratio.

The term "oxo," as used herein alone or in combination with other groups, refers to =0.

In the present application, the term "comprising" generally refers to including the features explicitly specified but not excluding other elements. The terms "above" and "below" generally refer to the case where the number is inclusive.

In this application, the term "about" generally refers to a variation within a range of 0.5%-10% above or below a specified value, for example, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% above or below a specified value.

Unless otherwise indicated, the structures described herein may also include compounds that differ only in the presence or absence of one or more isotopically enriched atoms. For example, compounds that are consistent with the structures of the present application except that a hydrogen atom is replaced by deuterium or tritium, or a carbon atom is replaced by carbon 13 or carbon 14, are within the scope of the present application.

The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating one or more symptoms of a target disorder or condition.

As used herein, the term "effective amount" (e.g., "therapeutically effective amount" or "prophylactically effective amount") refers to the amount of active ingredient that, after administration, will achieve the desired effect to some extent, such as alleviating one or more symptoms of the condition being treated or preventing the occurrence of the condition or its symptoms.

As used herein, unless otherwise indicated, the terms "treat," ...

As used herein, "individual" includes human or non-human animals. Exemplary human individuals include human individuals (referred to as patients) suffering from diseases (e.g., diseases described herein) or normal individuals. "Non-human animals" in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

Those skilled in the art will appreciate that, since nitrogen requires available lone pairs of electrons to be oxidized to oxides, not all nitrogen-containing heterocycles are capable of forming nitrogen oxides. Those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming nitrogen oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming nitrogen oxides. The synthetic methods for preparing nitrogen oxides of heterocycles and tertiary amines are well known to those skilled in the art, including oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and metachloroperbenzoic acid (mCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate and dioxirane such as dimethyl dioxirane. These methods for preparing nitrogen oxides have been extensively described and reviewed in the literature, see, for example: T.L.Gilchrist, Comprehensive Organic Synthesis, vol.7, pp748-750 (A.R.Katritzky and A.J.Boulton, Eds., Academic Press); and G.W.H.Cheeseman and E.S.G.Werstiuk, Advances in Heterocyclic Chemistry, vol.22, pp 390-392 (A.R.Katritzky and A.J.Boulton, Eds., Academic Press).

In any process for preparing the compounds of the invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming a chemically protected form of the compounds of the invention. This can be achieved by conventional protecting groups, for example, those described in T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 2006, which references are incorporated herein by reference. Protecting groups may be removed at an appropriate subsequent stage using methods known in the art.

The present invention also encompasses methods for preparing the compounds described herein. It should be understood that the compounds of the present invention can be synthesized using the methods described below and synthetic methods known in the field of synthetic organic chemistry or variations thereof known to those skilled in the art. Preferred methods include (but are not limited to) those described below. The reaction can be carried out in a solvent or solvent mixture suitable for the reagents and materials used and suitable for achieving the transformation.

Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

The reagents and raw materials used in the present invention are commercially available.

The positive and progressive effects of the present invention are that the antibody drug conjugates of the present invention have one or more of the following advantages:

(1) The antibody-drug conjugate of the present invention has high stability in circulation, reducing the shedding of non-target drugs in non-target cells;

(2) The antibody-drug conjugate of the present invention can increase the effective release of biologically active molecules in cells, thereby achieving the purpose of increasing efficacy and reducing toxicity;

(3) The antibody-drug conjugate of the present invention has good tumor tissue targeting ability;

(4) The antibody-drug conjugate of the present invention has a good therapeutic effect on tumor animal models.

The drug conjugates of the present invention have one or more of the following advantages:

(1) High stability;

(2) having a high drug loading capacity. In some embodiments, the DAR value of the conjugate can reach 7-8;

(3) It has a very high coupling efficiency. In some embodiments, the coupling efficiency can reach 95%.

In addition, the coupling method disclosed in the present invention has a high application range and can be widely used for the coupling of biologically active molecules with antibodies or targeted small molecule ligands. The payload and ADC of the present invention have great therapeutic potential in various tumor cell lines, such as solid tumors and hematological tumors such as MKN-45, HCT-15, SW480, PC-9, A549, Lu-65, A431, A375, etc. At the same time, the unique mechanism of action of TAS-106 is expected to overcome the drug resistance problems of existing cytotoxic drugs, such as camptothecins, gemcitabine, cytarabine, etc. In summary, the cytotoxic agents, linkers, antibodies and ADCs of the present invention have great clinical value.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a comparison chart showing the trend of changes in the anti-tumor activity of the antibody-drug conjugate AA1-1 after a single administration and the blank control group.

DETAILED DESCRIPTION

The present invention includes all combinations of the described specific embodiments. Further embodiments of the present invention and the full scope of applicability will become apparent from the detailed description provided below. However, it should be understood that although the detailed description and specific examples indicate preferred embodiments of the present invention, these descriptions and examples are provided only by way of illustration, because various changes and modifications within the spirit and scope of the present invention will become apparent to those familiar with the art from this detailed description. For all purposes, all publications, patents and patent applications cited herein, including citations, will be fully incorporated herein by reference. The present invention is further described below by way of example, but the present invention is not therefore limited to the scope of the embodiments. The experimental methods for which specific conditions are not indicated in the following examples are selected according to conventional methods and conditions, or according to the product specifications.

Mass spectrometry (MS) was measured using an Agilent (ESI) mass spectrometer, manufacturer: Agilent, model: Agilent 6120B.

Preparative high performance liquid chromatography (HPLC) was performed using a Shimadzu LC-8A preparative liquid chromatograph (YMC, ODS, 250×20 mm column).

Thin layer chromatography purification was performed using GF 254 (0.4-0.5 nm) silica gel plates produced in Yantai.

The reaction is monitored by thin layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS), and the developing solvent system used includes but is not limited to: dichloromethane and methanol system, n-hexane and ethyl acetate system, and petroleum ether and ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound, or adjusted by adding triethylamine or the like.

Column chromatography generally uses Qingdao Ocean 200-300 mesh silica gel as the stationary phase. The eluent system includes but is not limited to the dichloromethane and methanol system and the n-hexane and ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine can also be added for adjustment.

If not otherwise specified in the examples, the reaction temperature is room temperature (20°C to 30°C).

Unless otherwise specified, the reagents used in the examples were purchased from Acros Organics, Aldrich Chemical Company, Nanjing Yaoshi Technology, or Shanghai Shuya Pharmaceutical Technology.

The above-described embodiments do not limit the scheme of the present application in any way. Except those described herein, according to the foregoing description, multiple modifications of the present invention will be apparent to those skilled in the art. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in the present application (including all patents, patent applications, journal articles, books and any other disclosures) is incorporated by reference in its entirety.

In conventional synthesis methods, preparation examples, embodiments and intermediate synthesis examples, the meanings of the abbreviations are shown in the following table.

Preparation of Linker Intermediates

Preparation Example 1: Preparation of Intermediate Int1

The crude product of glycyl-L-phenylalanine (3 g, 10.7 mmol) was dissolved in 50 ml of dichloromethane, and 2,5-dioxypyrrolidin-1-yl 6-(2,5-dicarbonyl-2-,5-dihydro-1H-pyrrol-1-yl)hexanoate (16.1 mmol, 4.93 g) and DIEA were reacted at 25°C for 16 h. TLC (PE/EA=1/1) showed complete reaction. The solvent was dried by rotation, and 1N hydrochloric acid (1 mol/L aqueous hydrochloric acid solution) was added.

(50 ml), extracted with EA (50 ml) three times, dried over anhydrous sodium sulfate, and the organic phase was driven by rotation. It was washed with MTBE (20 ml) and filtered to obtain the intermediate Int1, 2.62 g of white powder, yield 52%.

The following compounds were synthesized by the method of Preparation Example 1:

Preparation Example 2: Preparation of Intermediate Int5

Compound Int5-1 (500 mg, 1.42 mmol) was dissolved in DMF (5 ml), HATU (810 mg, 2.13 mmol) and DIEA (549 mg, 4.26 mmol) were added, and then stirred at room temperature for 30 minutes, and compound Int5-2 (369 mg, 1.42 mmol) was added, and the reaction was continued for 2 hours. After the reaction was completed, ethyl acetate was added, and the pH was adjusted to about 6 with 2M citric acid under stirring, and the liquid was separated, and the organic phase was washed twice with saturated brine, and the organic phase was dried, concentrated, and purified by reverse phase HPLC to obtain compound Int5 (422 mg, 50%).

The following intermediates were synthesized by the method of Preparation Example 2:

Preparation Example 3: Preparation of Intermediate P1

Step 1: Synthesis of compound P1-2

In a _N2 environment, TFA (1.2 mL) was added to a DMF (6 mL) solution of compound TAS-106 (150 mg, 0.56 mmol) and compound P1-1 (620 mg, 1.68 mmol) at 0°C. The reaction was naturally heated to 25°C and stirred for 4 h. After the reaction was complete as monitored by TLC, the reaction solution was cooled to 0°C, quenched with water (20 mL), extracted with EA (20 mL) 3 times, the organic layers were combined, dried, filtered, concentrated, and purified by Pre-TLC to obtain compound P1-2 (55 mg, 28%).

Step 2: Synthesis of compound P1

In a _N2 environment, a mixed solution of compound P1-2 (55 mg, 0.16 mmol) in DMF (1.0 mL)/diethylamine (1.0 mL) was stirred at 25°C for 2 h, and the reaction was complete after monitoring by LC-MS. The reaction solution was concentrated to dryness and slurried with petroleum ether (2 mL) to obtain a light yellow solid (45 mg), which was directly used in the next reaction.

The intermediate P2 was synthesized by referring to the method of Preparation Example 3:

Example 1: Preparation of linker-payload for ligand drug conjugates

Example 1.1: Synthesis of Compound C1

In a nitrogen environment, 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine hydrochloride (50 mg, 0.17 mmol) was added to a DMF (1.5 mL) solution containing compound P1 (45 mg, 0.14 mmol) and compound Int1 (60 mg, 0.14 mmol) at 25°C and stirred for 2 h. After the reaction was completed as monitored by LC-MS, compound C1 (14 mg, yield 13%) was directly purified by reverse HPLC.

ESI-MS (m/z): 808.3 [M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ8.05 (d, J＝7.6Hz, 1H), 7.31–7.23 (m, 4H), 7.23–7.16 (m, 1H), 6.78 (s, 2H), 6.05 (d,J＝6.5Hz,1H),6.01(d,J＝7.6Hz,1H),4.75(d,J＝10.2Hz,1H),4.66(d,J＝10.2Hz,1H),4.53(dd ,J＝9.3,5.7Hz,1H),4.25(d,J＝6.5Hz,1H),4.14 (t,J＝2.9Hz,1H),3.92(d,J＝17.0Hz,1H),3.88–3.75(m,7H),3.48(t,J＝7.1Hz,2H),3.22(dd,J＝ 13.9,5.6Hz,1H),3.10(s,1H),3.01(dd,J＝13.9,9.3Hz,1H),2.26(t,J＝7.5Hz,2H),1.68–1.53(m,4H), 1.32(dd,J＝15.4,8.1Hz,2H).

Example 1.2: Preparation of Compound C10

Step 1: Preparation of compound C10-1

In a nitrogen environment, at 25°C, 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine hydrochloride (100 mg, 0.34 mmol) was added to a DMF (3 mL) solution containing compound P1 (90 mg, 0.28 mmol) and compound Int4 (122 mg, 0.28 mmol) and stirred for 2 h. After the reaction was completed as monitored by LCMS, it was directly purified by reverse HPLC to obtain compound C10-1 (100 mg, yield 46%).

Step 2: Preparation of compound C10

Compound C10-1 (100 mg, 0.13 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) at 25 °C, and then N-methylmorpholine (27.3 mg, 0.26 mmol) and tetrakistriphenylphosphine palladium (14.5 mg, 0.013 mmol) were added. After nitrogen replacement, the reaction was continued at room temperature for 2 h. After LCMS showed that the reaction was complete, the reaction solution was concentrated to dryness, and the residue was purified by preparative HPLC to obtain compound C10 (10 mg, yield 11%).

ESI-MS (m/z): 733.3 [M+H] ⁺ .

The following compounds were synthesized according to the method of Example 1.1

Example 1.3: Preparation of Compound C17

Step 1: Preparation of compound C17-2

In a nitrogen environment, at 25°C, 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine hydrochloride (93 mg, 0.34 mmol) was added to a DMF (5 mL) solution containing compound P1 (100 mg, 0.28 mmol) and compound C17-1 (142 mg, 0.28 mmol) and stirred for 2 h. After the reaction was completed as monitored by LCMS, it was directly purified by reverse HPLC to obtain compound C17-2 (110 mg, yield 47%).

Step 2: Preparation of compound C17-3

In a nitrogen environment, a mixed solution of compound C17-2 (110 mg, 0.13 mmol) in DMF (1.0 mL)/diethylamine (1.0 mL) was stirred at 25°C for 2 h, and the reaction was complete after monitoring by LCMS. The reaction solution was concentrated to dryness and slurried with petroleum ether to obtain compound C17-3 (80 mg), which was directly used in the next step.

Step 3: Preparation of compound C17

In a nitrogen environment, compound C17-3 (40 mg, 0.065 mmol) and DIEA (25 mg, 0.195 mmol) were dissolved in anhydrous dichloromethane (5 mL), cooled to 0°C, and bromoacetic anhydride (18.6 mg, 0.072 mmol) was added at this temperature, and the reaction was kept warm for 1 hour. After the reaction was completed, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by reverse HPLC to obtain compound C17 (5 mg, yield 11%).

ESI-MS (m/z): 735.2 [M+H] ⁺ .

The following compounds were synthesized by referring to the methods of Examples 1.3 and 1.2:

Example 1.4: Preparation of Compound C26

Step 1: Synthesis of compound C26-1

In a nitrogen environment, at 25°C, 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine hydrochloride (93 mg, 0.34 mmol) was added to a DMF (5 mL) solution containing compound P1 (100 mg, 0.28 mmol) and compound Int8 (172 mg, 0.28 mmol) and stirred for 2 h. After the reaction was completed as monitored by LCMS, it was directly purified by reverse HPLC to obtain compound C26-1 (150 mg, yield 56%).

Step 2: Preparation of compound C26-2

In a nitrogen environment, a mixed solution of compound C26-1 (150 mg, 0.16 mmol) in DMF (1.0 mL)/diethylamine (1.0 mL) was stirred at 25°C for 2 h, and the reaction was complete after monitoring by LCMS. The reaction solution was concentrated to dryness and slurried with petroleum ether to obtain compound C26-2 (100 mg), which was directly used in the next step.

Step 3: Preparation of compound C26

2-Methylsulfonyl-5-pyrimidinecarboxylic acid (20 mg, 0.08 mmmol) was dissolved in DMF (2 mL), and EDCI (56 mg, 0.3 mmol) and HOBT (26 mg, 0.2 mmol) were added and stirred at 25 ° C for 30 minutes. Then compound C26-2 (58 mg, 0.08 mmol) was added and stirred for 1 h. After the reaction was completed, water was added to quench the reaction and extracted with ethyl acetate. The organic phase was dried, concentrated and purified by reverse phase HPLC to obtain compound C26 (5 mg, yield 7%).

MS (ESI) m/z: 912.3 [M+H]+.

The following compounds were synthesized by referring to the methods of Examples 1.4 and 1.2:

Example 1.5: Preparation of Compound D31

Step 1: Synthesis of compound D31-1

TAS-106 (267 mg, 1.0 mmol) was dissolved in anhydrous dichloromethane (15 mL), imidazole (136 mmol, 2.0 mmol) was added, the temperature was lowered to 0°C, and then TBSCl (165 mg, 1.1 mmol) was added. The reaction was continued for 6 h at this temperature. After TLC detection showed that the reaction was complete, water and ethyl acetate were added, stirred and separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound D31-1 (360 mg, yield 94%).

Step 2: Synthesis of compound D31-2

In a nitrogen environment, at 25°C, 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine hydrochloride (312 mg, 0.34 mmol) was added to a DMF (5 mL) solution containing compound D31-1 (360 mg, 0.94 mmol) and compound Int11 (172 mg, 0.94 mmol) and stirred for 2 h. After the reaction was completed as monitored by LCMS, it was directly purified by reverse HPLC to obtain compound D31-2 (200 mg, yield 25%).

Step 3: Synthesis of compound D31-3

In a nitrogen environment, a mixed solution of compound D31-2 (200 mg, 0.24 mmol) in DMF (1.0 mL)/diethylamine (1.0 mL) was stirred at 25°C for 2 h, and the reaction was complete after monitoring by LCMS. The reaction solution was concentrated to dryness and slurried with petroleum ether to obtain compound D31-3 (135 mg), which was directly used in the next step.

Step 4: Synthesis of compound D31-4

2-Methylsulfonyl-5-pyrimidinecarboxylic acid (20 mg, 0.08 mmmol) was dissolved in DMF (2 mL), and EDCI (56 mg, 0.3 mmol) and HOBT (26 mg, 0.2 mmol) were added and stirred at 25 ° C for 30 minutes. Then compound D31-3 (58 mg, 0.09 mmol) was added and stirred for 1 h. After the reaction was completed, water was added to quench the reaction and extracted with ethyl acetate. The organic phase was dried, concentrated and purified by reverse phase HPLC to obtain compound D31-4 (20 mg, 31%).

Step 5: Synthesis of compound D31

Compound D31-4 (20 mg, 0.025 mmol) was dissolved in anhydrous dichloromethane (3 mL), cooled to 0°C, 0.5 mL TFA was added, and the reaction was maintained at this temperature for 2 h. The product was then concentrated to dryness under reduced pressure, and the residue was purified by reverse phase HPLC to obtain compound D31 (2 mg, 11%). MS (ESI) m/z: 707.2 [M+H] +.

The following compounds were synthesized by referring to the method of Example 1.5:

Example 2: Preparation of Antibody-Drug Conjugate ADC

The antibody is prepared according to conventional methods, for example, after constructing the vector, it can be transfected into eukaryotic cells such as HEK293 cells and CHO cells for purification and expression. Trastuzumab, Sacituzumab, and anti-GPC-3 antibody Codrituzumab (prepared with reference to WO2006006693) are used as examples to prepare ligand-drug conjugates.

Amino acid sequence of Trastuzumab:

Light chain (SEQ ID NO: 1)

DIQMTQSPSSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGL SSPVTKSFNRGEC

Heavy chain (SEQ ID NO: 2)

EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNT KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKN

Amino acid sequence of sacituzumab:

Light chain (SEQ ID NO: 3)

DIQLTQSPSSSLSASVGDRVSITCKASQDVSIAVAWYQQKPGKAPKLLIYSASYRYTGVPDRFSGSGSGTDFTLTISSLQPEDFAVYYCQQHYITPLTFGAGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLS SPVTKSFNRGEC

Heavy chain (SEQ ID NO: 4)

Question PSNTKVDKRVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK

Amino acid sequence of anti-GPC-3 antibody Codrituzumab

Light chain (SEQ ID NO: 5)

DVVMTQSPLSLPVTPGEPASISCRSSQSLVHSNRNTYLHWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQNTHVPPTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC

Heavy chain (SEQ ID NO:6)

QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYEMHWVRQAPGQGLEWMGALDPKTGDTAYSQKFKGRVTLTADKSTSTAYMELSSLTSEDTAVYYCTRFYSYTYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK VDKKVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPGK

Example 2.1: Preparation of AA1-1

At 37°C, the prepared tris(2-carbonylethyl)phosphine hydrochloride (10mM, 0.135mL, 1.35μmol) was added to the buffer of the antibody Trastuzumab (14.0mM succinic acid-sodium hydroxide + 108mM NaCl pH 6.0; 20mg, 10.0mg/mL, 0.135μmol), and the mixture was placed in a water bath shaker and shaken at 37°C for 3 hours. After stopping the reaction, the excess TCEP was removed by ultrafiltration with 14.0mM succinic acid-sodium hydroxide + 108mM NaCl pH 6.0 buffer;

Compound C1 (1.305 mg, 1.62 μmol) was dissolved in 0.2 mL DMSO, added to the above solution, placed in a water bath shaker, and oscillated at 22° C. for 2 hours to stop the reaction. The reaction solution was desalted and purified using a Sephadex G25 gel column (elution phase: 20 mM histidine-hydrochloric acid pH 5.5) to obtain a solution of the exemplary product AA1-1 (20 mM histidine-hydrochloric acid pH 5.5; 17.94 mg, 4.96 mg/mL, yield: 89.7%), which was stored at 4° C.

The DAR value q was calculated by LC-MS analysis and detection = 7.90.

Example 2.2: Preparation of AA3-1

At 37°C, the prepared tris(2-carbonylethyl)phosphine hydrochloride (10 mM, 0.135 mL, 1.35 μmol) was added to the antibody codrituzumab buffer (14.0 mM succinic acid-sodium hydroxide + 108 mM NaCl pH 6.0; 20 mg, 10.0 mg/mL, 0.135 μmol), placed in a water bath shaker, and shaken at 37°C for 3 hours. After stopping the reaction, the excess TCEP was removed by ultrafiltration with 14.0 mM succinic acid-sodium hydroxide + 108 mM NaCl pH 6.0 buffer;

Compound C1 (1.305 mg, 1.62 μmol) was dissolved in 0.2 mL DMSO, added to the above solution, placed in a water bath shaker, and oscillated at 22° C. for 2 hours to stop the reaction. The reaction solution was desalted and purified using a Sephadex G25 gel column (elution phase: 20 mM histidine-hydrochloric acid pH 5.5) to obtain a solution of the exemplary product AA3-1 (20 mM histidine-hydrochloric acid pH 5.5; 16.56 mg, 4.03 mg/mL, yield: 83%), which was stored at 4° C.

The DAR value q was 7.96 as detected and calculated by LC-MS analysis.

The following ADC compounds were synthesized by referring to the methods of Examples 2.1 and 2.2:

Biological Testing

Example 3: In vitro cell proliferation inhibition activity test of antibody-drug conjugates

Example 3.1: In vitro proliferation inhibition activity test of NCI-N87 cells

use The chemiluminescent cell viability assay (CTG method) was used to evaluate the inhibitory effect of the anti-Her2 Trastuzumab-TAS-106 ADC drug AA1-1 on cell proliferation in Her2-positive human gastric cancer cells NCI-N87 after incubation for 6 days.

Cells in the logarithmic growth phase were collected and plated at a density of 6000 cells/well. The cell plates were placed in a 37°C, 5% CO ₂ incubator for overnight culture. On the second day of the experiment, AA1-1 was diluted 3 times with complete medium to obtain 9 concentration gradients (starting with the highest concentration of 300nM). After the drug, 100μL/well was added to the cell culture plate, and the complete medium was used as a blank control. Three replicates were set up; the cells were continued to be incubated in a 37°C, 5% CO ₂ incubator for 6 days. After the incubation, the cell culture plate was removed, equilibrated to room temperature, and 50μL CTG detection reagent (Promega, Cat#: G7573) was added to each well. After shaking and mixing, it was placed in the dark for 10 minutes, and the signal value was read using an enzyme marker. GraphPad Prism software was used to draw an S-type dose-response curve using a nonlinear regression model and calculate the IC ₅₀ value. The cell viability calculation formula = (Lum _{test drug} - Lum _{blank control} ) / (Lum _{solvent blank control -} Lum _{blank control} ) × 100%.

The experimental results are shown in Table 1 below:

Table 1: Anti-proliferation activity of antibody-drug conjugates on human gastric cancer cells

Experimental conclusion: According to the results in Table 1, the antibody-drug conjugate AA1-1 of the present application has significant proliferation inhibitory activity against Her2-positive human gastric cancer cell NCI-N87, and the effect is significantly better than TAS-106.

Example 3.2: In vitro proliferation inhibition activity test of A549 cells

use The chemiluminescent cell viability assay (CTG method) was used to evaluate the inhibitory effect of the anti-Her2 Trastuzumab-TAS-106 ADC drug AA1-1 on cell proliferation in Her2-positive human non-small cell lung cancer cells A549 after incubation for 6 days.

Cells in the logarithmic growth phase were collected and plated at a density of 6000 cells/well. The cell plates were placed in a 37°C, 5% CO ₂ incubator for overnight culture. On the second day of the experiment, AA1-1 was diluted 3 times with complete medium to obtain 9 concentration gradients (starting with the highest concentration of 300nM). After the drug, 100μL/well was added to the cell culture plate, and the complete medium was used as a blank control. Three replicates were set up; the cells were continued to be incubated in a 37°C, 5% CO ₂ incubator for 6 days. After the incubation, the cell culture plate was removed, equilibrated to room temperature, and 50μL CTG detection reagent (Promega, Cat#: G7573) was added to each well. After shaking and mixing, it was placed in the dark for 10 minutes, and the signal value was read using an enzyme reader. GraphPad Prism software was used to draw an S-type dose-response curve using a nonlinear regression model and calculate the IC ₅₀ value. The cell viability calculation formula = (Lum _{test drug} - Lum _{blank control} ) / (Lum _{solvent blank control -} Lum _{blank control} ) × 100%. The results are shown in Table 2.

Table 2: Antibody-drug conjugates' inhibitory activity on proliferation of human non-small cell lung cancer cells

Experimental conclusion: The antibody-drug conjugate AA1-1 of the present application has significant proliferation inhibitory activity on Her2-positive human non-small cell lung cancer cells A549.

Example 3.3: In vitro proliferation inhibition activity test of HepG2 cells

use The chemiluminescent cell viability assay (CTG method) was used to evaluate the inhibitory effect of the anti-GPC3 Codrituzumab-TAS-106 ADC drug AA3-1 on cell proliferation in GPC3-positive human liver cancer cells HepG2 after incubation for 6 days.

Cells in the logarithmic growth phase were collected and plated at a density of 6000 cells/well. The cell plates were placed in a 37°C, 5% CO ₂ incubator for overnight culture. On the second day of the experiment, AA4-1 was diluted 3 times with complete medium to obtain 9 concentration gradients (starting with the highest concentration of 300nM). After the drug, 100μL/well was added to the cell culture plate, and the complete medium was used as a blank control. Three replicates were set up; the cells were continued to be incubated in a 37°C, 5% CO ₂ incubator for 6 days. After the incubation, the cell culture plate was removed, equilibrated to room temperature, and 50μL CTG detection reagent (Promega, Cat#: G7573) was added to each well. After shaking and mixing, it was placed in the dark for 10 minutes, and the signal value was read using an enzyme marker. GraphPad Prism software was used to draw an S-type dose-response curve using a nonlinear regression model and calculate the IC ₅₀ value. The cell viability calculation formula = (Lum _{test drug} - Lum _{blank control} ) / (Lum _{solvent blank control -} Lum _{blank control} ) × 100%. The results are shown in Table 3.

Table 3: Antibody-drug conjugates' inhibitory activity on proliferation of human hepatoma cells

Experimental conclusion: The antibody-drug conjugate AA3-1 of the present application has significant proliferation inhibitory activity against human liver cancer cells HepG2 that positively express GPC3.

Example 4: In vivo tumor inhibition test of antibody drug conjugates

To evaluate the inhibitory effect of AA1-1 on tumor formation in vivo, the antitumor effect of AA1-1 was evaluated after the Her2-positive human breast cancer cells JIMT-1 were used to form transplanted tumors in mice.

Evaluation of the efficacy of antibody-drug conjugate AA1-1 on JIMT-1 human breast cancer cell-bearing mice

1. Test drugs and materials

Blank control group (control group): normal saline

AA1-1 (treatment group): 5 mg/kg, single dose

2. Preparation method: All samples were diluted with physiological saline.

3. Experimental animals: 8-week-old female BALB/c-nude mice were purchased from Jicui Pharmaceutical Biotechnology Co., Ltd.

4. Test methods:

1×10 ⁷ JIMT-1 cells were inoculated subcutaneously at the right anterior shoulder of 8-week-old female BALB/c-nude mice. When the tumor grew to about 125 mm ³ , the tumor-bearing mice were randomly divided into groups using StudyDirectorTM and injected with A1-1 intravenously (iv) starting on the same day (day 0), once every 7 days for a total of 2 injections, with a dose of 5 mg/kg. Tumor volume and body weight were measured twice a week and the data were recorded.

There were 5 mice in each vehicle control group or treatment group. The tumor inhibition rate was calculated by measuring the tumor volume. Tumor inhibition rate (TGI%) = 100% - (tumor volume of the treatment group on the day of measurement - tumor volume of the treatment group on day 0) / (tumor volume of the control group on the day of measurement - tumor volume of the control group on day 0).

The experimental results are shown in Table 4 and Figure 1. The antibody drug conjugate AA1-1 showed significant anti-tumor activity after a single administration.

Table 4: In vivo tumor inhibition effect of antibody drug conjugate AA1-1 on JIMT-1 tumor-bearing mice

Treatment Group Day35 tumor inhibition rate AA1-1 80.35%

.

Claims (30)

1. A compound of formula I, a pharmaceutically acceptable salt, stereoisomer, solvate or a solvate of a pharmaceutically acceptable salt thereof: Ab is the ligand that binds to the target; q is an integer or decimal from 1 to 16; ^L1 is ^L2 is -(C(R ^L21 R ^L22 ) _n -, Where n is a natural number, Any -C(R ^{L21 RL22} )- in L ² is each independently optionally replaced by the following structural units: -Cyr-, -N(R ^L23 )C(O)-, -C(O)N(R ^L23 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR ^L23 -, -O-, -S-, -SO-, -SO ₂ -, -P(R ^L23 )-, -P(＝O)(R ^L23 )-, -N(R ^L23 )SO ₂ -, -SO ₂ N(R ^L23 )-, -C(＝S)-, -C(＝NR ^L23 )-, -N＝N-, -C＝N-, -N＝C-, Instead, -Cyr- is phenylene, 5- to 8-membered heteroarylene, 3- to 10-membered heterocyclylene or 3- to 10-membered cycloalkylene, wherein the -Cyr- is optionally substituted by 1 or more R ^cx , each of ^RL21 , ^RL22 , ^RL23 and ^Rcx is independently hydrogen, deuterium, halogen, _-NO2 , -CN, -OR ^L2a , -SR ^L2a , -N( ^RL2a ) ₂ , -C(O) ^RL2a , -CO2RL2a ^, -C(O)C( _O ) ^RL2a , -C(O) _CH2C (O) ^RL2a , -S(O) ^RL2a , -S(O) ^2RL2a , -C(O)N( ^RL2a ) ₂ , _-SO2N ( ^RL2a ) ₂ , -OC ₍ O) ^RL2a , -N( ^RL2a ) ^SO2RL2b , -N( ^RL2a )COR ^L2b , - _{( CH2} ) _y -CO-(N(Me) _CH2 C(O)) _m -OR ^L2a , -(CH ₂ ) _y -CO-(N(Me)CH ₂ C(O)) _m -NHR ^L2a , -(CH ₂ ) _y -CO-(N(Me)CH ₂ C(O)) _m -N ⁺ (R ^L2a ) ₃ , -(CH ₂ ) _y -NHCOCH ₂ (OCH ₂ CH ₂ )OR ^L2a , -(CH ₂ ) _y -NH (COCH ₂ (N(Me)) _m -R ^L2a , -(CH ₂ ) _y -CONH-(CH ₂ CH ₂ O) _m -R ^L2a , -(CH ₂ ) _y -NHCO-(CH ₂ CH ₂ O) _m -R ^L2a , -(CH ₂ CH ₂ O) _m -R ^L2a , -(COCH ₂ N(Me)) _m -R ^L2a , -COCH ₂ (OCH ₂ CH ₂ ) _m -OR ^L2a , -CO-(CH ₂ CH ₂ O) _m -R ^L2a , -CO-(CH ₂ ) _y -CONH-(CH ₂ CH ₂ O) _m -R ^L2a , -CO-(CH ₂ ) _y -NHCO-(CH ₂ CH ₂ ^O ) _m -R ^L2a , -C _1-6 alkyl, -C _2-6 alkenyl, -C 2-6 alkynyl, _3-8 membered cycloalkyl, 4-10 membered heterocycloalkyl, 6-10 membered aryl or 3-10 membered heteroaryl which is unsubstituted or substituted with one or more R L2a , Each m and y is independently a natural number from 0 to 40, each ^RL2a and ^RL2b is independently hydrogen, deuterium, halogen, _-NO2 , -CN, -OH, -SH, _-NH2 , -N(Me) ₂ , _-CO2H , -S(O) _2Me , -S( _O ) _2OH , -C(O)NH2, _{-SO2NH2 , -C1-6alkyl} , _-C2-6alkenyl , -C2-6alkynyl, _3-8 membered cycloalkyl, 4-10 membered heterocycloalkyl, 6-10 membered aryl, or 5-10 membered heteroaryl; L ³ is a chemical bond or a short peptide consisting of 1 amino acid residue, 2-10 amino acid residues, One or more of, wherein the amino acid residue is a natural amino acid residue or a non-natural amino acid residue; Tr is a chemical bond, Each of R ^Tr , R ^Tr1 and R ^Tr2 is each independently hydrogen, deuterium, halogen, -NO ₂ , -CN, -OH, -SH, -NH ₂ , -CO ₂ H, -S(O) ₂ OH, -C(O)NH ₂ , -SO ₂ NH ₂ , -OC(O)NH ₂ , -CH ₂ CO-(N(Me)CH ₂ C(O)) _z -OR ^Tra , -CH ₂ CO-(N(Me)CH ₂ C(O)) _z -NHR ^Tra , -(CH 2 CH ₂ O) _z -R ^Tra , -CONH-(CH ₂ CH ₂ O) _z -R ^Tra , -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, 3-8 membered cycloalkyl, 4-10 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl _, the -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, 3-8 membered cycloalkyl, 4-10 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl. _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, 3-8 membered cycloalkyl, 4-10 membered heterocycloalkyl, 6-10 membered aryl and 5-10 membered heteroaryl are optionally substituted with one or more R ^Tra ; R ^Tra is hydrogen, deuterium, halogen, -NO ₂ , -CN, -OH, -SH, -NH ₂ , -N(Me) ₂ , -S(O) ₂ Me, -CO ₂ H, -S(O) ₂ OH, -C(O)NH ₂ , -SO ₂ NH ₂ , -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, 3-8 membered cycloalkyl, 4-10 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl, z is a natural number 0 or greater; The heteroatoms in the 5- to 8-membered heteroarylene group, the 3- to 10-membered heterocyclylene group, the 5- to 10-membered heterocyclylene group and the 4- to 10-membered heterocycloalkyl group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4. 2. The compound of formula I according to claim 1, its pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a pharmaceutically acceptable salt, characterized in that: Ab is a target-binding polypeptide, antibody or antigen-binding fragment thereof; preferably, Ab is an antibody or an antigen-binding fragment thereof; more preferably, Ab is a monoclonal antibody. 3. The compound of formula I according to claim 2, its pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a pharmaceutically acceptable salt, characterized in that Ab satisfies one or more of the following conditions: (1) The antibody is a fully human antibody, a humanized antibody, a chimeric antibody, a probody, a bispecific antibody, a multispecific antibody, a monoclonal antibody or a polyclonal antibody; preferably, the antibody is an anti-HER2 antibody (e.g., trastuzumab or pertuzumab or variants thereof, or a Trop-2 antibody (e.g., sacituzumab, M1, M2 or M3) or variants thereof, or an anti-GPC-3 antibody (codrituzumab) or variants thereof; more preferably, the antibody is selected from Scheme 1 or Scheme 2: Scheme 1: The antibody is an anti-HER2 antibody (e.g., trastuzumab) or pertuzumab or variants thereof Preferably, the antibody is trastuzumab; Scheme 2: The antibody is an anti-HER2 antibody (e.g., trastuzumab or pertuzumab) or a variant thereof, or an anti-GPC-3 antibody (e.g., codrituzumab) or a variant thereof; preferably, the antibody is trastuzumab or codrituzumab; (2) The antigen-binding fragment is a Fab, Fab', F(ab')2, Fv, scFv, diabody, Fd, dAb, VHH, monoclonal antibody or complementarity determining region (CDR) fragment; (3) Ab specifically binds to an antigen selected from the group consisting of 5T4, AGS-16, ANGPTL4, ApoE, CD19, CTGF, CXCR5, FGF2, MCPT8, MFI2, MS4A7, NCA, Sema5b, SLITRK6, STC2, TGF, 0772P, 5T4, ACTA2, ADGRE1, AG-7, AIF1, AKR1C1, AKR1C2, ASLG659, Axl, B7H 3. BAFF-R, BCMA, BMPR1B, BNIP3, C1QA, C1QB, CA6, CADM1, CCD79b, CCL5, CCR5, CCR7, CD1lc, CD123, CD138, CD142, CD147, CD166, CD19, CD19, CD22, CD21, CD20, CD205, CD22, CD223, CD228, CD25, CD30, CD33, CD3 7. CD38, CD40, CD45, CD45(PTPRC), CD46, CD47, CD49D(ITGA4), CD56, CD66e, CD70, CD71, CD72, CD74, CD79a, CD79b, CD80, CDCP1, CDH11, CDllb, CEA, CEACAM5, c-Met, COL6A3, COL7A1, CRIPTO , CSF1R, CTSD, CTS S, CXCL11, CXCL10, DDIT4, DLL3, DLL4, DR5, E16, EFNA4, EGFR, EGFRvIII, EGLN, EGLN3, EMR2, ENPP3, EpCAM, EphA2, EphB2R, ETBR, FcRH2, FcRHl, FGFR2, FGFR3, FLT3, FOLR-α, GD2, GEDA, GPC-1, GPC- 3.GPNMB,GP R20, GZMB, HER2, HER3, HLA-DOB, HMOX1, IFI6, IFNG, IGF-1R, IGFBP3, IL10RA1, IL-13R, IL-2, IL20Ra, IL-3, IL-4, IL-6, IRTA2, KISS1R, KRT33A, LIV-1, LOX, LRP-1, LRRC15, LUM, LY64, LY6E, Ly8 6, LYPD3, MDP, MMP10, MMP14, MMP16, MPF, MSG783, MSLN, MUC-1, NaPi2b, Napi3b, Nectin-4, Nectin-4, NOG, P2X5, pCAD, P-Cadherin, PDGFRA, PDK1, PD-L1, PFKFB3, PGF, PGK1, PIK3AP1, PIK3CD, PLOD2, PSCA, PSCAhlg, PS MA,P SMA, PTK7, P-cadherin, RNF43, NaPi2b, ROR1, ROR2, SERPINE1, SLC39A6, SLTRK6, STAT1, STEAP1, STEAP2, TCF4, TENB2, TGFB1, TGFB2, TGFBR1, TNFRSF21, TNFSF9, Trop-2, TrpM4, Tyro7, UPK1B, VEGFA, WNT5A, epidermal growth factor factor, brevican, mesothelin, sodium phosphate cotransporter 2B, Claudin18.2, endothelin receptor, mucin (such as mucin 1 and mucin 16), guanylate cyclase C, integrin a4p7, integrin a5p6, trophoblast cell glycoprotein, or tissue factor; preferably, the Ab specifically binds to an antigen selected from the group consisting of 5T4, AGS-16, ANGPTL4, ApoE, CD19, CTGF, CXCR5, FGF2, MCPT8, MF I2, MS4A7, NCA, Sema5b, SLITRK6, STC2, TGF, 0772P, 5T4, ACTA2, ADGRE1, AG-7, AIF1, AKR1C1, AKR1C2, ASLG659, Axl, B7H3, BAFF-R, BCMA, BMPR1B, BNIP3, C1QA, C1QB, CA6, CADM1, CCD79b, CCL5, CCR5, CCR7, CD1 lc, CD123, CD138, CD142, CD147, CD166, CD19, CD19, CD22, CD21, CD20, CD205, CD22, CD223, CD228, CD25, CD30, CD33, CD37, CD38, CD40, CD45, CD45(PTPRC), CD46, CD47, CD49D(ITGA4), CD56, CD66e, CD70, CD71 , CD72, CD74, CD79a, CD79b, CD80, CDCP1, CDH11, CDllb, CEA, CEACAM5, c-Met, COL6A3, COL7A1, CRIPTO, CSF1R, CTSD, CTSS, CXCL11, CXCL10, DDIT4, DLL3, DLL4, DR5, E16, EFNA4, EGFR, EGFRvIII, EGLN ,EGLN3,E MR2, ENPP3, EpCAM, EphA2, EphB2R, ETBR, FcRH2, FcRHl, FGFR2, FGFR3, FLT3, FOLR-α, GD2, GEDA, GPC-1, GPNMB, GPR20, GZMB, HER2, HER3, HLA-DOB, HMOX1, IFI6, IFNG, IGF-1R, IGFBP3, IL10RA1, IL-13R ,IL-2,I L20Ra, IL-3, IL-4, IL-6, IRTA2, KISS1R, KRT33A, LIV-1, LOX, LRP-1, LRRC15, LUM, LY64, LY6E, Ly86, LYPD3, MDP, MMP10, MMP14, MMP16, MPF, MSG783, MSLN, MUC-1, NaPi2b, Napi3b, Nectin-4, N ectin-4,NOG,P2 X5, pCAD, P-Cadherin, PDGFRA, PDK1, PD-L1, PFKFB3, PGF, PGK1, PIK3AP1, PIK3CD, PLOD2, PSCA, PSCAhlg, PSMA, PSMA, PTK7, P-Cadherin, RNF43, NaPi2b, ROR1, ROR2, SERPINE1, SLC39A6, SLTRK6, STAT1, STEAP1, S TEAP2, TCF4, TENB2, TGFB1, TGFB2, TGFBR1, TNFRSF21, TNFSF9, Trop-2, TrpM4, Tyro7, UPK1B, VEGFA, WNT5A, epidermal growth factor, brevican, mesothelin, sodium phosphate cotransporter 2B, Claudin18.2, endotene receptor, mucins (such as mucin 1 and mucin 16), guanylate cyclase C, integrin a4p7, integrin Preferably, the Ab specifically binds to an antigen selected from the group consisting of HER2, HER3, B7H3, TROP2, Claudin18.2, CD30, CD33, CD70, EGFR, or GPC-3; and most preferably, the Ab specifically binds to an antigen selected from the group consisting of HER2, HER3, B7H3, TROP2, Claudin18.2, CD30, CD33, CD70, or EGFR. 4. A compound of formula I as claimed in any one of claims 1 to 3, a pharmaceutically acceptable salt, a stereoisomer, a solvate or a solvate of a pharmaceutically acceptable salt thereof, characterized in that q is an integer or decimal from 2 to 8, preferably an integer or decimal from 7 to 8, for example, in Scheme 1 or Scheme 2: Scheme 1: q is 7.8 or 7.9; Scheme 2: q is 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9 or 7.96, for example, 7.9 or 7.96. 5. The compound of formula I according to any one of claims 1 to 4, its pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a pharmaceutically acceptable salt, characterized in that L ¹ is Preferably, ^L1 is More preferably, ^L1 is More preferably, ^L1 is Still more preferably, ¹ is 6. The compound of formula I according to any one of claims 1 to 4, its pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a pharmaceutically acceptable salt, characterized in that L ¹ is Wherein, a is connected to the antibody, b is connected to ^L2 ; preferably, ^L1 is Wherein, a is connected to the antibody, b is connected to ^L2 ; more preferably, ^L1 is Among them, a is connected to the antibody, b is connected to ^L2 ; optimally, Among them, a is connected to the antibody and b is connected to ^L2 . 7. The compound of formula I according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a pharmaceutically acceptable salt thereof, characterized in that: ^L2 is -(CHR ^L21 ) _n -; Where n is a natural number from 0 to 20; Any -CHR ^L21 - in ^L2 can be independently replaced by the following structural units: -Cyr-, -N(R ^L23 )C(O)-, -C(O)N(R ^L23 )-, -C(O)-, -NR ^L23 -, -O-, Replacement; -Cyr- is phenylene, 5- to 6-membered heteroarylene, 4- to 10-membered heterocyclylene, or 3- to 6-membered cycloalkylene, wherein said -Cyr- is optionally substituted with 1 to 3 R ^cx ; each of ^RL21 , ^RL23 and ^Rcx is independently hydrogen, halogen, -OR ^L2a , -N( ^RL2a ) ₂ , _-C (O) ^RL2a , -S(O) ^2RL2a , -C(O)N( ^RL2a ) ₂ , _-SO2N ( ^RL2a ) ₂ , -N( ^RL2a ) _SO2RL2b , -N( ^{RL2a )COR L2b ,} -( _CH2 ) _y -CO-(N(Me) _CH2C (O)) _m -OR ^L2a , -( _CH2 ) _y -CO-(N(Me) _CH2C (O)) _m -NHR ^L2a , -( _CH2 ) _y -CONH-( _CH2CH2O ) _m ^-RL2a _, -( _CH2 ) _y -NHCO-(CH ₂ CH ₂ O) _m -R ^L2a , -(CH ₂ ) _y -NHCOCH ₂ (OCH ₂ CH ₂ )OR ^L2a , -(CH ₂ ) _y -NH(COCH ₂ (N(Me)) _m -R ^L2a , -(CH ₂ ) _y -NHCO-(CH ₂ CH ₂ O) _m -R ^L2a , -(CH ₂ CH ₂ O) _m -R ^{L2 a} , -(COCH ₂ N(Me)) _m -R ^L2a , -COCH ₂ (OCH ₂ CH ₂ ) _m -OR ^L2a , -CO-(CH ₂ CH ₂ O) _m -R ^L2a , -C _1-6 alkyl, -C _2-6 alkenyl, -C The -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, _3-8 membered cycloalkyl, 4-10 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more R ^Tra ; m is a natural number from 0 to 8; y is 0, 1, 2, 3, 4; Each ^RL2a , ^RL2b is independently selected from hydrogen, halogen, -CN, -OH, _-NH2 , -N(Me) ₂ , _-CO2H , -C(O) _NH2 or _-C1-6alkyl ; The heteroatoms in the 5- to 6-membered heteroarylene group, the 4- to 10-membered heterocyclylene group and the 4- to 10-membered heterocycloalkyl group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4; Preferably, ^L2 is -( _CH2 ) _n- ; Where n is a natural number from 0 to 14; Any -CH ₂ - in L ² may be independently replaced by the following structural units: phenylene, 5- to 6-membered heteroarylene, 4- to 6-membered heterocyclylene, 3- to 6-membered cycloalkylene, -N(R ^L23 )C(O)-, -C(O)N(R ^L23 )-, -C(O)-, -NR ^L23 -, -O-, Replacement; Each R ^L23 is independently hydrogen, -OR ^L2a , -C(O)R ^L2a , -S(O) ₂ R ^L2a , -C(O)N(R ^L2a ) ₂ , -SO ₂ N(R ^L2a ) ₂ , -(CH ₂ ) _y -CO-(N(Me)CH ₂ C(O)) _m -OR ^L2a , -(CH ₂ ) _y -CO-(N(Me)CH ₂ C(O)) _m -NHR ^L2a , -(CH ₂ ) _y -CONH-(CH ₂ CH ₂ O) _m -R ^L2a , -(CH ₂ ) _y -NHCOCH ₂ (OCH ₂ CH ₂ )OR ^L2a , -(CH ₂ CH ₂ O) _m -R ^L2a , -(COCH ₂ N(Me)) _m -R ^L2a , -COCH ₂ (OCH ₂ CH ₂ ) _m -OR ^L2a , -CO-(CH ₂ CH ₂ O) _m -R ^L2a , or -C _1-6 alkyl; the -C _1-6 alkyl is optionally substituted by one or more Several were replaced by R ^L2a ; m is a natural number from 0 to 8; y is 0, 1, 2, 3, or 4; Each ^RL2a is independently selected from hydrogen, halogen, -CN, -OH, _-NH2 , -N(Me) ₂ , _-CO2H , -C(O) _NH2 or _-C1-6alkyl ; The heteroatoms of the 5- to 6-membered heteroarylene group and the 4- to 6-membered heterocyclylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; More preferably, ^L2 is -(CHR ^L21 ) _n -; Where n is a natural number from 1 to 10; Any -CHR ^L21 - in L ² may be independently replaced by the following structural units: -Cyr-, -N(R ^L23 )C(O)-, -C(O)N(R ^L23 )-, -C(O)-, -NR ^L23 - or -O-; -Cyr- is a 4- to 6-membered heterocyclylene group or a 3- to 6-membered cycloalkylene group; Each of ^RL21 and ^RL23 is independently hydrogen or -( _CH2CH2O ) _m - ^RL2a _; m is a natural number from 0 to 4; Each R ^L2a is hydrogen; The heteroatoms in the 4- to 6-membered heterocyclylene group are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; More preferably, L ² is -(CHR ^L21 ) _n -; wherein n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; Any -CHR ^L21 - in L ² may be independently replaced by the following structural units: -Cyr-, -C(O)-, -NR ^L23 - or -O-; -Cyr- is a 4- to 6-membered heterocyclylene group or a 3- to 6-membered cycloalkylene group; the heteroatom in the 4- to 6-membered heterocyclylene group is N, and the number of heteroatoms is 1 or 2; Each of ^RL21 and ^RL23 is independently hydrogen or -( _CH2CH2O ) _m - ^RL2a _; m is 0, 1, 2, 3 or 4; Each R ^L2a is hydrogen; Further and preferably, ^L2 is Each of t1, t2, t3, t4 and m is independently an integer from 0 to 8; each of t5 and t6 is independently 0 or 1; -Cyr- is a 4- to 6-membered heterocyclylene group or a 3- to 6-membered cycloalkylene group; preferably, -Cyr- is Further preferably, -Cyr- is Further preferably, ^L2 is Each of t1, t3 and m is independently 0, 1, 2 or 3; Each t2 is independently 0 or 1; Each t5 is independently 0 or 1; Every t6 is 1; -Cyr- is a 4- to 6-membered heterocyclylene group or a 3- to 6-membered cycloalkylene group; the heteroatom in the 4- to 6-membered heterocyclylene group is N, and the number of heteroatoms is 1 or 2; Further preferably, ^L2 is Each of t1 and t3 is independently 0, 1, 2 or 3; Each t2 is independently 0 or 1; Each t5 is independently 0 or 1; 1 for every t6; -Cyr- is a 4- to 6-membered heterocyclylene group or a 3- to 6-membered cycloalkylene group; the heteroatom in the 4- to 6-membered heterocyclylene group is N, and the number of heteroatoms is 1 or 2; Further preferably, ^L2 is Each of t1 and t3 is independently 0, 1, 2 or 3; Each t2 is independently 0 or 1; Each t5 is independently 0 or 1; 1 for every t6 Further and better, For Option 1 or Option 2: Scenario 1: for Preferably, for Among them, c is connected to L ₁ , and d is connected to L ³ ; Scenario 2: for (For example for Wherein, c is connected to L ₁ , d is connected to L ³ ); preferably, (For example, wherein c is connected to L ₁ , and d is connected to L ³ ); more preferably, (For example, Among them, c is connected to _L1 , and d is connected to ^L3 ). 8. The compound of formula I according to any one of claims 1 to 7, its pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a pharmaceutically acceptable salt, characterized in that the compound of formula I satisfies one or more of the following conditions: (1) Any -CHR ^L21 - in L ² can be independently replaced by the following structural units: -Cyr-, -N(R ^L23 )C(O)-, -C(O)N(R ^L23 )-, -C(O)-, -NR ^L23 - or -O-; preferably, any -CHR ^L21 - in L ² can be independently replaced by the following structural units: -Cyr-, -C(O)-, -NR ^L23 - or -O-; (2) -Cyr- is a 4- to 6-membered heterocyclylene group or a 3- to 6-membered cycloalkylene group; preferably, -Cyr- is a 4- to 6-membered heterocyclylene group or a 3- to 6-membered cycloalkylene group, the heteroatom in the 4- to 6-membered heterocyclylene group is N, and the number of heteroatoms is 1 or 2; (3) _each of ^RL21 , ^RL23 and ^Rcx is independently hydrogen or -( _CH2CH2O ) _m - ^RL2a ; (4)-TAS-106 Preferably 9. The compound of formula I according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a pharmaceutically acceptable salt thereof, characterized in that: For Option 1 or Option 2: Scenario 1: for Each of t1, t2, t3, t4 and m is independently an integer from 0 to 8; Each t5 and t6 is independently 0 or 1; -Cyr- is a 4- to 6-membered heterocyclylene group or a 3- to 6-membered cycloalkylene group; preferably, -Cyr- is Further preferably, -Cyr- is More preferably, for More preferably, for Scenario 2: for Each of t1, t2, t3, t4 and m is independently an integer from 0 to 8; Each t5 and t6 is independently 0 or 1; -Cyr- is a 4- to 6-membered heterocyclylene group or a 3- to 6-membered cycloalkylene group; Preferably, for Each of t1, t3 and m is independently 0, 1, 2 or 3; Each t2 is independently 0 or 1; Each t5 is independently 0 or 1; 1 for every t6; -Cyr- is a 4- to 6-membered heterocyclylene group or a 3- to 6-membered cycloalkylene group; the heteroatom in the 4- to 6-membered heterocyclylene group is N, and the number of heteroatoms is 1 or 2; More preferably, for Each of t1, t3 and m is independently 0, 1, 2 or 3; Each t2 is independently 0 or 1; Each t5 is independently 0 or 1; 1 for every t6; -Cyr- is a 4- to 6-membered heterocyclylene group or a 3- to 6-membered cycloalkylene group; the heteroatom in the 4- to 6-membered heterocyclylene group is N, and the number of heteroatoms is 1 or 2; Further preferably, for Each of t1 and t3 is independently 0, 1, 2 or 3; Each t2 is independently 0 or 1; Each t5 is independently 0 or 1; 1 for every t6; Further and better, for Among them, position "1" is connected to Ab, and position "2" is connected to L ³ ; Further and better, for Among them, position "1" is connected to Ab, position "2" is connected to L ³ ; optimally, for Among them, the "1" position is connected to Ab, and the "2" position is connected to ^L3 . 10. The compound of formula I according to any one of claims 1 to 9, its pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a pharmaceutically acceptable salt, characterized in that L ³ is a chemical bond, 1 amino acid residue, a short peptide consisting of 2 to 7 amino acid residues, The amino acid residue is Val, D-Val, Nva, Phe, Lys, Leu, Ile, Gly, Ala, D-Ala, Cit, Asp, Asn, Glu, Gln, Pro, Arg, Lys(Ac), Lys(Me), Lys(Et), Lys(nPr), Nva or AA; AA Preferably, ^L3 is Scheme 1 or Scheme 2: Scheme 1: ^L3 is a chemical bond, Val, D-Val, Phe, Lys, Leu, Ile, Gly, Ala, D-Ala, Cit, Asp, Asn, Glu, Gln, AA, Val-Cit, Val-Ala, Val-Lys, Val-Lys(Ac), Phe-Lys, Phe-Lys(Ac), Leu-Lys, Leu-Lys(Ac), Ala-Ala, D-Ala-Ala, Gly-Glu, Gly-Asp, Gly-Asn, Val-Glu, Val-Asp, Val-Asn, Asn-Asn, Val-AA, Ala-AA, Phe-AA, Glu-Val-Cit, Ala-Ala-Ala, Ala-(D-Ala)-Ala, Ala-Ala -Asn, Ala-(D-Ala)-Asn, Ala-Ala-Asp, Val-Lys-Gly, D-Val-Leu-Lys, Gly-Gly-Arg, Gly-Gly-Gly, Gly-Glu-Gly, Lys-Ala-Asn, Gly-Phe-Gly, Gly-Gly-Phe, Asn-Pro-Val, Val-AA-Gly, Ala-AA-Gly, Gly -AA-Gly, Gly-Gly-Gly-Gly, Gly-Gly-Phe-Gly, Gly-Gly-Glu-Gly, Lys-Ala-Ala-Asn, Lys-Ala-Ala-Asp, Ala-Ala-Pro-Val, Ala-Ala-Pro-Nva, AA Preferably, ^L3 is a chemical bond, Lys, Cit, Asp, Asn, Glu, Gln, Val-Cit, Val-Ala, Ala-Ala, Gly-Glu, Gly-Asp, Gly-Asn, Asn-Asn, Gly-Glu-Gly, Gly-Gly-Phe-Gly, Gly-Gly-Gly-Gly or Gly-Gly-Glu-Gly; More preferably, ^L3 is a chemical bond, Val-Ala, Ala-Ala, Gly-Glu, Gly-Asn, Gly-Asp, Gly-Glu-Gly, Gly-Gly-Glu-Gly, or Gly-Gly-Phe-Gly; further preferably, L ³ is a chemical bond, Val-Ala, Ala-Ala, Gly-Glu, Gly-Asn, Gly-Asp, Gly-Glu-Gly, Gly-Gly-Glu-Gly or Gly-Gly-Phe-Gly; Scheme 2: L ³ is chemical bond, Val, D-Val, Phe, Lys, Leu, Ile, Gly, Ala, D-Ala, Cit, Asp, Asn, Glu, Gln, AA, Val-Cit, Val-Ala, Val-Lys, Val-Lys(Ac), Phe-Lys, Phe-Lys(Ac), Leu-Lys, Leu-Lys(Ac), Ala-Ala, D-Ala-Ala, Gly-Glu, Gly-Asp , Gly-Asn, Val-Glu, Glu-Gly, Val-Asp, Val-Asn, Asn-Asn, Val-AA, Ala-AA, Phe-AA, Glu-Val-Cit, Ala-Ala-Ala, Ala -(D-Ala)-Ala,Ala -Ala-Asn, Ala-(D-Ala)-Asn, Ala-Ala-Asp, Val-Lys-Gly, D-Val-Leu-Lys, Gly-Gly-Arg, Gly-Gly-Gly, Gly-Glu -Gly, Lys-Ala-Asn, Gly-Phe-Gly, Gly-Gly-Phe, Asn-Pro-Val, Val-AA-Gly, Ala-AA-Gly, Gly-AA-Gly, Gly-Gly-Gly -Gly, Gly-Gly-Phe-Gly, Gly-Gly-Glu-Gly, Lys-Ala-Ala-Asn, Lys-Ala-Ala-Asp, Ala-Ala-Pro-Val, Ala-Ala-Pro-Nva , AA Preferably, L ³ is a chemical bond, Lys, Cit, Asp, Asn, Glu, Gln, Val-Cit, Val-Ala, Ala-Ala, Gly-Glu, Glu-Gly, Gly-Asp, Gly-Asn, Asn -Asn, Gly-Glu-Gly, Gly-Phe-Gly, Gly-Gly-Phe-Gly, Val-Lys-Gly, Gly-Gly-Gly-Gly or Gly-Gly-Glu-Gly; or, L ³ is Chemical bond, Val-Ala, Ala-Ala, Gly-Glu, Glu-Gly, Gly-Asn, Gly-Asp, Gly-Glu-Gly, Gly-Phe-Gly, Gly-Gly-Glu-Gly, or Gly-Gly-Phe-Gly; More preferably, ^L3 is a chemical bond, Val-Ala, Ala-Ala, Gly-Glu, Glu-Gly, Gly-Asn, Gly-Asp, Gly-Glu-Gly, Gly-Phe-Gly, Gly-Gly-Glu-Gly or Gly-Gly-Phe-Gly; further preferably, ^L3 is Glu-Gly, Val-Ala, Ala-Ala, Gly-Glu-Gly, Gly-Phe-Gly, Gly-Gly-Glu-Gly or Gly-Gly-Phe-Gly; further preferably, it is Glu-Gly, Val-Ala, Gly-Phe-Gly, Ala-Ala, Gly-Glu-Gly, Gly-Gly-Glu-Gly or Gly-Gly-Phe-Gly; most preferably, it is Gly-Gly-Phe-Gly. 11. The compound of formula I according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a pharmaceutically acceptable salt thereof, characterized in that: for or, for Preferably, for The "1" position is connected to Ab, and the "2" position is connected to Tr; More preferably, The "1" position is connected to Ab, and the "2" position is connected to Tr; Best for The "1" position is connected to Ab, and the "2" position is connected to Tr. 12. The compound of formula I according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a pharmaceutically acceptable salt thereof, characterized in that: Tr is a chemical bond, Each of R ^Tr , R ^Tr1 and R ^Tr2 is independently hydrogen, halogen, -NO ₂ , -CN, -OH, -NH ₂ , -CO ₂ H, -S(O) ₂ H, -C(O)NH ₂ , -SO ₂ NH ₂ , _-OC (O) _NH2 , _-CH2CO- (N(Me)CH2C(O)) _z - ^ORTra , _-CH2CO- (N(Me) _CH2C (O)) _z - ^NHRTra , -( _CH2CH2O ) _z - ^RTra , -CONH-( _CH2CH2O ) _z - ^RTra , or _{-C1-6alkyl ;} said _C1-6alkyl is optionally substituted with _one or more ^R3a ; R ^3a is hydrogen, deuterium, halogen, -NO ₂ , -CN, -OH, -NH ₂ , -N(Me) ₂ , -S(O) ₂ Me, -CO ₂ H, -S(O) ₂ OH, -C(O)NH ₂ , -SO ₂ NH ₂ , or -C _1-6 alkyl; z is an integer of 0 or more; (e.g., Tr is a chemical bond or wherein the "1" position is connected to ^L3 , the "2" position is connected to TAS-106, each R ^Tr1 and R ^Tr2 are independently hydrogen, deuterium, halogen or -C _1-6 alkyl; more preferably, R ^Tr1 and R ^Tr2 are hydrogen or deuterium, for example, Tr is wherein the "1" position is connected to ^L3 , the "2" position is connected to TAS-106, and R ^Tr1 and R ^Tr2 are hydrogen or deuterium); Preferably, Tr is a chemical bond, Tr is preferably a chemical bond, (For example, Tr is a chemical bond or More preferably, More preferably, Tr is a chemical bond, wherein, e is connected to L ³ , f is connected to TAS-106; more preferably, Tr is a chemical bond or Among them, e is connected to L ³ , f is connected to TAS-106, and optimally, Among them, e is connected to L ³ and f is connected to TAS-106. 13. The compound of formula I according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a pharmaceutically acceptable salt thereof, characterized in that the compound of formula I is Scheme 1, Scheme 2, Scheme 3 or Scheme 4: Scheme 1: The Ab is a target-binding polypeptide, an antibody or an antigen-binding fragment thereof; preferably, the Ab is an antibody or an antigen-binding fragment thereof; more preferably, the Ab is trastuzumab or Trop-2 antibody (Sacituzumab); q is an integer or decimal from 1 to 16; preferably, q is an integer or decimal from 2 to 8; for example, q is an integer or decimal from 7 to 8; ^L1 is ^L2 is -(CHR ^L21 ) _n -; Where n is a natural number from 1 to 10; Any -CHR ^L21 - in L ² may be independently replaced by the following structural units: -Cyr-, -N(R ^L23 )C(O)-, -C(O)N(R ^L23 )-, -C(O)-, -NR ^L23 - or -O-; -Cyr- is a 4- to 6-membered heterocyclylene group or a 3- to 6-membered cycloalkylene group; the heteroatom of the heterocycloalkyl group is N, and the number of heteroatoms is 1 or 2; Each of ^RL21 and ^RL23 is independently hydrogen or -(CH ₂ CH ₂ O) _m ^-RL2a ; m is a natural number from 0 to 4; each ^RL2a is hydrogen; L ³ is a chemical bond, Val-Ala, Ala-Ala, Gly-Glu, Gly-Asn, Gly-Asp, Gly-Glu-Gly, Gly-Gly-Glu-Gly or Gly-Gly-Phe-Gly; Tr is a chemical bond, Scheme 2: The Ab is an anti-HER2 antibody or a variant thereof, or an anti-GPC-3 antibody or a variant thereof; q is an integer or decimal between 7 and 8; ^L1 is ^L2 is Each of t1, t3 and m is independently 0, 1, 2 or 3; Each t2 is independently 0 or 1; Each t5 is independently 0 or 1; 1 for every t6; -Cyr- is a 4- to 6-membered heterocyclylene group or a 3- to 6-membered cycloalkylene group; the heteroatom in the 4- to 6-membered heterocyclylene group is N, and the number of heteroatoms is 1 or 2; L ³ is Glu-Gly, Val-Ala, Ala-Ala, Gly-Glu-Gly, Gly-Phe-Gly, Gly-Gly-Glu-Gly or Gly-Gly-Phe-Gly; Tr is a chemical bond or wherein the "1" position is connected to L ³ , and the "2" position is connected to TAS-106; each of R ^Tr1 and R ^Tr2 is independently hydrogen, deuterium, halogen or -C _1-6 alkyl; -TAS-106 Scheme 3: The Ab is an anti-HER2 antibody or a variant thereof, or an anti-GPC-3 antibody or a variant thereof; q is an integer or decimal between 7 and 8; for Each of t1, t3 and m is independently 0, 1, 2 or 3; Each t2 is independently 0 or 1; Each t5 is independently 0 or 1; 1 for every t6; -Cyr- is a 4- to 6-membered heterocyclylene group or a 3- to 6-membered cycloalkylene group; the heteroatom in the 4- to 6-membered heterocyclylene group is N, and the number of heteroatoms is 1 or 2; L ³ is Glu-Gly, Val-Ala, Ala-Ala, Gly-Glu-Gly, Gly-Phe-Gly, Gly-Gly-Glu-Gly or Gly-Gly-Phe-Gly; Tr is a chemical bond or The "1" position is connected to ^L3 , and the "2" position is connected to TAS-106; each R ^Tr1 and R ^Tr2 is independently hydrogen or deuterium; -TAS-106 Scheme 4: the Ab is trastuzumab or codrituzumab; q is an integer or decimal between 7 and 8; for Each of t1 and t3 is independently 0, 1, 2 or 3; Each t2 is independently 0 or 1; Each t5 is independently 0 or 1; Every t6 is 1; L3 is Gly-Gly-Phe-Gly; Tr is The "1" position is connected to L ³ , and the "2" position is connected to TAS-106; R ^Tr1 and R ^Tr2 are hydrogen or deuterium; -TAS-106 14. The compound of formula I according to claim 1, its pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a pharmaceutically acceptable salt, characterized in that: The compound of formula I is any of the following compounds: Preferably, the compound of formula I is any of the following compounds: q is an integer or decimal from 1 to 16, preferably an integer or decimal from 2 to 8, for example, q is an integer or decimal from 7 to 8; Preferably, the compound of formula I is any of the following compounds: 15. A compound of formula II, or a salt or stereoisomer, solvate or solvate of a salt thereof, characterized in that ^L1a - ^L2 - ^L3 -Tr-(TAS-106) Formula II L ^1a Wherein Lg ¹ is a leaving group; Lg ¹ is but not limited to halogen, OTf, sulfone group (eg, MeSO ₂ -) or tertiary amine salt group (eg, Me ₃ N ⁺ , Et ₃ N ⁺ ), diazonium salt group, -OMs, The definitions of L ² , L ³ and Tr are as described in any one of claims 1-14. 16. The compound of formula II according to claim 15, or a salt or stereoisomer, solvate or solvate of a salt thereof, characterized in that: The compound of formula II is represented by formula IIa or formula IIb 17. The compound of formula II according to claim 15 or 16, or a salt or stereoisomer, solvate or solvate of a salt thereof, characterized in that: L ^1a is Preferably, ^L1 is More preferably, ^L1 is 18. The compound of formula II according to claim 15 or 16, or a salt or stereoisomer, solvate or solvate of a salt thereof, characterized in that: ^L2 is -(CHR ^L21 ) _n -; Where n is a natural number from 0 to 20; Any -CHR ^L21 - in ^L2 can be independently replaced by the following structural units: -Cyr-, -N(R ^L23 )C(O)-, -C(O)N(R ^L23 )-, -C(O)-, -NR ^L23 -, -O-, Replacement; -Cyr- is phenylene, 5- to 6-membered heteroarylene, 4- to 10-membered heterocyclylene, or 3- to 6-membered cycloalkylene, wherein said -Cyr- is optionally substituted with 1 to 3 R ^cx ; each of ^RL21 , ^RL23 and ^Rcx is independently hydrogen, halogen, -OR ^L2a , -N( ^RL2a ) ₂ , _-C (O) ^RL2a , -S(O) ^2RL2a , -C(O)N( ^RL2a ) ₂ , _-SO2N ( ^RL2a ) ₂ , -N( ^RL2a ) _SO2RL2b , -N( ^{RL2a )COR L2b ,} -( _CH2 ) _y -CO-(N(Me) _CH2C (O)) _m -OR ^L2a , -( _CH2 ) _y -CO-(N(Me) _CH2C (O)) _m -NHR ^L2a , -( _CH2 ) _y -CONH-( _CH2CH2O ) _m ^-RL2a _, -( _CH2 ) _y -NHCO-(CH ₂ CH ₂ O) _m -R ^L2a , -(CH ₂ ) _y -NHCOCH ₂ (OCH ₂ CH ₂ )OR ^L2a , -(CH ₂ ) _y -NH(COCH ₂ (N(Me)) _m -R ^L2a , -(CH ₂ ) _y -NHCO-(CH ₂ CH ₂ O) _m -R ^L2a , -(CH ₂ CH ₂ O) _m -R ^{L2 a} , -(COCH ₂ N(Me)) _m -R ^L2a , -COCH ₂ (OCH ₂ CH ₂ ) _m -OR ^L2a , -CO-(CH ₂ CH ₂ O) _m -R ^L2a , -C _1-6 alkyl, -C _2-6 alkenyl, -C The -C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, _3-8 membered cycloalkyl, 4-10 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more R ^Tra ; m is a natural number from 0 to 8; y is 0, 1, 2, 3, 4; Each ^RL2a , ^RL2b is independently selected from hydrogen, halogen, -CN, -OH, _-NH2 , -N(Me) ₂ , _-CO2H , -C(O) _NH2 or _-C1-6alkyl ; The heteroatoms in the 5- to 6-membered heteroarylene group, the 4- to 10-membered heterocyclylene group and the 4- to 10-membered heterocycloalkyl group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4; Preferably, ^L2 is -( _CH2 ) _n- ; Where n is a natural number from 0 to 14; Any -CH ₂ - in L ² may be independently replaced by the following structural units: phenylene, 5- to 6-membered heteroarylene, 4- to 6-membered heterocyclylene, 3- to 6-membered cycloalkylene, -N(R ^L23 )C(O)-, -C(O)N(R ^L23 )-, -C(O)-, -NR ^L23 -, -O-, Replacement; Each R ^L23 is independently hydrogen, -OR ^L2a , -C(O)R ^L2a , -S(O) ₂ R ^L2a , -C(O)N(R ^L2a ) ₂ , -SO ₂ N(R ^L2a ) ₂ , -(CH ₂ ) _y -CO-(N(Me)CH ₂ C(O)) _m -OR ^L2a , -(CH ₂ ) _y -CO-(N(Me)CH ₂ C(O)) _m -NHR ^L2a , -(CH ₂ ) _y -CONH-(CH ₂ CH ₂ O) _m -R ^L2a , -(CH ₂ ) _y -NHCOCH ₂ (OCH ₂ CH ₂ )OR ^L2a , -(CH ₂ CH ₂ O) _m -R ^L2a , -(COCH ₂ N(Me)) _m -R ^L2a , -COCH ₂ (OCH ₂ CH ₂ ) _m -OR ^L2a , -CO-(CH ₂ CH ₂ O) _m -R ^L2a , or -C _1-6 alkyl; the -C _1-6 alkyl is optionally substituted by one or more Several were replaced by R ^L2a ; m is a natural number from 0 to 8; y is 0, 1, 2, 3, or 4; Each ^RL2a is independently selected from hydrogen, halogen, -CN, -OH, _-NH2 , -N(Me) ₂ , _-CO2H , -C(O) _NH2 or _-C1-6alkyl ; The heteroatoms of the 5- to 6-membered heteroarylene group and the 4- to 6-membered heterocyclylene group are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; More preferably, ^L2 is -(CHR ^L21 ) _n -; Where n is a natural number from 1 to 10; Any -CHR ^L21 - in L ² may be independently replaced by the following structural units: -Cyr-, -N(R ^L23 )C(O)-, -C(O)N(R ^L23 )-, -C(O)-, -NR ^L23 - or -O-; -Cyr- is a 4- to 6-membered heterocyclylene group or a 3- to 6-membered cycloalkylene group; Each of ^RL21 and ^RL23 is independently hydrogen or -( _CH2CH2O ) _m - ^RL2a _; m is a natural number from 0 to 4; Each R ^L2a is hydrogen; The heteroatoms in the 4- to 6-membered heterocyclylene group are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; Further preferably, ^L2 is Each of t1, t2, t3, t4 and m is independently an integer from 0 to 8; Each t5 and t6 is independently 0 or 1; -Cyr- is a 4- to 6-membered heterocyclylene group or a 3- to 6-membered cycloalkylene group; preferably, -Cyr- is Further preferably, -Cyr- is Further preferably, for Further preferably, for Among them, c is connected to _L1 and d is connected to ^L3 . 19. The compound of formula II according to any one of claims 15 to 18, or a salt or stereoisomer, solvate or solvate of a salt thereof, wherein L ³ is a chemical bond, 1 amino acid residue, a short peptide consisting of 2 to 7 amino acid residues, The amino acid residue is Val, D-Val, Nva, Phe, Lys, Leu, Ile, Gly, Ala, D-Ala, Cit, Asp, Asn, Glu, Gln, Pro, Arg, Lys(Ac), Lys(Me), Lys(Et), Lys(nPr), Nva or AA; AA Preferably, L ³ is chemical bond, Val, D-Val, Phe, Lys, Leu, Ile, Gly, Ala, D-Ala, Cit, Asp, Asn, Glu, Gln, AA, Val-Cit, Val-Ala , Val-Lys, Val-Lys(Ac), Phe-Lys, Phe-Lys(Ac), Leu-Lys, Leu-Lys(Ac), Ala-Ala, D-Ala-Ala, Gly-Glu, Gly- Asp, Gly-Asn, Val-Glu, Val-Asp, Val-Asn, Asn-Asn, Val-AA, Ala-AA, Phe-AA, Glu-Val-Cit, Ala-Ala-Ala, Ala-(D -Ala)-Ala、Ala-Ala -Asn, Ala-(D-Ala)-Asn, Ala-Ala-Asp, Val-Lys-Gly, D-Val-Leu-Lys, Gly-Gly-Arg, Gly-Gly-Gly, Gly-Glu-Gly , Lys-Ala-Asn, Gly-Phe-Gly, Gly-Gly-Phe, Asn-Pro-Val, Val-AA-Gly, Ala-AA-Gly, Gly-AA-Gly, Gly-Gly-Gly-Gly , Gly-Gly-Phe-Gly, Gly-Gly-Glu-Gly, Lys-Ala-Ala-Asn, Lys-Ala-Ala-Asp, Ala-Ala-Pro-Val, Ala-Ala-Pro-Nva, AA More preferably, L ³ is chemical bond, Lys, Cit, Asp, Asn, Glu, Gln, Val-Cit, Val-Ala, Ala-Ala, Gly-Glu, Gly-Asp, Gly-Asn, Asn-Asn, Gly -Glu-Gly, Gly-Gly-Phe-Gly, Gly-Gly-Gly-Gly or Gly-Gly-Glu-Gly; Preferably, ^L3 is a chemical bond, Val-Ala, Ala-Ala, Gly-Glu, Gly-Asn, Gly-Asp, Gly-Glu-Gly, Gly-Gly-Glu-Gly, or Gly-Gly-Phe-Gly; For example Still preferably, ^L3 is a chemical bond, Val-Ala, Ala-Ala, Gly-Glu, Gly-Asn, Gly-Asp, Gly-Glu-Gly, Gly-Gly-Glu-Gly or Gly-Gly-Phe-Gly. 20. The compound of formula II according to any one of claims 15 to 19, or a salt or stereoisomer, solvate or solvate of a salt thereof, characterized in that Tr is a chemical bond, Each of R ^Tr , R ^Tr1 and R ^Tr2 is independently hydrogen, halogen, -NO ₂ , -CN, -OH, -NH ₂ , -CO ₂ H, -S(O) ₂ H, -C(O)NH ₂ , -SO ₂ NH ₂ , _-OC (O) _NH2 , _-CH2CO- (N(Me)CH2C(O)) _z - ^ORTra , _-CH2CO- (N(Me) _CH2C (O)) _z - ^NHRTra , -( _CH2CH2O ) _z - ^RTra , -CONH-( _CH2CH2O ) _z - ^RTra , or _{-C1-6alkyl ;} said _C1-6alkyl is optionally substituted with _one or more ^R3a ; R ^3a is hydrogen, deuterium, halogen, -NO ₂ , -CN, -OH, -NH ₂ , -N(Me) ₂ , -S(O) ₂ Me, -CO ₂ H, -S(O) ₂ OH, -C(O)NH ₂ , -SO ₂ NH ₂ , or -C _1-6 alkyl; z is an integer of 0 or greater; Preferably, Tr is a chemical bond, More preferably, Tr is a chemical bond, Wherein, e is connected to L ³ , f is connected to TAS-106; Tr is preferably a chemical bond, 21. The compound of formula II according to any one of claims 15 to 20, or a salt or stereoisomer, solvate or solvate of a salt thereof, characterized in that: for Each of t1, t2, t3, t4 and m is independently selected from an integer from 0 to 8; Each t5 and t6 is independently 0 or 1; -Cyr- is a 4- to 6-membered heterocyclylene group or a 3- to 6-membered cycloalkylene group; preferably, -Cyr- is Further preferably, -Cyr- is Preferably, for More preferably, for 22. The compound of formula II according to claim 15, or a salt or stereoisomer, solvate or solvate of a salt thereof, characterized in that the compound of formula II is any of the following compounds: 23. A compound comprising a structure represented by formula III, or a salt, stereoisomer, solvate or solvate of a salt thereof, characterized in that: in, The definitions of L ¹ , L ² , L ³ and Tr are as described in any one of claims 1 to 13, and L ¹ is used to directly or indirectly connect to a ligand. 24. The compound comprising the structure shown in formula III according to claim 23, or a salt, stereoisomer, solvate or solvate of a salt thereof, characterized in that the structure shown in formula III is a structure shown in formula IIIa or IIIb 25. The compound comprising formula III, or a salt, stereoisomer, solvate or solvate of a salt thereof as claimed in claim 23 or 24, characterized in that the compound comprising the structure represented by formula III satisfies one or more of the following conditions: (1) L ¹ is (2) ^L2 is -(CHR ^L21 ) _n -; Where n is a natural number from 1 to 10; Any -CHR ^L21 - in L ² may be independently replaced by the following structural units: -Cyr-, -N(R ^L23 )C(O)-, -C(O)N(R ^L23 )-, -C(O)-, -NR ^L23 - or -O-; -Cyr- is a 4- to 6-membered heterocyclylene group or a 3- to 6-membered cycloalkylene group; the heteroatom of the heterocycloalkyl group is N, and the number of heteroatoms is 1 or 2; Each of ^RL21 and ^RL23 is independently hydrogen or -(CH ₂ CH ₂ O) _m ^-RL2a ; m is a natural number from 0 to 4; each ^RL2a is hydrogen; (3) L ³ is a chemical bond, Val-Ala, Ala-Ala, Gly-Glu, Gly-Asn, Gly-Asp, Gly-Glu-Gly, Gly-Gly-Glu-Gly or Gly-Gly-Phe-Gly; (4) Tr is a chemical bond, 26. A pharmaceutical composition comprising a compound of formula I as described in any one of claims 1 to 14, a compound of formula II as described in any one of claims 15 to 22, or a compound comprising a structure shown in formula III as described in any one of claims 23 to 25, or a pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a pharmaceutically acceptable salt thereof. 27. A pharmaceutical preparation comprising a compound of formula I as claimed in any one of claims 1 to 14, a compound of formula II as claimed in any one of claims 15 to 22, or a compound comprising a structure shown in formula III as claimed in any one of claims 23 to 25, or a pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a pharmaceutically acceptable salt thereof. 28. A use of a substance S in preparing a drug for preventing or treating cancer; the substance S is a compound of formula I as claimed in any one of claims 1 to 14, a compound of formula II as claimed in any one of claims 15 to 22, or a compound comprising a structure represented by formula III as claimed in any one of claims 23 to 25, or a pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a pharmaceutically acceptable salt thereof, a pharmaceutical composition as claimed in claim 26, or a pharmaceutical preparation as claimed in claim 27; preferably, the cancer is a solid tumor or a non-solid tumor; for example, selected from esophageal cancer (e.g., esophageal adenocarcinoma and esophageal squamous cell carcinoma), brain tumor, lung cancer (e.g., small cell lung cancer and non-small cell lung cancer), squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colorectal cancer, liver cancer, kidney cancer, non-Hodgkin's lymphoma, central nervous system tumors (e.g., glioma, glioblastoma multiforme, glioma or sarcoma), prostate cancer or thyroid cancer. 29. A use of a substance S in the preparation of a drug for preventing or treating a disease associated with abnormal cell activity, wherein the substance S is a compound of formula I as described in any one of claims 1 to 14, a compound of formula II as described in any one of claims 15 to 22, or a compound comprising a structure represented by formula III as described in any one of claims 23 to 25, or a pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a pharmaceutically acceptable salt thereof, a pharmaceutical composition as described in claim 26, or a pharmaceutical preparation as described in claim 27; the cancer is a solid tumor or a non-solid tumor; for example, selected from esophageal cancer (e.g., esophageal adenocarcinoma and esophageal squamous cell carcinoma), brain tumor, lung cancer (e.g., small cell lung cancer and non-small cell lung cancer), squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colorectal cancer, liver cancer, kidney cancer, non-Hodgkin's lymphoma, central nervous system tumors (e.g., glioma, glioblastoma multiforme, glioma or sarcoma), prostate cancer or thyroid cancer. 30. Use of a substance S in the preparation of a drug; the substance S is a compound of formula I as described in any one of claims 1 to 14, a compound of formula II as described in any one of claims 15 to 22, or a compound comprising a structure represented by formula III as described in any one of claims 23 to 25, or a pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a pharmaceutically acceptable salt thereof, a pharmaceutical composition as described in claim 26, or a pharmaceutical preparation as described in claim 27; the drug is used to treat a disease associated with a target A; the target A is The target corresponding to the antibody; preferably, the drug is used to treat a disease associated with target A, which is cancer; for example, selected from esophageal cancer (such as esophageal adenocarcinoma and esophageal squamous cell carcinoma), brain tumor, lung cancer (such as small cell lung cancer and non-small cell lung cancer), squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colorectal cancer, liver cancer, kidney cancer, non-Hodgkin's lymphoma, central nervous system tumors (such as glioma, glioblastoma multiforme, glioma or sarcoma), prostate cancer or thyroid cancer.